Clinical importanceAbnormalities of

Blood flowMetabolismFluids

Composition Pressure

Affect brain function profoundlyDecrease blood flow for 5-19sec

loss of consciousnessIncrease in H+ ions

depresses neuronal activity decreases brain activity

OutlineVascular anatomy of brainControl of cerebral blood flow

Determinants of cerebral perfusion pressureLocal regulation of cerebral blood flowRegulation of CBF by arterial pO2 and pCO2

Neurohumoral regulationCushing reflexControl by neuropeptides

Conditions related to altered cerebral blood flow

(From E. Gardner, Fundamentals of Neurology. W.B. Saunders, 1963)

Circleof Willis

Cerebral blood flowNormal blood flow 50-65mls/100gr/minEntire brain=750-900 mls/min

15 % of resting cardiac ou put

Regulation of cerebral circulationConstant total cerebral blood flow is

maintained under varying conditions.1.ABP at brain level.2.Venous pressure at brain level.3.Intracranial pressure.4.Blood viscosity.5.Degree of active constriction or dilation of

cerebral vessels.

Regulation of blood flowHighly related to tissue metabolism

1. Concentration of carbondioxide2. Hydrogen ions concentration3. Oxygen concentration

Excess CO2 or H+ Increase cerebral blood flow

Vasodilator effect

Indirect effect of CO2 CO2 + H2O= H+ + HCO3-

Others Metabolic acids

Lactic acid & Pyruvic acid

Importance of cerebral blood flowIncreased H+ conc greatly depresses neuronal

activityIncreased H+ leads to increased blood flow

In turn carries H+ , CO2 and other acids forming substances from the brain tissue Decreased H+ conc

Achieves normal neuronal activity

Oxygen deficiencyNormal oxygen utilization 3.5+/- 0.2 mls

O/100gr/min Decreased oxygen supply below normal Vasodilatation

increased blood flow and O2 transport to the tissue

Normal PO2 in cerebral blood is 35-40mmHgDecreased in cerebral tissue PO2 below

30mmHg increase blood flowBelow 20mmHg comma ensues

Measurement of blood flowInject radio active substance in carotid arteryRecord radioactivity of each cerebral

segmentPress detectors against the surface of the

cortexDetect rapidity of rise and decay of

radioactivity in each tissue segmentRecord increased blood flow where there is

activity

2. Autoregulation of cerebral blood flowAutoregulation:Ability of tissue to regulate their blood flow

according to their activity.When the arterial pressure changesCBF is auto regulated extremely wellBetween arterial pressure limits60-140mmHgthere is no significant changes in cerebral

blood flow

CerebralBloodFlow

Mean Arterial Pressure (mmHg)

0 200100

Autoregulatory

Range

CerebralHypoxia

HeadachesBBB disruptionEdema

CerebralBloodFlow

Mean Arterial Pressure (mmHg)

0 200100

Normal

Chronic HypertensionAcute Sympathetic Stimulation

Cerebral Autoregulation(Possible Mechanisms)

MetabolicDecreased perfusion pressure leads to:

pO2 (decreased O2 delivery) pCO2 (decreased CO2 washout) H+ (decreased H+ washout plus lactic acid) adenosine (hypoxia resulting in net loss of ATP)

Each of the above changes produces vasodilation

MyogenicDecreased perfusion pressure decreases

stretching of arteriolar smooth muscle which causes relaxation

3. Autonomic ControlSympathetic

Innervation from superior cervical ganglion primarily to larger cerebral arteries on brain surface

Very weak sympathetic vascular toneSympathetic blockade has little effect on flowMaximal sympathetic stimulation increases

resistance by 20-30% (cp >500% in muscle)Shifts autoregulatory curve to right

ParasympatheticInnervation from facial nerve (VII)Weak dilator effect on pial vessels

Baroreceptor reflexesVery weak

Cer

ebra

l Blo

od F

low

(ml/m

in•1

00g)

Level of Sympathetic Activity

0

50

100

None Maximal

(From Lassen, N.A., Brain. In: Peripheral Circulation, P.C. Johnson, ed. Wiley, 1978)

Role of sympathetic NS in controlling CBFThere is strong sympathetic innervations in the

brainInhibition or mild to moderate sympathetic

stimulation has mild or no effect in CBF changesAuto regulation overrides the nervous effect

Important in preventing stroke Cerebral vascular accidentsIncase of acute increase of Arterial pressure

Strenuous exercise Excessive circulatory activity

Constrict large and intermediate sized brain arteries High pressure is prevented reaching smaller brain vessels

Prevent vascular hemorrhages

4. Effects of Intracranial Pressure(CNS Ischemic Reflex)

Increased intracranial pressure leads to mechanical compression of cerebral vasculature and decreased flow

Increased intracranial pressure elicits arterial hypertension (“Cushing reflex”)May be caused by bulbar ischemia, which in

turn stimulates medullary cardiovascular centers and increases sympathetic outflow to systemic vasculature

Bradycardia often accompanies the hypertension because of baroreceptor activation of vagal efferents to the heart

5. Humoral ControlCatecholamines

Weak alpha-adrenergic vasoconstriction is masked by autoregulation although very high doses of epinephrine can decrease flow

Beta-adrenoceptors cause vasodilation; however, this is masked by autoregulation

Angiotensin IIVery little or no effect

Neuropeptides and Other Vascular Control MechanismsVasodilation

Calcitonin gene-related peptide (CGRP)Substance-PVasoactive intestinal peptide (VIP)

VasoconstrictionNeuropeptide-Y (NPY)Endothelin (vascular and neuronal ET-1 and

neuronal ET-3 acting primarily on ETA receptors)

Cerebrospinal Fluid systemCapacity of entire

cerebral cavity enclosing the brain and spinal cord1600-1700 mls

150mls is CSF 1450-1550 mls Brain &

spinal cordAreas CSF formed

Chambers in the brain Ventricles

Cisterns around the outside of the brain

Subarachnoid space around both & spinal cord Chambers are

interconnected Pressure of the fluid is

maintained at a constant level

Function of Cerebrospinal Fluid The purpose of this

fluid is to protect the brain and spinal cordacting as a shock

absorber.It also carries away

disposed materials.

Functions of CSF, continued,…

2. Facilitation of pulsatile cerebral blood flow,

3.Distribution of peptides, hormones, neuroendocrine factors and other nutrients and essential substances to cells of the body,

4.Wash away waste products.

Formation, flow and absorptionRate per day

500mls/day 3-4 times its volume

2/3rds secreted by choroid plexus in ventriclesMainly 2 lateral

ventriclesEpendymal surface of

all ventriclesArachnoid membranesBrain itself

Composition of the CSF

The composition of CSF is essentially the same as brain ECF

Substance CSF Plasma

Na+ 147 150

K+ 2.9 4.6

HCO3- 25 24.8

PCO2 50 39.5

pH 7.33 7.4

OsmolalityGlucose

28964

289100

flow1. From lateral ventricles 2. to 3rd ventricles3. to Aqueduct of sylvius4. to 4th ventricle5. then passes through the three small openings

1. Two lateral foramina of lushka2. Foramen magandie on the middle3. And then enters cisterna magna

6. Then upwards through the subarachnoid space surrounding the cerebrum

7. Finally to large sagital venous sinuses

Choroid plexusIs a cauliflower like growth of blood vessels

covered by a thin layer of epithelial cellsMechanism of CSF formation

Na+ actively pumped outside the epithelial cells

Pulls along with it Cl- ionsCreates osmotically active environmentWater flows by osmosis

Absorption of CSFThrough arachnoidal villiAre microscopic fingerlike inward projections

of arachnoidal membraneHave vesicular passages in them that allows

the passage of CSF Dissolved protein molecules Particles as large as RBC & WBC

into the venous blood

Perivascular spaceSpace existing between pia matter and blood

vessels in the brainAct as a specialized lymphatic system for the

brainExcess protein in the brain tissue leaves the

tissue flowing with fluid through perivascular spaces into subarachnoid space

Also transport extraneous particulate matter of the brainsuch as dead WBC and other debris after

brain infection

Cerebrospinal fluid pressureNormal average 10 mm HgRegulated by arachnoidal villiMechanism

Arachnoidal villi function as a valve systemAllows CFS and its contents to flow readily in the

blood of the venous sinuses while not allowing blood to flow backwards in the

opposite direction

Operate when CSF pressure is about 1.5 mmHg greater than the pressure in the venous sinuses

Disorders of CSF circulationDisease states

Blocks the system Increase CSF pressure

1.Large brain tumors- decrease reabsorbption of CSF into the blood

Increase 4x above normal

2.Haemorhage3.Infection

In cranial vault Release Large number of RBC+/- WBC in CSF block the system

Disorders of CSF circulation4. Abnormal villi system

Few arachnoid villiOr abnormal absorptive properties

HydrocephallusExcess water in the cranial vaultCause

Obstruction of CSF flowTypes

Communicating Non communicating

Disorders of CSF circulationCommunicating

Fluid flow normal from ventricular system to arachnoid spaces

Non communicatingThere is blockage in fluid flow from one or two

ventricles Blockage of aqueduct of sylvius secondary top atresia

(closure) before birth Brain tumor at any age

CommunicatingBlockage of arachnoid villi or subarachnoid spacesFluids collects outside the brain

Brain barriers1. Blood cerebral spinal fluid barrier

Barrier formed between blood and cerebral spinal fluid

2. Blood brain barrier Barrier formed between blood and brain fluid

Permeability CharacteristicsHighly permeable to H2O,CO2,O2, and most lipid

soluble substances e.g alcoholic & anaestheticsSlightly permeable to electrolytes Na+, Cl- and

K+Glucose : its passive penetration is slow, but is

transported across brain capillaries by GLUT1totally impermeable to placenta proteins and non

lipid soluble large organic molecules

Cause of barrierManner in which the endothelial cells of the

brain tissue capillaries are joined to one another

Joined by tightly junctionsMembranes of adjacent endothelial cells are

tightly fused rather than having large slit spores between them

Unlike other capillaries which have large pores

Functions of BBBMaintanins the constancy of the environment

of the neurons in the CNS.Protection of the brain from endogenous and

exogenous toxins.Prevent escape of the neurotransmitters into

the general circulation.

Development of BBBPremature infants with hyperbilirubinemia,

free bilirubin pass BBB, and may stain basal ganglia causing damage (Kernicterus).

Clinical implicationsSome drugs penetrate BBB with difficulty e.g.

antibiotics and dopamine.BBB breaks down in areas of infection, injury,

tumors, sudden increase in blood pressure, and I.V injection of hypertonic fluids.

Injection of radiolabeled materials help diagnose tumors as BBB is broken down at tumor site because of increased vascularity by abnormal vessels.

Circumventricular organs• Posterior pituitary.• Area postrema.• Organum vasculosum of the lamina terminalis (OVLT).• Subfornical organ (SFO).These areas are outside the blood brain barrier. They

have fenestrated capillaries .Functions:- Chemoreceptor trigger zone. As area postrema that

trigger vomiting & cardiovascular control.- Ang II acts on SFO and OVLT to increase H2O intake.- IL2 induce fever by (+) circumventricular organs.