“Neurovascular Coupling basics"

Cerebral Blood Flow (CBF) Total occlusion of CBF  unconsciousness within seconds. - No storage of nutrients (glycogen) ! - No anaerobic metabolism (high metabolic rate of neurons) !  No O 2 to brain  no metabolism

The normal blood flow through the brain tissue of the adult averages ml / 100g brain / minute. For the entire brain, this amounts to a total of 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 O 2 / glucose / amino-acids / fatty-acids and removal of CO 2 / 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) 1 Pellerin L and Magistretti PJ (1994) Proc Natl Acad Sci USA 91: & J Neurol Mar;250(3): Pellerin L and Magistretti PJ (1994) Proc Natl Acad Sci USA 91: J Neurol 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 (CO 2 ) concentration - Hydrogen ion (H+) concentration - Oxygen (O 2 ) concentration

Effect of increasing metabolism on tissue blood flow

An increase in CO 2 concentration in the arterial blood perfusing the brain greatly increases the CBF. 70%  in arterial PCO 2 almost doubles the blood flow. Relationship between arterial PCO 2 and cerebral blood flow

CO 2 + H 2 O  H 2 CO 3 (carbonic acid)  H+ CO 2 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 CO 2 and other acid forming substances from the brain.  Loss of the CO 2 removes H 2 CO 3 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 O 2 !  oxygen-lack (theory) mechanism immediately causes vasodilatation During first seconds O 2 concentration  (early-response)  beginning of aerobic cerebral metabolism. Then huge O 2 concentration  (late-response)  increase in cerebral blood flow overcompensates the metabolic demand for O 2. (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) - CO 2 - Histamine - Potassium ions (K+) - H+ ions  formation due to reaction on O 2 deficiency  diffusion to precapillary sphincters + arterioles

Adenosine (phosphate compounds) believed most important ! Metabolism  = O 2 deficiency = ATP  = release Adenosine = vasodilation Arteriole with sidebranch and precapillairy sphincter (smooth muscle) responsible for vasoregulation Smooth Muscle

O 2 coupling for vasoregulation (oxygen-lack theory) smooth muscle needs O 2 to remain contracted - high O 2 concentration results in more contraction by sphincters - low O 2 concentration results in less contraction by sphincters Metabolism   O 2 deficiency  ATP   release Adenosine  vasodilation  O 2 concentration     formation vasodilator substance   O 2 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) Cerebral Blood Flow (ml/min100g) NoneMaximal Level of Sympathetic Activity  Slow & minimal effect !