“Neurovascular Coupling basics"

Cerebral Blood Flow (CBF)

Total occlusion of CBF unconsciousness within 5 - 10 seconds.

- No storage of nutrients (glycogen) !

- No anaerobic metabolism (high metabolic rate of neurons) !

No O2 to brain no metabolism

The normal blood flow through the brain tissue of the adult averages 50 - 65 ml / 100g brain / minute.

For the entire brain, this amounts to a total of 750 - 900 ml / min. (15% of the average cardiac output).

Weight of Entire Brain (750 ml / 50 ml) x 100 g = 1500 g

Cardiac Output (75 ml / contraction) x (heart frequency) = ± 5000 ml/min

(750 ml / 5000 ml) x 100% = 15%

Neurovascular Coupling

Neuronal metabolism & CBF can change 100 – 150% within seconds to respond to local neuronal activity.

Increase in blood flow to the occipital regions of the brain when light is shined into the eyes which demands neuronal activity

Function of neurovascular coupling is to maintain an adequate supply of O2 / glucose / amino-acids / fatty-acids and removal of CO2 / H+ ions / hormones, for varying neuronal metabolism.

(the role of amino acids / fatty acids to vasoregulation has to be investigated)

(astrocytes seem to play a prominent role in coupling neuronal activity to energy metabolism) 1Pellerin L and Magistretti PJ (1994) Proc Natl Acad Sci

USA 91:10625-10629 & J Neurol. 2003 Mar;250(3):384-6

Neurovascular coupling between brain activation and cerebrovascular physiology

3 physiological effects:

- bloodflow velocity

- bloodflow volume

- bloodoxygenation level

HOW IS THIS POSSIBLE ???

- Acute control = vasodilation + vasoconstriction (sphincters)

(- Long term control = physical sizes + collaterals + humoral)

CBF Regulation by Metabolic Factors

CBF Regulation by Arterial Pressure

CBF Regulation by Sympathetic Nervous System

Metabolic Factors

At least 3 metabolic factors have potent effects in regulating cerebral blood flow:

- Carbon dioxide (CO2) concentration

- Hydrogen ion (H+) concentration

- Oxygen (O2) concentration

Effect of increasing metabolism on tissue blood flow

An increase in CO2 concentration in the arterial blood

perfusing the brain greatly increases the CBF.

70% in arterial PCO2 almost doubles the blood flow.

Relationship between arterial PCO2 and cerebral blood flow

CO2 + H2O H2CO3 (carbonic acid) H+

CO2 diffuses through blood-brain barrier into the CSF to form H+

H+ ions cause vasodilatation of the cerebral vessels

(Vasodilatation increase H+ ion concentration, up to a blood flow limit of about twice normal)

Other substances that increases the acidity of the brain tissue, and therefor also increases H+ ion concentration:

- lactic acid

- pyruvic acid

- other acidic material formed during metabolism

Increased H+ ion concentration greatly depresses neuronal activity and increases CBF. This increased CBF carries away substances like CO2 and other acid

forming substances from the brain.

Loss of the CO2 removes H2CO3 from the tissues.

Conclusion: this mechanism helps to maintain a constant H+ ion concentration in the cerebral fluids and thereby helps to maintain a normal constant level of neuronal activity.

Blood flow to the brain insufficient to the demanded amount of O2 !

oxygen-lack (theory) mechanism immediately causes vasodilatation

During first seconds O2 concentration (early-response)

beginning of aerobic cerebral metabolism.

Then huge O2 concentration (late-response) increase in

cerebral blood flow overcompensates the metabolic demand for O2. (Late-response max. 3-9 seconds after beginning of

neuronal activation).

(identical mechanisms found in coronary – and skeletal muscle circulations)

Neuronal activation and cerebrovascular coupling.

A: Situation at rest

B: During neuronal activation

C: Timecourse of the change of OxyHb concentration upon regional neuronal activation

D: Sequence of cerebrovascular changes leading eventually to an increased T2* signal

ER

LR

ER = Early Response

LR = Late Response

Mechanisms of Metabolic Vasoregulation

Metabolism = formation vasodilator substance (vasodilator theory)

- Adenosine (phosphate compounds)

- CO2

- Histamine

- Potassium ions (K+)

- H+ ions

formation due to reaction on O2 deficiency

diffusion to precapillary sphincters + arterioles

Adenosine (phosphate compounds) believed most important !

Metabolism = O2 deficiency = ATP = release Adenosine = vasodilation

Arteriole with sidebranch and precapillairy sphincter (smooth muscle) responsible for vasoregulation

Smooth Muscle

O2 coupling for vasoregulation (oxygen-lack theory)

smooth muscle needs O2 to remain contracted

- high O2 concentration results in more contraction by sphincters

- low O2 concentration results in less contraction by sphincters

Metabolism O2 deficiency ATP release Adenosine vasodilation O2 concentration

formation vasodilator substance O2 concentration vasoconstriction smooth muscle contraction

Nice coupling !

CBF = Upstreaming larger arteries (e.g. a. carotis interna / externa) must also dilate to comply with demand !

Vasodilation by Nitric Oxide (NO).

Endothelial Derived Relaxing Factor (EDRF) = NO.

Rapid blood flow shear stress endothelial cells (viscous drag of blood against vessel wall) release NO relaxation arterial wall vasodilation.

Shear stress induces increase NO which results in (cGMP) relaxation of smooth muscle cell (media) of arterial wall (+ antiplatelet aggregation).

Arterial Pressure

60 mmHg – 140 mmHg no significant change in cerebral blood flow

Hypertension upshift to higher pressure levels with maximum 180 – 200 mmHg, autoregulating a normal cerebral blood flow.

Effect of changes in (mean) arterial pressure, from hypotension – normal tension – hypertension on cerebral blood flow (left) and blood flow through muscle (right).

- Constancy of CBF between 60 – 180 mmHg

- Arterial pressure below 60 mmHg CBF will extremely decrease.

- Arterial pressure above 180 mmHg CBF increases rapidly.

(Possible rupture of cerebral blood vessels which can result in brain edema or cerebral hemorrhage)

Mechanisms of Pressure Vasoregulation

- Metabolic Theory = vasodilator theory + oxygen-lack theory

- Myogenic Theory = high arterial pressure passively stretches the vessel reactive vasoconstriction reduction of bloodflow

Sympathetic Nervous System

Sympathetic innervations supply large superficial brain arteries (e.g. carotiden).

When arterial pressure (exceptional high level) due to exercise etc. sympathetic nervous system constricts larger brain arteries.

(prevent high pressures reaching the smaller brain vessels !)

(Regulation is important in preventing the occurrence of vascular hemorrhages and strokes in the brain)

Sympathetic innervations.

Areas of the brain that play important roles in nervous regulation of CBF.

Vasomotor center transmits sympathetic impulses to all blood vessels (Adventitia) of the body, which leads to vasodilation / vasoconstriction.

Hierarchy (+ = vasoconstriction)

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

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Level of Sympathetic Activity Slow & minimal effect !