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Acute CNS injury:

anoxia, re-oxygenation &


oxidative stress
(or What happens to brain cells
during a stroke)

Overview
1. Introduction: What is a disability?

Important CNS regions (disabilities)

2. Oxygen and CNS function


3. Cerebral blood flow & Oxygen transport
4. CNS Hypoxia / Anoxia

Stroke
Head Injury & intracranial hypertension
Respiratory failure

5. Re-oxygenation (blood flow is restored)


6. Disturbed electrical signaling

1. What is a Disability?
Neuromuscular impairment
Sensory deprivation (vision, hearing or
speech)
Cognitive dysfunction (learning, higher
processing)

Motor (muscle) system

Neuromuscular junction (NMJ)

http://www.fi.au.dk/uk/jl/bc14/fig1403.jpg

Sensory: Vision

http://general.rau.ac.za/psych/Resources/Honours/Neuropsych/Images.htm

Sensory: Hearing

http://www.brainconnection.com/med/medart/l/anat/990705.jpg

Sensory: Speech

http://home.uchicago.edu/~skipp
er/pages/skipper.et.al.2005b.html

Sensory: Speech
http://www.cerebromente.org.br/n02/historia/areabroca.gif

Brocass Area -- Broca's aphasia involves a lack of ability to produce coherent


language, including spoken, written and signed forms.
Wernicke's area have difficulty understanding language in any form. They can
speak fluently, forming long and complex sentences, but their strings of words
often lack coherent meaning.

Cognition

http://ifcsun1.ifisiol.unam.mx/Brain/speech.htm

The cortical association areas are thought to be the anatomical basis for
thought and perception, since stimulation of these areas produce little or no
obvert behavioral changes, but receive sensory input from high-order sensory
systems and project to motor cortex.

2. Oxygen and CNS Function

http://health.allrefer.com/health/stroke-secondary-to-cardiogenic-embolism-central-nervous-system.html

Neuron

http://www.mb.jhu.edu/tins/media/2004%20Neuron%20Schema1.jpg

http://www-ermm.cbcu.cam.ac.uk/02004477h.htm

http://caspar.bgsu.edu/~courses/Images/Neur/Synapse.jpg

Mitochondria
Mitochondria are structures that turn oxygen and glucose into energy. This
process is especially vital to brain cells. Although the brain accounts for only 2%
of the body's weight, it consumes more than 20% of the body's oxygen. All of
this energy is required because neurons transmit signals among themselves to
an even greater extent than do cells in the rest of the body.

Three-dimensional model was


reconstructed by electron tomography.
The outer membrane and cristae are
shown in purple and yellow,
respectively.
http://www.scripps.edu/mem/biochem/ayagi/mito.html

Transmission electron micrograph


(TEM) of mitochondrion

http://www.cytochemistry.net/Cell-biology/mitoch1.htm

Aerobic metabolism
O2
fuel (glucose)

ADP CELLULAR
ATP
RESPIRATION

CO2 H2O

CO2 + H2O

biosynthetic work
mechanical work
transport work

H2CO3 H+ + HCO3

pH

PET can yield metabolic information with high-resolution images, and thus it
has the ability to detect small malignant lesions with increased metabolism for
enhanced cell proliferation.

Sensory: Vision

http://general.rau.ac.za/psych/Resources/Honours/Neuropsych/Images.htm

CNS Oxygen Consumption

Eyes open

Congenital blindness

Eyes closed

Blind, recently

http://www.topo.ucl.ac.be/neuro_blindness.html

CNS Oxygen Consumption


regional metabolic activity = glucose utilization

Children, epilepsy

http://www.md.ucl.ac.be/gren/Projets/Adv/childhoodEpilepsy.html

infants

Normal adult

Electrical signaling = energy (ATP) production & consumption to maintain


ionic gradients, biosynthesis, action potentials & synaptic transmission

Hyperoxia: Dorsal medulla oblongata

D.K. Mulkey et al. (2003) J Appl Physiol 95:910-921

CNS Oxygen Consumption


CBF PtO2

Changes in brain oxygenation correlate with execution of a mental task (i.e. numerical calculation)

Cerebral pulse pressure & tissue PO2

http://ccforum.com/content/9/6/R670

What is a normal O2 level in the


brain (Normoxia)?
Normoxia (CNS): <10 to 35 mm Hg
Inspired air: 21% O2 at sea level, PB=760 mmHg
PIO2= 0.21 x 760 = 159.6 mm Hg O2
Lung (Alveoli): PAO2 = 100 mm Hg O2
Arterial blood: PaO2 = 85-100 mm Hg O2

Gas exchange & O2-CO2 homeostasis


3 general processes

Figure 1

Figure 2

Plumbing

From J.B. Wests


Respiratory Physiology
the essentials

Pathway for Diffusion of O2 & CO2


Alveolar-capillary membrane: where the respiratory
and cardiovascular systems come together.

Berne &Levy:

Fig. 32-9, p.525; Fig. 32-5, p.522

Pathway for Diffusion of O2 & CO2


J.B.Wests Respiratory
Physiologythe essentials

O2
Berne&Levy: Figs. 32-6, p. 522

Hb

CO2

3. Cerebral Blood Flow &


Oxygen Transport

J.B.Wests Respiratory
Physiologythe essentials

O2
HbO2

PaO2

O2 Transport

Review of important points in oxygen


transport
Blood carries O2 in two forms:
1.

in physical solution as O2 dissolved in the aqueous


phase (~5% of the total blood O2 content).

2.

in a loose reversible chemical combination with


hemoglobin: Hb + O2 HbO2 (~95% of the total
blood O2 content).

In both cases, the amount of O2


held depends on the PO or loading
pressure to which the blood is
exposed.
2

Cerebral Vasculature
MR Angiography

http://www.mgh-interventional-neurorad.org/diagnostic/mra.html

http://www.psyweb.com/Brain/Bimages/blood2.gif

O2 Carrying Capacity
The maximum amount of O2 that can be made to combine
chemically with Hb in a unit volume of blood. Where...
1g Hb combines with 1.34 ml O2
normal Hb content = 15 g Hb/100 ml of blood
O2 carrying capacity = (15 g Hb/100 ml) (1.34 ml/1 g Hb)
= 20.1 ml O2/100 ml of blood
% saturation of Hb =

HbO2
O2 carrying
capacity

100

PO2 of blood vs. HbO2

http://www.cvm.okstate.edu/Courses/vmed5412/FIGURES/lecture03/fig3_12.gif

1. CNS Hypoxia / Anoxia


( Hypoxemia )
Recall
Normoxia (CNS): <10 to 35 mm Hg
Inspired air: 21% O2 at sea level, PB=760 mmHg
PIO2= 0.21 x 760 = 159.6 mm Hg O2
Lung (Alveoli): PAO2 = 100 mm Hg O2
Arterial blood: PaO2 = 85-100 mm Hg O2

Stroke

http://www.mcg.edu/medart/images/2002-AR-Stroke.jpg

What is a stroke?
A stroke is the sudden death of brain cells
due to interruption of blood supply. When
blood flow to the brain is impaired, oxygen
and important nutrients cannot be
delivered. The result is abnormal brain
function.
A stroke is also referred to as a
cerebrovascular accident or CVA.

http://www.medicinenet.com/stroke/article.htm

http://www.ling.upenn.edu/courses/Summer_2004/ling001/images/brain_localization.gif

Causes of stroke, 1
Blockage of artery
Hardening of the arteries leading to the
brain

Causes of stroke, 2
Blockage of artery
Clogging of arteries within the brain (e.g.
lacunar stroke)

http://www.strokecenter.org/education/ais_vessels/ais050.html

Causes of stroke, 3
Blockage of artery
Embolism to the brain from the heart or an
artery

http://health.allrefer.com/health/stroke-secondary-to-cardiogenicembolism-stroke-1.html

Causes of stroke, 4
Rupture of an artery
(i.e. hemorrhage)
Cerebral hemorrhage (bleeding
within the brain substance)

Subarachnoid hemorrhage (bleeding


between the brain and the inside of
the skull)

Necrosis
http://medic.uth.tmc.edu/edprog/PATH/NeuroIIa.HTM

Anemic Infarct. (In general from in


situ thrombotic occlusion).

Hemorrhagic Infarct. There is necrosis in


addition to the hemorrhage. (In general results
from embolic occlusion). Distribution of middle
cerebral artery. (Infarct of end-arterial zone).

Head trauma

This is what's left of a Mustang that was being driven by a 17 year


old high school student who decided that they needed a few beer's
before going to school to "loosen up" before class. Bad idea!! A Palm
tree got in his way.

Cranial Volumes
10%
Blood
10%
CSF
10%
Extracellular
70% Intracellular

(35% Neuronal - 35% glial)

100% Total Cranial Volume

How is ICP measured?

Monitoring ICP
Intraventricular Pressure Catheter

Intracranial Pressure

brain swelling
blood
(tumor)

The pressure-volume curve of the intracranial contents. As the volume of an


expanding mass increases, ICP rises only slightly until the compensatory
mechanisms are overcome. This point is reached at the elbow of the curve
when further expansion of the mass causes a steep rise in ICP.
http://www.fsm.ac.fj/sms/anaesthesia/WFSA/html/u09/u09_019.htm

Normally Blood Pressure > Intracranial Pressure

Causes of stroke
Rupture of an artery
(i.e. hemorrhage)
Cerebral hemorrhage (bleeding
within the brain substance)

Subarachnoid hemorrhage (bleeding


between the brain and the inside of
the skull)

Increased Tissue Mass

ICP

What does intracranial hypertension do to


neurological function?
Cerebral Perfusion Pressure =
(mean arterial blood pressure) - (ICP)
If ICP > MAP then blood flow to the CNS ceases!

MAP

ICP

Acute Respiratory Failure

( drug overdose )

Disorders of Ventilatory Control


Acute respiratory failure results from overdosing:
sedatives
opiates
narcotics
anesthesia
In each case, lung ventilation due to:
input from brainstem reticular activating system
input from respiratory rhythm generator
CO2 sensitivity of the central & peripheral chemoreceptors
cells that increase breathing)

(brain

Respiratory Failure

Ultimately, results in abnormal breathing patterns


which pulmonary ventilation,
which decreases ventilation-perfusion matching,
leading to poor blood gases,
CNS hypoxia
and eventually, death (brain cells cease to function).

5. Re-oxygenation
???

Reactive Oxygen Species (ROS)

J.D. Balentine (1982), p. 53

Reperfusion Injury

http://www.theresurrector.com/img/freeradicals.jpg

Re-oxygenation: superoxide

Hyperoxia: excess oxygen &


Superoxide production
(CA1 hippocampus)

Oxidative Stress
SIGMA-ALDRICH

Re-oxygenation injury

Reactive Oxygen Species

( = oxidative stress, too many O2 free radicals )

6. Disturbed Electrical Signaling

http://cti.itc.virginia.edu/~psyc220/kalat/JK237.fig8.8.principle_area.jpg

http://camilolab.slu.edu/444/graphics/Leeson6-12.jpg

http://www.alscenter.org/images/human_motor_system_400pix.gif

http://stuserv.fullcoll.edu/images/Wheel%20chair%20student2.jpg

http://www.ia.wvu.edu/~magazine/issues/spring2003/htmlfiles/wheelchair.html

Homunculus

http://www.phrenology.com/homunculus.html

http://lcbr.ss.uci.edu/Courses/cog_neuro/lecture_slides/motor_system/Slide4.jpg

Neuron

http://www.mb.jhu.edu/tins/media/2004%20Neuron%20Schema1.jpg

http://www.awa.com/norton/figures/fig0209.gif

Action Potential

http://www.awa.com/norton/figures/fig0209.gif

Action Potential

http://www.awa.com/norton/figures/fig0209.gif
http://gargoyle.arcadia.edu/psychology/blustein/neuro/Lecture_Notes/
Week_1/Week_2/Action_Potential.jpg

D.K. Mulkey et al. (2003) J Appl Physiol 95:910-921

March 1999 (Volume 40, Number 3) CMJ


Early Effects of Hypoxia on Brain Cell Function
Kreimir Krnjevi
Anaesthesia Research Department, McGill University, Montral, Quebec, Canada

http://www.cmj.hr/1999/40/3/400311.htm

CA1 population spike response to CA3


stimulation during HBO2

Evoked Population
Spike

Evoked Field EPSP

Overview
1. Introduction: What is a disability?

Important CNS regions (disabilities)

2. Oxygen and CNS function


3. Cerebral blood flow & Oxygen transport
4. CNS Hypoxia / Anoxia

Stroke
Head Injury & intracranial hypertension
Respiratory failure

5. Re-oxygenation (blood flow is restored)


6. Disturbed electrical signaling