Cerebral circulation & CSF formation

Clinical importance Abnormalities of Affect brain function profoundly Blood flow Metabolism Fluids Composition Pressure Affect brain function profoundly Decrease blood flow for 5-19sec loss of consciousness Increase in H+ ions depresses neuronal activity decreases brain activity

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

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

Cerebral blood flow Normal blood flow 50-65mls/100gr/min Entire brain=750-900 mls/min 15 % of resting cardiac ou put

Regulation of cerebral circulation Constant total cerebral blood flow is maintained under varying conditions. ABP at brain level. Venous pressure at brain level. Intracranial pressure. Blood viscosity. Degree of active constriction or dilation of cerebral vessels.

Regulation of blood flow Highly related to tissue metabolism Concentration of carbondioxide Hydrogen ions concentration 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 flow Increased H+ conc greatly depresses neuronal activity Increased 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 deficiency Normal 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 35-40mmHg Decreased in cerebral tissue PO2 below 30mmHg increase blood flow Below 20mmHg comma ensues

Measurement of blood flow Inject radio active substance in carotid artery Record radioactivity of each cerebral segment Press detectors against the surface of the cortex Detect rapidity of rise and decay of radioactivity in each tissue segment Record increased blood flow where there is activity

2. Autoregulation of cerebral blood flow Ability of tissue to regulate their blood flow according to their activity. When the arterial pressure changes CBF is auto regulated extremely well Between arterial pressure limits 60-140mmHg there is no significant changes in cerebral blood flow

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

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

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

3. 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

Sympathetic Control Level of Sympathetic Activity 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)

Role of sympathetic NS in controlling CBF There is strong sympathetic innervations in the brain Inhibition or mild to moderate sympathetic stimulation has mild or no effect in CBF changes Auto regulation overrides the nervous effect Important in preventing stroke Cerebral vascular accidents Incase 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 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

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.

Neural Innervation of Cerebral Vasculature

Cerebrospinal Fluid system Capacity of entire cerebral cavity enclosing the brain and spinal cord 1600-1700 mls 150mls is CSF 1450-1550 mls Brain & spinal cord Areas 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 cord acting as a shock absorber. It also carries away disposed materials.

Functions of CSF, continued,… 2. Facilitation of pulsatile cerebral blood flow, Distribution of peptides, hormones, neuroendocrine factors and other nutrients and essential substances to cells of the body, Wash away waste products.

Formation, flow and absorption Rate per day 500mls/day 3-4 times its volume 2/3rds secreted by choroid plexus in ventricles Mainly 2 lateral ventricles Ependymal surface of all ventricles Arachnoid membranes Brain 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 Osmolality Glucose 289 64 100

flow From lateral ventricles to 3rd ventricles to Aqueduct of sylvius to 4th ventricle then passes through the three small openings Two lateral foramina of lushka Foramen magandie on the middle And then enters cisterna magna Then upwards through the subarachnoid space surrounding the cerebrum Finally to large sagital venous sinuses

Choroid plexus Is a cauliflower like growth of blood vessels covered by a thin layer of epithelial cells Mechanism of CSF formation Na+ actively pumped outside the epithelial cells Pulls along with it Cl- ions Creates osmotically active environment Water flows by osmosis

Absorption of CSF Through arachnoidal villi Are microscopic fingerlike inward projections of arachnoidal membrane Have vesicular passages in them that allows the passage of CSF Dissolved protein molecules Particles as large as RBC & WBC into the venous blood

Perivascular space Space existing between pia matter and blood vessels in the brain Act as a specialized lymphatic system for the brain Excess protein in the brain tissue leaves the tissue flowing with fluid through perivascular spaces into subarachnoid space Also transport extraneous particulate matter of the brain such as dead WBC and other debris after brain infection

Cerebrospinal fluid pressure Normal average 10 mm Hg Regulated by arachnoidal villi Mechanism Arachnoidal villi function as a valve system Allows 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 circulation Disease states Blocks the system Increase CSF pressure Large brain tumors- decrease reabsorbption of CSF into the blood Increase 4x above normal Haemorhage Infection In cranial vault Release Large number of RBC+/- WBC in CSF block the system

Disorders of CSF circulation 4. Abnormal villi system Few arachnoid villi Or abnormal absorptive properties Hydrocephallus Excess water in the cranial vault Cause Obstruction of CSF flow Types Communicating Non communicating

Disorders of CSF circulation Communicating Fluid flow normal from ventricular system to arachnoid spaces Non communicating There 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 Blockage of arachnoid villi or subarachnoid spaces Fluids collects outside the brain

Brain barriers Blood cerebral spinal fluid barrier Blood brain barrier Barrier formed between blood and cerebral spinal fluid Blood brain barrier Barrier formed between blood and brain fluid Permeability Characteristics Highly permeable to H2O,CO2,O2, and most lipid soluble substances e.g alcoholic & anaesthetics Slightly permeable to electrolytes Na+, Cl- and K+ Glucose : its passive penetration is slow, but is transported across brain capillaries by GLUT1 totally impermeable to placenta proteins and non lipid soluble large organic molecules

Cause of barrier Manner in which the endothelial cells of the brain tissue capillaries are joined to one another Joined by tightly junctions Membranes of adjacent endothelial cells are tightly fused rather than having large slit spores between them Unlike other capillaries which have large pores

Functions of BBB Maintanins 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 BBB Premature infants with hyperbilirubinemia, free bilirubin pass BBB, and may stain basal ganglia causing damage (Kernicterus).

Clinical implications Some 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.