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NEUROSCIENCE

SCIENCE OF THE BRAIN

AN INTRODUCTION FOR YOUNG STUDENTS

British Neuroscience Association

European Dana Alliance for the Brain
This booklet was prepared and edited on behalf of the British Neuroscience Association and the European Dana Alliance for
the Brain by Richard Morris (University of Edinburgh) and Marianne Fillenz (University of Oxford). The graphic design was by
Jane Grainger (Grainger Dunsmore Design Studio, Edinburgh). We are grateful for contributions from our colleagues in the
Division of Neuroscience, particularly Victoria Gill, and others in the neuroscience community in Edinburgh. We also thank
members of the University Department of Physiology in Oxford, particularly Colin Blakemore, and helpful colleagues in other
institutions. Their names are listed on the back page.

The British Neuroscience Association (BNA) is the professional body in the United Kingdom that represents
neuroscientists and is dedicated towards a better understanding of the nervous system in health and disease.
Its members range from established scientists holding positions in Universities and Research Institutes through to
postgraduate students. The BNA’s annual meetings, generally held in the spring, provide a forum for the presentation of the
latest research. Numerous local groups around the country hold frequent seminars and these groups often organise
activities with the general public such as school visits and exhibitions in local museums. See http://www.bna.org.uk/ for
further information.

The goal of The European Dana Alliance for the Brain (EDAB) is to inform the general public and decision makers about the
importance of brain research. EDAB aims to advance knowledge about the personal and public benefits of neuroscience and
to disseminate information on the brain, in health and disease, in an accessible and relevant way. Neurological and
psychiatric disorders affect millions of people of all ages and make a severe impact on the national economy. To help
overcome these problems, in 1997, 70 leading European neuroscientists signed a Declaration of Achievable Research Goals
and made a commitment to increase awareness of brain disorders and of the importance of neuroscience. Since then, many
others have been elected, representing 24 European countries. EDAB has more than 125 members.
See http://www.edab.net/ for further information.

Published by The British Neuroscience Association

The Sherrington Buildings
Ashton Street
Liverpool
L69 3GE
UK
Copyright British Neuroscience Association 2003

This book is in copyright. Subject to statutory

exception and the provisions of relevant collective
licensing agreements, no reproduction of any part
may take place without the written permission of
The British Neuroscience Association

First Published 2003

ISBN: 0-9545204--0-8

The images on this page are of neurons of the cerebral cortex visualised using special dyes inserted into the adjacent cells.
Neuroscience: the Science of the Brain
1 The Nervous System P2

2 Neurons and the

Action Potential P4

3 Chemical Messengers P7

4 Drugs and the Brain P9

5 Touch and Pain P11

6 Vision P14

Inside our heads, weighing about 1.5 kg, is an astonishing living organ consisting of
7 Movement P19
billions of tiny cells. It enables us to sense the world around us, to think and to talk.
The human brain is the most complex organ of the body, and arguably the most
8 The Developing P22 complex thing on earth. This booklet is an introduction for young students.
Nervous System
In this booklet, we describe what we know about how the brain works and how much
9 Dyslexia P25 there still is to learn. Its study involves scientists and medical doctors from many
disciplines, ranging from molecular biology through to experimental psychology, as
well as the disciplines of anatomy, physiology and pharmacology. Their shared
10 Plasticity P27
interest has led to a new discipline called neuroscience - the science of the brain.

11 Learning and Memory P30 The brain described in our booklet can do a lot but not everything. It has nerve cells
- its building blocks - and these are connected together in networks. These
12 Stress P35 networks are in a constant state of electrical and chemical activity. The brain we
describe can see and feel. It can sense pain and its chemical tricks help control the
uncomfortable effects of pain. It has several areas devoted to co-ordinating our
13 The Immune System P37
movements to carry out sophisticated actions. A brain that can do these and many
other things doesn’t come fully formed: it develops gradually and we describe some
14 Sleep P39 of the key genes involved. When one or more of these genes goes wrong, various
conditions develop, such as dyslexia. There are similarities between how the brain
15 Brain Imaging P41 develops and the mechanisms responsible for altering the connections between
nerve cells later on - a process called neuronal plasticity. Plasticity is thought to
underlie learning and remembering. Our booklet’s brain can remember telephone
16 Artificial Brains and P44
numbers and what you did last Christmas. Regrettably, particularly for a brain
Neural Networks that remembers family holidays, it doesn’t eat or drink. So it’s all a bit limited.
But it does get stressed, as we all do, and we touch on some of the hormonal and
17 When things go wrong P47 molecular mechanisms that can lead to extreme anxiety - such as many of us feel in
the run-up to examinations. That’s a time when sleep is important, so we let it have
18 Neuroethics P52 the rest it needs. Sadly, it can also become diseased and injured.

19 Training and Careers
20 Further Reading and
Acknowledgements
New techniques, such as special electrodes that can touch the surface of cells,
P54
optical imaging, human brain scanning machines, and silicon chips containing
artificial brain circuits are all changing the face of modern neuroscience.
P56 We introduce these to you and touch on some of the ethical issues and social
implications emerging from brain research.

The Neuroscience Community

at the University of Edinburgh
The European
Dana Alliance
for the Brain

To order additional copies: Online ordering: www.bna.org.uk/publications

Postal: The British Neuroscience Association, c/o: The Sherrington Buildings, Ashton Street, Liverpool L68 3GE
Telephone: 44 (0) 151 794 4943/5449 Fax: 44 (0) 794 5516/5517
 The Nervous
System
Human central nervous system showing the brain and
spinal cord
Basic structure
The nervous system consists of the brain, spinal cord and
peripheral nerves. It is made up of nerve cells, called
neurons, and supporting cells called glial cells.
There are three main kinds of neurons. Sensory neurons are
coupled to receptors specialised to detect and
respond to different attributes of the internal and external
environment. The receptors sensitive to changes in light,
sound, mechanical and chemical stimuli subserve the sensory
modalities of vision, hearing, touch, smell and taste.
When mechanical, thermal or chemical stimuli to the skin
exceed a certain intensity, they can cause tissue damage
and a special set of receptors called nociceptors are
activated; these give rise both to protective reflexes and to
the sensation of pain (see chapter 5 on Touch and Pain).
Motor neurons, which control the activity of muscles, are
responsible for all forms of behaviour including speech.
Interposed between sensory and motor neurons are
Interneurones. These are by far the most numerous (in the
human brain). Interneurons mediate simple reflexes as well
as being responsible for the highest functions of
the brain. Glial cells, long thought to have a purely
supporting function to the neurons, are now known to make
an important contribution to the development of the
nervous system and to its function in the adult brain.
While much more numerous, they do not transmit
information in the way that neurons do.
2
Neurons have an architecture that consists of a cell body
and two sets of additional compartments called
‘processes’. One of these sets are called axons; their job is
to transmit information from the neuron on to others to
which it is connected. The other set are called dendrites -
their job is to receive the information being transmitted by
the axons of other neurons. Both of these processes
participate in the specialised contacts called synapses
(see the Chapters 2&3 on Action Potential and Chemical
Messengers). Neurons are organised into complex chains
and networks that are the pathways through which
information in the nervous system is transmitted.
The brain and spinal cord are connected to sensory
receptors and muscles through long axons that
make up the peripheral nerves. The spinal cord has two
functions: it is the seat of simple reflexes such as the knee
jerk and the rapid withdrawal of a limb from a hot object or a
pinprick, as well as more complex reflexes, and it forms a
highway between the body and the brain for information
travelling in both directions.
These basic structures of the nervous system are the same
in all vertebrates. What distinguishes the human brain is its
large size in relation to body size. This is due to an enormous
increase in the number of interneurons over the course of
evolution, providing humans with an immeasurably wide choice
of reactions to the environment.
Anatomy of the Brain
The brain consists of the brain stem and the cerebral
hemispheres.
The brain stem is divided into hind-brain, mid-brain and a
‘between-brain’ called the diencephalon. The hind-brain is an
extension of the spinal cord. It contains networks of
neurons that constitute centres for the control of vital
functions such as breathing and blood pressure. Within
these are networks of neurons whose activity controls these
functions. Arising from the roof of the hind-brain is the
cerebellum, which plays an absolutely central role in the
control and timing of movements (See Chapters on
Movement and Dyslexia).
The midbrain contains groups of neurons, each of which seem
to use predominantly a particular type of chemical
messenger, but all of which project up to cerebral
hemispheres. It is thought that these can modulate the
activity of neurons in the higher centres of the brain
 The human brain seen from above, below and the side. Side view of the brain
showing division between
the cerebral hemisphere
and brain stem, an
to mediate such functions as sleep, attention or reward. extension of which is the
The diencephalon is divided into two very different areas cerebellum
called the thalamus and the hypothalamus: The thalamus
Cerebral Hemisphere
relays impulses from all sensory systems to the cerebral Cerebellum
cortex, which in turn sends messages back to the thalamus. Brain Stem
This back-and-forward aspect of connectivity in the brain is
intriguing - information doesn’t just travel one way.
The hypothalamus controls functions such as eating and
drinking, and it also regulates the release of hormones Cross section through
involved in sexual functions. the brain showing the
thalamus and
hypothalamus
The cerebral hemispheres consist of a core, the basal
ganglia, and an extensive but thin surrounding sheet of Thalamus
neurons making up the grey matter of the cerebral cortex. Hypothalamus
The basal ganglia play a central role in the initiation and
control of movement. (See Chapter 7 on Movement).
Packed into the limited space of the skull, the cerebral cortex
is thrown into folds that weave in and out to enable a much
larger surface area for the sheet of neurons than would
otherwise be possible. This cortical tissue is the most highly
developed area of the brain in humans - four times bigger Cross section through
the brain showing the
than in gorillas. It is divided into a large number of discrete basal ganglia and corpus
areas, each distinguishable in terms of its layers and callosum
connections. The functions of many of these areas are
known - such as the visual, auditory, and olfactory areas, the Cerebral Hemisphere
sensory areas receiving from the skin (called the Corpus Callosum
Basai Ganglia
somaesthetic areas) and various motor areas.
The pathways from the sensory receptors to the cortex and
from cortex to the muscles cross over from one side to the
other. Thus movements of the right side of the body are
controlled by the left side of the cortex (and vice versa).
Similarly, the left half of the body sends sensory signals to
The father of modern
the right hemisphere such that, for example, sounds in the neuroscience, Ramon y
left ear mainly reach the right cortex. However, the two Cajal, at his microscope
halves of the brain do not work in isolation - for the left and in 1890.
right cerebral cortex are connected by a large fibre tract
called the corpus callosum.

The cerebral cortex is required for voluntary actions,

language, speech and higher functions such as thinking and
remembering. Many of these functions are carried out by
both sides of the brain, but some are largely lateralised to
one cerebral hemisphere or the other. Areas concerned with Cajal’s first pictures
some of these higher functions, such as speech (which is of neurons and their
dendrites.
lateralised in the left hemisphere in most people), have been
identified. However there is much still to be learned,
particularly about such fascinating issues as consciousness, Cajal’s exquisite
and so the study of the functions of the cerebral cortex is neuron drawings -
one of the most exciting and active areas of research these are of the
in Neuroscience. cerebellum.
g

Internet Links: http://science.howstuffworks.com/brain.htm

http://faculty.washington.edu/chudler/neurok.html http://psych.hanover.edu/Krantz/neurotut.html
3
 Neurons and the
Action Potential

Whether neurons are sensory or motor, big or small, they Spinal motor neuron Pyramidal cell Purkinje cell of cerebellum
all have in common that their activity is both electrical and
chemical. Neurons both cooperate and compete with each
other in regulating the overall state of the nervous
system, rather in the same way that individuals in a
society cooperate and compete in decision-making
processes. Chemical signals received in the dendrites from
the axons that contact them are transformed into
electrical signals, which add to or subtract from electrical
signals from all the other synapses, thus making a decision Cell Body
about whether to pass on the signal elsewhere. Electrical Cell Body
potentials then travel down axons to synapses on the Cell Body
Axon
dendrites of the next neuron and the process repeats. Axon Axon

The dynamic neuron

As we described in the last chapter, a neuron consists of
dendrites, a cell body, an axon and synaptic terminals.
This structure reflects its functional subdivision into
receiving, integrating and transmitting compartments.
Roughly speaking, the dendrite receives, the cell-body
integrates and the axons transmit - a concept called
polarization because the information they process
supposedly goes in only one direction.
Dendrites Cell Body Axon
Receiving Integrating Transmitting
The key concepts of a neuron
3 different types of Neurons
Inside neurons are many inner compartments. These
consist of proteins, mostly manufactured in the cell body,
that are transported along the cytoskeleton. Tiny
protuberances that stick out from the dendrites called
dendritic spines. These are where incoming axons make
most of their connections. Proteins transported to the
spines are important for creating and maintaining neuronal
connectivity. These proteins are constantly turning over,
Synapse being replaced by new ones when they’ve done their job.
All this activity needs fuel and there are energy factories
(mitochondria) inside the cell that keep it all working. The
end-points of the axons also respond to molecules called
growth factors. These factors are taken up inside and then
transported to the cell body where they influence the
expression of neuronal genes and hence the manufacture of
new proteins. These enable the neuron to grow longer
dendrites or make yet other dynamic changes to its shape
or function. Information, nutrients and messengers flow to
and from the cell body all the time.

Like any structure, it has to hold together. The outer

membranes of neurons, made of fatty substances, are
draped around a cytoskeleton that is built up of rods of
tubular and filamentous proteins that extend out into
dendrites and axons alike. The structure is a bit like a canvas
stretched over the tubular skeleton of a frame tent.
The different parts of a neuron are in constant motion, a
process of rearrangement that reflects its own activity and
that of its neighbours. The dendrites change shape,
sprouting new connections and withdrawing others, and the
axons grow new endings as the neuron struggles to talk a bit Dendritic spines are the tiny green protuberances sticking
more loudly, or a bit more softly, to others. out from the green dendrites of a neuron. This is where
synapses are located.

4
Receiving and deciding
On the receiving side of the cell, the dendrites have close
contacts with incoming axons of other cells, each of which is
separated by a miniscule gap of about 20 billionths of metre.
A dendrite may receive contacts from one, a few, or even
thousands of other neurons. These junctional spots are
named synapses, from classical Greek words that mean “to
clasp together”. Most of the synapses on cells in the
The action-potential
To communicate from one neuron to another, the neuronal
signal has first to travel along the axon. How do neurons
do this?
The answer hinges on harnessing energy locked in physical
and chemical gradients, and coupling together these forces
in an efficient way. The axons of neurons transmit electrical

cerebral cortex are located on the dendritic spines that pulses called action potentials. These travel along nerve
stick out like little microphones searching for faint signals. fibres rather like a wave travelling down a skipping rope.
Communication between nerve cells at these contact points This works because the axonal membrane contains ion-
is referred to as synaptic transmission and it involves a channels, that can open and close to let through electrically
chemical process that we will describe in the next Chapter. charged ions. Some channels let through sodium ions (Na+),
When the dendrite receives one of the chemical messengers while others let through potassium ions (K+). When channels
that has been fired across the gap separating it from the open, the Na+ or K+ ions flow down opposing chemical and
sending axon, miniature electrical currents are set up inside electrical gradients, in and out of the cell, in response to
the receiving dendritic spine. These are usually currents electrical depolarisation of the membrane.
that come into the cell, called excitation, or they may be
currents that move out of the cell, called inhibition. All these
positive and negative waves of current are accumulated in
the dendrites and they spread down to the cell body. If they
don’t add up to very much activity, the currents soon die
down and nothing further happens. However, if the currents
add up to a value that crosses a threshold, the neuron will
send a message on to other neurons.

So a neuron is kind of miniature calculator - constantly

adding and subtracting. What it adds and subtracts are the
messages it receives from other neurons. Some
synapses produce excitation, others inhibition. How these
signals constitute the basis of sensation, thought and
movement depends very much on the network in which the
neurons are embedded.

The action potential

5
 When an action potential starts at the cell body, the first
channels to open are Na+ channels. A pulse of sodium ions Research Frontiers
flashes into the cell and a new equilibrium is established
within a millisecond. In a trice, the transmembrane voltage
switches by about 100 mV. It flips from an inside membrane
voltage that is negative (about -70 mV) to one that is
positive (about +30 mV). This switch opens K+ channels,
triggering a pulse of potassium ions to flow out of the cell,
almost as rapidly as the Na+ ions that flowed inwards, and
this in turn causes the membrane potential to swing back
again to its original negative value on the inside. The action-
potential is over within less time than it takes to flick a
domestic light switch on and immediately off again.
Remarkably few ions traverse the cell membrane to do this,
and the concentrations of Na+ and K+ ions within the
cytoplasm do not change significantly during an action
potential. However, in the long run, these ions are kept in
balance by ion pumps whose job is to bale out excess sodium The nerve fibres above (the purple shows the axons) are
ions. This happens in much the same way that a small leak in wrapped in Schwann cells (red) that insulate the electrical
transmission of the nerve from its surroundings.
the hull of a sailing boat can be coped with by baling out
The colours are fluorescing chemicals showing a newly
water with a bucket, without impairing the overall ability of discovered protein complex. Disruption of this protein
the hull to withstand the pressure of the water upon which complex causes an inherited disease that leads to muscle-
the boat floats. wasting.

The action potential is an electrical event, albeit a complex

one. Nerve fibres behave like electrical conductors (although
they are much less efficient than insulated wires), and so an
action potential generated at one point creates another
gradient of voltage between the active and resting
membranes adjacent to it. In this way, the action potential
is actively propelled in a wave of depolarisation that spreads
from one end of the nerve fibre to the other.
An analogy that might help you think about the conduction
of action potentials is the movement of energy along a
firework sparkler after it is lit at one end. The first ignition
triggers very rapid local sparks of activity (equivalent to the
ions flowing in and out of the axon at the location of the
action potential), but the overall progression of the sparkling
wave spreads much more slowly. The marvellous feature of
nerve fibres is that after a very brief period of silence (the
refractory period) the spent membrane recovers its
explosive capability, readying the axon membrane for the next
action potential.
New research is telling us about the proteins that make up
this myelin sheath. This blanket prevents the ionic currents
from leaking out in the wrong place but, every so often the
glial cells helpfully leave a little gap. Here the axon
concentrates its Na+ and K+ ion channels. These clusters of
ion channels function as amplifiers that boost and maintain
the action potential as it literally skips along the nerve.
This can be very fast. In fact, in myelinated neurons,
action-potentials can race along at 100 metres per second!
Action potentials have the distinctive characteristic of being
all-or-nothing: they don’t vary in size, only in how often they
occur. Thus, the only way that the strength or duration of a
stimulus can be encoded in a single cell is by variation of the
frequency of action potentials. The most efficient axons can
conduct action potentials at frequencies up to 1000 times
per second.

Much of this has been known for 50 years based on

wonderful experiments conducted using the very large Alan Hodgkin and Andrew
neurons and their axons that exist in certain Huxley won the Nobel Prize
sea-creatures. The large size of these axons enabled for discovering the
scientists to place tiny electrodes inside to measure the mechanism of transmission
changing electrical voltages. Nowadays, a modern electrical of the nerve impulse.
recording technique called patch-clamping is enabling They used the "giant axon"
neuroscientists to study the movement of ions through of the squid in studies
individual ion-channels in all sorts of neurons, and so make at the Plymouth Marine
very accurate measurements of these currents in brains Biology Laboratory
much more like our own.

Insulating the axons

In many axons, action-potentials move along reasonably well,
but not very fast. In others, action potentials really do skip
along the nerve. This happens because long stretches of the
axon are wrapped around with a fatty, insulating blanket,
made out of the stretched out glial cell membranes, called a
myelin sheath.
g

Internet Links: http://psych.hanover.edu/Krantz/neurotut.html

6 http://www.neuro.wustl.edu/neuromuscular/
Chemical
Messengers
Action potentials are transmitted along axons to
specialised regions called synapses, where the axons
contact the dendrites of other neurons. These consist of
a presynaptic nerve ending, separated by a small gap from
the postsynaptic component which is often located on a
dendritic spine. The electrical currents responsible for the
propagation of the action potential along axons cannot
bridge the synaptic gap. Transmission across this gap is
accomplished by chemical messengers called
neurotransmitters.
Chemical transmitter packed in
spherical bags is available for release
across synaptic junctions
Storage and Release
Neurotransmitters are stored in tiny spherical bags called
synaptic vesicles in the endings of axons. There are vesicles
for storage and vesicles closer to nerve endings that are
ready to be released. The arrival of an action potential leads
to the opening of ion-channels that let in calcium (Ca++).
This activates enzymes that act on a range of presynaptic
proteins given exotic names like “snare”, “tagmin” and “brevin”
- really good names for the characters of a recent scientific
adventure story. Neuroscientists have only just discovered
that these presynaptic proteins race around tagging and
trapping others, causing the releasable synaptic vesicles to
fuse with the membrane, burst open, and release the
chemical messenger out of the nerve ending.
This messenger then diffuses across the 20 nanometre gap
called the synaptic cleft. Synaptic vesicles reform when
their membranes are swallowed back up into the nerve ending
where they become refilled with neurotransmitter, for
subsequent regurgitation in a continuous recycling process.
Once it gets to the other side, which happens amazingly
quickly – in less than a millisecond - it interacts with
specialised molecular structures, called receptors, in the
membrane of the next neuron. Glial cells are also lurking all
around the synaptic cleft. Some of these have miniature
vacuum cleaners at the ready, called transporters, whose
job is to suck up the transmitter in the cleft. This clears the
chemical messengers out of the way before the next action
potential comes. But nothing is wasted - these glial cells
then process the transmitter and send it back to be stored
in the storage vesicles of the nerve endings for future use.
Glial-cell housekeeping is not the only means by which
neurotransmitters are cleared from the synapse.
Sometimes the nerve cells pump the transmitter molecules
back directly into their nerve endings. In other cases, the
transmitter is broken down by other chemicals in the
synaptic cleft.
Messengers that open ion channels
The interaction of neurotransmitters with receptors
resembles that of a lock and key. The attachment of the
transmitter (the key) to the receptors (the lock) generally
causes the opening of an ion channel; these receptors are
called ionotropic receptors (see Figure). If the ion channel
allows positive ions (Na+ or Ca++) to enter, the inflow of
positive current leads to excitation. This produces a swing
in the membrane potential called an excitatory post-synap-
tic potential (epsp). Typically, a large number of synapses
converge on a neuron and, at any one moment, some are
active and some are not. If the sum of these epsps reaches
the threshold for firing an impulse, a new action potential is
set up and signals are passed down the axon of the receiving
neuron, as explained in the previous chapter.
Transmitter Receptor Transmitter
(ligand) Receptor G-protein
Extracellular
Plasma Membrane
Intracellular
Second Messenger
Effector
Ionotropic receptors (left) have a channel through which
ions pass (such as Na+ and K+). The channel is made up of
five sub-units arranged in a circle. Metabotropic receptors
(right) do not have channels, but are coupled to G-proteins
inside the cell-membrane that can pass on the message.
7
 The main excitatory neurotransmitter in the brain is
glutamate. The great precision of nervous activity requires
that excitation of some neurons is accompanied by
suppression of activity in other neurons. This is brought
about by inhibition. At inhibitory synapses, activation of
receptors leads to the opening of ion channels that allow the
inflow of negatively charged ions giving rise to a change in
membrane potential called an inhibitory post-synaptic
potential (ipsp) (see Figure). This opposes membrane
depolarisation and therefore the initiation of an action
potential at the cell body of the receiving neuron. There are
two inhibitory neurotransmitters – GABA and glycine.
Synaptic transmission is a very rapid process: the time
taken from the arrival of an action potential at a synapse to
the generation of an epsp in the next neuron is very rapid -
1/1000 of a second. Different neurons have to time their
delivery of glutamate on to others within a short window of
opportunity if the epsps in the receiving neuron are going to
add up to trigger a new impulse; and inhibition also has to
operate within the same interval to be effective in shutting
things down.
The excitatory synaptic potential (epsp) is a shift in
membrane potential from -70 mV to a value closer to 0 mV.
An inhibitory synaptic potential (ipsp) has the opposite
effect.
Messengers that modulate
The hunt for the identity of the excitatory and inhibitory
neurotransmitters also revealed the existence of a large
number of other chemical agents released from neurons.
Many of these affect neuronal mechanisms by interacting
with a very different set of proteins in the membranes of
neurons called metabotropic receptors. These receptors
don’t contain ion channels, are not always localised in the
region of the synapse and, most importantly, do not lead to
the initiation of action potentials. We now think of these
receptors as adjusting or modulating the vast array of
chemical processes going on inside neurons, and thus the
action of metabotropic receptors is called neuromodulation.
Metabotropic receptors are usually found in complex
particles linking the outside of the cell to enzymes inside the
cell that affect cell metabolism. When a neurotransmitter is
recognised and bound by a metabotropic receptor, bridging
molecules called G-proteins, and other membrane-bound
enzymes are collectively triggered. Binding of the
transmitter to a metabotropic recognition site can
be compared to an ignition key. It doesn’t open a door for
g
An excellent web site about synapses is at: http://synapses.mcg.edu/index.asp
8
ions in the membrane, as ionotropic receptors do, but
instead kick-starts intracellular second messengers into
action, engaging a sequence of biochemical events (see
Figure). The metabolic engine of the neuron then revs up and
gets going. The effects of neuromodulation include changes
in ion channels, receptors, transporters and even the expres-
sion of genes. These changes are slower in onset and more
long-lasting than those triggered by the
excitatory and inhibitory transmitters and their effects
extend well beyond the synapse. Although they do not
initiate action potentials, they have profound effects on the
impulse traffic through neural networks.
Identifying the messengers
Among the many messengers acting on G-protein coupled
receptors are acetylcholine, dopamine and noradrenaline.
Neurons that release these transmitters not only have a
diverse effect on cells, but their anatomical organisation is
also remarkable because they are relatively few in number but
their axons project widely through the brain (see Figure).
There are only 1600 noradrenaline neurons in the human
brain, but they send axons to all parts of the brain and spinal
cord. These neuromodulatory transmitters do not send out
precise sensory information, but fine-tune dispersed
neuronal assemblies to optimise their performance.
Noradrenaline is released in response to various forms of
novelty and stress and helps to organise the complex
response of the individual to these challenges. Lots of
networks may need to “know” that the organism is under
stress. Dopamine makes certain situations rewarding for
the animal, by acting on brain centres associated with
positive emotional features (see Chapter 4). Acetylcholine,
by contrast, likes to have it both ways. It acts on both
ionotropic and metabotropic receptors. The first
neurotransmitter to be discovered, it uses ionic mechanisms
to signal across the neuromuscular junction from motor
neurons to striated muscle fibres. It can also function as a
neuromodulator. It does this, for example, when you want to
focus attention on something - fine-tuning neurons in the
brain to the task of taking in only relevant information.
Noradrenaline cells are located in the locus coeruleus (LC).
Axons from these cells are distributed throughout the
midbrain such as the hypothalamus (Hyp), the cerebellum (C)
and cerebral cortex.
Drugs and the Brain
Many people seem to have a constant desire to alter their
state of consciousness using drugs. They use stimulant
drugs to help them stay awake and dance the night away.
Others use sedatives to calm their nerves. Or even
substances that enable them to experience new forms of
consciousness and to forget the troubles of everyday life.
All of these drugs interact in different ways with
neurotransmitter and other chemical messenger systems
in the brain. In many cases, the drugs hijack natural brain
systems that have to do with pleasure and reward -
psychological processes that are important in eating,
drinking, sex and even learning and memory.
The Path to Addiction and Dependence
Drugs that act on the brain or the blood supply of the brain
can be invaluable - such as those that relieve pain.
Recreational drug use has a very different purpose, and the
problem with it is that it can lead to abuse. The user can, all
too easily, become dependent or even addicted. He or she
will then suffer very unpleasant physical and psychological
withdrawal symptoms when they interrupt their drug habit.
This state of dependence can lead a user to crave the drug,
even though doing so is clearly damaging to their work, health
and family. In extreme cases the user may be drawn into
crime in order to pay for the drug.
Fortunately not everyone who takes a recreational drug
becomes dependent on it. Drugs differ in their dependence
liability - ranging from high risk in the case of cocaine, heroin
and nicotine to lower risk in the case of alcohol, cannabis,
ecstasy and amphetamines. During the development of drug
76% Tobacco
92% Alcohol
46% Marijuana
Tranquilizers &
13% Prescription Drugs
16% Cocaine
2% Heroin
Percentage of people who have ever used the drug
dependence the body and brain slowly adapt to the repeated
presence of the drug, but exactly what changes go on in the
brain remain mysteries. Although the primary sites of action
of heroin, amphetamines, nicotine, cocaine and cannabis are
all different, these drugs share an ability to promote the
release of the chemical messenger dopamine in certain brain
regions. Although this is not necessarily akin to triggering a
“pleasure” mechanism, it is thought that the drug-induced
release of dopamine may be an important final common
pathway of “pleasure” in the brain. It represents the signal
that prompts a person to carry on taking the drug.
Individual Drugs - How they work and
the hazards of taking them.
Alcohol
Alcohol acts on neurotransmitter systems in the brain to
dampen down excitatory messages and promote inhibition of
neural activity. Alcohol’s action proceeds through stages of
relaxation and good humour, after one drink, through to
sleepiness and loss of consciousness. That is why the police
are so strict about drinking and driving, and why there is so
much public support for this strict attitude. Some people
become very aggressive and even violent when they drink, and
about one in ten of regular drinkers will become dependent
alcoholics. Long-term alcohol use damages the body,
especially the liver, and can cause permanent damage to the
brain. Pregnant mothers who drink run the risk of having
babies with damaged brains and low IQ’s. More than 30,000
people die every year in Britain from alcohol-related diseases.
32%
15%
9%
9%
17%
23%
Percentage of users who became dependent
9

“Skull with a burning cigerette” by Vincent Van Gogh 1885.
Nicotine
Nicotine is the active ingredient in all tobacco products.
Nicotine acts on brain receptors that normally recognise the
neurotransmitter acetylcholine; it tends to activate natural
alerting mechanisms in the brain. Given this, it’s not
surprising that smokers say that cigarettes help them
concentrate and have a soothing effect. The trouble is that
nicotine is highly addictive and many inveterate smokers
continue to smoke for no better reason than to avoid the
unpleasant signs of withdrawal if they stop. The pleasure
has long gone. While there appears to be no deleterious
effect on the brain, tobacco smoke is extremely damaging
to the lungs and long-term exposure can lead to lung cancer
and also to other lung and heart diseases. More than
100,000 people die every year in Britain from smoking-
related diseases.
Cannabis
Cannabis presents us with a puzzle, for it acts on an
important natural system in the brain that uses neurotrans-
mitters that are chemically very like cannabis. This system
has to do with the control of muscles and regulating pain
sensitivity. Used wisely, and in a medical context, cannabis
can be a very useful drug. Cannabis is an intoxicant which can
be pleasurable and relaxing, and it can cause a dream-like
state in which one’s perception of sounds, colours and time
is subtly altered. No-one seems to have died from an over-
dose, although some users may experience unpleasant panic
attacks after large doses. Cannabis has been used at least
once by nearly half the population of Britain under the age of
30. Some people believe it should be legalised - and doing so
could cut the link between supply of the drug and that of
other much more dangerous drugs. Unfortunately, as with
nicotine, smoking is the most effective way of delivering it to
the body. Cannabis smoke contains much the same mixture
of poisons as cigerettes (and is often smoked with tobacco).
g
Related Internet Sites: www.knowthescore.info, www.nida.nih.gov/Infofax/ecstasy.html,
10 www.nida.nih.gov/MarijBroch/Marijteens.html
Cannabis smokers tend to develop lung diseases and they
run the risk of developing lung cancer - although this has not
yet been proved. About one in ten users may become
dependent, which people who sell the drug are well aware of.
Repeated heavy use is incompatible with the skill of driving
and with intellectually demanding work; experiments have
established that people intoxicated with cannabis are unable
to carry out complex mental tasks. Although not yet proven,
there is some evidence that heavy use by young people might
trigger the mental illness schizophrenia (see p.51) in
susceptible individuals.
Amphetamines
Amphetamines are man-made chemicals that include
“Dexedrine”, “Speed”, and the methamphetamine derivative
called “Ecstasy”. These drugs act in the brain by causing the
release two naturally occurring neurotransmitters. One is
dopamine - which probably explains the strong arousal and
pleasurable effects of amphetamines. The other is serotonin
- which is thought to account for their ability to cause a
sense of well-being and a dream-like state that can include
hallucinations. Dexedrine and Speed promote mainly
dopamine release, Ecstasy more serotonin. The even more
powerful hallucinogen d-LSD also acts on serotonin
mechanisms in the brain. Amphetamines are powerful
psychostimulants and they can be dangerous - especially in
overdose. Animal experiments have shown that Ecstasy can
cause a prolonged, perhaps permanent reduction of
serotonin cells. This might account for the “mid-week blues”
suffered by weekend ecstasy users. Every year, dozens of
young people die after taking it. Frightening schizophrenia-
like psychosis can happen after Dexedrine and Speed. You
might be lured into thinking that Speed could help you in an
exam - but don’t. It won’t.
Heroin
Heroin is a man-made chemical derivative of the plant
product morphine. Like cannabis, heroin hijacks a system in
the brain that employs naturally occurring neurotransmit-
ters known as endorphins. These are important in pain
control - and so drugs that copy their actions are very
valuable in medicine. Heroin is injected or smoked whereupon
it causes an immediate pleasurable sensation - possibly due
to an effect of endorphins on reward mechanisms. It is highly
addictive, but, as dependence develops, these pleasurable
sensations quickly subside to be replaced by an incessant
“craving”. It is a very dangerous drug that can kill in even
modest overdose (it suppresses breathing reflexes). Heroin
has ruined many people’s lives.
Cocaine
Cocaine is another plant-derived chemical which can cause
intensely pleasurable sensations as well as acting as a
powerful psychostimulant. Like the amphetamines, cocaine
makes more dopamine and serotonin available in the brain.
However, like heroin, cocaine is a very dangerous drug. People
intoxicated with it, especially the smoked form called “crack”,
can readily become violent and aggressive, and there is a life-
threatening risk of overdose. The dependence liability is high,
and the costs of maintaining a cocaine habit draw many
users into crime.
Touch & Pain
Touch is special - a handshake, a kiss, a baptism.
It provides our first contact with the world. Arrays of
receptors throughout our bodies are tuned to different
aspects of the somatosensory world – touch, temperature
and body position - with yet others for the sensations of
pain. The power of discrimination varies across the body
surface, being exquisitely sensitive at places such as the
tips of our fingers. Active exploration is important as well,
pointing to important interactions with the motor
system. Pain serves to inform and to warn us of damage to
our bodies. It has a strong emotional impact, and is
subject to powerful controls within the body and brain.
Meissner’s
corpuscle
Axons
Merkel’s
disc
Sweat gland
Ruffini end organ
A variety of very small
sensory receptors are
embedded in the surface
of your skin. Pacinian corpuscle
It begins in the skin
Embedded in the dermal layers of the skin, beneath the
surface, are several types of tiny receptors. Named after the
scientists who first identified them in the microscope,
Pacinian and Meissner corpuscles, Merkel’s disks and Ruffini
endings sense different aspects of touch. All these
receptors have ion channels that open in response to
mechanical deformation, triggering action potentials that can
be recorded experimentally by fine electrodes. Some amazing
experiments were conducted some years ago by
scientists who experimented on themselves, by inserting
electrodes into their own skin to record from single sensory
nerves. From these and similar experiments in anaesthetised
animals, we now know that the first two types of receptor
adapt quickly and so respond best to rapidly changing inden-
tations (sense of vibration and flutter), Merkel’s disk
responds well to a sustained indentation of the skin (sense
of pressure), while Ruffini endings respond to slowly changing
indentations.
An important concept about somatosensory receptors is
that of the receptive field. This is the area of skin over which
each individual receptor responds. Pacinian corpuscles have
much larger receptive fields than Meissner’s corpuscles.
Together, these and the other receptors ensure that you can
feel things over your entire body surface. Once they detect a
stimulus, the receptors in turn send impulses along the sen-
sory nerves that enter the dorsal roots of the spinal cord.
The axons connecting touch receptors to the spinal cord are
large myelinated fibres that convey information from the
periphery towards the cerebral cortex extremely rapidly.
Cold, warmth and pain are detected by thin axons with
“naked” endings, which transmit more slowly. Temperature
receptors also show adaptation (see Experiment Box). There
are relay stations for touch in the medulla and the thalamus,
before projection on to the primary sensory area in
the cortex called the somatosensory cortex. The nerves
cross the midline so that the right side of the body is
represented in the left hemisphere and the left in the right.
t
An Experiment on Temperature
Adaptation
This experiment is very simple. You need a metal
rod about a metre long, such as a towel rail, and two
buckets of water. One bucket should contain fairly
hot water, the other with water as cold as possible.
Put your left hand in one bucket and your right hand
in the other, and keep them there for at least a
minute. Now take your hands out, dry them very
quickly and hold the metal rod. The two ends of the
rod will feel as though they are at different
temperatures. Why?
The input from the body is systematically “mapped” across
the somatosensory cortex to form a representation of the
body surface. Some parts of the body, such as the tips of
your fingers and mouth, have a high density of receptors and
a correspondingly higher number of sensory nerves.
Areas such as our back have far fewer receptors and nerves.
However, in the somatosensory cortex, the packing density
11
 of neurons is uniform. Consequently, the ‘map’ of the body
surface in the cortex is very distorted. Sometimes called
the sensory homunculus, this would be a curiously distorted
person if it actually existed with its complement of touch
receptors spread at a uniform density across the body
surface.
You can test this differential sensitivity across the body
with the two-point discrimination test. Bend some paper
clips into a U-shape, some with the tips 2-3 cm apart,
others much closer. Then, with a blindfold on, get a friend to
touch various parts of your body with the tips of the paper
clips. Do you feel one tip or two? Do you sometimes feel one
tip when you are actually being touched by two? Why?
The homunculus. The image of a person is drawn across the
surface of the somatosensory cortex in proportion to the
number of receptors coming from that part of the body.
They have a most distorted shape.
The exquisite power of discrimination
The ability to perceive fine detail varies greatly across
different parts of the body and is most highly developed in
the tips of the fingers and lips. Skin is sensitive enough to
measure a raised dot that is less than 1/100th of a
millimetre high – provided you stroke it as in a blind person
reading Braille. One active area of research asks how the
different types of receptor contribute to different tasks
such as discriminating between textures or identifying the
shape of an object.
Touch is not just a passive sense that responds only to what
it receives. It is also involved in the active control of
movement. Neurons in the motor cortex controlling the
muscles in your arm that move your fingers get sensory
input from touch receptors in the finger tips. How better to
detect an object that is starting to slip out of your hand
than via rapid communication between the sensory and
motor systems? Cross-talk between sensory and motor
systems begins at the first relays in the spinal cord,
12
including proprioceptive feedback on to motor neurons, and it
continues at all levels of the somatosensory system.
The primary sensory and motor cortices are right beside
each other in the brain.
Active exploration is crucial for the sense of touch. Imagine
that you are discriminating fine differences in texture, such
as between different fabrics or grades of sandpaper. Which
of the following conditions do you think generates the finest
discriminations:
• Placing your finger-tips on the samples?
• Running your finger-tips over the samples?
• Having a machine run the samples over your finger-tips?
The outcome of such behavioural experiments leads to
questions about where in the brain the relevant sensory
information is analysed. Functional brain imaging suggests
that the identification of textures or of objects by touch
involves different regions of cortex. Brain imaging is also
starting to produce insights about cortical plasticity by
revealing that the map of the body in the somatosensory
area can vary with experience. For example, blind Braille
readers have an increased cortical representation for the
index finger used in reading, and string players an enlarged
cortical representation of the fingers of the left hand.
Pain
Although often classed with touch as another skin sense,
pain is actually a system with very different functions and a
very different anatomical organisation. Its main attributes
are that it is unpleasant, that it varies greatly between
individuals and, surprisingly, that the information conveyed
by pain receptors provides little information about the
nature of the stimulus (there is little difference between the
pain due an abrasion and a nettle sting). The ancient Greeks
regarded pain as an emotion not a sensation.
Recording from single sensory fibres in animals reveals
responses to stimuli that cause or merely threaten tissue
damage - intense mechanical stimuli (such as pinch), intense
heat, and a variety of chemical stimuli. But such experi-
ments tell us nothing directly about subjective experience.
Molecular biological techniques have now revealed the
structure and characteristics of a number of nociceptors.
They include receptors that respond to heat above 460 C,
to tissue acidity and - again a surprise - to the active
ingredient of chilli peppers. The genes for receptors
responding to intense mechanical stimulation have not yet
been identified, but they must be there. Two classes of
peripheral afferent fibres respond to noxious stimuli:
relatively fast myelinated fibres, called Αδ fibres, and very
fine, slow, non-myelinated C fibres. Both sets of nerves
enter the spinal cord, where they synapse with a series of
neurons that project up to the cerebral cortex. They do so
through parallel ascending pathways, one dealing with the
localisation of pain (similar to the pathway for touch), the
other responsible for the emotional aspect of pain.

Ascending pathways for pain from a region of the spinal
cord (bottom) up to several areas in the brainstem and
cortex including ACC (anterior cingulate) and the insular.
This second pathway projects to quite different areas than
the somatosensory cortex, including the anterior cingulate
cortex and the insular cortex. In brain-imaging experiments
using hyponosis, it has been possible to separate mere pain
sensation from the ‘unpleasantness’ of pain.
Subjects immersed their hands in painfully hot water and
were then subjected to hypnotic suggestion of increased or
decreased pain intensity or pain unpleasantness.
Using positron emission tomography (PET), it was found
that during changes in experienced pain intensity there was
activation of the somatosensory cortex, whereas the
experience of pain unpleasantness was accompanied by
activation of the anterior cingulate cortex.
A life without pain?
Given our desire to avoid sources of pain, such as the
dentist, you might imagine that a life without pain would be
good. Not so. For one of the key functions of pain is to
enable us to learn to avoid situations that give rise to pain.
Action potentials in the nociceptive nerves entering the
spinal cord initiate automatic protective reflexes, such as
the withdrawal reflex. They also provide the very information
that guides learning to avoid dangerous or threatening
situations.
Another key function of pain is the inhibition of activity -
the rest that allows healing to occur after tissue damage.
Of course, in some situations, it is important that activity
and escape reactions are not inhibited. To help cope in these
situations, physiological mechanisms have evolved that can
either suppress or enhance pain. The first such modulatory
mechanism to be discovered was the release of endogenous
analgesics. Under conditions of likely injury, such as soldiers
in battle, pain sensation is suppressed to a surprising degree
– presumably because these substances are released.
Animal experiments have revealed that electrical stimulation
of brain areas such as the aqueductal gray matter causes a
marked elevation in the pain threshold and that this is
mediated by a descending pathway from the midbrain to the
spinal cord.
g
Want to read more about acupuncture?
Try this web site.... http://acupuncture.com/Acup/AcuInd.htm
Morphine Met-enkaphalin
A number of chemical transmitters are involved including
endogenous opioids such as met-enkaphalin. The pain-killer
morphine acts on the same receptors at which some of the
endogenous opioids act.
The converse phenomenon of enhanced pain is called
hyperalgesia. There is a lowering of the pain threshold, an
increase in the intensity of pain, and sometimes both a
broadening of the area over which pain is felt or even pain in
the absence of noxious stimulation. This can be a major
clinical problem. Hyperalgesia involves sensitisation of the
peripheral receptors as well as complex phenomena at
various levels of the ascending pain pathways. These include
the interaction of chemically mediated excitation and
inhibition. The hyperalgesia observed in chronic pain states
results from the enhancement of excitation and depression
of inhibition. Much of this is due to changes in the
responsiveness of the neurons that process sensory
information. Important changes occur in the receptor
molecules that mediate the action of the relevant
neurotransmitters. In spite of the great advances in our
understanding of the cellular mechanisms of hyperalgesia,
the clinical treatment of chronic pain is still sadly
inadequate.
Research Frontiers
Traditional Chinese Medicine uses a procedure called
"acupuncture" for the relief of pain. This involves fine
needles, inserted into the skin at particular positions in the
body along what are called meridians, which are then rotated
or vibrated by the person treating the patient. They
certainly relieve pain but, until recently, no one was very
sure why.
Forty years ago, a research laboratory was set up in China to
find out how it works. Its findings reveal that electrical
stimulation at one frequency of vibration triggers the
release of endogenous opoiods called endorphins, such as
met-enkephalin, while stimulation at another frequency
activates a system sensitive to dynorphins. This work has
led to the development of an inexpensive electrical acupunc-
ture machine (left) that can be used for pain relief instead of
drugs. A pair of electrodes are placed at the "Heku" points
on the hand (right), another at the site of pain.
13
 Vision
Humans are highly visual animals constantly using their
eyes to make decisions about the world. With forward
facing eyes like other primates, we use vision to sense
those many aspects of the environment that are remote
from our bodies. Light is a form of electromagnetic energy
that enters our eyes where it acts on photoreceptors in
the retina. This triggers processes by which neural
impulses are generated and then travel through the
pathways and networks of the visual brain. Separate
pathways to the midbrain and the cerebral cortex mediate
different visual functions - detecting and representing
motion, shape, colour and other distinctive features
of the visual world. Some but not all are accessible to
consciousness. In the cortex, neurons in a large number of
distinctive visual areas are specialised for making different
kinds of visual decisions.
Light on the eye
Light enters the eye through the pupil and is focused, by the
cornea and the lens, on to the retina at the back of the eye.
The pupil is surrounded by a pigmented iris that can expand
or copntract, making the pupil larger or smaller as light levels
vary. It is natural to suppose that the eye acts like a
camera, forming an ‘image’ of the world, but this is a mislead-
ing metaphor in several respects. First, there is never a
static image because the eyes are always moving. Second,
even if an image on the retina were to send an image into the
Pupil
Iris Cornea
Lens
Retina
Fovea
Blind spot
Optic nerve
The human eye. Light entering the eye is focused by the lens
onto the retina located at the back. Receptors there
detect the energy and by a process of transduction initiate
action-potentials that travel in the optic nerve.
14
brain, “seeing” this next image would then need another
person to look at it - a person inside the brain! To avoid an
infinite regression, with nothing really explained along the
way, we confront the really big problem that the visual brain
has to solve - how it uses coded messages from the eyes to
interpret and make decisions about the visual world.
Once focused on the retina, the 125 million photoreceptors
arranged across the surface of the retina respond to the
light that hits them by generating tiny electrical potentials.
These signals pass, via synapes through a network of cells in
the retina, in turn activating retinal ganglion cells whose
axons collect together to form the optic nerve. These enter
the brain where they transmit action potentials to different
visual regions with distinct functions.
Ganglion cell
Bipolar cell
Horizontal cell
Rods
Cones
Light
Optic nerve
Retina Amacrine cell
The retina. Light passes through the fibres of the optic
nerve and a network of cells (eg. bipolar cells) to land on the
rods and cones at the back of the retina.
Much has been learned about this earliest stage of visual
processing. The most numerous photoreceptors, called rods,
are about 1000 times more sensitive to light than the other,
less numerous category called cones. Roughly speaking, you
see at night with your rods but by day with your cones.
There are three types of cones, sensitive to different wave-
lengths of light. It is oversimplification to say it is the cones
simply produce colour vision - but they are vital for it. If over-
exposed to one colour of light, the pigments in the cones
adapt and then make a lesser contribution to our perception
of colour for a short while thereafter (see Experiment Box).
Over the past 25 years, important discoveries have been
made about the process of phototransduction (the conver-
sion of light into electrical signals in the rods and cones), the
genetic basis of colour blindness which is due to the absence
of certain visual pigments, the function of the retinal
network and the presence of two different types of ganglion
cells. About 90% of these cells are very small, while another
5% are large M-type or magnocellular cells. We shall see
later that abnormalities in the M-Type cells may underlie
certain cases of dyslexia (Chapter 9).

t
An Experiment on Colour Adaptation

Focus on the small fixation cross (+) between the two

large circles for at least 30 sec. Now transfer your
gaze to the lower fixation cross. The two “yellow” The pathways from eye to brain.
circles will now appear to be different colours. Can you
think out why this might have happened?
The visual cortex consists of a number of areas, dealing with
the various aspects of the visual world such as shape, colour,
movement, distance etc. These cells are arranged in columns.
An important concept about visually responsive cells is that
of the receptive field - the region of retina over which the cell
will respond to the prefered kind of image. In V1, the first
stage of cortical processing, the neurons respond best to
lines or edges in a particular orientation. An important
discovery was that all the neurons in any one column of cells
fire to lines or edges of the same orientation, and the
neighbouring column of cells fires best to a slightly different
orientation, and so on across the surface of V1. This means
cortical visual cells have an intrinsic organisation for
interpreting the world, but it is not an organisation that is
immutable. The extent to which an individual cell can be
driven by activity in the left or right eye is modified by
experience. As with all sensory systems the visual cortex
displays what we call plasticity.

David
Hubel

The next steps in visual processing Torsten

Wiesel
The optic nerve of each eye projects to the brain. The fibres
of each nerve meet at a structure called the optic chiasm; Electrical recordings made from cells
half of them “cross” to the other side where they join the in the visual cortex (left) by David
other half from the other optic nerve that have stayed Hubel and Torsten Wiesel (above) have
“uncrossed”. Together these bundles of fibres form the optic revealed some amazing properties.
tracts, now containing fibres from both eyes, which now These include orientation selectivity,
the beautiful columnar organisation of
project (via a synaptic relay in a structure called the lateral
such cells (below) and the plasticity
geniculate nucleus) to the cerebral cortex. It is here that of the system. These discoveries led
internal “representations” of visual space around us are to the award of the Nobel Prize.
created. In a similar way to touch (previous Chapter), the
left-hand side of the visual world is in the right-hemisphere
and the right-hand side in the left-hemisphere. This neural
representation has inputs from each eye and so the cells in
the visual areas at the back of the brain (called area V1, V2
etc.) can fire in response to an image in either eye. This is
called binocularity.

15
 Research Frontiers
Can you see if you are blind? Surely not. However, the
discovery of multiple visual areas in the brain has shown
that some visual abilities occur without conscious
awareness. Certain people who have sustained damage to
the primary visual cortex (V1) report being unable to see
things in their field of view but, when asked to reach for the
things they claim they cannot see, they do so with
remarkable accuracy. This curious but fascinating
phenomenon is known as “blindsight”. This is probably
mediated by parallel connections from the eyes to other
parts of the cortex.
Being unaware of things one sees is an everyday
phenomenon in normal people too. If you chat with a
passenger whilst driving your car, your conscious
awareness may be directed entirely to the conversation -
yet you drive effectively, stopping at lights and avoiding
obstacles. This ability reflects a kind of functional
blindsight.
The intricate circuitry of the visual cortex is one of the great
puzzles that has preoccupied neuroscientists. Different
types of neurons are arranged across the six cortical layers,
connected together in very precise local circuits that we are
only now starting to understand. Some of their connections
are excitatory and some inhibitory. Certain neuroscientists
have suggested there is a canonical cortical microcircuit -
like chips in a computer. Not everyone agrees. We now think
the circuitry in one visual area has many similarities to that
in another, but there could be subtle differences that reflect
the different ways in which each bit of the visual brain inter-
prets different aspects of the visual world. Study of visual
illusions has also given us insight into the kind of processing
that may be going on at different stages of visual analysis.
The tiles of this famous café wall in Bristol (left) are
actually rectangular - but they don’t look it. The tiling
arrangement creates an illusion caused by complex
excitatory and inhibitory interactions amongst neurons
processing lines and edges. The Kanizsa Triangle (right)
doesn’t really exist - but this doesn’t stop you seeing it!
Your visual system “decides” that a white triangle is on top
of the other objects in the scene.
Decision and Indecision
A key function of the cerebral cortex is its ability to form and
act upon sensory information received from many sources.
Decision making is a critical part of this capability. This is
the thinking, knowledge-based, or “cognitive” part of the
process. Available sensory evidence must be weighed up and
choices made (such as to act or refrain from acting) on the
best evidence that can be obtained at that time. Some
decisions are complex and require extended thinking while
16
Just black and white
dots? It is at first hard
to identify to edges or
surfaces of the image.
But once you know it is a
Dalmation dog, the image
“pops out”. The visual
brain uses internal
knowledge to interpret
the sensory scene.
others can be simple and automatic. Even the simplest
decisions involve an interplay between sensory input and
existing knowledge.
One way to try to understand the neural basis of decision-
making would be to let an individual go about their normal
daily activity and record the activity of neurons as they do
various things. We might imagine being able to record, with
millisecond precision, the activity of every single one of the
1011 neurons of the brain. We would then have not only a lot
of data, but also a formidable task in processing it all. We
would have an even greater problem in interpreting it. To
understand why, think for a moment about the different
reasons why people do things. A person we see walking to a
railway station may be going there to catch a train, to meet
someone off a train, or even to go “train-spotting”. Without
knowing what their intentions are, it might prove very
difficult to interpret the correlations between any patterns
of activation in their brain and their behaviour.
Experimental neuroscientists like, therefore, to bring
behavioural situations under precise experimental control.
This can be achieved by setting a specific task, ensuring that
the human subjects are doing it to the best of their ability
after extensive practice, and then monitoring their
performance. The best kind of task is one that is sufficiently
complex to be interesting, yet sufficiently simple to offer a
chance of being able to analyse what is going on. A good
example is the process of making a visual decision about the
appearance of stimuli - often no more than two stimuli - with
the response being a simple choice (e.g. which spot of light is
bigger, or brighter?). Although such a task is simple, it does
incorporate a complete cycle of decision-making. Sensory
information is acquired and analysed; there are correct and
incorrect answers for the decision made; and rewards can be
assigned according to whether performance was correct or
not. This sort of research is a kind of “physics of vision”.
Decisions about motion and colour
A subject of great current interest is how neurons are
involved in making decisions about visual motion. Whether or
not an object is moving, and in which direction, are critically
important judgements for humans and other animals.
Relative movement generally indicates that an object is
different from other nearby objects. The regions of the
visual brain involved in processing motion information can be
identified as distinct anatomical regions by examining the
patterns of connections between brain areas, by using
human brain imaging techniques (Chapter 14), and by record-
ing the activity of individual neurons in non-human animals.
 A B

C D

Motion sensitivity. A. A side-view of the a monkey’s brain with the primary visual cortex (V1) at the left and an
area called MT (sometimes called V5) in which motion-sensitive neurons are found. B. A motion-sensitive
neuron in which action potentials (vertical red lines) occur frequently in response to motion in the northwest
direction, but rarely in the opposite direction. Different columns of cells in MT (or V5) code for different
directions of movement. C. A circular TV screen used in experiments on motion sensitivity in which dots move
about in random directions (0% coherence) or all in one direction (100% coherence). D. The monkey’s indication
of the likely direction of the dots increases as their coherence increases (yellow line). Electrical microstimula-
tion of the columns of different orientations shifts the estimate of preferred direction (blue line).

Neurons in one of these areas, area MT or V5, have been

recorded in a monkey, while it makes a simple visual decision
about a pattern of moving dots. Most of the dots are made
to move randomly in different directions but a small fraction
of them are moving consistently in a single direction - up,
down, left or right. The observer has to judge the overall
direction of movement of the pattern. The task can be made
very easy by arranging for a large percentage of the dots to
be moving consistently in one direction, as opposed to
randomly, or harder by decreasing the proportion of dots
that move consistently. It turns out that activity of cells in
V5 accurately reflects the strength of the movement signal.
Neurons here respond selectivity to particular directions of
movement, increasing their activity systematically and
accurately when the proportion of dots moving in their
preferred motion direction increases.

Amazingly, some individual neurons perform just as well at

detecting the movement of dots as is an observer, whether
a monkey or a human, at making a behavioural judgement.
Microstimulation of such neurons through the recording
electrode can even bias the judgement of relative movement
that the monkey is making. This is remarkable given that
very large numbers of neurons are sensitive to visual motion
and one might have expected decisions to be based on the
activity of many neurons rather than just a few. Decisions
about colour proceed in a similar way (see Research
Frontiers Box - above).
The Necker cube is constantly reversing perceptually.
The retinal image doesn’t change, but we see the cube first
with the top left corner nearer to us and then as if it is
receding. Rarely, it is even seen as a set of intersecting
lines on a flat surface. There are many types of reversible
figure, some of which have been used to explore the neural
signals involved when the visual brain makes decisions
about which configuration is dominant at any one time.

17
 Research Frontiers
Colour sensitive cells. Certain neurons show different patterns of activity to different wavelengths of light.
Some respond best to long wavelengths, others to short. You might think this would be enough to perceive colour,
but this may not be so. Compare the cell firing on the left to that on the right. Can you tell the difference?

Left. Clever design of a coloured patchwork called a
Mondrian (after the artist Piet Mondrian). This is illu-
minated with different combinations of long, middle
and short wavelength light so that each panel in turn
reflects exactly the same mixture of light, even
though we always perceive them as being different
colours because of the presence of the surrounding
patches. The cell on the left, recorded in V1, fires
about the same extent in all cases. It does not
"perceive" colour, it simply responds to the identical
wavelength mixture reflected from each patch.
Right. A true colour-sensitive cell in V4 fires to an
area of the Mondrian that we see as red, but much
less to other areas. This differential response occurs
even though the same triplet of wave energies was
reflected from each. V4 may therefore be the area of
the brain that enables us to perceive colour, though
some neuroscientists suspect it is not the only area
involved.

Believing is seeing
Area V5 does more than just register the motion of visual
stimuli, it registers perceived motion. If visual tricks are
played such that an area of dots are perceived as moving in
one direction or another only by virtue of the motion of
surrounding dots, i.e. an illusion of movement, the neurons
corresponding to the area of the illusion will fire differently to
rightwards or leftwards perceived movement. If the move-
ment is completely random, neurons that normally prefer
rightwards movement fire slightly more on trials when the
observer reports that the random motion signal is moving
“rightwards” (and vice versa). The difference between neu-
ronal decisions of “rightwards” or “leftwards” reflects what
the observer judges about the appearance of motion, not the
absolute nature of the moving stimulus.
Other examples of visual decision and indecision include
reactions to perceptual targets that are genuinely
ambiguous, such as the so-called Necker cube (Figure).
With this type of stimulus the observer is placed in a state
of indecision, constantly fluctuating from one interpretation
to another. A similar rivalry is experienced if the left eye sees
a pattern of vertical lines while the right eye sees a pattern
of horizontal lines. The resulting percept is termed binocular
rivalry, as the observer reports first that the vertical lines
dominate, then the horizontal lines and then back again to
vertical. Once again, neurons in many different areas of the
visual cortex reflect when the observer’s perception switch-
es from horizontal to vertical.
g
Our visual world is an astonishing place. Light entering the
eyes enables us to appreciate the world around us ranging
from the simplest of objects through to works of art that
dazzle and beguile us. Millions and millions of neurons are
involved, with their duties ranging from the job of a retinal
photoreceptor responding to a speck of light through to a
neuron in area V5 that decides whether something in the
visual world is moving. All of this happens apparently effort-
lessly within our brains. We don’t understand it all, but
neuroscientists are making great strides.
Colin Blakemore has contributed to
understanding how the visual system
develops. This includes pioneering
studies using cell-culture to study
interactions between different parts of
a pathway in the embryonic brain (left).
On the right, we see axons (stained
green) growing down from the develop-
ing cortex to meet other fibres (stained
orange) that perform a “handshake”
before growing up to the cortex.

Internet Links: faculty.washington.edu/chudler/chvision.html

18 http://www.ncl.ac.uk/biol/research/psychology/nsg.
Movement
Think about catching a ball. Easy? It may seem so, but to
perform even this simple movement, your brain has to do
some remarkable things. We take it all for granted, yet
there is the planning: Is the ball light or heavy? From what
direction is it coming and how fast will it be going? There is
the coordination: How does one automatically coordinate
one’s limbs for catching and what way would be best? And
there is the execution: Does your arm get to the right
place and do your fingers close at the right time?
Neuroscientists now know that there are many areas of
the brain that get involved. Neural activity in these areas
combines to form a loose chain of command – a motor hier-
archy - from the cerebral cortex and basal ganglia to the
cerebellum and spinal cord.
The neuromuscular junction
At the lowest extreme of the motor hierarchy, in the spinal
cord, hundreds of specialised nerve cells called motor
neurons increase their rate of firing. The axons of these
neurons project out to the muscles where they activate
contractile muscle fibres. The terminal branches of the
axons of each motor neuron form specialised neuromuscular
junctions on to a limited number of muscle fibres within one
muscle (see Figure below). Each action potential in a motor
neuron causes the release of neurotransmitter from nerve
endings and generates a corresponding action potential in
the muscle fibres. This causes Ca2+ ions to be released from
intracellular stores inside each muscle fibre. This in turn
triggers contraction of the muscle fibres, producing force
and movement.
To make muscles contract, the nerves form specialized
contacts with individual muscle fibres at the
neuromuscular junction. As they develop, multiple nerve
fibres go to each muscle fibre but, due to competition
between neurons, all but one is eliminated. The final
successful nerve is then left to release its
neurotransmitter acetylcholine on to specialised molecular
detectors at the “motor endplate” (stained red).
This image was made using a confocal microscope.
Recordings of the electrical activity associated with
muscles (electro-myographic activity).
The electrical events in the muscles of the arm can be
recorded with an amplifier, even through the skin, and these
electro-myographic recordings (EMGs) can be used to
measure the level of activity in each muscle (see Fig. above).
The spinal cord plays an important part in the control of the
muscles through several different reflex pathways. Among
these are the withdrawal reflexes that protect you from
sharp or hot objects, and the stretch reflexes that have a
role in posture. The well-known ‘knee-jerk’ reflex is an example
of a stretch reflex that is rather special because it involves
only two types of nerve cell - sensory neurons that signal
muscle length, connected through synapses to motor
neurons that cause the movement. These reflexes combine
together with more complex ones, in spinal circuits that
organise more or less complete behaviours, such as the
rhythmic movement of the limbs when walking or running.
These involve coordinated excitation and inhibition of
motor neurons.
Motor neurons are the final common path to the muscles
that move your bones. However, the brain has a major
problem controlling the activity of these cells. Which muscles
should it move to achieve any particular action, by how much,
and in what order?
The top of the hierarchy -
the motor cortex
At the opposite end of the motor hierarchy, in the cerebral
cortex, a bewildering number of calculations have to be made
by many tens of thousands of cells for each element of
movement. These calculations ensure that movements are
carried out smoothly and skilfully. In between the cerebral
19
 t
An Experiment on Movement

Who moves me? Try this experiment with a friend.

Pick up a fairly heavy book on the palm of your right
hand. Now lift the book from your right hand with
your left. Your task is to keep your right hand still!
You should find this easy. Now try again, keeping
your hand absolutely still while your friend lifts the
book off your hand. Few people can do that. Don’t
worry; it takes very many trials to be able to get
even close to the performance you found easy when
you did it yourself.

This experiment illustrates that the sensorimotor

The several regions of the brain involved in controlling areas of your brain have more knowledge about
movements. what you do entirely yourself than it receives when
you watch others give the trigger for your actions.
cortex and motor neurons of the spinal cord, critical areas in
the brain stem combine information about the limbs and
muscles ascending from the spinal cord with descending
information from the cerebral cortex.

The motor cortex is a thin strip of tissue running across the

surface of the brain, directly in front of the somatosensory
cortex (see p.12). Here is a complete map of the body: nerve
cells that cause movements in different limbs (via connec-
tions onto the motor neurons in the spinal cord) are
topographically arranged. By using a recording electrode,
neurons may be found in any part of this map that are active
about 100 milliseconds before activity in the appropriate
muscles. Quite what is coded in the motor cortex was the
subject of a long debate - do the cells in the cortex code for
actions that a person wants to perform or for the individual
muscles that must be contracted to perform it. The answer
to this question turned out to be somewhat different –
individual neurons do not code for either. Instead a
population code is used in which actions are specified by the
firing of an ensemble of neurons.

Just in front of the motor cortex lie important pre-motor

areas that are involved in planning actions, in preparing spinal
circuits for movement, and in processes that establish links after a stroke, can cause misreaching for objects or even
between seeing movements and understanding gestures. neglect or denial of parts of the world around us. Patients
Striking new findings include the discovery of mirror neurons with so-called parietal neglect fail to notice objects (often
in monkeys that respond both when the monkey sees a hand on their left side) and some even ignore the left side of their
movement and when the animal performs that same move- own body.
ment. Mirror neurons are likely to be important in imitating
and understanding actions. Behind the motor cortex, in the
parietal cortex, a number of different cortical areas are
The basal ganglia
concerned with the spatial representation of the body and of
The basal ganglia are a cluster of interconnected areas
visual and auditory targets around us. They seem to hold a
located beneath the cortex in the depths of the cerebral
map of where our limbs are, and where interesting targets
hemispheres. They are crucial in the initiation of movements,
are with respect to us. Damage to these areas, for example

“…mirror neurons will do for psychology what DNA did for biology: they will provide a
unifying framework and help explain a host of mental abilities that have hitherto
remained mysterious and inaccessible to experiments. They are the great leap
forward of primate brain evolution”. V.S.Ramachandran

20
though quite how they do this is far from clear. The basal
ganglia seem to act rather like a complex filter, selecting
information from amongst the enormous numbers of diverse
inputs they receive from the anterior half of the cortex (the
sensory, motor, prefrontal and limbic regions). The output of
the basal ganglia feeds back to the motor cortical areas.
A common human motor disorder, Parkinson’s disease, is
characterised by tremor and difficulty in initiating move-
ments. It is as if the selective filter in the basal ganglia is
blocked. The problem is the degeneration of neurons in an
area of the brain called the substantia nigra (so-called
because it is black in appearance) whose long, projecting
axons release the neurotransmitter dopamine into the basal
ganglia (see Research Frontiers box below). The precise
arrangement of the dopamine axons onto their target
neurons in the basal ganglia is very intricate, suggesting an
important interaction between different neurotransmitters.
Treatment with the drug L-Dopa, which is converted into
dopamine in the brain, restores dopamine levels and restores
movement (see Chapter 16).
The basal ganglia are also thought to
be important in learning, allowing the
selection of actions that lead to
rewards.
The cerebellum
The cerebellum is crucial for skilful
smooth movements.
It is a beautiful neuronal machine
whose intricate cellular architecture
has been mapped out in great detail.
Like the basal ganglia, it is extensively
interconnected with the cortical
areas concerned with motor control,
and also with brainstem structures.
Damage to the cerebellum leads to
poorly coordinated movements, loss
of balance, slurred speech, and also a
number of cognitive difficulties.
Sounds familiar? Alcohol has a
powerful effect on the cerebellum.
The cerebellum is also vital for motor
learning and adaptation. Almost all voluntary actions rely on
fine control of motor circuits, and the cerebellum is
important in their optimal adjustment - for example with
respect to timing. It has a very regular cortical arrangement
and seems to have evolved to bring together vast amounts
of information from the sensory systems, the cortical motor
areas, the spinal cord and the brainstem. The acquisition of
skilled movements depends on a cellular learning mechanism
called long-term depression (LTD), which reduces the
strength of some synaptic connections (see chapter on
Plasticity). There are a number of theories of cerebellar
function; many involve the idea that it generates a “model” of
how the motor systems work – a kind of virtual reality
simulator of your own body, inside your head. It builds this
model using the synaptic plasticity that is embedded into
its intricate network. So, catch that ball again, and realise
that almost all levels of your motor hierarchy are involved -
from planning the action in relation to the moving visual
g
Learn a bit about the history of how neuroscientists found out about the control of movement at:
http://www.pbs.org/wgbh/aso/tryit/brain/
target, programming the movements of your limbs, and
adjusting the postural reflexes of your arm. At all stages,
you would need to integrate sensory information into the
stream of signals leading to your muscles.
A Purkinje cell of the cerebellum showing the extensive
‘arborisation’ of its dendritic tree. This serves to receive
the myriad of inputs required for the precise timing of
skilled movements that we learn.
Research Frontiers
Basal ganglia
cortical
afferents
10,000
Caudate
cortical
terminals
Putamen 1000 dopamine
synapses on
dendritic spines
dopamine
afferent
striatal
SN neuron
Substantia
Nigra (SN)
An unexpected story about dopamine
The chemistry underlying actions and habits involves the
neurotransmitter dopamine that is released on to
neurons in the basal ganglia where it acts at
metabotropic receptors (Chapter 3). There it serves as
both an incentive to act and as a reward signal for acting
appropriately. An intriguing new discovery is that the
release of dopamine is highest when the reward is
unexpected. That is, the dopamine neurons fire most
strongly at a stage of learning when it really helps to give a
strong reinforcement to the motor system for having
produced the right output. Movements can then be
strung together in a sequence through the release of
successive bursts of dopamine. Later on, particularly if
complex movements become habitual, the system
free-runs without the dopamine reward. At this point,
particularly if movements have to be accurately timed,
the cerebellum starts to play a role.
21
 The Developing
Nervous System

The basic plan of the brain is virtually identical from person

to person and recognisably similar across all mammals.
It is largely genetically determined, but fine details of the
networks are influenced by the electrical activity of the A
brain, especially during early life. Such is its complexity, we
are still far from a complete understanding of how the
brain develops, but clear insights have emerged in recent
years by virtue of the genetic revolution.

Take one fertilised egg, and then follow B

the instructions
The human body and brain develop from a single cell - the
fertilized egg. But how? The governing principle of
developmental biology is that the genome is a set of
instructions for making an organ of the body, not a blueprint.
The genome is the 40,000 or so genes that orchestrate the
process. Carrying out these instructions is a bit like the
Chinese art of paper folding - a limited set such as fold, bend
and unfold produces a structure that would take many draw-
ings to describe as a blueprint. Beginning with the embryo, a
comparatively small set of genetic instructions is able to
C
generate the huge diversity of cells and connections of the
brain during development.

Amazingly, many of our genes are shared with the fruit fly,
D
Drosophila. Indeed, thanks to studies of the fruit fly, the
majority of the genes known to be important in human
E
nervous system development were first identified. F
Neuroscientists studying brain development examine a wide
variety of animals - zebrafish, frog, chick and mouse – each
having advantages for examining particular molecular or
cellular events. The zebrafish embryo is transparent -
allowing each cell to be watched under the microscope as it
develops. The mouse breeds rapidly - its genome has been
mapped and almost completely sequenced. Chicks and frogs
are less amenable to genetic studies, but their large embryos
allow microsurgical manipulations - such as examining what
happens when cells are moved to abnormal positions.

First steps…
The first step in brain development is cell division. Another
key step is cell differentiation in which individual cells stop
dividing and take on specific characteristics - such as those
of neurons or glial cells. Differentiation orders things
spatially. Different kinds of neurons migrate to various
locations in a process is called pattern formation.
The first major event of pattern formation takes place in the
third week of human gestation when the embryo is just two
The neural plate folds into the neural tube. A. A human
embryo at 3 weeks after conception. B. The neural plate
forming the top (dorsal) surface of the embryo. C. A few
days later, the embryo develops enlarged head folds at the
front (anterior) end. The neural plate remains open at both
head and tail ends but has closed in between. D, E, F.
Different levels of the axis from head to tail showing
various stages in neural tube closure.

22
connected sheets of dividing cells. A small patch of cells on
the upper surface of the bilayer is instructed to make the
entire brain and spinal cord. These cells form a tennis racket-
shaped structure called the neural plate, the front of which
is destined to form the brain, the rear to be the spinal cord.
Signals directing the destiny of these cells come from the
layer beneath that goes on to form the midline skeleton and
muscles of the embryo. Various regions of the early nervous
system express different subsets of genes, presaging the
emergence of brain areas - forebrain, midbrain and hindbrain -
with distinct cellular architecture and function. A
26 Days
Rolling around
A week later, the neural plate rolls up, closes into a tube and
sinks into the embryo, where it becomes enveloped by the
future epidermis. Further profound changes happen in the
next few weeks, including changes in cell shape, division and
migration, and cell-cell adhesion. For example, the neural tube
flexes such that the head region is bent at right angles to
the trunk region. This patterning progresses to finer and

neural groove
B
28 Days
neural crest

C
D 35 Days

E
D
49 Days

The morphogenesis of the human brain between (a)

4 weeks, and (d) 7 weeks after conception. Different
F regions expand and there are various flexures along the
head-tail axis.

23
 finer levels of resolution, ultimately conferring individual
identity on to young neurons. Things can go wrong. Failure of
the neural tube to close results in spina bifida, a condition
that is usually confined to the lower spinal cord. While
distressing, it is not lifethreatening. By contrast, failure of
closure at the head end can result in the complete absence
of an organised brain, a condition known as anencephaly.
Know your position in life
The underlying principle of patterning is that cells get to
know their position relative to the principal axes of the
nervous system - front to back and top to bottom. In effect,
each cell measures its position with respect to these
orthogonal coordinates much as a map-reader figures out
his or her position by measuring distance from defined
points. The way this works at the molecular level is that the
embryo sets up a number of localised polarizing regions in
the neural tube that secrete signal molecules. In each case,
the molecule diffuses away from its source to form a
gradient of concentration with distance. An example of this
position-sensing mechanism is the top to bottom
(dorsoventral) axis of the spinal cord. The bottom part of
the neural tube expresses a secreted protein with a
wonderful name - Sonic hedgehog. Sonic hedgehog diffuses
away from the floor plate and affects cells on the
dorsoventral axis according to their distance from the floor
plate. When close, Sonic hedgehog induces the expression of
a gene that makes a particular type of interneuron. Further
away, the now lower concentration of Sonic hedgehog
induces expression of another gene making motor neurons.
Staying put or knowing where
you are going
Once a neuron acquires its individual identity and stops
dividing, it extends its axon with an enlarged tip known as a
growth cone. A bit like a nimble mountain guide, the growth
cone is specialized for moving through tissue, using its skills
to select a favourable path. As it does so, it plays out the
axon behind it, rather like a dog on an extending leash. Once
its target has been reached the growth cone loses its power
of movement and forms a synapse. Axonal guidance is a
supreme navigational feat, accurate over short and long
distances. It is also a very single-minded process for not
only is the target cell selected with high precision but, to get
there, the growth cone may have to cross over other growth
cones heading for different places. Along the path, guidance
cues that attract (+) or repel (-) the growth cones help
them find their way, although the molecular mechanisms
responsible for regulating the expression of these cues
remain poorly understood.
Sculpting by electrical activity
Although a high degree of precision in both the spatial
arrangement of neurons and their connectivity is achieved
from the outset, the wiring of some parts of the nervous
system is later subject to activity-dependent
refinement, such as the pruning of axons and the death of
neurons. These losses may appear wasteful, but it is not
always possible or desirable to make a complete and perfect
brain by construction alone. Evolution has been said to be
“a tinkerer” - but it is also a sculptor. For example, point-to-
g
250,000 cells get added to your brain every minute at certain stages of its development.
24 Read more about it at: http://faculty.washington.edu/chudler/dev.html
Various types of guidance cues encountered by neurons
(blue) as they extend their axons and growth cones (spikes
at the front end). Both local and distant cues can be
attractive to the growth cone (+) or repulsive (-). Some
examples are given of specific molecular guidance cues.
point mapping between neurons in the eye and the brain,
absolutely required for sharp vision, is achieved in part
through the influence patterned electrical activity in the
retina. Also, an initial exuberant set of connections is
sculpted during a critical period, after which the basic
pattern of the visual system is complete, at around eight
weeks of age in monkeys, perhaps a year in humans.
An intriguing question is whether such early developmental
programs can ever be re-activated in cases of pathological
neuronal loss (such as in Alzheimer and Parkinson’s diseases)
or of spinal cord damage that results in paralysis. In the
latter, axons can be encouraged to re-grow following injury
but whether they can be made to re-connect appropriately
remains an area of intense investigation.
The genomic revolution
We are rapidly acquiring a complete catalogue of the genes
needed to build a brain. Thanks to the prodigious power of
molecular biological methods, we can test the function of
genes by modulating their expression wherever and whenever
we want during development. The major task now is to work
out the hierarchy of genetic control that converts a sheet of
cells into a working brain. It is one of the grand challenges of
neuroscience.
Research Frontiers
Stem cells are cells of the body with the potential to
change into all sorts of different kinds of other cells.
Some, called embryonic stem cells, proliferate very early in
development. Others are found in bone marrow and in the
umbilical cord that connects a mother to her newborn baby.
Neuroscientists are trying to
find out if stem cells can be
used to repair damaged
neurons in the adult brain.
Most of the work at the
moment is being done with
animals, but the hope is that
we may eventually be able to
repair areas of the brain
damaged by diseases such as
Parkinson’s Disease.
Dyslexia
Do you remember how difficult it was to learn to read?
Unlike speaking, whose evolutionary origins are very old,
reading and writing are relatively recent human inventions.
It may only have been a thousand years ago that
communities in scattered parts of the world realised that
the thousands of spoken words are made up of a smaller
number of separate sounds (44 phonemes in English) and
that these can be represented by an even smaller number
of visual symbols. Learning these symbols takes time and
some children experience exceptional difficulties. This is
not through any lack of intelligence but because their
brains find the particular requirements of reading difficult
to master. As many as 1 in 10 of us may have had this
condition, now known by its neurological name,
developmental dyslexia.
Dyslexia is very common. As children who have it cannot
understand why they find reading so difficult when they know
they are as intelligent as friends who find it easy, dyslexia is
a real cause of misery. Many children lose confidence, and
this can lead to a downward spiral of frustration, rebellion,
aggression and even delinquency. Yet many dyslexics go on to
display great talents in other spheres - sport, science,
computing, commerce or the arts – provided their early
problems with reading have not caused them to lose all hope
and self- esteem. Hence understanding the biological basis
of dyslexia is not only important in itself, but also a
contribution to preventing a burden of misery. Understanding
the process of reading better may lead us to a way of
overcoming or treating the problem.
Learning to read
Reading depends on being able to recognise alphabetic visual
symbols in their right order - the orthography of whatever
language a child is learning - and to hear the separate
sounds in words in their right order. This involves extracting
what is called the phonemic structure, so that the symbols
can be translated into the correct sounds. Unfortunately
most dyslexics are slow and inaccurate at analysing both
the orthographic and phonological features of words.
KLO
ABCDEF GH
O IKJ MN
UQ
T Z
P
X
W
Y
S
The ability to sequence letters and sounds accurately
depends on both visual and auditory mechanisms.
For unfamiliar words, and all are unfamiliar to the beginning
reader, each letter has to be identified and then to be put in
the right order. This process is not as easy as it sounds,
because the eyes make small movements flicking from one
letter to the next. The letters are identified during each
fixation of the eye but their order is given by where the eye
was pointing when each letter was seen. What the eyes see
has to be integrated with motor signals from the eye
movement system; and it is with this visuomotor integration
that many dyslexics have problems.
Eye movements during reading. Up and down movements
of the pen recorder correspond to left and right.
Visual control of the eye movement system is dominated by
a network of large neurons known as the magnocellular
system. It gets this name because the neurons (cells) are
very large (magno). This network can be traced right from
the retina, through the pathway to the cerebral cortex and
cerebellum, to the motor neurons of the eye-muscles. It is
specialised to respond particularly well to moving stimuli and
it is therefore important for tracking moving targets. An
important feature of this system is that it generates
motion signals, during reading, when the eyes move off
letters they are meant to be fixating. This motion error
signal is fed back to the eye-movement system to bring the
eyes back on target. The magnocellular system plays a
crucial part in helping to point the eyes steadily at each
letter in turn, and hence in determining their order.
parvocellular
layers
magnocellular
layers
100 µm
Control Dyslexic
Histological stain of the lateral geniculate nucleus show-
ing well organized parvo and magnocellular cells in a normal
person and disorganization in some kinds of dyslexia.
25
 Neuroscientists have found that the visual magnocellular
system is mildly impaired in many dyslexics. Looking at brain
tissue directly is one way to reveal this (Figure) but, in
addition, the sensitivity to visual motion of dyslexics is
poorer than that of normal readers and their brain wave
responses to moving stimuli are abnormal. Brain imaging has
also revealed altered patterns of functional activation in
regions sensitive to visual motion (see Chapter 15 on Brain
Imaging). The control of the eye in dyslexics is less steady;
hence they often complain that letters seem to move around
and change places when they are trying to read. These visual
confusions are probably the result of the visual magnocellular
system failing to stabilise their eyes as well as it does in
good readers.
Putting sounds into the right order
Many dyslexics also have problems putting the sounds of
words in the right order so that they tend to mispronounce
words (such as pronouncing lollypop as pollylop) and they
are very bad at tongue twisters. When they come to reading,
they are slower and more inaccurate at translating letters
into the sounds they stand for. Like their visual problems,
this phonological deficiency is probably rooted in a mild
deficiency of basic auditory skills.
We distinguish letter sounds, called phonemes, by detecting
the subtle differences in the sound frequency and intensity
changes that characterise them. Detecting these acoustic
modulations is carried out by a system of large auditory
neurons that track changes in sound frequency and
intensity. There is growing evidence that these neurons fail
to develop as well in dyslexics as in good readers and that
the categorical boundaries between similar sounds, such as
‘b’ and ‘d’, are harder for them to hear (see Figure).
Many dyslexics show evidence of impaired development of
brain cells, extending beyond the visual and auditory
problems they have with reading. These are problems in
neurons that form networks throughout the brain that seem
to be specialised for tracking temporal changes. The cells all
have the same surface molecules by which they recognise
and form contacts with each other, but which may make
them vulnerable to antibody attack.
The magnocellular system provides a particularly large input
to the cerebellum (see Chapter 7 on Movement).
Interestingly, some dyslexics are remarkably clumsy and
g
Related Internet Sites about dyslexia and learning difficulties:
http://www.sfn.org/content/Publications/BrainBriefings/dyslexia.html
26 http://www.learningdisabilities.com/programs.shtml
their handwriting is often very poor. Neuroimaging (see p.41)
and metabolic studies of the cerebellum have indicated that
its function can be impaired in dyslexics and this may be at
the root of their difficulties with handwriting. Some neuro-
scientists believe the cerebellum is involved in much more
than the execution of movements such as writing and
speaking, even including aspects of cognitive planning.
If correct, deficits in cerebellar function could add to
problems with learning to read, write and spell.
What can be done?
There are a number of treatments for dyslexia, each
indicated by the different hypotheses about its underlying
cause. Sum focus on the magnocellular hypothesis, but
other accounts distinguish different forms of the acquired
condition, known as surface and deep dyslexia, which may
require different kinds of treatment. All treatments rely on
early diagnosis.
Scientists do not always agree on things and the best
treatment for dyslexia is one such area of disagreement.
It has been suggested recently that problems in sound
processing result in some dyslexics going down the wrong
path for learning about sounds using the brain’s normal
mechanisms of plasticity. The idea is that children can get
back on the ‘straight and narrow’ if they are encouraged to
play computer games in which they hear sounds that have
been slowed down to the point where phonemic boundaries
are much clearer. The sounds are then gradually speeded up.
It is claimed that this works very well, but independent tests
are still being done. What is scientifically interesting about
the idea is that perfectly normal brain processes interact
with an early genetic abnormality to produce an exaggerated
effect. It’s a striking example of how genes and the
environment can interact.
It is important to stress that dyslexics may be slightly
better than even good readers at some perceptual
judgements such as colour distinctions and global, rather
than local, shape discriminations. This hints at a possible
explanation of why many dyslexics may be superior in seeing
long-range associations, unexpected associations and at
‘holistic’ thinking in general. Remember that Leonardo da
Vinci, Hans Christian Andersen, Edison and Einstein and
many other creative artists and inventors were dyslexic.
Plasticity
Throughout our lives our brains constantly change.
This ability of the brain to change is called plasticity - by
analogy with plasticine model whose internal components
can be constantly re-shaped. Not the brain as a whole, but
the individual neurons can be modified for different reasons
- during development when we are young, in response to
brain injury, and during learning. There are various
mechanisms of plasticity, of which the most important is
synaptic plasticity – the science of how neurons alter their
ability to communicate with one another.
Moulding our futures
As we saw in the last chapter, the connections between
neurons early in life require fine-tuning. As we interact with
our environment, these synaptic connections start to
change – with new ones being made, useful connections
becoming stronger, and connections that are infrequently
used becoming weaker or even lost for good. Synapses that
are active and those that are actively changing are kept while
the rest are pruned. This is a kind of use it or lose it
principle by which we mould the future of our brains.
Synaptic transmission involves the release of a chemical
neurotransmitter that then activates specific protein
molecules called receptors. The normal electrical response
to neurotransmitter release is a measure of synaptic
strength. This can vary and the change may last for a
few seconds, a few minutes or even for a lifetime.
Neuroscientists are particularly interested in long-lasting
changes in synaptic strength that can be produced by brief
periods of neuronal activity, notably in two processes called
long-term potentiation (LTP), which enhances their
strength, and long-term depression (LTD), which
depresses them.
A flavour of how it all works
Glutamate is a common amino acid used throughout our
bodies to build proteins. You may have come across it as the
flavour enhancer called mono-sodium glutamate. It is the
neurotransmitter that functions at the most plastic
synapses of our brains - those that exhibit LTP and LTD.
Glutamate receptors, which are mainly on the receiving side
of the synapse, come in four varieties: three are ionotropic
receptors and have been given the names AMPA, NMDA and
kainate. The fourth type is metabotropic and is called
mGluR. Although all the types of glutamate receptors
respond to the same neurotransmitter, they perform very
different functions. The ionotropic glutamate receptors use
their ion channels to generate an excitatory post-synaptic
potential (epsp) while the metabotropic glutamate
receptors, like the neuromodulatory actions we described
earlier (p. 8), modulate the size and nature of this response.
All types are important for synaptic plasticity, but it is the
AMPA and NMDA receptors about which we know the most
and that are often thought of as memory molecules. Much
of this knowledge has come about because of pioneering work
developing new drugs that act on these receptors to modify
their activity (see box p. 29).
AMPA receptors are fastest into the act. Once glutamate
is bound to these receptors, they rapidly open their ion
channels to produce a transient excitatory postsynaptic
potential (epsps are described in Chapter 3). The glutamate
is only bound to AMPA receptors for a fraction of a second
and, once it leaves and is removed from the synapse, the ion
channels close and the electrical potential reverts to its
resting state. This is what happens when neurons in the
brain send information to each other quickly.
Glutamate is
released from
synaptic
terminals,
crosses the
synaptic cleft,
and binds to the
different kinds of
glutamate
receptors -
AMPA, NMDA and
mGLUR.
Some glutamate
synapses also
have kainate
receptors.
27
 NMDA receptors (red) are the molecular machinery for
learning. Transmitter is released during both baseline
activity and the induction of LTP (top left). The site where
Mg2+ (small black circle, top right) blocks the Ca2+ channel
is inside the cell membrane and it is displaced by intense
depolarization (next diagram down). This happens when
neurons need to change their connectivity with other
neurons. LTP can be expressed as either a larger number of
AMPA receptors (yellow receptors, bottom left) or as more
efficient AMPA receptors (bottom right).
28
NMDA receptors: molecular machines
for triggering plasticity.
Glutamate also binds to NMDA receptors on the
postsynaptic neuron. These are the critical molecular
machines that trigger synaptic plasticity. If the synapse is
activated quite slowly, the NMDA receptors play little or no
role. This is because as soon as NMDA receptors open their
ion channels these channels become plugged by another ion
present in the synapse – magnesium (Mg2+). But, when
synapses are activated by several pulses very quickly to a
set of inputs on to a neuron, the NMDA receptors
immediately sense this excitement. This greater synaptic
activity causes a large depolarisation in the postsynaptic
neuron and this dispels the Mg2+ from the NMDA ion
channels by a process of electrical repulsion. NMDA
receptors are then immediately able to partake in the
synaptic communication. They do this in two ways: first, and
just like AMPA receptors, they conduct Na+ and K+ which
adds to the depolarisation; second, they allow calcium (Ca2+)
to enter the neuron. In other words, NMDA receptors sense
strong neuronal activity and send a signal to the neuron in
the form of a surge of Ca2+. This Ca2+ surge is also brief,
lasting for no more than about a second while glutamate is
bound to NMDA receptors. However, Ca2+ is a crucial
molecule as it also signals to the neuron when NMDA
receptors have been activated.
Apparatus used for monitoring the tiny electrical voltages
that occur at synapses.
Once inside the neuron, the Ca2+ binds to proteins located
extremely close to the synapses where the NMDA receptors
were activated. Many of these proteins are physically
connected to the NMDA receptors in what constitutes a
molecular machine. Some are enzymes that are activated by
Ca2+ and this lead to chemical modifications of other
proteins within or close to the synapse. These chemical
modifications are the first stages of the formation of the
memories.
AMPA receptors: our molecular
machines for storing memories.
If NMDA receptor activation triggers plastic changes in the
connectivity of neurons, what expresses the change in
strength? It could be that more chemical transmitter is
released. This can occur, but we are fairly certain that one
set of mechanisms involves AMPA receptors on the
post-synaptic side of the synapse. There are various ways
of doing this. One way might be to enable AMPA receptors
to work more efficiently, such as to pass more current into
the neuron upon activation. A second way would be to enable
more AMPA receptors to be inserted into the synapse. In
both cases this leads to a larger epsp - the phenomenon of
LTP. The opposite change, a reduction in the efficiency or
number of AMPA receptors can result in LTD. The beauty of
this mechanism for inducing LTP or LTD is its elegance yet
relative simplicity – it can all occur within a single dendritic
spine and thereby alter synaptic strength in a highly
localised manner. It is the stuff that memories might
actually be made of - an issue to which we return in the
next chapter.
g
Related Internet Sites: http://www.cf.ac.uk/plasticity/index.html
http://www.bris.ac.uk/synaptic/public/brainbasic.html
Exercising the brain
Changes in the functioning of AMPA receptors are not the
whole story. As memories become more permanent,
structural alterations occur in the brain. Synapses with
more AMPA receptors inserted following the induction of LTP
change their shape and may grow bigger, or new synapses
may sprout out from the dendrite so that the job of one
synapse can now be done by two. Conversely, synapses that
lose AMPA receptors following the induction of LTD may
wither and die. The physical substance of our brains is
altering in response to brain activity. Brains like exercise –
mental exercise of course! Just as our muscles grow
stronger when we engage in physical exercise, so it now
seems that our synaptic connections become more
numerous and better organised when we use them a lot.
Mind over memory
How well we learn is greatly influenced by our emotional state
- we tend to remember events associated with particularly
happy, sad or painful experiences. We also learn better when
we pay attention! These states of mind involve the release of
neuromodulators, such as acetylcholine (during heightened
attention), dopamine, noradrenaline and steroid hormones
such as cortisol (during novelty, stress and anxiety).
Modulators have multiple actions on neurons, several of
which act via changes in the functioning of NMDA receptors.
Other actions include the activation of special genes
specifically associated with learning. The proteins that they
make help to stabilise LTP and make it last longer.
The doctor within
Synaptic plasticity plays another critical function in our
brains – it can help the brain recover from injury. For example,
if the neurons that control particular movements are
destroyed, as happens during a stroke or serious head injury,
all is not necessarily lost. Under most circumstances, the
neurons themselves do not grow back. Instead other
neurons adapt and can sometimes take on similar
functional roles to the lost neurons, forming another
network that is similar. It is a process of re-learning and
highlights certain recuperative abilities of the brain.
Jeffery Watkins
a medicinal chemist who transformed the
study of excitatory transmission in the
brain by developing drugs like AP5 (below)
that act on specific glutamate receptors.
29
 Learning & Memory
Memories are central to our individuality. What each of us
remember is different from what others remember, even of
situations we have been in together. Yet, in our distinct
ways, all of us remember events, facts, emotional feelings
and skills - some for a short time, others for a lifetime.
The brain has multiple memory systems with different
characteristics and mediated by different neuronal
networks. The formation of new memories is now widely
thought to depend on synaptic plasticity, as described in
the last chapter, but we are still uncertain about the
neural mechanisms of information retrieval. While we all
complain about our memories, they are in the most part
pretty good, only starting to fail in old age or certain
neurological diseases. It might be good to try to improve
our memory, but doing so could be at the cost of
remembering many things that it is as well to forget.
The organisation of memory
There is no single brain area to which all the information we
ever learn is shuttled for storage. Working-memory holds
information in your mind for a short time in an active
conscious state. The much larger, more passive storehouse
of information is called long-term memory.
Inner Scribe
Visuo-Spatial Sketch Pad
Central Executive System
Auditory Short Term Store
Silent Rehearsal Loop
The short-term working-memory system of the brain
Working Memory
Like a pad on a desk for jotting down names or telephone
numbers that we need to remember only briefly, the brain has
a system for holding on to and working with small amounts
30
HER
calculus
FACE
AME
MY N
R ESS
ADD
Shoppin
g AGE
List
of information very accurately. We use it to remember
speech for long enough to interpret the flow of conversation,
for doing mental arithmetic, and for remembering where and
when we put our keys down a moment ago. Fidelity is central
to the system - a feature that comes at the cost of limited
capacity and persistence. It is often said that you can
remember 7 ± 2 items in working memory; this is why so
many telephone numbers are no longer than 7 or 8 digits.
But remembering these accurately is essential. You can
demonstrate the capacity and limited persistence of
working memory in a simple experiment you can do with
your friends.
t An Experiment on Short-Term Memory
A simple test of short-term or working memory is
called “letter-span”. You need a minimum of 2
people, although it works better with the whole
class. Privately, one of you writes down a series of
letters beginning with as few as 2, taking care they
do not spell out a word (e.g. XT). This person then
produces further letter strings, one letter longer
at a time (e.g. a 5-letter string such as QVHKZ and
a 10-letter string such as DWCUKQBPSZ).
The experiment begins after these are prepared.
The other person (or class) listens to each letter
string in turn and, after about 5 seconds, tries to
write down the letters in the correct order from
memory. Starting with the easy 2-letter string,
the memory test moves on to longer ones. Most
people can do it perfectly up to about 7 or 8 letters
- and then errors creep in. Very few can do 10 let-
ters correctly. The capacity of short-term memory
has been described as “the magical number 7 plus or
minus 2”.
A central executive system controls the flow of information,
supported by two additional memory stores. There is a
phonological store alongside a silent rehearsal loop - the bit
of your brain that you use to say things to yourself. Even if
you read words or numbers visually, the information will be
transcribed into a phonological code and stored for a short
while in this two-part system. There is also a visual
sketchpad that can hold on to images of objects for long
enough for you to manipulate them in your mind’s eye.
Working memory is largely located in the frontal and parietal
lobes. Brain imaging studies (see p. 41) using PET and fMRI
brain imaging indicate that the auditory parts of working-
memory are generally lateralised to the left frontal and pari-
etal lobes where they interact with neuronal networks involved
in speech, planning and decision-making. These are activities
for which a good working-memory is essential. The visual
sketchpad is in the right hemisphere (see Box at end of
chapter).
How did working-memory evolve? Animals, even most
mammals, probably do not have quite the same sort of
short-term memory system as we have, and it clearly didn’t
evolve to help early hominids remember telephone numbers!
Studies with young children point to a critical role for working-
memory in learning language, suggesting that this memory
system may have co-evolved with speech. The precision
required for keeping track of words and their order in a
sentence is critical for accurately working out the correct
meaning.
Long-term memory
Long-term memory is also sub-divided into different
systems located in widely dispersed networks of the brain.
The different networks do very different jobs. Broadly
speaking, information enters sensory systems and then
passes down pathways that provide increasingly specialised
processing. For example, information entering the visual
system passes down a so-called ventral pathway from the
striate cortex to the medial temporal lobe through a
cascade of networks that work out shape, colour, object
dentity, whether the object is familiar or not, until finally,
some kind of memory is formed of this particular object and
when and where it has been seen.
The cascade of brain areas through which visual information
is first processed perceptually and then for the purpose
of memory.
There are several ways of thinking about this cascade of
analysis. First, there are areas in the cortex that extract a
perceptual representation of what we are looking at.
This is used to store and later recognise things around us.
Our ability to identify familiar people in newspaper cartoons,
such as politicians, reflects this system. Very closely
related is a system called semantic memory - the vast
storehouse of factual knowledge that we have all accumulated
about the world. We know that Paris is the capital of France,
that DNA encodes genetic information as a sequence of base
pairs, and so on. The critical property is that facts are
organised into categories. This is vital for memory retrieval as
the search process can then shuttle through tree diagrams in
this storehouse to find things efficiently. If semantic memory
were organised in the way that many people organise things in
the attic of their houses - pretty randomly - we would have
terrible trouble remembering anything. Fortunately, the brain
sorts the information that we encode into categories, though
it helps to have a skilled teacher for the complex things we
learn at school. Indeed, gifted teachers build these
structures in their pupils effortlessly.
Objects
Inanimate Animate
Mammals Birds
Flying birds Flightless birds
Sing birds Other birds
Canaries Penguins
The facts we know about animals are organized in a
tree-structure. We do not yet know how the networks of
the brain do this.
We also learn skills and acquire emotional feelings about
things. Knowing that a piano is a piano is one thing: being able
to play it is another. Knowing how to ride a bicycle is useful,
but being aware that certain situations on the road can be
dangerous is no less important. Skills are learned through
deliberate and extensive practice, whereas emotional learning
tends to be much more rapid. Often it has to be fast,
particularly for the things we learn to be afraid of. Both are
types of learning called conditioning. Specialised brain areas
are involved - the basal ganglia and cerebellum being very
important for skill learning, and the amygdala for emotional
learning. Many animals learn skills - it is very important for
their survival.
Chimpanzees have learned the skill of fishing for termites
using a stick. Young chimpanzees learn this by watching
their parents.
31
 Memory failure and the localisation of Amazingly, amnesic patients can learn some things that they
cannot consciously remember! They can be taught motor
episodic memory in the brain skills or to read backwards very quickly.

The last type of memory system in the brain is called
episodic memory. It is what you use to keep track of person-
al experience. Remembering events is different from learning
facts in one very important respect - events happen only
once. If you forget what you ate at breakfast today (unlike-
ly), or what happened last Christmas (possibly), or all the
things that happened on your very first day at school
(probably), you cannot re-run any of these events like an
extra lesson in class. This system learns quickly because it
has to.
We have learned a lot about what episodic memory is by
studying neurological patients who, following a stroke, brain
tumours or viral infections such as herpes encephalitis,
sometimes have very specific deficits in this type of memory.
Studying such patients carefully has been the major way to
work out the anatomical organization of this and other
memory systems.
Training to read backwards quickly takes a while
This is true for amnesics no less than for us, but whereas
we would remember being taught to do this, they do not.
This is a fascinating dissociation in their conscious
awareness. Amnesics are certainly conscious when they
learn, but are later unaware of having learned. They cannot
recover conscious awareness from the past.
The damage that causes this distressing condition can occur
in a number of brain circuits. Areas of the midbrain called
mamillary bodies and the thalamus seem to be critical for
normal memory, as is a structure in the medial temporal lobe
called the hippocampus. Damage in these regions seems
particularly to affect the formation of episodic and
semantic memories.

“It is not so much the injury that captures our

attention as how, through injury or disease, normal
function is laid bare.”
(Sir Henry Head - 20th C Neurologist).
People affected by a condition known as amnesia cannot
remember meeting other people only half an hour earlier.
They cannot remember whether they have recently eaten a
meal or ought to have one, and even such simple necessities
of life as where things have recently been put down around
the house. Shown a complex drawing - such as the one in the
inset - they can copy it accurately but they cannot draw it
as well as most of us could do from memory as little as 30
minutes later. Often, they cannot remember things that
happened before they became ill. This is called retrograde
amnesia.

Such a life lacks all structure in time and place and has been
described by one extensively studied amnesic patient as like
continually “waking from a dream”. Yet this same person
retains his command of
language and the meaning
of words, and enough
NC working-memory to carry on
a sensible conversation. It
Copy Delayed Recall is not until one has exactly
the same conversation with
him a few minutes later
A
that the devastating
isolation of his existence
is revealed.

Amnesics (A) can see just fine and copy complex drawings Two structures are very important for episodic memory -
like this one quite accurately, but they cannot remember the perirhinal cortex (PRH) which mediates the sense of
them for very long compared to normal control familiarity about the past and the hippocampus (HIPPO)
subjects (NC). which encodes events and places.

32
Other memory systems
Damage elsewhere in the brain affects other memory
systems. Degenerative conditions, such as certain types of
semantic dementia (a type of Alzheimer’s Disease), can
cause fascinating patterns of breakdown of semantic
memory. Early on, patients will be quite capable of telling you
that the pictures they are being shown in an experiment are
of a cat, or a dog, or of a car, or a train. Later on in the
disease, they may hesitate to call a picture of a mouse a
mouse, saying instead that it is a dog. What this confirms is
that factual information is organised categorically, with
animate information stored together in one place well away
from inanimate information.
The neurobiology of memory
Studying neurological patients carefully helps us to discover
where memory functions are in the brain, but finding out how
They work in terms of neurons and chemical transmitters
involves carefully conducted research using laboratory
animals.
Neuroscientists now believe that many aspects of the
fine-tuning of neural connections in the developing brain are
also used during early learning. The attachment that
develops between an infant and its mother has been studied
in young chicks in a process called imprinting. We now know
The Hippocampus
This Golgi stain shows a
subset of neurons
in black
where this learning process takes place in the young chick’s
brain and the chemical transmitters that are released to act
on receptors involved in storing some kind of an ‘image’ of the
mother. This image is quite precise, such that the young
chick will follow its mother but not another. Young animals
also need to know what foods are safe to eat by tasting
small amounts of food at a time, and learning those that
taste bad. This cannot be left to genetic predispositions
alone - developmentally tuned learning mechanisms are at
work. Downstream of the receptors activated during
imprinting or the tasting of food, a cascade of second-
messenger chemicals transmit signals to the nucleus of
brain cells where genes are activated to make special
proteins that can literally fix the memory.
Place cells are another important discovery. These are
neurons in the hippocampus that fire action-potentials only
when an animal explores a familiar place. Different cells code
for different parts of the environment such that a
population of cells is involved in mapping a whole area. Other
cells in a nearby brain area code for the direction the animal
is moving in. The two areas working together - the map of
space and the sense of direction - help the animal learn to
find its way around the world. This is clearly very important
for animals, because finding food and water and then their
way back to the burrow, nest, or other home is vital for their
survival. This navigational learning system relates to both
semantic and episodic memory. Animals form a stable
representation of where things are in their territory - just
like the factual knowledge we acquire about our world. And
this map of space provides a memory framework in which to
remember events - such as where a predator was last seen.
Place cells may code more than just place - they may help
animals to remember where events have happened.
Four recording wires near cells in the hippocampus reveal
nerve impulses on two of the wires (1 and 2, occasionally 4)
that represent neurons firing at a particular place (red hot
spot in the circular enclosure). Expanding the time scale
(red circle) shows the shape of the spikes in the brain.
How are these maps and other memory traces formed?
One emerging view is that synaptic plasticity based on
NMDA receptors is involved. In the last chapter, we
described how activating synaptic plasticity changes the
strength of the connections in a network of neurons and
that this is a way of storing information. Learning about
places is impaired when a drug that blocks NMDA receptors
33
 is applied to the hippocampus. For example, rats and mice
can be trained to swim in a pool of water to find an escape Research Frontiers
platform hidden at one place underneath the water surface.
They use their place cells and head-direction cells to help find
their way, and they encode the correct location of the
platform into memory using plasticity triggered by NMDA
receptors. Also gene knockout animals have been engineered
in which NMDA receptors have been deleted in the
hippocampus. These animals are also bad at learning and
they also have very inaccurate place cells. In the last
chapter, we explained that changes in synaptic weights are
expressed through alterations in excitatory AMPA
receptors. We still don’t know if that is true of memory - it is
a topic of intense research just now.

The rat has swum in the pool to the hidden platform on
which it is standing.
London taxi drivers have to know the city very well before
they are allowed to ply the city for fares. When researchers
put experienced taxi drivers in a brain scanner and asked
them to imagine a trip from Marble Arch to Elephant and
Castle, they saw greater activation in the right
parahippocampal cortex (red areas). Structural MRI scans
of taxi drivers show changes in the relative size of different
parts of their hippocampus that may be related to how
much of the city they are able to remember - although there
could be other factors as well.

Can we improve memory?
We all think that it would be good to improve the capacity or
persistence of our memory. Older people often complain
about their memory. However, improving memory would
almost certainly come at a price. This is because a good
memory is a balance between remembering and forgetting.
If we were we to improve it, we might then have difficulty
forgetting all the trivial things that happened during the day
that there is no need to remember. The ‘yin and yang’ of a
good memory is one that remembers and organises the right
things in the brain, but forgets things that seem less
important. It seems unlikely that we shall ever have a pill
that will act like a magic bullet to improve memory, at least in
normal people. Evolution has ensured that the system is
optimally balanced.
drugs, but it is no less important. The idea is to take
advantage of what has been learned about how information
is encoded, stored, consolidated (the ‘fixing’ process) and
then retrieved. Paying attention, spacing out learning
sessions, and getting frequent reminders to help the ‘fixing’
process are all examples. Some elderly patients with
memory problems are finding a paging system called
“NeuroPage” quite helpful - it reminds them of what they
should be doing next and so helps them structure their day
in a manner that they might otherwise forget to do.
Recognising the different operating principles of episodic
memory and skill learning is also essential - you will never
learn a skill by merely hearing about it, although this works
fine for episodic memory. Anyone trying to learn a skill must
practice often, as the pupils of any music teacher are
always reminded.

Having said that, really serious forgetfulness might be Alan Baddeley

alleviated by drugs that make NMDA or AMPA receptors who developed the idea
work better, or drugs to stimulate the cascade of second- of working memory, which consists of
messenger signals that studies of learning in young animals a number of different interacting systems.
have identified. It would be helpful also to find some way of
stemming the course of neurodegenerative diseases such as
Alzheimer’s Disease that affect memory early on. One of the
exciting adventures in neuroscience today, for scientists in
universities, research institutes and pharmaceutical The phonological store, visuospatial sketch pad and
companies, is working on projects of this kind. With the central executive are located in various parts of the brain.
population demography of virtually all developed countries
veering towards a greater preponderance of older people,
treatments that could help them lead independent lives for
longer would be greatly valued.

However, some scientists believe that cognitive engineering

will be needed alongside drugs. You do not hear so much
about cognitive engineering in the newspapers as about new
g

Want to try some more memory experiments? Try

34 http://www.exploratorium.edu/brain_explorer/memory.html
Stress
Stress affects even the most seemingly tranquil lives.
We all experience it - during exams, competing in sports, or
when falling out with friends and enemies alike. Why does it
occur and what causes its unpleasant sensations? Is it
good for anything? What happens when it goes wrong?
Neuroscientists are beginning to understand how the brain
generates a coordinated chemical response to stress.
What is stress and why do we need it?
Stress is tricky to pin down. It isn’t just being under
pressure - for this is not always stressful - but some kind of
mismatch between what the body and brain anticipate and
what challenges we actually experience or feel.
Many challenges that we face are psychological - reflecting
the difficulties of interacting with others as we work
towards academic success, compete for a place in the school
team or, later in life, for a job. Other stresses are physical
such as an acute illness or a broken leg in a car accident.
Most stressors are mixed: the pain and other physical
afflictions of an illness are coupled with worry and concern.
Stress is a fundamental process. It affects all organisms,
from the simplest bacterium and protozoan, to complex
eukaryotes such as mammals. In single-celled organisms and
in the individual cells of our bodies, molecules have evolved
which provide a series of emergency systems that protect
key cellular functions from unexpected external challenges
and their internal consequences. For example, special
molecules called heat-shock proteins guide damaged
proteins to where they can be repaired or harmlessly
degraded, thus protecting cells from toxicity or dysfunction.
In complex organisms such as ourselves, stress systems
have evolved as highly sophisticated processes to help deal
with out-of-the-ordinary challenges that may afflict us.
These use the cellular protection mechanisms as building
blocks in a larger network of stress protection.
Stress and the brain
Stress is perceived and the response co-ordinated by the
brain. Our cognitive appraisal of a situation in the brain
interacts with bodily signals in the blood stream such as
hormones, nutrients, and inflammatory molecules, and with
information from peripheral nerves monitoring vital organs
and sensations. The brain integrates these to produce a
series of specific and graded responses. Our understanding
of how it does this has come from the study of
neuroendocrinology. Circulating hormones in the blood are
monitored by the brain to enable the body to cope
with stress.
Fight or Flight?
The easiest response to recognise is the immediate
activation of what is - endearingly - called the sympathetic
nervous system. After receiving a stressful challenge and
computing the right response, the brain rapidly activates
nerves originating from control centres in the brainstem.
These cause the release of noradrenaline in a variety of
structures and of adrenaline from the adrenal glands
(situated just above the kidney). Their release underpins the
fight or flight response - the classical, immediate reaction
that has to be made in response to danger. We all recognise
the initial tingling sensation, sweating, heightened
awareness, rapid pulse rate, higher blood pressure and
general feelings of fear that we all feel in the moments
immediately after a stressful challenge.These changes
happen because of receptors that are found on blood
vessels, causing them to constrict and so our blood pressure
to shoot up, and in the heart, causing it to accelerate and
produce the pounding sensation in the chest known as
palpitations. There are also receptors in the skin causing
hairs to erect (goosebumps) and in the gut causing those
disconcerting abdominal sensations that we all sense as
stress. These changes are there to prepare us to fight or to
flee - and to concentrate blood flow to vital organs, the
muscles and the brain.
The hypothalamic-pituitary-adrenal
(HPA) axis
The HPA Axis. The hypothalamus at the centre controls the
release of hormones from the pituitary that act on the
adrenal glands. Negative feedback of the hormonal release
is provided at various levels of the axis.
35
 The second major neuroendocrine response to stress is
activation of a circuit linking the body and brain called the
HPA axis. This links together the hypothalamus, pituitary
gland, adrenal cortex and hippocampus by a bloodstream
highway carrying specialised hormones.

The hypothalamus is the key brain area regulating many of

our hormones. It has strong inputs from areas of the brain
processing emotional information, including the amygdala,
and from regions of the brainstem controlling sympathetic
nervous responses. It integrates these to produce a
co-ordinated hormonal output that stimulates the next part
of the circuit - the pituitary gland. In turn, this releases a
hormone called adrenocorticotrophin (ACTH) into the blood.
ACTH then stimulates a part of the adrenal gland to
secrete cortisol.
Cortisol is a steroid hormone that is the key to
understanding the next phase of the stress response.
It raises blood sugar and other metabolic fuels such as fatty
acids. This often occurs at the expense of proteins that are
broken down into fuels required immediately - instant
‘chocolate bars’ for the muscles and brain. Cortisol also
helps adrenaline to raise blood pressure and, in the short
term, makes you feel good. Faced with the challenge of
singing a solo at the school concert, the last thing you want
to do is dwell on worrying things. You just want to do it right
with as little self-consciousness as possible. Cortisol also
turns off growth, digestion, inflammation, and even wound-
healing - clearly things that can be better done later on.
It also turns off sex. The last step of the circuit is cortisol
feedback to the brain. The highest density of cortisol
receptors is in the hippocampus, a key structure for learning
and memory, but cortisol also acts on the amygdala, which
processes fear and anxiety. The net effect is to turn on the
amygdala - to allow learning of fear-related information; and
to turn off the hippocampus - to ensure that resources are
not wasted on more complex but unnecessary aspects of
learning. Cortisol is focus juice.
STRESS IS INEVITABLE, SOMETHING WE ALL
EXPERIENCE. IT MAY BE PSYCHOLOGICAL,
PHYSICAL OR (USUALLY) BOTH.
A tale of two cortisol receptors and the
shrinking hippocampus
The hippocampus has high levels of the two receptors for
cortisol - let’s call them the low MR and the high GR
receptor. The low MR receptor is activated by the normally
circulating levels of cortisol in the bloodstream highway of
the HPA axis. This keeps our general metabolism and brain
processing ticking over nicely. However, as cortisol
levels begin to rise, particularly in the morning, the high GR
receptor becomes progressively more occupied. When we
become stressed, cortisol levels become very high indeed,
activation of this receptor is sustained and the
hippocampus is then shut down by a genetically controlled
program. Put all this together and you have what is called a
bell-shaped curve. This is the classical curve relating stress
to brain function - a little bit is good for you, a bit more is
better, but too much is bad!
g
The bell-shaped curve for stress. A little bit of stress can
make things better, but too much makes things worse.
Depression and stress-system
overactivity
An excess of cortisol in the blood is seen in some chronic
brain diseases. In particular, in severe depression cortisol is
over-produced and recent work suggests that the
hippocampus also shrinks in this condition. Such findings
have led psychiatrists to think of severe depression as
severe long-term stress. It is not at all certain that the
increased cortisol is the primary cause of this illness rather
than it being simply a consequence of severe psychological
upset and its attendant stress. However, patients can be
markedly helped by blocking the production or action of
cortisol, particularly those in whom classical anti-
depressant drug treatments do not work. Anti-depressant
drugs often help to normalise the overactive HPA axis. One
idea is that they do so, in part, by adjusting the density of
MR and GR receptors in the brain, particularly in the
hippocampus. Neuroscientists working on this hope to
develop more effective treatments for stress disorders that
work by resetting the feedback control system and reducing
excessive hormonal stress responses.
Stress and ageing
Ageing of the brain is accompanied by a general decline in
function, but a decline that varies a great deal between
individuals. Some individuals maintain good cognitive abilities
with age (successful ageing), whilst others do not do so well
(unsuccessful ageing). Can we get a molecular understand-
ing of this? Cortisol levels are higher in unsuccessful than in
successful ageing. This rise precedes the fall in mental
abilities and the associated decline in the size of the
hippocampus seen in brain scans. Experiments in rats and
mice have shown that keeping stress hormone levels low from
birth, or even from middle age onwards, prevents the
emergence of memory defects otherwise seen in untreated
populations. So it appears that individuals with excessive
hormone responses to stress - not necessarily those who
had most stress, but those who make the greatest
responses to stressors - are those who get more memory
loss and other cognitive disorders with advancing years.
If this is true in humans as well, we may able to reduce the
burden of such effects, perhaps by exploiting antidepressant
drugs that keep the HPA stress system under control.
Stress is a major feature of modern life - and there is more
to the story. But to describe this, we will have to bring in the
immune system.

Related Internet Site: http://www.brainsource.com/stress_&_health.htm

36
The Immune System

Until just a few years ago, the brain was thought to be an
“immune privileged organ” because it was not affected by
immune responses or inflammation. It is certainly
protected to some extent from external events by the
“blood brain barrier”. This is not really a barrier, but
specialised endothelial cells in the brain blood vessels that
are relatively resistant to the passage of large molecules
or immune cells from the blood into the brain. However, this
view of the brain as privileged has changed dramatically
over the last decade as the result of research on
brain-immune system interactions. Neuroimmunology
is now a very active area of research.
Body defences
The immune system is our first line of defence against
malicious invaders. These invaders, viruses, bacteria and
yeast, range from common and mild, such as the all too
familiar cold, to severe and life threatening, e.g. HIV,
meningitis or tuberculosis.
Our defences work in many ways. The first is locally within
the tissue that is infected, injured or inflamed, causing
swelling, pain, changes in blood flow and release of local
inflammatory molecules. More generally, activation of the
immune system triggers cells called leucocytes and
macrophages, and acute phase proteins that travel to the
site of attack, to identify, kill and then remove invading
pathogens. In addition, the acute phase response generates
the symptoms we have all felt (fever, aches and pains,
sleepiness, loss of appetite, disinterest). Each of these
responses helps to combat infection, conserve energy and
aid repair, but when activated too much or for too long they
can be very damaging. So they need to be carefully
controlled.
The brain and defence responses
The view of the brain an immunologically privileged organ has
now given way to a very different conception of its
relationship to the immune system. This is because it is now
known that the brain can, and does, respond to signals from
the immune system and from damaged tissues. The old
orthodoxy has been overthrown. Experiments have revealed
that the brain exhibits an array of local immune and
inflammatory responses, and indeed is an important
controller of the immune system and of the acute phase
response. Many responses to disease, such as fever (body
temperature), sleep, and appetite, are regulated primarily by
the hypothalamus.

The brain receives signals from injured or infected tissues

STRESS, SOCIAL FACTORS that may be neural in origin (via sensory nerves) or humoral
(via circulating molecules). Neural signals seem to be via C-
fibres (which also communicate pain – see Chapter 5) and via
Brain the vagus nerve from the liver – a key site for production of
acute phase proteins. The nature of the main circulating
Hypothalamus signals to the brain are not fully understood, but are believed
to include prostaglandins (which are inhibited by aspirin),
and complement proteins (a cascade of proteins important
in killing invader cells). But perhaps the most important
Humoral CRP
& neural signals are a group of proteins which came to light only in the
afferents last 20 years – known as cytokines.
Sympathetic Pituitary

Infection
Nervous System Cytokines as defence molecules
Injury ACTH
Cytokines are the body’s retaliators. There are now well over
Inflammation
100 of them - and more are being discovered all the time.
Adrenal These proteins are normally produced in the body at very low
levels, but are switched on quickly in response to disease or
Local efferents Glucocorticolds injury. They include interferons, interleukins, tumour
Immune & Endocrine necrosis factors and chemokines. Many are produced
Systems locally within damaged tissues and act on cells nearby, but
some enter the blood stream where they send signals to
distant organs including the brain. It is cytokines that cause
Many brain mechanisms come together to coordinate the most of the responses to disease and infection.
brain and the immune system.

37
 The triggers for cytokine production include bacterial or viral
products, damage to cells or threats to cell survival such as
toxins or low levels of oxygen. Another important regulator
of cytokine production is the brain that, through neural
signals to tissues (mainly via the sympathetic nervous
system) or hormones (such as cortisol from the adrenal
gland), can switch cytokines on or off.
Cytokines are protein molecules with many actions,
particularly on the immune system. Most stimulate the
immune system and the key components of inflammation
such as swelling, local changes in blood flow, and the release
of a second wave of inflammatory molecules. They act on
almost all physiological systems, including the liver where
they stimulate the acute phase proteins. However, although
cytokines share many actions, they also vary significantly.
Some are anti-inflammatory and inhibit pro-inflammatory
process; most act locally on cells close to where they are
produced, while others are released into the circulation,
like hormones.
Stress and immune system
We have all heard that stress and worry can lower our
defences and can make us ill. We are now starting to
understand not only how stress can affect the brain directly
by activating the HPA axis (described in the previous
chapter), but also how it can influence the immune system –
not surprisingly by an indirect route that is also through the
brain. Stress can influence the immune system and
susceptibility to disease, but it depends on the type of
stress and how we respond - some people clearly thrive on it.
It is the sorts of stress that we cannot cope with that can
g
Related Internet Sites: http://science.howstuffworks.com/immune-system.htm
38
inhibit our defence responses, such as excessive work or
major tragedies. The precise mechanisms responsible for the
link between stress and the immune system are not fully
worked out, but we do know that an important feature is
activation of the hypothalamic-pituitary-adrenal axis.
One of the main responses to stress in the brain is increased
production of a protein in the hypothalamus called
corticotrophin releasing factor (CRF). CRF travels the
short distance from the hypothalamus to the pituitary
gland to release another hormone, adrenocotrophin
releasing factor (ACTH). This hormone travels via the
circulation to the adrenal gland to release steroid hormones
(cortisol in humans), which are some of the most potent
suppressors of immune function and inflammation. But the
story seems to be more complex than this because there are
other hormonal and neural elements, and we also know that
some forms of mild stress can actively improve our immune
function.
Immune and inflammatory responses
within the brain
Recent research has shown that many of the defence
molecules such as cytokines are also active contributors to
brain diseases such as multiple sclerosis, stroke and
Alzheimer’s. It seems that over production of such
molecules within the brain itself can damage neurons -
particularly certain cytokines. Various new treatment
strategies for brain disease are now being developed with the
idea of inhibiting immune and inflammatory molecules.
So neuroimmunology – a newcomer to the field of
neuroscience may provide some clues and possible
treatments for major brain diseases.
Sleep
Z Z
Every night we retire to our bedroom, climb into bed, and
drift off into the unconscious state of sleep. Most of us
sleep for about 8 hours, which means we spend roughly a
third of our lives unconscious - part of it dreaming. If you
try to avoid sleep to use this precious time for other
activities, such as late night parties or burning the
midnight oil cramming for exams, your body and brain will
soon tell you that you shouldn’t. We can stave it off for a
while but never for long. The sleep/wake cycle is one of a
number of rhythmical activities of the body and brain. Why
do they exist, what parts of the brain are involved and how
do they work?
A rhythm to life
The sleep-wake cycle is an endogenous rhythm that
gradually becomes locked to the day-night cycle through the
first years of life. It is what is called a circadian rhythm -
so called because ‘circa’ is Latin for around, and ‘dies’ for day.
It is important throughout life: babies sleep for short periods
during both the day and the night, young children often take
a nap after lunch, while adults generally sleep only at night.
Sleep is good for you - Winston Churchill, the Prime Minister
during World War II, was said to be partial to short naps of
five minutes or so - sometimes during cabinet meetings!
The normal pattern locking in sleep and wakefulness to the
day-night cycle is partly controlled by a small group of cells in
the hypothalamus just above the optic chiasm called the
suprachiasmatic nucleus. The neurons here, which are
unusual in having lots of synapses between their dendrites
to synchronise their firing together, are part of the brain’s
biological clock. In humans, it ticks away at a rate just a bit
slower than a day, but is normally kept in register by inputs
from the eye telling it when it is day-time or night-time. We
know this because people who have participated in sleep
experiments by living in deep caves for long
periods of time, away from all clues as to the true time of
day, adopt patterns of activity that free-run to a sleep-
waking cycle of about 25 hours.
SCN active in daylight SCN quiescent at night
The suprachiasmatic nucleus is the brain’s own
personal clock.
Z Z
The stages of sleep
Sleep is not quite the passive process it seems. If a person is
wired up with electrodes to their scalp in a sleep laboratory
(which has beds not benches!), the brain’s
electroencephalogram (EEG) passes through several
discrete stages. When awake, our brains show low-amplitude
electrical activity. As we fall asleep, the EEG becomes flatter
at first but then, gradually, it shows increases in amplitude
and decreases in frequency as we move through a series of
discrete stages of sleep. These stages are called slow-wave
sleep (SWS). The reasons for these changes in electrical
activity are still not fully understood. However, it is believed
that as neurons in the brain become unresponsive to their
normal inputs, they gradually become synchronised with each
other. You lose muscle tone as the neurons controlling skele-
tal muscle movements are actively inhibited but,
thankfully, the ones controlling respiration and heart rate
carry on working normally!
Throughout the night, we cycle back and forth between these
different stages of sleep. In one of them, the EEG becomes
like the waking state again and our eyes jerk back and forth
beneath our closed eyelids. This is the so-called rapid eye
movement (REM) stage of sleep when we are more likely to
dream. If people are woken during REM sleep, they almost
invariably report dreaming - even those who habitually claim
that they never dream (try it as an experiment on a member
of your family!). In fact, most of us will have about 4 to 6
short episodes of REM sleep each night. Babies have a bit
more REM sleep and even animals show REM sleep.
Awake
REM
Stage 1
Stage 2
Stage 3
Stage 4
0 1 2 3 4 5 6 7 8
Hours of
Hours of Sleep
Sleep
A normal night’s sleep of 8 hours consists of a pattern of
different sleep stages, with short bursts of REM sleep
(red areas) occurring about 4 times each night
Sleep Deprivation
Some years ago, an American teenager called Randy Gardner
resolved to try and win his place in the Guinness book of
Records by going without sleep for the longest period ever
recorded. His ambition was to last 264 hours without sleep -
and he did it! It was a carefully controlled experiment
39
 supervised by doctors in the American Navy - not one we
recommend you repeat! Amazingly, he survived very well.
The main difficulties he had (apart from feeling very sleepy)
were difficulties with speech, an inability to concentrate,
lapses of memory and hallucinatory daydreaming. But his
body remained in excellent physical condition and he never
became psychotic or lost contact with reality. After the
experiment was over, he showed a small rebound, sleeping for
nearly fifteen hours the first night and short extra periods
on succeeding nights. This and many other similar
experiments have convinced sleep researchers that it is
primarily the brain and not the body that really gains from
sleep. Similar conclusions have come from other studies,
including carefully controlled animal experiments.

Why do we sleep?
Many issues in neuroscience remain an enigma and sleep is
one of them. Some people have argued that sleep is just a
convenient way for animals to be kept immobile and so out of
danger. But there must be more to it than that. The sleep
deprivation experiments lead us to think that REM sleep and
certain phases of SWS enable the brain to recover. We have
this kind of sleep during the first 4 hours of the night.
Perhaps it helps to reset things in the brain and that a good
time to do this necessary task is, by analogy with a ship in
dry dock, when the brain is not processing sensory
information, or being vigilant and attentive, or having to
control our actions. Research also suggests that sleep is
the time when we consolidate what we have learned the day
before - an essential process in memory.
How do rhythms work?
A great deal has been learned about the neural mechanisms
of rhythmical activities such as sleep by recording the
activity of neurons in various brain areas during the
transitions between different sleep stages. These have
revealed a brain-stem activating system involving various
neuromodulatory transmitters, including one called
adenosine, in a kind of molecular chain reaction that takes
us through the various sleep stages. Synchronisation
mechanisms enable networks to pass from one sleep state
to another.
A big leap forward has come from neurogenetics. Various
genes have been identified that, like the cog-wheels and
escapement of a clock, are the molecular components of
rhythmical pacemakers. Much of this work has been done in
Drosophila (fruit flies) where it has been found that two
genes - per and tim - produce proteins that interact
together to regulate their own synthesis. mRNA and protein
synthesis begins early in the day, the proteins accumulate,
link up together and this linkage then stops their own
synthesis. Daylight helps to degrade the proteins whose
level eventually drops to a point where the genes that make
PER and TIM protein get going again. This cycle goes round
and round, and will even carry on if the neurons are kept alive
in a dish. The clock in mammals such as ourselves operates in
a remarkably similar way to the one in flies. As circadian
rhythms are very old in evolutionary terms, it is perhaps no
surprise that the same types of molecules drive the clock in
such different organisms.

Research Frontiers
Light Dark Light Dark Light Dark Light Dark
10

20
Days

30

Normal Mice show "jet-lag"

40 Mutant mice "clock-shift" immediately

Mice who don’t show jet-lag!

To try to understand the molecular mechanisms of circadian rhythms better, neuroscientists have genetically engineered mice
in which genes expressed in the suprachiasmatic nucleus are “knocked out”. These VIPR2 mice live fine and show changes in
activity patterns between night and day just like normal mice. The black dots of the pattern above show when the mice are
active - a daily rhythm with activity at night (grey areas). However, when the time that the lights are turned out is suddenly
shifted forward by 8 hr (around day 25), normal mice show “jet-lag” by taking a few days to shift their activity patterns.
The knock-out mice shift immediately. These kinds of studies should help us learn about the molecular mechanisms by which
light entrains circadian pacemaker genes.
g

Related Internet Sites: http://www.hhmi.org/lectures/2000/

40 http://www.cbt.virginia.edu, http://science.howstuffworks.com/sleep.htm
Brain Imaging
Phrenologists thought they could understand the brain by
examining the bumps on the surface of the skull. If this
seems far-fetched now, their ambition to understand the
brain by looking at it from outside the skull has fascinated
many throughout the ages. Now we really can do this –
through the advent of modern brain imaging techniques.
Modern scanners use a variety of means to give us
wonderful images of neuronal and fibre pathway structure,
of blood flow and energy metabolism in the brain, and of the
changes in neural activity that occur when we do
different things.
The walkway to modern techniques
In attempts to relate structure to function, a great deal has
been learned by neurologists and neuropsychologists who
correlate any oddities of mind or behaviour with
measurements of brain structure at postmortem. It was in
this way that the speech areas of the brain were identified
by Broca. This approach has had many successes, but it also
has limitations. One cannot make the simple assumption
that the loss of a function due to damage to a region of the
brain represents the normal function of that region.
For instance, a deficit might occur because that region is
cut-off or disconnected from other regions with which it
normally communicates. It is also possible that brain areas
that are undamaged may take over some functions that are
performed by the damaged area under normal
circumstances; this is known as plasticity. Finally, very few
pathological lesions are confined to a precise functional area.
And there may be long delay between the study of a patient
when they are alive and the later analysis of their brain.
Structural brain imaging techniques began to be developed
about 30 years ago. The recent development of functional
imaging methods by medical physicists has attracted
particular attention. These enable us – literally - to see
inside the skull and so peer into the human brain - as it
thinks, learns or dreams.
Left: The profits made by E.M.I. from the sale of records by ‘The Beatles’ helped to pay for the development of the first brain
scanners. These and later machines have enabled neuroscientists to look into the brain in new ways.
Right: A modern MRI scanner. The subject lies on a table that is moved into the ring of magnets for the scan that may take
anything from 30 min to 1 hour.
How it all works
Electrophysiological techniques for monitoring neuronal
activity are based on changes in the membrane potential of
activated neurons. Brain scanning techniques work by
monitoring changes in energy metabolism required by
activate neurons.
The electrochemical gradients that move charged ions in and
out of neurons (that underlie synaptic and action
potentials) require energy for their operation. The source of
this energy is oxidation of glucose. Glucose and oxygen are
delivered to the brain by the cerebral circulation. By virtue of
the neurovascular link, there is a local increase in cerebral
blood flow in active areas. This occurs very quickly. Modern
neuroimaging devices measure these changes in local
cerebral blood flow and use them as an index of
neural activity.
The first functional technique to be developed was called
Positron Emission Tomography (PET). This procedure
involves the injection, into the humansubjects, of radioactive
tracers that are attached to compounds of biological
interest (such as drugs that bind to neurotransmitter
receptors). Rings of detectors around the subject’s head
record the timing and position of gamma particles emitted
by the nuclear isotope as it traverses the brain and decays.
PET can be used to produce maps of changes in local cerebral
blood flow (CBF). Such measurements have led to the
localisation in the human brain of sensory, motor and
cognitive brain functions. There are several disadvantages of
PET, the major one being that it requires the injection of
radioactive tracers. This means that many people cannot
have a PET scan, such as children and women of child-bearing
age, and the number of measures taken during a scan
are limited.
A different technique, called Magnetic Resonance Imaging
(MRI), was developed that is non-invasive and does not
41

Images of blood vessels in the brain. Changes in blood flow
can be detected and serve as an index of neural activity.
With computer technology, the images obtained by PET and
MRI scanners show exactly where the changes in blood flow
occur within the brain.
42
require radioactive substances. This allows people of any age
to be scanned. MRI can be used to provide very fine-grained
images of brain structure, and a recent development called
diffusion tensor imaging (DTI) permits detailed images of
the white matter tracts of fibres that connect brain regions.
One of the most exciting applications of MRI technology
provides images of brain function: this is called functional
Magnetic Resonance Imaging (fMRI). This technique is
based on the difference in magnetic properties of
oxyhaemoglobin and deoxygenated haemoglobin in blood
(hence the signal in fMRI is called the Blood-Oxygenation-
Level-Dependent signal – BOLD). As increased neuronal
activity leads to movements of ions that activate
energy-requiring ion pumps, there is an increase in energy
metabolism and oxygen consumption. This leads to an
increase in deoxygenated haemoglobin and a decrease of the
magnetic signal. However increased oxygen consumption is
followed within seconds by an increase in local cerebral blood
flow. The increase in cerebral blood flow exceeds the increase
in oxygen consumption; there is therefore a relative increase
in oxyhaemoglobin and the size of the signal. The exact
mechanism of the increased cerebral blood flow is still
unclear, but neurotransmitter–related signalling is now
thought to be responsible.
Putting it to use
You’re probably pretty good at subtracting numbers. But
have you ever tried subtracting brains? No wonder the boy
looks confused (cartoon). Subtracting brain images in 2- and
3 - dimensions turns out to be critical for the data analysis.
Most fMRI studies involve measuring the BOLD signal while
people are engaged in carefully controlled tasks. During a
scan, subjects lie within the bore of a magnet, and their
behavioural responses to stimuli are monitored. A wide range
of stimuli can be presented, either visually, projected onto a
screen for the subject to view, or in the auditory domain via
headphones. It is possible to examine covert phenomena
such as perception, learning, remembering, thinking or
planning. Often two very similar tasks are designed with one
to be done immediately after the other. The idea is that the
first task should involve the brain process an
experimenter is interested in whereas the other should not.
The succession of brain images obtained are then subtracted
from each other to yield a pixellated 2D image of what
changes in activity are specifically associated with
performing the critical brain process. These images are
stacked up by the computer to yield an effective subtraction
of the image in 3 dimensions (see cartoon previous page).
Recent developments mean that even very brief thoughts or
brain events (as little as one or two seconds in duration) can
be measured. This is known as event-related fMRI.
Activation of area V5 reflects the perception of motion.
Sophisticated methods of data analysis are used to test This area’s inputs come from V2 of the cortex and the
whether changes in the signal during performance of a task pulvinar (Pul) that is deeper in the brain. The posterior
are statistically reliable. One widely-used analysis package parietal cortex (PPC) controls the flow of information.
Effective connectivity analyses enable the relative
contributions of these to be worked out.

see the medial temporal lobe lighting up routinely in long term

A person in the scanner might be shown a variety of visual
images. All of these would ‘light up’ the primary areas of
the visual cortex, V1 and V2. Use of clever subtraction
techniques has revealed that colour processing (left) is in
area V4, while motion processing (of random dots moving
about on a screen – right) activates V5.
memory tasks. However, newer testing paradigms – some
including virtual reality - are now revealing its activity in
memory processing along with other areas such as the
prefrontal cortex and precuneous. Coupled with new
neuropsycholgical and other imaging findings, this diversity
of brain areas involved has led to a revision of our
understanding of the memory systems of the brain.
New mathematical techniques are also being developed to
look at how the neural activity of different brain regions
interacts and correlates during complex tasks - known as
effective connectivity). This measure allows us to
appreciate how brain areas work as a team and not merely as
isolated functional hot spots. The hope is that these new
techniques, with magnets of high field strength providing
even more precise images, will tell us about the dynamics of
networks of neurons talking to each other in the seamless
control of perception, thought and action.

that has standardized the processing of imaging data is Research Frontiers

called statistical parametric mapping (SPM). SPM maps are
often given colours, with a fiery yellow used for the ‘hottest’
areas of activity through to blue and black for ‘cooler’ areas.

Brain imaging scientists speak of areas ‘lighting up’ when

certain functions are carried out. If a person watches a
constantly changing checkerboard pattern, substantial
activation is observed in the primary visual cortex. The use
of moving and coloured colour patterns and other clever
stimuli designed to activate different areas of the visual
system has given us a great deal of new information about
the organisation of the human visual system. Similar Nikos Logothetis is a young researcher making a major
studies have been conducted for other sensory modalities. contribution to understanding the relationship between
the activity of neurons in the brain and the signals seen in
This localisational way of thinking has also helped to identify
brain-imaging experiments.
the brain areas involved in distinct components of reading –
such as transforming visual words into a phonological code, Recent experiments in which electrical recording is
the grouping of phonemes into whole words, the process of combined with fMRI have shown a much closer correlation
extracting the meaning of words, and so on. Learning tasks between synaptic activity and the BOLD signal than action
have also been studied, including work dissociating the brain potential discharge. The BOLD signal is therefore a more
areas involved in anticipating and perceiving pain. reliable index of synaptic processing within a brain region
than its action-potential output. This has important
However, as research has proceeded, various surprises have implications for the interpretation of the BOLD signal in
emerged. One early example was the unexpected failure to terms of localisation of function.
g

Related Internet Sites: http://www.dcn.ed.ac.uk/bic/

http://www.fil.ion.ucl.ac.uk/
43
 Neural Networks &
Artifical Brains
The real brain is squishy stuff. Its neurons, blood vessels
and fluid- filled ventricles are made of lipid membranes,
proteins and a great deal of water. You can poke the brain
with your finger, cut it on a microtome, insert electrodes
into its neurons and watch the blood pulsing through it.
The study of the brain seems firmly anchored in biology and
medicine. However, there’s another way of thinking about it
that has attracted the attention of mathematicians,
physicists, engineers and computer scientists. They think
about the brain by writing equations, making computer
models and even hardware devices that mimic the real
neurons inside our heads.
Real brains are highly adaptable. They are able to do things
like read handwriting that we have never seen before and to
understand the speech of complete strangers. And they can
tolerate things going wrong. They function reasonably well
for a life-time even though cells are dying and, even in old age,
brains are still capable of learning new tricks. Todays’ robots
are very good at doing the restricted range of tasks for
which they have been designed, like building a bit of a car, but
much less tolerant when things go wrong.
All real brains consist of highly interconnected neuronal
networks. Their neurons need energy and the networks need
space. Our brain contains roughly 100 billion nerve cells, 3.2
million kilometers of ‘wires’, a million-billion connections, all
packed into a volume of 1.5 litres, but weighing only 1.5 kg and
consuming a mere 10 watts. If we tried to build such a brain
using silicon chips, it would consume about 10 megawatts, i.e.
enough electricity to power a town. To make matters worse,
the heat produced by such a silicon brain would cause it to
melt! The challenge is to discover how brains operate so
efficiently and economically, and to use similar principles to
build brain-like machines.
Your brain is 100,000,000,000 cells and
3,200,000 kilometres of wires, with
1,000,000,000,000,000 synaptic
connections, all packed into 1.5 litres and
weighing 1.5 kg. Yet it consumes only
about the same amount of electric power
as a night-light!
t
44
Building brain circuits in silicon
The energy cost of signaling - from one neuron to another -
has probably been a major factor in the evolution of brains.
About 50-80% of the total energy consumption of the brain
is consumed in the conduction of action potentials along
nerve fibres and in synaptic transmission. The rest is taken in
manufacturing and maintenance. This is as true for the brain
of a bee as it is for ours. However, compared to the speed of
3
digital computers, the speed of nerve impulses is very
slow - only a few metres per second. In a serial processor like
a digital computer, this would make life impossible. Biological 1
brains, however, are constructed as highly parallel networks.
Most neurons connect directly to many thousands of
others. To do this, the brain exploits its three-dimensional
volume to pack everything in - bending the sheets of cells 2
into folds and weaving the connections closely together into
bundles. By contrast, making connections between even
modest numbers of silicon neurons is limited by the
two-dimensional nature of chips and circuit boards. So unlike
the brain, direct communication between silicon neurons is
severely restricted. However, by exploiting the very high
speed of conventional electronics, the impulses from many
silicon neurons can be ‘multiplexed’ - a process of carrying
many different messages along the same wire. In this way,
silicon engineers can begin to emulate the connectivity of
biological networks.
To reduce power but increase speed, neurally-inspired
engineers have adopted the biological strategy of using
analogue rather than digital coding. Carver Mead, one of the
‘gurus’ of silicon valley in California, coined the description
‘neuromorphic engineering’ to describe the translation of
neurobiology into technology. Instead of coding digitally in
0’s and 1’s, analogue circuits code in continuous changes in
voltages, as do neurons in their sub-threshold state
(Chapter 3). Calculations can then be done in fewer steps
because the basic physics of the silicon devices is exploited.
Analogue computation easily provides the primitives of a cal-
culus: addition, subtraction, exponentials and integration, all
of which are complicated operations in digital machines.
When neurons - whether biological or silicon - compute and
make ‘decisions’ they transmit impulses down axons to
communicate the answer to target neurons. Because spike
coding is energetically costly, efficient coding maximizes the
amount of information represented in a pattern of spikes by
reducing what is called redundancy. Energy efficiency is also
increased by using as small a number of active neurons as
possible. This is called sparse coding and it provides another
important design principle for engineers building artificial
neural networks.
offcenter
A silicon retina
One simple artificial version of a biological network has been
built consisting of a silicon retina that captures light and
adapts its output automatically to changes in
overall lighting conditions. It connects to two silicon neurons
that, like real neurons in the visual cortex, have the job of
extracting information about the angles of lines and
contrast boundaries in the retinal image.
The neurons in this prototype are called integrate-and-fire
neurons and neuromorphic engineers use them a lot.
They get this name because they ‘add up’ the weighted
inputs, coded as voltages that are arriving at their
synapses, and only ‘fire’ an action potential if the voltage
reaches a set threshold. The silicon neurons themselves are
built of transistors, but instead of using the transistors as
switches and driving the voltages to saturation as in
conventional digital systems, the transistors are operated
in their subthreshold range. In this range, they act more like
the cell membranes of real neurons. Additional transistors
provide active conductances to emulate the voltage- and
time-dependent current flows of real ion channels. This small
visual system is a prototype for much more elaborate
artificial visual systems that are under development, but
even it illustrates how a very noisy real-world input can be
processed rapidly to produce a simple decision. It can do
what it is designed to do - tell the orientation of a line in a
scene - and neuroscientists are already using this simple
silicon visual system to test equipment and train students.
The most important things about artificial networks is that
they operate in the real world, in real time and use very
little power.
A camera lens is located in front of the silicon retina.
Artificial Neural Networks
Artificial neural networks (ANNs) are often used to study
learning and memory. Usually they software on a
conventional digital computer, they consist of a number of
simple processing units that are highly interconnected in a
network. The simplest form of ANN is a feedforward
associator, which has layers of interconnected input and
output units. An associative memory is encoded by
modifying the strengths of the connections between the
layers so that, when an input pattern is presented, the
stored pattern associated with that pattern is retrieved
(See Mathematical Puzzle Box on the next page). A more
complex ANN is a recurrent neural net. This consists of a
single layer where every unit is interconnected and all the
units act as input and output. It sounds a bit strange, but
this design enables the net to store patterns rather than
merely pairs of items. Decoding this kind of autoassociative
network is achieved by a recursive search for a stored
pattern. It has been shown that for a network of 1000
units, about 150 patterns can be retrieved before errors in
the retrieval patterns become too large.
The similarity of ANNs to brains lies in the way they store
and process information. The ‘knowledge’ that they process
resides in the network itself. They have no separate memory
location like the digital computer, for which the arithmetic
processor and memory addresses are separate. Instead,
they have content-addressable storage. In an ANN,
information is stored in the weights of the connections, the
same way that synapses change their strength during
learning. Nor are ANNs programmed to perform any given
procedure. Each ‘neuron’ inside is ‘dumb’ and simply responds
according to the sum of its weighted inputs. Still, they can
be trained to clever things. The learning rules that train
networks do so by modifying the strength of the
connections between the neurons, a common one being a rule
that takes the output of the network to a given input
pattern and compares it with the desired pattern. Any ‘error’
in the comparison is then used to adjust the weights of the
connections to achieve a closer output to the desired one.
The network gradually reduces the error signal to a minimum.
This works - but only slowly.
Mistakes turn out to be important - no learning is possible if
the network cannot make mistakes. This is a feature of
learning that can get overlooked. Over-trained networks
that made no errors would end up responding only to one
type of input. Such networks are metaphorically called
grandmothered - a reference to mythical ‘grandmother cells’
in the human brain that might respond only when one’s
grandmother comes into view and must never make a
mistake! This is not very useful in real world applications
because everything we had to learn would require a separate
network. On the contrary, the neat thing about ANNs lies in
their ability to generalize to input patterns they have never
been exposed to in training. They see relationships, capture
associations and discover regularities in patterns. And they
are fault - tolerant just like real brains. They can still retrieve
a stored pattern even when the input pattern is noisy or
incomplete. These are very important properties for biological
brains and ANNs can do these things too.
45
 The paradox of modern
computing technology
The paradox of present-day ANNs is that they are simulated
mathematically on digital computers. This makes their use in
real - world situations much more limited, because the
simulation takes time and so the ANNs cannot operate in
real time. ANNs might seem well-suited to drive an
automobile, or fly an aircraft, because they are robust in the
face of noise and keep going when some units in the network
cease to work. However, the expert systems that are
generally used in automatic pilots are digital computers
programmed with conventional deterministic software and,
for safety, this always require a backup. If things ever go
badly wrong with the aircraft, such expert systems cannot
cope. The human pilot must take over. Present-day training
algorithms for ANNs are too slow for such emergencies.
If silicon neurons could learn, which so far they can’t, then
many of these problems would fall away. As we learn more
about the way in which brains work, we will be able to build
more sophisticated neural networks that will provide real
brain-like performance.
NOMAD is a fidgety yet thoughtful progenitor of thinking
machines to come. It stands 2-feet tall with a
cylindrically-shaped torso, it has “eyes”, “ears”, gripper
“arms” and other sensors to help it navigate. What makes
NOMAD different from most robots is that it operates
without coded instructions or rules. Instead, it has a
computer-simulated brain with 10,000 simulated brain
cells and more than a million connections among them to
perceive and react to its environment. It can handle novel
situations and learn from its mistakes, as it wanders
around in a pen scattered with small painted cubes.
Some of the cubes are striped and electrically conductive,
making them “tasty”. Other cubes are spotted and don’t
conduct electricity so well, making them less tasty. By
looking for cubes and “tasting” them with the electrical
sensors on its gripper, NOMAD learns to pass over the
spotted cubes and go for the tasty striped ones.
g
Related Internet Sites: www.artificialbrains.com
46 http://www.ini.unizh.ch/
k Mathematical Puzzle Box
A Content-Addressable Distributed Memory
Imagine a set of wires running horizontally, intersecting
with 4 running vertically, with “switches” at their point
of intersection (panel A). This matrix is to be a memory.
Information is presented to it in the form of binary
numbers, such as 0011 and 1010, and we arrange for the
switches to turn on whenever a 1 meets a 1 (B shown in
blue). These store the pairing of these two numbers.
The matrix can store other numbers on top of the first
pair as well, such as 1010 and 0110. The final state of
the matrix should have 7 switches on as shown in C. If
you now present the first number again - 0011 - to the
final state of the matrix and arrange for current to be
induced in the vertical wires wherever a switch is on (D),
you’ll end up with current coming out of the vertical
wires at the bottom proportional to the number 2120.
This isn’t the number that 0011 was first paired with.
But, if you divide 2120 by the total number of 1s in the
number used as a recall cue (0+0+1+1 which equals 2)
using integer division (the type where you forget about
the remainder), you end up with 1010. So the matrix has
“remembered” that 0011 goes with 1010 even though
another message has been stored on top of the first
one. You can check this works with the second pair of
numbers as well.
1 0 1 0
0
0
1
1
0 1 1 0
1 0
0 0
1 1
0 1
2 2 1 2 0
Integer Division by 2 1 0 1 0
This is the kind of memory we think the brain has.
It doesn’t store information at specific locations - like in
a PC. Information is distributed across the network,
stored as changes in synaptic weight, and so can be
retrieved with reference to its content. A problem is
that this kind of memory gets saturated very quickly,
particularly when there are only 4 wires. However, with
1000 pairs of wires, a matrix could store a lot of
overlapping pairs of messages without too much
interference.
The brain is a delicate organ. Accidents can cause head
injury and the brain can become diseased and stop working
normally. Diseases of the brain can produce an astonishing
range of symptoms and understanding these can be
difficult. The assessment of brain disorders requires the
clinical skills of the neurologist or psychiatrist at the
bedside as well as sophisticated biomedical assays and
brain imaging. Research about brain disorders requires an
even wider range of expertise. Some disorders, such as
epilepsy and depression, are quite common - even in
children and teenagers. Others are less common, such as
Schizophrenia, or only common in old-age, such as
Alzheimer’s Disease, but they are no less disabling.
Some have a strong genetic component, raising difficult
questions about whether each of us would want to know if
we had relevant mutations predisposing us to such
conditions.
Disorganised signalling – Epilepsy
During a seizure (an epileptic fit), the person loses
consciousness and may fall to the ground, become stiff and
shake. When they come round, they may find that they have
bitten their tongue or wet themselves. They may be
confused or sleepy afterwards. Many children are affected,
but they may go on to have very few attacks later in their
life. For some, unfortunately, these can be every week or even
every day.
So what is going wrong? During seizures, there is an increase
in the firing of action potentials by neurons followed by a
period of reduced excitability. This cyclical process is
modulated by inhibitory (GABA) and excitatory (glutamate)
neurotransmitters. When the reduction in excitability is
incomplete, seizures may be triggered by the uncontrolled
recruitment of neighbouring neurons. This recruitment may
be localised (causing a partial seizure), or may spread to the
entire cortex (a generalized seizure). During a generalised
seizure, the normal alpha rhythym of the
electroencephalogram (EEG) is replaced by large, slow,
synchronous waves of electrical activity in both
cerebral hemispheres (see backdrop).
Isolated seizures are fairly common, but recurring seizures –
epilepsy - is both less frequent and more troublesome.
Its immediate causes are still unclear. In people with epilepsy,
attacks may be provoked by tiredness, missed meals, low
blood sugar, alcohol, or flickering television screens.
Those afflicted have to be careful.
Backdrop shows the EEG during an epileptic fit
Neuroscience research has made two major contributions to
improving the lives of people with epilepsy. First, through our
developing understanding of excitatory transmission, we can
now design drugs that dampen down abnormal seizure
activity without damping down normal brain activity.
Older drugs tended to act as generalised sedatives, whereas
modern ones are much more selective. Second, improve-
ments in the quality of brain imaging means that for some
people with severe disabling seizures, it is possible to localise
the source of their seizures quite accurately. It is then
sometimes possible for a neurosurgeon to cut out this
diseased brain tissue with a resulting decrease in seizure
frequency and a reduced risk of it spreading to brain tissue
that is still unaffected. The surgical management of epilepsy
is sometimes thought to be a bit drastic, but it is remarkable
how often it works.
Headache and Migraine
Most people experience headache at some time. Usually this
is caused by muscle tension and is nothing serious to worry
about. Very occasionally - especially if the headache comes
on very quickly, or is associated with a skin rash or with
vomiting – there can be a serious underlying cause. In these
conditions the pain comes not from the brain itself, but from
irritation or stretching of
the meninges - the lining of
the brain.
A more common cause of
headache is migraine. As
well as a sore head (often
on one side), people feel
sick, find bright lights or
loud noises discomforting,
and experience a
migrainous aura consisting
of flashing lights or jagged
lines. The aura generally
precedes the headache.
It now seems likely that
migraine starts in the part
of the brain that processes pain sensations coming from
cerebral blood vessels. Brain imaging reveals increased
activity in these regions at the start of a migraine. In
response, there is a brief increase in local blood supply (which
brings on symptoms like flashing lights), immediately followed
by reduced blood flow (reflected in temporary weakness).
The last decade has seen a revolution in the treatment of
migraine attacks following advances in our understanding of
47
 serotonin (5-HT) receptors. A new class of drugs was
discovered which activated a particular subgroup of
serotonin receptors. These drugs – triptans - are very
effective at stopping a migraine headache in its tracks.
This is one of a number of ways in which neuroscience
research has made a huge contribution to improving the lives
of millions of people around the world.
Not enough fuel – Stroke
When people suddenly develop a weakness down one side of
the body, this is usually due to a stroke affecting the
opposite side of the brain. Balance, sensation or language
and speech may also be affected. Sometimes these
abnormalities get better with time, even to the point of
apparent normality, but stroke is still a very common cause
of death and disability. Strokes come in different shapes
and sizes, and the consequences depend very much on the
part of the brain that is affected.
What has gone wrong has to do with interruption of the
energy supply that the brain needs to function. Neurons
and glia need fuel to work and to survive. That fuel is
delivered through the four major blood vessels that supply
the brain. The most important fuels are oxygen, and
carbohydrate in the form of glucose; together these provide
the raw materials to make ATP - the energy currency of cells.
This energy (see Chapters 2 and 3) is necessary for driving
the flow of charged ions that underlie the electrical activity
of neurons. About two thirds of a neuron’s energy is used to
fuel an enzyme called Sodium/ Potassium ATPase which
recharges the ionic gradients of sodium and potassium after
an action potential has occurred.
Drawing showing brain damage in a stroke and the
penumbral region around that is at risk of damage.
48
In what is called a transient ischaemic attack (TIA), the
blood supply to a part of the brain fails and the supply of ATP
is interrupted. Neurons cannot recharge their ionic
gradients and so can no longer conduct action potentials.
If, for example, the blood supply to the motor cortex of the
left hemisphere were to be cut off, the right arm and leg
would become paralysed. If the obstruction passes quickly,
neurons can again make ATP, recharge their membranes and
normal function will resume. Fortunately, no permanent
damage occurs in TIA.
A stroke is more serious. If the blood supply is cut off for a
prolonged period, irreversible damage can occur. In the
absence of ATP, cells cannot maintain homeostasis and they
may swell up and burst. Neurons may also spontaneously
depolarise, releasing potentially toxic neurotransmitters
such as glutamate. And glial cells, that normally mop up
excess glutamate through an ATP-dependent pump, also
stop working. In the absence of energy, the life of a brain cell
becomes very precarious.
Through careful study of what happens during a stroke,
neuroscientists have been able to develop new treatments.
Most strokes are caused by blood clots blocking vessels and
treatment with a “clot-busting” drug called tissue
plasminogen activator (TPA) can break up the clot and
restore blood flow. Given quickly enough, TPA can have a
dramatic effect on the outcome. Unfortunately, getting
such a drug to a stroke patient quickly isn’t easy as it may
not be obvious to a victim’s family what is happening.
Another new treatment is a class of drugs that block
neurotransmitters including glutamate that accumulate to
toxic levels during a stroke. These drugs can either block
glutamate receptors themselves or the intracellular
signalling pathways that are turned on by glutamate.
Many such drugs are in development. Sadly, none has yet
had an impact on stroke.
Genetic Diseases
Doctors have long recognised and diagnosed brain disease
according to the region affected. For many diseases, the
name is a description of what appears to be wrong and the
part of the brain involved, often dressed up in Latin or Greek,
such as “parietal apraxia”. The explosion of genetic
information in the last ten years has changed things
completely. For many inherited diseases, the problem
lies elsewhere.
Some people inherit a problem with the fine control of
movements that makes them increasingly unsteady on their
feet as the years go by. Called spinocerebellar ataxia - a
name that reflects the classical history in the naming of
diseases – we now know the precise gene defects that
cause it. Many other conditions can now be classified
according to their cause and diagnostic genetic testing is
now routine for patients suspected of spinocerebellar ataxia
or other genetic conditions. The diagnosis can be made more
quickly and with much greater certainty than before.

A family tree showing the generations of a family prone to
learning disability and schizophrenia. Notice how these
afflictions can sometimes skip a generation.
Huntington’s disease is a neurodegenerative disease
associated with abnormal involuntary movements of the
body - in this case named after the doctor who first
described the condition. It is entirely due to a repeat
mutation in one of the largest genes in the human genome
called huntingtin. Some early onset forms of Parkinson’s
disease (a disease causing slowness, stiffness, tremor and
unsteadiness) are due to problems in genes coding for Parkin.
As well as helping with diagnosis, genetic testing can be used
to advise other family members about their risks of develop-
ing diseases, or passing it on to their children.
However, much as the genetics revolution has changed the
way that doctors deal with diseases of the nervous system,
it is only the start of a long voyage of discovery. The same
gene defect can cause different diseases in different people,
and different gene defects can cause very similar diseases.
Understanding what it is that defines these differences, and
how your genetic makeup interacts with the world in which
you live and which you build around you, is one of the next
great challenges for the genomic era in which we live.
Discussion Point
If you discovered you were at risk for developing a
genetic disease, would you want to know for sure?
Would it be right to identify the gene prior to birth
and abort those who would develop the disease?
What about all the useful and productive years lived
by sufferers before the disease develops?
Learning Disability
Schizophrenia
Inflammation – Multiple Sclerosis
Multiple sclerosis is a disease of young adults. It is
characterised by repeated episodes of weakness, numbness,
double vision or poor balance, that last for a few weeks
before recovery - apparently back to normal. The cycle
between periods of illness and remission is a feature of
the disease.
Multiple sclerosis is caused by inflammation in the nervous
system that flares up and then settles down again.
Our immune system is designed to fight infections caused by
bacteria or viruses. Sometimes it gets confused and starts
attacking parts of us instead. We call such conditions
autoimmune diseases and they can affect almost any
tissue. If the immune system attacks the myelin that wraps
around neurons, there will be a local area of inflammation
that causes demyelination. In time, the inflammation usually
settles down, the myelin is repaired, and things return to
normal. Quite what sparks off the inflammation in the first
place is not clear, and many people with demyelination only
ever have one brief episode. However, some people seem to
have a tendency to have recurrent bouts affecting different
parts of the brain.
Because we do not yet know what triggers inflammation in
multiple sclerosis, we cannot completely stop it. However, we
now do know that the attacks can be made shorter using
drugs such as steroids that dampen down the immune
system. For patients with severe MS, some doctors believe
that permanently dampening down certain parts of the
immune system with drugs like azathioprine or ß-interferon
can be beneficial. There is still considerable uncertainty
about their use.
The immune system can also attack the junctions where
nerves connect with muscles, causing a disease called
myasthenia gravis, or the nerves as they emerge from the
spinal cord, resulting in a condition called Guillain
Barré syndrome.
Jacqueline du Pré – a well
known musician who
suffered from multiple
sclerosis
49
 Neurodegeneration – genetically altered laboratory animals have been bred that
show features of the disease. Research on these has to be
Alzheimer’s disease interpreted very carefully, and not over-interpreted, but they
can help us get a grasp on the biology of the
It is our brains that make us who we are: how we react in disease process.
different situations, with whom we fall in love, what we fear,
what we remember. This fundamental aspect of human Treatments that stem the progression of Alzheimer’s
nature is laid bare when our brains fail in the progressive Disease still do not exist, although they are eagerly sought -
disorder known as Alzheimer’s Disease. Alzheimer’s disease and this is where the animal research is so valuable. It is
is a form of dementia – a global loss of faculties that known that nerves cells utilising the chemical transmitter
affects approximately 5% of 65 years olds and 25% of those acetylcholine are particularly vulnerable to attack in the
aged 85 or older. This is a heartbreaking illness: the condition. Drugs that boost the action of the remaining
condition usually starts with memory failure, and progresses acetylcholine by blocking the effect of enzymes that normally
to a loss of normal personhood and ultimately death. destroy this neurotransmitter have a modest treatment
To watch loved ones lose themselves in this fashion is an effect in both animal models and some clinical cases.
exceptionally difficult experience for relatives. Ultimately, However, these drugs do nothing to slow the progression of
sufferers may be unable to recognise those closest to them this still incurable disease. Drawing together genetic clues,
and will require help with everyday activities such as understanding relationships between brain chemistry and
dressing, eating, bathing and toileting. Consequently, their psychological function, and learning more about the
carer’s life is changed dramatically also. mechanisms by which cells are damaged seems to be the way
forward in ultimately defeating the disorder.
“ Dad doesn’t know who I am these days. He just
doesn’t seem to recognise me any more. He gets Depressive Disorder
angry and frightened at the least thing - I don’t think
he understands what is going on around him. At first, It may come as a surprise to learn that depression and
he just seemed to be forgetful, always losing things. neurodegeneration can be bedfellows – but we now know that
Then it got worse. He wouldn’t go to bed, didn’t seem severely depressed patients can lose brain cells.
to know what time it was or even where he was.
Now he’s lost control of his bowels and needs help to A depressive illness is very
eat and dress. I can’t cope.” different from the low
feelings we all experience
from time to time. We are
What is going wrong? As Alzheimer’s disease develops, brain dealing with a truly serious
cells die: the cortex thins and the ventricles (the fluid filled medical condition when low
spaces in the brain) enlarge. The diagnosis is usually made in mood becomes prolonged
life on the basis of the characteristic clinical features, but for weeks and months. It
can only be confirmed definitively at a post-mortem when then begins to take over
microscopic examination of the brain reveals the cell loss, everything – to the extent
and the widespread abnormal deposition of an amyloid that sufferers want to die
protein in scattered small degenerating amyloid plaques and and may try to kill themselves. Sufferers display other
a tangled mess of rod-like proteins that are normal characteristic symptoms: disturbed sleep, lowered appetite,
constituents of brain cells - fibrillary tangles. Current failing concentration and memory, and a loss of interest in
research projects are trying to improve diagnosis in life with life. Fortunately, it is eminently treatable. Antidepressant
new neuropsychological testing procedures focused on drugs, which enhance the effects of neuromodulatory
distinguishing the mental changes in the earliest stages of transmitters such as serotonin and noradrenaline can
Alzheimer’s from those in, for example, depression. rapidly (within weeks) treat
the illness. Specialised
Staining of the brain shows talking treatments are also
amyloid plaques (e.g. in the effective, and a
rectangle) and the darkly combination of chemical
stained tangles (arrow). and psychological
treatments can be
especially helpful.
Again, genetics has provided a handle to get us started in The condition is surprisingly
understanding the disease – pointing to mutations in genes common – 1 in 5 may suffer
that encode amyloid precursor protein (from which amyloid at some time in their lives
is made) and the presenilins (which encode enzymes that from some degree of
break the precursor protein down). Inheritance of a depressive
particular variation of the apolipoprotein E (apoE) gene disorder.
designated apoE-4 is also a major risk factor in the disease.
However, genetic factors do not tell the whole story: Being severely and
environmental factors, such as toxins and other insults such
Vincent Van Gogh – chronically depressed has
the impressionist painter – an unbalancing effect on
as traumatic brain injury, may also play an important role. suffered from severe
But genetic factors are sufficiently important that depression
the control of stress

50
hormones, such as cortisol, that are beneficially released
acutely during stressful situations (Chapter 12). However,
when chronically activated, stress hormones may actually
damage brain cells, particularly in the frontal and temporal
lobes of the brain. It has recently been found that
antidepressant drugs promote the integrity of brain cells
and increase the rate at which new neurons are produced in
the hippocampus. In this way, they may go some way to
protect against and even reverse the toxic effects of stress
on the brain.
Schizophrenia
Another psychiatric disorder that draws together
abnormalities of brain chemistry and brain structure is
schizophrenia. This is a progressive and potentially very
disabling condition that affects 1 in 100. The condition often
starts in early adulthood and is said to blight more lives
than cancer.
The core symptoms of schizophrenia are delusions
(abnormal beliefs – commonly bizarre ideas which are often
persecutory in nature) and hallucinations (disorders of
perception where sufferers experience abnormal sensory
impressions, such as hearing voices when there is no one
there). There is often a progressive decline in cognitive
ability, social interaction and ability to work.
The condition is much misunderstood: it has nothing to do
with “split personality” with which it is often confused, nor as
a rule are sufferers in any way violent. Indeed, most people
with schizophrenia are fearful rather than dangerous. There
are clearly genetic factors at work in the genesis of the
illness, but as with other conditions, environment and stress
are also important. Nonetheless, for all the obvious
psychological changes, the condition is primarily a brain
disease. It has long been known that the ventricles of the
brain enlarge in the condition, and that the activity of the
frontal lobes becomes impaired.
Drugs that block dopamine receptors are helpful in reducing
the frequency and impact of symptoms, but they do not
cure the condition. The latest research suggests that, when
activated experimentally using drugs such as amphetamine,
it is possible to detect abnormalities in the release of
dopamine in people with schizophrenia. There is much more
to be discovered about the disorder: post-mortem studies
suggest that the way that neurons have connected up
during development may be abnormal, and that other
neurotransmitter systems, such as glutamate, may be
malfunctioning.
Our efforts to understand the nature of mental disorders
represents the last great frontier for medical neuroscience.
Organisations such as the Medical Research Council and the
Wellcome Trust have put mental health high on their agenda
for research over the next decade. One important current
project is capitalising on both genetic knowledge and brain
scanning equipment to study the disease prospectively - in
families at risk (see Box). Bridging the gaps from “molecules
to bedside” remains one of the most challenging research
endeavours.
Research Frontiers
Result
Investigators
Psychiatrists

GP’s
“At first, we didn’t know what was happening to our
daughter, Sue. She had started well at University and
coped easily with the exams in her first year. Then she
began to change - she became quiet and withdrawn Subjects
when she was at home, quite unlike her former
outgoing self. She stopped seeing friends - later we
found she hadn’t been going to classes either and was High Risk
staying in bed all day. Then one day she told us she had Families
received a special message from the television set
saying that she had special powers, and that
satellites were controlling her thoughts by telepathy.
She laughed for no reason, and then she would cry. A prospective study of Schizophrenia
Obviously something was very wrong. She said that
she could hear voices all around her who spoke about Most studies of neurological and psychiatric disease
everything she did. It turned out that she was are on people who already have the condition.
suffering from schizophrenia. Researchers in Scotland are using genetic information
She was in hospital the first time for about two to study members of families that are at risk of
months. Now she takes regular medication. Although developing the condition. Brain scanning and careful
she has been much better recently - she doesn’t have tests of mental function and physical features are being
strange ideas about satellites any more - she still done at regular intervals to see if markers of the
doesn’t take much interest in things. She had to stop incipient development of the disease can be identified.
her studies at University and though she worked for a This information could prove very useful in developing
while in a local shop, she had to go into hospital again new treatments.
for a couple of weeks and lost her job. She just isn’t
the same person. “
g

Related Internet Sites: Brain and spine foundation: http://www.bbsf.org.uk

British epilepsy association: http://www.epilepsy.org.uk Stroke: http://www.strokecenter.org
National Institute of Neurological disorders and stroke: http://www.ninds.nih.gov 51
 Neuroethics
Once upon a time, a very long time ago (as the fairy-tale so
often begins), there was a clear distinction between
science and technology. Scientists pursued an unbridled
path in search of truth, wherever that might lead, for no
more reward than the “the pleasure of finding out”.
Engineers and technologists applied the fruits of scientific
endeavour to change the world in which we live. However
beguiling this sharp distinction may seem, it is and always
has been a fairy-tale. Nowadays, scientists are ever more
aware of the social context in which they work, and how
that context can affect what they study.
Questions relating to the impact of neuroscience on society
are collected under the general heading of neuroethics - the
intersection of neuroscience, philosophy and ethics.
This includes how discoveries about the brain affect our
sense of ourselves as human beings (such as the neural basis
of morality). It is about the implications for social policy
(such as a child’s educational potential) and how research is
itself conducted (such as the ethics of animal
experimentation or the use of deception with human
subjects). And it is about how neuroscientists should best
engage with the public in communicating what they do and
sharing idea about what they should be doing.
“THINKING ABOUT THE BRAIN TOUCHES US ALL,
IT IS LITERALLY HEADY STUFF”
Zach Hall, University of California
52
The social context
While some neuroscientists believe that their concepts are
divorced from social reality, this is rarely so. In the 17th C,
Descartes used a hydraulic metaphor to explain how the
“humours” of the brain moved the muscles - a metaphor
borrowed from the water engineering he saw in the gardens
of French chateaux. At the turn of the 20th C, reflecting
the industrial age, neurophysiologists described the
intricate wiring of the brain as “an enchanted loom” or later
as a giant “telephone exchange”. Now, at the start of the
21st C, computational metaphors abound, such as the
fanciful speculation that “the cerebral cortex operates not
unlike a private world wide web”. These are partly shorthand
to help convey complex ideas, but also concepts that are
actually built into sophisticated brain theories.
Neuroscientists can and do engage in thinking about
scientific problems divorced from the everyday world.
Often this escape is into an abstract, jargon-filled world in
which something quite close to a monastic search for truth
really is underway. Whether it is working out the ionic
currents that underlie the propagation of the action-
potential, how chemical messengers are released and act, or
how cell-firing in the visual cortex represents aspects of the
visual world - many problems in neuroscience can be cast in
an isolated but tractable manner.
But the real world is never far away. Once we know how
chemical transmitters work, it is natural to think about
smart drugs that may help us remember better. Some
might think about designing neurotoxins (nerve agents) that
disrupt this critical process, such as enzyme inhibitors that
are but a step from the agents of biological warfare.
If a drug were available that could help you pass
examinations, would you take it? Is there any difference
between this and an athlete using steroids to improve their
performance or a person taking an anti-depressant?
Less fanciful ethical dilemmas surround the future of
brain-imaging. For example, brain-imaging techniques may
soon make it feasible, with appropriate testing procedures,
to distinguish a person’s real memories from their false ones.
The variability in response is too big just now, but courts may
one day have brain-scanning technology at their disposal - a
kind of “cerebral fingerprinting” that could help establish the
veracity of witnesses. This raises interesting issues about
what one might call cognitive privacy.
New findings about the brain are all the time revising our
sense of ourselves. Influential ideas about the evolution of
the brain include many related to social cognition. There is
an emerging awareness that morality and conscience are
closely coupled to the emotional brain that processes sig-
nals of reward and punishment – a possibility that some have
argued under the rubric of evolutionary ethics. Learning
more about these could be an immense force for good, helping
us to be more aware of each other’s feelings. Building these
ideas into our presently primitive concepts of neuronal plas-
ticity could yet have an impact on education beyond the
immediate academic goals that are so often the only focus
of discussion.
It is also important to appreciate that neuroscientists do
not agree about the future directions of their subject.
For some molecular neurobiologists, ultimate truth lies
embedded in the molecular constituents of the nervous
system - with new DNA and proteomic technologies
promising fuller explanations of the brain that will finesse the
problems faced by other neuroscientists. This is the reduc-
tionist agenda, whose full philosophical and
technological flowering is so often celebrated in media
accounts. But is such a reductionist confidence justified?
Or are there higher-level explanations of brain and mind that
are not reducible in this way? Are there emergent
properties arising from the brain’s organization?
Interactionist neuroscientists firmly believe in a different
agenda. They argue for a more eclectic approach to modern
neuroscience, an approach that explores its interaction with
the social sciences as well. These are not issues easily
discussed in a public forum, but questions about what sorts
of research should be undertaken are matters about which
society should be consulted. After all, people’s taxes help
to pay for it.
Neuroethics - some concrete examples
Certain issues in neuroethics yield to little more than
common-sense. Suppose a brain scan of a volunteer subject
in an experiment was unexpectedly to reveal a cerebral
abnormality - such as brain tumour. Or imagine that a
subject in a human neurogenetics screen was found to have a
mutation that rendered them susceptible to a
neurodegenerative disease. In each of these cases - should
the subject be told? Common sense suggests that
responsibility should be passed to the volunteer who, in
advance, would be asked to offer or decline their consent
that any relevant medical information discovered in the
course of the scan be passed on.
However, informed consent is a funny business. Suppose a
brain researcher was conducting a trial of a new treatment
for stroke in which either the drug or a placebo had, in a blind
fashion, to be given within a few hours of the stroke.
There are sound scientific reasons for such a randomised
protocol. But we cannot anticipate who will suffer a stroke
and it may be impossible for the person affected to give
informed consent. If this prevents the patient participating
g
Related Internet Sites: http://www.stanford.edu/dept/news/report/news/may22/neuroethics.html
http://www.dana.org/books/press/neuroethics/
in such a research project, it would be to their long-term
detriment and that of later patients. Relatives also may not
be in a state of mind where it is easy for them to make a
judgement of consent in the time available. Dare we abandon
informed consent and introduce waivers, for the greater
good? Or is that a slippery slope?
Another important aspect of neuroethics relates to animal
experiments. Animals are not in a position to offer consent
for invasive experiments to be conducted on their brains.
To some people, the prospect of such work is disturbing.
To others, the opportunity it offers for advancing our
understanding of the nervous system in health and disease
is such that not to pursue it is irrational. These are not easy
issues to debate dispassionately, but it is important that
we do - and that we do so respectfully.
In most European countries, animal experiments are
regulated in an extremely strict manner. Researchers must
attend courses and pass examinations that test their
knowledge of the law and their competence in ensuring that
unnecessary animal suffering does not occur. There is a
widespread acceptance that three Rs - reduction,
refinement and replacement - are good principles for
biomedical scientists to comply with. They do so willingly,
within a framework of law, and so command widespread if
not unanimous public acceptance. Many new findings in
neuroscience are emerging from replacement techniques,
such as tissue culture and computational modelling.
But these cannot replace all studies of the living brain from
which many new findings and treatments for neurological and
psychiatric diseases are coming. For instance, the use of
L-DOPA to treat Parkinson’s disease emerged from Nobel
Prize winning work on the rat brain. And new techniques offer
new opportunities to help sick people and sick animals.
Only communicate…
It is a puzzling truth that countries in which scientists do
most to communicate to the general public tend to be those
in which there are lower levels of trust in scientists. But cor-
relation is not the same as cause, and it is unlikely that this
responsible effort to engage the public in discussing the
impact of science on society - and the growing sense of duty
to do so - is the cause of this growing distrust. Rather it is
that the interested public is getting more sophisticated,
properly more sceptical of new “miracle drugs”, and more
aware of the slow and sometimes uncertain progress of
science. Reducing distrust is no reason to favour a return to
blind ignorance.
One reason to engage with young people and the interested
public about neuroscience is that neuroscientists still
disagree about many of the central tenets of their field.
Instead of focusing on isolated discoveries, the media would
do well to think more about science as a process. A process
riddled with uncertainty and debate.
Neuroethics is a new field. There is curious irony that it was
Richard Feynman, a theoretical physicist, who described his
reason for doing science as being for “the pleasure of finding
out”. Ironic - because it was Feynman who threw himself
headlong into working out why one of the American Space
Shuttles, Challenger, exploded soon after take-off.
The impact of science on society creeps up on us all.
53
 Training & Careers

When many young students think of a career in science, it

can conjure up images of white coats and laboratories.
Hopefully, this booklet will have gone some way to showing Rosamund Langston,
that there are many different aspects to neuroscience Neuroscience PhD
and that research on the brain will touch peoples’ lives in student at Edinburgh University
many ways. From the laboratory to the hospital to many
other walks of life, there is a diverse range of exciting “I studie d scie nces and English at
A-level and the n we nt on to study
opportunities within the field.

University Neuroscience Courses biological scie nces in Edinburgh.

I spe cialise d in Ne uroscie nce in my
Many universities now offer undergraduate degrees in final ye ar and re ally found my niche.
I was luck y e nough to be offe re d
neuroscience. Often the subject is taken as a specialisation
after earlier years training in such subjects as biology,
physiology, pharmacology and psychology. A knowledge of a position as a rese arch assistant in
genetics and molecular biology can also be valuable. the Cognitive Ne uroscie nce depart-
me nt of Edinburgh Unive rsity and this
However, you do not necessarily have to be doing only
science subjects in the sixth form to get into some of eve ntually le ad to a PhD.
these courses. Find out about neuroscience courses and
their entry requirements by looking at the UCAS pages on
the internet. You can look through these by subject or in
relation to the universities to which you may be interested
in applying.
Thomas Petty,
Medicine Medical student
at Edinburgh University
Medicine in Britain is an undergraduate degree. Many
universities have Medical Schools and there has recently
been an expansion in the number of students being trained “I have be e n set on me dicine as a
through the creation of several new Medical Schools. care e r eve r since school and I
Specialization in subject areas such as neurology,
neurosurgery, psychiatry and radiology comes in the later applie d to Edinburgh be cause of its
years of training, but there are often opportunities to work good reputation. In third ye ar I
in neuroscience research laboratories during summer was give n the opportunity to do an
vacations and intercalating years. The competition to get
into medical courses is considerable, but so are the rewards
inte rcalate d Bsc course and I chose
of a career in medicine. to study Ne uroscie nce. T he ye ar
gave me an opportunity to study the
“The privilege of a job in a University is the intellectual core rese arch be hind the me dicine and
freedom. No day is the same. Every day you learn
something new, every day you are stretched and I took a gre at de al from it and
challenged” re ally e njoye d it.”
Maria Fitzgerald, Professor in London University.

“The appeal was, and still is, the prospect of finding

out, being pleasantly surprised by discoveries, and the
small leaps of insight that result”

Richard Ribchester, Neurophysiologist in the

University of Edinburgh

54
 Industry (Pharmaceutical Industry)
New medicines are constantly being discovered and
developed and the brain is a critical target for drug
treatment. Pharmaceutical companies, as well as financially
supporting academic institutions, conduct their own
research. Many co-operate with universities to offer years in
industry to help develop laboratory skills and experience.
Graduates from a variety of biomedical science courses
including neuroscience make desirable employees, particularly
when they have had associated laboratory experience.

Neuroscience Research
There are a huge variety of opportunities in research. The field
has many elements ranging from brain-imaging and behaviour-
al studies through to neurophysiology and molecular-genetic
research. Researchers within universities are always happy
to encourage keen students to find a path of academic study
that suits them.

Computing Industry
Neuroscience may not spring to mind as a subject to do at
university if you are interested in a career in computing or
information technology. Still, as we have seen in the booklet,
there is growing interest in ‘brain-style’ computing and this is
set to grow with the development of the world-wide web.
There is increasing interest in non-medical applications of
brain science.

School Teaching
Neuroscience is not taught as a subject in schools. However,
graduates with a degree in neuroscience will be well placed to
teach biology and will have many other skills, including
numerical skills, that would be invaluable in a teaching career.

Science and the Media

From journalism to radio and television, a career in the media
is competitive and demanding. However, many opportunities
to enter the field of science communication are available.
Science is continually advancing and new findings need to be
reported for the purposes of both education and public
interest. Work on brain research is no exception. There is
huge social interest, well recognised by the media, and the
latest findings have the potential to have considerable social
impact. With a good scientific background and understanding
of research, obtained while doing a university degree, it would
be much easier to communicate complex findings accurately
and effectively both with other scientists and the public.

Science and art

Science and art are not mutually exclusive. Design which
captures the imagination is crucial in the presentation of
science to a wider audience. Museums, galleries and the
media, and other organisations encourage and fund creative,
experimental collaborations between scientists and artists.
g

Related Internet Sites: http://www.abpi-careers.org.uk/

www.gsk.com www.sciart.org
55
 Acknowledgements
We are indebted to many people who kindly contributed text and diagrams that are included in this booklet. We hope the list
below is inclusive and apologise to anyone who has helped us but whose contribution has slipped through the net.
Cartoons throughout the booklet: Maddelena Miele and Robert Filipkowski. Front cover illustrations: Peter Brophy, Beverley
Clark, Michael Hausser, David Linden, Richard Ribchester. Inside front cover: Peter Somogyi, Elaine Snell, Lisa Cokayne-Naylor.
Ch 1 (The nervous system): Marina Bentivoglio, Nobel Forum. Ch 2 (The action potential): Tobias Bonhoeffer, Peter Brophy,
Eric Kandel, Nobel Forum. Ch 3 (Chemical messengers): Marianne Fillenz, Ch 4 (Drugs and the brain): Leslie Iversen. Ch 5 (Touch
and pain): Susan Fleetwood-Walker, Han Jiesheng, Donald Price. Ch 6 (Vision): Colin Blakemore, Andy Doherty, Bill Newsome,
Andrew Parker. Ch 7 (Movement): Beverley Clark, Tom Gillingwater, Michael Hausser, Chris Miall, Richard Ribchester, Wolfram
Schultz. Ch 8 (The developing nervous system): Andrew Lumsden. Ch 9 (Dyslexia): John Stein. Ch 10 (Neuronal plasticity):
Graham Collingridge, Andrew Doherty; Kathy Sykes. Ch 11 (Learning and Memory): Ted Berger, Livia de Hoz, Graham Hitch, Eleanor
Maguire, Andrew Doherty, Leslie Ungerleider, Fareneh Vargha-Khadem. Ch 12 (Stress): Jonathan Seckl. Ch 13: (Brain and Immune
System): Nancy Rothwell. Ch 14 (Sleep and Rhythms): Anthony Harmar. Ch 15 (Brain Imaging): Mark Bastin, Richard Frackowiak,
Nikos Logothetis, Eleanor Maguire, Lindsay Murray, Elisabeth Rounis, Semir Zeki. Ch 16 (Neural Networks and Artificial Brains):
Rodney Douglas, Gerry Edelman, Jeff Krichmar, Kevan Martin. Ch 17 (When things go wrong): Malcolm Macleod, Eve Johnstone,
Walter Muir, David Porteous, Ian Reid. Ch 18 (Neuroethics): Colin Blakemore, Kenneth Boyd, Stephen Rose, William Saffire. Ch 19
(Careers) Yvonne Allen (BNA), Victoria Gill. Inside back cover illustration: Eric Kandel (for Hippocrates Quotation), Richard Morris.

Back cover illustration and words: Jennifer Altman, David Concar; Spike Gerrell.

The British Neuroscience Association is a non-profit making body and is registered as a charity No. 264450.

Further Reading
There are many fascinating books available for continued reading about science and neuroscience. Here is a list of a few of them:

V.S. Ramachandran, (Sandra Blakeslee) Phantoms in the Brain: Human Nature and the Architecture of the Mind
Fourth Dimension Publications
(Paperback - 6 May, 1999) ISBN: 1857028953
A fascinating account of phantom-limb pain and related disorders of the nervous system.

Oliver Sacks, The Man Who Mistook His Wife for a Hat (Picador)
Picador
(Paperback - 7 November, 1986) ISBN: 0330294911
An amusing and well-written account of the effects of brain damage on the mind.

Jean-Dominique Bauby, The Diving-bell and the Butterfly

Fourth Estate
(Paperback - 7 May, 2002) ISBN: 0007139845
A very personal and moving account of the consequences of a stroke.

Richard P. Feynman, Surely You’re Joking, Mr Feynman: Adventures of a Curious Character

Paperback
19 November, 1992 ISBN: 009917331X
Physicist, bongo-drum man, and all round polymath. A hero for all young scientists.

Nancy Rothwell, Who Wants to Be a Scientist?: Choosing Science as a Career

Smudge (Illustrator) Cambridge University Press
(Paperback - 19 September, 2002) ISBN: 0521520924
Sound practical advice on choosing science as a career.

To order additional copies: Online ordering: www.bna.org.uk/publications

56 Postal: The British Neuroscience Association, c/o: The Sherrington Buildings, Ashton Street, Liverpool L68 3GE
Telephone: 44 (0) 151 794 4943/5449 Fax: 44 (0) 794 5516/5517
 “Men ought to know that from the brain, and from the brain only,
arise our pleasures, joys, laughters and jests,
as well as our sorrows, pains, griefs and fears.
Through it, in particular, we think, see,
hear and distinguish the ugly from the beautiful,
the bad from the good,
the pleasant from the unpleasant”

Hippocrates- 5th Century B.C.

Financial Support
This project was supported by the British Neuroscience Association, Neurology & GI Centre of Excellence for
Drug Discovery, GlaxoSmithKline and the Centre for Neuroscience of the University of Edinburgh. The
authors are grateful for their generous support.
Cartoon by Spike Gerrell; words by Jennifer Altman and David Concar
 A Companion Publication to BrainFacts.org

A PRIMER ON THE BRAIN AND NERVOUS SYSTEM

A PRIMER ON THE BRAIN AND NERVOUS SYSTEM

A companion to BrainFacts.org

A PUBLIC INFORMATION INITIATIVE OF:

 P r e fa c e
Over the past two decades, scientific knowledge about the structure and function of the brain and
nervous system and understanding of brain-based disorders have increased exponentially. Neuroscientists
are using remarkable new tools and technologies to learn how the brain controls and responds to the body,
drives behavior, and forms the foundation for the mind. Research is also essential for the development of
therapies for more than 1,000 nervous system disorders that affect more than 1 billion people worldwide.
As these strides occur, it is crucial that scientists communicate with the general public, helping
students, teacher, parents, medical caregivers, policymakers, and others stay informed of developments in
neuroscience. In particular, students — the scientists, policymakers and scientifically literate citizens of the
future — need access to clear, easy-to-use information on this important topic.
As part of its enduring commitment to public education and outreach, the Society for Neuroscience
(SfN) is pleased to present the seventh edition of Brain Facts: A Primer on the Brain and Nervous
System. This edition has been substantially revised. Research progress has been updated throughout the
publication, and a new section on animal research added. The information also has been reorganized into
six sections to make it easier for readers to glean the “big ideas” covered, and the specific topics that fall
under each category.
The publication of the Brain Facts seventh edition coincides with the launch of BrainFacts.org,
a public information initiative of The Kavli Foundation, The Gatsby Charitable Foundation, and
SfN. BrainFacts.org brings to digital life the historic Brain Facts book, and augments it with hundreds
of additional, scientifically vetted public information resources available from leading neuroscience
organizations worldwide. BrainFacts.org is envisioned as a dynamic and unique online source for
authoritative public information about the progress and promise of brain research. It will be updated
frequently with the latest neuroscience information from around the globe, while the Brain Facts book will
continue to be a vital teaching and outreach tool.
We encourage you to visit BrainFacts.org frequently to supplement information found within this
companion book, and to join us in the quest for continuing revolutionary advances in understanding the
brain and mind.

2 Society for NeuroScieNce

coNteNtS
N NtS
Introduction .................................................................................................................. 4

Part 1: Introduction to the Brain

Chapter 1: Brain Basics .................................................................................................. 6

Chapter 2: The Developing Brain ................................................................................... 13

Part 2: Sensing, Thinking, and Behaving

Chapter 3: Senses and Perception .................................................................................. 18

Chapter 4: Learning, Memory, and Language .................................................................. 25

Chapter 5: Movement................................................................................................... 29

Chapter 6: Sleep ......................................................................................................... 32

Part 3: Across the Lifespan

Chapter 7: Stress ......................................................................................................... 36

Chapter 8: Aging ........................................................................................................ 39

Part 4: Brain Research

Chapter 9: Kinds of Research ........................................................................................ 42

Part 5: Diseases and Disorders

Chapter 10: Childhood Disorders ................................................................................... 49

Chapter 11: Addiction .................................................................................................. 52

Chapter 12: Degenerative Disorders ............................................................................... 57

Chapter 13: Psychiatric Disorders ................................................................................... 62

Chapter 14: Injury and Illness ........................................................................................ 66

Part 6: Treating Brain Disorders

Chapter 15: Potential Therapies ..................................................................................... 73

Chapter 16: Neuroethics ............................................................................................... 76

Glossary .................................................................................................................... 80
Neuroscience Resources ............................................................................................... 86
Index ......................................................................................................................... 88

Society for NeuroScieNce 3

iNtroductioN
The huMAN BRAIN — a spongy, three-
pound mass of tissue — is the most complex living structure
in the universe. With the capacity to create a network
of connections that far surpasses any social network and
stores more information than a supercomputer, the brain
has enabled humans to achieve breathtaking milestones —
walking on the moon, mapping the human genome, and
composing masterpieces of literature, art, and music. What’s
more, scientists still have not uncovered the extent of what
the brain can do. This single organ controls every aspect
of our body, ranging from heart rate and sexual activity to
emotion, learning, and memory. The brain controls the
immune system’s response to disease, and determines, in part,
how well people respond to medical treatments. Ultimately,
it shapes our thoughts, hopes, dreams, and imaginations. It is
the ability of the brain to perform all of these functions that
makes us human.
Neuroscientists, whose specialty is the study of the
brain and the nervous system, have the daunting task of
deciphering the mystery of how the brain commands the
body. Over the years, the field has made enormous progress.
For example, neuroscientists now know that each person
has as many as 100 billion nerve cells called neurons, and
the communication between these cells forms the basis of all
brain function. However, scientists continue to strive for a
deeper understanding of how these cells are born, grow, and
organize themselves into effective, functional circuits that
usually remain in working order for life.
The motivation of researchers is to further our
understanding of human behavior, including how we read
and speak and why we form relationships; to discover ways
to prevent or cure many devastating disorders of the brain as
well as the body under the brain’s control; and to advance
the enduring scientific quest to understand how the world
around us — and within us — works.
The importance of this research cannot be overstated.
More than 1,000 disorders of the brain and nervous system
result in more hospitalizations than any other disease group,
including heart disease and cancer. Neurological illnesses
affect more than 50 million Americans annually and
cost more than $500 billion to treat. In addition, mental
4 BraiN factS | introduction
disorders strike 44 million adults a year at a cost of $148
billion. Advances in research could reduce these costs. For
example, discovering how to delay the onset of Alzheimer’s
disease by five years could save $50 billion in annual health
care costs.
In the past two decades, neuroscience has made
impressive progress in many of the field’s key areas. Now,
more than ever, neuroscience is on the cusp of major
breakthroughs.
Recently, significant findings have been documented in
the following areas.
Genetics Disease genes have been identified that
are key to several disorders, including the epilepsies,
Alzheimer’s disease, Huntington’s disease, Parkinson’s disease,
and amyotrophic lateral sclerosis (ALS). These discoveries
have provided new insight into underlying disease
mechanisms and are beginning to suggest new treatments.
With the mapping of the human genome, neuroscientists
have been able to make more rapid progress in identifying
genes that either contribute to or directly cause human
neurological disease. Mapping animal genomes has aided
the search for genes that regulate and control many
complex behaviors.
Gene-environment Interactions Most major
diseases have a genetic basis strongly influenced by the
environment. For example, identical twins, who share the
same DNA, have an increased risk of getting the same
disease compared with nonidentical siblings. However, if
one twin gets the disease, the probability the other will
also be affected is between 30 percent and 60 percent,
indicating that there are environmental factors at play
as well. Environmental influences involve factors such as
exposure to toxic substances, diet, level of physical activity,
and stressful life events.
Brain Plasticity The brain possesses the ability
to modify neural connections to better cope with new
circumstances. Scientists have begun to uncover the
molecular basis of this process, called plasticity, revealing
how learning and memory occur and how declines might
be reversed. In addition, scientists have discovered that
the adult brain continually generates new nerve cells — a
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 process known as neurogenesis. Interestingly, one of the most This book provides a glimpse of what is known about
active regions for neurogenesis in the brain, the hippocampus, the nervous system, the disorders of the brain, and some
is also an area heavily involved in learning and memory. of the exciting avenues of research that promise new
New Therapies Researchers have gained insight therapies for many neurological diseases. In the years
into the mechanisms of molecular neuropharmacology, or ahead, neuroscience research funded by public and private
how drugs affect the functioning of neurons in the nervous support will continue to expand our knowledge of how this
system, providing a new understanding of the mechanisms of extraordinary organ and the entire nervous system function.
addiction. These advances have also led to new treatments
for depression and obsessive-compulsive disorder. In
addition, neuroscientists have discovered that many of the
toxic venoms used by animals can be adapted into new
pharmacological treatments. For example, the poison of a
puffer fish, tetrodotoxin (TTX), halts electrical signaling in
nerve cells. However, in discrete, targeted doses, TTX can be
used specifically to shut down those nerve cells involved in
sending constant signals of chronic pain.
Imaging Revolutionary imaging techniques,
including positron emission tomography (PET), functional
magnetic resonance imaging (fMRI), and optical imaging with
weak lasers, have revealed the brain systems underlying
attention, memory, and emotions. These techniques also
have pointed to dynamic changes that occur in schizophrenia
and other disorders.
Cell Death Two major advances in neuroscience —
the discovery of how and why neurons die, along with the
discovery of stem cells, which divide and form new neurons
— have many clinical applications. These findings have
dramatically improved the chances of reversing the effects
of injury in both the brain and the spinal cord. The first
effective treatments for stroke and spinal cord injury based on
these advances are under study.
Brain Development New understanding of brain
function, as well as newly discovered molecules responsible
for guiding nervous system development, have given
scientists greater insight into certain disorders of childhood,
such as cerebral palsy. Together with the discovery of stem
cells, these advances are pointing to novel strategies for
helping the brain or spinal cord regain functions lost as a
result of injury or developmental dysfunction.

Society for NeuroScieNce introduction | BraiN factS 5

chaPter 1:
haPter
BraiN BaSicS
in this chapter
n Anatomy of the Brain and the
Nervous System
n The Neuron
n Neurotransmitters and
Neuromodulators
Anatomy of the Brain and the Nervous System
The brain is the body’s control center, managing just
about everything we do. Whether we’re thinking, dreaming,
playing sports, or even sleeping, the brain is involved in
some way. A wonder of evolutionary engineering, the brain
is organized into different parts that are wired together in
a specific way. Each part has a specific job (or jobs) to do,
making the brain the ultimate multitasker. Working in
tandem with the rest of the nervous system, the brain sends
and receives messages, allowing for ongoing communication.
Mapping the Brain The cerebrum, the largest
part of the human brain, is associated with higher order
functioning, including the control of voluntary behavior.
Thinking, perceiving, planning, and understanding language
all lie within the cerebrum’s control. The cerebrum is divided
into two hemispheres — the right hemisphere and the
left hemisphere. Bridging the two hemispheres is a bundle
of fibers called the corpus callosum. The two hemispheres
communicate with one another across the corpus callosum.
Covering the outermost layer of the cerebrum is a
sheet of tissue called the cerebral cortex. Because of its gray
color, the cerebral cortex is often referred to as gray matter.
The wrinkled appearance of the human brain also can be
attributed to characteristics of the cerebral cortex. More than
two-thirds of this layer is folded into grooves. The grooves
increase the brain’s surface area, allowing for inclusion of
many more neurons.
The function of the cerebral cortex can be understood
by dividing it somewhat arbitrarily into zones, much like the
geographical arrangement of continents.
6 BraiN factS | introduction to the brain
The frontal lobe is responsible for initiating and
coordinating motor movements; higher cognitive skills, such
as problem solving, thinking, planning, and organizing; and
for many aspects of personality and emotional makeup.
The parietal lobe is involved with sensory processes,
attention, and language. Damage to the right side of
the parietal lobe can result in difficulty navigating spaces,
even familiar ones. If the left side is injured, the ability to
understand spoken and/or written language may be impaired.
The occipital lobe helps process visual information,
including recognition of shapes and colors.
The temporal lobe helps process auditory information and
integrate information from the other senses. Neuroscientists
also believe that the temporal lobe has a role to play in
short-term memory through its hippocampal formation, and in
learned emotional responses through its amygdala.
All of these structures make up the forebrain. Other
key parts of the forebrain include the basal ganglia, which are
cerebral nuclei deep in the cerebral cortex; the thalamus; and
the hypothalamus. The cerebral nuclei help coordinate muscle
movements and reward useful behaviors; the thalamus passes
most sensory information on to the cerebral cortex after
helping to prioritize it; and the hypothalamus is the control
center for appetites, defensive and reproductive behaviors, and
sleep-wakefulness.
The midbrain consists of two pairs of small hills called
colliculi. These collections of neurons play a critical role
in visual and auditory reflexes and in relaying this type of
information to the thalamus. The midbrain also has clusters
of neurons that regulate activity in widespread parts of the
central nervous system and are thought to be important for
reward mechanisms and mood.
The hindbrain includes the pons and the medulla
oblongata, which control respiration, heart rhythms, and
blood glucose levels.
Another part of the hindbrain is the cerebellum
which, like the cerebrum, also has two hemispheres. The
cerebellum’s two hemispheres help control movement and
cognitive processes that require precise timing, and also play
an important role in Pavlovian learning.
The spinal cord is the extension of the brain through the
vertebral column. It receives sensory information from all parts
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 small concentrations of gray matter called ganglia, a
term specifically used to describe structures in the PNS.
Overall the nervous system is a vast biological computing
device formed by a network of gray matter regions
interconnected by white matter tracts.
The brain sends messages via the spinal cord to
peripheral nerves throughout the body that serve to
control the muscles and internal organs. The somatic
nervous system is made up of neurons connecting the
CNS with the parts of the body that interact with
the outside world. Somatic nerves in the cervical
region are related to the neck and arms; those in
the thoracic region serve the chest; and those in the
lumbar and sacral regions interact with the legs.
The autonomic nervous system is made of neurons
connecting the CNS with internal organs. It is divided
into two parts. The sympathetic nervous system mobilizes
energy and resources during times of stress and arousal,
while the parasympathetic nervous system conserves energy
and resources during relaxed states, including sleep.
Messages are carried throughout the nervous
system by the individual units of its circuitry: neurons.
The next section describes the structure of neurons,
how they send and receive messages, and recent
discoveries about these unique cells.

The Neuron
The top image shows the four main sections of the cerebral cortex: the frontal lobe, the Cells within the nervous system, called neurons,
parietal lobe, the occipital lobe, and the temporal lobe. Functions such as movement are
controlled by the motor cortex, and the sensory cortex receives information on vision,
communicate with each other in unique ways. The
hearing, speech, and other senses. The bottom image shows the location of the brain’s neuron is the basic working unit of the brain, a
major internal structures. specialized cell designed to transmit information
to other nerve cells, muscle, or gland cells. In fact,
of the body below the head. It uses this information for reflex the brain is what it is because of the structural
responses to pain, for example, and it also relays the sensory and functional properties of interconnected neurons. The
information to the brain and its cerebral cortex. In addition, mammalian brain contains between 100 million and 100
the spinal cord generates nerve impulses in nerves that control billion neurons, depending on the species. Each mammalian
the muscles and the viscera, both through reflex activities and neuron consists of a cell body, dendrites, and an axon. The cell
through voluntary commands from the cerebrum. body contains the nucleus and cytoplasm. The axon extends
The Parts of the Nervous System The forebrain, from the cell body and often gives rise to many smaller
midbrain, hindbrain, and spinal cord form the central branches before ending at nerve terminals. Dendrites extend
nervous system (CNS), which is one of two great divisions from the neuron cell body and receive messages from other
of the nervous system as a whole. The brain is protected by neurons. Synapses are the contact points where one neuron
the skull, while the spinal cord, which is about 17 inches (43 communicates with another. The dendrites are covered with
cm) long, is protected by the vertebral column. synapses formed by the ends of axons from other neurons.
The other great division of the human brain is the When neurons receive or send messages, they transmit
peripheral nervous system (PNS), which consists of nerves and electrical impulses along their axons, which can range

Society for NeuroScieNce introduction to the brain | BraiN factS 7


The nervous system has two great divisions: the central nervous system (CNS), which consists of
the brain and the spinal cord, and the peripheral nervous system (PNS), which consists of nerves and-off switches for the next cell. Each receptor
and small concentrations of gray matter called ganglia. The brain sends messages via the spinal
cord to the body’s peripheral nerves, which control the muscles and internal organs.
in length from a tiny fraction of an inch (or centimeter)
to three feet (about one meter) or more. Many axons are
covered with a layered myelin sheath, which accelerates the
transmission of electrical signals along the axon. This sheath
is made by specialized cells called glia. In the brain, the glia
that make the sheath are called oligodendrocytes, and in the
peripheral nervous system, they are known as Schwann cells.
The brain contains at least ten times more glia than
neurons. Glia perform many jobs. Researchers have known
for a while that glia transport nutrients to neurons, clean
up brain debris, digest parts of dead neurons, and help hold
neurons in place. Current research is uncovering important
new roles for glia in brain function.
8 BraiN factS | introduction to the brain
Nerve impulses involve the opening and
closing of ion channels. These are selectively
permeable, water-filled molecular tunnels that
pass through the cell membrane and allow
ions — electrically charged atoms — or small
molecules to enter or leave the cell. The flow of
ions creates an electrical current that produces
tiny voltage changes across the neuron’s cell
membrane.
The ability of a neuron to generate an
electrical impulse depends on a difference in
charge between the inside and outside of the
cell. When a nerve impulse begins, a dramatic
reversal in the electrical potential occurs on the
cell’s membrane, as the neuron switches from an
internal negative charge to a positive charge state.
The change, called an action potential, then passes
along the axon’s membrane at speeds up to several
hundred miles per hour. In this way, a neuron
may be able to fire impulses multiple times every
second.
When these voltage changes reach
the end of an axon, they trigger the release
of neurotransmitters, the brain’s chemical
messengers. Neurotransmitters are released at
nerve terminals, diffuse across the synapse, and
bind to receptors on the surface of the target
cell (often another neuron, but also possibly a
muscle or gland cell). These receptors act as on-
has a distinctly shaped region that selectively
recognizes a particular chemical messenger. A
neurotransmitter fits into this region in much
the same way that a key fits into a lock. When
the transmitter is in place, this interaction alters the target
cell’s membrane potential and triggers a response from the
target cell, such as the generation of an action potential, the
contraction of a muscle, the stimulation of enzyme activity,
or the inhibition of neurotransmitter release.
An increased understanding of neurotransmitters in
the brain and knowledge of the effects of drugs on these
chemicals — gained largely through animal research —
comprise one of the largest research efforts in neuroscience.
Scientists hope that this information will help them
become more knowledgeable about the circuits responsible
for disorders such as Alzheimer’s and Parkinson’s diseases.
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Sorting out the various chemical circuits is
vital to understanding the broad spectrum of
the brain’s functions, including how the brain
stores memories, why sex is such a powerful
motivation, and what makes up the biological
basis of mental illness.
There are many different kinds of
neurotransmitters, and they all play an essential
role in the human body. The next section
provides a summary of key neurotransmitters
and neuromodulators, chemicals that help shape
overall activity in the brain.

Neurotransmitters and
Neuromodulators
Acetylcholine The first neurotransmitter
to be identified — about 80 years ago — was
acetylcholine (ACh). This chemical is released
by neurons connected to voluntary muscles,
causing them to contract, and by neurons that
control the heartbeat. ACh is also a transmitter
in many regions of the brain.
ACh is synthesized in axon terminals.
When an action potential arrives at the nerve
terminal, electrically charged calcium ions
rush in, and ACh is released into the synapse,
where it attaches to ACh receptors on the target
cells. On voluntary muscles, this action opens
sodium channels and causes muscles to contract.
ACh is then broken down by the enzyme Neurons are cells within the nervous system that transmit information to other nerve cells, muscle,
acetylcholinesterase and resynthesized in the or gland cells. Most neurons have a cell body, an axon, and dendrites. The cell body contains
nerve terminal. Antibodies that block one the nucleus and cytoplasm. The axon extends from the cell body and often gives rise to many
smaller branches before ending at nerve terminals. Dendrites extend from the neuron cell body
type of ACh receptor cause myasthenia gravis, and receive messages from other neurons. Synapses are the contact points where one neuron
a disease characterized by fatigue and muscle communicates with another. The dendrites are covered with synapses formed by the ends of
weakness. axons from other neurons.

Much less is known about ACh in the

brain. Recent discoveries suggest that it may be
critical for normal attention, memory, and sleep. Because
ACh-releasing neurons die in Alzheimer’s patients, finding
ways to restore this neurotransmitter is a goal of current
research. Drugs that inhibit acetylcholinesterase — and
increase ACh in the brain — are presently the main drugs
used to treat Alzheimer’s disease.
Amino Acids Amino acids, widely distributed
throughout the body and the brain, serve as the building
blocks of proteins. Certain amino acids can also serve as
neurotransmitters in the brain. The neurotransmitters
glycine and gamma-aminobutyric acid (GABA) inhibit the
firing of neurons. The activity of GABA is increased by
benzodiazepines (e.g., valium) and by anticonvulsant drugs.
In Huntington’s disease, a hereditary disorder that begins
during midlife, the GABA-producing neurons in brain
centers that coordinate movement degenerate, causing
uncontrollable movements. Glutamate and aspartate act as
excitatory signals, activating, among others, N-methyl-d-

Society for NeuroScieNce introduction to the brain | BraiN factS 9

aspartate (NMDA) receptors which, in developing animals,
have been implicated in activities ranging from learning
and memory to development and specification of nerve
contacts. The stimulation of NMDA receptors may promote
beneficial changes in the brain, whereas overstimulation can
cause nerve cell damage or cell death. This is what happens
as a result of trauma and during a stroke. Developing
drugs that block or stimulate activity at NMDA receptors
holds promise for improving brain function and treating
neurological and psychiatric disorders.
Catecholamines The term catecholamines includes
the neurotransmitters dopamine and norepinephrine.
Dopamine and norepinephrine are widely present in the
brain and peripheral nervous system. Dopamine is present
in three principal circuits in the brain. The dopamine
circuit that regulates movement has been directly linked
to disease. Due to dopamine deficits in the brain, people
with Parkinson’s disease show such symptoms as muscle
tremors, rigidity, and difficulty in moving. Administration of
levodopa, a substance from which dopamine is synthesized,
is an effective treatment for Parkinson’s, allowing patients to
walk and perform skilled movements more successfully.
Another dopamine circuit is thought to be important for
cognition and emotion; abnormalities in this system have been
implicated in schizophrenia. Because drugs that block certain
dopamine receptors in the brain are helpful in diminishing
psychotic symptoms, learning more about dopamine is
important to understanding mental illness. In a third circuit,
dopamine regulates the endocrine system. Dopamine directs
the hypothalamus to manufacture hormones and hold them in
the pituitary gland for release into the bloodstream or to trigger
the release of hormones held within cells in the pituitary.
Deficiencies in norepinephrine occur in patients with
Alzheimer’s disease, Parkinson’s disease, and Korsakoff’s
syndrome, a cognitive disorder associated with chronic
alcoholism. These conditions all lead to memory loss and a
decline in cognitive functioning. Thus, researchers believe
that norepinephrine may play a role in both learning and
memory. Norepinephrine is also secreted by the sympathetic
nervous system throughout the body to regulate heart
rate and blood pressure. Acute stress increases release of
norepinephrine from sympathetic nerves and the adrenal
medulla, the innermost part of the adrenal gland.
Serotonin This neurotransmitter is present in the
brain and other tissues, particularly blood platelets and the
10 BraiN factS | introduction to the brain
lining of the digestive tract. In the brain, serotonin has been
identified as an important factor in sleep quality, mood,
depression, and anxiety. Because serotonin controls different
switches affecting various emotional states, scientists believe
these switches can be manipulated by analogs, chemicals
with molecular structures similar to that of serotonin. Drugs
that alter serotonin’s action, such as fluoxetine, relieve
symptoms of depression and obsessive-compulsive disorder.
Peptides Short chains of amino acids that are linked
together, peptides are synthesized in the cell body and greatly
outnumber the classical transmitters discussed earlier. In
1973, scientists discovered receptors for opiates on neurons
in several regions of the brain, suggesting that the brain must
make substances very similar to opium. Shortly thereafter,
scientists made their first discovery of an opiate peptide
produced by the brain. This chemical resembles morphine,
an opium derivative used medically to kill pain. Scientists
named this substance enkephalin, literally meaning “in
the head.” Soon after, other types of opioid peptides
were discovered. These were named endorphins, meaning
“endogenous morphine.” The precise role of the naturally
occurring opioid peptides is unclear. A simple hypothesis is
that they are released by brain neurons in times of stress to
minimize pain and enhance adaptive behavior. Some sensory
nerves — tiny unmyelinated C fibers — contain a peptide
called substance P, which causes the sensation of burning
pain. The active component of chili peppers, capsaicin,
causes the release of substance P, something people should be
aware of before eating them.
Trophic Factors Researchers have discovered several
small proteins in the brain that act as trophic factors, substances
that are necessary for the development, function, and survival
of specific groups of neurons. These small proteins are made in
brain cells, released locally in the brain, and bind to receptors
expressed by specific neurons. Researchers also have identified
genes that code for receptors and are involved in the signaling
mechanisms of trophic factors. These findings are expected to
result in a greater understanding of how trophic factors work
in the brain. This information should also prove useful for the
design of new therapies for brain disorders of development and
for degenerative diseases, including Alzheimer’s disease and
Parkinson’s disease.
hormones In addition to the nervous system, the
endocrine system is a major communication system of the
body. While the nervous system uses neurotransmitters as
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its chemical signals, the endocrine system uses hormones.
The pancreas, kidneys, heart, adrenal glands, gonads, thyroid,
parathyroid, thymus, and even fat are all sources of hormones.
The endocrine system works in large part by acting on
neurons in the brain, which controls the pituitary gland. The
pituitary gland secretes factors into the blood that act on
the endocrine glands to either increase or decrease hormone
production. This is referred to as a feedback loop, and it
involves communication from the brain to the pituitary to
an endocrine gland and back to the brain. This system is very
important for the activation and control of basic behavioral
activities, such as sex; emotion; responses to stress; and eating,
drinking, and the regulation of body functions, including
growth, reproduction, energy use, and metabolism. The way the
brain responds to hormones indicates that the brain is very
malleable and capable of responding to environmental signals.
The brain contains receptors for thyroid hormones
(those produced by the thyroid) and the six classes of
steroid hormones, which are synthesized from cholesterol
— androgens, estrogens, progestins, glucocorticoids,
mineralocorticoids, and vitamin D. The receptors are found
in selected populations of neurons in the brain and relevant
organs in the body. Thyroid and steroid hormones bind to
receptor proteins that in turn bind to DNA and regulate the
action of genes. This can result in long-lasting changes in
cellular structure and function.
The brain has receptors for many hormones; for
example, the metabolic hormones insulin, insulin-like
growth factor, ghrelin, and leptin. These hormones are taken
up from the blood and act to affect neuronal activity and
certain aspects of neuronal structure.
In response to stress and changes in our biological
clocks, such as day and night cycles and jet lag, hormones
enter the blood and travel to the brain and other organs. In
the brain, hormones alter the production of gene products
that participate in synaptic neurotransmission as well as
affect the structure of brain cells. As a result, the circuitry of
the brain and its capacity for neurotransmission are changed
over a course of hours to days. In this way, the brain adjusts
its performance and control of behavior in response to a
changing environment.
Hormones are important agents of protection and
adaptation, but stress and stress hormones, such as the
glucocorticoid cortisol, can also alter brain function,
including the brain’s capacity to learn. Severe and prolonged
stress can impair the ability of the brain to function
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normally for a period of time, but the brain is also capable of
remarkable recovery.
Reproduction in females is a good example of a regular,
cyclic process driven by circulating hormones and involving
a feedback loop: The neurons in the hypothalamus produce
gonadotropin-releasing hormone (GnRH), a peptide that
acts on cells in the pituitary. In both males and females,
this causes two hormones — the follicle-stimulating hormone
(FSH) and the luteinizing hormone (LH) — to be released
into the bloodstream. In females, these hormones act on
the ovary to stimulate ovulation and promote release of
the ovarian hormones estradiol and progesterone. In males,
these hormones are carried to receptors on cells in the testes,
where they promote spermatogenesis and release the male
hormone testosterone, an androgen, into the bloodstream.
Testosterone, estrogen, and progesterone are often referred to
as sex hormones.
In turn, the increased levels of testosterone in males and
estrogen in females act on the hypothalamus and pituitary
to decrease the release of FSH and LH. The increased levels
of sex hormones also induce changes in cell structure and
chemistry, leading to an increased capacity to engage in
sexual behavior. Sex hormones also exert widespread effects
on many other functions of the brain, such as attention,
motor control, pain, mood, and memory.
Sexual differentiation of the brain is caused by sex
hormones acting in fetal and early postnatal life, although
recent evidence suggests genes on either the X or Y
chromosome may also contribute to this process. Scientists
have found statistically and biologically significant
differences between the brains of men and women that are
similar to sex differences found in experimental animals.
These include differences in the size and shape of brain
structures in the hypothalamus and the arrangement of
neurons in the cortex and hippocampus. Sex differences go
well beyond sexual behavior and reproduction and affect
many brain regions and functions, ranging from mechanisms
for perceiving pain and dealing with stress to strategies for
solving cognitive problems. That said, however, the brains of
men and women are more similar than they are different.
Anatomical differences have also been reported between
the brains of heterosexual and homosexual men. Research
suggests that hormones and genes act early in life to shape
the brain in terms of sex-related differences in structure
and function, but scientists are still putting together all the
pieces of this puzzle.
introduction to the brain | BraiN factS 11
 Gases and Other unusual Neurotransmitters
Scientists have identified a new class of neurotransmitters
that are gases. These molecules — nitric oxide and carbon
monoxide — do not act like other neurotransmitters. Being
gases, they are not stored in any structure, certainly not in
storage structures for classical and peptide transmitters. Instead,
they are made by enzymes as they are needed and released
from neurons by diffusion. Rather than acting at receptor sites,
these gases simply diffuse into adjacent neurons and act upon
chemical targets, which may be enzymes.
Working in tandem with
the rest of the nervous system,
the brain sends and receives
messages, allowing for
ongoing communication.
Although exact functions for carbon monoxide have
not been determined, nitric oxide has already been shown
to play several important roles. For example, nitric oxide
neurotransmission governs erection in the penis. In nerves
of the intestine, it governs the relaxation that contributes
to the normal movements of digestion. In the brain, nitric
oxide is the major regulator of the intracellular messenger
molecule cyclic GMP. In conditions of excess glutamate
release, as occurs in stroke, neuronal damage following the
stroke may be attributable in part to nitric oxide.
Lipid Messengers In addition to gases, which
act rapidly, the brain also derives signals from lipids.
Prostaglandins are a class of compounds made from lipids
by an enzyme called cyclooxygenase. These very small and
short-lived molecules have powerful effects, including the
induction of a fever and the generation of pain in response
to inflammation. Aspirin reduces a fever and lowers pain
by inhibiting the cyclooxygenase enzyme. A second class of
membrane-derived messenger is the brain’s own marijuana,
12 BraiN factS | introduction to the brain
referred to as endocannabinoids, because they are in essence
cannabis made by the brain. These messengers control the
release of neurotransmitters, usually by inhibiting them,
and can also affect the immune system and other cellular
parameters still being discovered. Endocannabinoids play an
important role in the control of behaviors. They increase in
the brain under stressful conditions.
Second Messengers After the action of
neurotransmitters at their receptors, biochemical
communication within cells is still possible. Substances that
trigger such communication are called second messengers.
Second messengers convey the chemical message of
a neurotransmitter (the first messenger) from the cell
membrane to the cell’s internal biochemical machinery.
Second messenger effects may endure for a few milliseconds
to as long as many minutes. They also may be responsible for
long-term changes in the nervous system.
An example of the initial step in the activation of a
second messenger system involves adenosine triphosphate
(ATP), the chemical source of energy in cells. ATP is present
throughout the cytoplasm of all cells. For example, when
norepinephrine binds to its receptors on the surface of the
neuron, the activated receptor binds a G protein on the
inside of the membrane. The activated G protein causes the
enzyme adenylyl cyclase to convert ATP to cyclic adenosine
monophosphate (cAMP), the second messenger. Rather than
acting as a messenger between one neuron and another, cAMP
exerts a variety of influences within the cell, ranging from
changes in the function of ion channels in the membrane to
changes in the expression of genes in the nucleus.
Second messengers also are thought to play a role in
the manufacture and release of neurotransmitters and in
intracellular movements and carbohydrate metabolism in the
cerebrum — the largest part of the brain, consisting of two
hemispheres. Second messengers also are involved in growth
and development processes. In addition, the direct effects
of second messengers on the genetic material of cells may
lead to long-term alterations in cellular functioning and,
ultimately, to changes in behavior.
The intricate communication systems in the brain and
the nervous system begin to develop about three weeks after
gestation. How this process unfolds and how it is relevant to
an understanding of brain-based conditions and illnesses are
discussed in Chapter 2.
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chaP ter 2:
haPter
the develoPiNg BraiN
in this chapter
n The Journey of Nerve Cells
n Critical Periods
n Plasticity
The amazing capabilities of the human brain arise from
exquisitely intricate communication among its billions
of interacting brain cells. Although the specific patterns
of connectivity are forged by the ever-changing interplay
between a person’s genes and his specific environment,
much of the development of brain cells occurs during the
prenatal period. Understanding the processes underlying
how brain cells are formed, become specialized, travel to
their appropriate location, and connect to each other in
increasingly elaborate adaptive networks is the central
challenge of developmental neurobiology.
Advances in the study of brain development have
become increasingly relevant for medical treatments.
For example, several diseases that most scientists
once thought were purely disorders of adult function,
such as schizophrenia, are now being considered in
developmental terms; that is, such disorders may occur
because pathways and connections to the brain did
not form correctly early in life. Other research suggests
that genes important for brain development may also
play a role in susceptibility to autism spectrum disorders.
And by applying knowledge about how connections
form during development, regeneration following injury
to the brain is now viewed as a future possibility.
Knowing how the brain is constructed is essential for
understanding its ability to reorganize in response to external
influences or injury. As the brain evolves from the embryo
to the adult stage, unique attributes evolve during infancy
and childhood that contribute to differences in learning
ability as well as vulnerability to specific brain disorders.
Neuroscientists are beginning to discover some general
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principles that underlie developmental processes, many of
which overlap in time.
The Journey of Nerve Cells
The development of neurons occurs through a delicate
process. Signaling molecules “turn on” certain genes and “turn
off” others, beginning the process of nerve cell induction.
Even more astonishing is that this process takes place as the
embryo is developing. Induction and proliferation are followed
by migration, during which the newly formed neurons travel
to their final destination. Throughout life, the nervous system
is active, making new connections and fine-tuning the way
messages are sent and received. The activities of the ever-
changing nervous system are explained in more detail in the
following sections.
Induction During the early stages of embryonic
development, three layers emerge — the endoderm, the
ectoderm, and the mesoderm. These layers undergo many
interactions to grow into organ, bone, muscle, skin, or
nerve tissue. How does this process of differentiation occur,
especially since each cell contains 25,000 genes, the entire
sequence of DNA instructions for development? The answer
lies in signaling molecules released by the mesoderm. These
molecules turn on certain genes and turn off others, triggering
some ectoderm cells to become nerve tissue in a process called
neural induction. Subsequent signaling interactions further
refine the nerve tissue into the basic categories of neurons or
glia (support cells), then into subclasses of each cell type. The
remaining cells of the ectoderm, which have not received the
signaling molecules diffusing from the mesoderm, become skin.
The proximity of cells to the signaling molecules largely
determines their fate. That’s because the concentration of
these molecules spreads out and weakens the farther it moves
from its source. For example, a particular signaling molecule,
called sonic hedgehog, is secreted from mesodermal tissue
lying beneath the developing spinal cord. As a result, the
adjacent nerve cells are converted into a specialized class of
glia. Cells that are farther away, however, are exposed to lower
concentrations of sonic hedgehog, so they become the motor
neurons that control muscles. An even lower concentration
promotes the formation of interneurons, which relay messages
to other neurons, not muscles. Interestingly, the mechanism of
introduction to the brain | BraiN factS 13
The human brain and nervous system begin to develop at about three weeks’ gestation with the closing of the neural tube (left image). By four weeks, major
regions of the human brain can be recognized in primitive form, including the forebrain, midbrain, hindbrain, and optic vesicle, from which the eye develops.
Ridges, or convolutions, can be seen by six months.
this basic signaling molecule is very similar in species as diverse
as flies and humans.
Migration Once neural induction has occurred, the
next step for new neurons is a journey to the proper position
in the brain. This process is called migration, and it begins
three to four weeks after a human baby is conceived. At
this time, the ectoderm starts to thicken and build up along
the middle. As the cells continue to divide, a flat neural
plate grows, followed by the formation of parallel ridges,
similar to the creases in a paper airplane, that rise across its
surface. Within a few days, the ridges fold in toward each
other and fuse to form a hollow neural tube. The top of the
tube thickens into three bulges that form the hindbrain, the
midbrain, and the forebrain. Later in the process, at week
seven, the first signs of the eyes and the brain’s hemispheres
appear. As neurons are produced, they move from the neural
tube’s ventricular zone, or inner surface, to near the border of
the marginal zone, or outer surface.
After neurons stop dividing, they form an intermediate
zone, where they gradually accumulate as the brain develops.
The neurons then migrate to their final destination— with
the help of a variety of guidance mechanisms. The most
common guidance mechanism, accounting for about 90
percent of migration in humans, are glia, which project
radially from the intermediate zone to the cortex. In this way,
glia provide a temporary scaffolding for ushering neurons to
their destination. This process of radial migration occurs in an
“inside-out” manner; that is, the cells that arrive the earliest
(the oldest ones) form the deepest layer of the cortex, whereas
14 BraiN factS | introduction to the brain
the late-arriving (the youngest) neurons form the outermost
layer. Through another mechanism, inhibitory interneurons,
small neurons with short pathways usually found in the central
nervous system, migrate tangentially across the brain.
Migration is a delicate process and can be affected by
different factors. External forces, such as alcohol, cocaine,
or radiation, can prevent proper migration, resulting in
misplacement of cells, which may lead to mental retardation
or epilepsy. Furthermore, mutations in genes that regulate
migration have been shown to cause some rare genetic forms
of retardation and epilepsy in humans.
Making Connections Once the neurons reach their
final location, they must make the proper connections so
that a particular function, such as vision or hearing, can
emerge. Unlike induction, proliferation, and migration, which
occur internally during fetal development, the next phases of
brain development are increasingly dependent on interactions
with the environment. After birth and beyond, such activities
as listening to a voice, responding to a toy, and even the
reaction evoked by the temperature in the room lead to more
connections among neurons.
Neurons become interconnected through (1) the growth
of dendrites — extensions of the cell body that receive signals
from other neurons and (2) the growth of axons — extensions
from the neuron that can carry signals to other neurons.
Axons enable connections between neurons at considerable
distances, sometimes at the opposite side of the brain, to
develop. In the case of motor neurons, the axon may travel
from the spinal cord all the way down to a foot muscle.
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 Growth cones, enlargements on the axon’s tip, actively shown to guide neurons around the worm’s “nerve ring.”
explore the environment as they seek out their precise Later, vertebrate netrins were found to guide axons around
destination. Researchers have discovered many special the mammalian spinal cord. Receptors for netrins were then
molecules that help guide growth cones. Some molecules found in worms, a discovery that proved to be invaluable in
lie on the cells that growth cones contact, whereas others finding the corresponding, and related, human receptors.
are released from sources found near the growth cone. The Once axons reach their targets, they form connections
growth cones, in turn, bear molecules that serve as receptors with other cells at synapses. At the synapse, the electrical
for the environmental cues. The binding of particular signals signal of the sending axon is transmitted by chemical
with receptors tells the growth cone whether to move neurotransmitters to the receiving dendrites of another
forward, stop, recoil, or change direction. These signaling neuron, where they can either provoke or prevent the
molecules include proteins with names such as netrin, generation of a new signal. The regulation of this transmission
semaphorin, and ephrin. In most cases, these are families of at synapses and the integration of inputs from the thousands
related molecules; for example, researchers have identified at of synapses each neuron receives are responsible for the
least fifteen semaphorins and at least nine ephrins. astounding information-processing capacity of the brain.
Perhaps the most remarkable finding is that most of For processing to occur properly, the connections
these proteins are common to many organisms—worms, must be highly specific. Some specificity arises from the
insects, and mammals, including humans. Each protein mechanisms that guide each axon to its proper target area.
family is smaller in flies or worms than in mice or people, Additional molecules mediate target recognition when
but its functions are quite similar. As a result, it has been the axon chooses the proper neuron. They often also
possible to use the simpler animals as experimental models mediate the proper part of the target once the axon arrives
to gain knowledge that can be applied directly to humans. at its destination. Over the past few years, several of these
For example, the first netrin was discovered in a worm and recognition molecules have been identified. Dendrites also
are actively involved in the process
of initiating contact with axons and
recruiting proteins to the “postsynaptic”
side of the synapse.
Researchers have successfully
identified ways in which the synapse
differentiates once contact has been made.
The tiny portion of the axon that contacts
the dendrite becomes specialized for the
release of neurotransmitters, and the tiny
portion of the dendrite that receives the
contact becomes specialized to receive and
respond to the signal. Special molecules
pass between the sending and receiving
cells to ensure that the contact is formed
properly and that the sending and receiving
specializations are matched precisely.
These processes ensure that the synapse
can transmit signals quickly and effectively.
Finally, still other molecules coordinate
the maturation of the synapse after it has
This is a cross-sectional view of the occipital lobe, which processes vision, of a three-month-old monkey formed so that it can accommodate the
fetus brain. The center shows immature neurons migrating along glial fibers. These neurons make
transient connections with other neurons before reaching their destination. A single migrating neuron, changes that occur as our bodies mature
shown about 2,500 times its actual size (right), uses a glial fiber as a guiding scaffold. and our behavior changes. Defects in some

Society for NeuroScieNce introduction to the brain | BraiN factS 15

of these molecules are now thought to make people susceptible
to disorders such as autism. The loss of other molecules may
underlie the degradation of synapses that occurs during aging.
A combination of signals also determines the type of
neurotransmitters that a neuron will use to communicate
with other cells. For some cells, such as motor neurons, the
type of neurotransmitter is fixed, but for other neurons, it is
not. Scientists found that when certain immature neurons
are maintained in a dish with no other cell types, they
produce the neurotransmitter norepinephrine. In contrast, if
the same neurons are maintained with specific cells, such as
cardiac, or heart, tissue, they produce the neurotransmitter
acetylcholine. Just as genes turn on and off signals to regulate
the development of specialized cells, a similar process leads
to the production of specific neurotransmitters. Many
researchers believe that the signal to engage the gene, and
therefore the final determination of the chemical messengers
that a neuron produces, is influenced by factors coming from
the location of the synapse itself.
Neurons communicate with electrical and chemical signals at special
contact points called synapses. [Credit: Meagan A. Jenkins, et al., The Journal of
Neuroscience 2010, 30(15): 5125-5135]
16 BraiN factS | introduction to the brain
Myelination Insulation covering wires preserves
the strength of the electrical signals that travel through
them. The myelin sheath covering axons serves a similar
purpose. Myelination, the wrapping of axons by extensions
of glia, increases the speed at which signals may be sent
from one neuron to another by a factor of up to 100x. This
advantage is due to how the sheath is wrapped. In between
the myelin are gaps, called nodes of Ranvier, that are not
covered in myelin. The electrical signal moves faster over
the insulated portion, jumping from one node to another.
This phenomenon, known as saltatory conduction (the word
“saltatory” means “to jump”), is responsible for the rapid
transmission of electrical signals. The process of myelination
occurs throughout the lifespan.
Paring Back After growth, the neural network is
pared back to create a more efficient system. Only about
half the neurons generated during development survive to
function in the adult. Entire populations of neurons are
removed through apoptosis, programmed cell death initiated
in the cells. Apoptosis is activated if a neuron loses its
battle with other neurons to receive life-sustaining chemical
signals called trophic factors. These factors are produced
in limited quantities by target tissues. Each type of trophic
factor supports the survival of a distinct group of neurons.
For example, nerve growth factor is important for sensory
neuron survival. Recently, it has become clear that apoptosis
is maintained into adulthood and constantly held in check.
On the basis of this idea, researchers have found that injuries
and some neurodegenerative diseases kill neurons not by
directly inflicting damage but rather by activating the cells’
own death programs. This discovery — and its implication
that death need not follow insult — have led to new avenues
for therapy.
Brain cells also form excess connections at first. For
example, in primates, the projections from the two eyes
to the brain initially overlap and then sort out to separate
territories devoted to one eye or the other. Furthermore, in
the young primate cerebral cortex, the connections between
neurons are greater in number and twice as dense as those
in an adult primate. Communication between neurons
with chemical and electrical signals is necessary to weed
out the connections. The connections that are active and
generating electrical currents survive, whereas those with
little or no activity are lost. Thus, the circuits of the adult
brain are formed, at least in part, by sculpting away incorrect
connections to leave only the correct ones.
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Critical Periods
Genes and the environment converge powerfully
during early sensitive windows of brain development to form
the neural circuits underlying behavior. Although most
neuronal cell death occurs in the embryo, the paring down
of connections occurs in large part during critical periods
in early postnatal life. During these moments in time, the
developing nervous system must obtain certain critical
experiences, such as sensory, movement, or emotional input,
to mature properly. Such periods are characterized by high
learning rates as well as enduring consequences for neuronal
connectivity.
After a critical period, connections diminish in number
and are less subject to change, but the ones that remain are
stronger, more reliable, and more precise. These turn into
the unique variety of sensory, motor, or cognitive “maps”
that best reflect our world. It is important to note that
there are multiple critical periods, organized sequentially,
as individual brain functions are established. The last step
in the creation of an adult human brain, the frontal lobes,
whose function includes judgment, insight, and impulse
control, continues into the early 20s. Thus, even the brain of
an adolescent is not completely mature.
Injury or deprivation of environmental input occurring
at specific stages of postnatal life can dramatically reshape
the underlying circuit development, which becomes
increasingly more difficult to correct later in life. In one
experiment, a monkey raised from birth to 6 months of age
with one eyelid closed permanently lost useful vision in that
eye because of diminished use. This gives cellular meaning
to the saying “use it or lose it.” Loss of vision is caused by the
actual loss of functional connections between that eye and
neurons in the visual cortex. This finding has led to earlier
and better treatment for the eye disorders of congenital
cataracts and “lazy eye” in children. Similarly, cochlear
implants introduced in infancy are most effective in restoring
hearing to the congenitally deaf. Cognitive recovery from
social deprivation, brain damage, or stroke is also greatest
early in life. Conversely, research suggests that enriched
environments or stimulation may bolster brain development,
as revealed by animals raised in toy-filled surroundings. They
have more branches on their neurons and more connections
than isolated animals.
Many people have observed that children can learn
languages or develop musical ability (absolute pitch) with
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greater proficiency than adults. Heightened activity in the
critical period may, however, also contribute to an increased
incidence of certain disorders in childhood, such as epilepsy.
Fortunately, as brain activity subsides, many types of epilepsy
fade away by adulthood.
Plasticity
The ability of the brain to modify itself and adapt to
challenges of the environment is referred to as plasticity.
Plasticity itself is not unique to humans, but the degree to
which our brains are able to adapt is the defining attribute
of our species. Plasticity can be categorized as experience-
expectant or experience-dependent.
Experience-expectant plasticity refers to the integration
of environmental stimuli into the normal patterns of
development. Certain environmental exposures during limited
critical, or sensitive, periods of development are essential for
healthy maturation. For example, finches need to hear adult
songs before sexual maturation in order for them to learn to
sing at a species-appropriate level of intricacy.
Scientists hope that new insight into brain development
will lead to treatments for those with learning disabilities,
brain damage, and neurodegenerative disorders, as well
as help us understand aging. If we can figure out a way
to lift the brakes that restrict adult plasticity — either
pharmacologically or by circuit rewiring — it may be possible
to correct damage done through mistimed critical periods
or other means. By understanding normal functions of the
brain during each developmental stage, researchers hope to
develop better age-specific therapies for brain disorders.
This chapter discussed how cells differentiate so that
they can perform specific functions, such as seeing and
hearing. Those are just two of the senses we rely on to learn
about the world. The senses of taste, smell, and touch also
provide key information. Through intricate systems and
networks, the brain and the nervous system work together
to process these sensory inputs. Part 2, called Sensing,
Thinking, and Behaving, describes how these systems work
and complement each other. It begins with a look at senses
and perception.
introduction to the brain | BraiN factS 17
chaP ter 3:
haPter
SeNSeS aNd PercePtioN
As in a camera, the image on the retina is reversed: Objects
to the right of center project images to the left part of the retina
in this chapter and vice versa; objects above the center project to the lower
part and vice versa. The size of the pupil, which regulates how
n Vision
much light enters the eye, is controlled by the iris. The shape
n Hearing of the lens is altered by the muscles just behind the iris so that
near or far objects can be brought into focus on the retina.
n Taste and Smell Primates, including humans, have well-developed vision
using two eyes, called binocular vision. Visual signals pass from
n Touch and Pain each eye along the million or so fibers of the optic nerve to the
optic chiasm, where some nerve fibers cross over. This crossover
allows both sides of the brain to receive signals from both eyes.
When you look at a scene with both eyes, the objects to
Vision
your left register on the right side of the retina. This visual
The wonderful sense of sight allows us to experience
information then maps to the right side of the cortex. The result
the world, from the genius of Michelangelo’s Sistine Chapel
is that the left half of the scene you are watching registers in
ceiling to the mist-filled vista of a mountain range. Vision
the cerebrum’s right hemisphere. Conversely, the right half of
is one of our most delicate and complicated senses. Many
the scene registers in the cerebrum’s left hemisphere. A similar
processes must occur simultaneously in order for us to see
arrangement applies to movement and touch: Each half of the
what is happening around us. Information about image size
cerebrum is responsible for processing information received
and shape, color, motion, and location in space all must be
from the opposite half of the body.
gathered, encoded, integrated, and processed. Performing
Scientists know much about the way cells encode visual
these activities involves about 30 percent of the human
information in the retina, but relatively less about the lateral
brain — more than for any other sense.
geniculate nucleus — an intermediate way station between the
Vision has been studied intensively. As a result,
retina and visual cortex — and the visual cortex. Studies about
neuroscientists may know more about it than any other
the inner workings of the retina give us the best knowledge we
sensory system. Most information about initial stages of
have to date about how the brain analyzes and processes sensory
visual transduction, or how light is converted into electrical
information.
signals, comes from studies of Drosophila (fruit flies) and
Photoreceptors, about 125 million in each human eye,
mice, whereas visual processing has been mostly studied in
are neurons specialized to turn light into electrical signals.
monkeys and cats.
Two major types of photoreceptors are rods and cones. Rods are
It all Starts with Light Vision begins with light
extremely sensitive to light and allow us to see in dim light,
passing through the cornea, which does about three-quarters
but they do not convey color. Rods constitute 95 percent of all
of the focusing, and then the lens, which adjusts the focus.
photoreceptors in humans. Most of our vision, however, comes
Both combine to produce a clear image of the visual world
from cones that work under most light conditions and are
on a sheet of photoreceptors called the retina, which is part of
responsible for acute detail and color vision.
the central nervous system but located at the back of the eye.
The human eye contains three types of cones (red,
Photoreceptors gather visual information by absorbing
green and blue), each sensitive to a different range of colors.
light and sending electrical signals to other retinal neurons
Because their sensitivities overlap, cones work in combination
for initial processing and integration. The signals are then
to convey information about all visible colors. You might be
sent via the optic nerve to other parts of brain, which
surprised to know that we can see thousands of colors using
ultimately processes the image and allows us to see.
only three types of cones, but computer monitors use a similar

18 BraiN factS | sensing, thinking, and behaving Society for NeuroScieNce

 input from many cells in the previous layer,
and the number of inputs varies widely
across the retina. Near the center of the gaze,
where visual acuity is highest, each ganglion
cell receives inputs — via the middle layer
— from one cone or, at most, a few, allowing
us to resolve very fine details. Near the
margins of the retina, each ganglion cell
receives signals from many rods and cones,
explaining why we cannot see fine details
on either side. Whether large or small, the
region of visual space providing input to a
visual neuron is called its receptive field.
how Visual Information Is
Processed About 60 years ago,
scientists discovered that each vision cell’s
receptive field is activated when light hits
a tiny region in the center of the field
and inhibited when light hits the area
surrounding the center. If light covers the
entire receptive field, the cell responds
weakly. Thus, the visual process begins by
comparing the amount of light striking any
small region of the retina with the amount
of surrounding light.
Visual information from the retina
Vision begins with light passing through the cornea and the lens, which combine to produce a clear
is relayed through the lateral geniculate
image of the visual world on a sheet of photoreceptors called the retina. As in a camera, the image nucleus of the thalamus to the primary
on the retina is reversed: Objects above the center project to the lower part and vice versa. The visual cortex — a thin sheet of tissue (less
information from the retina — in the form of electrical signals — is sent via the optic nerve to other
than one-tenth of an inch thick), a bit
parts of the brain, which ultimately process the image and allow us to see.
larger than a half-dollar, which is located
in the occipital lobe in the back of the
process to generate a spectrum of colors. The central part of the
brain. The primary visual cortex is densely packed with
human retina, where light is focused, is called the fovea, which
cells in many layers, just as the retina is. In its middle layer,
contains only red and green cones. The area around the fovea,
which receives messages from the lateral geniculate nucleus,
called the macula, is critical for reading and driving. Death of
scientists have found responses similar to those seen in
photoreceptors in the macula, called macular degeneration, is
the retina and in lateral geniculate cells. Cells above and
a leading cause of blindness among the elderly population in
below this layer respond differently. They prefer stimuli in
developed countries, including the United States.
the shape of bars or edges and those at a particular angle
The retina contains three organized layers of neurons.
(orientation). Further studies have shown that different
The rod and cone photoreceptors in the first layer send signals
cells prefer edges at different angles or edges moving in a
to the middle layer (interneurons), which then relays signals
particular direction.
to the third layer, consisting of multiple different types of
Although the visual processing mechanisms are not
ganglion cells, specialized neurons near the inner surface of the
yet completely understood, recent findings from anatomical
retina. The axons of the ganglion cells form the optic nerve.
and physiological studies in monkeys suggest that visual
Each neuron in the middle and third layer typically receives

Society for NeuroScieNce sensing, thinking, and behaving | BraiN factS 19

signals are fed into at least three separate processing
systems. One system appears to process information mainly
about shape; a second, mainly about color; and a third,
movement, location, and spatial organization. Human
psychological studies support the findings obtained through
animal research. These studies show that the perception of
movement, depth, perspective, the relative size of objects,
the relative movement of objects, shading, and gradations in
texture all depend primarily on contrasts in light intensity
rather than on color. Perception requires various elements to
be organized so that related ones are grouped together. This
stems from the brain’s ability to group the parts of an image
together and also to separate images from one another and
from their individual backgrounds.
How do all these systems combine to produce the vivid
images of solid objects that we perceive? The brain extracts
biologically relevant information at each stage and associates
firing patterns of neuronal populations with past experience.
Research Leads to More effective Treatment
Vision studies also have led to better treatment for visual
disorders. Information from research in cats and monkeys has
improved the therapy for strabismus, a condition in which
Mutations in the RPe65 protein (labeled in retinal cells in red) cause an
inherited form of blindness that may be corrected by gene therapy. [Credit:
National eye Institute, National Institutes of health]
20 BraiN factS | sensing, thinking, and behaving
the eyes are not properly aligned with each other and point
in different directions. It is also termed squint, cross-eye, or
walleye. Children with strabismus initially have good vision in
each eye. But because they cannot fuse the images in the two
eyes, they tend to favor one eye and often lose useful vision in
the other. Vision can be restored in such cases, but only during
infancy or early childhood. Beyond the age of 8 or so, the
blindness in one eye becomes permanent. Until a few decades
ago, ophthalmologists waited until children reached the age
of 4 before operating to align the eyes, prescribing exercises, or
using an eye patch. Now strabismus is corrected very early in
life — before age 4 — when normal vision can still be restored.
Extensive genetic studies and use of model organisms
have allowed us to identify defects in inherited eye diseases,
making it possible to design gene or stem cell-based therapy
and discover new drugs for treatment. Loss of function or death
of photoreceptors appears to be a major cause of blindness
in many diseases that are currently incurable. Recently, gene
therapy for a small group of patients with severe blindness
allowed them to see. Work also is in progress to bypass lost
photoreceptors and send electrical signals directly to the brain
via ganglion cells.
hearing
Often considered the most important sense for humans,
hearing allows us to communicate with each other by receiving
sounds and interpreting speech. Hearing also gives information
vital to survival; for instance, by alerting us to an approaching
car, it enables us to get out of harm’s way.
Like the visual system, our hearing system picks up
several qualities in the signals it detects (for example, a
sound’s location, its loudness, and its pitch). Our hearing
system does not blend the frequencies of different sounds, as
the visual system does when different wavelengths of light
are mixed to produce color. Instead, it separates complex
sounds into their component tones or frequencies so that
we can follow different voices or instruments as we listen to
conversations or to music.
Whether from the chirping of crickets or the roar of a
rocket engine, sound waves are collected by the external ear
— the pinna and the external auditory canal — and funneled
to the tympanic membrane (eardrum) to make it vibrate.
Attached to the tympanic membrane, the malleus (hammer)
transmits the vibration to the incus (anvil), which passes the
vibration on to the stapes (stirrup). The stapes pushes on the
oval window, which separates the air-filled middle ear from the
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fluid-filled inner ear to produce pressure waves in the inner ear’s
snail-shaped cochlea. The separation of frequencies occurs in the
cochlea, which is tuned along its length to different frequencies,
so that a high note causes one region of the cochlea’s basilar
membrane to vibrate, while a lower note has the same effect on
a different region of the basilar membrane.
Riding on the vibrating basilar membrane are hair cells
topped with microscopic bundles of hairlike stereocilia, which
are deflected by the overlying tectorial membrane. Hair cells
convert the mechanical vibration to electrical signals, which in
turn excite the 30,000 fibers of the auditory nerve. The auditory
nerve then carries the signals to the brainstem. Because each
hair cell rides on a different part of the basilar membrane, each
responds to a different frequency. As a result, each nerve fiber
carries information about a different frequency to the brain.
Auditory information is analyzed by multiple brain centers as it
flows to the superior temporal gyrus, or auditory cortex, the part
of the brain involved in perceiving sound.
In the auditory cortex, adjacent neurons tend to respond to
tones of similar frequency. However, they specialize in different
combinations of tones. Some respond to pure tones, such as
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Sound waves are collected by the external ear
— the pinna and the external auditory canal —
and funneled to the tympanic membrane
(eardrum) to make it vibrate. Attached to the
tympanic membrane, the malleus (hammer)
transmits the vibration to the incus (anvil),
which passes the vibration on to the stapes
(stirrup). hair cells convert the mechanical
vibration to electrical signals, which in turn
excite the 30,000 fibers of the auditory nerve.
The auditory nerve then carries the signals to
the brainstem. From there, nerve fibers send the
information to the auditory cortex, the part of
the brain involved in perceiving sound.
those produced by a flute, and some to complex sounds like
those made by a violin. Some respond to long sounds and some
to short, and some to sounds that rise or fall in frequency. Other
neurons might combine information from these specialist
neurons to recognize a word or an instrument.
Sound is processed in different regions of the auditory
cortex on both sides of the brain. However, for most people,
the left side is specialized for perceiving and producing speech.
Damage to the left auditory cortex, such as from a stroke, can
leave someone able to hear but unable to understand language.
Taste and Smell
Although most of us don’t think of it in this way, the
related senses of taste and smell help us interpret the chemical
world. Just as sound is the perception of changes in air pressure
and sight the perception of light, tastes and smells are the
perception of chemicals in the air or in our food. Separate
senses with their own receptor organs, taste and smell are
nonetheless intimately entwined.
This close relationship is most apparent in how we
perceive the flavors of food. As anyone with a head cold
sensing, thinking, and behaving | BraiN factS 21
 and on to a specific area of the cerebral
cortex, which makes us conscious of the
perception of taste.
Airborne odor molecules, called
odorants, are detected by specialized
sensory neurons located in a small patch
of mucus membrane lining the roof of the
nose. Axons of these sensory cells pass
through perforations in the overlying bone
and enter two elongated olfactory bulbs lying
against the underside of the frontal lobe of
the brain.
Odorants stimulate receptor proteins
found on hairlike cilia at the tips of the
sensory cells, a process that initiates a
neural response. An odorant acts on
more than one receptor, but does so to
varying degrees. Similarly, a single receptor
interacts with more than one different
odorant, though also to varying degrees.
Therefore, each odorant has its own pattern
Taste and smell are separate senses with their own receptor organs, yet they are intimately entwined.
of activity, which is set up in the sensory
Tastants, chemicals in foods, are detected by taste buds, which consist of special sensory cells. When neurons. This pattern of activity is then
stimulated, these cells send signals to specific areas of the brain, which make us conscious of the sent to the olfactory bulb, where other
perception of taste. Similarly, specialized cells in the nose pick up odorants, airborne odor molecules.
neurons are activated to form a spatial map
Odorants stimulate receptor proteins found on hairlike cilia at the tips of the sensory cells, a process that
initiates a neural response. ultimately, messages about taste and smell converge, allowing us to detect of the odor. Neural activity created by this
the flavors of food. stimulation passes to the primary olfactory
cortex at the back of the underside, or
can attest, food “tastes” different when the sense of smell is orbital, part of the frontal lobe. Olfactory
impaired. Actually, what is really being affected is the flavor of information then passes to adjacent parts of the orbital cortex,
the food, or the combination of taste and smell. That’s because where the combination of odor and taste information helps
only the taste, not the food odors, are being detected. Taste itself create the perception of flavor.
is focused on distinguishing chemicals that have a sweet, salty,
sour, bitter, or umami taste (umami is Japanese for “savory”). Touch and Pain
However, interactions between the senses of taste and smell Touch is the sense by which we determine the
enhance our perceptions of the foods we eat. characteristics of objects: size, shape, and texture. We do this
Tastants, chemicals in foods, are detected by taste buds, through touch receptors in the skin. In hairy skin areas, some
special structures embedded within small protuberances on the receptors consist of webs of sensory nerve cell endings wrapped
tongue called papillae. Other taste buds are found in the back of around the base of hairs. The nerve endings are remarkably
the mouth and on the palate. Every person has between 5,000 sensitive. They can be triggered by the slightest movement of
and 10,000 taste buds. Each taste bud consists of 50 to 100 the hairs.
specialized sensory cells, which are stimulated by tastants such Signals from touch receptors pass via sensory nerves to
as sugars, salts, or acids. When the sensory cells are stimulated, the spinal cord, where they synapse, or make contact with,
they cause signals to be transferred to the ends of nerve fibers, other nerve cells, which in turn send the information to
which send impulses along cranial nerves to taste regions in the the thalamus and sensory cortex. The transmission of this
brainstem. From here, the impulses are relayed to the thalamus information is highly topographic, meaning that the body

22 BraiN factS | sensing, thinking, and behaving Society for NeuroScieNce

Pain messages are picked up by receptors and transmitted to the spinal cord via small myelinated fibers and very small unmyelinated fibers. From the spinal cord,
the impulses are carried to the brainstem, thalamus, and cerebral cortex and ultimately perceived as pain. These messages can be suppressed by a system of
neurons that originates in the midbrain. This descending pathway sends messages to the spinal cord where it suppresses the transmission of tissue damage signals
to the higher brain centers.

Society for NeuroScieNce sensing, thinking, and behaving | BraiN factS 23

is represented in an orderly fashion at different levels of the
nervous system. Larger areas of the cortex are devoted to
sensations from the hands and lips; much smaller cortical
regions represent less sensitive parts of the body.
Different parts of the body vary in their sensitivity to tactile
and painful stimuli. These varying responses are based largely
on the number and distribution of receptors. For example, the
cornea is several hundred times more sensitive to painful stimuli
than are the soles of the feet. The fingertips are good at touch
discrimination, but the torso is not.
Neurologists measure sensitivity by determining the
patient’s two-point threshold, the distance between two points
on the skin necessary in order for the individual to distinguish
two distinct stimuli from just one. This method involves
touching the skin with calipers at two points. Not surprisingly,
acuity is greatest in the most densely nerve-packed areas of the
body. The threshold is lowest on the fingers and lips.
The sensory fibers that respond to stimuli that damage
tissue and can cause pain are called nociceptors. Different
nociceptor subsets produce molecules that are responsible for
the response to noxious (i.e., painful) thermal, mechanical,
or chemical stimulation. Interestingly, these same molecules
respond to plant-derived chemicals, such as capsaicin, garlic,
and wasabi, that can produce pain. Some nociceptors in the
skin respond to chemical stimuli that cause itch. Histamine
is an example of such a nociceptor, and it can be released in
response to certain bug bites or allergies.
Tissue injury also causes the release of numerous chemicals
at the site of damage and inflammation. Prostaglandins enhance
the sensitivity of receptors to tissue damage and ultimately
can induce more intense pain sensations. Prostaglandins also
contribute to the clinical condition of allodynia, in which
innocuous stimuli can produce pain, as when sunburned skin is
touched.
Persistent injury can lead to changes in the nervous system
that amplify and prolong the “pain” signal. The result is a
state of hypersensitivity in which pain persists and can even
be evoked by normally innocuous stimuli. Persistent pain is
in many respects a disease of the nervous system, not merely a
symptom of some other disease process.
Sending and Receiving Pain and Itch
Messages Pain and itch messages are transmitted to the
spinal cord via small, myelinated fibers and C fibers, very small,
unmyelinated fibers. The myelinated nerve fibers are very pain-
sensitive, and they probably evoke the sharp, fast pain that is
24 BraiN factS | sensing, thinking, and behaving
produced by, for example, a pinprick. C fiber-induced pain, by
contrast, is generally slower in onset, dull, and more diffuse.
In the ascending system, impulses are relayed from the
spinal cord to several brain structures, including the thalamus
and cerebral cortex. These structures are involved in the process
by which pain or itch messages become a conscious experience.
The experience of pain or itch is not just a function of the
magnitude of the injury or even the intensity of the impulse
activity generated. Other factors, such as the setting in which
the injury occurs (e.g., in childbirth or in a car accident), as well
as the emotional impact, also determine our overall response to
the experience.
Pain messages can be suppressed by systems of neurons
that originate within the gray matter in the brainstem. These
descending systems suppress the transmission of pain signals
from the dorsal horn of the spinal cord to higher brain centers.
Some of these descending systems use naturally occurring
chemicals, the endogenous opioids, or endorphins, which are
functionally similar to morphine. Recent findings indicating
that endorphins act at multiple opioid receptors in the brain
and spinal cord have had important implications for pain
therapy. For example, scientists began studying how to deliver
opioids into the spine after discovering a dense distribution
of opioid receptors in the spinal cord horn. After a technique
for delivering opioids into the spine was used successfully in
animals, such treatments were begun in humans; the technique
is now common in treating pain after surgery.
Modern imaging tools are used to help scientists
better understand what happens in the brain when pain is
experienced. One finding is that no single area in the brain
generates pain; rather, emotional and sensory components
together constitute a mosaic of activity leading to pain.
Interestingly, when people are hypnotized so that a painful
stimulus is not experienced as unpleasant, activity in only some
areas of the brain is suppressed, showing that the stimulus is still
experienced. It just doesn’t hurt anymore. As such techniques
for brain study improve, it should be possible to monitor the
changes in the brain that occur in people with persistent pain
more effectively and to better evaluate the different painkilling
drugs being developed.
Processing information from the sensory systems is only
one of many functions of the brain. Such information is often
the first step in other brain activities, including learning and
retaining knowledge. The next chapter discusses what we
know about these key functions as well as where gaps in our
understanding remain.
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chaPter
haPter 4:
learNiNg, MeMory, aNd laNguage
organizing, consolidating, and retrieving memory, it
is the cortical areas that are important for long-term
in this chapter storage of detailed knowledge about facts and events and
how this knowledge is used in everyday situations.
n Learning and Memory
Different Facets of Memory Our ability to learn
n Language and consciously remember everyday facts and events is called
declarative memory. Studies using functional brain imaging
have identified a large network of areas in the cerebral
cortex that work together with the hippocampus to support
declarative memory. These cortical areas play a distinct
role in complex aspects of perception, movement, emotion,
Learning and Memory
and cognition, each of which contributes to the overall
A major breakthrough in understanding how the
experiences captured in declarative memories.
brain accomplishes learning and memory began with the
When we have new experiences, information initially
study of a person known by his initials, H.M. As a child,
enters working memory, a transient form of declarative
H.M. developed a severe, difficult-to-treat form of epilepsy.
memory. Working memory depends on the prefrontal
When traditional therapies didn’t help, H.M. underwent
an experimental surgical treatment — the removal of the
medial regions of his temporal lobes. The surgery worked in
that it greatly alleviated the seizures, but it left H.M. with
severe amnesia. He could remember recent events for only
a few minutes and was unable to form explicit memories of
new experiences. For example, after talking with him for a
while and then leaving the room, upon returning, it would
be clear that H.M. had no recollection of the exchange.
Despite his inability to remember new information,
H.M. remembered his childhood very well. From these
unexpected observations, researchers concluded that the
parts of H.M.’s medial temporal lobe that were removed,
including the hippocampus and parahippocampal region,
played critical roles in converting short-term memories of
experiences to long-term, permanent ones. Because H.M.
retained some memories of events that occurred long before
his surgery, it appeared that the medial temporal region was
not the site of permanent storage but instead played a role
in the organization and permanent storage of memories
elsewhere in the brain.
Since that time, scientists have learned that
the medial temporal region is closely connected to Different areas and systems of the brain are responsible for different kinds of
memory. The hippocampus, parahippocampal region, and areas of the cerebral
widespread areas of the cerebral cortex, including the
cortex (including the prefrontal cortex) work together to support declarative, or
regions responsible for thinking and language. Whereas cognitive, memory. Different forms of nondeclarative, or behavioral, memory are
the medial temporal region is important for forming, supported by the amygdala, striatum, and cerebellum.

Society for NeuroScieNce sensing, thinking, and behaving | BraiN factS 25

cortex as well as other cerebral cortical areas. Studies on
animals have shown that neurons in the prefrontal cortex
maintain relevant information during working memory and
can combine different kinds of sensory information when
required. In humans, the prefrontal cortex is highly activated
when people maintain and manipulate memories.
Distinct areas within the prefrontal cortex support
executive functions, such as selection, rehearsal, and
monitoring of information being retrieved from long-term
Memory involves a persistent
change in synapses, the
connections between neurons.
memory. To serve these functions, the prefrontal cortex also
interacts with a large network of posterior cortical areas that
encode, maintain, and retrieve specific types of information
— visual images, sounds, and words, for example — as well
as where important events occurred and much more.
Semantic memory is a form of declarative knowledge
that includes general facts and data. Although scientists are
just beginning to understand the nature and organization
of cortical areas involved in semantic memory, it appears
that different cortical networks are specialized for processing
particular kinds of information, such as faces, houses, tools,
actions, language, and many other categories of knowledge.
Studies using functional imaging of normal humans
have revealed zones within a large cortical expanse that
selectively process different categories of information, such
as animals, faces, or words.
Our memories of specific personal experiences
that occurred at a particular place and time are called
episodic memories. The medial temporal lobe areas are
generally believed to serve a critical role in the initial
processing and storage of these memories. Studies have
shown that different parts of the parahippocampal
26 BraiN factS | sensing, thinking, and behaving
region play distinct roles in processing “what,” “where,”
and “when” information about specific events. The
hippocampus links these elements of an episodic memory.
The linkages are then integrated back into the various
cortical areas responsible for each type of information.
The fact that H.M. and other people with amnesia show
deficits in some types of memories and not others indicates
that the brain has multiple memory systems supported
by distinct brain regions. Nondeclarative knowledge,
the knowledge of how to do something, often called
procedural memory, is expressed in skilled behavior and
learned habits and requires processing by the basal ganglia
and cerebellum. The cerebellum is specifically involved
in motor tasks that involve coordinated timing. The
amygdala appears to play an important role in the emotional
aspects of memory, attaching emotional significance to
otherwise neutral stimuli and events. The expression of
emotional memories also involves the hypothalamus and
the sympathetic nervous system, both of which support
emotional reactions and feelings. Thus, the brain appears
to process different types of memories in separate ways.
Storing Memories How exactly are memories
stored in brain cells? After years of study, much evidence
supports the idea that memory involves a persistent
change in synapses, the connections between neurons.
In animal studies, researchers found that such changes
occur in the short term through biochemical events that
affect the strength of the relevant synapses. Turning on
certain genes may lead to modifications within neurons
that change the strength and number of synapses,
stabilizing new memories. Researchers studying the
sea slug Aplysia californica, for example, can correlate
specific chemical and structural changes in relevant cells
with several simple forms of memory in the animal.
Another important model for the study of memory is the
phenomenon of long-term potentiation (LTP), a long-lasting
increase in the strength of a synaptic response following
stimulation. LTP occurs prominently in the hippocampus,
as well as in the cerebral cortex and other brain areas
involved in various forms of memory. LTP takes place as
a result of changes in the strength of synapses at contacts
involving N-methyl-d-aspartate (NMDA) receptors.
Subsequently, a series of molecular reactions plays a
vital role in stabilizing the changes in synaptic function
that occur in LTP. These molecular events begin with the
release of calcium ions into the synapse, activating the
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Researchers identified cellular mechanisms of memory by studying the sea slug Aplysia californica.
[Credit: Thomas J. Carew, PhD, New York university]
cyclic adenosine monophosphate (cAMP) molecule in
the postsynaptic neuron. This molecule then activates
several kinds of enzymes, some of which increase the
number of synaptic receptors, making the synapse more
sensitive to neurotransmitters. In addition, cAMP activates
another molecule, called cAMP-response element binding
protein (CREB). CREB operates within the nucleus of
the neuron to activate a series of genes, many of which
direct protein synthesis. Among the proteins produced are
neurotrophins, which result in growth of the synapse and
an increase in the neuron’s responsiveness to stimulation.
Many studies have shown that the molecular cascade
leading to protein synthesis is not essential to initial learning
or to maintaining short-term memory; however, this cascade
is essential for long-term memory. In addition, studies using
genetically modified mice have shown that alterations
in specific genes for NMDA receptors or CREB can
dramatically affect the capacity for LTP in particular brain
areas. What’s more, the same studies have shown that these
molecules are critical to memory.
The many kinds of studies of human and animal
memory have led scientists to conclude that no single
brain center stores memory. Instead, memory is most
likely stored in distributed collections of cortical
processing systems that are also involved in the
perception, processing, and analysis of the material being
learned. In short, each part of the brain most likely
contributes differently to permanent memory storage.
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Language
One of the most prominent human
abilities is language, a complex system
involving many components, including
sensory-motor functions and memory
systems. Although language is not fully
understood, scientists have learned a
great deal about this brain function from
studies of patients who have lost speech
and language abilities as a result of a
stroke. Genetic analyses of developmental
disorders of speech and language, as well
as brain imaging studies of normal people,
also have added to our knowledge.
It has long been known that damage
to different regions within the left
hemisphere produces different kinds of
language disorders, or aphasias. Damage to the left frontal
lobe can produce nonfluent aphasias, such as Broca’s
aphasia, a syndrome in which speech production abilities are
impaired. Speech output is slow and halting, requires effort,
and often lacks complexity in word or sentence structure.
Although speaking is impaired, nonfluent aphasics still
comprehend heard speech, although structurally complex
sentences may be poorly understood.
Damage to the left temporal lobe can produce
fluent aphasia, such as Wernicke’s aphasia, in which
comprehension of heard speech is impaired. Speech output,
although of normal fluency and speed, is often riddled
with errors in sound and word selection and tends to be
unintelligible gibberish.
Damage to the superior temporal lobes in both
hemispheres can produce word deafness, a profound inability
to comprehend auditory speech on any level. Whereas
Wernicke’s aphasics can often comprehend bits and pieces of
a spoken utterance, as well as isolated words, patients with
word deafness are functionally deaf for speech, lacking the
ability to comprehend even single words, despite being able
to hear sound and even identify the emotional quality of
speech or the gender of the speaker.
Research on aphasia has led to several conclusions
regarding the neural basis of language. Researchers
once believed that all aspects of language ability were
governed only by the left hemisphere. Recognition of
speech sounds and words, however, involves both left
sensing, thinking, and behaving | BraiN factS 27
and right temporal lobes. In contrast, speech production
is a strongly left-dominant function that relies on frontal
lobe areas but also involves posterior brain regions in
the left temporal lobe. These appear to be important
for accessing appropriate words and speech sounds.
Although the understanding of how language is both
produced and understood by the brain is far from complete,
several techniques, including genetic studies and imaging
methods, have increasingly been put to use. Through
the use of these tools, we can expect to gain important
insights into this critical aspect of brain function.
under intense investigation as a site that may participate
in some aspect of sentence-level comprehension.
Recent work has also identified a sensory-motor
circuit for speech in the left posterior temporal lobe, which
is thought to help the systems for speech recognition
and speech production communicate with each other.
This circuit is involved in speech development and
is thought to support verbal short-term memory.
Equally important is the brain’s role in movement.
For example, part of language is using the muscles
of the mouth and jaw correctly to produce sounds.
Throughout the body, muscles allow us to move in many
complex ways. The next chapter discusses the intricate
interplay between the brain and muscles in our body.

Scientists have learned a

great deal about language
by studying patients
who have lost speech
and language abilities.

During the last decade, novel insights have emerged

through molecular genetic studies of inherited disorders that
impede the development of fluent speech and language.
For example, rare mutations of a gene called FOXP2
impede learning to make sequences of mouth and jaw
movements that are involved in speech, accompanied by
difficulties that affect both spoken and written language.
The FOXP2 gene codes for a special type of protein that
switches other genes on and off in particular parts of the
brain. Changes in the sequence of this gene may have been
important in human evolution. Researchers are studying
the differences in this gene between humans and animals
to learn more about the development of language.
Functional imaging methods, too, have identified
new structures involved in language. Systems involved
in accessing the meaning of words appear to be located
(in part) in the middle and inferior portions of the
temporal lobe. In addition, the anterior temporal lobe is

28 BraiN factS | sensing, thinking, and behaving Society for NeuroScieNce

chaPter 5:
haPter
MoveMeNt
in this chapter
n Involuntary Movements
n More Complex Movements
From the stands at sports events, we marvel at the
perfectly placed serves of professional tennis players
and the lightning-fast double plays executed by big
league baseball infielders. But in fact, each of us in
our daily activities performs a host of complex, skilled
movements — such as walking upright, speaking, and
writing — that are just as remarkable. What’s more,
movement also reflects our mood and state of mind. For
example, posture and patterns of movement can indicate
whether we are happy or sad. Facial expressions such
as a smile and a frown have a universal meaning.
These and all of our actions are made possible
by a finely tuned and highly complex central nervous
system, which controls the actions of hundreds of
muscles. Through new experiences — and the formation
of new neural connections — the nervous system
can adapt to changing movement requirements to
accomplish these everyday marvels. With practice, these
movements can be performed even more skillfully.
To understand how the nervous system performs such
feats, we have to start with the muscles, the body parts
that produce movement under the control of the brain and
spinal cord. Most muscles attach to points on the skeleton
and cross one or more joints. The close relationship of
these muscles to the skeleton gives them their name —
skeletal muscles. Activation of a given muscle can open or
close the joints that it spans, depending on whether it is a
joint flexor (closer) or an extensor (opener). Flexors and
extensors work in opposition to each other, causing the
contraction of some muscles and the lengthening of others.
For example, bending the elbow involves contraction of
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the biceps and lengthening of the triceps. Muscles that
move a joint in an intended direction are called agonists,
and those that oppose this direction of movement are
antagonists. Skilled movements at high speed are started
by agonists and stopped by antagonists, thus ensuring that
the joint or limb is returned to the desired position.
Each skeletal muscle is made up of thousands of
individual muscle fibers, and each muscle fiber is controlled
by one alpha motor neuron in either the brain or the
spinal cord. Furthermore, each single alpha motor neuron
controls many muscle fibers (ranging from a few to 100
or more); an alpha motor neuron and all the muscle
fibers it contains form a functional unit referred to as a
motor unit. Motor units are the critical link between the
brain and muscles. If the motor neurons die, which can
happen in certain diseases, such as amyotrophic lateral
sclerosis (ALS), a person is no longer able to move.
Some muscles act on soft tissue, such as the
muscles that move the eyes and tongue and those that
control facial expressions. These muscles also are under
control of the central nervous system. They operate in
much the same way as those that attach to bone.
Involuntary Movements
Perhaps the simplest and most fundamental movements
are reflexes. These are relatively fixed, automatic muscle
responses to particular stimuli, such as the slight extension of
the leg when a physician taps the knee with a small rubber
hammer. All reflexes involve the activation of small sensory
receptors in the skin, the joints, or even in the muscles
themselves. For example, the reflexive knee movement is
produced by a slight stretch of the knee extensor muscles
when the physician taps the muscle tendon at the knee.
This slight muscle stretch is “sensed” by receptors in the
muscle called muscle spindles. Innervated by sensory
fibers, the spindles send information to the spinal cord
and brain about the length and speed of the shortening
or lengthening of a muscle. This information is used to
control both voluntary and involuntary movements. A
sudden muscle stretch sends a barrage of impulses into
the spinal cord along the muscle spindle sensory fibers. In
turn, these fibers activate motor neurons in the stretched
muscle, causing a contraction called the stretch reflex. The
same sensory stimulus causes inactivation, or inhibition,
of the motor neurons of the antagonist muscles through
connecting neurons, called inhibitory interneurons,
sensing, thinking, and behaving | BraiN factS 29
within the spinal cord. Thus, even the simplest of
reflexes involves a coordination of activity across motor
neurons that control agonist and antagonist muscles.
The brain can control not only the actions of motor
neurons and muscles but even the nature of the feedback
received as movements occur. For example, the sensitivity
of the muscle spindle organs is monitored by the brain
through a separate set of gamma motor neurons that
control the specialized muscle fibers and allow the brain to
fine-tune the system for different movement tasks. Other
specialized sense organs in muscle tendons — the Golgi
tendon organs — detect the force applied by a contracting
30 BraiN factS | sensing, thinking, and behaving
muscle, allowing the brain to sense and control the muscular
force exerted during movement. These complex feedback
systems are coordinated and organized to respond differently
for tasks that require precise control of position, such as
holding a full teacup, than they do for those requiring
rapid, strong movement, such as throwing a ball.
Another useful reflex is the flexion withdrawal
that occurs when the bare foot encounters a sharp
object. The leg is immediately lifted from the source of
potential injury (flexion), but the opposite leg responds
with increased extension so that we can maintain our
balance. The latter event is called the crossed extension
The stretch reflex (top) occurs when a doctor taps
a muscle tendon to test your reflexes. This sends
a barrage of impulses into the spinal cord along
muscle spindle sensory fibers, activating motor
neurons to the stretched muscle. This series of
events cause a contraction, completing the stretch
reflex. Flexion withdrawal (bottom) occurs when
your bare foot encounters a sharp object. Your
leg is immediately lifted (flexion) from the source
of potential injury, but the opposite leg responds
with increased extension so that you can maintain
your balance. The latter event is called the crossed
extension reflex.
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reflex. These responses occur very rapidly and without
your attention because they are built into systems of
neurons that are located within the spinal cord itself.
More Complex Movements
Networks of spinal neurons also participate in
controlling the alternating action of the legs during normal
walking, maintaining posture, and, to a large degree, in all
movements. In fact, the basic patterns of muscle activation
that produce coordinated walking can be generated not
only in four-footed animals, but also in humans, within the
spinal cord itself. These spinal mechanisms, which evolved
in primitive vertebrates, are being studied to determine the
degree to which spinal circuitry can be used to recover basic
postural and locomotor function after severe paralysis.
The most complex movements that we perform,
including voluntary ones that require conscious planning,
involve control of these basic spinal mechanisms by
the brain. Scientists are only beginning to understand
the complex interactions that take place among
different brain regions during voluntary movements,
mostly through careful experiments on animals.
One important brain area that is responsible for
voluntary movement is the motor cortex, which exerts
powerful control over the spinal cord, in part through
direct control of its alpha motor neurons. Some neurons
in the motor cortex appear to specify the coordinated
action of many muscles to produce the organized
movement of a limb to a particular point in space.
Others appear to control only two or three functionally
related muscles, such as those of the hand or arm, that
are important for finely tuned, skilled movement.
In addition to the motor cortex, movement control
involves the interaction of many other brain regions,
including the basal ganglia, thalamus, cerebellum, and
a large number of neuron groups located within the
midbrain and brainstem — regions that send axons
to the spinal cord. Scientists know that the basal
ganglia and thalamus have widespread connections
with motor and sensory areas of the cerebral cortex.
Dysfunction of the basal ganglia can lead to serious
movement disorders. The neurotransmitter dopamine,
which helps control movement, is supplied to the
basal ganglia by the axons of neurons located in the
substantia nigra, a midbrain cell group. People with
Parkinson’s disease experience degeneration of the
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nigral neurons. The supply of dopamine is depleted,
resulting in the hallmark symptoms of Parkinson’s —
tremor, rigidity, and akinesia, the inability to move.
Another brain region that is crucial for coordinating
and adjusting skilled movement is the cerebellum.
A disturbance of cerebellar function leads to poor
coordination of muscle control, disorders of balance
and reaching, and even difficulties in speech, one of
the most intricate forms of movement control.
The cerebellum helps us adjust
motor output to deal
with changing conditions.
The cerebellum receives direct information from all
the sensory receptors in the head and the limbs and from
most areas of the cerebral cortex. The cerebellum apparently
acts to integrate all this information to ensure smooth
coordination of muscle action, enabling us to perform
skilled movements more or less automatically. Considerable
evidence indicates that the cerebellum helps us adjust motor
output to deal with changing conditions, such as growth,
disability, changes in weight, and aging. It tunes motor
output to be appropriate to the specific requirements of
each new task: Our ability to adjust when picking up a cup
of coffee that is empty or full depends on the cerebellum.
Evidence suggests that as we learn to walk, speak, or play
a musical instrument, the necessary, detailed control
information is stored within the cerebellum, where it can
be called upon by commands from the cerebral cortex.
Just as the brain controls movement, it also is
responsible for one of the body’s most important functions
— sleep. As explained in Chapter 6, the brain switches back
and forth between different stages of sleep all night long.
sensing, thinking, and behaving | BraiN factS 31
chaPter 6:
haPter
SleeP
in this chapter
n Brain Activity during Sleep
n Sleep Disorders
n How Is Sleep Regulated?
n The Sleep-Wakefulness Cycle
We spend nearly one-third of our lives asleep. Sleep is
crucial for concentration, memory, coordination, and even
emotional health. Without enough sleep, people have trouble
focusing and responding quickly when they need to, such as
when they’re behind the wheel of a car. In fact, sleep loss can
have as great an effect on performance as drinking alcohol.
And growing evidence suggests that a lack of sleep increases
the risk of a variety of health problems, including diabetes,
cardiovascular disease and heart attacks, stroke, depression, high
blood pressure, obesity, and infections.
Although much research has been done on sleep, it
remains one of the great mysteries of modern neuroscience.
Over the past few years, however, researchers have made
tremendous headway in understanding some of the brain
circuitry that controls wake-sleep states.
Scientists now recognize that sleep consists of several
different stages. What’s more, the choreography of a night’s
sleep involves the interplay of these stages, a process that
depends on a complex switching mechanism between sleep-
wake states. Sleep stages are accompanied by daily rhythms in
hormones, body temperature, and other functions.
There are pressing reasons why understanding the
mechanisms behind sleep is so important. Sleep disorders are
among the nation’s most common health problems, affecting
up to 70 million people, most of whom are undiagnosed and
untreated. These disorders are one of the least recognized
sources of disease, disability, and even death, costing an
32 BraiN factS | sensing, thinking, and behaving
estimated $15.9 billion annually. Research holds promise for
devising new treatments to allow millions of people to get a
good night’s sleep.
Brain Activity During Sleep
Although sleep appears to be a passive and restful time,
it actually involves a highly active and well-scripted interplay
of brain circuits, resulting in sleep’s various stages. These
stages were discovered in the 1950s through experiments
using electroencephalography (EEG) to examine human brain
waves. Researchers also measured movements of the eyes and
the limbs.
The results of these experiments were telling. Researchers
found that each night, over the course of the first hour or so
of sleep, the brain progresses through a series of stages during
which brain waves slow down. This period of slow wave sleep is
accompanied by relaxation of the muscles and the eyes. Heart
rate, blood pressure, and body temperature all fall. If awakened
during this time, most people recall only fragmented thoughts,
not active dreams.
Over the next half hour or so, brain activity alters
drastically, from deep slow wave sleep to rapid eye movement
(REM) sleep, characterized by neocortical EEG waves similar to
those observed during waking. Paradoxically, the fast, waking-
like EEG activity is accompanied by atonia, or paralysis of the
body’s muscles. Only the muscles that allow breathing and
control eye movements remain active. During REM sleep,
active dreaming takes place. Heart rate, blood pressure, and
body temperature become much more variable. Men often have
erections during this stage. The first REM period usually lasts 10
to 15 minutes.
During the night, these cycles of slow wave and REM sleep
alternate, with the slow wave sleep becoming less deep and the
REM periods more prolonged until waking occurs. Over the
course of a lifetime, the pattern of sleep cycles changes. Infants
sleep up to 18 hours per day, and they spend much more time
in deep slow wave sleep. As children mature, they spend less
time asleep and less time in deep slow wave sleep. Older adults
may sleep only six to seven hours per night. What’s more, adults
often complain of early waking that they cannot avoid and
spend very little time in slow wave sleep.
Sleep Disorders
The most common sleep disorder, and the one most
people are familiar with, is insomnia. Some insomniacs
have difficulty falling asleep initially, but others fall asleep
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In eeG, electrodes placed around the head record electrical activity of the
human brain in response to a variety of stimuli and activities — even sleep.
and then awaken partway through the night and cannot fall
asleep again. Although a variety of short-acting sedatives
and sedating antidepressant drugs are available to help, none
produces a truly natural and restful sleep state because they
tend to suppress the deeper stages of slow wave sleep. They also
are not effective in helping people stay asleep.
Many of the most common disorders, listed below, disrupt
sleep and result in inadequate amounts of sleep, particularly of
the deeper stages.
• Excessive daytime sleepiness, which has well and may even enter a dreaming state while still
many causes.
• Obstructive sleep apnea occurs as sleep deepens and
the airway muscles in the throat relax to the point
of collapse, closing the airway. The individual has
difficulty breathing and wakes up without entering
the deeper stages of slow wave sleep. This condition
can cause high blood pressure and may increase the
risk of heart attack. Increased daytime sleepiness that
results from sleep apnea can lead to an increased risk
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of daytime accidents, especially automobile accidents.
Treatment may include a variety of strategies to reduce
airway collapse during sleep. Whereas simple things
like losing weight, avoiding alcohol and sedating drugs
prior to sleep, and avoiding sleeping on one’s back
can sometimes help, most people with sleep apnea
require devices that induce continuous positive airway
pressure to keep the airway open. One such device
is a small mask that fits over the nose to provide an
airstream under pressure during sleep. In some cases,
surgery is needed to correct the airway anatomy.
• Periodic limb movements of sleep are intermittent
jerks of the legs or arms that occur as the individual
enters slow wave sleep. These movements can cause
arousal from sleep. A related disorder, called REM
behavior disorder, occurs when muscles fail to become
paralyzed during REM sleep, As a result, people
literally act out their dreams by getting up and moving
around. Needless to say, this disorder can be very
disruptive to a normal night’s sleep. Both disorders are
more common in people with Parkinson’s disease, and
both can be treated with drugs for Parkinson’s or with
a benzodiazepine called clonazepam.
• Narcolepsy is a relatively uncommon condition
— only one case per 3,000 people — in which the
switching mechanisms controlling the transitions
into sleep, particularly REM sleep, do not work
properly. This problem is due to the loss of nerve
cells in the lateral hypothalamus that contain the
neurotransmitter orexin (also known as hypocretin).
People with narcolepsy have sleep attacks during
the day, in which they suddenly fall asleep. This is
socially disruptive, as well as dangerous; for example,
if a sleep attack strikes while someone with narcolepsy
is driving, it could result in an accident. People with
narcolepsy tend to enter REM sleep very quickly as
partially awake, a condition known as hypnagogic
hallucination. They also have attacks during which
they lose muscle tone — a state similar to what occurs
during REM sleep but instead happens while they are
awake. These attacks of paralysis, known as cataplexy,
can be triggered by emotional experiences, even by
hearing a funny joke.
Recently, studies into the mechanism of narcolepsy have
given researchers important insights into the processes that
sensing, thinking, and behaving | BraiN factS 33
This chart shows the brain waves of a young adult recorded by an electroencephalogram (eeG) during a night’s sleep. As the adult passes into deeper
stages of sleep, the brain waves slow down and become larger. Throughout the night, the individual goes through these stages multiple times, with brief
periods of ReM sleep, during which the eeG is similar to wakefulness.
control these mysterious transitions between waking, slow
wave sleep, and REM sleep states.
how Is Sleep Regulated?
What is the difference between sleep and wakefulness?
Much of it depends on which brain systems are activated.
Wakefulness is maintained by several brain systems, each
regulating different aspects of this state. Many of the systems
are located in the upper brainstem, where nerve cells using the
neurotransmitters acetylcholine, norepinephrine, serotonin,
and glutamate connect with the forebrain. Nerve cells
containing orexin, in the hypothalamus, are also important
in wakefulness — and, as mentioned above, their loss
causes narcolepsy. Hypothalamic nerve cells containing the
neurotransmitter histamine play a key role as well. Activation
of the thalamus and the basal forebrain by acetylcholine is
particularly important in maintaining activity in the cerebral
cortex and consciousness. This level of alertness is reflected in
an activated, low-voltage EEG.
During non-REM sleep, these arousing systems become
much less active, and the transmission of information from
the senses through the thalamus is curtailed. Consciousness
lessens, and wakefulness gives way to the slow wave pattern
typical of the first stage of sleep. During this state, there is
active suppression of arousal systems by a group of nerve cells
in the hypothalamus, called the ventrolateral preoptic (VLPO)
nucleus. The cells in the VLPO contain the inhibitory
34 BraiN factS | sensing, thinking, and behaving
neurotransmitters galanin and GABA. Damage to the VLPO
nucleus produces irreversible insomnia.
The state of REM sleep is characterized by an internally
activated brain and an activated EEG — but with external
input suppressed. Internal activation during REM comes from
a cyclically active REM sleep generator made up of neurons in
the brainstem. Signals from these neurons cause the forebrain
to become excited and lead to the rapid eye movements and
muscle suppression — hallmark signs of this state. In the
absence of external input, forebrain excitation from internal
sources is the driving force behind the vivid dreams experienced
during REM sleep. Interestingly, our motor cortex nerve cells
fire as rapidly during REM sleep as they do during waking
movement, a fact that explains why movement can coincide
with dreams. The periodic recurrence of REM sleep about
every 90 minutes during sleep is thought to be caused by the
on-off switching of REM-generating neurons, which produce
acetylcholine and glutamate, and REM-suppressive neurons,
which produce norepinephrine, serotonin, and GABA.
The Sleep-Wakefulness Cycle
Why do we get sleepy? There are two main determining
factors: the circadian system (time of day or night) and how long
we have been awake. The circadian timing system is regulated
by the suprachiasmatic nucleus, a small group of nerve cells
in the hypothalamus that acts as a master clock. These cells
express clock proteins, which go through a biochemical cycle
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Wakefulness is maintained by activity in two systems of neurons, shown
in green and red. The green pathway shows neurons that make the
neurotransmitter acetylcholine in the brainstem, while the red pathway is
in the forebrain. The brainstem arousal center supplies the acetylcholine
for the thalamus and brainstem, and the forebrain center supplies the
cerebral cortex. Activation in these centers alone can create rapid eye
movement sleep. Activation of other neurons that make the neurotransmitters
norepinephrine, serotonin, and histamine, shown in the blue pathways, is
needed for waking.
of about 24 hours, setting the pace for daily cycles of activity,
sleep, hormone release, and other bodily functions. Researchers
first identified these proteins and determined their important
roles in sleep by studying the fruit fly Drosophila melanogaster.
The suprachiasmatic nucleus also receives input directly from
the retina, and the clock can be reset by light so that it remains
linked to the outside world’s day-night cycle. In addition, the
suprachiasmatic nucleus provides signals to an adjacent brain
area, called the subparaventricular nucleus, which in turn
contacts the dorsomedial nucleus of the hypothalamus. The
dorsomedial nucleus then contacts the ventrolateral preoptic
nucleus and the orexin neurons in the lateral hypothalamus. It is
these neurons that directly regulate sleep and arousal.
Orexin provides an excitatory signal to the arousal
system, particularly to the norepinephrine neurons. Indeed,
recent work using selective stimulation of orexin neurons
by artificially inserted receptors sensitive to fiberoptic light
pulses — a process referred to as optogenetic stimulation
— produces arousal. This arousal is mediated by orexin
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activation of norepinephrine neurons in the locus coeruleus.
Orexin activation plays a critical role in preventing abnormal
transitions into REM sleep during the day, as occurs in
narcolepsy. In experiments with mice, in which the gene for
the neurotransmitter orexin was experimentally removed, the
animals became narcoleptic. In humans with narcolepsy, the
orexin levels in the brain and spinal fluid are abnormally low.
The second system regulating sleepiness is the homeostatic
system, which responds to progressively longer wake periods
by increasing the urge to sleep. The subjective sense of
the increasing need to sleep coinciding with increasing
wakefulness suggests that there might be a brain physiological
parallel; that is, the longer a person is awake, the greater
the likelihood of an increase in sleep-inducing factor(s).
Evidence now suggests that one important sleep factor is
the inhibitory neurochemical adenosine. With prolonged
wakefulness, increasing levels of adenosine are evident in the
brain, initially in the basal forebrain and then throughout
the cortex. The increased levels of adenosine serve the
purpose of slowing down cellular activity and diminishing
arousal. Adenosine levels then decrease during sleep.
These studies of adenosine prompted examination of the
compound adenosine triphosphate (ATP), the cellular energy
source that powers nerve cells in the brain. Brain adenosine
may be produced by ATP breakdown in the course of the high
brain activity that takes place during wakefulness. Since nerve
cell activity decreases and adenosine levels decline in non-
REM sleep, the logical assumption is that ATP increases during
sleep. Indeed, studies in animals found that brain ATP levels
soared during the initial hours of non-REM sleep. Because
ATP is needed to produce adenosine, which is essential for
wakefulness, it makes sense that ATP is produced during sleep.
This finding also supports the commonly held notion that sleep
is necessary for providing restorative energy.
Part 2 of this book has focused on how the brain controls
important functions, ranging from sensory perception to
learning to movement to sleep. Part 3 emphasizes how the
brain changes over time as we grow and age. The next chapter
discusses how the brain controls our reaction to danger,
manifested as the “fight or flight” response. In the hectic world
in which we live, this response is often experienced as stress.
Although stress can set off a cascade of negative physiological
reactions, it also can serve as a motivation to take action.
Therefore, it is important to understand the difference between
good and bad stress.
sensing, thinking, and behaving | BraiN factS 35
chaPter 7:
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StreSS
in this chapter
n Immediate Response
n Chronic Stress
The ability to react quickly in response to threatening
events has been with us since the time of our earliest
ancestors. In response to impending danger, muscles are
primed, attention is focused, and nerves are readied for
action — the “fight or flight” response. In today’s complex
and fast-paced world, stressors are more consistently
psychological or socially based, and we face them with less
reprieve.
Stress is difficult to define because its effects vary with
each individual. Specialists now define stress as any external
stimulus that threatens homeostasis — the normal equilibrium
of body function. Stress also can be induced by the belief that
homeostasis might soon be disrupted. Lack or loss of control
is a particularly important feature of severe psychological
stress, which can have physiological consequences. Most
harmful are the chronic aspects of stress.
During the past several decades, however, researchers
have found that stress can help the body, too. When
confronted with a crucial physical challenge, properly
controlled stress responses can provide the extra
strength and energy needed to cope. Moreover, the acute
physiological response to stress protects the body and
brain and helps re-establish or maintain homeostasis. But
stress that continues for prolonged periods can repeatedly
elevate physiological stress responses or fail to shut them
off when they are not needed. When this occurs, the same
physiological mechanisms that are helpful can upset the
body’s biochemical balance and accelerate disease.
Scientists also believe that the individual variation in
responding to stress is somewhat dependent on a person’s
perception of external events. This perception ultimately
36 BraiN factS | across the lifespan
shapes our internal physiological response. Thus, if we can
control our perception of mild to moderate stressors, it may
be possible to avoid some of their harmful consequences.
Immediate Response
A stressful situation activates three major
communication systems in the brain, all of which regulate
bodily functions. Scientists came to understand these
complex systems through experiments, primarily with rats,
mice, and nonhuman primates such as monkeys. Scientists
then verified the action of these systems in humans.
The first of these systems is the voluntary nervous
system, which sends messages to muscles so that we may
respond to sensory information. For example, the sight of a
shark in the water may prompt people to run from the beach
as quickly as possible.
The second communication system is the autonomic
nervous system, made up of the sympathetic and the
parasympathetic branches. Each of these systems has a
specific task in responding to stress. The sympathetic
branch causes arteries supplying blood to the muscles
to relax in order to deliver more blood, allowing greater
capacity to act. At the same time, blood flow to the
skin, kidneys, and digestive tract is reduced. The stress
hormone epinephrine, also known as adrenaline, is
quickly released into the bloodstream. The role of
epinephrine is to put the body into a general state of
arousal and enable it to cope with the challenge.
In contrast, the parasympathetic branch helps regulate
bodily functions and soothe the body once the stressor has
passed, preventing the body from remaining in a state of
mobilization too long. If these functions are left mobilized
and unchecked, disease can develop. Some actions of the
calming branch appear to reduce the harmful effects of the
emergency branch’s response to stress.
The brain’s third major communication process is the
neuroendocrine system, which also maintains the body’s
internal functioning. Various stress hormones travel through
the blood and stimulate the release of other hormones,
which affect bodily processes such as metabolic rate and
sexual function.
The Role of Glucocorticoids In response to signals
from a brain region called the hypothalamus, the adrenal
glands secrete glucocorticoids, hormones that produce an
array of effects in response to stress. These include mobilizing
energy into the bloodstream from storage sites in the body,
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increasing cardiovascular tone and delaying long-term
processes in the body that are not essential during a crisis,
such as feeding, digestion, growth, and reproduction. Some
of the actions of glucocorticoids help mediate the stress
response, while other, slower actions counteract the primary
response to stress and help re-establish homeostasis. Over
the short run, epinephrine mobilizes energy and delivers it to
muscles for the body’s response. The glucocorticoid cortisol,
however, promotes energy replenishment and efficient
cardiovascular function.
A stressful situation activates
three major communication
systems in the brain, all of which
regulate bodily functions.
Glucocorticoids also affect food intake during the
sleep-wake cycle. Cortisol levels, which vary naturally over a
24-hour period, peak in the body in the early-morning hours
just before waking. This hormone helps produce a wake-up
signal, turning on appetite and physical activity. This effect
of glucocorticoids may help explain disorders such as jet lag,
which results when the light-dark cycle is altered by travel
over long distances, causing the body’s biological clock to
reset itself more slowly. Until that clock is reset, cortisol
secretion and hunger, as well as sleepiness and wakefulness,
occur at inappropriate times of day in the new location.
Acute stress also enhances the memory of earlier
threatening situations and events, increases the activity
of the immune system, and helps protect the body from
pathogens. Cortisol and epinephrine facilitate the movement
of immune cells from the bloodstream and storage organs,
such as the spleen, into tissue where they are needed to
defend against infection.
Glucocorticoids do more than help the body respond
to stress. They also help the body respond to environmental
change. In these two roles, glucocorticoids are in fact
essential for survival.
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Chronic Stress
What do standing frustrated in a supermarket checkout
line or sitting in a traffic jam have in common with fleeing
predators, as was done in the early days of human beings?
Clearly, these activities are very different, yet they provoke
the same responses in the body— the release of hormones
(glucocorticoids and epinephrine) to improve memory, boost
immune function, enhance muscular activity, and restore
physiological balance. Over long periods of time, as these
hormones continue to be released, the consequences can be
negative: memory is impaired, immune function is suppressed,
and energy is stored as fat.
Overexposure to glucocorticoids leads to weakened
muscles. Elevated glucocorticoids and epinephrine
contribute to hypertension (high blood pressure),
atherosclerosis (hardening of the arteries), and abdominal
obesity. Epinephrine also increases the release and activity
of body chemicals that cause inflammation, adding to the
body’s chronic stress burden. This continual chemical
activity can lead to arthritis and accelerated aging of the
brain.
These findings have been verified in animal
experiments. Aging rats show impaired neuron function
in the hippocampus — an area of the brain important
for learning, memory, and emotion — as a result of
increased glucocorticoid secretion throughout their lives.
Overexposure to glucocorticoids also increases the number
of neurons damaged by stroke. Moreover, prolonged
glucocorticoid exposure before or immediately after birth
causes a decrease in the normal number of brain neurons and
smaller brain size.
What’s more, scientists have identified a variety of
stress-related disorders, including high blood pressure,
clogged arteries, impotency and loss of sex drive in males,
irregular menstrual cycles in females, colitis, and adult-
onset diabetes. Stress also can contribute to sleep loss when
people get caught in a vicious cycle: elevated glucocorticoids
delaying the onset of sleep, and sleep deprivation raising
glucocorticoid levels.
Different Body Systems Affected Many different
body systems are affected by stress. The immune system
receives messages from the nervous system, and it is also
sensitive to many of the body’s circulating hormones,
including stress hormones. Although short-term elevations
of stress hormones facilitate immune function and can be
across the lifespan | BraiN factS 37
protective against disease pathogens, sustained exposure to
glucocorticoids suppresses the immune system, often with
negative consequences.
That said, however, glucocorticoid-induced
immunosuppression also has its benefits. Normally,
glucocorticoids rein in the immune system boost brought
on by stress. Without this brake, there is an increased
chance of autoimmune disorders caused by an overactive
immune system. Such autoimmune disorders occur when
the body’s immune defenses turn against itself. Then the
individual must be treated with synthetic, man-made forms
of glucocorticoids (e.g., hydrocortisone and prednisone) in
order to keep the immune system in check.
One important determinant of resistance or
susceptibility to disease may be a person’s sense of
control, as opposed to a perceived lack of control or
helplessness. This psychological factor may help explain
the large individual differences in the physical response
38 BraiN factS | across the lifespan
to stress. Scientists are actively pursuing this line of
research. They are trying to identify how perception
of control can alter physiological responses to stress,
including the regulation of immune function.
The cardiovascular system also receives messages from
the autonomic nervous system, and stressful experiences
have immediate and direct effects on heart rate and blood
pressure. In the short term, these changes help facilitate a
quick response to stressors. But when stressors are chronic
and psychological, the effect can be harmful and result
in accelerated atherosclerosis and increased risk for heart
attack. Research supports the idea that people holding jobs
that carry high demands and low control, such as telephone
operators, waiters, and cashiers, have higher rates of heart
disease than people who can dictate the pace and style of
their working lives.
In addition, personality or behavioral type affects an
individual’s susceptibility to heart attack. People at greatest
risk are hostile and irritated by trivial things. One study
illustrates this point. Researchers studied two groups of
men categorized as having high or low hostility. Both were
subjected to harassment. Scientists found that harassed
men with high hostility scores had larger increases in levels
of stress hormones, muscle blood flow, and blood pressure.
Thus, for those people with personality traits that include
high levels of hostility, learning to reduce or avoid anger
could be important to avoid cardiovascular damage.
Another way that the brain changes over time is by
growing older. Chapter 8 explores what we can expect during
the normal aging process.
When stress occurs, the sympathetic nervous system is triggered.
Norepinephrine is released by nerves, and epinephrine is released by
the adrenal glands. By activating receptors in blood vessels and other
structures, these substances ready the heart and working muscles for
action. Acetylcholine is released in the parasympathetic nervous system,
producing calming effects. The neuroendocrine system also maintains the
body’s normal internal functioning. Corticotrophin releasing hormone
(CRh) is released from the hypothalamus and travels to the pituitary gland,
where it triggers the release of adrenocorticotropic hormone (ACTh).
ACTh travels in the blood to the adrenal glands, where it stimulates the
release of cortisol.
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chaPter
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in this chapter
n Aging in Different Ways
n What We Know — and Don’t Know —
About Aging
Aging in Different Ways
Neuroscientists believe that the brain can remain
relatively healthy and full-functioning as it ages.
They have concluded that severe declines in memory,
intelligence, verbal fluency, and other tasks reflect
disease processes; they are not a part of normal aging.
Researchers are investigating both the normal and
abnormal changes that occur over time and their
effect on reasoning and other intellectual activities.
The effects of age on brain function are subtle and very
selective. They are not as severe as scientists once thought,
and they do not include widespread cell loss. The mistaken
belief that pronounced, progressive mental decline is an
inevitable part of aging persists for several reasons. Until
recently, scientists knew little about how the brain aged.
This lack of knowledge applied both to the biology of aging
itself as well as to its consequences for brain function.
Second, because we are living longer, we have a much
larger “sample” of people with normal age-related decline.
In 1900, for example, the average life expectancy was about
47 years. At that time, three million people, or 4 percent
of the population, were older than age 65, and they were
typically in ill health. By 2007, life expectancy reached
approximately 78 years, and today, more than 39 million
people, or almost 13 percent of the population, are older
than age 65.
That said, however, almost everyone gets a bit forgetful
in old age, particularly in forming memories of recent
events. For example, once most people reach their 70s, they
may find themselves forgetting names, phone numbers, and
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where the car is parked more frequently. In addition, people
might respond more slowly to conflicting information.
These behaviors are not signs of disease. Rather, they are
considered part of the normal aging process. There are,
however, a small number of individuals whose mental
functioning seems relatively unaffected by age. These people
do well throughout life and continue to do well even when
they are old, at least until shortly before death. In fact, the
wisdom and experience of older people often make up for
deficits in performance. The oldest known human, Jeanne
Calment, kept her wits throughout her 122-year life span.
Unfortunately, some individuals do develop dementia,
a progressive and severe impairment in mental function
that interferes with the activities of daily living. The term
dementia includes a number of different diseases, of which
Alzheimer’s disease is the most common. Other dementias
include cerebrovascular disease, Pick’s disease, and Lewy
body disease. Together, the dementias affect as many as 6.8
million people in the U.S, and at least 1.8 million of those
cases are severe.
What We Know — and Don’t Know —
About Aging
Our best insights into how the normal brain ages come
from long-term studies of the nervous system that began
decades ago. These are just now bearing results. Coupled
with these long-term studies, modern technological advances
now make it possible to explore the structure and function
of the living brain in more depth than ever before and to ask
questions about what actually happens in its aging cells.
We now know that the brain reaches its maximum
weight near age 20, and subtle changes in the brain’s
chemistry and structure begin at midlife for most people.
During a lifetime, the brain is at risk for losing some of its
neurons, but normal aging does not result in widespread
neuron loss. This distinguishes normal aging from the
neurodegenerative changes that occurs as part of the disease
process in Alzheimer’s or Parkinson’s disease or after a stroke.
Brain tissue can respond to damage or loss of neurons
in several ways. The remaining healthy neurons are able
to expand their dendrites and fine-tune their connections
with other neurons. If the cell body of the neuron remains
across the lifespan | BraiN factS 39
intact, a damaged brain neuron can readjust by inducing
changes in its axon and dendrites. Unlike damaged skin
or liver, however, a damaged brain cannot respond with a
robust generation of new neurons. Relatively small stem cell
populations remain in a healthy adult brain, but our current
knowledge suggests that they contribute to only a few of the
many different types of neurons found, and these neuron
types are found in only a few regions of the normal brain.
Compounding the problem is the fact that the number of
even these stem cells declines as part of the aging process.
Changes in Intellectual Capacity From the first
large studies monitoring the mental functioning of the same
group of healthy humans over many years, scientists have
uncovered unexpected results. They report declines in some
mental functions and improvements in others. In several
studies, the speed of carrying out certain tasks becomes
slower, but vocabulary improves. Other findings demonstrate
less severe declines in the type of intelligence relying on
learned or stored information compared with the type that
depends on the ability to deal with new information.
40 BraiN factS | across the lifespan
This research is supported by animal studies in which
scientists find that changes in mental function are subtle. For
example, in rodents and primates with only minor detectable
brain abnormalities, certain spatial tasks, such as navigating
to find food, tend to become more difficult with age.
It is also becoming clear that the aging brain is only
as resilient as its circuitry. Scientists debate whether this
circuitry is changed by neuron atrophy alone or whether
some neuron loss over time is inevitable. In any event,
when the circuitry begins to break down, remaining neurons
can adapt by expanding their roles, and larger portions of
the brain can be recruited so that older people can reach
performance levels similar to those of younger adults.
In addition, learning conditions may dictate what
happens to brain cells. Studies of rats shed light on
some of the changes that occur in brain cells when the
animals live in challenging, stimulating environments.
Middle-aged rats exposed to such environments formed
more and longer dendrite branches in the cerebral cortex
than did rats housed in isolated conditions. In response
Studies show that many areas of
the brain, especially in the cortex,
maintain most of their neurons
throughout life. The connectivity
between neurons changes with
aging, indicating that the brain
is capable of being modified or
improved.
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 neurons? In a given neuron, does atrophy lead to a higher
likelihood of death? How does aging affect gene expression
in the brain — the organ with the greatest number
of active genes? Do hormonal changes at menopause
The brain can remain contribute to gender differences in brain aging?
relatively healthy and Neuroscientists, too, speculate that certain genes may be
linked to events leading to cell death in the nervous system.
full-functioning as it ages. By understanding the biology of the proteins produced by
genes, scientists hope to be able to influence the survival of
neurons and develop ways to improve their functioning.
Our understanding of brain function has evolved over
many years of research. Much of this research has been
to enriched environments, older rats tend to form conducted with animals. In recent years, other technologies,
new dendrite outgrowths and synapses, just as younger such as imaging techniques, have emerged as powerful
animals do. But the response is more sluggish and not as tools to reveal brain functioning in real time. The next
large. Compared with younger rats, older rats have less chapter highlights several different ways neuroscientists
growth of the new blood vessels that nourish neurons. conduct research and how they have contributed to
Another study showed that when rats were given our knowledge of the brain and the nervous system.
acrobatic training, their brain cells had more synapses
per cell than rats given only physical exercise or
rats that were inactive. These findings led scientists
to conclude that motor learning generates new
synapses. Physical exercise alone, however, improved
blood circulation in the brain. In humans, aerobic
exercise can also improve cognitive performance.
Despite these advances, most causes of normal brain
aging remain a mystery. Dozens of theories abound. One
says that specific “aging genes” are switched on at a certain
time in life. Another points to the accumulation of
genetic mutations or other types of DNA damage. Other
researchers implicate hormonal influences or suggest that
an immune system gone awry plays a central role in aging.
Finally, many researchers advance a theory of brain aging
that emphasizes the inexorable accumulation of oxidative
damage caused by free radicals, cell byproducts that
destroy fats and proteins vital to normal cell function.
As a logical consequence of this uncertainty about
what causes normal brain decline, we are equally uncertain
about what sustains healthy brain function as we grow
older. Increasingly, both physical and mental exercise
is viewed as an effective means of slowing the effects
of brain aging, perhaps by altering the levels of certain
neurotropic factors that are beneficial to brain functioning.
Although much has been learned about the aging
brain, many questions remain. For instance, does the
production of proteins decline with age in all brain

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chaPter 9:
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n Animal Research
n Sample Research Methods
n Imaging
n Gene Diagnosis
The field of neuroscience has been built on a
foundation of research. This chapter explores three
different approaches to research — animal research,
imaging techniques, and genomic investigations — and the
knowledge that has been gained. These represent a small
sample of the ways neuroscientists study the brain.
Animal Research
Because many animal species are genetically and
biochemically similar to humans, animal research has been
vital to uncovering the secrets of brain function. In fact, the
use of animals has touched every aspect of neuroscience.
Without studies with rats and mice, scientists would not
have discovered the role of neurotransmitters in cell
communication. Other mammals, such as rabbits and cats,
have proven to be important models for studies of vision
and other senses.
Invertebrates can be used to learn more about the
human nervous system. Although the fruit fly’s brain is
much less complex than that of vertebrates and humans,
many features of its nervous system, such as the eye, share
striking similarities to humans. Zebrafish, whose fertilized
eggs are transparent, have turned out to be good models
for developmental neuroscience research. Sea slugs have
proven to be important in the study of learning and
memory.
Below are a few detailed examples of findings that have
emerged from animal research. This research is conducted
42 BraiN factS | brain research
within national and international guidelines and standards
for responsible animal care and use. These guidelines are
designed to ensure the humane and appropriate use of
animals in all forms of biomedical research.
Chemical Connections in the Nervous System
Treatments for brain disorders such as Parkinson’s disease
and attention deficit hyperactivity disorder (ADHD) target
the synapse. The advances in medicine that led to this
type of treatment were made possible by studies using rats
and mice. New staining techniques enabled scientists to
look at the pathways and connections between different
areas of the brain, as well as the neurons that contain and
use specific neurotransmitters, so that a roadmap of the
brain’s connections could be drawn. These techniques
were then used in rodents, monkeys, and even in humans
who had died to understand more about chemicals and
pathways that can be affected by disease, such as the death
of neurons containing the neurotransmitter acetylcholine in
Alzheimer’s disease.
Knowledge about another neurodegenerative disease,
Parkinson’s disease, has emerged through studies with
rabbits and mice. These experiments, conducted by Nobel
Laureate Arvid Carlsson, revealed that the neurotransmitter
dopamine was being depleted. Using pigeons, scientists
then discovered that this neurotransmitter was highly
concentrated in the basal ganglia, the part of the brain
involved in motor function. From there, researchers
concluded that Parkinson’s disease causes cells in the
basal ganglia to die, limiting the production of dopamine.
This finding led to the discovery of the first treatment for
Parkinson’s — a drug called levodopa, which is converted to
dopamine in brain cells.
Rats have proven to be helpful in uncovering changes
to the brain as a result of drug addiction. The first step in
this work was determining whether nonhuman species
could become addicted to drugs. Experiments showed that
when rats were given free access to the same drugs that
humans become addicted to, they will also take these drugs
compulsively. Further studies showed that the part of the
brain affected by drugs is the reward pathway, especially
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the dopamine neurons of the ventral tegmental area, which
communicates with the nucleus accumbens. As shown in
rats — and consistent with what happens in humans —
this pathway is also activated by natural rewards, such as
food, water, and sex, but drugs of abuse can take over the
reward system by mimicking or blocking the function of
neurotransmitters.
Other animal studies have shown that drugs of abuse
can affect brain systems concerned with learning and
memory; as a result, cues or habits associated with taking
drugs can elicit a craving for that drug, even after long
periods of abstinence. These findings are helping scientists
understand how changes in the brain can lead to addiction
and why some people are more likely to become addicted
than others. This work, of which animal research is a crucial
part, has enabled researchers to develop treatments for
addiction.
Learning and Memory In his work on learning
and memory, Nobel Laureate Eric Kandel began his
investigations using mammals, but soon found they were too
complex to enable him to study basic memory processes. So
he turned to a simpler organism — the sea slug—and was
successful in uncovering how short- and long-term memories
are retained.
Kandel found that certain stimuli resulted in a more
robust protective reflex, a form of learning for the sea slug.
Furthermore, the strengthened reflex could remain in place
for days and weeks as a short-term memory. Additional
work showed that a stronger synapse was responsible for the
retention of this information.
Researchers have learned a great deal about the basis of behavior by
studying animal models, including the fruit fly Drosophila melanogaster.
[Credit: edward Kravitz, PhD, harvard Medical School]
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Long-term memories form in a different way. Stronger
stimuli activate genes, resulting in an increase of some
proteins and a decrease in others. These changes ultimately
lead to the growth of new synapses. After demonstrating
that both short- and long-term memory in sea slugs involve
the synapse, Kandel was able to illustrate that similar
mechanisms are at work in mice and other mammals.
understanding Critical Periods Animal studies led
to the understanding of the concept of critical periods in the
development of vision. Experiments with monkeys and cats
helped determine that treatment for amblyopia, a condition
in which the vision of one eye is greatly reduced because the
eyes do not work well together, has the best outcome when
it is started early in life, before the age of eight. During this
period of time, visual experiences guide the development
of the visual circuits. After the critical period comes to an
end, the circuits cannot be easily modified. These animal
studies showed the importance of the critical period in
modifying visual circuits, leading to the realization that there
is currently no cure for amblyopia in adults. For this work,
neuroscientists David Hubel and Torsten Wiesel won the
Nobel Prize in 1981.
More recently, studies with mice are starting to
reveal what factors change in the brain to prevent
rewiring after a certain age. Modifying or removing
these factors seems to allow for changes in vision later
in life. This has been borne out in the lab, where vision
has been restored in older amblyopic mice. Scientists
hope that these experiments can be applied to humans,
resulting in a cure for adults with this condition.
Sample Research Methods
Psychologists, chemists, geneticists, computer scientists,
and physicists can all study the brain. Because neurons
communicate by both chemical and electrical means, many
researchers study these properties and how they are affected
by experience or disease. A variety of techniques make these
studies possible.
For example, researchers use a technique called
microdialysis to measure the amount of a particular brain
chemical found in a specified area of the brain. Following
the discovery that chemicals and other molecules are
transported within neurons, methods have been developed
to visualize brain activity and precisely track nerve fiber
connections within an animal’s nervous system. This can be
done by injecting a radioactive amino acid into brain cells,
brain research | BraiN factS 43
allowing activities in the nervous system to show up on film.
In another technique, the enzyme horseradish peroxidase
is injected and taken up by nerve fibers that later can be
identified under a microscope.
The study of the electrical properties of neurons is called
electrophysiology. The discovery of action potentials, the
way neurons communicate, and long-term potentiation, the
cellular event that makes learning and memory possible,
both relied on this technique.
Electrophysiology is now being used to study the
human brain and even to diagnose some conditions, such
as hearing loss. This function is assessed in infants through
electrophysiological recordings of auditory brainstem
responses to sound. During this procedure, electrodes are
placed on specific parts of the head, which make recordings
that are then processed by a computer. The computer makes
an analysis based on the time lapse between stimulus and
response. It then extracts this information from background
activity. Similarly, in EEG, electrodes placed around the
head record electrical activity of the human brain in
response to a variety of stimuli and activities.
These are examples of research techniques developed on
animals that are now being used to study and even diagnose
humans. Similarly, brain imaging techniques have allowed
detailed examination of the human brain.
Imaging
Positron emission Tomography (PeT) PET is
one of the most important techniques for measuring blood
flow or energy consumption in the brain. This method
of measuring brain function is based on the detection of
radioactivity emitted when positrons, positively charged
particles, undergo radioactive decay in the brain.
Small amounts of a radioisotope are introduced into the
blood, which then carries the radioisotope to different brain
areas. The radioisotope shows up in the brain in proportion to
how hard local neurons are working. Computers build three-
dimensional images of changes in blood flow based on the
amount of radiation emitted in different brain regions. The
more brain activity, the more vivid the picture that is created.
PET studies have helped scientists understand more
about how drugs affect the brain and what happens while
people are working on different activities, such as learning
and using language. PET studies also have been helpful
in understanding certain brain disorders, such as stroke,
44 BraiN factS | brain research
depression, and Parkinson’s disease. For example, PET
allows scientists to measure changes in the release of some
neurotransmitters. This information can be used to pinpoint
the relationship between a particular neurotransmitter and
a behavior or cognitive process. Within the next few years,
PET could enable scientists to identify the biochemical
nature of neurological and mental disorders and to determine
how well therapy is working in patients. Already, PET has
revealed marked changes in the depressed brain. Knowing
the location of these changes helps researchers understand
the causes of depression and monitor the effectiveness of
specific treatments.
Another technique, single photon emission computed
tomography (SPECT), is similar to PET, but its pictures are
not as detailed. SPECT is much less expensive than PET
because the tracers it uses break down at a slower rate and
do not require a nearby particle accelerator, typical of those
used in nuclear physics, to produce them.
Magnetic Resonance Imaging (MRI)
Providing a high-quality, three-dimensional image of
organs and structures inside the body without X-rays or
other radiation, MRIs are noninvasive and unsurpassed in
the anatomical detail they show. MRIs tell scientists when
structural abnormalities first appear in the course of a disease,
how they affect subsequent development, and precisely
how their progression correlates with mental and emotional
aspects of a disorder. In some instances, they can even reveal
minute changes that occur over time.
During the 15-minute MRI procedure, a patient lies
inside a massive, hollow, cylindrical magnet and is exposed
to a powerful, steady magnetic field. Different atoms in the
brain resonate to different frequencies of magnetic fields.
A background magnetic field lines up all the atoms in the
brain. Then a second magnetic field, oriented differently
from the background field, is turned on and off many times
a second; at certain pulse rates, particular atoms resonate to
and line up with this second field. When the second field is
turned off, the atoms that were lined up with it swing back
to align with the background field. As they swing back, they
create a signal that can be picked up and converted into an
image. Tissue that contains a lot of water and fat produces a
bright image; tissue that contains little or no water, such as
bone, appears black.
A different MRI procedure can also assess the path of
fiber tracts in the brain; that is, the connectivity between
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regions. This technology, referred to as diffusion tensor
imaging, takes advantage of diffusion rates of water, which
tend to be higher along fiber tracts, to produce high-
resolution images of how areas may connect in the brain.
MRI images can be constructed in any plane, and they
are particularly valuable in studying the brain and spinal
cord. The images reveal the precise extent of tumors rapidly
and vividly and provide early evidence of potential damage
from stroke, allowing physicians to administer proper
treatments early, when they can have an impact.
Magnetic Resonance Spectroscopy (MRS)
MRS, a technique related to MRI, uses the same machinery
but measures the concentration of specific chemicals — such
as neurotransmitters — in different parts of the brain instead
of blood flow. MRS also holds great promise: By measuring
the molecular and metabolic changes that occur in the
brain, this technique has already provided new information
about brain development and aging, Alzheimer’s disease,
schizophrenia, autism, and stroke. Because it is noninvasive,
MRS is ideal for studying the natural course of a disease or its
response to treatment.
Magnetic resonance imaging is a powerful technique to examine the
structure and observe the function of the human brain.
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Functional Magnetic Resonance Imaging (fMRI)
One of the most popular neuroimaging techniques today
is fMRI. This technique compares brain activity under
resting and active conditions. It combines the high-spatial
resolution, noninvasive imaging of brain anatomy offered
by standard MRI with a strategy for detecting increases in
blood oxygen levels when brain activity brings fresh blood
to a particular area of the brain — a correlate of neuronal
activity. This technique allows for more detailed maps of
brain areas underlying human mental activities in health
and disease. To date, fMRI has been applied to the study of
various functions of the brain, ranging from primary sensory
responses to cognitive activities. Given fMRI’s temporal
and spatial resolution, as well as its noninvasive nature, this
technique is often preferred for studies investigating dynamic
cognitive and behavioral changes.
Magnetoencephalography (MeG) MEG is a
recently developed technique that reveals the source of weak
magnetic fields emitted by neurons. An array of cylinder-
shaped sensors monitors the magnetic field pattern near
the patient’s head to determine the position and strength
of activity in various regions of the brain. In contrast with
other imaging techniques, MEG can characterize rapidly
changing patterns of neural activity — down to millisecond
resolution — and can provide a quantitative measure of the
strength of this activity in individual subjects. Moreover, by
presenting stimuli at various rates, scientists can determine
how long neural activation is sustained in the diverse brain
areas that typically respond.
One of the most exciting developments in imaging is
the combined use of information from fMRI and MEG. The
former provides detailed information about the areas of brain
activity while an individual is engaged in a particular task,
whereas MEG tells researchers and physicians when certain
areas become active. Together, this information leads to a
much more precise understanding of how the brain works in
health and disease.
Optical Imaging and Other Techniques Optical
imaging relies on shining weak lasers through the skull to
visualize brain activity. These techniques are inexpensive
and relatively portable. They are also silent and safe: Because
only extremely weak lasers are used, these methods can be
used to study everyone, even infants. In a technique called
near infrared spectroscopy (NIRS), technicians shine lasers
through the skull at near infrared frequencies, which renders
brain research | BraiN factS 45
the skull transparent. Blood with oxygen in it absorbs
different frequencies of light from blood in which the oxygen
has been consumed. By observing how much light is reflected
back from the brain at each frequency, researchers can track
blood flow. Diffuse optical tomography is then used to create
maps of brain activity.
A similar technique, the event-related optical signal,
records how light scatters in response to rapid cellular
changes that arise when neurons fire, potentially assessing
neural activity lasting milliseconds. Another technique,
called transcranial magnetic stimulation (TMS), works
by inducing electrical impulses in the brain. This is
accomplished by altering magnetic fields through the use
of an electromagnetic coil that emits powerful magnetic
pulses while held against the scalp. Repetitive TMS is being
used to investigate the role of specific brain regions during
behavior, and it can be combined with other neuroimaging
techniques. For example, when TMS is used with fMRI, a
functional correlation between a region and a behavior can
be established.
Gene Diagnosis
Genes form the blueprint, or set of instructions, needed
for our bodies to grow and function. They consist of short
sections or sequences of deoxyribonucleic acid (DNA) bases
represented by the letters A, C, G, and T. DNA strands are
often visualized as long, spiraling, double-helix structures
found within the 23 pairs of chromosomes in every human
cell. The exact number of human genes is uncertain and the
functions of many genes are still unknown, but the current
estimate is that humans have approximately 20,000–25,000
pairs of genes contained in these 23 chromosomes. Humans
inherit one copy of each gene from the mother and one from
the father and then pass down one copy of each of their
genes to their children. Thus, genes and their corresponding
traits are passed down through families.
More than 7,000 disorders, including many that affect
the brain and neurodevelopment, are suspected to have
a genetic basis. These problems occur because changes in
the DNA, such as “misspellings” in the gene instructions
or incorrect amounts of DNA, can prevent a gene from
functioning properly. These changes are called mutations. As
a result, DNA changes contribute to disease, and mutations
in genes important for brain development and function
can cause a wide variety of neurological and psychiatric
conditions.
46 BraiN factS | brain research
Genetic linkage studies, which studied families and
large groups of unrelated people diagnosed with specific
conditions, made it possible to find the chromosomal
location of many genes. Newer techniques, called
chromosome microarrays, look carefully at the overall
chromosome makeup of a person and find out if segments of
chromosomes, perhaps involving multiple genes, are missing
(called deletions) or present in more than the usual amount
(called duplications). Microarrays have recently helped
identify many types of rearrangements of chromosome
structure and specific genes that are associated with
developmental disabilities and neurological disorders.
Knowing such genetic information can clarify diagnoses
and improve understanding of the cause of symptoms,
allowing physicians to optimize methods of prevention
and treatment. This knowledge can also help individuals
understand the chance of a condition affecting other
members of their family and allow for prenatal testing and
carrier status evaluations. In some cases, genetic analysis
can even be helpful in evaluating the malignancy of specific
tumors and reactions to certain medications and treatments.
Tracking down Genes Early mapping techniques
allowed scientists to track down the genes responsible for
several neurological conditions. These include HTT, the
gene that is altered in patients diagnosed with Huntington’s
disease; RB1, which causes inherited retinoblastoma, a
rare, highly malignant, childhood eye tumor that can lead
to blindness and death; and the X-linked gene DMD,
responsible for Duchenne muscular dystrophy, a progressive
muscle disease. In some cases, mapping techniques have
shown that one condition may actually be due to mutations
in any one of a group of genes. This is the situation with a
condition called Walker-Warburg syndrome, which causes
severe problems involving the brain, eyes, and muscles,
leading to death in infancy or early childhood. Thus far, at
least five genes are known to be associated with this disease,
with still others yet to be discovered.
Many forms of intellectual disability, previously referred
to as mental retardation, are also due to genes that are not
working properly. Gene mapping enabled doctors to find the
FMR1 gene, which is abnormal in people diagnosed with
fragile X syndrome, the most common cause of inherited
intellectual disability in males. FMR1 is located on the X
chromosome and is important for neuronal communication.
Other groups of scientists are also investigating whether there
are genetic components to schizophrenia, bipolar disorder, and
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alcoholism, but to date, their findings are not conclusive. For
instance, people missing a certain segment of chromosome
22, due to 22q deletion syndrome, have a higher chance of
developing mental illness. However, not all people with this
chromosome deletion develop mental illness, nor do all people
with mental illness have such a genetic finding.
Rarely, genes passed down from parents can undergo
changes very early in fetal development so that a child
might have a genetic alteration that is not found in either
of his parents. In these cases, the child could have a genetic
condition that may potentially be passed on to offspring but
was not necessarily inherited from his parents. For example,

every trait and chemical process in the body are controlled by a gene or group of genes on 23 paired chromosomes in the nucleus of every cell (1). each gene is
a discrete segment along the two tightly coiled strands of DNA that make up these chromosomes. DNA strands have four different types of coding molecules —
adenine (a), cytosine (C), guanine (g), and thymine (T) — the sequence of which contains the instructions for making all the proteins necessary for life (2). During
protein production, a gene uses a molecule called mRNA to send a message with instructions for the amino acids needed to manufacture a protein (3).

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scientists have identified a gene called LIS1 that helps tell
the brain how to grow. People with mutations in the LIS1
gene have smoother brains than normal and may have
seizures. In addition, severe intellectual disability is common.
However, the parents of these individuals do not have
Genes form the blueprint, or set
of instructions, needed for our
bodies to grow and function.
mutations in their LIS1 genes, so there is a very low chance
of other children of those parents having the same diagnosis.
Importantly, a great deal of effort has been put into
better understanding the genetic basis of autism. Many
genetic changes have been associated with autism, or more
specifically, with conditions that can include autism or
autism-like features as symptoms. Such conditions include
tuberous sclerosis complex, due to mutations in the genes
TSC1 and TSC2, as well as Rett syndrome, associated with
the MECP2 gene. Chromosome abnormalities identified
through microarray technology have also been associated
with autism. Deletions of a certain portion of chromosome
16 can lead to a variety of neurological symptoms, including
autism in some individuals. However, at this point in time
no one gene or set of genes can be attributed to the majority
of autism diagnoses. Therefore, significant research efforts
continue, with the goal of better understanding genetic
contributions to autism spectrum disorders.
Overall, our understanding of the structure and function
of individual genes associated with diseases of the brain
and nervous system is progressing rapidly. Once genes are
implicated in a disease process and it is known who carries
certain gene variants, it becomes theoretically possible to
develop targeted therapies for specific conditions. There are
now very early interventional studies for some neurological
conditions, such as Angelman syndrome and tuberous
sclerosis complex. However, much remains to be learned
about these and other conditions before cures might emerge.
48 BraiN factS | brain research
For instance, it is still largely unknown why different people
who carry mutated versions of the same gene, even within a
family, can have different types or degrees of symptoms, or
sometimes no symptoms at all.
A new DNA sequencing technology, often referred
to as “next generation” sequencing, offers great hope
for uncovering the genetic basis of many neurological
conditions. But this technology also comes with many
challenges, not the least of which is the enormous volume
of data it promises to produce. This testing is expected
to uncover the functional sequence of all 20,000 or more
human genes (collectively called the exome) as well as the
remaining associated DNA that is thought to influence or
regulate these genes (together with the exome, this is called
the genome) for each person studied. So far, such studies
have revealed numerous types of genetic variants, making for
more variability in human genes than initially recognized.
Interpreting so many DNA variants at once, and
knowing which ones are truly associated with a disease
under study, is a complex and daunting task. Nevertheless,
this next generation of sequencing has already led to the
identification of the MLL2 gene responsible for Kabuki
syndrome, which causes congenital intellectual disabilities
along with certain abnormal facial features. Despite being
a distinctive condition, Kabuki syndrome long escaped
efforts to identify its genetic underpinnings. This is only one
example of the many expected genetic discoveries that will
result from evolving methods and techniques for studying
the genetics of the nervous system and conditions causing
human disease.
This chapter has focused on the tools of neuroscience,
with a focus on animal research, imaging, and gene diagnosis.
In Part 5, the emphasis in Chapters 10 through 14 is on
different kinds of neurological and psychiatric diseases and
disorders. In addition to explaining these disorders, in many
instances, information is given about which tools have helped
neuroscientists unravel the mystery surrounding each one.
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chaPter 10:
haPter
childhood diSorderS
in this chapter
n Autism
n Attention Deficit Hyperactivity Disorder
n Down Syndrome
n Dyslexia
Autism
Autism spectrum disorders (ASD) are characterized by
impaired social skills; verbal and nonverbal communication
difficulties; and narrow, obsessive interests or repetitive
behaviors. Common associated symptoms include intellectual
disabilities, seizures, and gastrointestinal problems. One of
every 110 babies born in the United States, approximately
40,000 new cases each year, is diagnosed with ASD, an
incidence far greater than in the 1970s. This increase is due,
in part, to changes in diagnostic criteria, detection of subtler
forms of autism, and enhanced parent and clinician referral
based on greater awareness. Mounting evidence, however,
indicates that there is a true increase in the number of children
with autism. As a result, research efforts are now focusing on
the interplay between genetic and environmental components
that might contribute to the diagnosis.
Based mainly on twin studies, ASDs are thought to
be highly genetic; already, more than 100 genes have been
linked to increased risk for autism. That said, however, there
is currently no single genetic or biochemical biomarker
specifically for autism, because no single gene mutation or
biological change will predict the disorder. Therefore, at this
time, there is no way to determine if a newborn child is at risk
for autism.
For this reason, ASD is typically diagnosed based on
behavioral symptoms detected in children about three years
of age. However, very sensitive measures of social engagement
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and interaction can detect differences in children between one
and two years old, a time when many affected children exhibit
abnormal, accelerated growth of the brain. This abnormal
growth may indicate that brain development has gone awry,
thus making it a potential marker for early evaluation. In
addition, recent evidence indicates that some forms of autism
may be due to dysregulation of the immune system, either in
the mother or the child. One day, genetic or other biological
tests may complement behavioral indicators to allow earlier
diagnosis and intervention, as well as the means to possibly
prevent or reduce ASD symptoms.
Brain alterations in autism are subtle; there is no obvious
change such as in Down syndrome or Alzheimer’s disease.
There is speculation that abnormal development of certain
regions of the brain involved in language, cognition, and
social communication leads to abnormal connections with
other parts of the brain.
Although no cure exists and no drugs for the major
symptoms of autism have been developed, many affected
children respond very well to specialized behavioral therapies
based on learning theory, with earlier interventions leading
to better outcomes. Many of the therapeutic approaches
to autism are guided by an increased understanding of how
the brain normally reacts to learning, bonding, and social
challenge as it develops.
One final note: It is now recognized that many of the
brightest and most creative individuals in history may have
had subtle forms of ASD. Therefore, researchers and others
working in the field need to be aware that some “higher
functioning” people with autism do not want to be “cured.”
Instead, they would like to be accepted for who they are.
Attention Deficit hyperactivity Disorder
Attention deficit hyperactivity disorder (ADHD) was
first described more than 100 years ago. Characterized by
excessively inattentive, hyperactive, or impulsive behaviors,
ADHD affects an estimated 5 to 8 percent of school-age
children. Studies show that as many as 60 percent of these
children will continue to experience ADHD symptoms
as adults. Children with ADHD are more likely to have
diseases and disorders | BraiN factS 49
problems in school, graduating from high school, maintaining Down Syndrome
a job, abusing drugs, or having healthy relationships. Down syndrome, the most frequently occurring
Symptoms of ADHD appear by middle childhood, last chromosomal condition, appears in 1 of every 691 babies, or
for six months or longer, and impair normal functioning to a about 6,000 babies annually in the United States. It typically
significant degree in the following settings: for children — at occurs when, at the time of conception, an extra copy of
school, among friends, and at home; for adults — at work chromosome 21 — or part of its long arm — is present in the
and at home. Currently, no objective diagnostic test for egg or, less commonly, in the sperm. It is not known why this
ADHD exists. Diagnosis requires a comprehensive evaluation, error occurs, and it has not been linked to any environmental
including a clinical interview, parent and teacher ratings or behavioral factors, either before or during pregnancy, but
for children, and self and other ratings for adults. Learning the risk is markedly increased with the age of the mother. At
disorder and psychological testing may also be used to clarify age 25, the risk is about 1 in 1,250 births; at age 40, it is 1 in
if other disorders are present along with the ADHD or if other 100. Because of higher fertility rates in younger women, 80
conditions that look like ADHD may be responsible for the percent of children with Down syndrome are born to women
behaviors in question. Thorough evaluation is required because under 35 years of age. Prenatal screening tests, such as the
problems with attention can be triggered by many other triple and quadruple screen blood tests, can accurately detect
conditions; in particular, adults may have attention issues along Down syndrome in about 70 percent of fetuses. Definitive
with other disorders such as depression. prenatal diagnoses can be obtained with either chorionic villus
Twin and family studies show that ADHD has a strong sampling or amniocentesis.
genetic influence, and genes encoding components of dopamine Down syndrome is associated with approximately 50
and norepinephrine transmission have been implicated. physical and developmental characteristics. An individual with
Increasingly, studies are finding correlations between ADHD Down syndrome is likely to possess, to various degrees, some of
and differences in brain function. Altered activity is often these characteristics: mild to moderate intellectual disabilities;
observed in circuits connecting the cortex, the striatum, and the low muscle tone; an upward slant to the eyes; a flat facial profile;
cerebellum, particularly in the right hemisphere. Recent studies an enlarged tongue; and an increased risk of congenital heart
show a delay in cortical development in some children with defects, respiratory problems, and digestive tract obstruction.
ADHD, although most individuals with ADHD do not outgrow
the disorder as they mature. Rather, their symptoms often
change as they grow older, with less hyperactivity as adults.
Problems with attention tend to continue into adulthood.
Recent imaging studies have shown reduced
catecholamine transmission in at least some patients with
this disorder. Because prefrontal circuits require an optimal
level of catecholamine stimulation, reduced catecholamine
transmission could lead to weakened prefrontal cortical
regulation of attention and behavior and symptoms of ADHD.
ADHD is commonly treated with parent education,
school-based interventions, and medications such as stimulants
(e.g., methylphenidate) and newer, nonstimulant drugs. Adults
benefit from the same medications as children and may find
some behavioral therapies helpful. The medications all act by
enhancing catecholamine transmission.
There is no cure for ADHD at this time. Treatment
effectiveness should be re-evaluated in each person on a
regular basis to determine if the current treatment continues
to be optimal. Brain-imaging studies show differences in the dyslexic brain during reading
tasks. [Credit: Guinevere eden, DPhil, Georgetown university.]

50 BraiN factS | diseases and disorders Society for NeuroScieNce

By age 40, nearly all people with Down syndrome show some
neurological changes similar to those seen in Alzheimer’s
disease, and most show cognitive decline by age 60.
Babies with Down syndrome develop much as typical
children do but at a somewhat slower rate. Just as their
peers do, they learn to sit, walk, talk, and toilet train. Early
intervention programs can begin shortly after birth and can
help foster an infant’s development.
Thanks to medical advances and a greater understanding
of the potential of those with this condition, people with
Down syndrome have been able to have longer and fuller
lives. They are being educated in their neighborhood schools,
participating in community activities, and finding rewarding
employment and relationships.
Although there is no cure for Down syndrome or means
of preventing it, scientists are moving closer to understanding
the role that the genes on chromosome 21 play in a person’s
development. There are several mouse models of Down
syndrome that are allowing scientists to focus on molecular
factors important in the condition. Once this mystery is
understood, researchers hope to decode the biochemical
processes that occur in Down syndrome and learn how to treat
or cure this disorder.
Dyslexia
An estimated 8 to 10 percent of children in the United
States have some form of learning disability involving
difficulties in the acquisition and use of listening, speaking,
reading, writing, reasoning, or mathematical abilities. These
problems often occur in people with normal or even high
intelligence.
Dyslexia, a specific reading disability, is the most common
and most carefully studied of the learning disabilities. It affects
80 percent of all those identified as learning disabled, or as many
as 15 to 20 percent of Americans. Dyslexia is characterized
by an unexpected difficulty in speaking and reading in
children and adults who otherwise possess the intelligence,
motivation, and schooling considered necessary for accurate
and fluent reading. Studies indicate that although there can be
improvement, dyslexia is a persistent, chronic condition.
There is now a strong consensus that the central
difficulty in most forms of dyslexia reflects a deficit within
the language system — more specifically, in a component
of the language system called phonology. This deficit results
in difficulty in both oral language and reading. There may
be mispronunciations of words, lack of fluency in speech,
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hesitations before responding, and word retrieval difficulties.
As a result, a person with dyslexia often needs time to summon
a verbal response when questioned.
As children approach adolescence, one manifestation of
dyslexia may be a very slow reading rate. Children may learn
to read words accurately, but their reading will not be fluent
or automatic, reflecting the lingering effects of a phonologic
deficit. Because they can read words accurately — albeit
very slowly — dyslexic adolescents and young adults may
mistakenly be assumed to have “outgrown” their dyslexia.
The ability to read aloud accurately, rapidly, and with good
expression, as well as facility with spelling, may be most useful
clinically in distinguishing students who are average from
those who are poor readers. In some languages that are more
consistent in the relationship between letters and sounds,
such as Finnish and Italian, slow reading may be the only
manifestation of dyslexia at any age.
A range of investigations indicates that there
are differences in brain regions between dyslexic and
nonimpaired readers involving three important left
hemisphere neural systems, two posteriorly (parieto-
temporal, occipito-temporal) and one anteriorly around
the left inferior frontal region (Broca’s area). Converging
evidence derived from functional brain imaging indicates
that dyslexic readers demonstrate a functional inefficiency
in an extensive neural system in the posterior portion of the
brain. The brain images that result from these studies are
referred to as the neural signature of dyslexia.
It is clear that dyslexia runs in families, but initial hopes
that dyslexia would be explained by one or just a few genes
have not been realized. Genome-wide association studies
(GWAS) in dyslexia have so far identified genetic variants
that account for only a very small percentage of the risk — less
than 1 percent — making it unlikely that a single gene or
even a few genes will identify people with dyslexia. Current
evidence suggests that dyslexia is best conceptualized within a
multifactorial model, with multiple genetic and environmental
risk and protective factors leading to dyslexia.
Interventions to help children with dyslexia focus on
teaching the child that words can be segmented into smaller
units of sound and that these sounds are linked with specific
letter patterns. In addition, children with dyslexia require
practice in reading stories, both to allow them to apply their
newly acquired decoding skills to reading words in context and
to experience reading for meaning and enjoyment.
diseases and disorders | BraiN factS 51
chaPter 11:
haPter
addictioN
in this chapter
n Nicotine
n Alcohol
n Marijuana
n Opiates
n Psychostimulants
n Club Drugs
Drug abuse is one of the nation’s most serious health
problems. About 9 percent of Americans, more than 22
million people, abuse drugs on a regular basis. Drug abuse,
including alcohol and nicotine, is estimated to cost the
United States more than $600 billion each year.
If continued long enough, drug abuse can eventually
alter the very structure and chemical makeup of the
brain, producing a true brain disorder. This disorder is
called drug addiction or drug dependence. Drug addiction
is characterized by a pathological desire for drugs, such
that drug-seeking and drug-taking behaviors occupy an
inordinate amount of an individual’s time and thoughts,
at the expense of other activities. These behaviors persist
despite many adverse consequences. Addiction is also
characterized by difficulty controlling frequency of use and
terminating use, despite a stated desire to do so.
People initially experiment with drugs for many
different reasons, a key one being that most drugs of abuse
produce feelings of pleasure or remove feelings of stress
and emotional pain. Neuroscientists have found that
almost all abused drugs produce pleasure by activating a
52 BraiN factS | diseases and disorders
specific network of neurons called the brain reward system.
The circuit is normally involved in an important type of
learning that helps us stay alive. It evolved to mediate the
pleasurable and motivating effects of natural rewards, such as
eating when we are hungry or drinking when we are thirsty.
Indeed, when a reward produces feelings of pleasure, we
learn to repeat the actions that got us the reward in the first
place. Drugs can activate this same system, thus promoting
continued drug use.
Neuroscientists have learned a great deal about how
drugs of abuse affect neurons to exert their influence.
Abused drugs alter the ways neurotransmitters carry their
messages from neuron to neuron. Some drugs mimic
neurotransmitters, while others block them. Still others
alter the way neurotransmitters are released or inactivated.
Ultimately, in all cases, the brain reward system is activated
inappropriately because drugs alter the chemical messages
sent among neurons in this circuit.
Finally, neuroscientists have learned that addiction
requires more than the activation of the brain reward system.
Over the past 20 years or so, research has indicated that the
drugs themselves change the brain of susceptible individuals
in complex ways, leading to symptoms of addiction. In
addition to the brain reward system, brain regions that
are changed by drugs include those involved in executive
functions and judgment. These latter brain systems are
important in inhibiting behavior and in decision-making.
The process of becoming addicted is influenced by many
factors that scientists are only beginning to understand.
Motivation for drug use is an important one. For example,
people who take opioids to get high may get addicted, but
people who use them properly to relieve pain rarely do.
Genetic susceptibility and environmental factors, such
as stress, can alter the way that people respond to drugs.
The characteristics of the drugs themselves, such as how
quickly they enter the brain, also play a role in addiction. In
addition, the development of tolerance — the progressive
need for a higher drug dose to achieve the same effect —
varies in different people, as does drug dependence — the
adaptive physiological state that results in withdrawal
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symptoms when drug use stops. Tolerance and dependence
are standard responses of the brain and body to drugs. At
the same time, the individual is starting to feel that it is
impossible to live without a drug. When this feeling starts to
grow, it means that the person is developing a motivational
form of dependence as well.
An important question for addiction research is to
understand how these many factors interact to predispose
individuals to addiction. The hope is that the knowledge
and insight into abuse and addiction that emerge from this
research will lead to new therapies.
Nicotine
In 2009, more than 70 million Americans smoked.
Despite definitive proof that smoking can be fatal, nicotine
still is one of the most widely abused substances. In fact,
tobacco kills more than 440,000 U.S. citizens each year —
more than alcohol, cocaine, heroin, homicide, suicide, car
accidents, and HIV combined. Tobacco use is the leading
preventable cause of death in the United States. The overall
cost of smoking in the United States is estimated to be
$193 billion each year. Nicotine, the addicting substance
in tobacco, acts through the well-known acetylcholine
nicotinic receptor. This drug can act as both a stimulant and
a sedative. Nicotine stimulates the adrenal glands, and the
resulting discharge of epinephrine causes a “kick” — a sudden
release of glucose paired with an increase in blood pressure,
respiration, and heart rate. In addition, nicotine releases
dopamine in the brain regions that control motivation,
which is one reason that people continue to smoke.
Much better understanding of addiction, coupled with
the identification of nicotine as an addictive drug, has been
instrumental in the development of treatments. Nicotine
gum, the transdermal patch, nasal spray, and inhalers are
equally effective in treating the more than one million
people addicted to nicotine. These techniques are used to
relieve withdrawal symptoms and are helpful in that they
produce less severe physiological alterations than using
tobacco products. They generally provide users with lower
overall nicotine levels than they receive with tobacco and
totally eliminate exposure to smoke and its deadly contents.
The first non-nicotine prescription drug, bupropion,
an antidepressant, has been approved for use as a
pharmacological treatment for nicotine addiction. An
exciting advance is the use of varenicline for smoking
cessation. This medication interacts directly with the
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acetylcholine nicotinic receptor in a key part of the brain’s
reward circuitry and prevents nicotine from activating this
circuit. The development of varenicline is a prime example
of how basic science research can lead to the production of
novel medications. Behavioral treatments also are important
in helping an individual learn coping skills for both short-
and long-term prevention of relapse.
Alcohol
Although legal, alcohol is addictive. Together, alcohol
abuse and alcohol addiction — sometimes referred to
as alcoholism or alcohol dependence — are among the
nation’s major health problems. It is clear that genetic and
environmental factors contribute to alcoholism, but at this
point, no single factor or combination of factors enables
doctors to predict who will develop an addiction to alcohol.
Nearly17.6 million people abuse alcohol or are alcoholic.
Fetal alcohol syndrome, affecting about 1 to 3 of every 1,000
babies born in the United States, is the leading preventable
cause of mental retardation. Cirrhosis, or scarring of
the liver, is the main chronic health problem associated
with alcohol addiction. Other chronic liver diseases are
responsible for more than 29,000 deaths each year. The
annual cost of alcohol abuse and addiction is estimated at
$185 billion.
Ethanol, the active ingredient in alcoholic beverages,
is a seductive drug. At first, it reduces anxiety, tension,
and behavioral inhibitions. In low doses, it may act as a
stimulant, but at higher doses, it acts as a depressant. In both
cases, it significantly alters mood and behavior. Too much
alcohol can also cause heat loss and dehydration.
The drug, which is easily absorbed into the bloodstream
and the brain, affects several neurotransmitter systems. For
example, alcohol’s interaction with the gamma-aminobutyric
acid (GABA) receptor can calm anxiety, impair muscle
control, and delay reaction time. At higher doses, alcohol
also decreases the function of N-methyl-d-aspartate
(NMDA) receptors, which recognize the neurotransmitter
glutamate. This interaction can cloud thinking and
eventually lead to coma.
In addition, animal research has shown that alcohol
works by activating the endogenous opioid system. This
means that susceptible individuals may feel an opioid-like
euphoria from their own endorphins when they drink.
Earlier, a medication called naltrexone had been developed
for heroin addiction, which also affects the opioid system.
diseases and disorders | BraiN factS 53
Naltrexone works by blocking opioid receptors. Researchers
thought that this medication might be effective for
alcoholics as well. Clinical trials began in 1983, and in 1995,
the U.S. Food and Drug Administration (FDA) approved
naltrexone for the treatment of alcoholism.
A central group of structures is common to the actions of all drugs. These
structures include a collection of dopamine-containing neurons found in
the ventral tegmental area. These neurons are connected to the nucleus
accumbens and other areas, such as the prefrontal cortex. Cocaine is
one drug that exerts its effects mainly through this system. Opiates also
act in this system and many other brain regions, including the amygdala.
Alcohol activates the core reward system and additional structures
throughout the brain because it acts where GABA and glutamate are used
as neurotransmitters.
54 BraiN factS | diseases and disorders
Marijuana
This drug distorts perception and alters the sense of
time, space, and self. In certain situations, marijuana can
produce intense anxiety. Researchers have made some
progress in uncovering the reasons for these responses.
In radioactive tracing studies, scientists found that
tetrahydrocannabinol (THC), the active ingredient in
marijuana, binds to specific receptors called cannabinoid
receptors, many of which coordinate movement. This may
explain why people who drive after they smoke marijuana
are impaired. The hippocampus, a structure involved with
memory storage and learning, also contains many receptors
for THC. This finding provides some insight into why heavy
users or those intoxicated on marijuana have poor short-term
memory and problems processing complex information.
Scientists recently discovered that cannabinoid
receptors normally bind to natural internal chemicals termed
endocannabinoids, one of which is called anandamide. A
large effort is now being made to develop medications that
target the endogenous, or internal, cannabinoid system.
The hope is that these medications will prove beneficial
in treating a number of different brain disorders, including
addiction, anxiety, and depression.
Opiates
Humans have used opiate drugs, such as morphine,
for thousands of years. Monkeys and rats readily self-
administer heroin or morphine and, like humans,
will become tolerant and physically dependent
with unlimited access. Withdrawal symptoms range
from mild, flulike discomfort to severe muscle pain,
stomach cramps, diarrhea, and unpleasant mood.
Opiates increase the amount of dopamine released in
the brain reward system and mimic the effects of endogenous
opioids. Heroin injected into a vein reaches the brain in 15
to 20 seconds and binds to opiate receptors found in many
brain regions, including the reward system. Activation of
the receptors in the reward circuits causes a brief rush of
intense euphoria, followed by a couple of hours of a relaxed,
contented state.
Opiates create effects like those elicited by the naturally
occurring opioid peptides. They relieve pain, depress
breathing, cause nausea and vomiting, and stop diarrhea —
important medical uses. But in large doses, heroin can make
breathing shallow or stop it altogether — the cause of death
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Crack cocaine enters the bloodstream through the lungs. Within seconds, it is carried by the blood to the brain. The basis for increased pleasure occurs at the
synapse. Dopamine-containing neurons normally relay their signals by releasing dopamine into many synapses. Dopamine crosses the synapse and fits into
receptors on the surface of the receiving cell. This triggers an electrical signal that is relayed through the receiver. Then, to end the signal, dopamine molecules
break away from the receptors and are pumped back into the nerve terminals that released them. Cocaine molecules block the pump, or transporter, causing
more dopamine to accumulate in the synapse. Pleasure circuits are stimulated again and again, producing a sense of euphoria.

in thousands of people who have died of heroin overdose.
A standard treatment for opiate addiction involves
methadone, a long-acting oral opioid that helps keep
craving, withdrawal, and relapse under control. Methadone
helps opiate addicts rehabilitate themselves by preventing
withdrawal symptoms that can motivate continued drug
use. Naloxone and naltrexone are available medications
that act as antagonists at opioid receptors; that is, they can
curb the allure of opiates by blocking the opiate receptors
so that opiates produce no pleasurable effects when they are
taken. The blockers alone are sometimes useful for addicts
who are highly motivated to quit. In addition, scientists are
developing a long-lasting version of naltrexone that needs to
be taken only once a month.
Another medication used to treat heroin addiction,
buprenorphine, causes a weaker effect on the receptors than
methadone and creates only a limited high, which deters an
addict from abusing the medication itself. Buprenorphine
has been prescribed for more than 500,000 patients in the
United States.

Society for NeuroScieNce diseases and disorders | BraiN factS 55

Psychostimulants to beverages and unknowingly ingested. These drugs have
This class of drugs includes cocaine and amphetamines. emerged as the so-called date-rape drugs. When mixed with
In 2009, in the United States, an estimated 4.8 million alcohol, rohypnol can incapacitate victims and prevent them
people age 12 and older had abused cocaine. A popular, from resisting sexual assault. Rohypnol may be lethal when
chemically altered form of cocaine, crack, is smoked. It mixed with alcohol and other depressants.
enters the brain in seconds, producing a rush of euphoria
and feelings of power and self-confidence. A form of
methamphetamine that can be smoked, “crystal meth,” also
has become popular. The key biochemical factor underlying
the reinforcing effects of psychostimulant drugs is their If continued long enough,
ability to greatly elevate the brain chemical dopamine
in specific brain regions, such as the nucleus accumbens.
drug abuse can eventually
Alterations in dopamine activity in the accumbens, alter the very structure and
induced by chronic cocaine intake, are thought to result
in a progressively increasing motivation to take the drugs,
chemical makeup of the brain.
eventually leading to addiction.
Cocaine users often go on binges, consuming a large
amount of the drug in just a few days. A crash occurs
after this period of intense drug-taking, resulting in such
symptoms as emotional and physical exhaustion and Since about 1990 in the United States, GHB has
depression. These symptoms may come from an actual been abused for its euphoric, sedative, and anabolic
shutdown, or crash, in dopamine and serotonin function, as (body-building) effects. It, too, has been associated with
well as an increased response of the brain systems that react sexual assault. Ketamine is another central nervous system
to stress. Vaccines to produce antibodies to cocaine in the depressant abused as a date-rape drug. Ketamine, or “Special
bloodstream are in clinical trials. K,” is a fast-acting general anesthetic. It has sedative,
hypnotic, analgesic, and hallucinogenic properties. It is
Club Drugs marketed in the United States and a number of foreign
Ecstasy, herbal ecstasy, rohypnol (“roofies”), GHB countries as a general anesthetic — a drug that brings about
(gamma hydroxy-butyrate), and ketamine are among the a reversible loss of consciousness — in both human and
drugs used by some teens and young adults as part of raves veterinary medical practice.
and trances. These drugs are rumored to increase stamina Many users tend to experiment with a variety of club
and to produce intoxicating highs that are said to deepen drugs in combination. This practice creates a larger problem,
the rave or trance experience. Recent research, however, because combinations of any of these drugs, particularly with
is uncovering the serious damage that can occur in several alcohol, can lead to unexpected adverse reactions and even
parts of the brain from use of some of these drugs. death after high doses. Physical exhaustion also can enhance
MDMA, called “adam,” “ecstasy,” or “XTC” on the some toxicities and problems.
street, is a synthetic psychoactive drug with hallucinogenic
and amphetamine-like properties. Users encounter problems
similar to those found with the use of amphetamines and
cocaine. Recent research also links chronic ecstasy use to
long-term changes in those parts of the brain critical for
thought, memory, and pleasure.
Rohypnol, GHB, and ketamine are predominantly
central nervous system depressants. Because they are often
colorless, tasteless, and odorless, they can be added easily

56 BraiN factS | diseases and disorders Society for NeuroScieNce

chaPter 12:
haPter
degeNerative diSorderS
in this chapter
n Alzheimer’s Disease
n Amyotrophic Lateral Sclerosis (ALS)
n Huntington’s Disease
n Parkinson’s Disease
Alzheimer’s Disease
One of the most frightening and devastating of all
neurological disorders is the dementia that can occur in the
elderly. The most common form of this illness is Alzheimer’s
disease. Rare before age 60 but increasingly prevalent in
each decade thereafter, Alzheimer’s affects 5 percent of
Americans age 65 to 74 and nearly half of those age 85 and
older. As many as 5.3 million Americans have Alzheimer’s.
The disease is predicted to affect approximately 14 million
individuals in the United States by the year 2050.
The earliest symptoms of Alzheimer’s include
forgetfulness; disorientation as to time or place; and
difficulty with concentration, calculation, language, and
judgment. As the disease progresses, some patients have
severe behavioral disturbances and may even become
psychotic. In the final stages, the affected individual is
incapable of self-care and becomes bedridden. Patients
usually die from pneumonia or some other complication of
immobility. Alzheimer’s disease is the seventh leading cause
of death in the United States and the fifth leading cause of
death for Americans aged 65 and older.
In the earliest stages, the clinical diagnosis of
possible or probable Alzheimer’s can be made with greater
than 80 percent accuracy. As the course of the disease
progresses, the accuracy of diagnosis at Alzheimer’s research
centers exceeds 90 percent. The diagnosis depends on
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medical history, physical and neurological examinations,
psychological testing, laboratory tests, and brain imaging
studies. New brain imaging strategies promise to enable
doctors to visualize Alzheimer’s neuropathology during
life. At present, however, final confirmation of the
diagnosis requires examination of brain tissue, usually
obtained at autopsy.
The causes and mechanisms of the brain abnormalities
underlying Alzheimer’s are not yet fully understood,
but great progress has been made through the study of
genetics, biochemistry, and cell biology, as well as the use
of experimental treatments. Neuroscientists do know that
reductions occur in markers for many neurotransmitters that
allow cells to communicate with one another. These include
acetylcholine, somatostatin, monoamines, and glutamate.
Damage to these neural systems, which are critical for
attention, memory, learning, and higher cognitive abilities,
is believed to cause the clinical symptoms.
Microscopic examination of brain tissue from people
who died from Alzheimer’s shows abnormal accumulations
of a small fibrillar peptide, termed beta amyloid, in the
spaces around synapses. These accumulations of tissue are
referred to as neuritic plaques. Another abnormal clump of
proteins, called neurofibrillary tangles, have been identified
as a modified form of the protein tau, which is found in the
cell bodies of neurons. In all forms of Alzheimer’s, plaques
and tangles mostly develop in brain regions important for
memory and intellectual functions. New brain imaging
strategies that may one day be used for diagnosis use a mildly
radioactive chemical marker that shows amyloid plaques and
tau tangles in living people.
Early-onset Alzheimer’s disease is a rare, dominantly
inherited form of the disease. Recently, scientists have
identified Alzheimer’s disease-associated mutations. The
gene encoding the amyloid precursor protein (APP) is
on chromosome 21. In some families with early-onset
Alzheimer’s, mutations have been identified in the presenilin
1 and 2 genes. Genes that cause dominant Alzheimer’s
appear to do so by causing beta amyloid plaques to
accumulate. Apolipoprotein E (apoE), which influences
diseases and disorders | BraiN factS 57
susceptibility for Alzheimer’s later in life, exists in three
forms. The variant known as APOE epsilon 4 is clearly
associated with enhanced risk.
Latest Research and Treatments Currently
approved treatments for Alzheimer’s disease do not modify
the course of the disease and offer only temporary mitigation
of some symptoms, such as agitation, anxiety, unpredictable
behavior, sleep disturbances, and depression. Five drugs
have been approved by the FDA to treat Alzheimer’s. Four
prevent the breakdown of acetylcholine, a brain chemical
important for memory and thinking. The fifth regulates
glutamate, a brain chemical that may cause brain cell death
when produced in large amounts. These agents temporarily
improve memory deficits and provide some symptomatic
relief but do not prevent progression of the disease. Several
other approaches, such as antioxidants, are being tested.
An exciting area of research is the introduction of
Alzheimer’s disease-causing genes in mice. These mice,
carrying mutant genes linked to inherited Alzheimer’s,
develop behavioral abnormalities and some of the
microscopic changes in tissue structure that occur in
humans. It is hoped that these mouse models will prove
Healthy Brain Advanced Alzheimer’s
Cortex Cortex
Hippocampus
Alzheimer’s disease primarily affects the hippocampus and cortex regions of
the brain, probably by damaging and destroying the connections between
brain cells and later by causing cell death. Although initial symptoms are
minor, this damage leads to impairments in learning, memory, and thinking
and is eventually fatal. [Credit: Adapted and reprinted with permission from the
Alzheimer’s Association. © 2008 Alzheimer’s Association.]
58 BraiN factS | diseases and disorders
useful for studying the mechanisms of the disease and
testing novel therapies, although appropriate caution
must be taken. Experimental therapies in models of other
neurodegenerative diseases — amyotrophic lateral sclerosis,
for example — have been effective in mice with the disease
but not in humans.
Researchers have begun to modulate the actions of
genes that play critical roles in the production of amyloid
in animal models. These genes encode beta and gamma
secretases, which cut amyloid peptide from a larger protein.
The amyloid peptide is then released from the neuron into
the space around synapses, where it can accumulate and form
Alzheimer’s disease plaques. Amyloid-destroying enzymes,
known as alpha secretases, break up the amyloid peptide,
preventing amyloid accumulation. Anti-amyloid therapies
for Alzheimer’s aim either to remove existing amyloid or
decrease production of new amyloid.
Within the past three to five years, greater appreciation
has developed for the surprisingly important roles that diet
and lifestyle play in determining risk for Alzheimer’s disease.
Cognitive activity, physical activity, and heart-healthy diets
lower the risk for Alzheimer’s, while obesity, high blood
pressure, high cholesterol, metabolic syndrome, and diabetes
raise the risk. Some evidence indicates that successful
management of these cardiovascular risks can delay the onset
or slow the progression of dementia.
Amyotrophic Lateral Sclerosis (ALS)
This progressive disorder strikes approximately
5,600 Americans annually, with an average survival time
of just two to five years from symptom onset. It is the most
common disorder within a group of diseases affecting motor
neurons. Typically, 30,000 Americans have the disease at
any given time. The costs of both care and treatment for
ALS are expensive, and they continue to rise as the disease
progresses. In the final stages, ALS can cost as much as
$200,000 a year per family, and costs Americans some $300
million annually.
Commonly known as Lou Gehrig’s disease, ALS affects
neurons that control voluntary muscle movements such as
walking. For reasons that are not completely understood,
motor neurons in the brain and spinal cord begin to
disintegrate. Because signals from the brain are not carried
by these damaged nerves to the body, the muscles begin to
weaken and deteriorate from the lack of stimulation and
resulting disuse.
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 The first signs of progressive paralysis are usually seen
in the hands and feet or in the muscles of speech and
swallowing. Early symptoms include weakness in the legs,
difficulty walking, clumsiness of the hands when washing and
dressing, and slurred speech. Eventually, almost all muscles
under voluntary control, including those of the respiratory
system, are affected. Despite the paralysis, however, the mind
and the senses remain intact. Death is usually caused by
respiratory failure or pneumonia.
No specific test identifies ALS, but electrical tests of
muscle activity, muscle biopsies, blood studies, computed
tomography (CT), and magnetic resonance imaging (MRI)
scans help diagnose the disease and rule out other disorders.
In more than 90 percent of cases, ALS is sporadic,
arising in individuals with no known family history of the
disorder. Potential causes or contributors to the disease
include an excess amount of the neurotransmitter glutamate,
which becomes toxic; oxygen in a dangerous form in
the body, resulting in what is called oxidative distress;
environmental factors; and an autoimmune response in
which the body’s defenses turn against body tissue. In the
other 5 to 10 percent of cases, ALS is familial — transmitted
to family members because of a gene defect.
Scientists have now identified several genes that are
responsible for some forms of ALS. The most common and
well-studied of these are mutations in the gene that codes
for superoxide dismutase, a defense against oxidative distress.
Scientists believe that whatever they learn from studying
this and other genes will have relevance for understanding
the more common, sporadic form of this motor neuron
disease.
Once ALS is diagnosed, there is little that can be
done to slow its progression. Various drugs can ease specific
problems, such as muscle cramping and neurological
stiffness, but there is no cure. An anti-glutamate drug slows
the disease’s progression modestly. Additional drugs are now
under study. Protecting or regenerating motor neurons using
nerve growth factors, other more potent drugs, and stem cells
may someday provide additional benefits for patients.
huntington’s Disease
Affecting some 30,000 Americans and placing 200,000
more Americans at risk for inheriting the disease from an
affected parent, Huntington’s disease is now considered one
of the most common hereditary brain disorders. The disease
progresses slowly over a 10- to 20-year period and eventually
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Affecting some 30,000 Americans
and placing 200,000 more at risk,
Huntington’s disease is now
considered one of the most common
hereditary brain disorders.
robs the affected individual of the ability to walk, talk, think,
and reason. Huntington’s disease usually appears between
the ages of 30 and 50. It affects both the basal ganglia, which
controls coordination, and the brain cortex, which serves as
the center for thought, perception, and memory.
The most recognizable symptoms include involuntary
jerking movements of the limbs, torso, and facial muscles.
These are often accompanied by mood swings, depression,
irritability, slurred speech, and clumsiness. As the disease
progresses, common symptoms include difficulty swallowing,
unsteady gait, loss of balance, impaired reasoning, and
memory problems. Eventually, the individual becomes
totally dependent on others for care, with death often due to
pneumonia, heart failure, or another complication.
Diagnosis consists of a detailed clinical examination and
family history. Brain scans may be helpful. The identification
in 1993 of the gene that causes Huntington’s has simplified
genetic testing, which can be used to help confirm a
diagnosis. Researchers and genetic counselors, however, have
established specific protocols for predictive genetic testing to
ensure that the psychological and social consequences of a
positive or negative result are understood. Predictive testing
is available only for adults, though children under the age
of 18 may be tested to confirm a diagnosis of juvenile-onset
Huntington’s disease. Prenatal testing may be performed.
The ethical issues of testing must be considered, and the
individual must be adequately informed, because there is
no effective treatment or cure, although medications are
available to help control some of the symptoms.
The Huntington’s disease mutation is an expanded
triplet repeat — a kind of molecular stutter in the DNA.
This abnormal gene codes for an abnormal version of the
protein called huntingtin. The huntingtin protein, whose
normal function is still unknown, is widely distributed in the
diseases and disorders | BraiN factS 59
brain and appears to be associated with proteins involved
in transcription (turning genes on), protein turnover, and
energy production. Scientists suspect that Huntington’s
disease is caused by the gain of a new and toxic function
among these proteins.
Cell and animal models can replicate many features
of the disease and are now being used to test new theories
and therapies. Although no effective treatments for slowing
disease progression currently exist, clinical and observational
trials are being conducted. Any of these may yield an
effective treatment that would slow the progression or delay
onset of the disease while researchers continue working
toward a cure.
Parkinson’s Disease
Parkinson’s disease is a progressive neurological disorder
that affects approximately 1.5 million individuals in the
United States. Typically, people start showing symptoms over
the age of 50. In fact, aging is the only known risk factor for
the development of this disorder.
Parkinson’s disease is characterized by slowness of
movement, muscular rigidity, and walking and balance
impairment. Many affected individuals may develop a
resting tremor as well. Besides impairment in motor
movement, Parkinson’s may also cause changes in non-motor
brain function.
On a cellular level, Parkinson’s disease is the result of
the loss of dopamine-producing cells in the region of the
brain called the substantia nigra pars compacta, found in the
midbrain. A large number, 40 percent, of cells must be lost
before symptoms occur, suggesting that perhaps the brain has
a way of warding off symptoms. Eventually, however, these
mechanisms begin to fail, or the continued loss of cells leads
to a threshold from which the brain can no longer recover.
Although the cause of Parkinson’s remains unknown,
most researchers believe that there are both genetic and
environmental factors that contribute to the injury and
eventual loss of these dopamine-producing cells. While
most cases of Parkinson’s do not appear to be inherited,
there are certain situations in which genetic factors may be
involved. For example, studies indicate that cases of early
onset Parkinson’s may be inherited. Research on various
forms of the disease may help provide clues about it, as well
as insights into potential new treatments.
60 BraiN factS | diseases and disorders
Deep brain stimulation shows promise at relieving symptoms for some
people with Parkinson’s disease. As shown in the X-ray image, the therapy
uses an implanted electrode to deliver electrical impulses deep within the
brain. [Credit: Courtesy of Robert S. Fisher, MD, PhD, Stanford Neurology and
Jaimie henderson, MD, PhD, Stanford Neurosurgery.]
Treatment Breakthroughs — and the Need for
More Research The discovery in the late 1950s that the
level of dopamine was decreased in the brains of Parkinson’s
patients was followed in the 1960s by successful treatment
with the drug levodopa, which is converted to dopamine in
the brain. This historical event is one of the greatest medical
breakthroughs in the field of neurology.
Since the discovery of levodopa, other drugs have
been developed to either boost the effect of dopamine, by
inhibiting its breakdown, or extend the length of dopamine-
like effects, through their ability to bind and act on similar
brain regions for longer periods of time. For example, a
drug called carbidopa is often combined with levodopa; the
combination is effective in that it reduces the breakdown
of levodopa in the bloodstream, allowing greater levels of
dopamine to reach the brain. It also reduces side effects, such
as nausea.
Although dopamine replacement therapy is very
effective in alleviating many of the motor symptoms of
Parkinson’s, there still remains a critical need to find better
treatments. For one thing, dopamine replacement therapy
neither cures the disease nor slows its progression. In
addition, dopamine replacement is not optimal for treating
non-motor aspects of the disease, such as anxiety and sleep
issues. What’s more, this treatment becomes less effective
over time in helping with gait and balance problems.
Because many unanswered questions remain
in our understanding of Parkinson’s, more medical
research is greatly needed. Using animal models is an
effective way to learn more about the disease and to
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identify new and better treatments and potential cures. dopamine. Replacement therapy with stem cells is being
Rodent and nonhuman primate models are among explored as well. In addition, gene transfer of trophic
the many valuable animal models used to investigate factors has been studied in animal models and is being
important, specific questions about the disorder. tested in clinical trials. Clinical trials also are testing the
One common rodent and nonhuman primate model hypothesis that gene therapy can provide symptomatic or
uses the neurotoxin MPTP (1-methyl-4-phenyl-1, 2, 3, 6 neuroprotective benefit to patients with Parkinson’s. While
tetrahydropyridine). MPTP was first discovered in the late there is clearly much work to do, neuroscience research
1970s, when it was accidentally synthesized by designers focusing on Parkinson’s is moving forward by exploring
of illicit drugs looking for ways to produce a heroin-like many avenues simultaneously. The hope is to find better
compound. The drug addicts who self-injected the MPTP- treatments — and eventually, perhaps, a cure.
contaminated preparations developed a neurological
condition that was indistinguishable from Parkinson’s.
Researchers soon found that MPTP is converted in the brain
to a substance that destroys dopamine neurons. This finding
led to using MPTP as a tool for medical studies.
Over the past several decades, scientists have shown
that in primate models of Parkinson’s, there are specific
regions in the basal ganglia, the group of cellular structures
deep in the brain, that are abnormally overactive. Most
important, they found that surgical deactivation or
destruction of these overactive structures — the pallidum
and subthalamic nucleus — can greatly reduce symptoms of
Parkinson’s disease.

Neuroscience research focusing

on Parkinson’s disease is moving
forward by exploring many
avenues simultaneously.

The past decade has witnessed a resurgence in

this surgical procedure, called pallidotomy. More
recently, chronic deep-brain stimulation has been
used. These techniques are highly successful for
treating patients who have experienced significant
worsening of symptoms and are troubled by the
development of drug-related involuntary movements.
Also on the horizon are attempts to treat Parkinson’s
patients whose disease is progressing rapidly with surgical
implantation of cells, such as fetal cells, capable of producing

Society for NeuroScieNce diseases and disorders | BraiN factS 61

chaPter 13:
haPter
PSychiatric diSorderS
in this chapter
n Anxiety Disorders
n Tourette Syndrome
n Major Depression
n Bipolar Disease
n Schizophrenia
Anxiety Disorders
Considered the most common mental illnesses,
anxiety disorders affect an estimated 18 percent of the
adult population in a given year, or 40 million Americans.
Anxiety disorders include obsessive-compulsive disorder
(OCD); panic disorder; phobias, such as acrophobia, or
fear of heights and; agoraphobia, or fear of open spaces;
social anxiety disorder; generalized anxiety disorder; and
post-traumatic stress disorder (PTSD). These disorders can
be crippling, to the point of keeping people completely
housebound. What’s more, anxiety disorders often occur
with depression, and individuals doubly afflicted are at a
high risk of suicide.
Discussed below are a few of the more prevalent anxiety
disorders. These summaries provide a snapshot of the nature
of anxiety disorders, how they are studied, and the treatments
that are currently being used.
OCD People with OCD become trapped, often for
many years, in repetitive thoughts and behaviors, which
they recognize as groundless but cannot stop. Such behavior
includes repeatedly washing hands or checking that doors
are locked or stoves turned off. The illness is estimated to
affect 2.2 million American adults annually. One-third of
adults develop their symptoms as children.
62 BraiN factS | diseases and disorders
Neuroscientists think that environmental factors and
genetics probably play a role in the development of the disorder.
Positron emission tomography (PET) scans reveal abnormalities
in both cortical and deep areas of the brain, implicating central
nervous system changes in individuals with OCD.
OCD is not limited to people either. Scientists have
recently discovered that certain breeds of large dogs develop
acral lick syndrome, severely sore paws from compulsive
licking. These dogs respond to the serotonergic antidepressant
clomipramine, which was the first effective treatment
developed for people with OCD. This and other serotonergic
antidepressants, as well as selective serotonin reuptake inhibitors
(SSRIs) such as sertraline and paroxetine, are effective in
treating OCD. A specialized type of behavioral intervention,
called exposure and response prevention, also is effective in
many patients.
Panic Disorder and Phobias With a lifetime
prevalence rate of 4.7 percent in the United States, panic
disorder usually starts unexpectedly. Patients experience an
overwhelming sense of impending doom, accompanied by
sweating, weakness, dizziness, and shortness of breath. With
repeated attacks, patients may develop anxiety in anticipation
of another attack. As a result, people may avoid public
settings where attacks might occur. If these individuals are
untreated, they may develop agoraphobia and become virtually
housebound. Antidepressants, including SSRIs, are effective, as
is cognitive behavioral therapy.
Phobia is an intense, irrational fear of a particular object or
situation. Individuals can develop phobias of almost anything,
including dogs, dating, blood, snakes, spiders, or driving over
bridges. Exposure to the feared object or situation can trigger
an extreme fear reaction that may include a pounding heart,
shortness of breath, and sweating. Cognitive behavioral therapy
is an effective treatment. It is likely that panic disorders and
phobias have similar neurochemical underpinnings that emerge
as the result of a particular “stressor.”
Post-Traumatic Stress Disorder Extreme stressors
such as trauma in combat, being a victim of assault or sexual
abuse, or experiencing or witnessing a crime can lead to a
form of stress that can last a lifetime. In the United States, this
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condition, called post-traumatic stress disorder, or PTSD, has a
lifetime prevalence rate of 6.8 percent (9.7 percent in women
and 1.8 percent in men). It is characterized by intense fear,
helplessness or horror, intrusive recollections of the traumatic
event, avoidance and numbing, and hyperarousal. In addition,
PTSD is associated with dysregulation of stress hormones,
disordered sleep, and major depressive disorder. Military
personnel are at elevated risk for exposure to trauma, so not
surprisingly, they have higher prevalence rates compared to the
general population.
Scientists have studied PTSD in depth and have learned
that the very high levels of norepinephrine released in the
brain during stress remain at heightened levels. Medications
that work well for patients with PTSD have emerged from
basic research into norepinephrine’s actions in different brain
regions. The alpha-1 blocker prazosin, a drug used to lower
blood pressure for more than 20 years, is now used to treat
nightmares experienced with PTSD. People treated with
prazosin include those with a very long-standing illness, such
as Holocaust survivors. Beta-blockers such as propranolol also
are being tested in individuals exposed to trauma, but these
agents must be administered shortly after the trauma, before
PTSD has been established, which brings up complex ethical
issues. PTSD also is treated with antidepressant and atypical
antipsychotic medications and psychotherapies, such as
cognitive behavioral therapy or eye movement desensitization
and reprocessing therapy.
The discovery of brain receptors for the benzodiazepine
antianxiety drugs has sparked research to identify the brain’s
own antianxiety chemical messengers. Benzodiazepines bind to
GABA receptors and enhance responsiveness to endogenous
GABA, the major inhibitory neurotransmitter in the brain.
Indeed, recent studies have revealed alterations in certain
GABA receptors in the central nervous system of patients with
PTSD, effectively providing an additional neurochemical link
between different anxiety disorders. This finding may lead to
new ways to modulate anxiety disorders.
Tourette Syndrome
One of the most common and least understood
neurobiological disorders, Tourette syndrome is an inherited
disorder that affects about 200,000 Americans. Males are
affected three to four times as often as females.
Symptoms usually appear between the ages of four and
eight, but in rare cases may emerge in the late teenage years.
The symptoms include motor and vocal tics — repetitive,
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involuntary movements or utterances that are rapid, sudden
and persist for more than one year. The types of tics may
change frequently and increase or decrease in severity over
time. In roughly one-half of individuals, this disorder lasts a
lifetime, but the remaining patients may experience a remission
or decrease in symptoms as they get older. A high percentage
of people with Tourette syndrome also have associated
conditions, such as problems with learning, difficulties with
attention, obsessive thoughts and compulsive rituals. Often
these manifestations are more troublesome to individuals than
the tics themselves, so physicians must consider them when
choosing a treatment regimen.
Tourette syndrome is inherited and seems to result from
abnormal activity in a brain system called the basal ganglia.
Research suggests that genes associated with Tourette’s, perhaps
together with in utero or early environmental conditions,
cause abnormalities in basal ganglia development or excesses in
certain chemicals, including the neurotransmitter dopamine.
The majority of people with Tourette syndrome are not
significantly disabled by symptoms, so they do not require
medication. However, antipsychotics and SSRIs, as well as
drugs to control tics, nausea, high blood pressure, seizures,
or anxiety, are available to help control symptoms when
they interfere with functioning. Stimulant medications such
as methylphenidate and dextroamphetamine, which are
prescribed for attention deficit hyperactivity disorder (ADHD),
have been reported to improve attention and decrease tics
in Tourette syndrome. For obsessive-compulsive symptoms
that interfere significantly with daily functioning, SSRIs,
antidepressants, and related medications may be prescribed.
Medication dosages that achieve maximum control of
symptoms vary for each person and must be gauged carefully
by a doctor. The medicine is administered in small doses,
with gradual increases to the point where there is maximum
alleviation of symptoms with minimal side effects. Some of
the undesirable reactions to medications are weight gain,
muscular rigidity, fatigue, motor restlessness, and social
withdrawal. Most of these side effects can be reduced with
specific medications. Other side effects, such as depression and
cognitive impairment, can be alleviated with dosage reduction
or a change of medication.
Other types of therapy also are helpful. Behavioral
therapies, such as those used to treat similar disorders that
emerge in childhood, have been receiving more attention.
Aimed at training circuits to control the specific behavior
related to the tic, these therapies have proven to be highly
diseases and disorders | BraiN factS 63
effective in reducing the severity of tics in some subtypes
of Tourette syndrome. Psychotherapy and counseling can
assist people with this disorder, as well as providing coping
mechanisms for family members.
Major Depression
Clinical or major depression, with its harrowing feelings
of sadness, hopelessness, pessimism, loss of interest in life, and
reduced emotional well-being, is one of the most common
and debilitating mental disorders. The disorder also comes
with disturbances of sleep and appetite, decreased energy, and
often cognitive disturbances such as difficulty concentrating
and remembering. Depression is as disabling as heart disease
or arthritis. What’s more, depressed individuals are at a
significantly elevated risk of suicide.
While both genes and the environment play a role in
an individual’s risk for depression, stress also can trigger a
depressive episode. We now know that the physical symptoms
may reflect disturbances in the hypothalamus, resulting in an
excessive production of stress hormones. This has been shown
in the laboratory: Many depressed patients fail to shut off
secretion of the stress hormone cortisol in response to potent
synthetic analogs that normally feed back to shut off secretion.
Experiments with positron emission tomography (PET)
imaging have also implicated a region of the anterior cingulate
gyrus within the prefrontal cerebral cortex in depression.
This region, which normally integrates aspects of cognition
and emotion, is the chief experimental target for deep brain
stimulation in severely depressed patients who have not
responded to other treatments.
In the United States, the lifetime risk of a depressive
episode severe enough to warrant treatment is approximately
18 percent. Put another way, in the past 12 months, 6.7
percent of U.S. adults experienced a major depression.
Fortunately, 80 percent of these individuals respond to drugs,
psychotherapy, or a combination of the two. Some severely
depressed patients can be helped with electroconvulsive
therapy. As mentioned above, those patients who do not
respond to the standard antidepressant drugs may be helped
by deep brain stimulation approaches, which were originally
developed for patients with neurodegenerative disease.
Currently, approved antidepressant drugs increase levels
of norepinephrine or serotonin in synapses. A few medications
also target dopamine. The well-known selective serotonin
reuptake inhibitors, or SSRIs, act on serotonin alone. The
increased levels of neurotransmitters then initiate plastic
64 BraiN factS | diseases and disorders
changes in cells and circuits, leading to an improvement
in symptoms over several weeks. In addition, cognitive
behavioral psychotherapies have been shown to be effective.
Recently, ketamine, a drug that blocks NMDA glutamate
receptors, has been shown to alleviate depressed symptoms
rapidly. Because ketamine has many side effects, it is not likely
to be used clinically, but these findings have set off an exciting
search for new pharmacologic approaches.
Depression is as disabling as
heart disease or arthritis.
Bipolar Disorder
People with bipolar disorder, previously known as
manic-depressive illness, usually experience episodes of deep
depression and manic highs. Many patients return to normal
moods in between acute episodes, but a large number continue
to have troubling symptoms, usually of depression. They also
have an increased risk of suicide. The depressive episodes are
indistinguishable from those of a major depression and are
characterized by sad mood, loss of interest, lack of energy,
disturbances of sleep and appetite, difficulty concentrating,
feelings of hopelessness and worthlessness, suicidal thoughts,
and sometimes suicidal acts.
Symptoms of mania include increased energy,
decreased need for sleep, a marked interest in goal-directed
activities, and poor judgment. For example, during manic
episodes, individuals may spend excessively or engage in
uncharacteristic drug abuse or sexual behaviors. Individuals
with mania may be euphoric, but some are predominantly
irritable. Typically, manic individuals are grandiose, and when
the mania is particularly severe, they may have delusions or
hallucinations. In such instances, patients may believe that
they are prophets, deities, or on a special mission. Sometimes,
too, mania can be mild. Then it is called hypomania.
Bipolar disorder that is characterized by full manic
episodes and depressions affects about 1 percent of the
population worldwide. When people who suffer from
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hypomania along with depressions are factored in, the
prevalence goes up to 2.6 percent. This finding is based on a
study of Americans over the age of 18. In addition, about the
same number of men and women suffer from bipolar disorder.
People with this disorder typically have recurrences of acute
mania or depression throughout their lives.
Bipolar disorder is highly influenced by genes. In fact,
many different genes contribute to the risk of the disorder.
Modern technology has allowed us to identify a small number
of these genes. The study of the genetic basis of bipolar
disorder continues to be a very active area of research.
Individuals with this disorder can benefit from a broad
array of treatments. One of these is lithium. During the late
1940s, researchers showed that when guinea pigs were injected
with lithium, they became placid, implying that the lithium
had a mood-stabilizing effect. When given to manic patients,
lithium improved all manic symptoms and stabilized their
moods. This enabled people with the disorder to return to
work and live relatively normal lives.
Although lithium is quite effective, many patients require
additional treatments, especially for their depression. Other
medications with mood-stabilizing effects used to treat bipolar
disorder include some drugs, such as valproate, that were first
developed as anticonvulsants. None of the existing drugs are
perfect, and they all have side effects. As a result, additional
research on bipolar disorder and its treatment continues to be
an important priority.
Schizophrenia
Marked by disturbances in thinking, cognition,
emotional reactions, and social behavior, schizophrenia
usually results in chronic illness and personality change.
Delusions, hallucinations, and thought disorder are common,
as are disturbances in attention, memory, and complex
thinking. Affecting about 1.1 percent of the population, or
2.4 million Americans, schizophrenia is disabling and costly.
Annual costs total about $62.7 billion.
Schizophrenia leads to changes that may be caused
by the disruption of neurodevelopment through a genetic
predisposition, which may be exacerbated by environmental
factors such as maternal infections or direct brain trauma.
Brain scans and postmortem studies show abnormalities in
some people with schizophrenia, such as enlarged ventricles
(fluid-filled spaces) and reduced size of certain brain regions.
Functional neuroimaging scans such as PET and functional
magnetic resonance imaging (fMRI) taken while individuals
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perform cognitive tasks, particularly those involving memory
and attention, show abnormal functioning in specific brain
areas of people with this illness. Brain systems using the
chemicals dopamine, glutamate, and GABA appear to be
particularly involved in the development of the disorder.
Recently, mutations in several genes involved in controlling
nerve cell communication have been identified that appear
to increase the risk of developing schizophrenia.
The disorder usually is diagnosed between the ages of 15
and 25. Few patients recover fully following treatment, and
most continue to have moderate or severe symptoms that may
be aggravated by life stressors. About 15 percent of individuals
return to a productive life after a single episode, 60 percent
will have intermittent episodes throughout their lives, and
an additional 25 percent will not recover their ability to live
as independent adults. Deficits in cognition are frequent,
lifelong manifestations in most patients, even those who show
good recovery from more acute “positive” symptoms, such as
hallucinations, delusions, and confused thinking. “Negative”
symptoms, such as inability to experience pleasure and lack of
motivation, may be the most debilitating part of the disorder.
These symptoms make it difficult for many people to lead
productive lives. Unfortunately, many of these symptoms are
generally resistant to drug treatment.
The first antipsychotic drug, chlorpromazine, was
discovered by accident in the 1950s and shown to reduce
symptoms of schizophrenia. Clinical trials demonstrated that
chlorpromazine was more effective than a placebo or a sedative.
Subsequently, more than 20 effective antipsychotic drugs were
developed. The first generation of antipsychotic drugs acts
by inhibiting certain dopamine receptors. This mechanism
accounts for the high prevalence of side effects, similar to those
seen with Parkinson’s, that are associated with the use of first-
generation antipsychotics. The mechanism also explains the
risk of developing an irreversible movement disorder, tardive
dyskinesia, which results in aimless, uncontrollable movements,
such as grimacing or rapid eye blinking.
The second generation of antipsychotic medications
were developed to be more effective in treating the positive
symptoms of schizophrenia. They do not have the same
likelihood of causing Parkinsonian effects but can lead to other
debilitating side effects, such as very large weight gain, blood
disorders, and muscle pain and dysfunction. As a result of
problems with both generations of antipsychotic medications,
safer drugs with fewer side effects are currently being sought.
diseases and disorders | BraiN factS 65
chaPter 14:
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iNjury aNd illNeSS
in this chapter
n Brain Tumors
n Multiple Sclerosis
n Neurological AIDS
n Neurological Trauma
n Pain
n Seizures and Epilepsy
n Stroke
Brain Tumors
Primary brain tumors develop within brain tissue. Such
tumors can spread throughout the brain, but they are not
always cancerous, or malignant. Malignant brain tumors can
originate in the brain or spread to the brain from other parts
of the body, a condition that becomes potentially lethal.
The likelihood to grow faster and invade, coupled with the
identification of specific cells within the tumor, are some of
the criteria used to classify the tumor’s severity, or grade. No
matter what grade a brain tumor is assigned — and whether
it’s malignant or not — these growths are always serious
because they can interfere with normal brain activity.
Brain tumors can be either primary or metastatic.
Primary brain tumors arise within the brain, whereas
metastatic (also called secondary) brain tumors spread from
other parts of the body through the bloodstream and enter
the brain. The incidence of primary brain tumors is about
19 cases per population of 100,000. About 35,000 new cases
occur in the United States annually.
Symptoms of brain tumors vary according to the
tumor’s location and size, but seizures and headaches are
among the most common. In particular, gliomas, typically
malignant brain tumors, release the neurotransmitter
66 BraiN factS | diseases and disorders
glutamate at toxic concentrations. The glutamate kills off
neurons near the tumor, making room for its expansion.
The released glutamate is largely responsible for the seizures,
which originate from tissue surrounding the tumor. An
expanding tumor can increase pressure within the skull,
causing headache, vomiting, visual disturbances, and
impaired mental functioning. Brain tumors are diagnosed
with MRI and CT scanning. Early imaging is beneficial
because it can mean that tumors are identified at a lower
grade, improving prognosis and outcome considerably.
Treatment options for primary brain tumors are limited.
Surgery is generally the first step if the tumor is accessible
and vital structures will not be disturbed. Radiation is used
to stop a tumor’s growth or cause it to shrink. Chemotherapy
destroys tumor cells that may remain after surgery and
radiation, but it is not very effective for gliomas, largely
because it is hard for chemotherapeutic drugs to reach the
brain. Steroid drugs relieve brain swelling and antiepileptic
drugs control seizures.
New therapies for brain tumors are being developed
in clinical trials. Many of these trials focus on targeted
therapy — treatment aimed at the biologic characteristics
of tumors. Targeted therapies include vaccines created from
the patient’s own tumor combined with substances that
boost the immune system or kill tumor cells; monoclonal
antibodies, which home in on receptors on the surface of
the tumor cells; anti-angiogenic therapy, during which the
tumor’s blood supply is restricted; immunotherapy, which
uses the body’s own immune system against the tumor;
gene therapy, which delivers bioengineered genes to the
cancer cells to kill them; and several approaches for a
targeted delivery of antibodies, toxins, or growth-inhibiting
molecules that attach specifically to the tumor cells and
interfere with their growth. A scorpion-derived toxin called
chlorotoxin, which interferes with the spread of the tumor,
has shown promise in clinical studies. This therapy extended
life expectancy significantly.
Researchers are exploring the role of stem cells in the
origin of brain tumors, and brain tumor research is being
strongly influenced by the wealth of research into neural
stem cells in particular. As the identification of the cellular
components that make up different tumors becomes easier
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(due to genomics technology and neural stem cell research),
scientists will be able to better target the cells in the tumor
that are most likely to be the most harmful. Epidemiologists,
or scientists studying disease in human populations, also
are looking into tumor genetics and patients’ lifestyles,
environments, occupations, and medical histories for clues
about the causes of these tumors. International efforts are
underway to increase awareness of brain tumors, encourage
research collaboration, and explore new and innovative
therapies.
Multiple Sclerosis
Multiple sclerosis (MS) is a lifelong ailment of unknown
origin that affects approximately 400,000 Americans and
2.5 million people worldwide. MS is diagnosed mainly in
individuals between the ages of 20 and 40. The disease
affects every aspect of a patient’s life. In fact, in the United
States, the disease results in earnings losses of about $10.6
billion annually for individuals with MS and their families.
MS is an autoimmune disease in which the body’s natural
defenses attack the myelin sheath covering the axons of
neurons in the central nervous system. While neuroscientists
do not know what causes this autoimmune assault, they have
discovered that the loss of myelin results in damage to the nerve
fibers. In some instances, the damage may be so severe that
the nerve fiber deteriorates. The effects are comparable to the
loss of insulating material around an electrical wire or cutting
of the wire, which interferes with the transmission of signals.
Following loss of myelin, the axon’s sheath is either repaired
or replaced by scars, or scleroses, of hardened patches of tissue.
Scarring is usually associated with further degeneration of the
nerve fibers. Areas of disease activity, called lesions or plaques,
appear in multiple places within the central nervous system.
Siblings of people with MS are at a 2 to 3 percent risk
of developing MS (10 to 15 times higher than the general
population), whereas the risk for an identical twin of
someone with MS is much higher — about 30 percent. In
addition, the disease is as much as five times more prevalent
in temperate zones, such as the northern United States and
northern Europe, than it is in the tropics. Caucasians are
more susceptible than other races. Thus, both genetic and
environmental factors probably play a role in determining
who contracts the disease. Previous studies had suggested
that those who developed MS before the age of 15 were
affected by environmental factors, but more recent, larger
studies suggest that there is no exact age cutoff.
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The symptoms of MS depend on the site of the damage.
Because the spinal cord, cerebellum, and optic nerve are
commonly affected, symptoms such as numbness, clumsiness,
and blurred vision often occur. However MS can affect many
other brain areas, including bundles of myelinated nerve fibers
(white matter) and areas rich in neurons (gray matter), so
symptoms may also include slurred speech, weakness, loss of
coordination, pain, uncontrollable tremors, loss of bladder
control, memory loss and other cognitive problems, depression,
and fatigue. Symptoms due to an acute attack may last from
several weeks to months and then spontaneously improve.
This form of MS is known as relapsing/remitting. If, however,
there is ongoing nerve fiber degeneration, symptoms become
permanent and gradually worsen, causing progressive MS. This
form of MS leads to a progressive accumulation of disability
usually affecting mobility, strength, balance, and coordination.
At this point, MS cannot be cured, but several
medications help control relapsing/remitting forms of MS
by lixmiting the immune attack and reducing associated
inflammation. Steroids, which have been used to treat MS
for more than three decades, may be effective in shortening
attacks, thus helping to speed recovery from MS-related
acute attacks. What’s more, an increasing range of newer,
more selective drugs are now becoming available or are
in clinical trials. While many medications and therapies
are available to control symptoms such as muscle stiffness
(spasticity), pain, fatigue, and mood swings, as well as
bladder, bowel, or sexual dysfunction, no treatments
are available for the nerve degeneration that causes the
progression of the disease.
Neurological AIDS
In 2009, about 2.5 million people worldwide became
infected with human immunodeficiency virus (HIV); 33
million are now living with HIV. Advanced HIV infection
is known as acquired immunodeficiency syndrome, or AIDS.
The epidemic is still the most intense in sub-Saharan Africa,
but it is gaining traction in Asia and Eastern Europe. The
impact of AIDS in the United States has been tempered by
more widespread use of life-prolonging drugs, making HIV
a chronic illness instead of a death sentence. In developing
countries, however, only about 36 percent of the people
who need therapy are receiving such treatment. In addition,
women now represent half of all cases worldwide.
Although the principal target of HIV is the immune
system, the nervous system may be affected in varying
diseases and disorders | BraiN factS 67
degrees. HIV-associated neurocognitive disorder (HAND)
is a common complication affecting more than 50 percent
of people with HIV. HAND also affects those receiving the
modern combination antiretroviral treatment (CART),
though not to the same degree. Individuals with HAND
have mental problems ranging from mild difficulty with
concentration, memory, complex decision-making or
coordination to progressive, fatal dementia.
Despite advances in treating other aspects of the
disease, HAND remains incompletely understood. Most
current hypotheses center on an indirect effect of HIV
infection related to secreted viral products or cell-coded
signal molecules called cytokines. Some proteins of the virus
itself are neurotoxic and may play a role in the ongoing
damage that occurs during infection. Viral Tat, released by
infected cells, has been among the proteins suspected of
neurotoxicity. In any case, HIV infection appears to be the
prime mover in this disorder because antiretroviral treatment
may prevent or reverse this condition in many patients.
Milder forms of HAND have been reported in 30
to 40 percent of HIV-infected people who are medically
asymptomatic. In advanced disease, patients can develop
increasing difficulty with concentration and memory and
experience general slowing of their mental processes. At
the same time, patients may develop leg weakness and a
loss of balance. Imaging techniques, such as CT and MRI,
show that the brains of these patients have undergone
some shrinkage. Examination of the brains of persons dying
with AIDS can reveal loss of neurons, abnormalities in the
white matter (tissue that serves to connect different brain
regions), and injury to cellular structures that are involved in
signaling between neurons. There also may be inflammation
and vessel disease.
Recent studies indicate that highly active combination
antiretroviral treatment — cocktails of three or more
drugs active against HIV — is effective in reducing the
incidence of severe HAND, termed AIDS dementia. Such
treatment also can reverse, but not eliminate, the cognitive
abnormalities attributed to brain HIV infection.
Peripheral neuropathy, a type of nerve injury in
extremities that causes discomfort ranging from tingling
and burning to severe pain, is also a major neurological
problem commonly seen in HIV patients. It is believed that
the virus triggers sensory neuropathy through neurotoxic
mechanisms. This reaction has often been unmasked or
exacerbated by certain antiretroviral drugs that produce
68 BraiN factS | diseases and disorders
mitochondrial toxicity, which tends to make the neuropathies
more frequent and serious. More than half of patients with
advanced disease have neuropathy, making it a major area
for preventive and symptomatic therapeutic trials.
Despite remarkable advances in new therapies, some
patients develop these neurological problems and fail to
respond to treatment, thus requiring the development of
additional ways to prevent and treat their symptoms. In
addition, because of immunodeficiency in HIV patients,
otherwise rare opportunistic infections and malignancies are
seen more often in those with HIV. Fortunately, however,
CART has greatly reduced the incidence of most of these
kinds of infections.
Neurological Trauma
Traumatic brain and spinal cord injuries can lead to
significant disabilities and death. In the United States, an
estimated 1.7 million people suffer traumatic head injuries
each year, and roughly 52,000 will die. The leading causes
of traumatic brain injury are falls and motor-vehicle related
events.
Those who survive a brain injury face a lifetime of
disability, with economic costs approaching $60 billion
annually. An estimated 265,000 individuals in the United
States are living with spinal cord injury. Each year, about
12,000 new injuries are reported, caused mostly by motor
vehicle accidents, sports injuries, violence, and falls. The
cost of caring for these individuals approaches $10 billion a
year. Such facts point to the pressing need to advance our
understanding of these injuries, with the goal of developing
strategies to support long-term recovery.
No magic bullet has yet been found, but doctors have
discovered methods to stave off severe neurological damage
caused by head and spinal cord injuries and to improve
neurological function. This is accomplished by working to
prevent secondary pathogenesis, or damage that occurs after
the initial insult; support regeneration and repair; and refine
and optimize rehabilitation techniques.
Traumatic Brain Injury Greater access to and
use of CT and MRI offer physicians the opportunity
to diagnose the extent of tissue damage and determine
medical management. In general, patients who arrive
in the emergency room and are diagnosed with a severe
head injury are monitored for pressure on the brain from
bleeding or swelling. Treatments for increased intracranial
pressure include the removal of cerebrospinal fluid, moderate
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hyperventilation to temporarily decrease blood volume, and
the administration of drugs to reduce cellular metabolism or
to remove water from the injured tissue.
In addition to helping the physician avoid cerebral
edema, or swelling as a result of excess accumulation of
water in the brain, and reductions in cerebral blood flow
following traumatic brain injury, imaging can reveal lesions
produced by the initial injury. These lesions can consist of
bleeding on the surface or within the brain as well as the
formation of contusions, or bruises. Once blood leaks from
vessels and comes into direct contact with brain tissue, it
causes localized pressure, reducing cerebral blood flow. The
blood itself also can be toxic to brain cells. Contusions can
be troubling because they can increase pressure as well as
contribute to the development of post-traumatic epilepsy.
As a last resort to reduce increased intracranial pressure, part
of the skull may be removed to allow the brain to swell, a
procedure known as a decompressive craniectomy.
No drug for improving outcomes of traumatic brain
injury has yet been approved. A recent pilot clinical trial for
patients with moderate to severe closed-head injury found
that the hormone progesterone cut the number of deaths
in severely injured patients by 50 percent. Those in the
moderately injured group had improved functional recovery
30 days after injury. Treatments for the injury-induced
reduction of cerebral blood flow include the administration
of drugs that increase mean arterial blood pressure. In
combination with the reduction of intracranial pressure, this
treatment results in an increase in blood flow, allowing more
blood to reach vital areas.
Spinal Cord Injury Methylprednisolone is the only
FDA-approved treatment for spinal cord injury. While there
is increasing controversy about the use of this steroid, earlier
studies showed efficacy when people with spinal cord injuries
received high intravenous doses within eight hours of the
injury. Building on these clues and insights into precisely
how and why spinal cord cells die after injury, researchers
hope to develop new therapies to reduce the extent of spinal
cord damage after trauma. In that context, there is a growing
interest in early intervention of the inflammatory response
to prevent secondary damage by this response and support
neurologic recovery.
Scientists have known that, after a spinal cord injury,
animals can regain the ability to bear their weight and walk
at various speeds on a treadmill belt. More recently, scientists
have recognized that the level of this recovery depends to a
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large degree on whether these tasks are practiced — that is,
trained for — after injury. People with spinal cord injury also
respond to training interventions.
Scientists have also discovered that new nerve cells
can be born in the adult brain, but these new cells do
not seem sufficient to help the injured brain regenerate.
Studies are underway to determine how to jump-start the
pathway that stimulates neurogenesis, the birth of new
nerve cells. Researchers are trying to decipher how certain
environmental cues can be used or overcome to attract these
new cells — or transplanted stem or progenitor cells — to
areas of brain injury to facilitate regeneration and repair.
These and other recent discoveries are pointing the
way toward new therapies to prevent secondary damage
and promote nerve regeneration after brain and spinal cord
injury. Although these new therapies have not yet reached
the clinic, several of them are on the path to clinical trials.
Pain
If there is a universal experience, it is pain. Each
year, more than 76.2 million Americans suffer chronic,
debilitating headaches or a bout with a bad back or the pain
of arthritis — all at a total cost of some $100 billion. But it
need not be that way. New discoveries about how chemicals
in the body transmit and regulate pain messages have paved
the way for new treatments for both chronic and acute pain.
Treating Pain Local anesthesia, or loss of sensation
in a limited area of a person’s body, is used to prevent pain
during diagnostic procedures, labor, and surgical operations.
Local anesthetics temporarily interrupt the action of all
nerve fibers, including pain-carrying ones, by interfering
with the actions of sodium channels. Historically, the most
familiar of these agents was Novocain, which has been used
by dentists for years. Lidocaine is more popular today.
Analgesia refers to the loss of pain sensation. The four
main types of analgesics, or painkillers, are nonopioids,
which refer to aspirin and related nonsteroidal anti-
inflammatory drugs, or NSAIDs. Common NSAIDs
include ibuprofen and naproxen. Opioids (morphine,
codeine), antiepileptic agents (gabapentin, topiramate),
and antidepressants (amitriptyline, duloxetine) are the
other three types of analgesics. Acetaminophen, the active
ingredient in Tylenol, has analgesic properties but does not
reduce inflammation.
NSAIDs are useful for treating mild or moderate pain,
such as headache, sprains, or toothache. Because NSAIDs
diseases and disorders | BraiN factS 69
are anti-inflammatory, they also are effective for treating
injuries or conditions such as arthritis and postoperative
pain. NSAIDs work by inhibiting the cyclo-oxygenase
(COX) enzymes that make the inflammatory and pain-
producing chemical prostaglandin. Often moderate pain
is treated by combining a mild opioid, such as codeine,
with aspirin or an NSAID. Opioids are the most potent
painkillers and are used for severe pain. Opioids, however,
have many adverse side effects, such as respiratory depression
and constipation, and in some individuals they have a high
potential for abuse.
Antiepileptic and antidepressant drugs are useful primarily
for neuropathic pain, which comes from injury to the nervous
system. Such pain includes the pain from diabetic neuropathy,
or damage to nerves in the body resulting from high blood sugar
levels; neuralgia, or nerve pain or numbness, from viruses such
as shingles; phantom limb pain; and post-stroke pain. The best
results have been reported with antidepressants that regulate
both serotonin and norepinephrine. Interestingly, SSRIs,
which selectively affect serotonin,
do not help relieve neuropathic
pain. For some neuropathic pain
conditions in which a light touch
to the skin can produce severe pain,
topical lidocaine may be effective.
control. It is now commonly used in humans to treat pain
after surgery, and to treat chronic pain in some patients by
having them use an implanted pump.
New targets are on the horizon. Molecular biology and
genetic approaches have identified many molecules, such as
ion channels and receptors, which are predominantly, if not
exclusively, expressed by the nociceptor, the peripheral nerve
fiber that initially responds to the injury stimulus. Because
adverse side effects of drugs arise from the widespread
location of the molecules targeted by analgesics — for
example, constipation results from morphine’s action on
opioid receptors in the gut — new analgesics that target only
the nociceptor may have fewer side effects. Among the many
nociceptor targets are specialized receptor channels — one
of which is activated by capsaicin, the pungent ingredient
in hot peppers, and another by mustard oil — as well as a
variety of acid-sensing sodium and calcium ion channels.
Blocking the activity of many of these molecules has proven
effective in animal studies, suggesting that the development

The Body’s Pain-Control

System Studies of the body’s
own pain-control system not only
demonstrated the existence of
naturally occurring opioids — the
endorphins — but also identified the
receptors through which opioids exert
their effects. The finding that opioid
receptors are concentrated in the
spinal cord led to the use of injections
of morphine and other opioids into
the cerebrospinal fluid in which
the spinal cord is bathed, without
causing paralysis, numbness, or other
severe side effects. This technique
came about through experiments
with animals that first showed that At the site of an injury, the body produces prostaglandins, which increase pain sensitivity. Aspirin prevents
the production of prostaglandins. Acetaminophen is believed to block pain impulses in the brain itself. Local
injecting morphine into the spinal anesthetics intercept pain signals traveling up the nerve. Opiate drugs, which act primarily in the central
fluid could produce profound pain nervous system, block the transfer of pain signals from the spinal cord to the brain.

70 BraiN factS | diseases and disorders Society for NeuroScieNce

of drugs that target these molecules in humans may have
great value for the treatment of acute and persistent pain.
Following from these findings, topical (skin) application of
high doses of capsaicin has recently been approved for some
neuropathic pain conditions. This treatment likely kills the
sensing portion of pain fibers, but because these nerve fibers
will regenerate, treatment needs to be repeated.
Pain is a complex experience that is largely a product
of brain function. The pain is in the brain, not in the
nociceptors that respond to the injury. Pain also involves
emotional factors, so previous experiences with pain can
have an impact on a more recent experience. All of these
variables must be addressed concurrently in order to treat
pain. The fact that placebos and hypnosis can significantly
reduce pain clearly illustrates the importance of these
psychological factors.
Seizures and epilepsy
Seizures occur because of sudden, disorderly discharges
of interconnected neurons in the brain that temporarily
alter one or more brain functions. They are associated with
epilepsy, a chronic neurological disorder characterized by the
occurrence of unprovoked seizures. More than 50 million
people have epilepsy worldwide, and 85 percent of those
cases occur in developing countries. It is estimated that,
globally, there are 2.4 million new cases each year.
Epilepsy can start at any age and be idiopathic — arising
from an uncertain cause — or symptomatic — having a
known or presumed cause. Most idiopathic epilepsies probably
are due to the inheritance of one or more mutant genes, often
a mutant ion channel gene. Symptomatic epilepsies result
from a wide variety of brain diseases or injuries, including
birth trauma, head injury, neurodegenerative disease, brain
infection, brain tumor, or stroke.
Epilepsies can be either generalized or partial.
Generalized seizures typically result in loss of consciousness
and can cause a range of behavioral changes, including
convulsions or sudden changes in muscle tone. They occur
when there is simultaneous excessive electrical activity over
a wide area of the brain, often involving the thalamus and
cerebral cortex. Partial epilepsies, however, are characterized
by seizures in which the individual maintains consciousness
or has altered awareness and behavioral changes. Partial
seizures can produce localized visual, auditory, and skin
sensory disturbances; repetitive uncontrolled movements;
or confused, automatic behaviors. Such seizures arise from
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excessive electrical activity in one area of the brain, such as
a restricted cortical or hippocampal area.
Many antiepileptic drugs are available. Their principal
targets are either ion channels or neurotransmitter receptors.
Generalized epilepsies often are readily controlled by
antiepileptic drugs, with up to 80 percent of patients
seizure-free with treatment. Unfortunately, partial epilepsies
are generally more difficult to treat. Often, they can be
controlled with a single antiepileptic that prevents seizures
or lessens their frequency, but sometimes a combination of
these drugs is necessary. Identification of the mutated genes
underlying epilepsy may provide new targets for the next
generation of antiseizure drugs.
Surgery is an excellent option for patients with specific
types of partial seizures who do not respond to antiepileptic
drugs. Electrical recordings of brain activity from patients
allow for precise localization of the brain area from which
the partial seizures originate. Once this area has been
found, neurosurgeons can then remove it. After surgery,
most properly selected patients experience improvement or
complete remission of seizures for at least several years.
A new form of epilepsy treatment, electrical stimulation
therapy, was introduced as another option for hard-to-
control partial seizures. An implanted device delivers small
bursts of electrical energy to the brain via the vagus nerve
on the side of the neck. While not curative, vagal nerve
stimulation has been shown to reduce the frequency of
partial seizures in many patients.
Stroke
A stroke occurs when a blood vessel bringing oxygen
and nutrients to the brain bursts or is clogged by a blood
clot or some other particle. As a result, the brain is deprived
of blood, causing the death of neurons within minutes.
Depending on its location, a stroke can cause many
permanent disorders, such as paralysis on one side of the
body and loss of speech.
Until recently, if you or a loved one had a stroke, your
doctor would tell your family there were few treatment
options outside of physical or speech therapy. In all
likelihood, the patient would live out the remaining months
or years with severe neurological impairment.
This dismal scenario is now brightening. For one, use of the
clot-dissolving bioengineered drug, tissue plasminogen activator
(tPA), is now a standard treatment in many hospitals. This
medication opens blocked vessels rapidly to restore circulation
diseases and disorders | BraiN factS 71
before oxygen loss causes permanent damage. Given within
three hours of a stroke, it often can help in limiting the ensuing
brain damage. Also, attitudes about the nation’s third leading
cause of death are changing rapidly. Much of this has come from
new and better understanding of the mechanisms that lead to
the death of neurons following stroke and the growing ability to
devise ways to protect these neurons.
Stroke affects roughly 795,000 Americans a year —
137,000 of whom die as a result. The total annual costs are
estimated at $73.7 billion. Stroke often occurs in individuals
over 65 years of age, but a third of people who have strokes
are younger. Stroke tends to occur more in males and
African Americans as well as in those with risk factors such
as diabetes, high blood pressure, heart disease, obesity, high
cholesterol, and a family history of stroke.
Controlling risk factors with diet, exercise, and certain
drugs may help prevent stroke. Other specific treatments
involving surgery or arterial stents can clear clogs in the
arteries of the neck region; these and other treatments
targeting heart disease can help prevent a cutoff of blood
72 BraiN factS | diseases and disorders
supply. Anticoagulant drugs can reduce the likelihood of
clots forming, traveling to the brain, and causing a stroke.
Other experimental therapies under investigation may
lead to even bigger payoffs for patients in the future. Some
strategies target mechanisms inside the neuron. In this way,
the vicious cycle of local damage followed by a widening
fringe of biochemical-induced neuronal death can be slowed.
A number of classes of drugs have been shown to be effective
in animal studies.
Emerging clinical evidence suggests that, following a
stroke affecting movement in one arm, encouraging use
of the weakened arm by temporarily restricting use of the
unaffected arm may help functional recovery. Another
promising possibility for improving recovery after stroke is
through the use of neural stem cells. Some animal studies have
shown that an injection of stem cells helps recovery even if
administered several days after the injury. Administration of
growth factors might further enhance the benefits of stem cell
transplantation. Further research will indicate whether these
therapies will translate from animals to humans.
A stroke occurs when a blood vessel bringing
oxygen and nutrients to the brain bursts or is
clogged by a blood clot, as shown in the image on
the upper left. This lack of blood leads to a cascade
of neurochemical abnormalities that can cause cell
death within minutes. Free radicals are released,
causing damage to endothelial cells and the
mitochondria of neurons. Normally the body readily
disarms free radicals, but in stroke, endothelial cell
damage allows many more than can be controlled
to move into brain tissue. Depending on its location,
a stroke can result in different problems, such as
paralysis on one side of the body or loss of speech.
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chaPter 15:
haPter
PoteNtial theraPieS
in this chapter
n New Drugs
n Trophic Factors
n Engineered Antibodies
n Small Molecules and RNAs
n Cell and Gene Therapy
New Drugs
Most medicines used today were developed using trial-
and-error techniques, which often do not reveal why a drug
produces a particular effect. But the expanding knowledge
gained from the methods of molecular biology — the ability
to determine the structure of receptors or other proteins —
makes it possible to design safer and more effective drugs.
In a test tube, the potency of an agent can be
determined by how well it attaches to a receptor or other
protein target. With this knowledge, scientists can vary
the drug’s structure to enhance its action on the desired
target. Thus, subsequent generations of drugs can be
designed to interact more selectively with the target or, in
many cases, with specific subtypes of the target, producing
better therapeutic effects and fewer side effects. While this
rational drug design holds promise for developing drugs for
conditions ranging from stroke and migraine headaches
to depression and anxiety, it will take considerable effort
to clarify the role of the different potential drug targets in
these disorders.
Other promising candidates for drug therapies include
growth, or trophic, factors; antibodies engineered to modify
the interactions and toxicity of misfolded proteins, which
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are the cause of many neurodegenerative diseases; small
molecules that take advantage of specific biochemical
pathways; interfering RNAs (RNAi) that reduce toxic levels
of individual proteins; and stem cells that could replace dead
or dying neurons.
Trophic Factors
One result of basic neuroscience research is the
discovery of numerous trophic factors, which control the
development and survival of specific groups of neurons. Once
the specific actions of these molecules and their receptors
are identified and their genes cloned, procedures can be
developed to modify trophic factor-regulated functions in
ways that might be useful in the treatment of neurological
disorders. For example, copies of the factor might be
genetically targeted to the area of the brain where this type
of cell has died. The treatment may not cure a disease but
could improve symptoms or delay the disease’s progression.
Already, researchers have demonstrated the possible
value of at least one of these factors, nerve growth factor
(NGF). NGF slows the destruction of neurons that use
acetylcholine. When infused into the brains of rats, NGF
prevented cell death and stimulated the regeneration and
sprouting of damaged neurons that are known to die in
Alzheimer’s disease. When aged animals with learning and
memory impairments were treated with NGF, scientists
found that these animals were able to remember a maze task
as well as healthy aged rats. NGF also holds promise for
slowing the memory deficits associated with normal aging.
Recently, several new factors have been identified. They
are potentially useful for therapy, but scientists must first
understand how they may influence neurons. In the future,
Alzheimer’s disease, Parkinson’s disease, and amyotrophic
lateral sclerosis (ALS) may be treated with trophic factors or
their genes.
In an interesting twist on growth factor therapy,
researchers have demonstrated that neutralizing molecules
that stop or inhibit growth can help repair damaged
nerve fiber tracts in the spinal cord. Using antibodies
that override the effect of Nogo-A, a protein that inhibits
treating brain disorders | BraiN factS 73
nerve regeneration, Swiss researchers succeeded in getting
some nerves of damaged spinal cords to regrow in rats and
monkeys. Treated animals of both species showed large
improvements in their ability to walk and use their forepaw
digits after spinal cord damage.
This research has been translated to a clinical setting,
where recently injured spinal cord injury patients are being
treated with anti-Nogo-A antibodies in a clinical trial.
engineered Antibodies
The immune system has evolved to target and modify
factors both inside and outside of cells. It is sometimes possible
to trick the immune system into attacking those proteins
that cause neurological diseases by “vaccinating” patients
74 BraiN factS | treating brain disorders
against them. This approach has shown some promise in
treating Alzheimer’s disease, although it also carries risks,
such as increased inflammation when the brain reacts to
the antibodies against its proteins. Another new approach
combines genetic engineering with immunology to engineer
antibodies or fragments of antibodies that can bind to and
alter the disease characteristics of specific proteins. These
therapies could be delivered either as proteins or as genes.
Therapies such as these have produced promising
preliminary results for Huntington’s, Parkinson’s, and
Alzheimer’s diseases, as well as neurodegenerative disorders
such as variant Creutzfeldt-Jakob disease (vCJD), known as
prion diseases. vCJD has been linked to bovine spongiform
encephalitis, or mad cow disease. In experiments with fruit
Therapies like stem cells and gene
therapy may one day help combat
disease. Researchers hope stem cells
will incorporate into the brain to replace
diseased or injured cells. Similarly, they
are studying a variety of viruses that
could carry therapeutic genes into the
brain to correct nervous system diseases
and disorders.
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Researchers are pursuing
a variety of new ways to
repair or replace neurons
and other cells in the brain.
flies (Drosophila), those modified to carry the mutant human
gene for Huntington’s disease are generally too weak and
uncoordinated to break out of their pupal case, the way
normal insects do. However, when they are treated so that
they also express the gene for an anti-HD antibody, all of
them emerge as young adults. Furthermore, these treated flies
live longer than the untreated ones that do manage to emerge,
and the treated ones show less pathology in their brains.
Small Molecules and RNAs
As our understanding of the processes that underlie
brain damage progresses, it is becoming possible to use
small-molecule drugs, such as antibiotics and anti-tumor
drugs, to alter these processes. Scientists have had some
success developing animal models that are treated with these
drugs, which appear to reduce the neuronal damage in ALS,
Huntington’s disease, and Parkinson’s disease.
Thousands of small-molecule drug candidates can
be tested using high-throughput screening, during which
hundreds or thousands of compounds are tested to find those
with the desired cellular effect. This process has been used to
find therapies for neurodegenerative diseases. Because many
of these diseases involve proteins that misfold and clump
abnormally, lasers are used to measure whether proteins are
clumped inside cells that have been robotically distributed
into tiny containers, along with the small molecules to be
tested. A machine then scans the containers and reports
whether particular drugs have changed the protein clumping.
Those drugs that are identified can then be tested further.
New leads for drugs to treat Alzheimer’s and prion diseases
have recently been described using these methods.
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Several neurodegenerative diseases are caused by the
accumulation of abnormal proteins. If the cells made many
fewer such proteins, then the disease presumably would
progress much more slowly. A new class of potential drugs
is based on removing the RNAs that code for the proteins
that are causing damage. Mouse models of Huntington’s
disease and ALS appear to have responded positively to such
treatments, which are delivered via gene therapies.
Cell and Gene Therapy
Researchers throughout the world are pursuing a variety
of new ways to repair or replace neurons and other cells in
the brain. For the most part, these experimental approaches
are still being worked out in animals and cannot be
considered therapies for humans at this time.
Scientists have identified neuronal stem cells —
unspecialized cells that give rise to cells with specific
functions — in the brain and spinal cord of embryonic and
adult mice. Stem cells can continuously produce all three
major cell types of the brain: neurons; astrocytes, the cells
that nourish and protect neurons; and oligodendrocytes,
the cells that surround axons and allow them to conduct
their signals efficiently. The production abilities of stem
cells may someday be useful for replacing brain cells lost to
disease. Recently, scientists have discovered how to convert
cells from adult tissue into stem cells, raising the possibility
that they might be pharmacologically directed to replace
damaged neurons tailored to a specific patient and disease.
In other work, researchers are studying a variety of
viruses that can carry therapeutic genes into the brain to
correct nervous system diseases. Studies in animal models of
human diseases have shown that gene transfer vectors can be
effective in correcting at least some aspects of neurological
disease. At this time, adeno-associated virus (AAV) and
lentivirus seem to be the safest and most efficient vectors.
These vectors are being used in clinical trials in patients
with Parkinson’s and in some rare genetic diseases. Herpes
simplex virus and adenovirus vectors have been evaluated in
early-stage human trials for treating brain tumors.
treating brain disorders | BraiN factS 75
chaPter 16:
haPter
NeuroethicS
in this chapter
n Personal Responsibility
and Punishment
n Diagnosis, Treatment,
and Enhancement
n Social Behavior
n Predicting Behavior
n Informed Consent in Research
n Effective and Ethical Science
Communication and Commercial
Enterprise
Breaking a confidence. Going along to get along.
Telling a white lie to protect a friend. Everyone faces ethical
dilemmas — in school, at home, and nearly everywhere in
everyday life.
Neuroscientists are no different. With tremendous
advances in the field, scientists and nonscientists alike
have sensed a critical turning point. Advancing knowledge
about how the brain controls normal behavior; how injury,
drugs, or disease affect it; and how diagnoses and treatments
could change brain function raises serious and novel ethical
questions.
For example, some recent brain imaging studies have
sought to define the processes responsible for phenomena such
as deception. The post-9/11 era has created much interest in
lie detection equipment that could be used to screen airline
passengers for security purposes. Is the technology accurate
enough to provide useful data upon which to base decisions?
How should privacy be balanced with security? Pursuing
these lines of scientific inquiry in a responsible way requires
neuroscientists to examine how what they do affects the world
beyond the laboratory or clinic.
This kind of questioning makes up a field known
as neuroethics. Scientists and ethicists are beginning to
reflect on the implications of neuroscience in areas of
behavioral research, such as moral reasoning and decision-
making, as well as the implications of new neuroscience
technologies, including brain scanning, brain stimulation,
and pharmaceuticals, which can manipulate cognition.
While many questions and methods within neuroethics
are similar to those in biomedical ethics, neuroethics
deals with brain-specific issues that touch no other area
of science — our sense of self, our personalities, and
our behavior. Furthermore, brain science is developing
interventions that can change the way our brains
function. Neuroethics links the science — what we can
do — with the question of what we should do, which
is guided by individual and shared value systems.
Neuroethics is the subject of a growing body of literature
and an increasing number of meetings and conferences
that have attracted a wide range of thinkers, students, basic
and clinical neuroscientists, economists, philosophers,
journalists, sociologists, lawyers, judges, and others. Included
among the major topics under discussion are those listed
below.
Personal Responsibility and Punishment
Neuroscience is teaching us about the neural substrates
of human characteristics, such as anger, impulse control,
and conscience. It is also giving us insight into the brain
mechanisms of conditions such as addiction and other
disorders that impair behavioral control. These discoveries
will shed new light on traditional questions of personal
responsibility. Our understanding of the brain as the control
center for all decisions and actions challenges the concept of
free will as the basis for personal responsibility. As a result,
questions emerge such as the following: If the brain is the
source of all action, do we hold the person less responsible
for his actions when the brain is damaged? Does antisocial
behavior itself provide evidence of a maladapted or miswired
brain, or do we need physical evidence of trauma or disease?
Neuroscience is not only interested in questions about
criminal behavior, but also in questions about how more
normal members of society create and enforce the laws

76 BraiN factS | treating brain disorders Society for NeuroScieNce

that criminals violate. Some commentators think that
increasing neuroscience knowledge may seriously challenge
fundamental tenets of criminal law, while others foresee
incremental changes that may lead to more just, accurate,
and fair judgments. Neuroethics can help society think
about how newfound knowledge of the brain as the basis
of behavior may affect our ideas of the way society should
function.
Diagnosis, Treatment, and enhancement
Neuroscience already has given rise to drugs and devices,
developed for the treatment of illness, that permit healthy
people to improve their cognitive performance or alter their
emotional states. In the future, drugs may be developed
that enhance memory or alter social behaviors. It is critical
that scientists engage policymakers and society at large in
discussions about the extension of treatments from the realm
of illness to the realm of enhancement. Neuroethical issues
in medicine arise when gaps exist between diagnosis and
treatment, treatments may offer tradeoffs in personality or
cognitive changes, and drugs or devices that can help unwell
patients also can boost performance of normal people.
For example, when diagnostic tests exist for brain-
based diseases that have no cure, such as Alzheimer’s,
how should the tests be used? Should emergency rooms
administer memory-altering drugs to patients who have
suffered a trauma and may be at risk for post-traumatic stress
disorder? If drugs that are effective for treating attention
deficit hyperactivity disorder also improve work or classroom
performance of normal people, do we need to regulate access,
and do we consider such use to be cheating? More questions
of this type will emerge as our knowledge increases.
Social Behavior
The neurobiological basis of social interaction
is now an exciting topic of research. While a major
goal of such research is the treatment of disabling
conditions such as autism spectrum disorders, the
knowledge gleaned may also permit us to delve into
other kinds of social behavior. Already, it is possible
to use brain imaging to observe emotional responses,
including such morally freighted responses as negative
reactions to members of minority groups within a society.
How should we use such information? Will it help us
understand prejudice, or could it be used to influence
decisions about individuals? It is critical that scientists
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explain the limitations of current technologies and help
formulate policies to minimize the chances of misuse.
Predicting Behavior
Neuroimaging and genetic screening may enable us
to predict behavior, personality, and disease with greater
accuracy than ever before. Neuroimaging technology is also
being researched and marketed for lie detection for consumer
targets, including national security, employment screening,
the legal system, and personal relationships. As individuals
and members of groups, people have long been interested in
predicting someone else’s behavior or detecting whether or
not they are truthful.
Neuroethics links the science
— what we can do — with the
question of what we should do.
Neuroscience technologies that enable more accurate
assessment of behavior also raise important concerns about
privacy and fairness that go beyond those in bioethics.
For example: Will we be able to use imaging to measure
intelligence? Empathy? Risk for violence? What degree of
privacy do we expect to have over our thoughts? If someone has
not yet committed a crime but shows inappropriate brain-based
reactions, such as sexual responses to pictures of children, would
we require further monitoring or even preventive detention?
The neuroimaging detection of lying has the potential to have
a major impact on society but will require careful controls and
years of further research before its validity can be established.
People lie for different reasons under different circumstances,
not all lies cause harm, and even brain correlates of deception
will never give us an objective determination of truth.
Predicting individual behavior and determining truthfulness
will be major areas of research in neuroimaging and behavioral
neuroscience in the coming years, and neuroethics will face
many challenges as technologies evolve.
treating brain disorders | BraiN factS 77
Informed Consent in Research
Special care must be taken when scientists seek consent
to conduct human research and throughout experiments,
especially when potential research subjects have thinking
or emotional impairments that might affect their decision-
making capacity. Consent is an ongoing process that should
involve education of the potential research participant
and, when appropriate, family members. Researchers are
discussing potential needs to exercise greater scrutiny,
ensure safeguards, and enhance participants’ grasp of a study,
including risks and benefits.
One of the hallmarks of neuroscience has been the drive
toward integrating information from disparate fields and
specializations to increase knowledge. Sorting through the
complex issues captured under the umbrella of neuroethics
provides an important opportunity for informed and rich
discussions among scientists and with the public. Continuing
study of neuroethics will help all segments of society deal
with the challenges posed by emerging technologies that
investigate the brain and how it works.

effective and ethical Science: Communication

and Commercial enterprise
Neuroethics will draw from the experience of bioethics
in handling scientific communication with the media and
responsible transfer of knowledge from basic science to
profit-driven venture. A major concern for neuroethicists is
the degree to which the media and the public’s fascination
with neuroscience can lead to overstatements and
inaccuracies in media communication. Early studies have
shown that neuroscience information and pictures of brain
images lend excessive credibility to scientific statements
in the media, which may underscore “neurorealism” —
the idea that anything neuroscientific must be definitive
and true. The powerful allure of neuroscience may also
entice commercialization of neurotechnologies before
the risks, benefits, and limitations of the science are fully
understood. Neuroethics has a critical role in protecting
the integrity of neuroscience by promoting responsible
and accurate scientific communication in the media;
supporting appropriate oversight of commercialized
neurotechnologies, including accurate advertising; and
urging proactive communication in the popular media to
promote public discussion of ethical, social, and legal issues
arising from neuroscience knowledge and technology.
At this stage, the field of neuroethics raises more
questions than it answers. It poses challenges to scientists,
ethicists, lawyers, policy-makers, and the public as
they strive to work through the social implications
of new discoveries. The issues are too broad-based to
expect that scientists alone will supply the answers.
But neuroscientists are well positioned to help shape
and contribute to the debate and discussion.

78 BraiN factS | treating brain disorders Society for NeuroScieNce

Society for Neuroscience treating brain disorders | Brain Facts 79
BraiN
rai fact
actS gloSSary
Acetylcholine A critical neurotransmitter that controls functions
such as memory, attention, sleep, heart rate, and muscular activity.
Action Potential An electrical charge that travels along the
axon to the neuron’s terminal, where it triggers the release of a
neurotransmitter. This occurs when a neuron is activated and
temporarily reverses the electrical state of its interior membrane
from negative to positive.
Adenosine A neurochemical that inhibits wakefulness, serving
the purpose of slowing down cellular activity and diminishing
arousal. Adenosine levels decrease during sleep.
Adrenal Cortex An endocrine organ that secretes steroid
hormones for metabolic functions; for example, in response
to stress.
Adrenal Medulla An endocrine organ that secretes epinephrine
and norepinephrine in concert with the activation of the
sympathetic nervous system; for example, in response to stress.
Agonist 1.) A neurotransmitter, drug, or other molecule that
stimulates receptors to produce a desired reaction. 2.) A muscle
that moves a joint in an intended direction.
Alzheimer’s Disease A major cause of dementia in the elderly,
this neurodegenerative disorder is characterized by the death
of neurons in the hippocampus, cerebral cortex, and other
brain regions. The earliest symptoms of the disease include
forgetfulness; disorientation as to time or place; and difficulty with
concentration, calculation, language, and judgment. In the final
stages, individuals are incapable of self-care and may be bedridden.
Amino Acid Transmitters The most prevalent neurotransmitters
in the brain, these include glutamate and aspartate, which
have excitatory actions on nerve cells, and glycine and gamma-
aminobutyric acid (GABA), which have inhibitory actions on
nerve cells.
Amygdala A structure in the forebrain that is an important
component of the limbic system and plays a central role in
emotional learning, particularly within the context of fear.
Amyotrophic Lateral Sclerosis (ALS) Commonly known as Lou
Gehrig’s disease, ALS causes motor neurons in the brain and
spinal cord to disintegrate, resulting in loss of control of voluntary
muscle movements such as walking.
80 BraiN factS | glossary
Androgens Sex steroid hormones, including testosterone, found in
higher levels in males than females. They are responsible for male
sexual maturation.
Antagonist 1.) A drug or other molecule that blocks receptors.
Antagonists inhibit the effects of agonists. 2.) A muscle that moves
a joint in opposition to an intended direction.
Aphasia Disturbance in language comprehension or production,
often as a result of a stroke.
Apoptosis Programmed cell death induced by specialized
biochemical pathways, often serving a specific purpose in the
development of an animal.
Auditory Nerve A bundle of nerve fibers extending from the cochlea
of the ear to the brain that contains two branches: the cochlear
nerve, which transmits sound information, and the vestibular nerve,
which relays information related to balance.
Attention Deficit hyperactivity Disorder (ADhD) A condition
characterized by excessively inattentive, hyperactive, or impulsive
behaviors.
Autism Spectrum Disorders (ASD) A condition characterized
by impaired social skills; verbal and nonverbal communication
difficulties; and narrow, obsessive interests or repetitive behaviors.
Autonomic Nervous System A part of the peripheral nervous
system responsible for regulating the activity of internal organs. It
includes the sympathetic and parasympathetic nervous systems.
Axon The fiberlike extension of a neuron by which it sends
information to target cells.
Basal Ganglia Structures located deep in the brain that play an
important role in the initiation of movements. These clusters of
neurons include the caudate nucleus, putamen, globus pallidus, and
substantia nigra. Cell death in the substantia nigra contributes to
Parkinson’s disease.
Bipolar Disorder Previously known as manic-depressive illness, this
disorder is characterized by episodes of deep depression and manic
highs. The depressive episodes are similar to those experienced
by people with depression. Symptoms of mania include increased
energy, decreased need for sleep, a marked interest in goal-directed
activities, and poor judgment.
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Brainstem The major route by which the forebrain sends
information to and receives information from the spinal cord and
peripheral nerves. The brainstem controls, among other things,
respiration and the regulation of heart rhythms.
Broca’s Area The brain region located in the frontal lobe of the
left hemisphere that is important for the production of speech.
Catecholamines The neurotransmitters dopamine, epinephrine,
and norepinephrine, which are active in both the brain and the
peripheral sympathetic nervous system. These three molecules
have certain structural similarities and are part of a larger class of
neurotransmitters known as monoamines.
Cell Body The part of a neuron that contains the nucleus (with
DNA) and the organelles, but not the projections such as the
axon or dendrites.
Cerebrum The largest part of the human brain associated with
higher order functioning, such as thinking, perceiving, planning,
and understanding language, as well as the control of voluntary
behavior.
Cerebellum A large structure located at the roof of in the hindbrain
that helps control the coordination of movement by making
connections to the pons, medulla, spinal cord, and thalamus. It also
may be involved in aspects of motor learning.
Cerebral Cortex A sheet of tissue covering the outermost layer of
the cerebrum.
Cerebrospinal Fluid A liquid found within the ventricles of the
brain and the central canal of the spinal cord.
Circadian Rhythm A cycle of behavior or physiological change
lasting approximately 24 hours.
Cochlea A snail-shaped, fluid-filled organ of the inner ear
responsible for converting sound into electrical potentials to
produce an auditory sensation.
Cognition The process or processes by which an organism
gains knowledge or becomes aware of events or objects in its
environment and uses that knowledge for comprehension and
problem-solving.
Cone A primary receptor cell for vision located in the retina. It is
sensitive to color and is used primarily for daytime vision.
Corpus Callosum The large bundle of nerve fibers linking the left
and right cerebral hemispheres.
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Cortisol A hormone manufactured by the adrenal cortex. In
humans, cortisol is secreted in the greatest quantities before dawn,
readying the body for the activities of the coming day.
Cranial Nerve A nerve that carries sensory and motor output for the
head and neck region. There are 12 cranial nerves.
Declarative Memory The ability to learn and consciously
remember everyday facts and events.
Depression A psychiatric disorder characterized by sadness,
hopelessness, pessimism, loss of interest in life, reduced emotional
wellbeing, and abnormalities in sleep, appetite, and energy level.
Dendrite A treelike extension of the neuron cell body. The dendrite
is the primary site for receiving and integrating information from
other neurons.
Dopamine A catecholamine neurotransmitter present in three
circuits of the brain: one that regulates movement; a second
thought to be important for cognition and emotion; and a third
that regulates the endocrine system. Deficits of dopamine in the
motor circuit are associated with Parkinson’s disease. Abnormalities
in the second circuit have been implicated in schizophrenia.
Down Syndrome A condition that typically occurs when, at the
time of conception, an extra copy of chromosome 21 is present
in the egg. This genetic anomaly is associated with physical
and developmental characteristics, including mild to moderate
intellectual disabilities; low muscle tone; and an increased risk of
congenital heart defects, respiratory problems, and digestive tract
obstruction.
Drug Addiction Loss of control over drug intake or compulsive
seeking and taking of drugs, despite adverse consequences.
endocannabinoids Lipid-derived messengers sometimes referred
to as the brain’s marijuana. These messengers control the release of
neurotransmitters, usually by inhibiting them, and can affect the
immune system and other cellular parameters. Endocannabinoids
also play an important role in the control of behaviors.
electroencephalography (eeG) A technology used to record
electrical activity of the human brain in response to a variety of
stimuli and activities.
endocrine Gland An organ that secretes a hormone directly into
the bloodstream to regulate cellular activity of certain other organs.
endorphins Neurotransmitters produced in the brain
that generate cellular and behavioral effects like those
of morphine.
glossary | BraiN factS 81
epilepsy A disorder characterized by repeated seizures, which
are caused by abnormal excitation of large groups of neurons in
various brain regions. Epilepsy can be treated with many types of
anticonvulsant medications.
epinephrine A hormone, released by the adrenal medulla and
specialized sites in the brain. During times of stress, epinephrine,
also known as adrenaline, is quickly released into the bloodstream.
It then serves to put the body into a general state of arousal, which
enables it to cope with the challenge.
estrogens A group of sex hormones found more abundantly
in females than males. They are responsible for female sexual
maturation and other functions.
excitation A change in the electrical state of a neuron that is
associated with an enhanced probability of action potentials.
Follicle-Stimulating hormone A hormone released by the pituitary
gland that stimulates the production of sperm in the male and
growth of the follicle (which produces the egg) in the female.
Forebrain The largest part of the brain, which includes the
cerebral cortex and basal ganglia. The forebrain is credited with
the highest intellectual functions.
Fovea The centermost part of the eye located in the center of the
retina and contains only cone photoreceptors.
Frontal Lobe One of the four subdivisions of the cerebral cortex.
The frontal lobe has a role in controlling movement and in the
planning and coordinating of behavior.
Functional Magnetic Resonance Imaging (fMRI)
A technology that uses magnetic fields to detect activity in the
brain by monitoring blood flow.
Gamma-aminobutyric Acid (GABA) An amino acid transmitter
in the brain whose primary function is to inhibit the firing of
nerve cells.
Glia Specialized cells that nourish and support neurons.
Glucocorticoids Hormones that produce an array of effects in
response to stress. Some of the actions of glucocorticoids help
mediate the stress response, while other, slower actions counteract
the primary response to stress and help re-establish homeostasis.
82 BraiN factS | glossary
Glutamate An amino acid neurotransmitter that acts to excite
neurons. Glutamate stimulates N-methyl-d-aspartate (NMDA)
and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid
(AMPA). AMPA receptors have been implicated in activities
ranging from learning and memory to development and specification
of nerve contacts in developing animals. Stimulation of NMDA
receptors may promote beneficial changes, whereas overstimulation
may be a cause of nerve cell damage or death in neurological trauma
and stroke.
Gonad Primary sex gland: testis in the male and ovary in the female.
Gray Matter Portions of the brain that are gray in color because
they are composed mainly of neural cell bodies, rather than
myelinated nerve fibers, which are white.
Growth Cone A distinctive structure at the growing end of most axons.
It is the site where new material is added to the axon.
hair Cells Sensory receptors in the cochlea that convert
mechanical vibrations to electrical signals; they in turn excite the
30,000 fibers of the auditory nerve that carry the signals to the
brainstem.
hindbrain The most posterior part of the brain comprises the pons,
medulla oblongata, and cerebellum.
hippocampus A seahorse-shaped structure located within the brain
and considered an important part of the limbic system. One of the
most studied areas of the brain, it is involved in learning, memory,
and emotion.
homeostasis The normal equilibrium of body function.
hormones Chemical messengers secreted by endocrine glands
to regulate the activity of target cells. They play a role in sexual
development, calcium and bone metabolism, growth, and many
other activities.
huntington’s Disease A genetic disorder characterized by
involuntary jerking movements of the limbs, torso, and facial
muscles, often accompanied by mood swings, depression, irritability,
slurred speech, and clumsiness.
hypothalamus A complex brain structure composed of many
nuclei with various functions, including regulating the activities
of internal organs, monitoring information from the autonomic
nervous system, controlling the pituitary gland, and regulating sleep
and appetite.
Interneuron A neuron that exclusively signals another neuron.
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Inhibition A synaptic message that prevents a recipient neuron
from firing.
Ions Electrically charged atoms or molecules.
Ion Channels Selectively permeable water-filled channels that
pass through the cell membrane and allow ions or other small
molecules to enter or leave the cell.
Long-Term Memory The final phase of memory, in which
information storage may last from hours to a lifetime.
Magnetic Resonance Imaging (MRI) A technique that uses
magnetic fields to create a high-quality, three-dimensional
image of organs and structures inside the body. This technology
is noninvasive and does not expose the body to X-rays or other
radiation.
Magnetic Resonance Spectroscopy (MRS) Using the same
machinery as MRI, MRS measures the concentration of certain
chemicals, such as neurotransmitters, instead of blood flow.
Magnetoencephalography (MeG) A technique that can
quantitatively measure the strength of activity in various regions
of the brain at millisecond resolution.
Metabolism The sum of all physical and chemical changes that
take place within an organism and all energy transformations that
occur within living cells.
Midbrain The most anterior segment of the brainstem. With the
pons and medulla, the midbrain is involved in many functions,
including regulation of heart rate, respiration, pain perception,
and movement.
Migration The process whereby new neurons find their proper
position in the brain.
Mitochondria Small cylindrical organelles inside cells that provide
energy for the cell by converting sugar and oxygen into special
energy molecules, called adenosine triphosphate (ATP).
Motor Neuron A neuron that carries information from the central
nervous system to muscle.
Motor unit A functional unit made up of an alpha motor neuron
and all the muscle fibers it contains and controls, ranging from a
few to a hundred or more.
Mutations Changes in DNA, such as “misspellings” in the gene
sequence or incorrect amounts of DNA, that can prevent a gene
from functioning properly.
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Multiple Sclerosis (MS) An autoimmune disease in which the
body’s natural defenses attack the myelin sheath covering the
axons of neurons in the central nervous system. Symptoms include
numbness, clumsiness, and blurred vision.
Myasthenia Gravis A disease in which acetylcholine receptors on
muscle cells are destroyed so that muscles can no longer respond to
the acetylcholine signal to contract. Symptoms include muscular
weakness and progressively more common bouts of fatigue. The
disease’s cause is unknown but is more common in females than in
males; it usually strikes between the ages of 20 and 50.
Myelin Sheath Compact fatty material that surrounds and insulates
the axons of some neurons and accelerates the transmission of
electrical signals.
NMDA Receptors N-methyl-d-aspartate (NMDA) receptors, one of
three major classes of glutamate receptors, which have been implicated
in activities ranging from learning and memory to development and
specification of nerve contacts in a developing animal.
Nerve Growth Factor A substance whose role is to guide neuronal
growth during embryonic development, especially in the peripheral
nervous system. Nerve growth factor also probably helps sustain
neurons in the adult.
Nerve Terminal The tip of the axon where neurotransmitters
are released.
Neural Induction The process during embryonic development
whereby molecules trigger ectoderm tissue to become nerve tissue.
Neurogenesis The production and growth of new nerve cells
during development and, in select brain regions, throughout life.
Neuron A nerve cell specialized for the transmission of information
and characterized by long, fibrous projections called axons and
shorter, branchlike projections called dendrites.
Neuroscientist Scientists who specialize in the study of the brain
and the nervous system.
Neurotransmitter A chemical released by neurons at a synapse for
the purpose of relaying information to other neurons via receptors.
Nociceptors In animals, nerve endings that signal the sensation of
pain. In humans, they are called pain receptors.
glossary | BraiN factS 83
Norepinephrine A catecholamine neurotransmitter produced
both in the brain and in the peripheral nervous system.
Norepinephrine is involved in arousal and sleep regulation, mood,
and blood pressure.
Occipital Lobe One of the four subdivisions of the cerebral cortex.
The occipital lobe plays a role in processing visual information.
Olfactory Bulb A round, knoblike structure of the brain responsible
for processing the sense of smell. Specialized olfactory receptor cells
are located in a small patch of mucous membrane lining the roof of
the nose. Axons of these sensory cells pass through perforations in
the overlying bone and enter two elongated olfactory bulbs lying on
top of the bone.
Orexin Neurons Specialized neurons that provide an excitatory
signal to the arousal system, particularly to the norepinephrine
neurons. Orexin activation plays a critical role in preventing
abnormal transitions into REM sleep during the day, as occurs in
narcolepsy.
Parasympathetic Nervous System A branch of the autonomic
nervous system concerned with the conservation of the body’s
energy and resources during relaxed states.
Parietal Lobe One of the four subdivisions of the cerebral cortex.
The parietal lobe plays a role in sensory processes, attention,
and language.
Parkinson’s Disease A movement disorder caused by death of
dopamine neurons in the substantia nigra, located in the midbrain.
Symptoms include slowness of movement, muscular rigidity, and
walking and balance impairment.
Peptides Chains of amino acids that can function as
neurotransmitters or hormones.
Peripheral Nervous System A division of the nervous system
consisting of all nerves that are not part of the brain or spinal cord.
Photoreceptor A nerve ending, cell, or group of cells specialized to
sense or receive light.
Pituitary Gland An endocrine organ closely linked with the
hypothalamus. In humans, the pituitary gland is composed of two
lobes and secretes several different hormones that regulate the
activity of other endocrine organs throughout the body.
Plasticity The ability of the brain to modify its neural connections
to adapt to challenges in the environment.
84 BraiN factS | glossary
Pons A part of the hindbrain that, with other brain structures,
controls respiration and regulates heart rhythms. The pons is a major
route by which the forebrain sends information to and receives
information from the spinal cord and peripheral nervous system.
Positron emission Tomography (PeT) A method of measuring brain
function based on the detection of radioactivity emitted when
positrons, positively charged particles, undergo radioactive decay
in the brain. Computers then build three-dimensional images of
changes in blood flow based on the amount of radiation emitted in
different brain regions. The more brain activity, the more vivid the
picture that is created.
Psychosis A severe symptom of psychiatric disorders characterized
by an inability to perceive reality. Psychosis can occur in many
conditions, including schizophrenia, bipolar disorder, depression,
and drug-induced states.
Rapid eye Movement (ReM) Sleep Part of the sleep cycle when
active dreaming takes place. It is characterized by neocortical
EEG waves similar to those observed during waking. This state is
accompanied by paralysis of the body’s muscles; only the muscles
that allow breathing and control eye movements remain active.
Reflexes Considered the simplest and most fundamental
movements, they are relatively fixed, automatic muscle responses to
particular stimuli, such as the slight extension
of the leg when a physician taps the knee with a small
rubber hammer.
Retina A multilayered sensory tissue that lines the back of the eye
and contains the receptor cells to detect light.
Reuptake A process by which released neurotransmitters are
absorbed for later reuse.
Rod A sensory neuron located in the periphery of the retina.
The rod is sensitive to light of low intensity and is specialized for
nighttime vision.
Schizophrenia A chronic disorder characterized by psychosis (e.g.,
hallucinations and delusions), flattened emotions, and impaired
cognitive function.
Second Messengers Substances that trigger communication
after the actions of neurotransmitters at their receptors have been
completed. Second messengers convey the chemical message of a
neurotransmitter (the first messenger) from the cell membrane to the
cell’s internal biochemical machinery. Second-messenger effects may
endure for a few milliseconds to as long as many minutes. They also
may be responsible for long-term changes in the nervous system.
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Serotonin A monoamine neurotransmitter believed to play many
roles, including but not limited to temperature regulation, sensory
perception, and the onset of sleep. Neurons using serotonin as a
transmitter are found in the brain and gut. Several antidepressant
drugs are targeted to brain serotonin systems.
Thalamus A structure consisting of two egg-shaped masses of nerve
tissue, each about the size of a walnut, deep within the brain. The
key relay station for sensory information flowing into the brain, the
thalamus filters out information of particular importance from the
mass of signals entering the brain.

Short-Term Memory A phase of memory in which a limited Trophic Factors Small proteins in the brain that are necessary
amount of information may be held for several seconds for the development, function, and survival of specific groups of
or minutes. neurons.

Spinal Cord The extension of the brain through the vertebral
column that primarily functions to facilitate communication
between the brain and the rest of the body.
Stem Cell Unspecialized cells that renew themselves for long
periods through cell division.
Stimulus An environmental event capable of being detected by
sensory receptors.
Stress Any external stimulus that threatens homeostasis — the
normal equilibrium of body function. Many kinds of stress have a
negative effect on the body, but some kinds can be helpful.
Stroke A block in the brain’s blood supply. A stroke can be caused
by the rupture of a blood vessel, a clot, or pressure on a blood
vessel (as by a tumor). Without oxygen, neurons in the affected
area die, and the part of the body controlled by those cells cannot
function. A stroke can result in loss of consciousness and death.
Ventricles Comparatively large spaces filled with cerebrospinal
fluid. Of the four ventricles, three are located in the forebrain and
one in the brainstem. The lateral ventricles, the two largest, are
symmetrically placed above the brainstem, one in each hemisphere.
Vertebral Column The column of bones, or vertebrae,
that extends down the back and functions as a structural element for
the body while also surrounding and protecting the spinal cord.
Wernicke’s Area A brain region responsible for comprehension of
language and production of meaningful speech.
White Matter The part of the brain that contains myelinated nerve
fibers. The white matter gets its color from myelin, the insulation
covering nerve fibers.

Suprachiasmatic Nucleus A small group of nerve cells in the

hypothalamus that express clock proteins, which go through
a biochemical cycle of about 24 hours. This sets the pace for
daily cycles of activity, sleep, hormone release, and other bodily
functions.

Sympathetic Nervous System A branch of the autonomic nervous

system responsible for mobilizing the body’s energy and resources
during times of stress and arousal.

Synapse A physical gap between two neurons that

functions as the site of information transfer from one neuron to
another.

Taste Bud A sensory organ found on the tongue.

Temporal Lobe One of the four major subdivisions of each

hemisphere of the cerebral cortex. The temporal lobe functions in
auditory perception, speech, and complex visual perceptions.

Society for NeuroScieNce glossary | BraiN factS 85

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(Mexican Society of National Institute of Dental and
Physiological Sciences) Craniofacial Research
(301) 496–3571 World health Organization
www.smcf.org.mx
www.nidcr.nih.gov +41 22 791 2111
www.who.int
Wellcome Trust
+44 (0)20 7611 8888 National Institute on Drug Abuse
www.wellcome.ac.uk (301) 443–6480
www.nida.nih.gov

86 Society for NeuroScieNce

Copyright © 2012 Society for Neuroscience
1121 14th Street, NW, Suite 1010
Washington, DC 20005 USA
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All rights reserved. No portion of this publication may be reproduced, stored in a retrieval
system, or transmitted in any form or by any means, electronic, mechanical, photocopying,
recording, or otherwise without permission of the Society for Neuroscience (SfN).

Statistics for diseases and conditions were obtained from the Centers for Disease Control
and Prevention, World Health Organization, National Institutes of Health, and voluntary
organizations.

Brain Facts is produced as part of SfN’s commitment to advance public education and
information about the brain and nervous system. For more information or to download a free
copy, please go to http://brainfacts.org/about-neuroscience/brain-facts-book/.

The Society gratefully acknowledges the invaluable assistance of more than 60 neuroscientists
who volunteered their time, expertise, and guidance in the development and update of this
book. In particular, SfN recognizes the assistance and guidance of its Public Education and
Communication Committee, especially James McNamara, MD, committee chair, and the
following committee members who dedicated significant time as section editors: Judy Cameron,
PhD; Barry Kaplan, PhD; David Parfitt, PhD; Angela Jane Roskams, PhD; Patricia Trimmer,
PhD; Gary Westbrook, MD. SfN also recognizes the important contributions of Nicholas Spitzer,
PhD, inaugural editor-in-chief for BrainFacts.org.

Deputy Executive Director (Programs): Mona Miller

Executive Editor: Debra Speert, PhD
Contributing Editor: Todd Bentsen
Managing Editor: Marilyn Fenichel, Cassell & Fenichel, LLC

Illustrators: Lydia V. Kibiuk, Baltimore, MD; Devon Stuart, Hershey, PA

Printed and bound in the United States of America
Seventh Edition
iNdex

Acetaminophen 69, 70 Antibodies 9, 56, 66, 73-74 Cataplexy 33

Acetylcholine (ACh) 42, 53, 73, 80, 83 Antidepressants 53, 62-64, 69 Catecholamines 10, 81
and Alzheimer’s disease 9, 57-58, 42 Anvil, see Incus Caudal orbital cortex 22
and brain development 16 Anxiety 10, 53-54, 58, 60, 62-63, 73 Cell and gene therapy 73, 75
and sleep regulation 34, 35 Anxiety disorders 62-63 Cell bodies 57, 82
and stress 38 Aphasia 27, 80 Central nervous system 6-8, 8, 14, 18,
Acquired immunodeficiency syndrome Apolipoprotein E 57 29, 56, 62-63, 67, 70, 83
(AIDS) 66-68 Apoptosis 16, 80 Cerebellum 6, 25, 25-26, 31, 50, 67,
Action potential 8-9 Aspirin 12, 69-70 81-82
Addiction 5, 42-44, 52-56, 54, 76, 80, 82 Attention deficit hyperactivity disorder Cerebral cortex 6, 7, 64, 80, 81, 82, 84-85
Adenosine 12, 35, 80, 83 (ADHD) 42, 49, 50, 63, 77, 80 development 16
Adenosine triphosphate 12, 35, 83 Autism spectrum disorders (ASD) 13, and environment 40
Adenylyl cyclase 12 48-49, 77, 80 and learning and memory 25-26, 40
Adrenal glands 10-11, 36, 38, 53 Autoimmune disorders 38 and movement 31
Adrenal medulla 10, 82 Axons 7-9, 9, 14-16, 19, 22, 31, 67, and pain 23-24
Adrenocorticotropic hormone 82-84 parts and functions 7
(ACTH) 38 and seizures 71
Aging 16-17, 31, 37-39, 40, 41, 45, Balance 30-31, 36-37, 59-60, 67-68, 80, and sleep regulation 34-35
60, 73, 86 84 and taste 22
see also Alzheimer’s Disease Basal forebrain 34, 35 Cerebrovascular disease 39
Agonists (muscles) 29 Basal ganglia 6, 26, 31, 42, 59, 61, 63, Cerebrum 6, 7, 12, 18, 81
Agoraphobia 62 80, 82 C fibers 10, 24
AIDS 66-68 Benzodiazepines 9, 63 Chlorpromazine 65
Alcohol 14, 32-33, 52-54, 54, 56, 86 Beta amyloid 57 Chromosomal condition 50
Alcoholism 10, 47, 53-54, 86 Binocular vision 18 Chromosomes 46, 47
Allodynia 24 Biological clocks 11 Circadian rhythm 81
Alpha motor neurons 29, 30, 31, 83 Bipolar disorder 46, 64-65, 80, 84 see also Biological clocks
Alpha secretases 58 Blindness 19, 20, 46 Clomipramine 62
Alzheimer’s disease 6, 9, 31, 42, 45, 49, Blood clot 71, 72 Clonazepam 33
51, 58, 73-74, 80 Blood pressure 10, 32-33, 37-38, 53, 58, Cocaine 14, 53, 54, 55, 56
and aging 39 63, 69, 72, 84 Cochlea 17, 21, 80-82
annual costs 4 Brain Colliculi 6
diagnosis 57-58 development 5, 13-14, 17, 45-46, 49 Cones 18-19, 81
early-onset 57 parts and functions 6-7 Cornea 18-19, 19, 24
genetic basis 57 plasticity 4, 13, 17, 84 Corticotrophin releasing hormone
norepinephrine deficiency 10 reward system 43, 52, 54 (CRH) 38
potential treatments 58 tumors 66-67, 71, 75 Cortisol 11, 37-38, 38, 64, 81
prevalence 57 weight 39 Crack cocaine 55
risk factors 58 Brainstem 21-24, 31, 34, 35, 44, 81-83, 85 Craniectomy 69
symptoms 57 Broca’s aphasia 27 Creutzfeldt-Jakob disease (vCJD) 74
treatment 58 Broca’s area 51, 81 Critical periods 13, 17, 43
Amino acids 9-10, 43, 47, 84 Buprenorphine 55 Cyclic adenosine monophosphate
Amnesia 25, 26 Bupropion 53 (cAMP) 12, 27
Amygdala 6, 25, 26, 54, 80 Cyclic GMP 12
Amyloid precursor protein (APP) 57 cAMP-response element binding protein Cytokines 68
Amyotrophic lateral sclerosis (ALS) 4, (CREB) 27
29, 57-59, 73, 75, 80 Cancer 4, 66 Date-rape drugs 56
Analgesia 69 see also Brain tumors Dementia 39, 57, 58, 68, 80
Androgen 11, 80 Capsaicin 10, 24, 70, 71 see also Alzheimer’s disease
Animal research 8, 20, 42-43, 48, 53 Carbon monoxide 12 Dendrites 7, 9, 14-15, 39, 40, 81, 83
Antagonists 29-30, 55, 80 Cardiovascular system 38

88 BraiN factS | index Society for NeuroScieNce

Deoxyribonucleic acid (DNA) 4, 11, 13,
41, 46-48, 47, 59, 81, 83
Depression 5, 10, 32, 44, 50, 54, 56, 58-
59, 62-67, 70, 73, 80, 82, 84
Descending systems 24
Diagnostics 49, 50, 69, 77
Diffuse optical tomography 46
Diffusion tensor imaging 45
Dopamine 10, 31, 42-43, 50, 53-56, 60-
61, 63-65, 81, 84
and alcoholism 54
and antidepressants 64
and Attention deficit hyperactivity
disorder (ADHD) 50
and cocaine use 54, 55
and cognition and emotion 10
and endocrine system 10
and movement 10, 31
and opiate drug use 54
and Parkinson’s disease 10, 42-43, 60-61
and psychostimulants 56
and schizophrenia 10, 65, 81
and sleep regulation 34
and smoking 53
and Tourette syndrome 63
Dorsomedial nucleus 35
Down syndrome 49-51
Dreaming 6, 32-33, 84
Drug abuse 52, 56, 64
see also Addiction
Drug addiction, see Addiction
Drugs, see Neuropharmacology
Duchenne muscular dystrophy 46
Dyslexia 49-51, 50
Ear 20, 21, 80, 81
Ectoderm 13, 14, 83
Edema 69
Electrical stimulation therapy 71
Electroconvulsive therapy 64
Electroencephalogram (EEG) 32-34, 33,
34, 44, 81, 84
Endocannabinoids 12, 54, 81
Endocrine system 10-11, 36, 38, 81
Endogenous opioids, see Endorphins
Endorphins 52, 54, 70
and alcoholism 47, 53
and mimicry 53
and pain 24
and sleep 10
Engineered antibodies 73-74
Enkephalin 10
Epidemiologists 67
Epilepsy 14, 17, 25, 66, 69, 71, 82
Epinephrine 36-38, 53, 80-82
Estrogens 11, 82
Ethanol 53
Ethics 76-78
Event-related optical signal 46
Extensor muscles 29
Eye 14, 16-20, 19, 29, 32, 34-35, 42-43,
46, 50, 63, 65, 82, 84
Fetal alcohol syndrome 53
Flexion withdrawal 30
Fluoxetine 10
Follicle-stimulating hormone (FSH) 11,
82
Forebrain 6, 7, 14, 34-35, 80-82, 84-85
Fragile X syndrome 46
Free radicals 41, 72
Frontal lobe 6, 7, 17, 22, 27-28, 81, 82
Functional magnetic resonance imaging
(fMRI) 5, 45, 46, 65, 82
Galanin 34
Gamma-aminobutyric acid (GABA) 34,
80, 82
and alcohol 54, 54
and Huntington’s disease 9
as neurotransmitter 3, 4, 9, 63
and post-traumatic stress disorder
(PTSD) 63
and schizophrenia 65
and sleep 34
Gamma hydroxy-butyrate 56
Gamma motor neurons 30
Gamma secretases 58
Gases (neurotransmitters) 12
Gene 11, 12, 16, 20, 28, 35, 41, 48, 49,
51, 57, 59, 66, 71, 74, 75, 83
in brain development 13
diagnosis 46
disorders 41–44, 46–47, 54
recent discoveries 4
therapies 5, 20, 58, 60, 61
Genome-wide association studies 51
Glial fibers 15
Gliomas 66
Glucocorticoids 11, 36, 37, 38, 82
Glutamate 9, 34, 53, 54, 58-59, 64,
80, 82-83
activating NMDA receptors 83
and Alzheimer’s disease 57
and brain tumors 66
and schizophrenia 65
and stroke 12
Glycine 9, 80
Golgi tendon organs 30
Gonadotropin-releasing hormone
(GnRH) 11
Gray matter 6-8, 8, 24, 67, 82
Growth factor therapy 73
Head injuries 68-69, 71
Hearing 7, 14, 17, 20, 33, 44
Heart rhythm 6, 81, 84
Hemispheres 6, 12, 14, 16, 27, 50, 51, 81
Heroin 53-55, 61
see also Opiate drugs
Hindbrain 6, 7, 14, 81, 82, 84
Hippocampus 5, 11, 25, 26, 37, 54, 58,
80, 82
Histamine 24, 34, 35
Homeostasis 36, 37, 82, 85
Hormones 10-11, 32, 36-38, 63-64, 80,
82, 84
Human immunodeficiency virus (HIV)
53, 67-68
Huntington’s disease 4, 9, 46, 59-60, 75,
82
Hydrocortisone, see Cortisol
Hypersensitivity 24
Hypnagogic hallucination 33
Hypnosis 71
Hypocretin, see Orexin
Hypothalamus 33-36, 64, 82, 84-85
functions 6
hormone production 10, 11
and learning and memory 26
and sleep regulation 34
and stress 36, 38
Imaging techniques 5, 41-42, 44-46, 68
Immune system 4, 12, 37-38, 41, 49, 66,
67, 74, 81
Incus 20-21
Informed consent 78
Inner ear 21, 81
Insomnia 32, 34

Society for NeuroScieNce index | BraiN factS 89

Insulin 11 Motor neurons 13-14, 16, 29-31, 58, 59, Norepinephrine 10, 12, 16, 34-35, 38,
Interfering RNAs (RNAi) 73 80, 83 50, 63-64, 70
Interneurons 13, 14, 19, 29 Movement 6-7, 9-10, 17-18, 20, 25, 28- and neural disorders 10, 12, 16, 50,
Ion channels 8, 12, 70-71, 83 31, 33-35, 37, 54, 58-61, 63, 65, 72, 81, 63-64, 80-81, 84
Iris 18 82, 83, 84 and pain 70
MPTP 61 production 16
Jet lag 11, 37 Multiple sclerosis (MS) 67, 83 and sleep 34-35
Muscles 7-9, 13, 18, 28-33, 36-38, 46, and stress 10, 38, 63
Ketamine 56, 64 58-59, 82-84 Nucleus accumbens 43, 54, 56
Korsakoff’s syndrome 10 Muscle spindles 29
Muscular dystrophy 46 Obsessive-compulsive disorder (OCD) 5,
Language 6, 17, 21, 25-28, 44, 49, 51, 57, Myasthenia gravis 9, 83 10, 62
80, 81, 84, 85 Myelin 8, 10, 16, 23, 24, 67, 83, 85 Obstructive sleep apnea 33
Lateral geniculate nucleus 18, 19 Occipital lobe 6, 7, 15, 19, 84
Lateral hypothalamus 33, 35 Naloxone 55 Occipito-temporal neural system 51
Learning 4-6, 10, 13, 17, 24-25, 27-28, Naltrexone 53-55 Olfactory bulbs 22, 84
37-38, 40-44, 49-52, 54, 57, 58, 63, 73, Narcolepsy 33-35, 84 Olfactory cortex 22
80-83 Near infrared spectroscopy (NIRS) 45 Oligodendrocytes 8, 75
Learning disabilities 17, 51 Nerve growth factor (NGF) 59, 73 Opiate drugs 54-55, 70
see also Dyslexia Nervous system 2-10, 12-14, 17-18, 24, Opiate receptors 10, 54-55
Lens 18, 19 26, 29, 36-39, 41-44, 48, 56, 62, 63, 67, Opioid peptides 10, 54
Levodopa 10, 42, 60 70, 74-75, 80-85, 87 Opioids, see Endorphins
Long-term potentiation (LTP) 26, 44 Neural induction 13-14 Optical imaging techniques 5, 44-46
Lou Gehrig’s disease, see Amyotrophic Neural plate 14 Optic chiasm 18
lateral sclerosis (ALS) Neural tube 14 Optic nerve 18-19, 67
Luteinizing hormone (LH) 11 Neuritic plaques 57 Optic vesicle 14
Neurodegenerative disorders 17, 74 Orexin 33-35, 84
Magnetic resonance imaging (MRI) Neuroendocrine system 36, 38 Ovaries 11, 82
44, 45, 59, 66, 68, 83 Neuroethics 76-78
Magnetic resonance spectroscopy (MRS) Neurofibrillary tangles 57 Pain 5, 7, 10-12, 22-24, 52, 54, 65, 67-71 83
45, 83 Neurogenesis 5, 69, 83 Panic disorder 62
Magnetoencephalography (MEG) 45, 83 Neuromodulators 9 Papillae 22
Malleus 20, 21 Neurons 4-19, 21-24, 26, 27, 29, 30, 31, Parahippocampal region 25-26
Manic-depressive illness, see Bipolar 34-35, 37, 41-46, 52, 54-55, 57-59, 61, Parasympathetic nervous system 7, 36,
disorder 66-68, 71-73, 75, 80-85 38, 80, 84
Marijuana 12, 54, 81 aging 39-41 Parietal lobe 6, 7, 84
MDMA 56 development 13-14 Parieto-temporal neural system 51
Medial temporal lobe 25, 26 migration 14 Parkinson’s disease 4, 8, 10, 31, 33, 39,
Medulla 6, 10, 81, 82, 83 signaling 4, 6, 7, 9, 12 42, 44, 60, 60-61, 65, 73-75, 80-81,84
Memory 4-6, 9-11, 25-28, 32, 37, 39, Neuropharmacology (drugs) 5, 8-10, 20, dopamine deficiency 10, 31, 42, 60
42-44, 54, 56-59, 65, 67-68, 73, 77, 24, 33, 42-44, 49, 50, 52-54, 56, 58-61, norepinephrine deficiency 10
80-83, 85 63-73, 75-77, 81, 85 potential treatments 61, 73-75
Mesoderm 13 Neurotransmitters 8-10, 12, 15-16, 27, prevalence 60
Messenger RNA (mRNA) 47 31,33 34-35, 42-45, 52-54, 57, 59, 63- symptoms 10, 31, 33, 60
Methadone 55 64, 80-81, 83, 84 treatment 10, 42, 60-61, 73-75
Methamphetamine 56 Neurotrophins 27 Perception 20-22, 25, 27, 36, 38, 54, 59,
Methylprednisolone 69 Nicotine addiction 53 83, 85
Midbrain 6, 7, 14, 23, 31, 60, 83, 84 Nitric oxide 12 Peripheral nervous system 7-8, 10, 80,
Middle ear 20 N-methyl-d-aspartate (NMDA) 9-10, 26, 81, 83-84
Migration 13-14, 83 27, 53, 64, 82, 82-83 Peripheral neuropathy 68
Mineralocorticoids 11 Nociceptors 24, 70-71, 83 Phobias 62
Mitochondria 68, 72, 83 Nondeclarative knowledge 25, 26 Phonology disorders 51
Monoamine 57, 81, 85 Nonopioids 69 Photoreceptors 18-20, 82, 84
Morphine 10, 24, 54, 69, 70, 81 Nonsteroidal anti-inflammatory drugs Physical exercise 41, 72
see also Opiate drugs (NSAIDs) 69, 70 Pinna 20-21
Motor cortex 7, 31, 34 Pituitary gland 10-11, 38, 82, 84

90 BraiN factS | index Society for NeuroScieNce

Plasticity 4, 17, 84 Smell 21-22, 84 Thalamus 6, 19, 22, 23, 24, 31, 34, 35,
Pons 6, 81, 82, 83, 84 Smoking 53, 54, 56 71, 81, 85
Positron emission tomography (PET) 5, Somatic nervous system 7 and movement 6, 22, 31, 81
44, 62, 64, 84 Somatostatin 57 and pain 22-23, 24
Post-traumatic stress disorder (PTSD) Sonic hedgehog (protein) 13 and seizures 71
62-63, 77 Speech 7, 20-21, 27-28, 31, 51, 59, 67, and sensation 24
Prefrontal cortex 25-26, 50, 54, 64 71, 72, 81, 82, 85 and sleep 33, 34, 35,
Prion diseases 74, 75 Spinal cord 5-8, 14-15, 22-24, 29-31, 45, Thymine 47
Progesterone 11, 69 58, 67, 75, 80, 81, 84, 85 Thymus 11
Progestins 11 damage 5, 67-69, 73, 74 Touch 18, 22, 24, 42, 70
Prostaglandins 12, 24, 70 development 13 Tourette syndrome 63-64
Proteins 9-12, 15, 20, 22, 27-28, 34-35, and movement 7, 29-30 Transcranial magnetic stimulation
41, 43, 47, 57-60, 68, 73-75, 85 and pain 23, 24, 70 (TMS) 46
Psychostimulants 56 and touch 22 Traumatic brain injury 68-69
Pupil 18 Stapes 20-21 Trophic factors 10, 16, 61, 73, 85
Stem cells 5, 40, 59, 61, 66-67, 72, 73-75, Tumor(s) 45, 46, 66-67, 71, 75
Radiation 14, 44, 66, 83, 84 85 Two-point threshold 24
Rapid eye movement (REM) sleep Steroids 11, 66, 67, 69, 80
32-35, 84 Stirrup, see Stapes Vagal nerve stimulation 71
Rational drug design 73 Strabismus 20 Varenicline 53
Reflexes 6-7, 29-31, 43, 84 Stress 4, 7, 10-12, 35, 36-38, 52, 56, 62- Ventral tegmental area 43, 54
Reproduction 11, 37 65, 77, 80, 82, 85 Ventrolateral preoptic nucleus (VLPO)
Retina 18-20, 35, 81-82, 84 Stress hormone(s) 11, 36, 37, 38, 63, 64 34, 35
Retinoblastoma 46 Stretch reflex 29-30 Virus(es) 67, 68, 70, 74, 75
Reward system 6, 42-43, 52-54 Striatum 25, 50 Vision 7, 14, 15, 17, 18, 19, 20, 42, 43,
Rods 18-19 Stroke 5, 10, 12, 17, 21, 27, 32, 37, 39, 67, 81, 83
44-45, 70-73, 80, 82, 85 Visual cortex 17, 18, 19
Schizophrenia 5, 10, 13, 45-46, 65, 81, 84 costs 72 Vitamin D 11
Schwann cells 8 damage caused by 10, 12, 21, 37, 71-72, Voluntary movement 6, 7, 9, 29, 31, 36,
Second messengers 12, 84 80, 82, 85 58-59
Seizures 25, 48, 49, 63, 66, 71, 82 prevalence 72
Selective serotonin reuptake inhibitors treatment 5, 10, 70, 72, 73 Wakefulness 6, 32, 34, 35, 37, 80
(SSRIs) 62-64, 70 Subparaventricular nucleus 35 Wernicke’s aphasia 27
Sensation 10, 24, 69, 81, 83 Substance P 10 White matter 7, 67, 68, 85
Sensory 6, 7, 10, 16-18, 22, 24, 26-31, Substantia nigra 31, 60, 80, 84 Word deafness 27
36, 45, 68, 71, 81 Subthalamic nucleus 61
cortex 7, 22 Superior temporal lobes 21, 27
fibers and nerves 10, 24, 29, 30 Superoxide dismutase 59
neurons 16, 22, 84 Suprachiasmatic nucleus 34-35, 85
receptors 29, 31, 82, 85 Sympathetic nervous system 7, 10, 26,
Serotonin 10, 34, 35, 56, 62, 64, 70, 85 36, 38, 80, 81, 85
Sexual differentiation 11, 82 Synapse 15-16, 22, 26, 41, 43, 57, 58, 64, 83
Sight, see Vision and drugs 42, 55, 64
Single photon emission computed and memory 26-27, 43
tomography (SPECT) 44 definition 7-9, 85
Skeletal muscles 29 development 15-16, 41
Skin 13, 22, 24, 29, 36, 40, 70, 71
Sleep 6, 7, 9-10, 32-35, 37, 58, 60, 63,
64, 80, 82, 84, 85 Tardive dyskinesia 65
brain activity 6, 32-35 Taste 17, 21, 22, 85
disorders 32-33, 37, 63 Tau tangles 57
regulation 34-35, 80, 82, 84, 85 Tectorial membrane 21
REM sleep 32-35, 84 Temporal lobe 6, 7, 25, 26, 27, 28, 85
slow wave 32-34 Testes 11
stages 32-34 Testosterone 11, 80
Small-molecule drugs 73, 75 Tetrahydrocannabinol (THC) 54

Society for NeuroScieNce index | BraiN factS 91

FOUNDING PARTNERS

The Gatsby Charitable Foundation

Gatsby is a Trust set up by David Sainsbury to realise We are proactive in devising projects to achieve our aims.
his charitable objectives. We focus our support on a limited We are enthusiastic about supporting innovation. We are
number of areas: analytical as we believe it is important to understand the
opportunities and problems we tackle. We take a long-term
• Plant science research view as we do not think much can be achieved by short, one-
• Neuroscience research off projects. We are always enthusiastic to form partnerships
• Science and engineering education with other organisations who share our goals.
• Economic development in Africa
• Public policy research and advice
• The arts

The Kavli Foundation

The Kavli Foundation, established by Fred Kavli, is
dedicated to advancing science for the benefit of humanity,
promoting public understanding of scientific research, and
supporting scientists and their work. The Foundation’s mission
is implemented through an international program of research
institutes in the fields of astrophysics and theoretical physics,
nanoscience, and neuroscience, and through the support of
conferences, symposia, endowed professorships, journalism
workshops and other activities. The Foundation is also a
founding partner of the Kavli Prizes, biennial $1 million prizes
that recognize scientists for their seminal advances in three
research areas: astrophysics, nanoscience and neuroscience.

92 Society for NeuroScieNce

 The Society for Neuroscience is the world’s largest
organization of scientists and physicians dedicated to
understanding the brain, spinal cord, and peripheral
nervous system.
Neuroscientists investigate the molecular and cellular
levels of the nervous system; the neuronal systems responsible
for sensory and motor function; and the basis of higher order
processes, such as cognition and emotion. This research provides
the basis for understanding the medical fields that are concerned
with treating nervous system disorders. These medical specialties
include neurology, neurosurgery, psychiatry, and ophthalmology.
Founded in 1969, the Society has grown from 500 charter
members to more than 42,000 members worldwide. The Society
has more than 150 local or regional chapters. With activities
ranging from lectures to networking events and information
sharing, SfN chapters enable individual members to engage
their colleagues at the local level.
The mission of the Society is to:
• Advance the understanding of the brain and the
nervous system by bringing together scientists of
diverse backgrounds, by facilitating the integration
of research directed at all levels of biological
organization, and by encouraging translational
research and the application of new scientific
knowledge to develop improved disease treatments
and cures.
• Provide professional development activities, information about neuroscience to schoolteachers and
information, and educational resources
for neuroscientists at all stages of their
careers, including undergraduates, graduates,
and postdoctoral fellows, and increase
participation of scientists from a diversity
of cultural and ethnic backgrounds.
• P romote public information and general education
about the nature of scientific discovery and the
results and implications of the latest neuroscience
research. Support active and continuing
discussions on ethical issues relating to the
conduct and outcomes of neuroscience research.
• Inform legislators and other policy-makers about
new scientific knowledge and recent developments
in neuroscience research and their implications
for public policy, societal benefit, and continued
scientific progress.
The exchange of scientific information occurs at an
annual fall meeting where more than 16,000 reports of
new scientific findings are presented and more than 30,000
people attend. This meeting, the largest of its kind in the
world, is the arena for the presentation of new results in
neuroscience.
The Society’s weekly journal, The Journal of
Neuroscience, contains articles spanning the entire range of
neuroscience research and has subscribers worldwide. The
Society’s ongoing education and professional development
efforts reach teachers and help promote the education of
Society members. Print and electronic publications inform
members about Society activities.
A major goal of the Society is to inform the public
about the progress and benefits of neuroscience research.
The Society accomplishes this goal by providing
encouraging its members to speak to young people about the
human brain and nervous system.
 A Companion Publication to

A PUBLIC INFORMATION INITIATIVE OF:

Society for Neuroscience | 1121 14th Street, NW | Suite 1010 | Washington, DC 20005 | www.sfn.org