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9 Neurons & Glial Cells

Intro to Neurons
1. Exitability and Secretions
a. electrical signals invade presynaptic terminals and elicit the exocytosis of NTs which can excite or inhibit
the adjacent neuron
2. Influence on nearby cells
a. some neurons in CNS and ganglions of PNS synapse locally to influence neighbors but not to distant sites
3. Influence on distant cells
a. some neurons can influence distant cells, transmitting information over very long distances

Structure and Function

Often a MOTOR neuron

Often SENSORY neuron

Often SENSORY neuron

Most common neuron

very short axon, does NOT


use APs (usually chemical)

Ex: DRG

Usually seen in CNS


Ex: spinal motor neuron

Ex: retina

dendrites extend into PNS to


gather sensory and axon
extends into CNS to relay info

Notable Structures
Neurites
Soma cell body
Axon branches that release NTs into the synaptic cleft and are received by the dendrites
Dendrite arborized branches that receive signals
Synapse space between axon and dendrite, where NTs must travel across to continue signal transduction
Myelin Sheath see glial cells
Collateral Axon Branch branch of the main axon that feeds back onto soma providing modulation of cell firing
Presynaptic Terminal where the NT will be released from
Nissl Body histological sign of rough ER, site of protein synthesis
Axon Hillock/Initial Segment connects soma to axon
Synaptic Bouton contains NTs waiting to undergo exocytosis; dense vesicles carry catecholamines, serotonin or
peptides where clear vesicles seen in motor neurons carry acetylcholine.

Cytoskeleton
The cytoskeleton is made of three filaments joined to each other, ER and vesicles by protein bridges. It functions in
the support and maintenance of neuronal shape as well as the transport of material between soma and neurites.

1. Microtubules
a. Is 100m long and 20nm in diameter and is made of polar tubulin molecules creating a pos and neg pole
b. Growth takes place by adding tubulin at the positive pole
c. MAPs (microtubule associated proteins -Tau Proteins) stabilize the microtubule & assist in transport
2. Neurofilaments
a. Most common filament with a diameter of 10nm (will essentially determine the diameter of the axon)
b. Undergo little turnover (unlike microtubules and microfilaments)
c. Create a scaffolding for the cytoskeleton of the neuron
3. Microfilaments
a. Are basically actin filaments at 5nm which form a network just below the cell membrane
b. Participate in growth cone during growth or repair after injury

Propagation of Electircal Signals


1. Subthreshold signals pass along cells WITH Decrement
a. Small accumulations of charge at the synapse will change the membrane potential evoking an impulse; this
impulse is subthreshold, thus it will fade exponentially as it moves away from the synapse.
2. Impulses are propagated along axons WITHOUT Decrement
a. APs generated at the exitable region of the cell will propagate itself by continually regenerating itself
b. This will ensure the AP passes along without decrement
3. Fiber Diameter and Conduction Velocity
a. Simply put, larger diameter fibers will conduct faster

Transporting Materials Axons/Dendrites


MAPs play key roles in fast axonal transport of materials along microtubules at 100-500 mm/day.
2. Kinesin
a. is an ATPase that moves in the
anterograde direction
b. Allows attachment of large structures
such as vesicles (filled with peptides)
and mitochondria
(-) Soma

(+) Nerve
Ending

1. Dynein
a. is an ATPase that moves in the
retrograde direction
b. it is also the motor protein responsible
for the movement of cilia and flagella
c. Nerve growth factor is one material
in particular that is endocytosed and
taken to the soma via retrograde
(-) Soma

(+) Nerve
Ending

3. Axoplasmic Flow
b. Is continuous but very slow, moving at about 1 mm/day
c. If it were not for MAPs, material exchange rates would be unsatisfactory and the cell would die
i. This is seen with drug use and aging

Glial Cells
4. Central Nervous System
a. ASTROCYTES
i. Sole storage for glycogen in the CNS and can convert/deliver as lactate as alternate ATP source in
the event of glucose supply interruption
ii. Regulates K+ microenvironment via Na/K pump and Na/K/Cl-cotxp
1. neuronal activity will [K+] and without this regulation, K+ can disrupt neuronal signaling
2. Spatial Buffering: the K+ from the ECF is distributed across the cytoplasm and its
neighbors via gap junctions
iii. Take up NTs from ECF which is crucial in terminating their actions
b. EPENDYMAL CELLS
i. GROUP 1 are the secretor cells of the choroid plexus and joined by tight junctions to stop water
and solutes passing paracellularly from the blood to CSF (BBB)
ii. GROUP 2 ependymocytes line the ventricles and central canal. They are joined by gap
junctions which allow flow around the cells for exchange between CSF and interstitial fluid. They
are also involved in circulation of the CSF within the CNS.
c. MICROGLIA
i. Are the macrophages of the CNS as well as playing a role in immune response
ii. The phagycytose debris from damaged cells and participate in scar formation
d. OLIGODENDROCYTES
i. Wrap 100 membrane layers around 1mm (with gaps of 1m) segments of several axons in its
vicinity to electrically insulate and increase conduction velocity of APs
5. Peripheral Nervous System
a. SCHWANN CELLS
i. Primary function is to myelinate ONE section of ONE axon
1. The axon will call out the schwann cell and instruct it to begin myelination (NOT IN CNS)
ii. Non-myelinating Schwann cells will envelope several small axons to create a Remak Fiber which
serves to regulate K+ ion concentration
iii. Central role in regeneration, forming a guide tube for the axonal segment to grow in as well as
secreting growth factors to induce axonal growth

Clinical Correlations
1. Gliosis
a. Hyperplasia and hypertrophy of astrocytes in response to CNS injury
b. Causes glial scars which limits axonal regeneration in the CNS
2. Regeneration of axons in the PNS
a. The distal end of a severed axon will degenerate (wallerian/anterograde degeneration) and the proximal
end sprouts new axons at 2mm/day
b. This is done with Schwann cells guide tube and release of growth factors
c. Deinervated cells will die within 3 weeks w/o neuronal activity
3. Regeneration of axons in the CNS
a. This is virtually impossible as there is no glial cell in the CNS that secretes enough Nerve growth factor to
elicit axonal growth
b. Additionally, oligodendrocytes do not form guide tubes and Schwann cells do and with the addition of
glial scars, regeneration is impossible.
4. Glial Tumors
a. 50% of brain tumors and 25% of spinal cord tumors are of glial origin, thus nearly all tumors are of glial
origin
b. Tumors of neuronal origin are extremely rare in both CNS and PNS
5. Viruses use Retrograde Transport
a. Some viruses use retrograde transport to reach the soma and infect the neuron
b. Examples include herpes and rabies, which enter the skin and work back to the soma.

10 Resting Excitable Cells


Intro Membrane Potentials

Membrane potential (Vm) is known as the electrical difference between the interior and exterior of the cell wall
The separation of charge is always near the membrane where the Inside is Negative and the Outside is Positive
Enclosed in the cytosol or ECF there is macroscopic electroneutrality but at the membrane there IS a difference
Small changes in Ion flux (ie: 10-12 moles of Na+) will hardly affect the concentration gradient but it can
change the Vm by up to 100mV!
Resting Vm differences:
Resting Vm varies depending on the type of cell
Photoreceptors
-40mV
Skeletal Muscle
-90mV
Neurons
-65Mv

Ion Transport
1. Ion channels are responsible for allowing and
regulating ionic movement across the membrane
a. They are made of subunits surrounding a
central pore that is selective for a specific
ion.

2. Membrane Transport Proteins use ATP to carry


ions across the membrane
a. Examples include the Na/K-ATPase which
transfers 3-Na+ for 1-K+

Ionic Gradients
1. As stated, neurons have a Vm of about -65mV and the intra/extracellular ion concentrations are as follows

2. Potassium concentration can dramatically affect the resting potential in all excitable cells
a. Raising extracellular K+ decreases the amount of potassium loss, making the interior less negative

[K+]o Depolarization of the cell

keeps it in
b. Reducing extracellular K increases the amount of potassium loss, making the interior more negative
+

[K+]o Hyperpolarization of the cell

forces it out

Ion Channels
1. The open/close state of the ion channels determines the membrane potential of the cell.
2. They are usually closed at rest but can be gated open by changes in potential, second messengers, NTs, etc
3. Membrane Conductance is based on the number of open channels and the conductance of that channel, thus:

gx

Membrane
conductance

Nx

number of
open channels

channel
conductance

gm = gNa + gK + gCl

a. In neurons, the net membrane conductance is based on the sum of each individual ion
b. K+ is the major influence and dwarfs the effects of the remaining ions
c. The Resting Potential is strongly influenced by the flux of K+ as well

Electrochemical Gradient
1. In the absence of control mechanisms, each ion will move in/out of the cell until it reaches its individual
equilibrium potential.
a. This is established when the electrochemical gradient reaches a point where its driving force
counterbalances the driving force of the ions concentration gradient and can be calculated as such

Nernst Equation

EX = (61.5)log {[X+]o / [X+]i}

2. The electrochemical gradient of a given ion can be deduced from the equilibrium potential of the ion and the
membrane potential of the cell as seen in the following equation.
Electrochemical Gradient

= (Vm - EX)

Example-K+: (-65) (-80) = +15mV


a. This +15mV will work to repel K+ ions therefore active transport must be utilized to maintain balance
3. Individual ionic currents are constantly moving around and not at rest but the combined ionic currents of all the
ions, giving the Total Ionic Current will be ZERO

Ix = gx (Vm Ex)
Im = INa + IK + ICl
4. As it can be seen with algebra, the previous two equations can be combined and since Im must be zero, so will the
new equation

gNa (Vm ENa) + gK (Vm EK) + gCl (Vm ECl) = ZERO


5. With more algebra and the incorporation of the equation used for calculating the total membrane conductance, an
equation for Membrane Potential Vm can be deduced.

Vm = (gK /gm)EK + (gNa /gm)ENa + (gCl /gm)ECl


6. FOR NEURONS: membrane conductance and equilibrium potential can be replaced by actual values and it is
clear that the effect of K+ dwarfs the effects of the others

Vm = (0.7)EK + (0.1)ENa + (0.2)ECl (-56) + (6.2) + (-13) -62.8mV

Clinical Correlations
1. Death by Lethal Injection
a. Injection of KCl will increase extracellular potassium to the point where cells spontaneously depolarize and
in cardiac cells, will lead to death at high doses
2. Ischemic Cerebral Edema
a. Interruption of blood flow causes a failure of the Na/K-ATPase pump. This will result in the respective
ionic gradients dissipating where sodium will enter the cell causing water to follow and swell.

11 Stimulated Excitable Cells


Intro Exitable Cells
1. Efferent and Interneurons
a. Have membrane proteins that are chemoreceptors for NTs
2. Afferent Neuron
a. Have membrane receptors for a specific types of stimulus (ie: mechano, chemo and photoreceptors)
3. Stimulus and Receptor
a. A stimulating molecule binds to its receptor and each activated receptor acts as an open ion channel
b. Greater stimulus results in more molecules interacting with receptors, which will open more ion channels
i. Thus, gm and Vm change proportionately to the initial stimulus

Graded Potentials
1. A stimulus to the sensory end of an afferent neuron (dendrite) will cause a local depolarization
a. it will also depolarize adjacent regions but weaker and weaker as it gets further from original site
2. while traveling along, charges will leak out of the membrane of the axon thus dying out as it travels which is
known as Decrement

a. The Length Constant () defines this exponential fall of a given structure/substance and can be
calculated

V = Vo exp (-x/)

= (arm/2ri)

Vo = membrane potential @ stimulus

a = radius
rm = cell surface resistance
ri = resistance along interior

b. Note that as radius (a) increases, so will the length constant meaning less decrement

Stimulus Converted to Electrical Signal


1. Muscle Afferents and Mechanoreceptors
a. Mechanosensitive 1-a afferent fibers will detect a stretch (change in length) of the muscle spindle
theyre wrapped around
i. The stretch will stimulate stretch-gated Na+ channels to open and send a signal that is proportionate
to the size of the stretch
ii. If the stimulus is small, it will produce a small depolarization, but a large stretch will cause Vm to
reach threshold and generate an impulse
b. The Golgi Tendon Organ will work in a similar fashion only it will monitor the tension of muscle spindle
2. RODS and their response to Photons
a. In the dark, basal concentrations of cGMP will gate Na+ channels open to depolarize the Rods and thus be
able to see in the dark
b. In the presence of Photons, cGMP will decrease and close the Na+ channels which makes the interior of
the rod more negative thus hyperpolarizing the Rods
cGMP keeps cations
channels open in the
dark

Exposure
to
Light

Decrease
in
cGMP

Close
Na+
channels t

Decrease in [Na+]
hyperpolarizes
he Rod

3. Olfactory Epithelium and Odorants


a. An odorant molecule will reach its receptor on the cilia which is attached to a bipolar neuron
b. The receptor protein will activate the cAMP pathway and phosphorylate (open) Na+ and Ca+ channels
which will depolarize the neuron and Cl- channels will open to efflux Cl, thus helping to depolarize
c. Hence, the neuron will depolarize and it will be proportionate to the concentration of the stimulating
molecule
d. Local depolarizations spread into the cell body and if large enough will elicit a conversion into and action
potential into the olfactory nerve

Depolarization and Impulses


1. All-or-None Response
a. Changes in membrane potential due to
depolarizations are directly related to the magnitude
of the initial stimulus or current pulse created.
b. If and when the current pulse is large enough to reach
threshold, it stimulates the firing of an action
potential
i. anything larger than threshold will only make
it happen faster but the size of the AP is
constant

2. Spike Initiation Zone


a. The Spike initiation zone is the location with the highest density of voltage gated sodium channels
b. In Mulitpolar cells, it is at the axon hillock
c. In Bipolar and Pseudounipolar it is near the sensory endings
d. In Skeletal Muscle Fibers, it is close to the central region receiving Ach released by the motor neuron

Graded Potentials vs. Action Potentials


Graded Potentials
Local Response
No Threshold for response
Evoked by a variety of stimuli (light, chem, mechanical)
Response may be depolarization -OR- hyperpolarization
Mediated by a receptor
Amplitude is proportionate to stimulus
Summation of response occurs
Spreads with decrement
Fails to spread over long distances

Action Potentials
Propagated Response
Threshold for AP exists
Evoked by depolarization ONLY
Always overshoots zero mV
Mediated by voltage-gated channels
Amplitude independent of stimulus size All-or-None
No Summation
Amplitude is constant during propagation
Propagated over long distances

Clinical Correlations
1. Anosmia
a. Loss of olfactory sensation from head injury which severs/compressed the axons of the olfactory nerve
b. It may also develop as a function of aging; natural degeneration of a fraction of the olfactory nerves
2. Night Blindness
a. Vitamin A is where rhodopsin (the visual pigment in the rods) is derived from
b. Concequently, vitamin A deficient people will lack rhodopsin, hence night blindness as rods are
responsible for night vision

12 Action Potential Initiation and Conduction


Unmyelinated Impulse Generation
A stimulus applied to the sensory end of an unmyelinated axon will depolarize the axon to an extent; if the it is
large enough to reach threshold, it will elicit an impulse and self-regenerate to reach the secretory ending
1. RISING PHASE: Depolarization causes opening of Na+ channels.
a. Small depolarization Na+-in and K+-out oppose
b. Threshold-reaching depolarizations Na+-in will exceed K+-out, causing more depolarization, more Nachannels will open and drive Vm toward ENa
2. FALLING PHASE
a. K+ channels opening will ensure its efflux, thus ensuring the repolarization of the neuron
b. In this phase, Na+ channels will close as the K+ channels open as they should be at rest repolarization
c. Note that the K+ channels will close slowly, thus creating the hyperpolarizing undershoot of the AP

3. Na+, K+ and Ca+ Channel Structure


a. 4 subunits around central pore; each consisting
of 6 segments where #4 carries the voltagesensing element
b. Each of the 4-subunits has a pore loop hanging
in the central pore working as the specific ionselector

Refractoriness
1. Ball and Chain
a. Following a depolarization, the ball portion that carries a positive charge will lodge itself into the Na+
channel as it tried to exit the channel due to the positive charge intracellularly due to depolarization
rendering the channel INACTIVE.
b. Soon after, the ball will fall from the pore & the channel will close naturally, thus the channel is CLOSED

+
+

2. Absolute Refractory Period


a. A time when the Na+ channels are Inactivated (ball and chain) and regardless of the size of a second
stimulus, cannot be reopened, thus the cell cannot be depolarized again.
3. Relative Refractory Period
a. At this point some Na+ channels are open but because there are too few available and most are in the
normal closed state, it takes a much larger stimulus to evoke an impulse.

Unmyelinated Axons - Continuous Conduction


1. Propagation without loss in amplitude
a. An impulse in one region forces (+) charges to flow forward in the cells interior which depolarizes the
adjacent region to ensure reaching threshold and so on, thus ensuring continuous conduction.
2. Ion channels are evenly distributed across unmyelinated axons to ensure propagation (unlike myelinated axons)
3. Local Current Flow is central in allowing (+) charges to flow nicely from the region undergoing an impulse to
the next inactive region, thus an integral part in continuous conduction.

Myelinated Axons - Saltitory Conduction


1. Myelin
a. Electrically insulates axons by 1mm at a time with 1m Nodes of Ranvier between each myelin sheath
2. Voltage Gated Channels
a. Na+ are only found in the Nodes of Ranvier (note difference vs. unmyelinated axon)
b. K+ channels are only found in myelinated regions
3. Result of Atypical Distribution
a. Impulses only occur at nodes and do NOT have undershoot (absence of K+ channels)
b. K+ channels in myelinated region maintain resting potential of that region to allow proper conduction
c. If Demyelination occurs, conduction will be lost because Na+ channels are too far apart
4. Saltitory Conduction
a. Impulses are formed at one node and quickly jump to the next node down this electrical gradient between
the nodes and can do so because the myelin makes the very high (virtually no decrement)

Conduction Velocity Fiber Diameter


1. Unmyelinated Axon - SLOWER
a. smaller diameter results in more resistance; (velocity is 2x diameter)
b. Continuous conduction requires entire membrane sequentially be driven to threshold (time consuming)
2. Myelinated Axon FASTER
a. There is a finite time required for the depolarizing current to jump to the next node and drive it to
threshold which defines its maximum possible conduction velocity
b. The regeneration of the impulse at each node ensures the absence of decrement
c. Conduction velocity is about 6x the diameter of the fiber (more than unmyelinated)
3. Myelinated Axon THREE MAJOR ADVANTAGES
a. Enhanced speed of conduction because impulses are generated only at the nodes
b. Much larger velocities with relatively small diameters (velocity is usually 6x the diameter)
c. APs are confined to nodes, thus the energy required by Na/K-pump to re-establish balance is much less

Impulse Conduction Impairment


1. Tetrodotoxin (TTX) and Saxitoxin (STX)
a. From the Japanese puffer fish and crabs via Red Algae, respectively
b. Complete block of Na+ channels resulting in the inability to depolarize at all, thus respiratory and cardiac
arrest.
2. 4-Aminopyridine (4-AP)
a. Blocks exiting K+ to prolong impulse duration
b. Used to treat diseases affecting transmitter release at the NMJ
3. Local Anesthetics (lidocaine, etc)
a. Block Na+ channels at an intracellular site blocking impulse initiation and conduction
b. Acts first on small myelinated (A-delta) then small unmyelinated (C-fibers) then large myelinated

Deficits due to Demyelination


1. Impulse Conduction
a. If the myelin sheath is destroyed, it will leave the axon bare and jeopardize impulse conduction.
b. The safety factor built in (the current flowing to the next node is 5x higher than needed to excite that next
node) drops to dangerously low levels due to losses of (+) charges as it travels down the axon
c. Conduction velocity can decrease by up to 25-fold due to this leakyness
2. Multiple Sclerosis (CNS)
a. MS is an auto-immune disease against oligodendrocytes (possibly started from a virus)
3. Guillain-Barre Syndrome (PNS)
a. Auto-immune against the Schwann cells usually following a respiratory or intestinal infection beginning
lower in the body and working its way up (if it reaches diaphragm, could be fatal wait on respirator)
b. Sensory and Motor nerves experience demyelination but pt usually recovers
c. Similar situation arises due to Diptheria a toxin from a bacteria, but is treatable
4. Total Conduction Block
a. Demyelination is so severe that the depolarization current fails to reach proceeding node(s)
5. Crosstalk Between Axons
a. Leaking ions can trigger an unwanted impulse in an adjacent axon and will travel in both directions as
there is no refractory established from either direction.

Clinical Correlations
MULTIPLE SCLEROSIS
Incidence is 1 in1000; causes demyelination of the CNS leading to
1. Effects CN-II (only cranial nerve myelinated by oligodendrocytes thus the only cranial nerve affected in MS)
a. Blurred vision, partial vision loss (bilat/unilat)
2. Effects Brain Stem
a. Hearing Loss axons dealing with CN-VII
b. Eye Movements weak Lateral Rectus (CN-VI) conjugate eye movements in brain stem
3. Motor Deficits
a. Weak/poor coordination lower limbs corticospinal tract
b. Speech deficits cerebellum
4. Sensory Deficits
a. Altered sensations from lesions in spinal cord
b. Sometimes, loss of pain, temperature, and in others, loss of proprioception
c. Parastesias in legs
5. Temperature Sensitivity
a. Rise in environmental temperature is associated with faster conduction velocity but duration and amplitude
decrease; thus, playing into the built in safety factor MS patients are worse in warm weather and
sometimes better in cooler weather.

13 Synaptic Transmission
Electrical vs. Chemical Synapses
1. Electrical Synapse
a. In the CNS, occur in the spinal cord, hippocampus, mesensephalic nucleus and retina b/w horizontal cells
b. Gap Junctions are found at electrical synapses, spanning both cell membranes of adjacent cells
i. Gap junctions also occur b/w astrocytes allowing these glial cells to function in syncytium when
buffering K+ ions
c. Electrical synapses also play a role in cardiac signaling and some epithelial cells of various organs
d. NOTE: the number electrical synapses in the CNS are Dwarfed by chemical synapses, thus forgetem
2. Chemical Synapses
a. Most synapses are chemical, where a NT from the presynaptic bouton is released across the synapse and
play on a receptor in the postsynaptic cell
b. Active Zone: where exocytosis
occurs in presynaptic membrane
c. Dense Regions: where NT is received
in the postsynaptic membrane
3. Location of Synapse and Function
a. AxoDendritic excitatory on firing rate
b. AxoSomatic inhibitory on firing rate
c. AxoAxonic inhibitory on NT release

Chemical Synapse Transmission Characteristics


1. Ionotropic Receptor
a. Ion channel proteins that open (or close) when they are hit by the NT which leads to a change in gm & Vm
2. Metabotropic Receptor
a. Work via G-protein pathways to influence the activity of adjacent enzymes that induce 2nd messengers
3. Synaptic Delay
a. Delay between arrival of an impulse and the onset of a response
b. Ionotropic Receptors 0.5ms delay due to mechanisms of transmitter release
c. Metabotropic Receptors several hundred ms delay due to 2nd messenger system; slower = more control
4. Transmitter Termination
a. Diffusion significant mechanism for neuropeptides ONLY
b. Extracellular Enzymatic Degredation mechanism for Acetylcholine ONLY
c. Uptake into Nerve Ending or Glia important for catecholamines, glutamate, serotonin, GABA & glyince
i. after uptake some NTs (cat, glut & sero) are broken down by intracellular enzymatic degradation

1a Afferents Effect on Motor Neurons


1. Each 1a-afferent sensory neuron innervates about 100 motor neurons for the muscle it monitors
2. If a muscle is stretched, 1a afferent fibers will be exited consequently using GLUTAMATE to make about 5
excitatory synapses with each motor neuron it innervates in the ventral horn
3. These 1a-afferents will also stimulate interneurons (via glutamate) where these interneurons release GLYCINE
onto motor neurons responsible for controlling the antagonist muscle in an effort to inhibit said antagonist muscle

The Myotactic Reflex

Excitatory Action of Glutamate


1. Glutamate binds to its Ionotropic Receptor known as AMPA receptors which allows Na+ influx and K+ efflux
a. Na+ influx exceeds K+ efflux because the Na+ electrochemical gradient is much larger than K+
b. This ionic movement evokes a small depolarization known as EPSP - excitatory postsynaptic potential
2. EPSP Time Course
a. Has a rapid depolarization phase (1ms) and slow repolarization phase (20ms)
b. The glutamate is quickly uptaken by the nerve ending or by glial cells
3. EPSP Amplitude
a. The amplitude reflects the amount of glutamate released from the presynaptic neuron
b. The amplitude will hit a max as there are a finite number of glutamate-gated channels
4. Ionic Basis of EPSP from Glutamate
a. AMPA cannot distinguish between cations (Na+, K+) but if we use the Nernst equation and combine the
total ionic concentrations between both ions both inside and outside, we can estimate Vm
Inside [cation]i = 160mM
Outside [cation]o = 155mM
Ecation = (61.5)log {[cation]o / [cation]i} 61.5log(155/160) -0.85mV
b. Thus the electrochemical gradient (Vm Ecation) is just about -65mV meaning inwards
c. In Reality: there will be a large influx of Na and a small efflux of K causing a depolarization but this
depolarization falls far short of Ecation because the number of channels opened is small and there still
remains this opposition of K+ ions
5. Reversal Potential
a. When membrane potential is held at resting values (ex: -65mV), the opening of cation channels causes an
inward flow carried mainly by Na+ (depolarization)
b. When membrane potential is held at positive values (ex: +15mV) the opening of cation channels causes an
outward flow carried mainly by K+ (repolarization)
c. However, when the potential is set close to zero, opening channels does nothing because the influx of Na+
is counterbalanced by K+ which is known as the Reversal Potential
In the case of excitation responses, the reversal potential is at Ecation

Inhibitory Action of Glycine


1. 1a-afferents as seen before, can excite motor neurons via AMPA as well as excite interneurons via AMPA
2. The excitation of interneurons will actually illicit the release of Glycine which has an inhibitory effect on the
motor neuron they control (see myotactic reflex) by opening Cl- channels that will hyperpolarize the cell
3. This inhibition is known as an IPSP Inhibitory Postsynaptic Potential

Integration of Synaptic Potentials


1. Firstly, remember your trigger/spike initiation zones (see lecture 11)
2. EPSPs (as seen before with dendritic stimuli) will spread with decrement
a. therefore the threshold for excitation varies greatly along the neuron and is highest at the trigger zone as it
has the greatest density of Na+ channels

3. Spatial Summation
a. Very simply, the sum of the excitatory currents will add to yield a larger EPSP than either of then alone

4. Temporal Summation
a. Multiple impulses arriving so close together that they add to one another because the effect of the previous
impulse has not relaxed back to the resting state, thus adding on top of each other

5. Important Points
a. note that both temporal summation and spatial summation can occur together
b. These types of summation can occur with IPSPs as well

Clinical Correlations
1. Tetanus Toxin
a. Caused by infection of Colostridium tetani via skin wound
b. Prevents normal release of inhibitory NTs
i. Disables the inhibition portion of the reflex arc thus resulting in hyperreflexia
ii. Absence of reciprocal control of agonist/antagonist muscles produces muscle spasms
2. Strychnine Poisioning
a. A plant alkaloid that blocks Glycine receptors in the CNS with similar sx/sx to Tetanus
3. Cocaine
a. Affects reuptake of transmitters by nerve endings, particularly catecholamines
b. Prolongs their presence in the synaptic cleft, particularly serotonin (dopamine) thus its addictiveness
4. Morphine
a. Administered into the subarachnoid space for analgesic effects
b. Acts as an agonist for the receptors mediating the presynaptic inhibition of C-fibers that relay pain

14 Neuromuscular Transmission
Muscle Fibers Activated by Motor Neuron
1. Motor Unit
a. Comprised of a motor neuron (soma, myelinated axon, NMJ) and the skeletal muscle fiber it innervates
b. The number of muscles under control of a single neuron depends on location and the need for fine control
i. The extraocular muscles and some in the hand, have some 10 fibers per neuron (fine motor control)
ii. The postural muscles can have up to 2000 fibers controlled by one neuron (no need for fine motor)
2. Motor Nuclei
a. Have cell bodies distributed over more
than one spinal segment that fall within
a motor nucleus
b. The axons from this nucleus leave the
cord via ventral roots via spinal nerves
then join together in the peripheral
nerve to reach the target muscle
3. At the target fiber:
a. There is profuse branching, the axon loses its myelination and rests its presynaptic boutons on the fiber
b. The central region of the muscle that will revieve the NT is called the Motor End Plate
c. This presynaptic terminal and boutons are covered by Schwann cells without myelin (Remak Fiber)
4. Notable Features of NM Transmission
a. Each muscle fiber has only ONE NMJ
b. The NMJ is where ACh is released by Ca2+ dependant exocytosis and binds to its Ionotropic receptor
c. The transmission at each NMJ is so effective that each impulse in the neuron will release ACh to excite
the muscle
d. No inhibitory synapses on the muscle fiber, inhibition must be applied to the neuron, not the muscle.

Life Cycle of Acetylcholine


1. Synthesis
a. Made only in the cytosol of Cholinergic Neruons

2. Life Cycle
a. Unusual for a NT in
that it is Rapidly
degraded in the cleft
by AChE and the
product is reabsorbed to
be reformed into ACh

3. Receptor Types Depends on


a. Somatic Motor soma in the CNS, axon travels direct to skeletal muscle and releases ACh on N1
receptor at the muscle (nAChR)
b. Sympathetic soma in CNS, travels to ganglion and releases ACh onto N2 in postganglionic fiber, then
the postganglionic reaches target to release catecholamines onto -or- receptors
c. Parasympathetic identical to sympathetic, but ganglion is closer to target and the postganglionic fiber
releases ACh onto Muscarinic ACh Receptors (mAChR)

Microenvironment of NMJ
1. Acetylcholine Release Site
a. Remember the active zone from lecture 13; release site of NTthey are positioned directly opposite the
large number of ACh receptors in the postsynaptic cell (also see pic above)
b. Diffusion distance is very short and the diffusion time is virtually nil and the AChE is waiting to do its job
2. Voltage-Gated Channel Position in and around NMJ

a.
b.
c.
d.
e.

Voltage-gated Na+ channels in Nodes AP propagation along axon


Voltage-gated Ca2+ channels in nerve ending calcium influx causes exocytosis of ACh
ACh-gated channels at tip of junctional folds at End Plate Large depolarization at end plate
Na+ channels in junctional folds muscle depolarization
Voltage-gated Na/K channel in muscle membrane muscle action potential Propagation

Acetylcholine the Messenger


1. It takes about 0.5ms for the impulse to illicit the release of
ACh, an additional 1s to diffuse across the cleft and then
several hundred s to break it down in the cleft
2. In the postsynaptic cell, ACh causes the opening of
nAChR Ionotropic receptors that are all cation channels
3. Note the structure of the nAChR in the following diagram
is fetal and that in the adult, the is replaced by
4. Each -subunit has a binding site for ACh thus BOTH
binding sites must be activated to open the channel

5. Adult vs. Fetal nAChR


a. Adult receptors open and close fast where fetal receptors have longer mean open times
b. Adult nAChRs allow larger currents to flow and open more frequently, thus better equipped for the
needed fast activation of skeletal muscle fibers
6. Desensitization
a. Caused by prolonged binding of ACh to the nAChR
b. The long binding will cause further conformational change thus closing the channel
c. This rarely takes place because of the AChE working so quickly to break down the ACh in the cleft
7. ACh and a Graded EPP
a. The depolarization caused by ACh at the end plate will spread in both directions away from the end plate
b. Note that it travels WITH Decrement which is governed by the of the muscle fiber
c. The EPP from a nerve impulse is ALWAYS enough to evoke a muscle impulse at the end plate

Toxins and Drugs at the NMJ


TTX/STX

Blocks Na-channels to
irreversibly prevent the
arrival of the original impulse
No APs = cardiac/resp arrest

-condotoxin
Snail Toxin; irreversibly binds
to calcium channels thus
stopping the capacity for
exocytosis of ACh

Botulinum Toxin

-Latrotoxin

Bacterial; Irreversibly inhibits


exocytosis by stopping the
docking of the vesicles
causing flaccid paralysis

Black Widow Spider; will


cause massive ACh exocytosis
followed by irreversible failure
to release any more, thus
eventual flaccid paralysis

Neostigmine &
Physostigmine

Tubocurarine

Reversibly inhibits AChE to prolong


the affects of ACh in the cleft (used
clinically to treat certain diseases)

Arrrowhead Poison: Reversible


antagonist of nAChR

-bungaratoxin

Sarin and Tabun

Cobra Snake; irreversibly binds to


the ACh binding sites thus causing
flaccid paralysis

Irreversibly binds AChE which


prolongs depolarization and eventually
leads to paralysis of respiratory
muscles, thus death

AChRelease

Botulinium
-condotoxin
-Latrotoxin

Reduce AChE Activity

Physostegmine
Neostegmine
Sarin
Tabulin

ACh Agonist on nAChR

Carbachol (carbamylcholine)
Nicotine
succinylcholine

ACh Antagonist at nAChR

Turbocurarine (curare)
Pancuronium
-bungarotoxin

NMJ as a site for Treatment


1. Lambert-Eaton Syndrome
a. Autoimmune against Ca2+ channels in motor nerve terminals reducing the number of functional channels
b. Causes decreased release of ACh, thus unable to create an EPP to reach threshold
c. TREAT WITH:
i. 4-AP blocks K+ channels to increase duration of depolarization at presynaptic end to enhance
Ca2+ entry to illicit release of more ACh
ii. Neostigmine inhibit AChE increases concentration & prolongs effect of ACh in cleft & endplate
2. Myasthenia Gravis
a. Autoimmune against nAChR thus the end plate is less responsive to ACh leading to muscle weakness
b. TREAT WITH
i. Neostigmine inhibit AChE increases concentration & prolongs effect of ACh in cleft & endplate
3. Muscle Relaxation during Anesthesia and Surgery
a. Depolarizing Agents:
i. Succinylcholine short acting (within 1-minute) agonist of ACh on the nAChRs; not broken
down by AChE, only by plasma esterases; causes prolonged opening of cation channels (Na+)
which inactivates them and renders fibers inexcitable
b. Non-Depolarizing Agents:
i. Curare reversible antagonist of nAChR, blocks the effects of ACh on the receptor. This drug
has since been replaced with pancuronium.

Clinical Correlations
1. Muscle Relaxants
a. as seen above, are useful in surgery
2. Electromyographic Recordings (EMG)
a. Monitors muscle impulse activity via extracellular electrical recording electrodes inserted into the muscle
b. Used to diagnose various muscular disorders including Myasthenia Gravis based on irregular impulse
responses
3. Myopathies
a. Some types of muscle weaknesses do NOT originate in the NMJ, they originate in the muscle fiber itself
b. Other muscular dystrophies have malfunctioning cytoskeletons lacking certain vital proteins
c. Some myotonias have abnormally slow relaxation times for the muscle fibers due to ion channel deficits

15 Neurotransmitter Release
Storage in Vesicles
1. Each molecule stores a Small-Molecule Transmitter and a Neuropeptide
a. SMT synthesized in the cytosol and taken up into empty vesicles for pre-release storage at active zone
b. Neuropeptides synthesized in the soma, stored in vesicles and sent to nerve ending via anterograde txp
2. Two Populations of Vesicles
a. Clear Vesicles contain small molecular transmitters (ACh, Glutamate, etc)
i. Low nerve stimulation (10Hz) causes a rise in [Ca+] near the active zone causing preferential
exocytosis of the small clear vesicles
b. Dense Cored Vesicles most contain Peptides but some contain smts like NE and Serotonin
i. High nerve stimulation rates (100Hz) cause the rise in [Ca+] to spread further thus causing
exocytosis of the large dense cored vesicles
+
3. Absorption of NT into Vesicles
NT+/H+ NT
a. Dependant on an H+ gradient; the H+-ATPase pumps H+ into the
antiport
vesicle so that this created gradient can be used by an Antiport
H+
membrane protein releasing hydrogen in exchange for the given NT
H+-ATPase
(ie: dopamine)
H+ exch.
1. Proteins needed for Exocytosis in Vesicular Membrane
a. Synapsin: initially holds vesicle in place in the cytoskeleton then liberates said vesicles from cytoskeleton
b. Rab Proteins: trafficking/targeting vesicles to site of eventual exocytosis
c. Synaptobrevin & Synaptotagmin: docking-priming vesicle with nerve membrane
d. Synaptophysin: forms fusion pore in nerve terminal membrane

Calcium-Dependant Exocytosis
1. Ca+ channels are adjacent to active zones and open to allow Ca+ into the presynaptic ending in the event of an
action potential in an effort to liberate the vesicles containing the NT
2. The RISING PHASE of Ca+ is quick but the FALLING PHASE is slow which reflects the slow removal
mechanisms used to bring the concentration of Ca+ to its normal value
a. There is a calcium-ATPase and Ca+/Na+-exchanger used to extrude Ca+ ions
b. There is also a sequestering system within the smooth ER to save and use Ca+ ions later

SNARE Hypothesis
1.
2.
3.
4.
5.

Synapsin releases the vesicle


Rab proteins bring vesicle to site of soon-to-be exocytosis
Synaptobrevin (v-SNARE) binds to Syntaxin (t-SNARE); partially docks vesicle
Synaptotagmin (v-SNARE) binds to Neurexin (t-SNARE); now vesicle is fully docked
Now that the vesicle is docked, Synaptophysin finally forms fusion pore and the NT is released into the cleft

Vesicular Membrane Recovery


1. Transmitter Recovery
a. all transmitters (excluding cholinergic) are taken back into the nerve cells or uptaken by glial cells
2. Small Clear Vesicles
a. reminder: they contain such things like ACh, serotonin and Glycine
b. the membrane is recycled locally via endocytosis mediated by Clathrin which coats the vesicle
c. they are internalized, coats removed and fused to endosome to be recycled and refilled with a NT
3. Dense Core Vesicles
a. reminder: contain peptides
b. also retrieved by endocytosis and are transported via retrograde txp to the soma to be refilled with peptides

Transmitter Release
1. Exocytosis is governed by the probability of release (p) times the number of vesicles (n) thus, pn
2. Reducing Ca+ entry influences p
a. This can be seen if Mg2+ replaces Ca2+ which blocks the Ca2+-channel and reduces the EPP accordingly
b. This change in the EPP is also evident when noting the quantal fluctuations with reduced Ca2+
3. Spontaneous release of ACh from Nerve Ending
a. In the absence of stimulation, there exists small transient depolarizations (1mV) called miniEPPs
b. miniEPPs indicate spontaneous release of ACh, seen in all other synapses as well
QUANTA
4. Neurotransmitters are released in packets called quanta which contain a certain # of molecules of transmitter
a. In motor nerve endings ~7000 molecules
b. For glutamate ~4000 molecules
5. The number of quanta released for a single impulse is called the quantum size
a. this can be estimated for a NMJ bathed in low [Ca2+] by
Mean Quantum Content = (mean size of EPP) / (mean size of miniEPP)

b. IN TRIAL: low EPPs (close to a 1mV miniEPP) the mean quantum size was 1 (ie: one single vesicle)
IN REALITY: at the NMJ the mean quantum content is ~200 (ie: 200 vesicles each containing ~7000 molecules)
c. Note that at all other synapses the mean quantal size is usually only 1 vesicle (based on this equation)

Toxins/Drugs Interfering with Exocytosis


Remember to see the figure in lecture 14 notes regarding ACh release inhibition
1. Botulinum Toxin
a. Prevents vesicular release of ACh by irreversibly blocking synaptobrevin (docking)
b. Initial sx/sx include: diplopia, dysphasia (diff speaking), dysphagia (diff swallowing) and dry mouth
c. Eventual paralysis sets in and is life threatening when it reaches respiratory muscles
2. Tetanus Toxin
a. Blocks Glycine release by irreversibly blocking synaptobrevin (docking)
b. Also life threatening after several days when it begins to affect respiration
3. -Latrotoxin
a. black widow spider; promotes synaptotagmin/neurexin complex binding
b. massive ACh release ensues which depletes all ACh stores thus followed by flaccid paralysis (life threat!)

Drugs Interfering with Quantal Release


1. Antibiotics
a. Neomycin and Streptomycin inhibit ACh exocytosis and in high concentrations can actually block nAChR
2. 4-Aminopyridine (4-AP)
a. Blocks K+-channels thus increasing the duration of an impulse which [Ca2+]i thus ACh release
3. Neurotransmitters
a. At some Axo-Axonic synapses (inhibitory lec.13) the NT released (ie: GABA, serotonin, dopamine) will
reduce the transmitter release on the neuron it affects (seen common in the afferent spinal cord neurons)

Clinical Correlations
1. HYPOcalcemia (think of a differential diagnosis of diGeorge Syndrome)
a. Often a cause of hypoparathyroidism (physiology- PTH regulates calcium levels-bone/kidney/gut)
b. Extracellular calcium is needed to neutralize the negative charges in the extracellular matrix so in its
absence, the outside becomes more negative which makes the membrane difference from outside to inside
will get close to threshold, which will cause eventual unwanted depolarizations.
c. These depolarizations cause repetitive firing of APs resulting in tetany and parasthesia
d. Calcium also helps stabilize the membrane and without it, the cells becomes leaky which again causes
unwanted depolarizations resulting in the same sx/sx though this cause is reversible
2. Botulinum Toxin
a. Microinjections used to treat dystonias (irregular/troublesome clonic/rhythmic contractions)
b. Also used cosmetically to reduce facial wrinkles
3. Snake Venom
a. Some venom (not the same as alpha-bungarotoxin from cobra) blocks ACh release by irreversibly binding
to actin resulting in paralysis which can be fatal if it effects respiration.

16 Neurotransmitter Systems
Classes of Transmitters
1. Four General Classes
a. Amino Acids mediate fast responses (within ms) in the CNS
b. Amines some (ie: ACh and serotonin) also mediate fast responses in the PNS, NMJ & postganglionic
neurons of the ANS
c. Peptides include CCK, substance P, VIP, etc, all of which are Metabotropic thus have slow responses
d. Gases includes NO and CO

Neuropharmacology of Some Receptors


Neurotransmitter
Acetylcholine
Noradrenaline
Glutamate
GABA
Glycine

Receptor Type
Nicotinic (nAChR)
Muscarinic (mAChR)
Alpha adrenoceptor
Beta adrenoceptor
AMPA
NMDA
GABAA
GABAB
Glycine

Agonist
Nicotine
Muscarine
Phenylephrine
Isoproterenol
AMPA
NMDA
Muscimol
Baclofen
Glycine

Antagonist
D-tubocurarine
Atropine
Phenoxybenzamine
Propranolol
CNQX
AP5
Bicuculline
Phaclofen
Strychnine

Transmitter Removal/Degredation
1. Excluding ACh, NO and Peptides, all transmitters are removed rapidly via transporters in the nerve ending or
by glial cells
2. Noradrenaline and Serotonin are absorbed then broken down by MAOs from the outer mitochondrial membrane
in the nerve ending

Muscarinic Receptors
ACh released by postganglionic parasympathetic nerves (ANS) affect a muscarinic receptor to elicit a response which can be
defined by the subgroup that the mAChR falls into

1. Excitatory Muscarinic Receptors


a. M1 and M3 slow excitatory response working via IP3/DAG pathway
i. mediates responses in salivary, lacrimal and other exocrine glands
ii. also mediates smooth muscle contractions all over the body (gut, iris, bladder, respiratory, etc)
2. Inhibitory Muscarinic Receptors
a. M2 has an inhibitory response and also works via G-protein linked receptor pathway
i. mediates inhibitory responses in pacemaker cells by using an inhibitory G-protein which inhibits
the cAMP pathway to decrease Ca2+-channel activity resulting in weak depolarizations
ii. this system also has a shortcut pathway that increases K+-channel activity to hyperpolarize the
pacemaker cells and prolong the time to reach threshold in both causes Slowing the Heart Rate

Catecholamines
1. Synthesis
TYROSINE

L-DOPA

DOPAMINE

Dopa Decarboxylase
*Rate limiting Step

NOREPI

Dopamine -Hydroxylase

EPINEPHRINE
PMNT

2. Epi and NorEpi


a. Norepinephrine is released from postganglionic sympathetic neurons to act on glands, smooth muscle
and cardiac muscle
b. Epinephrine is released by chromaffin cells and enters the circulation to act on adrenoceptors
i. Isoproterenol is a synthetic form of epinephrine with an addl methyl group on the N-terminal
3. Sympathetic Neurons
a. Cardiac muscles have 1 receptors working via cAMP pathway to upregulate the heart and pacemaker
b. Eccrine Sweat glands have M3 receptors working via IP3/DAG pathway to increase sweat secretion

Amino Acids
1. Glycine
a. Main inhibitory NT in the spinal cord working via Ionotropic receptor selective to Cl- ions
b. The glycine-receptor has similar structure to nAChR but needs THREE molec of glycine to open channel
2. GABA
a. Main inhibitory NT in the brainstem
b. GABAA mediating fast IPSPs working via Ionotropic receptors similar to Glycine and nAChR
i. Needs TWO molecules to bind to the -subunit to open the channel
ii. The GABAA receptor also binds a wide range of inhibitory medications (ex: anit-epileptic meds)
c. GABAB work slowly via Metabotropic receptors to open potassium channels to inhibit the
postsynaptic neuron
3. Glutamate
a. AMPA Receptor
i. Typical Na+-channel
b. NMDA Receptor
i. Blocked by residing Mg2+ ion which leaves under influence
of a very large depolarization usually due to the summation
of many EPSPs
ii. When it is unblocked, it allows Ca2+ entry into the postsynaptic
cell where this calcium plays a role in alterations of enzyme
activity

Amines and Peptides


1. Arousal System
a. Cholinergic neurons in the Septal Nuclei, Basal Nucleus of Meynert and the Pons make widespread
connections to the brain to maintain peak excitability regulating a high level of consciousness
b. In particular the Basal Nucleus of Meynert and Pons form part of the Ascending Arousal System
which participates in LOC during REM sleep
i. The Locus Ceruleus nucleus in the Pons has 10000 noradrenergic neurons projecting
ipsilaterally to the hippocampus, amygdale, thalamus, hypothalamus, cerebellum and cortex
ii. Serotononergic neurons in the Rostral Raphe nuclei in the Brain Stem also make widespread
connections with cells in amgydala, hippocampus, hypothalamus thalamus and cortex
2. Norepinephrine and Serotonin influence Mood
a. Neurons in the Locus Ceruleus and Rostral Raphe innervate the limbic lobe & cortex which control mood
b. When NE and Serotonin transmission to these areas is decreased, we feel depressed and anxious

3. Dopamine
a. Receptors
i. D 1 - like (D 1 and D 5) increase cAMP production
ii. D 2 - like (D 2 , D 3 and D 4) inhibit cAMP production
b. Dopaminergic cells in the substantia nigra project to the basal ganglias striatum (caudate n. & Putnam)
i. Strial Neurons in the substantia nigra have both D1 and D2 receptors
c. Dopaminergic cells in the ventral tegmental area project to the hippocampus (memory formation),
nucleus accumbens and frontal lobe cortex (planning/attitude)
4. Enkephalin
a. An Opoid peptide released from local interneurons, exerts presynaptic inhibition at the synapses of
nociceptors (pain) on projected neurons

Therapeutic Drugs for Receptors in the CNS


1. Anti-Anxiety on GABAA
a. GABAA has a binding site on the -subunit for benzodiazepines and on & -subunits for barbiturates
b. These drugs will facilitate the inhibition of the amygdala to decrease fear and anxiety
2. Dopamine Receptor Drugs
a. Parkinsons Disease
i. Parkinsons Disease is associated with degeneration of dopaminergic cells in the substantia nigra
1. This degeneration leads to loss of movement, tremors and dysphasia
ii. Administration of a D2 agonist can help alleviate the sx/sx
b. Psychotic Conditions
i. Antagonists of D2 receptors are used for psychotic patients
3. Mood Disorders
a. Clinically depressed people thought to have serotonergic transmission impairment in the CNS are given
SSRIs (serotonin re-uptake inhibitors) which block serotonin reuptake to help improve the transmission
of serotonin across the cleft
b. Clinical depression is also associated with noradrenergic transmission thus drugs used to inhibit reuptake
of norepinephrine have also been prescribed.
c. MAOIs are also used to stop the breakdown of both norepinephrine and serotonin but it is not as
successful as the use of SSRIs

Clinical Correlations
1. Pilocarpine
a. ACh-mimmetic drug acting as a mAChR agonist in the parasympathetic nervous system
b. Acts on ciliary muscles and drains fluid via Canal of Schlemm which pressure and used to treat glaucoma
2. Beta-Blockers
a. Antagonist of 1-receptors; used to treat HTN by vasoconstriction, HR and contractility
3. Asthmatic Bronchodialator
a. Antagonist of 2-receptor, used to relax and dilate bronchiolar smooth muscles
4. Nasal Congestion Relief
a. Antagonist of 1-receptors used as a nasal vasoconstrictor hence a reduction in congestion
5. Horners Syndrome
a. Unilateral loss of sympathetic input causes this unopposed parasympathetic influence to manifest with a
constricted pupil (miosis), drooped eyelid, inactivated sweat glands (dry face) and a retracted eyeball
b. This unilateral lesion is in the CNS as such:
hypothalamus spinal cord superior cervical ganglion ciliary nerve

17 Transport within the CNS


Fluid Composition of CNS

Brain Volume (total) = 1200mL


Brain ICF = 720mL
Brain ECF = 480mL

Blood
Plasma
70ml (15%)

Interstitial Fluid
260ml (55%)

CSF
150ml (30%)

1. Circulation of CSF
a. Remember lateral ventricles are connected to third ventricle via Monroe
b. Third ventricle connected to fourth via Cerebral Aqueduct (Sylvius)
c. Fourth ventricle flows CSF into subarachnoid space of spinal cord via Magendie
2. Spinal Tap/Lumbar Puncture
a. Done at L3-L4
b. Used to attain and analyze CSF composition and abnormalities
c. Also used to test ICP (but can be inaccurate in the event of an obstruction)
3. Composition of CSF
a. 6 major differences between CSF and Plasma
NOTE:
1.
Protein
Component CSF Plasma
a. CSF is untrafiltrate thus,
pH
7.33
7.41
very little protein content
Protein
35
7000
2. pH
Glucose
60
90
CSF is LOWER
a. reflects said low protein
K+
2.8
4.5
count as well as a poor
Ca2+
1.1
2.4
buffering system
CSF is HIGHER
Cl120
100
4. Function of CSF
a. Maintains constant extracellular environment
b. Provides a means for removing the brains metabolites
c. Mediates ventilation rates via exhibiting pH
d. Mechanical cushion (trauma/movement)

Blood Brain Barrier


1. Tight Junctions
a. Prevent transport across endothelial cell wall via
paracellular route allowing transcellular txp ONLY
b. Transport across the phospholipid bilayer depends
on the lipid solubility of each individual solute
2. How do things get into the BBB then
a. Glucose transported using GLUT-1 via Facilitated Diffusion
b. L-dopa (precursor for dopamine) also uses a carrier protein to enter via Facilitated diffusion
c. Glycine enters via 2o-active cotransport dependant on Na+
3. Failure of BBB
a. Tight junctions can become pathologically permeable in the following conditions
i. Hyperosmolarity: high concentrations of certain substances in the blood can force open the BBB
ii. Trauma: can lead to ischemia, inflammation or pressure can also open the BBB
iii. HTN
iv. Infection
4. Clinically Induced BBB Opening
a. Administration of a hypertonic solution to the patient will shrink endothelial cells which will induce the
breakdown of the tight junctions
b. This is done in a situation if there is a need to administer lipid insoluble drugs to the CNS

Cerebrospinal Fluid
1. Choroid Plexus
a. Site of CSF production and is found in most of the lining of the ventricles (not found in cerebral aqueduct)
b. Constantly secreting isotonic CSF into the ventricles
c. Joined by tight junctions excluding paracellular transport thus creating the blood-CSF-barrier
d. Production is constant at 500ml/day and in normal conditions is absorbed at the same rate
i. HYDROCEPHALUS can be caused when absorption is too slow or production is too fast
2. Transport of Ions
a. There is much movement of ions via multiple channels and transporting proteins on both sides of the
secretory cell but the NET MOVEMENT of ions is Na+, K+ and Cl- into the ventricles followed by water
via osmosis
b. The ions being followed by osmosis ensures that the movement of fluid is ISOTONIC
3. Absorption
a. Takes place in the SSS by the Arachnoid Villi
b. It is a pressure driven absorption where the CSF is at higher pressure than the venous system
c. It is absorbed into vacuoles which cross thru the cell and are emptied into the venous sinus

CSF Abnormalities
1. Composition Changes Used as Diagnostic Tool

Condition

Cells (mm3)

Protein
(mg/dl)

Glucose
(mg/dl)

Normal
Bacterial Meningitis
Viral Meningitis
Brain Tumor/Abscess
MS
Guillian-Barre
Subarachnoid Hemorrhage

<5
HIGH 1000
High 500
High 500
Normal
~10
RBCs

35
HIGH 500
High 500
High 500
Normal
>50
High

60
Low 20
Normal
Normal/Low
Normal
Normal
Normal

2. Non-Communicating (obstructive) Hydrocephalus


a. Due to blockage of CSF flow thus an enlargement of the ventricles above the blockage
b. Enlargement of the Lateral Ventricles ALWAYS occurs in non-communicating/obstructive
3. Communicating Hydrocephalus
a. Due to malabsorption of CSF due to thickening of the arachnoid villi due to several pathologies
b. Enlargement of ALL ventricles will always occur in communicating
c. PAPILLOMAS: tumors of the choroid plexus can (but rarely) cause communicating by secreting CSF in
great excess
4. Normal Pressure Hydrocephalus
a. A form of communicating hydrocephalus where all ventricles are enlarged but in the absence of an
increase in pressure
b. Usually occurs in elderly (+60) and is assoc w/cognition, walking and urinary incontinence along with
flattening of the cortical gyri all caused by decrease in cellular volume of the brain
5. Intracranial Pressure ICP
a. Normally lies between 5-15mmHg (60-200mm water)
b. Can be measured via lumbar puncture but in the event of a tumor or block intraventricular measurement is
needed
c. ICP over 200mm water will decrease cerebral perfusion as the pressure now balances arterial pressure

Edema
Disturbances of the blood supply that interfere with the normal well regulated exchange of solutes and water between
blood and brain can cause edema and there are two types
1. Vasogenic Edema
a. Damage to brain capillaries rendering them more permeable than normal (ie: leaky)
b. Usually occurs in the White Matter
2. Cytotoxic Edema
a. Inadequate blood supply to neurons and glia thus failing to deliver proper O2 and Glucose
b. This starves the Na/K pump results in a dissipation of ionic gradients and the cell swells with ensuing
damage
c. Usually occurs in the Gray Matter

Clinical Correlations
1. Blood Supply for Tumors
a. Lack any tight junctions and the paracellular flow of nutrients only promotes the growth of the tumor
2. Congenital Hydrocephalus
a. Blockage of the cerebral aqueduct (or absence of the formation)
b. Dandy-Walker Syndrome: F.O. Lushka and Magendie fail to form
3. Adverse Effects of Increased ICP
a. Sx/sx of an increase above 15mmHg include
i. Nausea
ii. Bradycardia
iii. HTN
iv. LOC
v. Blurred Vision (due to papilledema increasing pressure in subarachnoid space near CN-2)

22 Sensory Systems
Introduction

The Sensory System is designed to detect physical stimulus and translate it into cell activity
o Translation of the stimuli is known as transduction
The Receptors transmit onto second-order neurons which are part of the particular sensory pathway
The information reaches cortex to be interpreted/perceived
o most sensory areas are within the parietal, occipital, temporal or insular lobes
Thus, the basic pattern is Stimulus Receptor Pathway Perceived Behavior

Receptors and Sensory Systems


There are four basic types of receptors that function together to facilitate the six major sensory systems

Sensory System

Sensory Receptor Class

Somatosensory

Mechanoreceptors
Thermoreceptors
Chemoreceptors
Photoreceptors
Mechanoreceptors
Mechanoreceptors
Chemoreceptors
Chemoreceptors

Visual
Vestibular
Auditory
Olfactory
Gustatory

Components of Sensory Receptor


1. Basic Components
a. Transduction Site
b. Axon
c. Cell Body
d. Synaptic Terminal
2. Receptor Potential
a. Generated at the transduction site
b. This potential is GRADED, thus NOT all-or-none
3. Action Potential
a. In the event of a receptor potential reaching threshold, it will create an AP at the trigger zone
i. Note that the generation of this AP is NOT at the hillock
4. Transmitter Release
a. Takes place at the synaptic terminal if an AP is generated and propagates as it should.
b. Transmitter release will stimulate postsynaptic cells (second order neuron of sensory pathway)
c. NOT all receptors are neurons, such as seen with hair cells which are specialized epithelial cells
i. They do NOT have axons, they are mechanically stimulated and release transmitter directly onto
the proceeding neuron (ie: the auditory nerve)

Stimulus Attributes
1. Intensity
a. Refers to the amplitude (ie: quantity) of the stimulus
b. Sub-threshold stimuli can elicit a small receptor potential but may not induce an Action Potential
c. FREQUENCY CODE
i. Assuming receptor potentials are above threshold, the higher the stimulus intensity is the more
action potentials will be generated per unit time
d. POPULATION CODE:
i. High intensity stimuli can activate more individual axons than a low intensity stimulus
ii. Ex: press harder and harder on your hand, stimulates a larger area, thus more axon stimulation

2. Duration
a. Defined by the difference between the start and end time of the stimulus
b. Receptor adaption: the disappearance of a sensation induced by a stimulus when the duration is too long
i. example: the disappearance of the feeling of wearing clothes all day even though you felt them
when you put them on
c. SLOW ADAPTING RECEPTORS
i. Used for constant monitoring; important for regulatory function of tight physiologic windows
ii. They remain depolarized for the duration of the stimulus and maintain a constant output of APs
d. RAPID ADAPTING RECEPTORS
i. Only signal at the onset of stimulus where the receptor potential quickly returns to baseline
ii. No further APs are generated despite the persistence of the stimulus
iii. Much better equipped for sensitivity to changes and not constant stimulation

4. Location
a. Understanding the location of a stimulus is defined by the
receptive field of the stimulated neuron
i. Receptive Field: the area monitored by a single neuron; ie:
the area where a stimulus would induce a response
b. If the stimulus is placed within the receptive field, assuming it is
above threshold, it will elicit an AP
c. If the stimulus is placed outside of the receptive field, there will
never be an AP on that particular neuron

Basic Wiring Mechanisms


1. Convergence
a. When a second-order neuron gets input from more than one first-order (receptor) neuron
b. The inputs will summate and give a larger stimulation than the parts alone
2. Divergence
a. The signal from one first-order neuron stimulates multiple second-order neurons

3. Lateral Inhibition
a. A situation where a first-order neuron stimulates an interneuron which will relay that stimulus to an
adjacent second-order neuron only it is inhibiting that adjacent neuron

23 Somatosensory System
Introduction

Comprised of 5 different modalities touch, vibration, proprioception, temperature and pain


All of the neurons within the somatosensory system are pseudounipolar neurons whos cell bodies are in the DRG
Their receptors are in the skin and in or close to the muscle
Merkel and Meissners
Closer to the surface with small receptive fields

Cutaneous Receptors

1. Touch
Ruffini and Pacinian
Deeper in tissue with large receptive fields
a. Merkels Disks discriminating touch
b. Ruffinis Endings skin stretch
2. Vibration
a. Meissners Corpuscles highest sensitivity for low frequencies 50Hz
b. Pacinian Corpuscles sensitivity for higher frequencies near 300Hz
3. Pain and Temperature
a. Transduced by free nerve endings (be it mechanosensitive or thermosensitive receptors)

Proprioception
1. Muscle Spindles
a. Found in the extrafusal fibers of working musculature
b. The receptor is of rapidly adapiting nature using
1-a afferents form afferent limb of the myotactic reflex

2. Golgi Tendon Organ


a. Positioned close to the border b/w muscle and tendon
b. 1-b afferents form afferent limb of the reverse
myotactic reflex

Fiber Types and Receptors


the different receptors use various afferent fibers to relay their message and it can be summed up in a chart:

Touch, Vibration and Proprioception

Pain and Temperature

Segmental Organization
1. Spinal Nerves
a. Remember Gross Anatomy:
i. spinal nerve-C1 emerges above vertebra-C1 and spinal nerve-C8 emerges below vertebra-C7
ii. spinal nerve-T1 emerges below vertebra-T1 and this pattern continues for the remainder
2. Dermatomes
C2: back of the head
C6: posterior forearm to thumb
C7: posterior forearm to pinkey
C8: middle finger
T4: nipple line
T10: umbilicus
L1: groin
L5: big toe
S1: little toe

Modalities and their Pathways


1. Dorsal Column/Medial Leminiscus System
a. Used to relay Touch, Vibration and Proprioception
b. Enter the dorsal column of the spinal cord
c. They ascent in the dorsal column of the white matter up to the medulla and synapse in the nuclei of the
dorsal column
i. cuneate nucleus for upper extremities
ii. gracile nucleus for lower extremities
d. Topographical organization can be seen in the figure below and correlates to the anatomical location of
the nuclei where the gracile is more medial thus lower extremities will travel more medially

2. Anterolateral System
a. Used to relay Pain and Temperature
b. Also enter dorsal root and synapse in dorsal horn onto second-order neurons that cross the anterior white
commissure and ascent in the ventral white matter (yellow)

3. Lissauers Tract
a. Very clinically relevant relative to the ALS
b. This tract gives an alternate route for pain and temperature to ascend in the event that there is an injury to
a section of the spinal cord as seen with a hemisection in Brown Sequard Syndrome
c. Pain and temperature can ascend one or two sections past the injury in the Dorsolateral Fasciculus
(aka Zone of Lissauer, then cross over and rejoin the ALS

Brown Sequard
Syndrome

Imagine this middle section


were to be blocked...
What would happen?
see text below

4. Brown Sequard Syndrome


a. Hemisection of the spinal cord due to trauma/mass/lesion interrupting ascending and descending fibers on
one side of that segment
b. AT THE LEVEL of the lesion:
i. loss of ALL somatosensory modalities TVP and TP
c. BELOW THE LESION:
i. Ipsilateral loss of TVP
1. Note that TP remains intact on the same side because it crosses over to the other side
naturally in the ALS tract (as stated, below the lesion) and continues to ascent, never
having been affected by the lesion
ii. Contralateral loss of TP
1. Note that TP remains intact on the opposite side because for 1-2 LEVELS ONLY as it
begins on the opposite side, it can ascend via Lissauers tract and bypass the lesion (purple
line); anything lower than 1-2 levels will be lose TP
d. OVERALL:
i. There is a loss of TVP on the same side both below and at the level of the lesion
ii. Although TP is lost at the level, with the help of Lissauers Tract, it is intact on both sides it can
remain functional for 1-2 levels below the lesion, but anything lower than that, TP is lost.
5. Syringomyelia
a. A pathologic enlargement of the central canal that presses on the anterior white commisure
b. Assuming there is no alternate pathway (ie: Lissauers) there will be bilateral loss of TP
c. TVP will remain intact as it does NOT need to cross thru the anterior white commisure

24 Touch
General Info for Touch Pathway

Consists of a 3-Neuron-Chain
o First-order neurons: somatosensory afferents (peripheral nerves)
o Second-order neurons: fibers crossing the midline and terminating in the thalamus
o Third-order neurons: running in posterior limb of internal capsule and ending in S1 (primary sensory)

Dorsal Column/Medial Lemniscus

This pathway carries Touch, Vibration and Proprioception


The pathway for the modalities differ depending on where the sensation originates (ie: body vs. face)

1. Body

a. Starts in the bodys surface or at the


muscle (remember lect.23
dermatomes/spindles/golgi tendon)

b. First-order neurons enter via dorsal roots


of spinal nerves (soma in DRG) and ascend
in the dorsal column ipsilaterally
i. They synapse in the Dorsal Column
Nucleus in the medulla (ie: cuneate
or gracile)
c. Second-order neurons begin at the dorsal
column nucleus and cross the bodys
midline
i. They ascend in the medial lemniscus
until they synapse in the
VPL Nucleus of the thalamus
d. Third-order neurons begin at the VPL
nucleus and ascend in the posterior limb
of the internal capusule
i. They eventually synapse in the
primary somatosensory cortex S1

2. Face Trigeminal Pathway

a. Deals solely with the face and its TVP


b. First-order neurons (soma in trigeminal
nucleus) enter at the pons
i. They synapse in the Principle
Sensory Nucleus of CN-V
c. Second-order neurons exit the nucleus
and immediately cross midline
i. They ascend in the Ventral
trigeminothalamic tract and
synapse in the VPM nucleus of
the thalamus
d. Third-order neurons exit the VPM and
travel through the Genu of the internal
capsule thereafter the coronoa radiata
i. They also eventually synapse in
the primary somatosensory
cortex S1

Broadmann Area S-1


Very simply, as we have seen this many times, the
postcentral gyrus is the location of the Primary Somatosensory
Area also known as Broadmann Areas 3,1 and 2 (pink)

Organization of S-1
1. Topographical Organization
a. A quick look at a topographical map of S1 can
quickly define where in S1 different parts of the
body are referred; such a map is known as a
Somatotopic Map
2. Organization in Columns
a. Input processing neurons are organized in the cortex
based on the speed of the receptor that is sending it the
information.
b. Thus, Slowly Adapting Receptors (SA) are organized in one column and Rapidly Adapting Receptors are
organized in the adjacent column; so you have a sequence of columns as SA-RA-SA-RAand so on.
3. Input Layer 4
a. As it is already know, the cortex has 6 layers (1 at the pia matter deeper to 6 at the white matter)
b. Layer-4 of S1 received input from the thalamus (VPL/VPM) where the 3rd-order neurons are from

Two-Point Discrimination
1. Variation Throughout the Body
a. The threshold and resolution varies across the body
b. Much higher resolutions (inverse of threshold) are found in the hands and feet and lower resolutions are
found in places like the forearm, lower leg and back
2. Dependant Factors
a. Receptor density
i. More receptors will increase resolution
b. Receptive field size
i. The smaller the field, the higher the resolution will be
c. Size of cortical area involved
i. The larger the cortical area involved in S1 the greater the resolution will be
d. Special mechanisms, if any
i. Mechanisms such as lateral inhibition can increase resolution (receptive fields, lec.22, p2)

Clinical Correlations
NEUROLOGIC EXAMINATIONS
1. Touch/Pain, Vibration and Proprioception
a. Touch and Pain: using a sharp and dull object, poke around and ask sharp or dull?
b. Vibration: often the first sense lost in peripheral neuropathies; test by touching tuning fork to bony
prominence and do it both with and without activating the fork to make sure the person is truthful
c. Proprioception: grasp the finger from the sides and pull up or down and ask up or down?
2. Complex Tactile Function
a. Two-Point Discrimination: use a bent paper clip at different widths and ask one or two?
b. Stereognosis: give the person a familiar object and ask what is this?
c. Graphesthesia: the patient should be able to identify letters drawn in the palm with a blunt object
i. Inability to do so might indicate a cortical lesion
NEUROPATHIES
1. Tabes Dorsalis
a. Destruction of DRG and large myelinated fibers due to infection with syphilis
b. TVP becomes very deficient but TP remain almost unaffected (think of what fibers control each modality)
2. Phantom Limb Sensations
a. A phenomenon where a person thinks they are feeling pain in a recently amputated limb and this pain is
exacerbated/elicited when other parts of the body are stimulated (think of hand and face example)
b. This can be explained by rearrangement of the cortical input from an existing part of the body to the
cortical area that once controlled this now missing limb
i. For example: the neurons from the face region of the cortex migrate to where the hand used to be

25 Pain
Major Classifications
1. Nociceptive pain
a. Direct stimuli of nociceptors and have the potential to cause tissue damage
2. Neuropathic pain
a. CANNOT be explained by simple activation of nociceptors by tissue damage
b. Includes pain where the mechanism is a site of atypical somatosensory processing the PNS or CNS

First and Second Pain


1. First Pain
a. A sharp and quick pain resulting from the activation of mechanical or thermal receptors
b. These receptors use A-delta fiber which are myelinated and thus very fast
c. This is known as the ouch effect
2. Second Pain
a. A much slower onset pain, more like a burning sensation resulting from polymodal nociceptors
b. These receptors use unmyelinated C-fibers that have a much slower velocity, thus slower onset

Pain from Internal Organs


1. Headaches
a. Most every tissue has nociceptors except for the brain
b. Headaches still arise due to an irritation of neighboring tissue, most often the meninges
2. Visceral Pain
a. As stated, most tissues including internal organs, have nociceptors
b. Visceral pain results from stimulation of visceral and deep somatic nociceptors
i. These conduct signal mainly via unmyelinated C-fibers
3. Referred pain
a. The simple explanation is that neurons in the dorsal gray matter of the spinal cord receive convergent input
from both somatic and visceral afferents at the same location and are projected into the ALS

Pain Pathway

Spinal Nerve Pathway

a. First-order neurons are the peripheral nerves and run


into dorsal horn via DRG
i. They synapse in the dorsal horn (substantia
Gelatinosa) onto second-order neurons
b. Second order neurons cross to the contralateral side
and ascend in the ALS tract t
i. They synapse in the VPL of the thalamus and
synapse onto third-order neurons
c. Third-order neurons leave the VPL and go thru
posterior limb of internal capsule & corona radiata
i. They finally synapse at S1 in the cortex

2. Trigeminal Pathway

a. First-order neurons (soma in trigeminal nucleus)


enter at the pons and slightly decend into the
medulla
i. They synapse in the Spinal Trigeminal
Nucleus (note diff nucleus from touch!)
b. Second-order neurons exit the nucleus and
immediately cross midline
i. They ascend in the Ventral
trigeminothalamic tract and synapse in
the VPM nucleus of the thalamus
c. Third-order neurons exit the VPM and travel
through the Genu of the internal capsule
thereafter the coronoa radiata
i. They also eventually synapse in the
primary somatosensory cortex S1

Nociceptors
1. Activation of Nociceptors
a. Nociceptors can be activated by mechanical or thermal stimuli
b. In the event of tissue damage, many chemicals are released which can activate chemical nociceptors
i. Bradykinin from the blood
ii. Histamine from mast cells
iii. Potassium from damaged cells (think of what extracellular K+ can do to membrane potential!)
2. Hyperalgesia
a. Enhanced sensitivity and responsivity to an area around damaged tissue
b. This is caused by increasing nociceptor sensitivity caused by chemicals released at the site of trauma
i. Prostaglandins and Leukotrienes from damaged cells
ii. Substance P from primary afferent pain fibers

Pain Control
1. Gate Control in the Spinal Cord
a. Very simply put, if a touch fiber is stimulated, it will meet
the pain fiber in the dorsal horn (similar to referred pain)
and activate an interneuron that will inhibit the synapse
between the first and second order pain fibers
b. The touch fiber causes the interneuron to release Enkephalin
(an endogenous opoid) which inhibits the pain fiber
c. Opoids can AP duration, EPSP duration and they can
also hyperpolarize the second-order neuron

2. Descending Regulation
a. Serotonergic and Noradrenergic fibers from the brainstem
will act identically as seen in the gate control pathway
b. They synapse on this opoidergic interneuron where they
control the transmission of the pain fibers

Clinical Correlations
1. Neurologic Examination of Pain and Temperature
a. Pain: can be tested along with touch using an object having a dull and sharp side (see lec. 24)
b. Temperature: tested using test tubes, one with hot water and the other with cold water, touch in random
places and ask the question is that hot or cold?
2. Headache
a. There are NO nociceptors in the brain so in order to feel pain, a neighboring structure must be stimulated
i. Blood vessel wall
ii. Dura matter
iii. Skull Periost, etc
3. Aspirin
a. As with other NSAIDs, it will cyclooxygenase resulting in a decrease of PGEs
b. PGEs are responsible for sensitizing sensory afferents, so in their absence, pain will be dulled
4. Surgical Management
a. In extreme cases, such as terminal cancer patients, the DRG is removed to stop pain transmission
b. This is known as a Dorsal Rhizotomy
5. Acupuncture
a. Causes a release of opioid peptides and will decrease pain fiber transmission (see above pain control)

26 Visual System
Anatomy of the Eye

Sclera: a continuation of the dura from the optic nerve


that wraps the eye and becomes the cornea anteriorly
Aqueous Humor: found in anterior and posterior chambers
Vitreous Humor: found in the remainder of the eyeball and
is much more viscous than aqueous humor
Pupil and Iris: path thru which light traverses
Cornea and Lens: make up the optic apparatus of the eye
Ciliary Muscles & Suspensory Ligaments: accommodation

Optic Disk/Blindspot

1. Occular Fundus (back of the eyeball)


a. OPTIC DISC (papilla)
i. location of optic nerve entering; there are NO photoreceptors, thus it is the Blindspot
ii. Remember the optic nerve has meninges and CSF so ICP can cause papilledema
b. FOVEA
i. Located exactly centered on the retina
ii. superficial layers of the retina are pushed laterally so there is easier exposure of the cones to light
iii. Also has highest density of cones combining to create the point of highest visual acuity.
c. MACULA
i. A region of high visual acuity that surrounds the fovea

Refraction and the Optic System


1. Refractive Power
a. Is the inverse of the focal distance in meters and is measured in Diopters D
b. The cornea has a refractive power of 42D
c. The lens can change from 13D to 26D; thus responsible for the modulation of refractive power (plasticity)
during accommodation
2. Accommodation
a. CILIARY MUSCLES
i. Preganglionic Parasympathetics originate in Edinger-Westphal Nucleus (CN-III) upper midbrain
ii. Synapse on second-order neurons in the Ciliary Ganglion
iii. Postganglionic Parasympathetics form the Short Ciliary Nerves and innervate the ciliary muscles
b. FAR VISION
i. Ciliary muscles are relaxed suspensory ligaments are tight and the lens is flattened
ii. The flattening of the lens will REDUCE its refractive power and allow the image to fall deeper in
the eye so it lands on the retina
c. NEAR VISION
i. Ciliary muscles are constricted suspensory ligaments are loose and the lens becomes round
ii. The round lens has an INCREASED refractive power which can now pull back on the image so it
is more forward in the eye so it can land properly on the retina
d. REFRACTIVE PLASTICITY
i. Defined as the refractive power variability of the lens from 13-26D
ii. This will decline with age where the lens will stay more flattened, thus better able to maintain far
sight but near sight diminishes thus the use of +D reading glasses

Visual Acuity
Defined as the ability to distinguish between two points and can be measured by the visual angle between them
1. Dependant Factors
a. Density of Photoreceptors best at the fovea, better at the macula and absent at the optic disk
b. Lens Accommodation inability to focus image on the retinal results in a blurry image which acuity

Pupil Diameter Control


1. Sympathetic Innervation
a. Originate in the Intermediolateral Cell Column (T1-T2) and are responsible for PUPIL DILATION
b. They synapse in the cervical chain ganglia and the postganglionics innervate the dilator pulilae muscle
2. Parasympathetic Innervation
a. Originate in the Edinger-Westphal nucleus of CN-III and are responsible for PUPIL CONSTRICTION
b. They synapse in the ciliary ganglion and the postganglionics innervate the constrictor pupilae muscle

Clinical Correlations
1. Emmetropia
a. Also knows as normal-sightedness
b. This is when the length of the eyeball matches correctly with the refractive power of the optical apparatus
2. Myopia
a. Also known as Nearsightedness
b. The lens is too powerful for the length of the eyeball so the image is focused before reaching the retina
c. Remember that near vision calls for high refractive power therefore with myopia near vision is still good
d. The use of Concave (-)D glasses will correctly place the image more posterior to match the retina

3. Hyperopia
a. Also known as Farsightedness
b. The lens is too weak for the length of the eye so the imaged is focused beyond the retina
c. Remember that far vision calls for lower refractive power therefore with hyperopia far vision is still good
d. The use of Convex (+)D glasses will correctly place image more anterior to match the retina

Clinical Correlations cont


4. Neurologic Exam of Visual Acuity
a. The use of a common eye chart can define how your vision is compared to normal 20/20
b. EX: a score of 20/100 means that you should read this from 100 but you have to be 20 away to see it
5. Pappiledema
a. Increased ICP will venous drainage leading to dilation of retinal veins; the disk appears white, not pink
6. Detached Retina
a. Retina separates from retinal pigment epithelium and those detached areas lose their function
b. Lazer surgery can stop the detachment process but will not correct the damage that already occurred
7. Macular Degeneration
a. Most common cause of vision loss; often due to neovascular (poor new blood vessel formation) causes
b. Usually due to aging, but sometimes from extreme myopia and intraocular infections
c. Most ppl can see enough to dress, eat, walk, etc
d. Lazer treatment is the only choice but has low effectiveness and recurrence is very common
8. Diabetic Retinopathy
a. Begins with the development of SCOTOMAS
i. pathological blind spot; ring of lost vision surrounded by ring of decreased light
b. Usually unnoticed by the patient until the macula is involved whereafter vision dramatically decreases
c. Retinal defects are caused by blood supply dysfunction including permeability and aneurisms

27 The Retina
Photoreceptors Rods & Cones
STRUCTURE
1. Outer Segment:
a. oriented toward the RPE
b. contains visual pigment for photoreceptor transduction
2. Inner Segment:
a. directed toward the center of the eyeball
b. forms synapses which transmit the visual info on the retinal cells (bipolar/horizontal cells)
3. Disk Shedding
a. The outer segment renews disks from the bottom up, the top disks are shed and phagocytosed by RPE cells
PROPERTIES
1. Rods
a. Cellular amplification mechanism is well developed which light sensitivity enables vision in the dark
b. Temporal summation is poor (distinguish between two flashes of light)
2. Cones
a. As there is no need, amplification is low, thus less sensitive to light, working better in bright conditions
b. Temporal summation is much better than rods
c. Three different types of cones allow color vision
d. Convergence is low, thus increasing spatial resolution (visual acuity) showing better vision in the light
3. Distriubtion
a. Rods/Cones are NOT evenly distributed, there are NO rods in the fovea, thus no central vision in the dark

Visual Pigment Phototransduction


1. Rhodopsin the visual pigment of rods (two components)
a. Opsin
i. protein synthesized in the photoreceptor
ii. has 7 membrane spanning domains
b. Retinal
i. light absorbing compound derived from vitamin-A and is the chromopore of the visual pigment
ii. covalently attached to the 7th domain of Opsin

Phototransduction
1. The Dark Current
a. Photoreceptors are depolarized in the dark; (ie: in the absence of light stimulation)
b. In the dark, visual pigment is inactive, thus the G-protein does NOT activate cGMP phosphodiesterase
c. If the cGMP phosphodiesterase is left inactive, the intracellular cGMP can gate the cGMP-gated Na+
channel to its open state (thus depolarization)
d. In its state of depolarization, the photoreceptor will release its NT, Glutamate (just as any other
depolarized would do)
2. Phototransduction Process
Light
i. Light activates visual pigment
ii. Visual pigment activates G-protein
iii. G-protein activates cGMP phosphodiesterase
iv. cGMP phosphodiesterase metabolizes intracellular cGMP
v. A intracellular cGMP will close the Na+ channel
vi. Closing Na+ hyperpolarizes, thus stopping glutamate

Cones Spectral Sensitivity


1. Blue
a. Are also called S-Cones as they have a max sensitivity to short waves at 430nm which is BLUE light
2. Green
a. Are also called M-Cones as they have a max sensitivity to medium waves of 530nm which is GREEN light
3. Red
a. Also called L-Cones as they have a max sensitivity to long waves of 560nm which is RED light
4. Relative Stimuation
a. The relative hyperpolarizations of the different cones will determine the color perception of the person
b. Thus, there is a mix of stimulation though regardless of the color, there is at least SOME stimulation of
ALL THREE

Processing of Visual Information


1. Five Major types of cells in the Retina
a. Retinal Photoreceptors (rods and cones) are the
input cells of the retina; depolarized during
darkness and hyperpolarized in the light
b. The retinal photoreceptors synapse on
bipolar cells in the outer plexiform layer which
transmit their information to the inner plexiform
layer on the retinal ganglion cells
c. Horizontal Cells are crucial for the indirect
wiring pathway and are responsible for
lateral inhibition
d. Amacrine Cells work like the Horizontal cells
only they are found in the inner plexiform layer
e. Retinal Ganglion Cells are the output cells of
the retina, transmitting information to the
LGN via the optic nerves, chiasm and tracts
2. Bipolar Cell Activation
Remember: photoreceptors are ALWAYS hyperpolarized in the light

a. ON vs, OFF
i. ON Bipolar cells named so because they are depolarized when the light is turned ON
ii. OFF Bipolar cells named so because they are depolarized in the dark, thus when the light is OFF
iii. The depolarization or hyperpolarization of the bipolar cell depends on the synapse between the
photoreceptor and the bipolar cell
b. OFF Bipolar Cell
i. Have Ionotropic glutamate receptors which when stimulated by the release of glutamate, will
depolarize the bipolar cell
ii. As we have seen, photoreceptors release glutamate in the dark, so OFF bipolar cells are therefore
depolarized in the dark
c. ON Bipolar Cells
i. Have Metabotropic glutamate receptors which have an inhibitory effect when stimulated by the
release of glutamate from photoreceptors
ii. When light hits the photoreceptor, it hyperpolarizes and stops glutamate release, therefore stopping
the release of the inhibitor transmitter glutamate
iii. In the absence of the inhibitor glutamate with, the ON bipolar cell will depolarize (dis-inhibited)

3. Horizontal Cells
a. Normally, ON bipolar cells are depolarized when light is being shined onto the center of its receptive field
b. Horizontal cells are responsible for the lateral inhibitory effect needed to depolarize an ON bipolar cell in
the event that the light has not been placed directly in its receptive field but in the surrounding area
c. The sequence of events is as follows:
The peripheral photoreceptor is hyperpolarized
due to light exposure thus stopping the release of
glutamate

LIGHT

I.

II. This absence of glutamate from the photoreceptor


will stimulate/depolarize the interneuron
III. The interneuron releases the inhibitory NT, GABA
onto the synapse between the adjacent
photoreceptor and the ON bipolar cell
IV. The inhibition of the presynaptic photoreceptor by
GABA will now act as if glutamate is removed
and allow that ON bipolar cell to become
depolarized

4. Ganglion Cells
a. ganglion cells are responsible for generating action potentials (see above)
b. The ganglion cells are named ON and OFF for the same reasons as the bipolar cells
c. ON Ganglion Cells
i. if the light is shining directly into the center of an ON center ganglion cell, the frequency and
number of APs generated will increase as they are meant to work better in the light
ii. if light is shining on the surrounding field, the APs from the ON ganglion cell will decrease
d. OFF Ganglion Cells
i. Work exactly opposite; light to the center will decrease the number and frequency of APs
ii. Light to the periphery will increase the number of APs generated as they are meant to work
better in the dark

Clinical Correlations
1. Retinitis Pigmentosa
a. Genetic disease in which rods preferentially degenerate
b. Night blindness is the earliest sx, followed by peripheral vision and tunnel vision, eventually causing
total blindness
c. The accumulation of pigment (seen thru opthalmoscope) gave the name of the disease
d. The photoreceptor degeneration is not cleaned up by the phagocytes of the RPE (see above disk shedding)
2. Night Blindness (Nyctalopia)
a. Effects vitamin-A deficient people as the Retinal is derived from it
b. A very necessary part of the Opsin/Retinal combination that forms the photoreceptor pigment
3. Color Blindness
a. Lack of a particular type of cone, most common is the x-linked red-green colorblindness prevalent in
b. There are two types/conditions that cause red-green colorblindess
i. Protanopia: loss of the red-cone (L-cones)
ii. Deuteranopia: loss of the green-cone (M-cones)

28 Visual Pathways
The Visual Field
Is the total space seen when the eye is fixed looking straight ahead toward the center of the visual field

1. Divisions
a. LEFT VS RIGHT
i. Divided into the left and right hemifield but more accurately called the nasal and temporal field
ii. Usually spans from 60o to 90o (so for the right eye that would be going from nasal to temporal)
b. UP VS DOWN
i. Top and bottom visual fields are split into superior and inferior fields
2. Pathway of Light
a. The Superior half of the Visual field is reflected
onto the Inferior half of the Retinal field
b. The Nasal half of the Visual field is reflected onto
the Temporal half of the Retinal field (and vice-versa)
c. SUMMARY: the visual field reflects upside down
and opposite on the retinal field

Neuronal Pathways
1. Projection of the Retinal Ganglion Cells
a. As seen before, the retinal ganglion cells are the output neurons of the retina
b. They send their info to eventually reach the primary visual cortex V1 via the following pathway
Retinal
Ganglion
Cells

Optic
Disk

Optic
Nerve

2. Visual Field Pathway


a. The image is pretty self explanatory
where the visual field is split into
quadrants with the macula at its center
b. Images from the superior visual field
will relay to the inferior portion of V1
via the Temporal Radiation
c. Images from the inferior visual field
will relay to the superior portion of V1
via the Parietal Radiation
d. Images from the LEFT visual field will
relay to the right LGN and finally to the
RIGHT portion of V1
e. Note that this is only one example but
you can see how the remaining fields
will relay to the different portions of V1

Optic
Chiasm

LGN
(thalamus)

Primary
Visual
Cortex V1

Organization of V1
1. Broadmann Area 17
a. The primary visual cortex V1 is located in
area-17, most of which is on the medial aspect
b. There is a superior and inferior bank divided by the
Calcarine sulcus (reminder: opposite relations to visual fields)
c. Blood supply primarily from the calcarine branches of
The posterior cerebral artery.
2. Retinoptic Organization of V1
a. This is much easier represented with a picture but in summary:
i. The left visual field reflects to the right V1 and vice-versa
ii. The superior visual field reflects to the inferior V1 and vice-versa
iii. Macular/central vision reflects to the superficial V1 and peripheral vision to the deeper V1

3. Columnar Organization of V1
a. OCCULAR DOMINANCE COLUMNS
i. As seen above, visual fields from both the left and right eye can relay to a single side of V1
however that information does not actually reach identical locations
ii. There are separate/individual areas (columns) dedicated to the input from each eye
iii. Thus there are (C) Contralateral Columns and (I) Ipsilateral Columns in both the left and right
V1
b. ORIENTATION COLUMNS
i. In this case, there are columns of V1 that have a preference to the orientation of the image in the
visual field
ii. There are various orientation columns which have varying preferences such as vertical and
horizontal light as well as the intermediate variations

Parallel Pathways
1. DEPTH & MOTION (Where?)
a. Starts in the Magnocellular neurons (M-ganglion cells) of the retina, synapse in 2-of-6 layers in the LGN
b. They leave the LGN and follow the Dorsal (parietal) pathway (similar to the inferior visual field)
2. FORM & COLOR (What?)
a. Starts in the Parvocellular neurons (P-ganglion cells) of the retina, synapse in 4-of-6 layers in the LGN
b. They leave the LGN and follow the Ventral (temporal) pathway (similar to the superior visual field)

Clinical Correlations
1. Neurologic Exam of Visual Fields
a. Using the confrontational visual field test each quadrant of the field can be tested individually
b. Patient is double-arms length away and stare at each other with opposite eyes then place hand gradually
into each field individually
c. Assuming the examiner has normal vision, the patient and examiner should see the hand at the same time!
2. Visual Pathway Lesions
Understand this summary table and be able to draw it onto a picture

3. Color Agnosia (achromotopsia)


a. Inability to distinguish colors due to cortical lesions in areas 18 and 37 (cortical color blindness)

29 Eye Movements
Types of Eye Movements
CONJUGATE EYE MOVEMENTS (eyes are moving together in stereo)
1. Saccadic Movement/Gaze
a. Voluntary movements where your eyes will jump from one point to point (ie: scanning a picture)
2. Vestibulo-occular Reflex
a. Uses the vestibular system in the event that the head is spun rapidly
b. Keeps the eyes in position of your former point of fixation
3. Optokinetic Reflex
a. Utilized in a situation such as watching the landscape pass rapidly while in a train
b. Eyes move rapidly to keep the object of focus in the center of the visual field for as long as possible
NON-CONJUGATE EYE MOVEMENTS (eyes move in different directions)
1. Vergence
a. Convergence and Divergence: eyes move away or toward each other
2. Dysconjugate Gaze
a. A pathological movement pattern; eyes move erratically and totally independent of one another

Control Units for Eye Movement


1. Muscular Control IO
Normal
Movement
LR
SO

SR

LR6(SO4)3

When testing the muscles it gets tricky


MR If you test IO, SO, SR, IR you have to have them look
in the opposite direction of normal function THEN up or
down. So for example, the SR will aDD and elevate, so
IR
have the patient aBD and then look up to test function

2. Brainstem (location of extraocular nerve nuclei)


a. MIDBRAIN
i. CN 3 & 4 Nuclei Located in the Tegmentum
ii. MLF for ascending neurons from abducens nucleus to occulomotor nucleus necessary for
conjugate eye movement
iii. Superior Colliculus(just behind occulomotor nucleus) which receives information from the
retinal ganglion cells and can participate in saccadic eye movements
b. PONS
i. CN 6 Nuclei located in the lower Pons
ii. PPRF initial activate CN-4 to begin conjugate eye movements (including saccadic eye
movements)
c. MEDULLA
i. Vestibular Nuclei extends from the Pons into the Medulla and controls the Vestibulo-Ocular
Reflex (see lecture 30)
d. CEREBELLUM
i. Particularly the vestibule-cerebellum which
ii. participates in the Optokinetic reflex (see lecture 31
3. Cortical Control Units
a. Frontal Eye Field (BA-8)
i. roles in planning and initiation of eye
movements (seen in saccadic eye movements)
b. Parieto-Occipital Eye Field
i. Located at junction b/w parietal and occipital
lobes and its output is involved in depth & motion

Saccadic Eye Movements


1. Purpose
a. Extremely fast eye movements used to keep the
target in focus, on the fovea (used for scanning)
2. Pathway
a. Begins in the Frontal Eye Field, the planning
location where such movements are triggered
b. Descends to the PPRF in the Pons and then
move to the Abducens Nucleus
c. Abducens Nucleus activates CN-6 but also sends
ascending fibers which cross the midline and
reach the Occulomotor Nucleus via the MLF
ensuring synchronization between the eyes
d. The Oculomotor Nucleus activates CN-3 to
match CN-6 such that both eyes move together
in the same direction

Clinical Correlations
1. H-Test
a. Used to test each of the extraocular muscles
b. See explanation of use on page 1, under extraocular muscles
2. Trochlear Nerve Palsy (CN-4)
a. Eye will deviate up-and-in in light of the unopposed Inferior Oblique
3. Occulomotor Nerve Palsy
a. Loss of MR, SR, IR and IO
b. Eye will deviate down-and-out due to unopposed LR and SO function
4. Abducens Nerve Palsy (CN-6)
a. Eye will deviate medially due to unopposed action of the Medial Rectus
5. Diplopia
a. Basically, caused by the fact that the image is
landing on different points on the visual field
for each eye because one eye is unable to focus
the image properly on the fovea
b. Therefore, when info gets relayed to V1, it is
registering as actually existing in two places in
space thus causing double vision
RED GLASS TEST
c. Holding a red glass over the right eye (Red and
Right) the patient looks at a white light
d. Normal People the image from both eyes will
match and merge properly in the cortex thus creating a Pink light (combining the red and white)
e. Mismatch the images do NOT match which creates two individual lights (white and red). The light
perceived to be in the center of the visual field will define the good eye and the light perceived to be in the
periphery will define the bad eye and the direction of the pathologic gaze
6. Internuclear Opthalmoplegia
a. Based on a lesion of the MLF which if lost (think of saccadic eye movements) the abducens nucleus will
not be able to transmit info to the oculomotor nucleus (CN-3) so the ipsilateral MR is unable to respond
7. PPRF Lesion
a. Will result in inability to trigger ipsilateral abducens nucleus, resulting in inability to activate the
ipsilateral CN-6 and inability to initiate and send info up the MLF (even if the MLF is intact) thus losing
CN-4 as well

30 Vestibular System
Hair Cells

The receptor cells of the vestibular and cochlear division of the inner ear
Responsible for transducing mechanical stimuli into neuronal stimuli onto the
afferent fibers of CN-8
The apex of the hair cell contains stereocilia which is surrounded by endolymph
o The endolymph has a very high K+ concentration which is essential for
the signal transduction process

CN-8
1. Depolarization of Hair Cells
a. Mechanical force from the endolymph against the hair cells (as seen in
the picture) will open or close the TRPA-1 channels causing either a depolarization or hyperpolarization
b. The tip-link between the stereocilia directly opens the hatch on top of the TRPA-1 channels causing
potassium influx that will depolarize the hair cell (these depolarizations are graded in the hair cell)
c. The depolarization of the hair cell (due to K+ influx) will open Calcium-gated channels
d. The influx of Ca2+ will cause the NT release on CN-8 causing a full Action Potential
i. The frequency of action potentials increases as the graded potential of the hair cell increases

Neutral

Depolarization

Hyperpolarization

Angular and Linear Acceleration Transduction


1. Otolith Organs Saccule and Utricle
a. Endolymph filled pockets whos walls are lined with hair cells
b. When these hair cells are tilted by gravity or linear acceleration, it forces the cilia to bend which either
depolarizes or hyperpolarizes them (as seen above)
c. Note that the hair cells and its cilia and kinocilium have alternating orientations relative to the striola
i. this allows a single stimulus to activate one group and inhibit another group at the same time
EXAMPLE
a. Linear acceleration to the RIGHT will tilt some of the cilia toward and others away from the kinocilium
b. Away from the kinocilium will inhibit the left half causing a decrease in NT release, thus decreasing
the frequency of AP relative to the neutral position
c. Toward the kinocilium excite the right half causing an increase in NT release, thus increasing the
frequency of APs relative to the neutral position

2. Semicircular Canal
a. Endolymph filled pipes whos walls are also lined with hair cells
b. When the endolymph moves relative to the walls of the canals (a phenomenon seen when the head spins) it
causes the cilia of the hair cells to bend (causing depol/hyperpol) which deduces angular acceleration
EXAMPLE
c. the semicircular canal will rotate to the LEFT but the endolymphs inertia is delayed (think of how
the water in a rotating bucket takes time to reach the speed of the walls of the bucket)
d. this effect of the endolymph moving much slower than the wall, which has the hair cell attached to it, will
cause the cupula/cilia to bend to the RIGHT relative to the walls
e. depending on their orientation, this bending will either cause excitation or inhibition

Basic Vestibular Pathways


1. Subcortical Operation
a. The vestibular system works largely at a
subconscious level, thus there is no primary
vestibular cortex area
2. Basic Pathway
a. Input received from the Vestibular System to
the Vestibular Nuclei of the brainstem via CN-8
b. Output sent from Vestibular Nuclei to the Cerebellum,
Motor neurons of the limbs, back, and neck as well as
the motor neurons controlling the extraocular muscles
which are particularly import for the VOR

Haines fig 7-30


pg.228 for more detail

Vestibulo-Ocular Reflex VOR


1. Head rotation to the LEFT causes the endolymph to flow to the RIGHT in both canals
2. This clockwise rotation causes Excitation in the LEFT endolymph and Inhibition in the RIGHT endolymph
a. This is because the ampulla containing the cupula/cilia are oriented toward the midline and the kinocilium
toward the back of the head, thus if pushed backward=excitation and if pushed forward= inhibition
3. The left endolymph will send excitatory synapses to the Vestibular Nucleus
4. From the vestibular nucleus, interneurons are sent to the Abducens Nucleus
5. The abducens nucleus sends TWO signals out
a. First sent via CN-6 (abducens) to the LR muscle of the RIGHT eye
b. Second sent via MLF to Oculomotor Nucleus telling CN-3 to activate the MR muscle of the LEFT eye
6. The right endolymph will send inhibitory synapses in an identical pathway but to the opposing muscles as seen in
the diagram
IN SUMMARY
1. Head rotation causes ipsilateral excitation and contralateral inhibition causing the eyes to look in the
opposite direction of the heads rotation
2. Thus, rotation to the left, causes left endolymph excitation and forces a rightward gaze
A.

B.

A. depicts the entire VOR in the event of a


head spinning to the left
(counterclockwise)
B. depicts a simplified VOR showing the
simple pathway for consensual horizontal
eye movements

Vestibular Nystagmus
1. Nystagmus
a. Alternating smooth pursuit in one direction followed by saccadic movement in the other direction
i. Slow Phase driven by reflex circuitry
ii. Fast Phase simply the reset mechanism driven by the saccadic circuitry
b. Note that there is a difference b/w physiological and pathological nystagmus
2. Vestibulo-Ocular Nystagmus
a. Very simply, is a physiological nystagmus induced by continuous rotation of the endolymph
b. This endolymph flow then activates the VOR
c. This stimulus is persistent (as seen when spinning on a chair) thus the eyes keep flipping back and forth
d. Once the eyes reach a maximum gaze that is opposite to the direction of the head spin, the eyes quickly
reset and then continuously repeat this process until the person stops spinning
SUMMARY
1. the slow phase is the part where the eyes swing in the opposite direction of the head spinning
2. the fast phase is the part where the eyes reset after reaching maximum gaze and is driven by saccadic
circuitry (which was seen in lecture 28)

Clinical Correlations
1. Occulocephalic Maneuver (Dolls eye maneuver)
a. The examiner forcibly turns the head of the patient and looks to see if the VOR is intact
b. This should work on comatose pts as well
2. Caloric Testing of VOR
a. Place water in the ear of the patient which changes the density of the endolymph and induces a spin
b. COLD WATER makes the endolymph sink thus inhibiting that side which will cause a reaction as if the
head were spinning in the direction OPPOSITE to ear with the cold water
c. WARM WATER makes the endolymph float, this exciting that side which causes a reaction as if the
head were spinning in the direction toward the SAME SIDE of the ear with warm water
SUMMARY
I. C.O.W.S. Cold=Opposite; Warm=Same
II. The opposite and same refer to the spin of the head
3. Menieres Disease
a. Abnormalities of endolymph circulation caused by dilation of the endolymph compartment and
degeneration of the hair cells.
b. Characterized by sudden and recurrent attacks of vertigo
4. Motion Sickness
a. Caused by a discrepancy between the vestibular and visual inputs
5. Alcohol Intoxication
a. This is commonly known as the bed spins
b. The alcohol interacts with the endolymph and induces abnormal spinning of the endolymph similar to
that seen in the caloric testing of the VOR
6. Antibiotics (streptomycin)
a. Can be toxic to the hair cells; so take with extreme caution as they can accumulate in the endolymph
7. Pathological Vestibular Nystagmus
a. Can be caused by damage to one side of the vestibular system (either the canals or CN-8)
b. This will induce a slow phase toward the side with the damaged labyrinth and a fast phase toward the
normally functioning side
c. This nystagmus will persist as this pathological stimulus also persists

31 Ocular Reflexes
Optokinetic Reflex and Smooth Pursuit

Parieto-Occipital Eye
Field

1. Definition
a. The OKR involuntarily realign the point of
fixation during movement of the entire visual
field or an object within the visual field
2. Visual Information Processing
a. Look at the following diagram and note that
the Parieto-occipital eye field is exactly where
the Magnocellular parallel pathway lands and
remember that this dorsal path receives info for Motion
b. The parieto-occipital eye field is then responsible for forming the efferent limb of the OKR that triggers
the necessary eye movements
3. Pathway of the OKR
a. Efferent fibers begin at the parieto-occipital eye
field and descend to the Pontine Nuclei located
in the Pons
b. From the synapse in the Pons they cross the
Midline and synapse in the vestibulocerebellum
c. From the vestibulocerebellum they go to the
Vestibular Nucleus where fibers are then sent to
The Abducens Nucleus
d. From this point onward, the pathway has already
been seen when we studied saccadic eye
movements and consensual horizontal movement

Optokinetic Nystagmus
1. Natural Occurrence
a. This would happen if you were trying to follow the passing telephone poles outside while in a train
i. The Slow phase would be controlled by the OKR which as we know, attempts to keep the object
within the visual field
ii. The Fast Phase (reset) is driven by saccadic circuitry in the opposite direction
b. The OKR keeps the pole in focus until it reaches the limit of vision thereafter using saccadic reset circuitry
to catch the next pole
2. Rotating Chair Experiment
VESTIBULAR CONTRIBUTION
a. The start of the rotation will cause the endolymph to being flowing in the direction opposite of the spin
b. This will induce the VOR but for the first ~30seconds it will cause Vestibulo-Ocular Nystagmus
i. The Slow phase is in the opposite direction of the spin and driven by the VOR
ii. The Fast phase is in the direction of the spin and is driven by saccade
c. The Vestibulo-Ocular Nysagmus will continue until the endolymph is rotating at the same speed as the
head where it is at this point that the Vestibular system is no longer stimulated and the OKR takes over
OPTOKINETIC CONTRIBUTION
d. Very simply, once the vestibular system no longer receives stimulation (which happens at the point
where endolymph and head spinning are equal) the Optokinetic system takes over
e. The OKR needs only visual information, thus the physical movement of the head makes no difference
f. From this point on, Optokinetic Nystagmus will persist exactly as it was seen when it occurs naturally
RE- CONTRIBUTION FROM VESTIBULAR
g. At the point when the spinning is eventually stopped, the endolymph will again begin to flow relative to
the head, but now its in the opposite direction thus the VO-Nystagmus will ensue in the other direction

Pupillary Light Reflex


1. General Info
a. Limits the amount of light falling on the retina and prevents potential damage by excessive light intensities
b. This reflex causes both pupils to react together, regardless of which eye experiences the light stimulus
c. Afferent fibers CN-2; Efferent fibers CN-3
2. Pathway
a. Light reflects on the retina sending afferents to
the Pretectal Nucleus in the midbrain
b. The pretectal nucleus sends a double synapse
to the Edinger-Westphal nucleus of CN-3
c. From the EW, CN-3 will send efferents to both
Ciliary ganglia
d. From the Ciliary ganglia, the Short Ciliary
nerves reach the pupillary constrictor muscles on
each eye and the pupils constrict consensually
note that the example only shows afferents from
the temporal hemiretina but the afferents can also
come from the nasal hemiretina which gives an
alternate pathway in the event that there is a lesion
on the Optic TRACT

Corneal Reflex

Clinical Correlations

CN-7

CN-5
Spinal Nucleus
of CN-5

Left
Eye
Poke Cornea

1. General Info
a. Causes the eyelid to blink if something touches the cornea
b. The trigeminal nerve sends pain fibers to the brainstem
CN-7
which activates the efferent limbs of the blink reflex
2. Pathway
Right
a. CN-5 sends afferent pain stimulus from the cornea,
Eye
entering at the Pons and then it is sent down to
synapse in the Spinal Nucleus of CN-5 (blue)
b. Smaller fibers leave the spinal nucleus of CN-5
and ascend to the Facial Nucleus
Facial Nucleus
c. From the facial nucleus, efferent motor fibers are
sent to BOTH Orbicularis Oculi muscles via CN-7 (purple)

**Remember**
Orbicularis Oris (CN-7) closes the eyelid
Levator Palpebrae Superioris (CN-3) opens eyelid

1. Optokinetic Nystagmus
a. Can be tested using OKN tape or a spinning drum with stripes (or animals/figures for children)
b. Simply move the tape and in healthy ppl, OKN should be seen
i. If it is not seen, it may be due to damage to the parieto-occipital eye field
2. Pupillary Light Reflex Test
a. Use a penlight to elicit the reflex and see if there is pupillary constriction and if so, is it consensual
b. Stimulating each eye individually and looking for the reaction in both eyes will define exactly where the
lesion is (afferent or efferent) if there is a deficit
3. Corneal Reflex Test
a. Identical principle to the pupillary light reflex only the stimulus is direct tactile stimulation to the cornea
4. Bells Palsy
a. Is caused by a peripheral lesion to CN-7; often acute onset due to swelling/compression of the nerve at the
bony facial canal (think of how this affects the corneal reflex; eyelid and the nasolabial fold)

32 Auditory System
The Nature of Sound

GENERATED by mechanical vibrations that generate pressure waves in the medium they are traveling in
o High Pressure waves have a higher number of molecules per volume
o Low pressure waves are the opposite, with a lower number of molecules per unit volume
FREQUENCY is the tone or pitch and is measured in Hz (cycles per second)
o Humans can hear a frequency range of 20-20,000Hz
AMPLITUDE is the intensity or loudness measured in dB
o For example: normal breathing is ~10dB and a jet engine is ~150dB

Functional Anatomy of the Ear


1. Sound Production
a. Sound pressure waves enter the EAM and produce
Vibrations on the tympanic membrane
b. The sound is amplified down the chain of ossicles
c. The amplified vibration of the final ossicle, the stapes
produces vibrations on the inner ears oval window
located in the cochlea
d. Signal Transduction done by the Organ of Corti in the
Cochlea (has hair cells, remember lec.30)
e. The hair cells transmit signal down CN-8 which is the
first element of the Auditory pathway
2. Pressure Amplification of the Middle Ear
a. Size Difference
i. Because the tympanic membrane is 20x larger than the oval window, the force increases by 20x
because the area decreased by 20x (remember that F=P/A so if A, F)
b. Lever Ratio Ossicular Chain
i. The chain of ossicles act like a lever-arm which further amplifies the sound
c. OVERALL the middle ear leads to a 70-100x amplification of the pressure force

The Cochlea
1. Fluid Compartments
a. The Scala Vestibuli and Tympani are continuous with
each other and are filled with perilymph which has an
ionic composition that is similar to ECF
b. The Scala Media is filled with endolymph and is high
in K+ due to secretions from the Stria Vascularis
c. The Basilar membrane separates the Media from the
Tympani and supports the Organ of Corti
i. The organ of corti contains the hair cells which
are bathed in the endolymph compartment and
is necessary because of the high K+ concentration needed by the hair cells for signal transduction
2. Traveling Waves in the Cochlea
a. Movement of the stapes produces pressure on the oval
window which moves the fluids within the cochlea
b. This movement of fluids (not compression) is best
described as traveling waves which are translated to the
basilar membrane as seen in the diagram

3. Basilar Membrane
a. Is base on a Place Code for sound frequencies which says the amount of deflection of the basilar
membrane is based on its mechanical properties at that particular point in the membrane
b. AT THE BASE
i. At the oval window, the basilar membrane is narrow and stiff, responding to HIGH frequencies
c. AT THE APEX
i. Near the helicotrema, the BM is wide and floppy therefore most responsive to LOW frequencies
d. ENVELOPE OF WAVES
i. Is the sum of the deflection of the BM at different stages of the travel of the wave; which as we
now know exhibits variations from base to apex
4. Inner Hair Cells
a. Responsible for signal transduction as seen in lecture 30
b. Traveling waves on the BM cause a deflection of cilia on
the hair cells that are attached to it
5. Outer Hair Cells
a. Responsible for amplifying the deflection of the basilar
membrane and therefore amplifying the output signal
b. The outer hair cells have motor proteins that cause them to shorten in the event of a depolarization
(which will happen if the cilia are deflected, similar to the inner hair cells)
c. If the shortening across many outer hair cells takes place in proper sync, they can help push and pull the
basilar membrane such that its deflection is maximized thus amplifying the outgoing signal.

Auditory Pathway
1. The Basics of the Auditory Pathway
a. Begins with the auditory portion of CN-8 and enters the brainstem at the level of the Ponto-Medullary
Junction
b. Fibers then synapse in the anterior and posterior Cochlear Nuclei then undergo extensive crossing over
until they reach the Primary Auditory Cortex (A1)
c. This extensive crossing over is why there are no lesions which produce unilateral hearing loss
i. This of course does not include the structures of the ear, CN-8 and the cochlear nuclei
2. Primary Auditory Cortex A1
a. Location
i. A-1 is located in Broadmann
Area 41 and 42 which comprise
the transverse temporal gyri
b. Tonotopic Organization
i. A-1 is organized by frequency
sensitivity along the rostro-caudal
axis as seen in the diagram
c. Columnar Organization
i. A-1 is organized in columns that
are grouped according to their
pattern of input
ii. EE columns are those that are Excited by both ears
iii. EI columns are those that are Excited by ONE ear and Inhibited by the OTHER ear
3. Input Layer IV
a. The primary auditory cortex, identical to the other primary sensory cortex areas, receive input from the
thalamus in layer-4 where the thalamo-cortical fibers synapse

Localization of Sound
1. Low Frequency Sound
a. Based on TIME; pressure waves from space will reach each ear at different times which is interpreted and
understood to come from the given location
b. The time delay is detected by the binaural pathways to the superior olive (MSO) by a mechanism known
as Coincidence Detection
i. If the EPSPs from each ear arrive at the superior
olive at the SAME TIME (coincidence) there
will be a large signal
ii. If the EPSPs from each ear arrive at the superior
olive at DIFFERENT TIMES (no coincidence)
there will be a smaller signal
c. The timing of EPSP arrival and signal size gives the
understanding of where the sound is coming from
2. High Frequency Sound
a. Based on AMPLITUDE/INTENSITY
b. The amplitude varies based on the sound shadow created by the head if the source is lateral to the midline
c. The amplitude received by one ear is dampened by the head causing a lower amplitude and a lower
signal versus the other ear who receives a signal without any dampening thus a higher signal
INTERPRETATION
d. Fibers from one ear synapse in the ipsilateral superior olive as well as collaterals to the Trapezoid nucleus
i. The ipsilateral superior olive sends the output info to the cortex
ii. The Trapezoid nucleus sends inhibitory fibers to the contralateral superior olive
iii. Thus, the superior olive on each side has direct excitation ipsilateral and indirect inhibition from
the contralateral side
e. The sum of the inputs at the superior olives result in contralateral inhibition and ipsilateral excitation as
seen in the schematic
i. If one side starts off with an intrinsically higher intensity, its inhibitory contralateral will
hyperpolarize the opposite superior olive

3. Summary of Localizations
a. LOW FREQ in the medial part of the superior olive, using coincidence detection
b. HIGH FREQ in the lateral part of the superior olive, using interaural amplitude differences

Clinical Correlations
NEUROLOGIC TESTING
1. Webers Test
a. Place the tuning fork on the forehead and see where the sound is louder, right or left?
b. Normally, the person should say it is equal
c. Conductive Problem sound lateralized to the AFFECTED side (ipsilateral)
d. Sensorineural Problem sound lateralized to the UNAFFECTED side (contralateral)
2. Rinnes Test
a. Now that we know which side has a problem, the Rinnes test will tell us what kind of problem we have
b. The tuning fork is places on the mastoid process and held there until the patient no longer hears the sound
as it travels thru bone
c. Once the patient states they no longer hear it (via bone), the fork is held in the air next to the ear
d. Normal the air conduction should last longer and is louder due to amplification mechanisms utilized in
air conduction
e. Conductive Hearing Loss diminished air conduction; thus bone conduction is better and we now know
that this is a problem with the conductive system and not the neurologic system
DISORDERS
1. Otosklerosis
a. Fusion of the bony labyrinth (stapes to oval window) causing Conductive hearing loss of up to 40dB
2. Vestibular Schwannoma
a. Tumor of Schwann cells in vestibular division of CN-8 causing Sensorineural hearing loss
3. Loss of Hair Cells
a. Can also cause Sensorineural hearing loss
b. May be due to aging or the exposure to high frequencies (+100dB)
c. This loss cannot be replaced by cell division
4. Cochlear Implants
a. Consists of a microphone, electronic processor and many stimulating electrodes in the cochlea to help
restore hearing
b. The apparatus delivers sound directly to the cochlear nerve in the event that the hair cells are
damaged/lost

33 Chemical Senses
The Gustatory System
1. Basic Taste Qualities
a. Salty sodium chloride
b. Sour acids and hydrogen ions
c. Sweet sugars (ie: sucrose)
d. Bitter toxic or poisonous components
2. Taste Bud Receptor Cells
a. The apical pole nearest the pore, is the site of
signal transduction
b. The basal pole is the site of transmitter release
onto afferent fibers
c. Basal cells, located at the basal pole, are able to differentiate into new taste receptor cells

Gustatory Signal Transduction


IONOTROPIC
1. Salty
a. sodium ions enter causing a depolarization of the
taste receptor cell which causes the opening of
voltage gated Ca2+ channels
b. The eventual Ca-influx will cause the releases the
neurotransmitter at the base of the cell
2. Sour
a. Based on hydrogen ions that can work in two ways
i. They can enter at the same time attached to Na+ ions which will cause depolarization
ii. The H+ ion can block the outward K+ channel, keeping K+ inside the cell, thus causing depolarization
METABOTROPIC
1. Sweet
a. Works via the cAMP pathway where cAMP will close K+ channels, thus causing the cell to depolarize
2. Bitter
a. Works via the IP3/DAG pathway which causes a rise in intracellular Ca2+, causing the depolarization

Gustatory Pathway
The gustatory pathway does NOT cross the midline, thus it is a completely IPSILATERAL tract
1. Innervation of the Tongue
a. Anterior 2/3rd Facial Nerve (7)
b. Posterior 1/3rd Glossopharyngeal Nerve (9)
c. Most Posterior including the Glottis Vagus Nerve (10)
2. Pathway
a. The primary afferent nerve is either CN-7,
CN-9 or CN-10 which are all psuedounipolar
neurons with their soma in the respective
ganglia (Geniculate, Inferior Glossopharyngeal
or Inferior Vagus Ganglia, respectively)

b. The given cranial nerve enters at the


Pontomedullary junction to the Solitary
Nucleus
c. Fibers from the solitary nucleus ascend
ipsilaterally to the VPM of the Thalamus
(remember facial TVP tract)

d. From the VPM, third order fibers reach the


Primary Gustatory Cortex in the Insular Lobe

The Olfactory System


1. Smell Qualities
a. Note the major difference between smell and taste is that we can smell tens of thousands of different
smells where we only have four (or five) different taste qualities.
2. Olfactory Receptor Neurons
a. The olfactory epithelium has receptor neurons
imbedded in it with their cilia hanging in the
nasal cavity
b. The Basal cells differentiate and replace the olfactory
receptor neurons every 60-days
c. Olfactory receptor neurons synapse on afferent fibers
i. These multiple small afferents from the
receptor cells will all combine to form CN-1 and
travel to provide input to the olfactory bulb
ii. The afferents are covered in a sheath that are neither
Oligodendrocytes or Schwann cells
iii. These afferents pass thru the cribriform and synapse
in the Golmerulus that is associated with the
particular receptor neuron type
Glomeruli are grouped based on
receptor neuron type expressing the
same receptor protein note the
colored grouping in the diagram

3. Signal Transduction
a. Is done solely by a Metabotropic cAMP pathway
b. The cAMP will open the cation channel allowing both Ca2+ and Na+ inside simultaneously that will cause
the depolarization of the olfactory receptor neuron
4. Odorant Receptors
a. Each receptor neuron expresses one of the 1000 different receptor proteins sensitive to a single odorant
b. Because we are sensitive to tens of thousands of odorant molecules and there are only 1000 proteins, it is
clear that we use these in multiple combinations to interpret and understand such an array of smells
i. ie: one odorant stimulates multiple receptor neurons at varying degrees to define specific odors
5. Olfactory Bulb and Pathways
a. Vertical information passes from the olfactory
receptor neuron, thru the cribriform plate and to
the bulb
b. Horizontal information exists similar to that seen
in the retina, where these inhibitory interneurons
assist in segregating the vast number of odorants
into individual smells based on the combination of
levels of excitement of each receptor type

6. Olfactory Pathway to Cortex First


a. The olfactory cortex includes the Peri-Amygdaloid cortex, Piriform cortex and the Entorhinal cortex
b. Unlike the other pathways, the olfactory pathway directly reaches the cortex without a thalamo-cortical
projection
7. Olfactory Cortex and Emotion
a. The olfactory cortex has close relation to the
limbic system which controls emotions, hence
why it is difficult to remain emotionally indifferent
when we experience good and bad smells

8. The Vomernasal Organ


a. First discovered in the 1800s, has been found to work with pheromone communication in mammals
b. Recently (1998) a study on female menstrual cycles showed that there is significant evidence for the
validity of human pheromones

Clinical Correlations
LOSS OF TASTE FUNCTIONS
1. Hypogeusea
a. Decreased taste function usually due to oral cavity pathology (secondary to salivary gland dysfunction)
leading to taste bud destruction
2. Ageusea
a. Total loss of taste function may be due to lesion on Chorda Tympani (CN-7)
b. Usually in conjunction with Bells Palsy (CN-7); causing ipsilateral taste loss to anterior 2/3rd of tongue
c. Can also be due to Wallenbergs Syndrome (lateral medullary syndrome) due to an infarction of the lateral
medulla caused by an occlusion to the PICA
LOSS OF SMELL FUNCTIONS
1. Hyposmia
a. Decreased smell function (is more common than hypogeuse) where the pt complains that they cant taste
anything but it is usually an inadequate taste because of the loss of the smell of the food
2. Anosmia
a. Total loss of smell most likely due to compression of the olfactory tract by tumors, particularly
meningiomas
3. Olfactory Hallucinations
a. Partical epileptic seizures originating in the vicinity of the uncus will commonly induce olfactory
hallucinations of pungent and unpleasant smells but they do not actually exist

38 Organization of Motor Pathways


The Big Picture
1. Cortex
a. Sends very coarse signals which need to be
modulated by the Basal Ganglia & Cerebellum
2. Voluntary Motor Systems
a. Corticospinal pyramidal cells from layer 5 PCG
b. Corticobulbar pyramidal cells from layer 5 PCG
c. Rubrosipinal from Red Nucleus midbrain
d. Pontine/medial Reticulospinal Reticular nuclei
e. Medullary/lateral Retuculospinal Reticular nuclei
3. Involuntary Motor Systems
a. Lateral Vestibulospinal LVN in the pons
b. Medial Vestibulospinal MVN in pons and medulla
**Note that there is NO CORTICAL control of these tracts!!

4. Other Motor Sensory Inputs


a. Muscle Spindles
b. Dorsal Column/Medium Leminiscus & ALS

Motor Tracts in the Spinal Cord


1. Descending Motor Tracts
a. Ventromedial Pathways
i. Pontine Retuculospinal
ii. Lateral Vestibulospinal
iii. Medial Vestibulospinal
b. Lateral Pathways
i. Medullary Reticulospinal
ii. Corticospinal
iii. Rubrospinal
2. Location Relative to Function

Lateral Paths
Flexor Bias

Medial Paths
Extensor Bias

**note that corticobulbar is


not included in this asit is
responsible for the face,
hence not in the cord**

Clinical Correlations
1. Amyotrophic Lateral Sclerosis (Lou Gehrigs Disease)
a. Progressively weakens and later destroys LMNs
b. It will eventually effect parts of the pyramidal tracts and precentral gyrus
c. Loss of respiratory function eventually causes death
d. Patients often within 3-5 years of Dx
2. Spinal Cord Diseases
a. Usually affect motor and somatosensory tracts in the white matter
b. May also affect motor neurons of anterior horn and sensory neurons of dorsal horn
3. Anterior Spinal Artery Syndrome
a. Caused by an infarction to the Anterior Spinal Artery which supplies circulation to the anterior 2/3rd of
the spinal cord (as seen in x.s.)
b. This will compromise:
i. Second order motor neurons in anterior horn
ii. Lateral & Anterior corticospinal tracts
iii. ALS sensory system
c. This will result in:
i. Spastic Paraparesis and/or
Paraplegia (anterior horn damage LMN)
ii. Bilateral loss of TP below (ALS remember lissauers)
iii. TVP intact
iv. Urine retention and sexual dysfunction
4. Central Medullary Syndrome
a. Most likely caused by Syringomyelia
b. Typically causes segmented muscle atrophy (usually hands and fingers)
c. Loss of TP
d. See lecture 23 for more details

39 Corticospinal & Corticobulbar Fibers


Corticospinal Tract
1. Initiation and Control of Motor Activity
Prefrontal and Limbic Cortex
Motor Planning
Premotor Cortex (BA-6)
Production of Motor Programs
Primary Motor Cortex (BA-4)
Execution of Motor Activity

2. Premotor Cortex BA-6


a. Project to the motor cortex (above)
b. Also have layer-5 pyramidal cells that project via the
corticospinal tract to excite motor neurons
c. The medial aspect of the premotor cortex contains the
supplemental motor area which does the same thing
3. Primary Motor Cortex BA-4
a. Lies in the precentral gyrus
b. Layer-5 pyramidal cells make excitatory synapses to LMNs
in the spinal cord directly and indirectly via interneurons
c. Has a distinct somatotropic map
4. Input to Motor and Premotor Cortex
a. Motor Cortex receives input from:
i. Primary Somatosensory (BA-1,2,3)
ii. Posterior Parietal Area (BA-5,7) integrates sensory info for motor planning
iii. Basal Ganglia and Cerebellum (via thalamus)
b. Premotor Cortex receives input from:
i. Posterior Parietal Area
ii. Basal Ganglia
5. Roles of Primary Motor Cortex
a. Simple Finger Movements activate motor cortex and somatosensory cortex are activated
b. Complex Finger Movements Premotor cortex and supplemental motor cortex are activated
c. Rehearsed Finger Movements only activate the supplemental cortex (programmed from rehearsal)
6. Predominant Role of Lateral Corticospinal Tract
a. Voluntary contraction of distal flexor muscles in the limbs REACHING AND WALKING
b. Sensory input is constantly processed by the cortex and modified by the basal ganglia and cerebellum
7. Start-End-Route
a. START Pyramidal cells Layer-5 of Precentral Gyrus
b. END contralateral anterior horn of the spinal cord where the UMN synapse on /-LMNs
c. ROUTE coronoa radiata internal capsule crus cerebri basilar pons lateral corticospinal tract /-LMNs
8. Motor Neurons of the Corticospinal Tract
a. UMN: Located in layer-5 and sends axons
down the pyramidal tract to the contralateral
ventral horn to synapse on the LMN
i. The point of crossing over is known

as the pyramidal decussation

b. LMN: exit from the ventral horn and extend


to innervate the target muscle

LMN - Lower Motor Neuron Lesions


1. Results in:
a. Paralysis or Paresis
b. Areflexia - Decrease/loss in reflexes due to loss of efferents
c. Muscle atrophy and eventual wasting due to denervation
d. Denervation may also cause faciculations (twitches) which show up on an EMG as fibrillations
e. All symptoms occur IPSILATERAL to the side of damage
2. Examples of LMN syndromes
a. ALS Lou Gehrigs Disease
b. Peripheral nerve damage (traumatic)

UMN - Upper Motor Neuron Lesions


1. Results in:
a. Initially flacicidity and arelfexia due to spinal shock
b. After a few weeks spinal cord circuits regain function and motor Sx/Sx emerge to include:
i. Spastic Paralysis (increase in muscle tone)
1. Thus NO wasting of muscles!!
ii. Positive Babinski Reflex (note infants do as well b/c Corticospinal tract remains immature)
iii. Hyperreflexia
2. Which side is affected?
a. Lesion ABOVE decussation CONTRALATERAL symptoms
b. Lesions BELOW decussation IPSILATERAL symptoms

Brown Sequard Syndrome


Hemisection of the Spinal Cord

Paraplegia

Paraplegia

1. Trauma
a. Often a result of trauma causing a BILATERAL impairment of
the spinal cord
b. Cells of the long tracts are cut or crushed contusion, compression or laceration
i. Note this is an UPPER Motor Neuron impairment
2. Symptoms
a. Flaccid paralysis below the lesion (spinal shock) followed by
development of spasticity
b. Increased deep tendon reflexes and clonus
c. Positive Babinski reflex
d. Urine retention, painless bladder distention and overflow
e. Decrease of flexor spasms several months after injury
f. Loss of ALL Somatosensory below

Corticobulbar Tract

Bulbus = Brainstem

Corticobulbar fibers innervate motor cranial nerve nuclei where their route depends on the CN being innervated
Corticobulbar Fibers to Hypoglossal Nucleus
a. Central (Upper) Lesion
i. Will cause contralateral denervation of the tongue
b. Peripheral (Lower) Lesion
i. Will cause ipsilateral denervation of the tongue

MLF

2. Corticobulbar Fibers to PPRF (conjugate eye movement)


a. Central Lesion (frontal eye field-BA8 or internal capsule)
i. The patient will have a gaze TOWARD the side of the
lesion
ii. Analyze the picture in depth to understand
b. Peripheral Lesion (exiting from abducens or occulomotor
nucleus)
i. Depending on the side, will lose the extraocular
muscle that
innervates it (ie: lateral rectus or medial rectus)

3. Corticobulbar Fibers to Facial Nucleus


a. Contralateral Central Facial lesion
i. Loss of lower facial muscles but still able
to move forehead due to partial innervation
from ipsilateral cortex
b. Ipsilateral Central Facial Lesion
i. No loss because the majority of the innervation
comes from the contralateral cortex
c. Peripheral Facial Lesion
i. Will result in total loss of muscle innervation
on the ipsilateral side

40 Other Motor Pathways


Rubrospinal Tract - FLEXOR
1. START
a. Red Nucleus Midbrain
b. Receives cortical input from motor cortex; hence VOLUNTARY activity
2. END
a. Alpha and Gamma motor neurons in the cervical anterior horns
3. ROUTE
a. Cortex Red Nucleus cross in midbrain descend in Rubrospinal Tract
synapse on / motor neurons
b. Third order motor neurons exit to reach Proximal Flexors of the Limbs
4. FUNCTION
a. Receives ipsilateral input from motor cortex and cerebellar nuclei
b. Each Red Nucleus synapses in cervical segments innervating proximal muscles of the Contralateral
arm

Medullary (lateral) Reticulospinal - FLEXOR


1. START
a. Medullary Reticular Nuclei - Midbrain
b. Receives bilateral cortical input
2. END
a. Interneurons that excite Alpha and Gamma motor neurons
3. ROUTE
a. Cortex Medullary Reticular Nucleus descent ipsilateral OR
cross in medulla then descend in Reticulospinal Tract
synapse on interneurons synapse on / motor neurons
4. FUNCTION
a. Receives info from cortex BILATERALLY as well as info from ALS regarding TP
b. Bilateral control of limb flexor muscles
c. Also does some inhibition of extensor muscles via interneurons synapsing on -motor neurons

Pontine (medial) Reticulospinal - EXTENSOR


1. START
a. Pontine Reticular Nucleus Pons
b. Receives bilateral cortical input
2. END
a. Ipsilateral anterior horn on MAINLY Gamma-motor neurons (some alpha)
to innervate axial and limb extensor muscles
3. ROUTE
a. Cortex Pontine Reticular Nucleus descent ipsilateral
in Reticulospinal Tract synapse on ipsilateral Gamma-motor neurons
4. FUNCTION
a. Receives info from cortex BILATERALLY
b. Also receives a STRONG input of sensory information from limbs and trunk
c. Most fibers facilitate extensor activity of limb muscles

Spinoreticular Tract - SENSORY


1. START
a. Peripheral Pain and Temperature receptors
2. END
a. Pontine and Medullary Reticular Nuclei
3. ROUTE
a. TP receptor Ascend via ALS (hence immediate crossover)
synapse in BOTH Reticular Nuclei
send Efferent signals to respond to stimuli (leg lift example)
4. FUNCTION
a. Relays info to Contralateral reticular nuclei regarding TP and crude touch
in the trunks and limbs
b. The reticular nuclei will then facilitate the contraction of extensor muscles
of the trunk and limbs

Lateral Vestibulospinal Tract - EXTENSOR


1. START
a. Lateral Vestibulospinal Nucleus
2. END
a. Synapse on excitatory interneurons of the anterior horn which
eventually synapse on alpha-motor neurons
3. ROUTE
a. Vestibular organs and cerebellum lateral vestibular nucleus
descend ipsilaterally in medulla and spinal cord
synapse on interneurons synapse on alpha-motor neurons
4. FUNCTION
a. Receives input from vestibular organs and cerebellum
b. Eventual excitatory influence to contract axial and limb extensor muscles
the so called anti-gravity muscles coordinating balance

Medial Vestibulospinal Tract - EXTENSOR


1. START
a. Medial Vestibulospinal Nucleus
2. END
a. Synapse alpha-motor neurons at the cervical and upper thoracic
levels of the spinal cord
3. ROUTE
a. Vestibular organs and cerebellum medial vestibular nucleus
descend in ipsilateral MLF of the spinal cord
synapse on alpha-motor neurons (cervical and thoracic)
4. FUNCTION
a. Receives input from vestibular organs and cerebellum
b. INHIBIT extensor muscles by releasing Glycine on the alpha-motor neurons
which innervate extensor muscles of the neck and back
c. Predominantly work toward stabilizing head position

The Gamma Loop


1. How It Works
a. The Extrafusal fibers are stimulated by Alpha-motor neuron and the muscle contracts/shortens
b. This causes the muscle spindle to loosen and decreases the 1-a axon firing rate
c. The decrease on the 1-a causes the Gamma-motor neuron to stimulate the intrafusal fiber/spindle to
contract and adapt to the new shortened length of the extrafusal fiber
2. Stimulation of Gamma ALONE
a. Stimulation of the gamma-motor neuron will contract the intrafusal fiber which stimulates the 1-a neuron
b. The 1-a axon stimulates the alpha-motor axon to contract the muscle, hence indirect muscle contraction
c. This is seen in use when the Pontine (medial) Reticulospinal Tract is used (stimulate mainly gamma)
3. Simultaneous Alpha and Gamma Stimulation
a. This is seen with the voluntary tracts (Corticospinal, both Reticulospinals and Rubrospinal)
4. 1-b Fibers from Golgi Tendon
a. Note that the 1-b fiber will synapse on an interneuron which eventually inhibits the alpha-motor fiber
b. This is a protective mechanism to ensure the muscle contraction does not reach the point of damage
c. This negative feedback is also responsible for fine motor acts like handling a delicate object.

Clinical Correlations
1. Decorticate Posturing
a. A lesion ABOVE the Red Nucleus impairing Corticorubral and Corticospinal fibers
b. The Red Nucleus is actove but there is NO cortical input
c. ARMS FLEXED
i. flexion due to most powerful Rubrospinal influence
d. LEGS EXTENDED
i. Extension by unopposed Pontine Reticulospinal and Vestibulospinal due to the fact that the
Rubrospinal intrinsically has little influence and the other flexor being the Corticospinal tract is
interrupted by the lesion
2. Decerebrate Posturing
a. A lesion BELOW the Red Nucleus impairing Corticospinal/bulbar/rubral Tracts
b. All flexors across the body are blocked/impaired thus, all extensors act unopposed.

41 Muscle Innervation & Motor Unit


Muscle Afferents
1. Afferent Cell Bodies
a. The cell bodies of ALL muscle afferents are in the DRG
2. Two Major Sensory Organs
a. Muscle Spindle measures length: 1-a Fiber
b. Golgi Tendon measures tension: 1-b Fiber
3. Additional Mechanoreceptors Thermo and nociceptors (TP)

Muscle Spindle
1. What are they?
a. Encapsulated structures found in most skeletal muscles used to monitor its length
b. The number of spindles in the muscle is directly related to the muscles function
i. Muscles involved in fine movement (hand) have more spindles than coarse moving muscles (back)
2. Components of the Spindle
a. Small group of 2-12 intrafusal () fibers central regions are non-contractile
b. Large diameter myelinated sensory axon (1a-axon) with sensory ending in the intrafusal belly
c. Small diameter myelinated motor axon that innervate the distal contractile regions (gamma-motor ending)
INTRAFUSAL FIBERS
3. Intrafusal Fibers
a. Lie w/in the spindle between/parallel to the
extrafusal fibers and are attached to the muscles
tendons
b. When the muscle contracts, the muscle shortens
and 1a firing rate
c. When the muscle stretches, 1a firing rate increases
4. THREE Types of Intrafusal Fibers
a. Dynamic Nuclear Bag Fibers sensitive to length
change & rate of change
b. Static Nuclear Bag Fibers sensitive to length change ONLY
c. Nuclear Chain Fibers sensitive only to length change ONLY
5. Innervation of Intrafusal Fibers
SENSORY INNERVATION
a. Group 1a is the primary sensory ending carrying STATIC & DYNAMIC (length and rate) afferents
b. Group II secondary ending carrying STATIC ONLY
MOTOR INNERVATION
c. A-Gamma small myelinated and low velocity axons carry motor innervation to the intrafusal fibers
**note that the A-Alpha fibers are responsible for the motor innervation of the extrafusal fibers**

PHYSIOLOGIC ROLE OF THE MUSCLE SPINDLE


6. Role in Stretch Reflex
a. If the muscle is stretched, the 1a-axon is stimulated sending a train of impulses to the ventral horn
b. There it synapses on and stimulates the alpha-motor neuron of the stretched muscle to contract
c. It also stimulates inhibitory interneurons to inhibit the alpha-motor neuron of the antagonist muscle
d. This phenomenon is known as reciprocal innervation
7. During Sustained Stretch
a. As the spindle is continually stretched, there is sustained AP firing in the muscle spindle afferent
8. Muscle Spindle During Alpha Motor Stimulation
a. When the alpha-motor is stimulated, the muscle shortens and briefly alleviates the stretch on the spindle
b. At this time, there is no stimulation of the 1a-axon, thus NO afferent discharge

9. Muscle Spindle During Simultaneous Alpha and Gamma Stimulation


a. If alpha and gamma are both stimulated, the intrafusal and extrafusal fibers will contract together
b. Because the intrafusal spindle consensually contracts, it continues to relay afferent information thus able to
continually measure/monitor the muscle length

Golgi Tendon Organ


1. Location and Function
a. Located in series between tendon and extrafusal fiber which are sensitive to tension
2. Innervation
a. Each golgi tendon is innervated by a single 1b-axon which is large, myelinated and has high velocity
b. The 1b-axon will lose its myelination once in enters the tendon organ and intertwines the collagen chains
c. Contraction of the muscle will compress the free, non-myelinated endings and firing rate on the 1b-axon
3. Physiological Response
a. Increasing 1b-axon firing rate will increase
inhibition on the alpha-motor neuron
b. This phenomenon will ensure an even distribution
of tension and contraction as well as avoiding
excessive contraction to the point of damage
c. This reflex is known as the Reverse Myotactic Reflex

Muscle Efferents
1. Two Types of Motor Neurons
a. A-alpha large, myelinated, high velocity passing via ventral horn to limb muscle Extrafusal fibers
b. A-gamma small, myelinated, lower velocity passing via ventral horns to limb muscle Intrafusal fibers
2. In the Spinal Cord
a. These alpha and gamma motor neurons are both located in the ventral horn of the cord
b. RENSHAW CELLS
i. Are inhibitory interneurons of the anterior horn that receive collaterals from the alpha motor
neuron and work to avoid damage in the event of excessive contraction (like golgi)
c. Spatial Distribution distal-proximal rule (see lecture 40)

Renshaw Cells

Motor Unit
1. Motor Unit
a. Includes the motor neuron and the muscle directly activated by it
2. Motor Nuclei
a. Consist of 100 motor neurons (on average) to control a typical muscle
b. They congregate to create this motor nucleus in the anterior horn of the spinal cord as well as the
brainstem for motor CNs
3. Distribution
a. A motor axon branches at its muscle and each fiber receives only one ending of the branching
b. The NMJ is located in the center of the muscle fiber and is where APs are generated
c. The number of muscle fibers in a motor unit decreases with increasing fine motor control
i. ie: muscles of the hand are about 10 fibers per unit where the back muscles are ~1000 fibers/unit
4. Three Types of Motor Units
a. Type I Slow-twitch muscle fibers; low tension; fatigue resistant; aerobic; innervated by relatively small
motor neuron and axon
b. Type IIA Fast fatigue-resistant (almost); large tension; some aerobic capacity; innervated by relatively
large motor neuron and axon
c. Type IIB Fast fatigable; large tension; anaerobic; innervated by relatively large motor neuron and axon
5. Factors Controlling Contraction
a. The force developed by the muscle fibers increases with increasing firing rate of the motor neuron
b. The force will also increase as more motor units are recruited to the excited state

Clinical Correlations
1. Hypotonia
a. Reduced muscle tone (atrophy) due to damage to either the 1a afferent or the alpha motor efferent
2. LMN Syndrome
a. Caused by destruction of the motor neuron in the anterior horn, the axons in the ventral roots or the
peripheral nerves
b. This can cause:
i. Atrophy
ii. Loss of voluntary and reflex responses
iii. Hyporeflexia
iv. Fasciculations and Fibrillations

42 Diseases of the NMJ & Motor Unit


Origin of Muscle Weakness
1. May originate in the nervous pathway in the motor neuron, its axon or at the NMJ(neurogenic)
2. May also originate in the muscle itself (myogenic/myopathic)

Sites of Lesions in the Motor Unit

Nerve Cell Lesions (soma or axon)

Schwann Cell Lesions

1. Various Types of Lesions


1. Various Types of Lesions
a. Diseases, Toxins/Drugs and Trauma
a. Toxins and Autoimmune Diseases
2. Symptoms
2. Symptoms
a. Atrophy/Weakness
a. Demyelination
b. Fibrillations and Fasciculations
b. Conduction Slowing or block
c. Muscle fiber replaced by fibrous connective tissue

NMJ Impairments
1. Botulism
a. Toxin of an anaerobic bacteria which stops ACh vesicles from docking at the NMJ
b. This will inhibit ACh exocytosis, resulting in paralysis
c. THREE WAYS TO BE INFECTED
i. Eating food containing botulism toxin
ii. Wound infected with Colostridium botulinum
iii. Ingesting spores of Colostridium botulinum
2. Alpha-Latrotoxin
a. BLACK WIDOW massive ACh release
b. Travels via lymph to the blood causing tetanus, painful muscle contraction and eventual paralysis
3. Beta-Bungarotoxin
a. OTHER SNAKE VENOM reduces ACh release by acting on exocytosis
4. Curare (turbocurarin)
a. ARROWHEAD POISON found in plants and is a reversible nAChR antagonist temporary paralysis

5. LAMBERT-EATON SYNDROME
a. Autoimmune against votage-gated Ca2+ channels which causes an insufficient release of ACh
b. Continued contractions will cause an [ACh] in the cleft until it reaches a concentration sufficient to elicit
an proper contraction
c. Often associated with Oat Cell Carcinoma of the lung
d. SIGNS & TESTS
i. On examination, weakness improves with activity
ii. Decreased reflexes
e. THERAPY
i. Remove underlying tumor and give Immunosuppressive drugs
ii. Calcium gluconate to enhance Ca2+ influx
iii. 4-AP will block K+ channels that increases presynaptic impulse duration causing Ca2+ release and
eventually improve ACh release (as acetylcholine release is Ca-dependant)

Synaptic Cleft Impairments


1. CONGENITAL MYASTHENIAS
a. AChE Deficiency
i. Causes increased and prolonged EPP
ii. Temporal summation will easily cause desensitization known as depolarization block
b. Slow Channel Syndrome
i. Binding of ACh to nAChR causes prolonged opening of the ACh receptor channel
ii. Channels open for too long causes prolonged depolarization resulting in depolarization block
iii. This results in muscle weakness, rapid fatigue and progressive atrophy
c. Other Congenital Myasthenias
i. Abnormal binding of ACh with nAChR
ii. ACh-gated channels have extremely brief open times
2. MYASTHENIA GRAVIS
a. Causes
i. Autoimmune antibodies against nAChR which blocks AChs ability to bind to its receptor
ii. Structural changes in the end plate include:
1. Fewer nAChR
2. Wider cleft
3. Smaller/shallow junctional folds
iii. Sometimes associated with thymus tumors
b. Symptoms
i. Weakness of voluntary muscles which improves
with rest and worsens with increasing activity
ii. Difficulty swallowing (frequent choking)
iii. Late-day paralysis
iv. Myasthenic Crisis difficulty breathing that may be
life threatening
c. Signs & Tests
i. EMG: waning pattern
ii. AChE test is usually positive
d. Treatment
i. Neostigmine/Pyridostigmine is an AChE inhibitor to increase ACh presence in the cleft
ii. Plasma Exchange temporary improvement of the patients condition
iii. Surgical removal of the thymus can sometimes put the pt into remissino
3. MYOTONIA CONGENITA
a. Autosomal Dominant Cl--channels are decreased in number causing a slower muscle relaxation
b. Cl-channels usually reset Vm after an AP, thus without the proper amount will excitability & relaxation
c. Increased excitability (smaller deopl needed) b/c K+ is unopposed causing spontaneous depols!
d. Pt suffers from muscle stiffness and hypertrophy

Myopathy Muscular Dystrophies


1. Duchennes Muscular Dystrophy
a. X-linked Recessive there is an absence of the muscle protein Dystrophin (usually affects boys)
b. Onset is early childhood (3-5y/o - usually boys) where muscle weakness develops progressively
c. By age 10-12 unable to walk and by age 20 will die of respiratory and/or cardiac failure

LMN Syndrome
1. What is it?
a. Second order neurons which stimulate the muscle are lost
b. The lesion is either on the motor axon or at the soma in the spinal cord or brainstem (CNs)
2. Causes
a. Viral Infection Poliomyelitis
b. Trauma
c. Neuro-degeneration
3. Sx/Sx
a. Weakness/paralysis
b. Loss of reflexes
c. Fasciculations
i. Irregular spontaneous contractions giving visible twitches
ii. Alone, is not a sign of motor neuron damage but together with fibrillations denotes denervation
d. Fibrillations
i. Spontaneous contractios of a single muscle fiber
ii. As the muscle becomes denervated, the fetal type nAChR spreads across the entire muscle fiber
iii. They now are hypersensitive to cations as more Na and Ca channels are inserted
e. Atrophy
POLIOMYELITIS
Poliovirus can affect the whole body but most cases the motor neurons in the ventral horns
Severe cases causes permanent paralysis or death
Transmission person-to-person contact (nose, mouth and fecal)
Prevention polio vaccine (90% effective)

43 PNS Disorders
Signs of PNS Lesions
1. Negative Signs loss of normal function
a. Muscle Weakness
b. Loss of Reflexes
c. ANS deficit (no sweat)
d. TP loss/impairment

2. Positive Signs (in addition to normal)


a. Parasthesia transmission b/w adjacent
hypersensitive nerves
b. Brief periods of pain acute periods of
nerve compression (trigeminal neuralgia)

Nerve Conduction Velocity


1. NCV Test
a. Used to measure the speed of electrical conduction thru an nerve where
b. If there is a deficit, it can help determine if any nerve damage or destruction exists.
2. Measure NCV
a. Use the median nerve and test the time it takes for a stimulus to traverse the nerve along two different
distances and get the difference between them (T2-T1)
b. Divide the distance between the two locations (D/T2-T1) to find the actual Conduction Velocity
c. Note that depending on the placement of the stimulators and recorders, this test will test either a motor or
sensory nerve (see diagrams)

3. Conduction Velocity Measurements (Clinical Correlations)


a. Motor Neuron Soma
i. little/no change in motor
ii. no change in sensory
b. Peripheral Nerve
i. Compression slowing of motor & sensory
ii. Demyelination marked slowing of motor & sensory
iii. Mild Axonal Degeneration slight/no reduction
c. NMJ and/or Muscle
i. No change in motor or sensory

Mechanical Nerve Trauma


1. Compression and Stretching
a. Peripheral nerve damage develops at the innermost
structures first and works toward the outermost
structures (see diagram)
CARPAL TUNNEL SYNDROME
a. Compression of the Median nerve at the wrist due to
swelling wrist tendons which eventually compress
the nerve
b. Pain, weakness & numbness in the hand and wrist
occur and radiate up the arm
c. Females are more likely to develop carpal tunnel syndrome
AXOTOMY
After nerve injury where axons are ruptured/cut, several mechanisms might occur
a. Wallerian Degeneration
a. degeneration of the distal part of the axon

b. Anterograde Transneural Degeneration


a. degeneration of the distal nerve

c. Retrograde Transneural Degeneration


a. degeneration of the proximal nerve

Regeneration/Regrowth in PNS
1.
2.
3.
4.

After dissection of a peripheral nerve, the terminal end sprouts


One of the sprouts will find the guide tube created by Schwann Cells and the axon will continue to grow
This is facilitated by nerve growth factor (from Schwann cells), laminin and adhesion molecules (1mm/day)
Schwann cells will then redevelop and re-myelinate the newly grown axon

Regeneration/Remyelination in the CNS does NOT occur because:


a. Oligodendrocytes do NOT release nerve growth factor
b. Astrocytes multiply in regions of trauma which create glial scars and stop the development of axonal sprouts
which is known as GLIOSIS
c. Inhibitory chemical messengers are released in the CNS that opposes axonal regeneration in adults
Reinnervation of Denervated Skeletal Muscle
a. Following nerve damage, motor axons regenerate and form new NMJs usually in the same place as before
b. The Basal Lamina is responsible for differentiating the growth cone into the nerve terminal
c. Different isoforms of Laminin exist
a. Laminin 11 seen in synaptic basal lamina
b. Laminin 2 seen in the extrasynaptic basal lamina

Peripheral Neuropathy
GUILLIAN-BARR SYNDROME
1. Demyelination of peripheral axons which begins several weeks after viral respiratory/GI infection
2. This is most likely due to an autoimmune response
3. Respiratory support is often needed until the Schwann cells can successfully re-myelinate the nerves
4. Normally, patients are able to recover from this syndrome
5. Treat patients with IV immune globulin
LEPROCY (Hansens Disease)
1. Caused by Mycobacterium Leprae
2. Characterized by skin lesions and profound sensory loss (TP) due to ischemia/compression of peripheral axons
3. The infection will also cause muscle weakness
4. Antibiotic treatments are successful
DIABETES MELLITUS
1. Usually seen in insulin-dependent diabetics
2. Will cause:
a. Autonomic Neuropathy
b. Motor Neuropathy
i. Usually asymmetric
c. Sensory Neuropathy
i. are usually symmetric and affect unmyelinated axons carrying TP in a stocking distribution
ii. unmyelinated axons and DRG cells are very vulnerable to hyperglycemia
iii. this may be due to a lack of nutrient and protein supply to distant parts (cytoskeleton problem)
ALCOHOLIC POLYNEUROPATHY
1. Caused by neurotoxic effects of alcohol-associated malnutrition (Vitamin B1Thiamin deficiency)
2. Starts with sensory loss in lower legs and progresses to motor losses in the legs
3. Nerve conduction velocity is usually normal
4. 10+ yrs of alcoholism establishes high risk
LEAD POISONING
1. Children are more susceptible because their brain and CNS are not fully developed
2. May lead to enecephalopathy, IQ, learning deficits, mental retardation, coma and death
3. Weakness in distal muscles more than proximal
4. Focal weakness in finger extensor muscles
5. Bilateral arm weakness and wasting/atrophy in chronic conditions
6. ADULTS causes memory and concentration problems as well as motor peripheral neuropathy
7. Virtually NO SENSORY SYMPTOMS

44 Spinal Reflexes
Reflexes
DEFINITIONS
LANDMARKS FOR REFLEX TESTING
1. Monosynaptic/Deep Tendon/Myotactic Reflex
a. afferent and efferent limbs are directly
connected (ie: ONE single synapse)
2. Polysynaptic Reflex
a. Afferent and efferent limbs are connected
by ONE OR MORE interneuron
3. Reflex Arc Components
a. Sensory receptor (spindle/golgi tendon)
b. Afferent neuron
c. Synapse on efferent (LMN) neuron
d. Muscle contraction
4. Types of Stretch Reflexes
a. Deep Tendon Reflex
b. Golgi Tendon Reflex (inverse myotactic)
c. Flexion Crossed Extension Reflex
5. Afferent Limbs
a. Spindle 1a fibers
b. Golgi Tendon 1b fibers
SCALE FOR REFLEX SCORING
4 very brisk, hyperactive, with clonus
3 brisker than average (high normal)
2 average (normal)
1 somewhat diminished (low normal)
0 no response

Stretch Reflex
1. Basic Reflex Arc
a. Is in response to passive muscle stretching
b. 1a-fibers from spindle directly stimulate
alpha-motor fiber to contract the stretched
muscle
c. 1a-fibers also stimulate inhibitory
interneurons that eventually inhibit the
alpha-motor neuron on the antagonist
muscle
2. Negative Feedback Loop
a. The stretch reflex works as a negative
feedback loop to maintain muscle length
at a desired value
3. Gamma-motor Neuron
a. Are responsible for contracting the ends of the muscle spindle to keep its length identical to the muscle
fibers in an effort to maintain monitoring of the muscle length at all times

Golgi Tendon Inverse Stretch Reflex


1. Location and Function
a. Located in series between tendon and extrafusal fiber which are sensitive to tension
2. Innervation
a. Each golgi tendon is innervated by a single 1b-axon which is large, myelinated and has high velocity
b. The 1b-axon will lose its myelination once in enters the tendon organ and intertwines the collagen chains
c. Contraction of the muscle will compress the free, non-myelinated endings and firing rate on the 1b-axon
3. Physiological Response
a. Increasing 1b-axon firing rate will increase
inhibition on the alpha-motor neuron
b. This phenomenon will ensure an even distribution
of tension and contraction as well as avoiding
excessive contraction to the point of damage
c. This reflex is known as the Inverse Myotactic Reflex
4. Primary Functions
a. Protection increased tension will increase inhibition
on contraction to avoid excessive contraction that can lead to
damage

b. Posture via the patellar tendon and the quadriceps muscles. When the muscle relaxes,
there is less tension and the inhibition is removed. The muscle will then contract to
maintain proper posture
Flexion & Flexion Crossed Extension Reflex
1. Flexion Reflex Withdraw Reflex
a. In response to painful stimuli, causing rapid flexion
as a protective mechanism
b. Pain afferents (A-delta and C-fibers) will stimulate
excitatory interneurons that synapse on alpha motor
neurons to flex the necessary muscle
2. Flexion Crossed Extension Reflex
a. The Flexion Reflex is often associated with this Flexion
Crossed Extension Reflex in the contralateral limb
b. This will support the contralateral leg to maintain balance
if the flexion reflex causes the ipsilateral leg to lift when
you step on a pin
c. SUMMARY
i. Ipsilateral flexor stimulation and extensor inhibition
ii. Contralateral flexor inhibition and extensor stimulation

Plantar Response Babinski


1. The external portion of the sole is stimulated from heel to toe Flexion=good; Fanning/extension=bad
2. Positive Babinksi UMN damage to spinal cord (thoracic/lumbar) or brain disease to Corticospinal tract
3. Newborns have immature tracts thus they will have a NON-pathological positive plantar reflex

Clinical Correlations
Hyperreflexia: is an UMN lesion in the cortex or somewhere in the Corticospinal tract (develops after spinal shock)
Spinal Shock: Acute damage to the cord causing immediate areflexia caudal to injury; reflexes return in weeks
Hyporeflexia: diminished reflex caused by LMN lesion, NMJ/muscle disease, sensory loss or peripheral nerve lesion

46 Movement Disorders: Basal Ganglia


Basal Ganglia - Introduction
1. Exchange information about motor
commands with prefrontal, premotor and
primary motor cortex
2. The Basal Ganglia has NO direct synaptic
connections with motor neurons
3. ROLE initiation and control of
voluntary movement
4. FOUR (4) NUCLEI
a. Striatum: caudate nucleus and
Putanem
b. Globus Pallidus: external (GPe)
and internal (GPi) segments
c. Subthalamic Nucleus (STN)
d. Substantia Nigra: pars reticulata (SNr)
and pars compacta (SNc)

Motor Loop
The Motor Cortex, Basal Ganglia and Thalamus are interconnected and form the MOTOR LOOP
GABA blue
o Inhibitory Effect
Glutamate red
o Excitatory Effect
Dopamine purple
o D1 Excitatory
o D2 Inhibitory
1. Inhibition from Basal Ganglia
a. Most neurons in the BG are inhibitory
as seen with the various GABA synapses
as well as some Dopamine Synapses
2. Substantia Nigra Pars Compacta
a. SNc neurons are dopaminergic and produce neuromelanin as a byproduct of dopamine metabolism
b. Degeneration of these dopaminergic cells are evident in autopsy as loss of the dark pigment neuromelanin
3. Striatum Dopamine Receptors
a. D1 receptor excitatory; mediating facilitation of striatum firing rate
b. D2 receptor mediates inhibition
c. These effects combine to reduce the tonic inhibitory output from the basal ganglia onto the thalamus

Striatial Neurons Synaptic Connections


1. Basal Ganglia sends Inhibitory signal to Thalamus
a. Note that the GPi and SNr function as a single unit
b. The GPi/SNr are tonically active and exert inhibition on the thalamus which will modulate the excitatory
signal between the thalamus and the SMA (BA-6)
2. Corticospinal/Corticobulbar Modulation
a. The Corticospinal and bulbar motor outputs are modulated by the inhibitory influence of the GPi/SNr
3. Extrapyramidal System
a. Formed by the Basal Ganglia which influence motor activity
4. Pyramidal System
a. Composed of the Corticospinal and bulbar tracts which exert direct control over LMSs

Direct and Indirect Pathways


DIRECT PATHWAY facilitate movement
The intrinsic effect of the direct pathway is to facilitate movement
The Cortex excites the inhibitory neuron leaving the Striatum
The Inhibitory neuron leaving the striatum, will inhibit the GPi/SNr
If the GPi/SNr is inhibited, it can no longer exert its own inhibitory influence on the Thalamus
The pathway removes the inhibition on the thalamus and EXCITES the Cortex to facilitate movement!
WITH DOPAMINE INFLUENCE facilitate movement
o Dopamine from the SNc will mimic/enhance the effect of the cortex on this pathway
o Thus, D1 receptors will assist in facilitating movement
Motor Cortex
Area 4

Area 6

Striatum
Thalamus
Spinal Cord

KEY:

Direct
Indirect
Inhibitory

GPe
GPi/SNr
Substantia Nigra
SNc

INDIRECT PATHWAY inhibits movement STN


The intrinsic effect of this pathway is to inhibit movement (in the absence of dopamine)
The Cortex stimulates the Striatum to up-regulate the exiting inhibitory neuron
The inhibitory neuron from the striatum will down-regulate the GPe
If the GPe is down-regulated, it can no longer exert its inhibitory effect on the STN
The STN, now in the absence of an inhibitory effect (from the GPe), will up-regulate the GPi/SNr
The up-regulation of the GPi/SNr will stimulate its inhibitory effect on the thalamus and inhibit movement
WITH DOPAMINE INFLUENCE facilitates movement
o Dopamine from the SNc will counteract/down-regulate the effect of the cortex on this pathway
o D2 receptors (under dopamine influence from SNc) will down-regulate the exiting inhibitory neuron from
the striatum
o This will alleviate the inhibitory effect on the GPe, and allow it to naturally inhibit the STN
o If the STN is inhibited (from the GPe) it will no longer up-regulate the GPi/SNr
o If the GPi/SNr is not up-regulated, it can no longer send its inhibitory effect to the thalamus
o Thus, the removal of inhibition on the Thalamus will EXCITE the cortex and facilitate movement
SUMMARY
The initiation of movement involves sharing of motor signals between the cortex and basal ganglia
The cortex (4) sends signals to the basal ganglia,
The info is modulated and sent back to the cortex (6) to initiate movement
Dopamine from the SNc has an excitatory effect on D1 receptors and an inhibitory effect on D2 receptors
DOPAMINE excites the direct pathway and inhibits the indirect pathway, thus
facilitating movement via BOTH pathways

Parkinsons Disease
MOTOR COREX

1. Etiology
a. BILATERAL Degeneration of dopaminergic cells in the SNc
b. This will cause overactivation of the inhibitory effect of
the indirect pathway
c. This will also cause an underactivation of the excitatory
effect of the direct pathway
d. OVERALL excessive inhibition, hence a
hypokinetic disorder
2. Symptoms
a. The Sx/Sx are exhibited bilaterally as degeneration is bilateral
b. Akinesia absence or poor movements
c. Bradykinesia abnormal slowness of movements
d. Resting tremors
e. Muscular Rigidity

Striatial Medium Spiny


Neurons
D2

Lower
Motor
Neurons

D1

SNc
Thalamus
GPe

STN

GPi/SNr

Huntingtons Chorea
MOTOR COREX
1. Etiology
a. BILATERAL degeneration Strial neurons (with D2 receptors)
b. This will cause a loss of any and all control between the
Striatum and the GPe
Striatial Medium Spiny
c. This results in a loss of the inhibitory effect from the indirect
Neurons
pathway hyperkinetic disorder
i. The GPe will inhibit the STN on its own (in the
D2
D1
absence of striatal control)
ii. The STN now being inhibited, will not stimulate
the GPi/SNr to inhibit the thalamus
SNc
iii. The loss of inhibition onto the thalamus causes
excessive motor activity
GPe
2. Symptoms
a. Irregular BILATERAL movements
b. Dyskinesia excessive motor activity
STN
GPi/SNr
c. Involuntary movement of head, arms and legs
d. Marked change in mental status dementia and psychological/psychiatric troubles

Thalamus

MOTOR COREX

Hemiballismus
1. Etiology
a. Lesions of the STN usually arising from stroke
b. Causes underactivity of the indirect pathway on one
side of the midline
c. Loss of indirect pathway leads to loss of inhibition
causing excessive movement hyperkinetic disorder
2. Symptoms
a. This leads to irregular movements of the limbs and trunk
on the contralateral side
b. Characterized by involuntary flinging of the arms and
writhing movements of the leg ON ONE SIDE

Lower
Motor
Neurons

Striatial Medium Spiny


Neurons
D2

Lower
Motor
Neurons

D1

SNc
Thalamus
GPe

STN

GPi/SNr

Other Motor Disorders of the Basal Ganglia


PARKINSONISMS Describes symptoms involving any combination of resting tremors, muscular rigidity,
bradykinesia and impaired postural reflexes
Drug Induced Parkinsonism
o Drugs (ie: phenothiazines) bocks D2 receptor which reduces dopamines ability to downregulate the
inhibitory effect of the indirect pathway, resulting in hypokinesia
o Drugs (ie: reserpine) depletes dopamine stores and results in an affect as if the SNc was absent
Vascular Parkinsonism
o Strokes affecting the basal ganglia can cause parkinsonism usually affecting the lower body and gait
Repetitive Head Trauma
o Often a boxing-like injury and is associated with dementia
Postencephalitic Parkinsonism
o Virally-induced degeneration of the SNc
CHOREAS other than Huntingtons
Sydenhams Chorea (autoimmune)
o A significant feature several months after rheumatic fever associated with inflammation of basal ganglia
o Often unilateral; Age of onset is b/w 5-15 y/o; recovery usually good within 6-weeks
Drug-induced Chorea
o Can be caused by L-dopa, anticonvulsants or antipsychotics as a result of enhancing dopaminergic
transmission within the basal ganglia

Drug Therapies for Parkinsons Disease


1. L-dopa
a. Increases the rate of dopamine synthesis in the remaining neurons of the SNc
b. Given orally, with cabidopa to prevent dopamine synthesis outside of the CNS
c. Effectiveness will decrease over time as the number of SNc neurons diminishes toward zero
2. Dopamine Agonists
a. Most common dopamine agonist drugs include
i. Bromocriptine D2 agonist
ii. Pergolide D1 and D2 agonist
3. Drugs that Enhance Dopamine Release
a. Amantadine has some beneficial effects on akinesia and rigidity but has psychiatric side-effects
4. MAO Inhibitors
a. Selegiline blocks dopamine breakdown
5. COMT Inhibitors
a. COMT will naturally breakdown dopamine, thus a drug that can inhibit this, will help dopamine
effects
6. Anticholinergic Drugs
a. Stimulatory cholinergic interneurons are found between
SNc neurons and the Striatum
b. Blocking these will decrease their antagonistic affect on the
SNcs attempt to inhibit the neuron exiting the striatum and
allow the dopamine from the SNc to have a greater effect
c. Such drugs include Benztropine, can reduce tremors
more effectively than rigidity
d. Side-effects include confusion, drowsiness and exacerbation
of dementia associated with Parkinsons disease

Surgical Treatments for Parkinsons


1. Bilateral Stereotaxic Surgical Lesions of STN
a. Reduces the excitatory drive on the GPi/SNr thereby reducing the inhibitory drive on the Thalamus
b. However, patients are at risk for developing hemiballismus
2. Bilateral Stereotaxic Surgical Lesions of GPi
a. Also will reduce the inhibitory drive on the Thalamus
3. Stereotaxic Surgical Lesions of the Thalamus
a. Has shown some success to limit the effects of an excessive inhibition from the GPi
4. Deep Brain Stimulation
a. >100Hz stimulation of the thalamus, GPi or STN has shown some success
b. Studies show GPi stimulation excite GABAergic neurons that decreases GPis inhibitory influence on
the thalamus

Therapy for Huntingtons Disease

The origin of the disease is genetic and to date, there is NO successful therapies to delay or slow its progression
Antidepressants are useful in managing clinical depression caused by HD

DRUGS USED TO LIMIT CHOREA


Antagonists of D2 receptors (ie: haloperidol) will increase inhibitory effect of the indirect pathway in an effort to
inhibit choreic movements
This may lead to difficulty swallowing, speaking and walking

47 Movement Disorders: Cerebellum


Cerebellum - Subcortical Motor System
The cerebellum is responsible for modulating movements to produce smooth, well-timed muscular contractions
Like the Basal Ganglia, the cerebellum has NO direct motor neuron connections but constantly influences movement by

FINE TUNING MOVEMENT


1. Comparison
a. Cerebellum compares descending motor output with ascending info regarding posture and movement
b. Cerebellar intervention coordinates movement to ensure it is smooth and accurate
2. Timing
a. Modifies descending sequences of motor signals to ensure smooth muscular activity
b. This is also coordinated with a part of the cerebellum concerned with maintaining balance and posture
3. Initiation & Storage of Motor Information
a. Synaptic Plasticity gives the cerebellum the ability to store and
update motor info so that learned movements can be accurately initiated
THREE FUNCTIONALLY DISTINCT REGIONS
1. Vestibulo-Cerebellum
a. Receives afferent information from vestibular system
b. Helps regulate balance and eye movements.
2. Spino-Cerebellum
a. Afferent information mostly from spinal cord
b. Helps regulate body and limb movement
3. Cerebro-Cerebellum
a. Receives afferent connections from the deep pontine nuclei
b. Involved in planning and monitoring movement
CEREBELLAR PEDUNCLES connection to the brainstem
1. Superior Cerebellar Peduncles
a. from cerebellum to midbrain and pons
2. Middle Cerebellar Peduncles
a. from pons to cerebellum
3. Inferior Cerebellar Peduncles
a. from spinal cord and medulla to cerebellum
b. between vestibular apparatus, lateral vestibular nucleus
and cerebellum
LAYERS OF THE CEREBELLAR CORTEX
1. Three Layers
a. Granule, Purkinje and Molecular Cell Layer
2. Two Fiber Inputs
a. Climbing fibers input from Inferior Olivary Nucleus
b. Mossy fibers carry all other inputs
3. One Output Fiber
a. GABAergic Purkinje fibers are the ONLY output
neurons of the cerebellar cortex
b. PURKINJE FIBERS
i. Are inhibitory fibers which end on the Deep
Cerebellar Nuclei
ii. The neurons leaving the Deep Cerebellar
Nuclei have excitatory actions on motor systems

Assistance to the Motor Cortex


1. Motor Cortex, Cerebellum and Thalamus form MOTOR LOOP
a. Cerebellum receives then relays info to and from the motor cortex modifying commands to the LMNs
b. Each half of the cerebellum also receives afferent information ipsilaterally
c. Output effects the movement on one side of the body
i. The contralateral side to the motor cortex info
ii. The ipsilateral side to the afferent input
CERBRO-CEREBELLUM coordinated movement
1. The SMA (6) has excitatory (glutamatergic) synapses
on the Lateral Hemisphere of the cerebellum
2. The Purkinje cells then have inhibitory synapses on
the Deep Cerebellar (dentate) nucleus
3. The deep cerebellar nucleus then has excitatory synapses
on the thalamus
4. The Thalamus then convey excitatory synapses to M1
5. The cortex then sends motor commands to LMNs via
Corticospinal and bulbar tracts
6. FUNCTION:
a. Initiation, timing and coordination of movements
of the Arm, Trunk and Leg which are
ipsilateral to the cerebellar hemisphere and
contralateral to the motor cortex
SPINO-CEREBELLUM limb and trunk muscles
1. Receives afferent info from limbs and trunk about
proprioception and LMN firing rates via four tracts
2. Each of these tracts start in the spinal cord on one
side
and end in the ipsilateral spino-cerebellum
3. This afferent info is relayed to the contralateral
motor
cortex via the deep cerebellar nucleus (interpositus)
4. The cortex then sends info back over the midline
(where info came from) to facilitate appropriate
movements of the limbs and trunk

VESTIBULO-CEREBELLUM from vestibular system


1. Receives head movement via CN-VIII from vestibular
apparatus
2. Information passes ipsilaterally to the flocculo-nodular lobe
of the vestibulocerebellum
3. Purkinje cells relay signals Bilaterally to Medial-VN
and Ipsilaterally to Lateral-VN
4. Bilateral Output from Medial-VN to control head/neck
and extraocular muscles is relayed via the Medial
Vestibulospinal Tract
5. Ipsilateral Output from Lateral-VN to control extensor
and axial muscles is relayed via the Lateral Vestibulospinal Tract
6. FUNCTION:
a. Overall, it is to maintain balance by contracting
extensor anti-gravity muscles

ATAXIA: An inability to coordinate muscle


activity
during voluntary movement, so that
Disorder Defines Lesion Site
smooth movements occur and is ipsilateral to
the side of the cerebellar lesion
1. Cerebellar Lesion causing Stance, Gate and Posture Disroder
a. Ataxic Stance
i. if pt is unable to maintain stance w/feet together and eyes open this indicates a cerebellum or
vestibular lesion; pt will maintain wide stance
b. Ataxic Gate
i. broad, unsteady and uneven gait is characteristic of a cerebellar lesion
c. Posture/Balance Disorder
i. if there is a unilateral lesion, the pt will tend to fall toward the side with the lesion
2. Cerebellar Lesion causing Movement Disorders
a. Speech
i. Slow, slurred and monotonous speech is typical of cerebellar lesions, known as DYSARTHIA
b. Muscle Tone
i. Hypotonia is an important feature but is often not easy to detect in slow, bilateral progression
ii. Rebound Phenomenon: patients arm hits their chest after being released under tension by the
examiner due to a poor myotactic reflex
c. Limb Ataxia dyssynergia
i. Composed of dysmetria (past pointing) and dysdiadochokinesia (cant
perform rapid repetitive movemtents ie: winding watch)
d. Intention Tremor of Limb Movement
i. Tremors provoked while attempting purposeful movement
ii. These can be magnified my maximizing the range of movement tested
e. Head Tremor
i. Nodding head tremors called titubation is seen in some forms of cerebellar
disease with a frequency of 3/second
f. Eye Movement Disorders
i. Jerkiness of smooth pursuit due to inability to suppress the VOR
ii. Nystagmus can accompany a vestibule-cerebellar lesion

Lesion Type Defines Disorder


1. Cerebellar Tumor may occur in midline region
a. Common in children; astrocytoma occurring in midline region
b. Symptoms ICP, headache, N/V, pappiledema and hydrocephalus
c. Signs wide-stance, truncal ataxia, hypotonia, balance disorder (heel/toe walking) and nystagmus
2. Cerebellar Stroke
a. Usually occludes an artery supplying ONE side of the cerebellum
b. Cerebellar Signs ipsilateral limb/trunk ataxia, dysarthia, intention tremor, dysmetria,
dysdiadochokinesia and rebound phenomenon
c. Addl Brainstem Signs ipsilateral facial weakness and sensory losses
3. Louis-Bar Syndrome damages Cerebellar Cortex
a. Autosomal recessive, causes loss of Purkinje cells, causing motor, growth and sexual dev. delays
b. Also causes humoral and cell-mediated immunity deficiency, fatal by age 30
c. Signs ataxia (see by first walk), dysarthia, facial weakness and occulomotor n. (horiz. saccades)
4. Alcohol Abuse anterior lobe of cerebellar cortex
a. Degeneration of anterior lobe and vermis probably due to associated malnutrition
b. Degenerative changes include neuronal loss (purkinje cells) and gliosis in cerebellar cortex
c. Signs dysmetria of legs, truncal ataxia, lurching gate, intention tremors of legs and trunk (not arms)
d. Nystagmus, dysarthia and hypotonia are NOT COMMON
e. Becoming and maintaining soberness with nutritional supplements will help but not back to 100%

Disorders Relative to Functional Anatomy


VESTIBULO-CEREBELLUM balance, head and eye movements
The vestibulocerebellum is concerned with trunk, head and eye movements using vestibular info to coordinate this
Lesions of the vestibule-cerebellum cause:
o Truncal Ataxia (imbalance), cant walk heel/toe, wide-stance, nystagmus, titubations and head tilt
SPINO-CEREBELLUM posture and limb movements
Regulates body and limb movements; concerned with maintenance of balance and gait
Lesions will cause:
o Imbalance (fall to side of lesion) as well as gait and arm ataxia
CEREBRO-CEREBELLUM plans and times movement
Primarily concerned with coordinating movements of skeletal/striated muscle (not cardiac) and is also responsible
for muscle memory (ie: playing the piano)
Lesions will cause:
o Ataxia, intention tremor, ipsilateral hypotonia, movement decomposition, dysarthia and ipsilateral
dyskiadochokinesia, rebound tenderness and dysmetria

48 Autonomic Nervous System


Introduction/Review
The ANS contributes to homeostasis; maintaining the internal environment WITHOUT voluntary control

HYPOTHALAMUS
The control center for the most basic life processes; receive info from two major systems
Neuronal Input
o Visceral afferent sensory info enters CNS via spinal nerves to the hypothalamus
o May also enter via cranial nerves but it will stop in the solitary nucleus of brainstem before hypothalamus
Humoral Input
o Received thru circumventricular organs in the walls of the ventricles which contain fenestrated capillaries
o Lack of BBB detect chemical changes in blood and relay the info to the internal regulatory system
ANTAGONIST SYSTEMS
Consists of the sympathetic and parasympathetic divisions

Three Divisions of the ANS


1. Sympathetic & Parasympathetic
a. Most organs receive motor innervation from both sympathetic and parasympathetic
2. Enteric Division
a. Formed by two layers of ganglia/plexus in the GIT
b. Each plexus receives sensor info from the gut wall (via afferents) and modulate their respective task
c. Note that the enteric division does NOT work completely independently and MAY be modified by efferent
fibers of the sympathetic and parasympathetic divisions
d. MYENTERIC (Auerbachs)
i. Between longitudinal and circular smooth muscle responsible for gut motility
e. SUBMUCOSAL (Meissners)
i. Adjacent to the mucosal epithelium; responsible for water/ion txp and digestive juice secretion

Cellular Organization of the ANS


This is very simply summed up with the following image

Pathways of the ANS


SYMPATHETIC PATHWAYS
Pre-ganglionic fibers leave the intermediolateral column of the spinal grey matter via ventral roots
Fibers enter either the paravertebral chain ganglia or prevertebral ganglia
Post-ganglionic fibers leave their respective ganglia to reach their target tissue
An EXCEPTION is when preganglionics leave the cord and synapse direcly on the adrenal medulla
o The adrenal medulla acts as the second-order neuron releasing adrenaline directly into the blood
o In this fashion, any adrenergic receptor in the entire body can react to sympathetic stimulation
PARASYMPATHETIC PATHWAYS
Pre-ganglionic fibers originate in the brainstem (as CNs) or in the spinal cord (as spinal nerves)
Unlike the sympathetics, with a long chain of ganglia, there are distinct parasympathetic ganglia
o Ciliary, Pterygopalatine, Otic and Submandibular Ganglia
Apart from these four distinct ganglia, post ganglionic fibers originate in their terminal ganglia found in the
wall of the target organ

Clinical Correlations
1. Pharmacological Influence of Autonomic Function
a. Directed toward the receptors on the target organ
b. Side effects are avoided by ensuring specificity
for the specific type/subtype of adrenergic receptor
c. Some examples are seen in the diagram
2. Hirschsprungs Disease Megacolon
a. Congenital absence of motility and peristalsis of the distal colon
b. This is caused by the absence of parasympathetic terminal ganglia in the distal colon
c. Feces is trapped and causes abnormal dilation, hence megacolon
3. Complex Regional Pain Syndrome
a. Chronic neuropathic pain syndrome follows injury to bone, soft tissue or nervous tissue
b. Pain persists after apparent healing is complete
c. Caused by an increase of sympathetic activity or sensitivity of nociceptors to NE
d. Increased sympathetic activity may also cause excessive sweating

49 ANS and the Hypothalamus


Hypothalamic Functions
1. Control of 5 Basic Processes
2. Control based on 3 major output pathways
a. Blood pressure and Electrolyte composition
a. Autonomic Functino
b. Temperature
b. Endocrine Function
c. Energy Metabolism
c. Motivation and Behavior
d. Reproduction
e. Emergency Responses
3. Example of BP Modulation via Three Pathways
a. Hypothalamus can influence ANS (sympathetic/parasympathetics) to change BP via HR and
contractility
b. Endocrine output of the hypothalamus can modulate ADH release from posterior pituitary to change BP
via kidney reabsorption
c. Hypothalamus can influence motivational system to either sit and rest or engage in exercise
4. Homeostatic Function
a. As our external environment has a wide range of variability, the hypothalamus maintains our internal
environment within a narrow physiological window via its regulatory mechanisms

Endocrine Function & Chemical Signaling


1. Phermones: released by a species and travel thru the air to
reach their target cell on another individual of that species
2. Autocrine & Paracrine: provide feedback to the releasing
cell itself or its neighbors
3. Endocrine: release hormone into the blood to reach their
target
4. Neurons: transmitter released on target to elicit action
5. Neuroendocrine: a hybrid which releases their neurohormone
into the blood; these are found in the hypothalamus and are
connected to the ant/post-pituitary

Structure of the Hypothalamus

Also see fig


5-34 of
Haines Atlas

CORONAL VIEW
1. Periventricular Zone adjacent to the 3rd Ventricle
2. Medial Zone contains most of the distinct nuclei of the hypothalamus
3. Lateral Zone contains less defined nuclei but is rich in fiber tracts
which connects the hypothalamus to other areas of the brain
SAGGITAL VIEW
Also see figure 2-28 in
the Haines Atlas; all
structures seen in this
diagram should be
familiar

Hypothalamo-Adenohypophyseal Pathway
1. Hypothalamic Control of the Anterior Pituitary
a. Parvocellular neuroendocrine cells from the Parvoventricular
and Arcuate nuclei terminate in the primary capillary
plexus of the superior hypophyseal artery in the infundibulum
b. Neuroendocrine substances are released into the primary
capillary plexus which drains into the portal vein
c. The portal vein then leads the blood flow toward the
anterior pituitary and into a second capillary plexus
d. Neurohormones controlling the anterior pituitary will
either induce or inhibition hormone release from the AP
2. Regulatory Hypothalamic Hormones Anterior Pituitary
a. Following hypothalamic stimulation, the
AP may release TSH,ACTH, LH, FSH,
GH or Prolactin
b. Of course, the AP hormone release depends
on the hormone released by the hypothalamus
c. The MOST IMPORTANT is the response to
stress where CRH causes a release of ACTH
which acts on the adrenal cortex to release the
stress hormone Cortisol into the blood which
acts on various target cells

Hypothalamo-Neurohypophyseal Pathway
1. Hypothalamic Control of the Posterior Pituitary
a. Magnocellular neuroendocrine cells from the
paraventricular and supraoptic nucleus send axons
directly to the posterior pituitary so called the
supraoptico-hypophyseal tract
b. These neuroendocrine cells release their
neurohoromone into capillaries of the inferior
hypophyseal artery thus entering the circulation
c. These neurohormones now in the blood can reach
their target tissues via the circulation

2. Hormones of the Posterior Pituitary


a. Firstly note that there are NO regulatory hormones
from the hypothalamus as the PP is controlled under
direct neurologic connections
b. The two neurohormone of the PP and their function
are outlined in the following chart (ADH & Oxytocin)

Hypothalamic Regulation of Feeding Behavior


1. Antagonist Elements of the Hypothalamus
a. The ventromedial nucleus decreases feeding behavior
b. The Lateral Hypothalamus increases feeding behavior
2. Proposed Feedback Mechanisms
a. Short term blood glucose levels
b. Long Term Leptin, released from adipose will reach
the arcuate nucleus which sends inhibitory interneurons
to the lateral hypothalamus to suppress eating

Hypothalamic Regulation of Water Balance


1. Information Received by Brain via Two Major Inputs
a. Angiotensin passes the BBB at the subfornical organ (in the circumventricular organs)
b. Vagus nerve sends BP info via mechanisensitive endings in the heart
2. Mechanism for Modulation
a. The hypothalamus influences water conservation by eliciting the PP to release ADH as a neuroendocrine
signal on the kidney
b. It also sends neuronal output to our motivational system controlling drinking behavior

Hypothalamic Regulation of Body Temp


1. Antagonist Elements of the Hypothalamus
a. The Anterior Hypothalamus decreases body temperature
i. Also has temperature sensitive cells to detect body
temp changes which is integrated with somatosensory
temperature information
b. The Posterior Hypothalamus increases body temperature
2. Mechanism for Modulation
a. Temp changes are induced via ANS which constrict/dilate vessels
b. Also uses signals to motivational centers to seek
warmer/cooler environments

Clinical Correlations
1. Ventromedial hypothalamic Syndrome (Frohlich Syndrome)
a. Disorder of caloric balance causing obesity attributed to damage of the ventromedial nucleus
2. Diabetes Insipidus
a. Absence of ADH causes excessive thirst and urination (10L/day)
b. This may be due to a lesion of the supraoptic or paraventricular nuclei somewhere in PP the tract
3. Hypothermia
a. May be due to lesions of the posterior hypothalamus leaving the anterior hypothalamus unopposed
b. This causes: MR and vasodilation resulting in a body temp
4. Hyperthermia
a. May be due to lesions of the anterior hypothalamus leaving the posterior hypothalamus unopposed
b. This causes: MR, shivering and vasoconstriction resulting in a body temp

50 Autonomic Control Functions


Review: Autonomic Pupil Control
1. Parasympathetics CONSTRICT
a. midbrain ciliary gangion short ciliary nerves
2. Sympathetics DILATE
a. Hypothalamo-spinal fibers (very important for moto efferents)
originating in the Hypothalamus descend to the upper
thoracic level of the spinal cord
b. The exit to reach the Superior Cervical Ganglion and
post ganglionics constrict the pupil

Autonomic Control of the Bladder


THREE LEVELS OF CONTROL
1. Supratentorial level
a. bladder control originates in the frontal cortex (motor strip) and hypothalamus
2. Below the Tentorium
a. The Pontine Micturition Center (controls micturition) located in the Posterior
3. Spinal Cord
a. Sympathetic efferents originate in the lower thoracic/upper lumbar segments
i. Relaxation of the Detrusor muscle
Allows for filling
ii. Constriction of Internal sphincter
b. Parasympathetic efferents originate in the sacral segments
i. Constriction of the Detrusor muscle
ii. Relaxation of the Internal sphincter Allows for emptying
c. Somatic efferents originate in the sacral segments as well
i. Relax the External sphincter Allows for emptying
FILLING AND EMPTYING THE BLADDER
1. Filling
a. Sympathetic innervation maintains the detrusor relaxed and the
sphincter constricted to allow filling
2. Emptying
a. Sensory afferents (soma in DRG) in the bladder wall relay back
to the ventral horn of S2-S4
b. They synapse on both parasympathetic efferents, one to the
detrusor and the other to the sphincter
c. Info is also relayed back to higher centers (pontine micturition
center) and the cortex to reach our consciousness
i. the cortex and the pons provide meaningful bladder control

Autonomic Control of Reproductive Organs


TWO MAJOR LEVELS OF CONTROL
1. Brain (cortex)
a. contributes to sexual arousal via erotic
stimuli including visual, olfactory and somatosensory
2. Spinal Cord
a. receives sensory input from the genitalia and
descending input from the brain.
b. It also controls reproductive function via ANS efferents
i. Sympathetic: prostate gland (ejaculation),
uterine & vaginal walls (contraction)
ii. Parasympathetics: vagina, clitoris and erectile
tissue of the penis

Circadian Rhythms and the Circadian Clock


1. Circadian Rhythm
a. Periods of Activity alternate with periods of Inactivity
i. Active periods are characterized by food intake, walking, working, etc
ii. Inactive periods are characterized by sleep
2. Physiological Parameters follow a Circadian Pattern
a. Some physiological parameters will vary as the active and
inactive periods vary as seen with body temp
b. Note that it does not follow the sleep/wake cycle exactly
but the temp begins to rise as the person approaches their
time of awakening triggered by the internal clock
3. Biological Clock drives Circadian Activity
a. In this first diagram, it is seen that the individual has a very
routine schedule with activities falling at the same time each day and follow
a regular 24-hour schedule. Note that this is of a normal person living in normal light/dark conditions
b. In the second diagram, it shows the individual lives three consecutive days in a normal light/dark
conditions however in the days to follow, he is placed in a deep bunker to achieve isolation from external
time cues such as light, social interactions, etc. (known as Zeitgeber)
c. The findings were as follows:
i. Daily activity patters (getting up, eating, bedtime, etc) persisted in the absence of external time
cues hence the concept of an internal clock
ii. The clock does NOT precisely represent the exact 24-hour cycle of a calendar day.
iii. Lastly, the clock is slow running on an average of 25-hour days illustrated by the drift to the right
4. Free Running Rhythm of the Biological Clock
a. It is important to note that in the absence of external time cues, the biological clock CANNOT maintain
precise timing
b. Biological clocks tend to run on a 25-hour plus sequence

Suprachiasmic Nucleus Home of the Clock


1. Light sensitive cells in the retina activate the clock
and it has been suggested that they differ from the
average photoreceptor
2. This signal is sent via the Retino-hypothalamic tract
and synapse in the suprachiasmic nucleus
3. The SCN is the actual clock generating rhytimic
output and resets every morning at the onset of
light.
a. Neuronal output from the SCN control
Melatonin from the Pineal gland which
acts as the dark hormone
i. Melatonin also influences MR
b. Humoral output from the SCN may also
include rhythmic secretion of ADH

Clinical Correlations
1. Horners Syndrome
a. Unilateral Myosis, Ptosis and Anhydrosis due to underactive ipsilateral sympathetic outflow
b. Caused by:
i. Lesion/transcetion of the hypothalamospinal pathway (in the cervical region)
ii. Preganglionic lesion (on the chain)
iii. Postganglionic lesion at the level of the internal carotid (tumor in cavernous sinus)
2. Automatic Bladder
a. Some patients with a transection of the spinal cord will regain sacral reflexes
b. In this case the reflex to empty the bladder recovers and when the bladder reaches threshold, the reflex
response will spontaneously empty the bladder
3. Atonic Bladder
a. Dorsal nerve root lesions interrupt afferent sensory fibers making the pt lose the sensation of fullness
b. As the bladder fills, a constant dribbling will occur
4. Jet Lag
a. Dark/light cycle no longer parallels the endogenous circadian clock system typically causing temporary
insomnia which is sometimes treated with mild doses of melatonin prior to falling asleep
5. Sleep/Wake Disorders in the Blind
a. Disorders of this nature are very common in their absence of visual input (zeitgeber)
b. Pacemakers are not entrained to social cues and suffer from sx similar to jet lag
6. Seasonal Affective Disorder (SAD)
a. Also known as winter depression changing mood and sleep patterns
b. Due to daylight changes and is treated with light therapy to suppress melatonin synthesis

51 Sexual Differentiation of the Brain


Is There a Difference?
1. Disease Frequency Based on Gender
a. Unequal distribution of many diseases based on gender is very common (ie: =Anorexia; =Tourettes)
b. This strongly indicates different levels of vulnerability for various disorders based on gender
2. Sexual & Non-sexual Behavior Differences
a. Sexual behavior, as with other behavior varies b/w gender, thus there must be a diff b/w vs brains
b. Variations in problem solving also exist b/w gender
i. Example: s better at verbal fluency tests where s are better at 3D problem solving
3. Hormonal Environment Differences
a. Remember that gonadotrophin release (LH, FSH) is under control of the hypothalamus via the AP
b. Since s are on a very cyclic patter of release and males are not at all, it can be concluded that there must
be a variation of the brain based on gender

Sexual Dimorphism of the Brain


1. Sexual Dimorphism in the Hypothalamus
a. To no surprise, as it controls the endocrine system, ANS, behavior and motivation, gender variation is here
b. Sexual Dimorphic areas of the Hypothalamus:
i. Sexually Dimorphic Nucleus (SDN aka INAH-1)
ii. Interstitial nuclei of the Anteriro hypothalamus (INAH-2,3,4)
iii. Suprachiasmic nucleus (SCN)
iv. Supraoptic nucleus (SON)
v. Paraventricular nucleus (PVN)
vi. Ventromedial nucleus (VMN)
c. Other areas expressing dimorphism include the corpus callosum and the anterior commissure
2. Nature of Sexual Dimorphism
a. Most sexual differences of morphological in nature such as size and the number of neurons in a nuclei
b. This is seen in the SDN where in the males it is larger and has more neurons than females
c. Neurotransmitter content, uptake, release and synthesis may also vary b/w gender

Hypothalamic Nuclei Sexual Orientation


1.
2.
3.
4.

INAH-3 is twice large in heterosexual males when compared to the INAH-3 of homosexual males
This difference in size is seen to have an identical size variation between hetero- and females
Additionally the SCN is larger in homosexual males versus heterosexual males
Thus, this concludes that sexual orientation is linked to structural dimorphisms

Mechanism of Sexual Differentiation


1. Basic Scheme
a. Seen in the figure, xx/xy gives rise to the particular gonad which releases
hormones that control differentiation of the brain and body
2. Genetics of Sex
a. As it is already known xx= and any other combination
including a y-chromosome will create a male
b. The SRY (sex determining region of the y-chr) codes for TDF
(testes determining factor) hence a y-chr will create a male
c. In the absence of SRY, TDF is also absent, thus ovaries will grow by default
d. In experiments where XX-genotypes have the SRY gene added,
it will develop testes, thus SRY = MALE

Role of Sex Hormones In Sexual Differentiation


1. Overview of the Hormones
a. Leydig cells of the testes produce testosterone and androgen makes a male
b. Ovaries produce estradiol and estrogen produce females
2. Androgen Insensitivity Syndrome
a. Mutated androgen receptor although leydig cells produce hormones, their receptor is absent
b. These pts undergo testicular feminization and have normal external female genitalia (breasts as well)
c. Their puberty is characterized by amenorrhea and sparse/absent pubic/axillary hair
3. Critical Period of Sexual Differentiation
a. Critical period is at 12-20 wks of gestation as a result of testosterone secretion to create a male
i. Note that there is no such phenomenon for female development
b. Testosterone released at this time leads to permanent structural differentiation of the body and brain
4. Molecular Mechanism of Testosterone Action
a. Although testosterone is responsible for male
differentiation, it does NOT act directly on the cells of the
developing nervous system (seen in figure)
b. Testosterone is converted to Estradiol (via aromatase)
which binds to its receptor on the nucleus and alters gene
transcription and translation
c. Thus, it is necessary to have both testosterone and
estradiol in the critical period to lead to this final
masculinization
5. Estradiol Receptors in Hypothalamus
a. Are in greatest concentration at the hypothalamus which
should not be surprising as it contains most of the sexually
dimorphic nuclei of the brain

Clinical Correlations
1. Fetal Exposure to Diethylsilbsetrol (DES)
a. Prenatal exposure during the critical period caused an enlarged SDN in females
b. The result was an increased occurrence of bisexual and homosexual girls DES Daughters

53 Consciousness
What is Consciousness?
DEFINITION
Awareness of ones self and ones place in the environment with the ability to respond appropriately to
environmental stimuli
CONSCIOUSNESS RESULTS FROM IMPORTANT FUNCTIONS OF THE BRAIN
Memory, learning, self from non-self and re-entry (where mechanisms located in thalamocortical system)
COMA
Non-sleep LOC lasting for extended period of time (unlike syncope)
LEVELS OF UNCONSCIOUSNESS
1. Lethargic pt can be fully aroused
2. Obtunded pt cannot be fully aroused
3. Stuporous sleep like status
4. Comatose no purposeful response
BRAIN STEM & CONSCIOUSNESS
1. Cells of the midbrain (reticular formation) receive ascending
info from the spinothalamic track and other
2. They are projected via 2 branches to higher cortical centers
a. To the thalamus activating and modulating
thalamic relay nuclei and intralaminar nuclei
b. To the lateral hypothalamic area which is joined
by ascending output from hypothalamic and basal forebrain cells
i. Lesions of either of these two branches, the thalamus, midbrain or cerebral hemispheres can impair
consciousness
c. The brainstem plays an important role for
i. Condition of consciousness, attentive vigilance and wake-sleep rhythm
EEG AND CONSCIOUSNESS
Thalamic relay neurons have two-physiological states
1. Transmission Mode wakefulness and awareness
a. Resting potential is near firing threshold
b. Cholinergic input from pons and basal forebrain is present
c. EEG shows desynchronized pattern low voltage and high frequency
2. Burst Mode deep sleep and coma
a. neurons hyperpolarized by inhibitory GABA from reticular formation input
b. EEG shows synchronized wave pattern high voltage and low frequency

Coma
1. Definition
a. A deep state of unconsciousness; unable to move or respond to environmental stimuli
b. Commonly caused by head injury or complications to another disease (ie: brain tumor or ICP)
c. Raw definition not opening eyes, not obeying commands and not uttering understandable words
2. Differentiation from Vegetative State Cortex/Higher Centers
a. A complete loss of higher brain function (cortex) however maintain breathing and circulatory functions
b. Spontaneous movements can occur such as eye opening to painful external stimuli but are unable to
respond to commands, to speak or respond meaningfully to environmental stimuli
c. Pt may cry, grimace or laugh but this is not the result of them interpreting and responding meaningfully.

3. Differentiation from Brain Death all brain including brainstem


a. Denotes the irreversible loss of all brain functions
b. determined by
i. No electrical brain activity (isoelectric EEG)
ii. Absence of brain no movement, response to stimuli, breathing or brainstem reflexes
c. Causes:
Brainstem Reflex losses
i. Anoxia (suffocation; can be drug, respiratory disease, etc)

No
response to speech/pain/etc
ii. Ischemia (vascular occlusion)

No
respirations
iii. Intracranial Hemorrhage
Pupils fixed/dialated
iv. Trauma
No VOR (cows/dolls eye)
v. Brain Tumors
No corneal reflex
vi. ICP and uncal herniation
4. Differentiation from Locked-in-Syndrome Pons
a. Blockage of basilar artery causing massive infarction to pons
b. Causes total paralysis of voluntary muscle except for vertical eye movement muscles and opening lid
c. Pts are fully aware but cant move and communicate via vertical eye movements and opening the eyelid
5. What Causes Coma
a. Supratentorial Mass Lesions
i. Epi/subdural/intracranial hemorrhage
ii. Cerebral infarc
iii. Brain tumor or abscess
b. Subtentorial Lesion
i. Brain stem infarc, tumor or hemorrhage
ii. Cerebellar hemorrhage or abscess
c. Metabolic & Diffuse Cerebral Disorders
i. Anoxia, ischemia, concussions, seizures, infection, subarachnoid blood
ii. Hypo/hyper glycemia, -natriemia
iii. Hypothyroidism, hypocortisolism, hypercarbia
iv. Drugs, liver failure, renal failure, sepsis,

Glasgow Coma Scale

Examination of a Comatose Patient


1. RESPIRATORY PATTERN
Respiratory patterns will vary based on the lesion site

2. LEVEL OF AROUSAL & MOTOR RESPONSE


a. Response to verbal instruction
b. Response to local painful stimulation
i. Upper midbrain (bilat) decorticate posturing
ii. Lower midbrain/Upper Pons decerebrate posturing
3. PUPILLARY LIGHT RESPONSE
a. Small reactive pupils
i. Diffuse forebrain impairment (metabolic encephalopathy)
b. Midposition Pupils and Loss of response
i. Damage of CN-III at midbrain
c. Unilateral Pupillary Dilation
i. Unilateral compression of CN-III at exit of brainstem (aneurism, tumor, ICP, uncal herniation)
d. Large, Unreactive
i. Pressure in pretectal area (pineal tumor)
4. OCCULOMOTOR RESPONSE
a. Metabolic encephalopathy
i. Dolls test & COWS test is Normal
b. Right Pontine Lesion
i. Dolls Test
1. Head to right normal (eyes to left)
2. Head to left no movement at all
ii. COWS
1. Cold in right no movement
2. Cold in left normal (eyes to left)
c. Midbrain Lesion
i. Dolls Test
1. Head to left right eye normal but left is unresponsive
This lesion involves both
2. Head to right left eye normal but right is unresponsive occulomotor nuclei causing
ii. COWS
loss in Medial Rectus, thus
1. Cold in right right eye normal but left is unresponsive
loss of aDduction
2. Cold in left left eye normal but right eye is unresponsive

52 Emotions
Theories of Emotions
1. James-Lange Theory
a. Emotional experience is induced by our somatic, autonomic and endocrine emotional expressions
b. we feel happy because we smile
c. New research shows that ppl who lack emotional experiences can still express emotions thus this is crap!
2. Cannon-Bard Theory
a. Emotional experiences (what we remember) triggers the emotional response of our body
b. our happiness makes us smile

Limbic System
1. Brocas Limbic Lobe
a. Consists of the Cingulate gyrus, Subcallosal gyrus, Isthmus,
Parahippocampal gyrus and Uncus
b. The term limbic system has developed to be synonymous
with the emotional system
2. The Papez Circuit
a. James Papez was first to note marked emotional outbursts
from patients with damage to their hippocampus and/or cingulate
gyrus
b. He created a mechanism of emotion based on his hippocampo-thalamo-cingulate-hippocampal circuit
now known as the Papez circuit

3. The Concept of the Limbic System


a. Paul MacLean added to this theory and incorporated the
cortex and amygdala is also involved and it together all
combine to form The Limbic System
b. Despite various interpretations of the components, it is
widely accepted that the cortex shares input to the
hypothalamus and therefore directly influences
somatic (behavioral), autonomic and endocrine responses

Brain Damage and Emotional Change


1. Phineas Gage
a. Iron rod impailed through his head which destroyed his frontal lobe
b. He went from being a respectable and responsible foreman to a nutjob
2. Frontal Lobotomy
a. Surgical destruction of the frontal lobe to treat schizophrenic patients who displayed uncontrolled
behavior
b. However, their change in personality was generally unacceptable (Gage) thus no longer practiced
3. Kluver-Bucy Syndrome
a. Removal/damage to temporal lobe including the amygdala results in a dramatic decrease in aggression
as well as an increase sexual drive
b. This was surgically done on monkeys
c. Pts who develop a similar lesion/trauma display the same Sx/Sx

Amygdala Fear, Anxiety, Anger & Aggression


1. Fear Conditioning Experiment
a. In an experiment where rats were trained to fear a stimulus by associating it with electric shock lost their
fear response following a bilateral removal of the amygdala
2. Human fMRI Studies Confirm Amygdala in the Emotional System of Fear
a. Humans were conditioned to fear a picture by associating it with a shock
b. They were then shown the picture while taking an fMRI which showed significant increases in the activity
of the Amygdala
c. In another experiment took fMRIs while subjects looked at pictures of ppl with different expressions
i. the highest level of amygdala activity was when looking at fearful faces
ii. the lowest levels of amygdala activity was when looking at happy faces
3. Neural Circuit for Learned Fear
a. An emotionally competent stimulus produces the input
signal to the basolateral nucleus of the amygdala
b. The amygdala will then send output to illicit behavioral,
autonomic and endocrine responses
c. SHORTCUT
i. Amygdala can directly receive nerve signals
(via thalamus unless its auditory which is direct)
ii. This cortical bypass saves time which allows faster
signaling of defense behaviors, autonomic
responses (HR/BP), endocrine responses
(stress hormone responses) and emotional responses (fear)

Clinical Correlations
1. Anxiety Disorders
a. Include panic disorders, OCD, PTSD, phobia and generalized
anxiety disorder
b. Attributable to an imbalance between the hippocamps (stress)
and the hippocampus (stress)
c. May also be attributable to an benzodiazepine receptors in
the frontal lobe
d. These findings define the key role of the amygdala as well as the i
nvolvement of other structures including the hippocampus,
hypothalamus and frontal lobe
2. Tumors
a. Temporal lobe tumors compromising the amygdala or its connections may lead to extreme aggression and
hostility
b. Tumors of the hypothalamus are often accompanied by spontaneous fits of anger or deep sadness
3. Psychomotor Epilepsy
a. Temporal lobe seizures with olfactory/gustatory hallucinations are followed by mood change (anxiety or
loneliness).

54 Language and Aphasias


Language

Is a system of communication that allows for the


exchange of infinite combinations of ideas. It can be by
means of sound or body language. It is species wide and
will spontaneously emerge in all normal children.

1. Language is Spontaneous
a. It does not need to be taught and emerges spontaneously
b. By this, it is distinguishable from writing/reading which does need to be explicitly taught
2. Thinking
a. It is NOT necessary for thinkning; while people do think in words, it is not necessary as ppl think in
images, abstract concepts and other non-linguistic forms
3. Lexeme
a. Different forms of a word that originate from one single word (ie: love loving, loved, etc)
4. Morpheme
a. Any word or word part that conveys meaning and which cannot be divided into smaller elements that also
can convey meaning
i. book is a morpheme; it cant be broken down further but books can be broken into book and s
5. Two Components of Language Design
a. WORD a combination between a sound and meaning
b. GRAMMER rules how lexemes are meaningfully combined
6. Morphology
a. Describes word structures and formation; combining word and affixes to larger words (adore able)
7. Syntax
a. Meaning sequence or order; describes how sentences are constructed and relations among words
8. Phonetics
a. Classification of sounds made in spoken language
b. Prosody describe the intonation, stress, rate, and rhythm, that provide speech with its melodic character
9. Production and Comprehension of Language
a. Production of a sentence
i. Choose words, grammatical rules to encode ideas and intentions and generate articulatory
commands in the motor system
b. Comprehension of a sentence
i. Coordinate sensory info from auditory (or visual) system with grammar and words and send the
info about interpretation to the memory and reasoning systems
ii. This takes a complex pattern of information flow to many parts of the brain

Development of Language
IN CHILDREN
1. Language development is spontaneous and the capacity to learn it is innate
2. The ability to learn language is due to the adaption of the human brain over evolution
3. Critical Time Markers
a. 5-7 months sounds
b. 7-8 months well formed syllables (ie: ma, da)
c. 1-2 years first word mama with an understanding of the connection between the word and their Mom
d. 2 years speaking in rich phrase (children language)
e. 3 years often correct use of grammar with a good understanding of the basic rules
IN HUMANS
1. Language most likely developed based on two parameters
a. Humans exploited the environment
b. Humans were involved in cooperation
2. Language has allowed for our ancestors to benefit from sharing acquired information

Roles of the Hemispheres


LEFT HEMISPHERE
96% of ppl use the left hemisphere for language processing (grammar, words, phonetics)
Sign Language also depends on the left hemisphere
RIGHT HEMISPHERE
Damage to the right hemisphere results in an inability to express emotion
Therefore, the speech is flat, lifeless and mechanical
Pts who lose the left hemisphere but have an intact right hemisphere can still sing songs and even learn new ones

Wernike-Geschwind Model of Language

Brocas Area organizes and coordinates the muscles during speech


Wernikes Area provides the transformation of auditory output into
meaningful information
Angular Gyrus combines sensory input to translate the visual patterns
of letters/words into meaningful information

LANGUAGE PROCESSING
1. Incoming Spoken Word
a. Auditory signals auditory pathway primary auditory cortex
Wernikes Area elicitation of the words meaning in the area near Wernikes Area
2. Outgoing Spoken Word
a. Nonverbal meaning conversion to acoustic image in Wernikes Area arcuate fasciculus
Brocas Area motor cortex
3. Reading
a. Input from left visual cortex Wernikes Area elicitation of the words meaning near Wernikes Area
4. Writing
a. Non-verbal meanings conversion to a motor/visual image in Wernikes Area arcuate fasciculus
Brocas Area premotor area (above broca)

Aphasias

Aphasias may include speech (aphasia), writing (agraphia) or


reading (alexia); damage to respective control center of the brain
Aphasias are divided into two major categories:
o Fluent (Wernikes)
o Nonfluent (Brocas)

FLUENT APHASIA - Characterized by fluent speech with difficulties in comprehension and repetition
1. Wernikes Aphasia wernikes area (22)
a. Have no problem pronouncing/articulating words but have poor comprehension and repetition
b. This has been described as WORD SALAD
2. Transcortical Sensory Aphasia sensory assoc. cortex
a. Inability to speak spontaneously; comprehension deficits are present but REPETITION IS NORMAL
b. This is caused by a lesion of the sensory associated cortex; pts also have difficulty naming things
3. In Gerstmann Syndrome angular gyrus
a. Translation of visual patterns of letters & words into meaningful information is impaired
4. Conduction Aphasia arcuate fasciculus
a. Connection b/w Wernike-Broca is lost (arcuate fasicuclus) causing understanding without ability to repeat
b. The pt can say something wrong and realize it but when attempting to correct it, will repeat the mistake

NON-FLUENT APHASIA non-fluent speech; difficulty in articulation though comprehension is preserved


1. Brocas Aphasia brocas area (44/45)
a. Difficulty in speaking and repeating but comprehension is intact;
b. They speak in slow and small sentences; b/c comprehension is intact, they are quickly frustrated/impatient
2. Transcortical Motor Aphasia left dorsolateral frontal area
a. Similar to Brocas but less severe; in this case REPETITION IS PRESERVED
b. Better in naming tests versus spontaneous speech
3. Global Aphasia
a. Unable to produce language nor able to comprehend language
b. This is a combination of Brocas, Wernikes and Conduction Aphasia
EXAMINATION OF APHASIC PATIENT classify pt, you must determine if the pt is able to do the following
Speak Fluently with normal articulation and rhythm; without syntactical, paraphasic or grammatical errors
Accurately Repeat able to repeat spoken words or phrases
Understand spoken language, proven with accurate responses and ability to follow spoken commands
Name common objects this should be done consistently
Read aloud and accurately
Name words spelled aloud
Write legibly and grammatically

Alexia
1.
2.
3.
4.

Disconnection b/w visual and language system


Damage to the Splenius Posterior Corpus Callosum
Disruption in transfer of visual information to the area of the left hemisphere
Patient can read words in the RIGHT visual field ONLY

Dyslexia

Damage to the left hemisphere of the brain which leaves child unable
to perform proper word-identification when reading
These ppl have a problem with print-to-sound translation meaning they will read
the word cat as car

LEFT HEMISPHERE & DYSLEXIA


PET studies suggest abnormal cerebral lateralization as the potential cause of this disorder
Tendancy to read words backward; most often left-handed people
Inability to process rapid sensory input (ie: rapid visual conduction is often impaired)
Cells of the magnocellular pathway and LGN are smaller than normal

55 Mental Illness
STATISTICS

Impairment of Thought & Volition


SCHIZOPHRENIA

Top ten most frequent cause of disability; 30% of all hospitalization


Affects 1% of the population and 30% of all homeless people
10% of cases will commit suicide

1. Symptoms
a. Impairment of cognition, emotion, thought, affect, perception, language and sense of self
b. Symptoms are acoustic, sometimes visual, olfactory, tactile or gustatory hallucination
c. TYPES OF SYMPTOMS
i. Positive addition of pathological symptoms
ii. Negative loss of normal function
iii. Disorganized disorder of thoughts, memory dysfunction and confusion
d. DISORGANIZED SPEECH
i. Frequent derailment or incoherence; word salad
e. GROSSLY DISORGANIZED or CAATONIC BEHAVIOR
i. Characterized by stupor/inactivity, mania and either rigidity or extreme flexibility
f. COGNITIVE SYMPTOMS
i. Disorganized/slow thinking, poor understanding, concentrating, expressing thoughts and memory
g. SOCIAL/OCCUPATIONAL DYSFUNCTION
i. Work, interpersonal relations and self care
2. Psychotic Episodes Include:
a. Social isolation/withdrawal
b. Odd behavior and impairment of normal responsibilities
c. Neglect of personal hygiene and a flat affet
3. Diagnosis
a. Exclusion of other diseases able to produce psychotic symptoms including
i. Encephalitis/meningitis
ii. Intoxication (amphetamins, PCP or diphenhydramine)
iii. Brain tumor
iv. Manic/Depressive illness
4. Prognosis
a. Generally poor; pts with negative symptoms have poorer prognosis
5. Pathogenesis
a. Genetic Aspect polygenetic (similar to HTN or diabetes)
b. Psychodynamic Aspect
6. Anatomical Abnormalities seen in pts with negative symptoms
a. Decreased blood flow to globus pallidus
(connection of basal ganglia to frontal lobe)
b. No increase in blood flow to frontal lobe
during memory tests
c. Thin cortex in medial temporal lobe and smaller
anterior hippocampus (defect in memory)
7. Treatment
a. Typical Antipsychotic Drugs High affinity to D2 receptors (see lecture 46)
i. Side-effects: blockage of D1 and D2 receptors
ii. Short-term effects: hand tremors and muscle rigidity
iii. Long-term effects: Tardive Dyskinesia; involuntary movements esp mouth and tongue
b. Atypical Antipsychotic Drugs High affinity to D3 & D4 receptors
i. Almost no side effects in the extrapyramidal system
c. All antipsychotic drugs have significant side effects and unfortunately do NOT treat the disease but only
help treat the symptoms

Impairment of Mood Affective Disorders


DEPRESSION & MANIA

STATISTICS

10% of the US suffer from a form of clinical depression;


average onset of 28y/o; women 2-3X more likely to be effected
Depressed pts typically dont seek care b/c they dont recognize
it as clinical and treatable

DEPRESSION
1. Symptoms
a. Affect mood, body and thoughts and can continue for weeks, months or years
b. Persistent sad, anxious or empty; hopeless, helpless, worthless, guilty
c. Loss of interest in fun/pleasurable hobbies (incl. sex)
d. Decreased energy, fatigue/slowing down
e. Difficulty concentrating, remembering, decision making
f. Appetite changes; weight loss/gain
g. Suicidal thoughts/attempts
h. Persistent physical symptoms that do not respond to treatment; headaches, digestive disorders and pain
2. Causes
a. Genetic vulnerability based on family history
b. Additional factors include, stressed home/work/school
c. Stroke, MI, Cancer, Parkinsons and hormonal disorders can also cause depression
d. Death, relationship issues, financial hardship
e. Overall, it is the combination of biological, psychological and environmental factors
3. Pathogenesis
a. Genetic Factor polygenetic
b. Morbidity rate: higher in 1st degree relatives of pts with depressive illnesses
4. Types of Depression
a. Major Depression
i. Effect work, focus, sleep eating and enjoying pleasurable activities
b. Dysthymia
i. Less severe; no disabling long-term symptoms; generally not functioning well or feeling good
5. Treatment
a. Selective Serotonin Re-uptake Inhibitors (SSRI)
b. Tricyclic anti-depressives
c. Monoamine Oxidase Inhibitors (MAOI)
d. Electroconvulsive Therapy (ECT) severe/life threatening depression; Rx is ineffective; causes seizures
6. Prophylactic Treatment
a. Mood stabilizers include lithium, cabamacepine, lamotrigine, valoproate and others
BIPOLAR DISORDER aka Manic-Depressive Illness
Cyclic mood changes, swinging from severe highs (manias) and lows (depression)
Depressed Phase
o Patient has some or all of the symptoms of major depression
Manic Phase
o Overactive, over-talkative, excessive energy
o Pts judgment, social behavior are distorted and pt causes problems and embarrassment
o Pt feels elated, ideas of grandiosity and if not treated can develop into a psychotic state
MANIA
Exhibit sx such as excessive elation, irritability, decreased need for sleep, grandiosity, social inappropriateness
AFFECTIVE DOSORDERS: Findings In Functional Imaging
Area in pre-frontal cortex, below the genu in the corpus callosum
o Reduced activity during depressive phase and increased activity during manic phase
The sub-genual region of the prefrontal cortex is important for mood disorders and connects to many structures
involved in emotional behavior including:
o amygdala, lateral hypothalamus, nucleus accumbens and noradren/seroto/dopaminergic brain systems

56 Addiction
Dependence
DEPENDENCE SYNDROME
1. Based on the past year, three or more of these must be present
2. Considered a bio-psycho-social disease

Cause of Dependence
Risk factors are plentiful including neurologic developmental effects, social interactions, self esteem, family and many more

BIOLOGICAL/GENETIC FACTORS

Studies with twins from alcoholic families that are raised separately show definitive evidence for a greater likelihood for
developing alcoholism
Serotonin seems to be lacking (often genetic) with addicted people

1. Ventral Tegmental Reward System


a. Addictive substances as well as electrical stimulation activate this reward system
b. Dopamine induces euphoric/orgasmic feelings
i. Addicted individuals tend to have low initial dopamine
ii. Use of substances dopamine release from the nucleus accumbens via dopaminergic neuron stim.
c. Sexual behavior and food pleasures can be artificially induced via cocaine injection to the nucleus
accumbens

2. Psychology and Upbringing


a. Majority of addicts have hx of abusive childhood
b. The mood change upon engaging in the addiction (drugs, gambling, sex) is what they crave
c. Their addiction is used to replace the uncomfortability of normal life
3. Learning Model Of Addiction
a. SHY MAN AT THE BAR:
i. Feels better and relaxed to be social after a few drinks positive, internal and short term
ii. Argument may develop from loose lips negative, external and short term
iii. Hangover the following day negative, internal and long term
iv. Negative consequences would presumably stop him from drinking but the short term effects are
remembered better than the long term, thus he will drink again

External and internal consequences


Long and Short Term consequences
Positive and negative consequences

SOCIO-CULTURAL FACTORS
1. Performance
a. Deadlines must be met, quantity of output predisposes for stimulants to work and sedatives to sleep
2. Consumption
a. Hunger satisfaction leads to excessive eating of different things and addiction of consumption (junk food)
3. Urbanization
a. Adaptation and dependence on technical environment
4. Mass Society
a. De-individualization leads to isolation and loneliness causing additive behaviors (depression=drugs)
5. There are many other to name but I think the point has been made

Effects of Drugs

Alcohol Detoxification
1. Withdrawl
a. As the body is accustomed to alcohol regularly, in the absence, the body exhibits withdrawal symptoms
making it exceedingly difficult to stop
2. Symptoms
a. Include: trembling, N/V, sweating, craving alcohol and in extreme cases, seizures
b. May also include tachycardia, hypertension and hallucinations
c. Last ~7 days
d. Delirium tremors (5% of pts) begin ~2-3 days after stopping and in extreme cases can be fatal
3. Detoxification
a. Most common Rx is benzodiazepines (valium)
b. Vitamin B1Thiamine
i. Thiamine is a co-enzyme needed to metabolize carbohydrates and without it can alter PPP and
cerebral energy metabolism
ii. Acute deficiency causes oculogyric crisis, ataxia and delirium similar to a diabetic coma
iii. Thus, giving glucose (D50) without thiamine can be very bad or fatal

Opiate Detoxification
2. Cold Opiate Detoxification
a. Symptoms present like GI-influenza
b. Non life threatening
c. Symptomatic Rx to combat
i. N/V/D, HTN & tachycardia
d. 2nd and 3rd days are the worst
e. No longer than 5-7 days
f. Hyposomnia can continue for weeks

1. Warm Opiate Detoxification


a. Substitute opiate with Methadone
b. Reduce methadone dose over 3-weeks
c. Symptomatic Rx to combat
i. N/V/D, HTN & tachycardia
d. Problem: long stay on cold ward
e. High chance of breaking off the treatment

57 EEG & Epilepsy


Electroencephalography

Surface recording of electrical activity of nerve cells


Electrodes are placed in a 10%-20% pattern (percentage of head circumference
Used to assess brain damage, epilepsy and brain death
Electrodes are wired into an amplifier (1K-100K) that records wave onto strip with an amplitude b/w 20-60V

TYPES OF BRAIN WAVES


1. Beta
a. Low amplitude with varying high frequencies (13-30Hz)
are present in awake, active and thinking pts with open
eyes in all electrodes
2. Alpha
a. Frequency 8-12Hz
b. Present over posterior regions (occipital) in awake
person with eyes closed in all electrodes
3. Theta
a. Frequency 4-8Hz
b. Found in drowsy adult and child pts; often detected in hypnagogic states (trance, light sleep/falling asleep)
4. Delta
a. Frequency no more than 4Hz
b. Seen in some encephalopathies and in deep sleeping adults
5. Waves Varying With Age
a. Infant delta
b. Young child theta and delta
c. Middle-age adults alpha and beta
d. Older adults low amplitudes with scattered theta and delta
EEG ABNORMALITIES
1. When comparing the hemispheres, the EEG should be symmetrical, where asymmetry indicates a lesion which
may be a bleed, infarc, tumor and others.
2. Comparing the difference, the speed can be measured where the slower the wave, the more severe the abnormality
INDICATIONS FOR EEG
1. Seizure Disorders locate focus and determine its type
2. TIAs evaluate residual ischemic deficits or complete infarction and define as TIA vs. syncope or hysteria
3. Intracranial Disease Process neoplasm or abscess
4. Diffuse Disturbance of Cerebral Function metabolic disorders, encephalitis and degenerative processes
5. Coma epileptic status, drug OD, hepatic coma
6. Brain Death isoelectric EEG

Epilepsy

Chronic condition of repetitive seizures; impaired brain function


The most common severe neurologic disease existing in all ages, races and social classes
Every person has a threshold for seizures that can be surpassed and cause a seizure in some situations however these pts
have a much lower threshold

TYPES OF SEIZURES
1. Primary (idiopathic)
a. Result from constitutional or genetic disposition, where threshold for seizure is below normal
b. No aura or focal symptoms with both hemispheres involved which can be with or without convulsions
c. Petit mal absence seizure 10second absence of motor activity without postictal period to follow
2. Secondary (focal and symptomatic)
a. Result from known pathogenic lesion or disease process
b. May be intracranial or extracranial
c. May be a focal lesion or diffuse/generalized process or disturbance of brain function
3. Grand-Mal Seizure (tonic-clonic)
a. Characterized by LOC, falling to the ground and rhythmic convulsions
b. May be triggered by light, sound or touch
c. Tonic Phase
i. Muscle rigidity for ~20sec followed by the clonic phase
ii. Abrupt onset with grunt (tonic contraction of the diaphragm)
iii. Cyanosis may ensue due to poor respirations while actively seizing
d. Clonic Phase
i. Jerking of the extremities
e. Postictal Phase
i. Sleepy and disoriented, often with headache and muscle soreness
INTRACRANIAL VS. EXTRACRANIAL
1. Intracranial Causes
a. Primary Causes
i. Unknown (genetic or biochemical predisposition)
b. Secondary Causes
i. Tumor
ii. Vascular or Arteriovenous
iii. Trauma
iv. Infection
v. Ccongenital/hereditary disease
2. Extracranial Causes
a. Metabolic electrolyte, biochemical or inborn errors of metabolism
b. Anoxia
c. Hypoglycemia
d. Drugs
e. Drug or Alcohol Withdrawal
POSITIVE VS. NEGATIVE SYMPTOMS
1. Positive Symptoms
a. Sensory seeing light flashes, feeling fear, hearing noises or people talking
b. Motor jerking of arms, leg or face
2. Negative Symptoms
a. Sensory slowing of normal brain function and depression of consciousness
b. Motor Todd paralysis (postictal condition)

DIAGNOSIS
1. Diagnostic processes usually started after onset
of epileptic seizures
2. Tests include
a. Blood work, EEG, CAT/MRI/PET scans
b. Note that these tests can neither rule-out or
definitively diagnose epilepsy
TREATMENT
1. Anti-epileptic drugs are successful in approx
70% of patients in preventing or at least
reducing the frequency of seizures but they
do NOT cure the disease
2. Surgery
a. Only in pts where the focus is in one distinct area of the brain and Rx is unsuccessful
3. Epileptic people help control their seizures by avoiding things that provoke them (sleep deprivation, alcohol, etc)
EPILEPTIC STATUS
1. Seizures are often self-limiting but in cases when one is quickly followed by another without a recovery period the
patient is said to be in ES
2. Possible causes include
a. Metabolic (hypoxia, hypotension, -glycemia, and academia) which cause brain damage
b. Systemic Complications include cardiac arrhythmias, PE, hyperthermia and rhabdomyolysis

58 Sleep
Introduction Sleep Phases
During a normal sleep period there are 4-6 cycles of NREM-REM each lasting ~90min
1. REM
a. Rapid Eye Movement sleep which increases in duration as the cycles progress throughout the night
b. Cortical activity does exist in REM sleep and resembles that of an awake state
2. NREM
a. Has 4 stages noted for an increasing depth of sleep with an increased stimulus to elicit arousal
b. Eventually becomes REM sleep
Establishes the phase of a
rhythm via an environmental
Regulated Sleep Sleep-Wake Cycle
signal, such as a light
INTERNAL CLOCK
1. The suprachiasmic nucleus (SCN) in the anterior hypothalamus serves as an internal clock (endogenous rhythm)
2. SCN receives input from retinal ganglion cells which entrains internal time based on day-light cycles
3. This endogenous rhythm of the SCN strongly influences pineal gland to release melatonin (the dark hormone)
INTRINSIC RHYTHM OF SLEEP-WAKE CYCLE
1. Entrained by SCN so that healthy ppl sleep around midnight and wake around 7am
2. Without environmental stimuli (light), the day cycle slides to about 25 hours (see lecture 50-circadian clock)
3. In addition to the normal physiological tendency to sleep at night, many ppl tend to crave late-afternoon naps
4. The Ascending Reticular Arousal System is found in brainstem, hypothalamus and basal forebrain
a. Regulates the excitability of the cortex and thalamus
b. this activity declines with onset of sleep with small periodic increases with onset of REM sleep
SLEEP PROMOTING AGENTS

Connections between immune and sleep systems are noted to have a strong drive to sleep seen with infectious diseases
Some substances produced by the immune system are associated with infection-induced sleep

1. Interleukin-1
a. IL-1 concentration increases in the CSF during NREM sleep
b. Moreover, intraventricular injection of IL-1 causes NREM sleep
2. Delta Sleep-Induced Peptide
a. This peptide has been isolated from sleeping mammals and causes NREM with intraventricular sleep
3. Melatonin
a. Hits a max extracellularly at 2am and dwindles very low by 7am
b. Proven useful in jet-lag treatment, insomnia
c. Interestingly, melatonin stimulates wakefulness in nocturnal animals
4. Muramyl Peptides from Bacterial cell walls
a. Also produces NREM with intraventricular injection
5. Adenosine
a. A sleep promoting agent stimulating adenosine A1-receptors which are found at high concentrations in the
basal forebrain which can induce NREM sleep
b. Caffeine is said to work as an A1-inhibitor which gives it the capacity to inhibit sleep

Sleep as a NON-Uniform Physiological Process


EEG RECORDINGS AND SYNAPTIC ACTVITY OF CORTICAL NEURONS
1. Desynchronized Cortical Activity
a. Causes LOW AMPLITUDE EEG waves
b. The neurons near the EEG electrode are NOT subject to simultaneous excitation or inhibition
c. This causes a canceling-out effect in given regions, thus low amplitude waves due to desynchronization

2. Synchronized Cortical Activity


a. Causes HIGH AMPLITUDE (voltage) EEG waves
b. Simultaneous excitation or inhibition reads as large amplitude waves on the EEG at the given region
c. The Awake Brain shows desynchronized, low amplitude (voltage) and high frequency
i. This represents rapid signaling within the cortex in the awake sate
d. The Sleeping Brain is in sync with high amplitude, low frequency waves except when in REM sleep
i. Cortical neurons fire in unison in the absence of incoming signals from the thalamus
FIVE STAGES OF SLEEP

HYPNOGRAM REPRESNING SLEEP STAGES

MAJOR DIFFERENCES BETWEEN NREM & REM SLEEP

SLEEP PATTERN CHANGES WITH AGE

The most notable point here is that the total


amount of sleep time spent in REM sleep
declines with age
Infants are over 60% where adults drop
below 20%

SLEEP FUNCTION THEORIES


1. Rest Theory NREM sleep provides necessary fall in neuronal and metabolic activity
2. Behavioral Advantage sleep protects us from nocturnal predators as we have relatively poor night vision
3. Maintenance NREM sleep rests some neuronal circuits while REM sleep ensures the activation of others
4. Memory Processing consolidation of short term to long term memory
5. Maturation REM sleep may be involved in maturation of the nervous system

Sleep Abnormalities
DOCUMENTED ABNORMAL PEOPLE
1. who sleeps for 1.5hours/night
2. war veteran with shrapnel in his pons exhibits virtually no REM sleep
3. observed in clinic experienced over 3hours of REM sleep
4. stayed awake for 11 straight days without any Rx and had no permanent harmful effects
HARMFUL EFFECTS OF SLEEP DEPRIVATION
1. Animals deprived of sleep die within several days
2. Legal execution of humans in the 1850s which could last for almost 19 days
3. Evidence of sleep deprivation is still used as a form of torture
4. Humans deprived of NREM sleep are irritable with marked performance in mental and manual skills
SLEEP DEPRIVATION - CONSEQUENCES
1. fMRI Tests Sleep vs. Non-Sleep
a. done on normal subjects during a mental tasks were compared to a sleep deprived person and it showed the
activity in the healthy person was nearly absent in the sleep deprived person
b. Sleep deprived people gave fewer answers and more incorrect
2. REM Sleep Deprivation
a. show an increased rebound need for more REM but not as much as for NREM
3. Cognitive deficits
a. NREM deprivation is much more significant that REM deprivation
4. Clinically Depressed People
a. have unusually large amounts of REM sleep where controlled deprivation can help alleviate their
symptoms either with behavior changes or Rx
5. Night Shift Workers
a. Even people who are accustomed to their late shift feel tired between 2-5am and is related to accidents
b. Night shift drivers in the UK are 5X more likely to have an accident
6. Blind Subjects
a. As seen previously, blind ppl have sleep issues which may be treated with prescribing melatonin

Sleep Abnormalities
1. ARAS (ascending reticular arousal system) Control of Wakefullness
a. Consists of three prominent neuron systems which use ACh, NE and Serotonin as the NT
b. Cell bodies located in the brain stem and basal forebrain
c. Keep cortex at proper level of excitability
d. Lesions of the brainstem can induce sleep/coma
e. General anasthetics lower consciousness by reducing the activity of the brainstem as part of the ARAS
2. Rhythmic Firing create Slow Waves
a. NREM (slow wave, low freq and synchronized) cortical activity w/o sensory input
b. Stage-2 NREM sleep spindles and K-complexes caused by these synchronized synapses in the cortex
i. Spindles: from rhythmic firing of thalamocortical neurons due to sensory and ARAS input
c. Stage-4 NREM delta waves caused by inherent synchronous firing of cortical cells
i. Due to absence of sensory input as well as direct ARAS input

3. Brainstem Evokes REM


a. Onset of REM Sleep
i. due to firing of the pontine cholinergic cells (part of ARAS) which firing rate in locus ceruleus
and raphe nucleus as well as an LGN excitability and Occipital Cortex V1 (dreams)
b. These pontine cells also have CN-III connections, thus causing eye-movements
c. REM characterized by high freq caused by desynchronized cortical activity (similar to awake state)
d. Also activates lateral (medullary) reticulospinal tract in the medulla causing hyperpolarization of some
cranial nerves and limb motor neurons which result in this muscle paralysis seen during REM sleep
e. Generally, when one set of neurons in the ARAS are stimulated the other two have depressed firing

Sleep Disorders
1. Insomnia
a. Can be transient, lasting ~3 weeks or chronic insomnia
b. Chronic can be caused by age, pain, psychiatric disorders, drugs or alcohol
2. Day-Time Sleepyness
a. Narcolepsy
i. Frequent day-time sleeping attacks, where pt enters REM sleep w/in 10min
ii. This is assoc. w/cataplexy (sleep paralysis) and hypnagogic hallucinations (pre-sleep dreams)
iii. This condition is treated with anphetamines (close watch on administration)
b. Sleep Apnea
i. Deprives people of night sleeping leaving them sleepy in the daytime
ii. Obstructive mechanical obstruction (upper airway)
iii. Central dysfunction of respiratory centers in the pons
iv. Mixed combined obstructive and central
v. Hypnograms show no stage 3 or 4 of NREM, thus NO REM causing severe sleep deprivation
vi. Latency to Sleep shortened from the normal 15min to ~3min (narcolepsy is ~2min)
c. Fatal Familial Insomnia
i. Untreatable; atrophy of thalamic nuclei; also includes memory and attention loss
ii. Overactivation of the ANS (sweating, hyperthermia, tachycardia, etc)
iii. This is a Prion Disease (prions are infectious lethal proteins)
3. Parasomnias
a. Sleepwalking
i. Occur w/in 1-2hrs of falling asleep at Stage-4 NREM
b. Nightmares and Sleep Tremors
i. Awakening from REM sleep with vivid memory of frightening dream
ii. Sleep Tremors are partial arousals from NREM, assoc w/sleep walking
c. Sleep Paralysis
i. Partial or complete flaccid paralysis and areflexia at the start or end of sleep
ii. Awareness is preserved and usually lasts a few seconds (often seen in narcoleptic pts)
4. Sleep Disorders and Abnormal Movement
a. Restless Leg Syndrome urge to move legs when sitting/lying down
i. Assoc w/ periodic limb movements every ~30sec during NREM, thus sleep
b. REM Behavior Disorder
i. Abnormal muscle movement during REM sleep assoc w/vivid dreams and are potentially harmful

59 Memory Systems
Forms of Memory
1. Declarative vs. Non-Declarative
a. Declarative conscious memory for facts, places and events
i. Involve hippocampal formation and diencephalon
b. Non-Declarative subconscious memory for skills, habits, emotional responses and some reflexes
i. Involve the striatum, cerebellum and amygdala; sometimes called procedural memory
2. Short vs. Long Term
a. New sensory information is processed into
intermediate memory for several seconds then into short term
b. This information, depending on the perceived importance,
may be consolidated into long term memory (days/yrs)
3. Amnesia
a. Retrograde loss of memory of past events before trauma
b. Anterograde inability to form new memories following trauma and remember only the past
4. Memory Traces Engram
a. An engram is a theory that states how memory is stored as a biophysical/biochemical change in the brain
b. Neural network or fragment of memory in a cluster of neurons connected together

Engrams
1. Location
a. Distributed in the neocortex grouped into association
areas which receive input from the primary visual,
auditory and somatosensory cortexes
b. The association areas then send new sensory info to
medial temporal lobes in the hippocampal formation
which then relays it right back to the association area
to consolidate into memory
c. Some areas are concerned with facts, events, places,
language and such while other are associated with
emotions, past events and people while others are for
working memory
2. Clinical Cases Reveal Engram Location
a. Removal of amygdala, uncus and most of hippocampus to treat epilepsy
i. Retained IQ, language, long term memory and ability learn new skills (procedural memory)
ii. Lost ability to make new memories (immediate/shortlong term impairment)
b. Lesion to thalamus, medial temporal lobe and mammillary body from fencing sword up the nose
i. Suffered anterograde amnesia
ii. Retained his IQ, language, procedural skill learning and 2yrs worth of long term memory
c. Stroke/TIA resulting in lesions to the hippocampus suffering marked loss of CA1 neurons
i. Suffered from anterograde amnesia and unable to form new declarative memories
ii. IQ, memories, & cognitive ability remained intact

Hippocampus Processing Info for Memory


1. General Info
a. Located in the hippocampal formation consisting of
the dentate gyrus, fields CA1-CA3, the subiculum
(parahippocampal gyrus) and of course, the hippocampus
b. All new sensory info meant for transfer to memory
is processed thru this formation
2. Information via Hippocampal Formation

a. Passage of information thru this loop induces synaptic plasticity at synapses on cells of the dentate gyrus,
hippocampus and subiculum
LONG TERM POTENTIATION - LTP
1. Hippocampus and Synaptic Plasticity
a. When CA1 is excited by CA3 impulse trains at high frequencies (100/s), the excitatory synapse
undergoes a long lasting increase in synaptic efficiency called long-term potentiation (LTP)
b. The potentiation takes place in glutamatergic synapses on dendritic spines in the CA1 neuron
2. LTP Caused by Postsynaptic Changes in CA1 Neurons
a. This long term potentiation is caused by an increase sensitivity to glutamate via insertion of new AMPA
receptors (review glutamate receptor AMPA/NMDA lecture 16)
b. Additionally, due to the formation of new dendritic spines between CA3 and CA1, the increased
number of synapses facilitates an increased responsiveness to synapses from CA3 to CA1

c. A single presynaptic impulse can open the AMPA receptors but the NMDAs remain blocked by the
resident Mg2+ ion however when a train of impulses arrive, it can open the NMDA channel and allows
Ca2+ ions to enter
d. These Ca2+ ions leads to activation of kinases which leads to AMPA receptors and eventual LTP
LTP SUMMARY
Increase in AMPA channel conduction (early)
Increase in the number of AMPA channels (early)
Increase in number of synapses via dendritic spine formation (late)

LONG TERM DEPRESSION - LTD


1. Hippocampus and Synaptic Plasticity
a. When CA1 is excited by CA3 impulse trains at low frequencies (1/s), the excitatory synapse undergoes a
large persistent fall in synaptic efficiency called long-term depression (LTD)
b. Thus, the same synapses showing LTP under intense stimulation will exhibit LTD under weak stimulation
c. The use of NMDA receptors is necessary for both LTP and LTD the difference is calcium concentration
i. the amount of NMDA activation dictates [Ca2+] I thus a direct influence on synaptic strength
CALCIUM CONCENTRATION REGULATES SYNAPTIC PLASTICITY
1. High Frequency Stimulation LTP
a. Induces large rise in [Ca2+]I which activates protein kinase who phosphorylates synaptic proteins
(including AMPA receptors) leading to LTP
2. Low Frequency Stimulation LTD
a. Induces very small rises in [Ca2+]I which activateds protein phosphatase which dephosphorylates
synaptic protens (including AMPA receptors) leading to LTD

Location of Procedural/Non-Declarative Memory

Remember that procedural/non-declarative memory is concerned with learned movements that can be recalled
Three major anatomical sites with functional synaptic connections to play a role:
o Supplemental & Premotor Cortex
o Striatum (in the basal ganglia)
o Cerebellum

SYNAPTIC PLASTICITY IN THE CEREBELLUM - LTD


1. Purkinje Cells
Are the sole output cells of the cerebellar cortex; each Purkinje cell receives two major excitatory inputs
i. Parallel Fiber found traversing the outer molecular layer and sends an input
ii. Climbing fiber makes several hundred synapses on the Purkinjes dendrites
2. LTD
Occurs only in parallel fibers that are activated at the same time as the climbing fibers.
If the parallel fiber is stimulated alone, it will NOT exhibit this LTD plasticity
3. Mechanism of LTD
Climbing fiber activation strongly depolarized the purkinje cell dendrite which leads to the activation of
voltage-gated Ca2+ channels
Parallel fiber activation leads to AMPA activation and subsequent Na+ influx
Parallel fiber activation also leads to stimulation of metabotropic receptors to eventually generate PKC
PKC then phosphorylates the AMPA receptor and causes them to be internalized where it is this reduction
of AMPA channels that cause the decreased sensitivity to glutamate and consequently LTD

LTD SUMMARY
A rise in intracellular calcium arising from the climbing fiber stimulation
A rise in intracellular sodium arising from the AMPA channel opening
An Activation of PKC from glutamate metabotropic receptor activation

Clinical Correlations

KORSAKOFFS SYNDROME
1. Occurring in chronic alcoholics with Thiamine deficiency
2. Atrophy of dorsomedial thalamus and mammillar bodies
3. Exhibit confusion, confabulation and severe memory impairment
a. Anterograde amnesia and severe retrograde amnesia prob due to damage to thalamus and hippocampus
4. May also exhibit lesions in neocortex, cerebellum and brainstem
ELECTROCONVULSIVE THERAPY
1. Employed to treat severe cases of clinical depression which electrically induces seizure
2. This is based on epileptics who are also depressed and showed marked improvement in depression following a
seizure
3. ECT may cause anterograde amnesia dating back several years but usually subsides a few months post-treatment
NEUROTOXINS FROM DINOFLAGELLATE PFIESTERIA PISCICIDA
1. This toxin released into the water can cause confusion, concentration, disorientation and severe memory loss
2. Contact may be inhaling or direct contact with the skin

60 Aging & Alzheimers Disease


Survival Curve
1. Homogenous Population Simple Survival Curve
a. Homogenous populations are those where people are equally susceptible to injuries, diseases and death
b. Mean Life expectancy (aka-lifespan) is the age where 50% are still surviving
c. Note that the real curve deviates slightly from the ideal curve

2. Rising Life Expectancy


a. Increasing life expectancy due to medical care and public health
b. Healthy Life Expectancy age where seriously debilitating disorders develop
i. usually 10yrs less than expected life expectancy; thus ppl suffer in their last 10 years
3. Variation of Life Expectancy
a. Highest occur in the most developed western-world countries and the lowest in AIDS suffering countries
4. Socio-economic Status (SES/SEP)
a. SES may help determine a persons lifespan; SES = longer lifespan and SES = shorter lifespan

Age Specific Illnesses


1. Increasing Number of Old People
a. The # of people in the eldest age group is increasing now more than ever due to the baby-boomers
b. As life expectancy rises, so does the incidence of dementias, expected to TRIPLE in the next 25yrs
2. Age-Specific Impairments
a. Older people are more susceptible to age-specific impairments (ie: osteoporosis)
b. Age-specific impairments occur in sensory-motor systems as well as cognitive abiliy
c. SENSORY
i. Visual acuity, accommodation and macular degeneration
ii. Olfactory olfactory neuron loss and damage to olfactory epithelium
iii. Hearing loss of inner and outer hair cells and spiral ganglion cells
iv. Vestibular Apparatus degenerative changes at several sites
v. Proprioceptors impairment seen particularly in lower limbs
d. MOTOR
i. Muscle loss of mass and replacement with fat deposition
ii. Gait impairment of gait and postural stability
iii. Basal Ganglia Parkinsons, Huntingtons
iv. Cerebellum ataxias
e. COGNITIVE
i. Dementias Alzheimers, Picks Disease
ii. Personality Disturbances
3. Aging of the Nervous System causes Infirmity
a. Brain weight begins to decline past age-30
b. Fall in neuronal size, dendritic arborization and number of synapses
c. Gyri are smaller and sulci are larger and deeper as cells shrink
d. Aging of the nervous system causes
i. losses of function, postural control, gait, reflexes, vision, sleep, memory and general intelligence

Alzheimers Disease
AGING ASSOCIATED WITH ONSET
1. Causes of Dementia
a. Causes range from cerebrovascular disease, CNS infection, tumor, trauma, neurologic diseases like
Huntingtons and Parkinsons as well as MS
b. The most common form of Dementia is Alzheimers Disease whose cause/origin is uncertain
2. Alzheimers Disease
a. First described in 1907 and eventually classified into two types
i. Type-1: late onset after 65yrs
ii. Type-2: early onset before 65yrs
THREE CARDINAL SIGNS OF AD
1. Neuritic Senile Plaques
a. Extracellular spherical deposits containing many neuritic and glial processes with amyloid protein core
2. Neurofibrillary Tangles
a. Intracellular paired helical filaments
3. Granulovacuolar Degeneration
a. Degeneration caused by formation of intracellular circular clear zones of cytoplasm (vacuolation)

REGIONS SHOWING DEGENERATION IN AD


1. Degenerating neurons exhibiting Sentile Neuritic Plaques and Neurofibrillary Tangles are often seen in
a. Hippocampus (CA1), neocortex, amygdala, basal forebrain, locus ceruleus, raphe nuceus and olfactory
cortex
2. Neuronal loss most notable in
a. hippocamps, entorhinal cortex, association cortexes and basal nucleus of Meynert
3. CNS exhibits selective losses in noradrenergic, dopaminergic and cholinergic neurons
4. Limbic system also exhibit pathology

AD Stem from Disordered Proteins


1. Neuritic Plaques contain Amyloid -Protein
a. The central core of the neuritic plaques is made of amyloid -protein with surrounding parts of damaged
neurons
2. Amyloid Precursor Protein in Cell Membrane
a. The APP located in the neuronal cell membrane; encoded for on Chromosome 21
b. The APP should normally be cleaved by an -secretase but in this case it is the or -secretase (bad!)
3. Abnormal Cleavage APP
a. Abnormal cleavage of APP results in releae of small peptides in to the ECF
b. Cleavage done by -secretase and -secretase causing the release of A1-40
c. These A molecules aggregate to form these plaques containing axon terminals, migroglia and astrocytes
4. TAU Proteins form Neurofibrillary Tangles (see lecture-9, page 2)
a. Remember that Tau proteins form the MAPs that assist in stabilization and axonal transport for
microtubules thus found in high concentration in axons
b. Hyperphosphorylated tau proteins in degenerating neurons are the major constituent of these tangles

CLINICAL COURSE IN ALZHEIMERS DISEASE

Other Age-Related Diseases of the CNS


1. Parkinsons Disease
a. Loss of neurons in the Substantia Nigra happens in the 6th to 8th decade
b. Characterized by tremors at rest, akinesia, rigidity, emotional changes and lack of facial expression
c. In addition to depigmentation substantia nigra, Lewy Bodies develop in associated areas including the
Substantia nigra, pars compacta, locus ceruleus, basal nucleus of Meynert, raphe nuclei and cerebral cortex
i. Lewy Bodies are granules (10m) made mostly of -synuclein found in presynaptic terminals
2. Huntingtons Disease
a. Typically appears in 5th decade with cognitive and emotional disturbances proceeded by chorea
b. Atrophy of frontal cortices, caudate nucleus and putamen and astrogliosis is evident
c. Marked decreases in GABA and glutamic decarboxylase
3. Amyotropic Lateral Sclerosis
a. Peaks incidence in 5th decade with i ntellectual capacity is being retained
b. loss of anterior horn cells, motor nuclei of brainstem & UMN loss causing initial weakness in
hands/limbs
c. Atrophy of motor neurons, gliosis and extensive loss of myelinated fibers in lateral Corticospinal tract
4. Friedreichs Ataxia Spinocerebellar Degeneration
a. First or second decade, progressive limb an gait ataxia with retained intellectual capacity
b. Loss of deep tendon reflexes and sensory axonal neuropathy
c. Atrophy of dorsal column, Corticospinal tracts and spinocerebellar tracts
5. Picks Disease initial resemblance of AD
a. Onset of 4th/5th decade; early on presents like AD and may be clinically difficult to distinguish
b. Fatal course within 10yrs; > usually with behavioral disturbances and aphasia
c. Cortical atrophy usually frontal/temporal and unilateral with marked astrogliosis
d. Cytoplasmic inclusions known as Pick Bodies densly packed neurofilaments; distinguishable from AD
6. Creuzfeld-Jakob Disease Prion Disease
a. Onset of 4th/5th decade but incubation of infectious protein (prion, PrP) may be 10-30yrs
b. Fatal w/in 2yrs; three origins infection, sporadic or familial (mutation of PrP)
c. Pts show dementia, motor weakness, ataxia, tremors, rigidity and myoclonus
d. Neuronal loss, astrogliosis and cytoplasmic vacuoles in the cortex and basal ganglia (giving a
spongiform appearance)

Clinical Correlations
1. Chromosome 21
a. Amyloid gene that encodes the A precursor Alzheimers Disease
b. Trisomy 21 gives rise to Downs Syndrome if they live past 40 will develop Alzheimers Disease
2. Prion Diseases
a. Is caused by an infectious protein known as a Prion
b. It is believed that the new variant of Creutzfeldt-Jakob disease was caused by eating contaminated beef
from a cow infected with a related animal prion disease known as bovine spongiform encephalopathy
3. Progeria
a. Rapid aging in children, evident by age 2 and death b/w 8-21 years of age from heart disease
b. Gene mutation causes defective protein that normally holds nucleus and cell together

61 Brain Stem Syndromes


Content of Brainstem - brief

Cranial Nerve Nuclei and many others (red nucleus, olive, raphe nuclei)
Tracts (ALS, Dorsal Column, Corticospinal, etc)
Reticular Formation

REVIEW Conjugate Eye Movements


1. Purpose
a. Extremely fast eye movements used to keep the
target in focus, on the fovea (used for scanning)
2. Pathway
a. Begins in the Frontal Eye Field, the planning
location where such movements are triggered
b. Descends to the PPRF in the Pons and then
move to the Abducens Nucleus
c. Abducens Nucleus activates CN-6 but also sends
ascending fibers which cross the midline and
reach the Occulomotor Nucleus via the MLF
ensuring synchronization between the eyes
d. The Oculomotor Nucleus activates CN-3 to
match CN-6 such that both eyes move together
in the same direction

MLF Syndrome Internuclear Opthalmoplegia


1. Caused by:
a. a unilateral damage to the MLF which interrupts ascending communication from the abducens nucleus (in
the pons) to the occulomotor nucleus (in the midbrain)
2. MLF Loss
a. Leaves the ipsilateral eye unable to aDDuct when trying to follow the lateral gaze of the other eye while
the contralateral eye exhibits nystagmus in the extreme gaze
3. Bilateral MLF Loss
a. causes an aDDuction deficit in both eyes upon lateral gazes and nystagmus in both eyes at the extreme
gaze
4. Convergence
a. INO and BINO pts are usually able to converge as the center that organizes convergence is usually intact
5. Diseases that can cause INO/BINO:
a. Multiple Sclerosis, S, Brainstem Infarction and brainstem tumors

PPRF Lesion
1. Result of PPRF Lesion
a. Causes an ipsilateral conjugate horizontal gaze palsy, thus unable to look toward the affected side
b. The frontal eye field cannot communicate with the PPRF causing
i. Inability to aBduct the ipsilateral eye because no info is passed from the PPRF to abducens
ii. Since no info reaches the abducens, the contralateral occulomotor is not triggered thus the
contralateral eye is unable to aDDuct
2. Unopposed PPRF
a. The other PPRF is working fine however, so it is working unopposed and leads to a forced gaze toward the
unaffected side

One And A Half Syndrome


1. Loss of the PPRF and the MLF on one side of the brainstem
2. ONE:
a. Loss of the PPRF results in inability to initiate a gaze ipsilateral to the PPRF lesion
3. HALF
a. Loss of the MLF results in the inability to initiate aDDuction in the eye which is ipsilateral to the MLF
lesion, (basically causing internuclear opthalmoplegia)
b. aBduction of the opposite eye is intact because the other PPRF can still be activated and initiate the
abducens to aBduct
4. Overall
a. results in the limitation only to be able to aBduct one eye and no other horizontal movements

Facial Palsy
1. Contralateral Central Facial lesion - UMN
a. Loss of lower facial muscles but still able to move forehead due to partial innervation from ipsilateral
cortex
2. Ipsilateral Central Facial Lesion - UMN
a. No loss because the majority of the innervation comes from the contralateral cortex
3. Peripheral Facial Lesion - LMN
a. Will result in total loss of muscle innervation on the ipsilateral side

Webers Syndrome
1. Cause
a. Lesion/infarction of the crus cerebri/cerebral peduncle in the midbrain
b. Usually due to infarction of the paramedian branches of the posterior cerebral arteries which supply
the area
2. Symptoms
a. Fibers passing thru or originating in this area which lost blood supply will manifest (see diagram)
3. Example of the Electrician (left infarction)
a. RIGHT SIDE (contralateral)
i. Arm/Leg weakness
ii. Facial weakness
iii. Hyperreflexia and rigidity in right arm
b. LEFT SIDE (ipsilateral)
i. Ptosis
ii. Medial Rectus paralysis
iii. CN-3 parasympathetic loss

Mid-Pontine Syndrome
1. Cause
a. Occlusion of short circumferential branches of the Basilar artery supplying the anterior pons
2. Symptoms (assuming Left-sided lesion)
a. RIGHT (contralateral)
i. Hemiplegia- weak extremities
b. LEFT (ipsilateral)
i. Face Trigeminal
1. Hemianasthesia
2. Paralyzed muscles of mastication
ii. Hemiataxia
1. Normal muscles but Ataxic

Wallenberg Syndrome
1. Cause
a. Stroke/infarc of brainstem caused by
occlusion to Vertebral artery or PICA
2. Symptoms
a. Aphagia
b. Hoarsness
c. Dizziness
d. N/V
e. Nystagmus
f. Improper gate and imbalance
g. No TP on one side of face
h. No TP on opposite side of body
i. Uncontrollable hiccups