1. Richard Klabunde, Ph.D. September 11, 2003
Cerebral Blood Flow
Richard Klabunde, Ph.D.
September 11, 2003

2. Outline Vascular anatomy of brain Control of cerebral blood flow
Determinants of cerebral perfusion pressure
Local regulation of cerebral blood flow
Regulation of CBF by arterial pO2 and pCO2
Neurohumoral regulation
Cushing reflex
Control by neuropeptides
Conditions related to altered cerebral blood flow

3. (From E. Gardner, Fundamentals of Neurology. W.B. Saunders, 1963)
Vascular Anatomy
Circle
of Willis
(From E. Gardner, Fundamentals of Neurology. W.B. Saunders, 1963)

4. Cerebral Blood Flow (Basic Facts)
~15% of cardiac output to only 2% of body weight
Blood flow supports an O2 consumption that is almost 20% of whole body O2 consumption at rest in adults (higher in infants)
Cerebral blood flow is relatively high on a tissue weight basis: ml/min/100g (cp. 80 ml/min/100g in heart)
A-V O2 extraction is about 6 ml O2/100 ml blood
Because of the rigid cranium, blood volume is nearly constant – this has important implications when hemorrhagic strokes occur and when intracranial pressures rise

5. Cerebral Perfusion Pressure
(normally 0-10 mmHg)

6. Coupling Between Cerebral Blood Flow and Brain Activity
The brain has an absolute requirement for O2 (for glucose oxidation) and has little anaerobic capacity
Reduction in blood flow (relative ischemia) impairs O2 delivery and causes cerebral hypoxia
Recall, O2 delivery = Flow x Arterial O2 Content
Recall, O2 consumption = Flow x (AO2-VO2 )
Unconsciousness results after only a few seconds of oxygen deprivation
Therefore, blood flow and metabolism need to be tightly coupled

7. Functional Hyperemia
Total brain blood flow is tightly coupled to cerebral oxygen consumption
Changes in mental activity alter oxygen consumption, which then either increases or decreases blood flow
Changes in activity in specific brain regions leads to parallel changes in blood flow to those regions

8. Functional Hyperemia cont.
Cerebral
Blood
Flow
Coma
Awake
Seizure
Increasing Oxygen Consumption

9. Mechanisms of Functional Hyperemia
 pO2
VO2
 pCO2
 H+
 K+
Arteriolar
Vasodilation ?
 Adenosine NO

10. Cerebral Autoregulation (Description)
Headaches
BBB disruption
Edema
Cerebral
Hypoxia
Cerebral
Blood
Flow
Autoregulatory
Range
100
200
Mean Arterial Pressure (mmHg)

11. Cerebral Autoregulation (Autoregulatory Shift)
Normal
Cerebral
Blood
Flow
Chronic Hypertension
Acute Sympathetic Stimulation
100
200
Mean Arterial Pressure (mmHg)

12. Cerebral Autoregulation (Possible Mechanisms)
Metabolic
Decreased 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
Myogenic
Decreased perfusion pressure decreases stretching of arteriolar smooth muscle which causes relaxation
Small decreases in tissue pO2 from a normal of to about 30 mmHg will cause pronounced vasodilation. Therefore, the brain vasculature is very sensitive to changes in tissue O2, but not to changes in arterial O2 (probably because when blood pO2 decreases, extraction increases to maintain tissue pO2 – however, there are limits to amount of extraction).

13. Effects of Arterial pO2
Systemic arterial hypoxia (pO2 < 50 mmHg) causes cerebral vasodilation and increased flow
Similar to the coronary circulation, although coronaries are more sensitive to decreased pO2
Unlike renal, splanchnic, and muscle circulations where systemic hypoxia causes sympathetic-mediated vasoconstriction

14. Effects of Arterial pO2 Arterial pO2 (mmHg) 100 Cerebral Blood Flow
(ml/min•100g) 50
100
200
Arterial pO2 (mmHg)
(From Lassen, N.A., Brain. In: Peripheral Circulation, P.C. Johnson, ed. Wiley, 1978)

15. Effects of Arterial pCO2
Increased arterial pCO2 (hypercapnea) causes cerebral dilation
CO2 diffuses through blood-brain barrier into the CSF to form H+ (via carbonic acid) which then causes the vasodilation
Decreased arterial pCO2 as occurs during hyperventilation causes cerebral vasoconstriction, decreased blood flow, and cerebral hypoxia

16. Effects of Arterial pCO2
100
Cerebral Blood Flow
(ml/min•100g) 50 20 40 60 80
Arterial pCO2 (mmHg)
(From Lassen, N.A., Brain. In: Peripheral Circulation, P.C. Johnson, ed. Wiley, 1978)

17. Autonomic Control Sympathetic Parasympathetic Baroreceptor reflexes
Innervation from superior cervical ganglion primarily to larger cerebral arteries on brain surface
Very weak sympathetic vascular tone
Sympathetic blockade has little effect on flow
Maximal sympathetic stimulation increases resistance by 20-30% (cp >500% in muscle)
Shifts autoregulatory curve to right
Parasympathetic
Innervation from facial nerve (VII)
Weak dilator effect on pial vessels
Baroreceptor reflexes
Very weak

18. Level of Sympathetic Activity
Sympathetic Control
100
Cerebral Blood Flow
(ml/min•100g) 50
None
Maximal
Level of Sympathetic Activity
(From Lassen, N.A., Brain. In: Peripheral Circulation, P.C. Johnson, ed. Wiley, 1978)

19. 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

20. Humoral Control Catecholamines Angiotensin II
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 II
Very little or no effect

21. Neuropeptides and Other Vascular Control Mechanisms
Vasodilation
Calcitonin gene-related peptide (CGRP)
Substance-P
Vasoactive intestinal peptide (VIP)
Vasoconstriction
Neuropeptide-Y (NPY)
Endothelin (vascular and neuronal ET-1 and neuronal ET-3 acting primarily on ETA receptors)
CGRP and VIP are released during headache. The 5-HT1B/D agonist, sumatriptan, can reverse the vasodilation caused by these substances.

22. Neural Innervation of Cerebral Vasculature

23. Conditions Related to Altered Cerebral Circulation
Syncope
Hypotension
Orthostatic
Vaso-vagal reflex
Both vascular occlusion (e.g., thrombus) and hemorrhage ultimately lead to ischemia and tissue hypoxia.

24. Stroke Hemorrhagic Ischemic Ruptured aneurism
Vascular weakening due to chronic hypertension
Ischemic
Thrombus formation or embolism
Vasospasm (ET-1?) associated with subarachnoid hemorrhage

25. Headache
Associated with (not caused by) neurovascular-mediated vasodilation in migraine and cluster headaches
Possible roles for CGRP and VIP