1. Pumps, Aqueducts, and Drought Management:
Cerebral Hemodynamics and Brain Function
Randolph S. Marshall, M.D., M.S.
Elizabeth K Harris Professor of Neurology
Chief, Stroke Division
Columbia University Medical Center
New York

2. Hydrodynamics of Roman Aqueducts
Sophisticated construction
gradient of 34cm per Km (descent of 17m over 50Km) – too steep  overflow; too flat  clog
Gravity-pressurized pipelines (siphons) to get through depressions of >50m
Supply and demand
Eleven combined aqueducts brought >50 million gallons to Rome

3. Cerebral Hemodynamics - Autoregulation
Loss of autoregulation

4. Cerebral Response to Hypotension
Stage 1
Stage 2
CBV
OEF
CMRO2
CBF
Limit of autoreg.
Critical perfusion.
Ischemia
Infarction
Declining perfusion pressure

5. Impact of Hemodynamics on Brain Function
Hyperacute setting: thresholds
Acute stroke management
Hemodynamic effects in the chronic setting

6. Functions of autoregulation
Protection of brain from extremes of hypoperfusion and hyperperfusion
Maintain homeostasis (dynamic): fluctuating perfusion pressures are continuously counter-regulated by changes in flow within normal range
Neurovascular coupling to ensure adequate blood flow for neural activity

7. Mechanisms of autoregulation
Vasodilation and vasoconstriction
Arterioles
“myogenic”: Resting tone – Ca++ mediated
“neurogenic”: Neurotransmitters – adrenergic (Zhang et al Circ 2002, Hammer et al Stroke 2010), and cholinergic (Hammer et al J Phys 2012)
NO to cause smooth muscle relaxation in response to acetylcholine and other stimuli
Capillaries
Pericytes constrict capillaries in response to noradrenaline
Neurovascular coupling
Local effects on small vessels
NO: accumulates with neuronal activity, short-lived, potent vasodilator
Adenosine, arachidonic acid, and PGE2 may modulate vasodilation through astrocyte endfeet
Upstream regional effects to avoid passive reduction in flow elsewhere

8. EM of pericyte constricting a capillary

9. Cellular communication at the neurovascular interface
The neurovascular unit consists of neurons (N), endothelial cells (EC) astrocytes (AC), pericytes (PC), vascular smooth muscle cells (vSMC), microglia (MG) and perivascular macrophages (PM). Endothelial cells form a blood–brain barrier characterized by tight, adherence and gap junctions, as well as a specialized transporter system. Pericytes share basement membranes with blood vessels and directly contact endothelial cells via peg–socket junction complexes. Astrocytes stretch their endfeet toward blood vessels and neuronal synapses to integrate neuronal activity with the vascular response. A single astrocyte contacts >105 neurons.
Lee et al. FEBS J Sep;276(17):

10. Cerebral autoregulatory pathways involving the astrocyte
Koehler RC et al. Trends Neurosci Mar;32(3):160-9

11. Causes of Cerebral Hypoperfusion
RSM 2012

12. Hypoperfusion affects Brain Function in hyperacute ischemia

13. Cerebral ischemic thresholds
CBF
cellular
clinical 50 40
protein synthesis inhibition
higher cerebral dysfunction 30
anaerobic glycoliysis
glucose metabolism declines, acidosis, edema, K+ / Ca++ transients 20
hemiparesis
EEG flattening in anesthetized patients
electrical failure 10
ischemic penumbra?
membrane failure
ischemic core

14. Hemodynamics of Circle of Willis
rCBF = rCPP / rCVR
rCVR
ACA
rCPP
rCBF
MCA
ICA
arterioles
PCA BA

15. Hemodynamic effects in acute setting: ICA Balloon Test Occlusion

16. CBF and clinical monitoring during BTO

17. Pt RG: failed balloon test occlusion
Lazar RM, Marshall RS et al , JNNP 1996;60(5):559-63

18. Pt RC: Pressure –dependent BTO
Lazar RM, Marshall RS et al , JNNP 1996;60(5):559-63

19. Correlation of CBF with 3 behavioral patterns during BTO
Behav. Gp.
CBF (cc/100g/min) U
47.5
D-R
37.3
D-NoR
25.5
p=.003
Marshall, Lazar, et al, Brain 2001

20. Hypoperfusion Affects Brain Function in acute ischemia

21. Hypertensive support in acute stroke – animal model
Spontaneously hypertensive rats with MCAO stroke
SBP maintained at
mmHg (gp 1) or
(gp 2)
Physiological and neurological outcomes at Day 1, Day 4, Day 7
Kang B-T et al. Brain Res 2012;1477:83-91

22. Induced hypertension in stroke – Human model
17 pts with DWI-PWI mismatch and stable or worsening aphasia, hemineglect or hemiparesis
All had ICA or MCA stenosis or ICA occlusion
Randomized to receive phenylephrine to 10-20% incr in MAP vs. conventional Rx
RESULTS:
performance tracked with MAP (figure)
DWI vol increased 1.9ml in treated and 6.0ml in untreated
Clinical improvement correlated with PWI deficit decrease
Fig. 2. Illustrations of the temporal relationship between MAP and performance on daily tests of cognitive function. ✦ = MAP; ■ = function. Note decrease in fxn when phenylephrine discontinued. A & b: picture naming, c & d: line cancellation.
Hillis AE et al Cerebrovasc Dis 2003;16: