Cerebral circulation and intracranial pressure, CSF formation, function and regulation

🖇 I. Cerebral Circulation and Arterial Anatomy

📌 Arterial Supply to the Brain

• Blood enters the brain via 4 main arteries:
• • 2 Internal Carotid Arteries
  • 2 Vertebral Arteries
• These 4 vessels join to form the Circle of Willis

📌 Major Branches from Circle of Willis

• Circle of Willis gives rise to 3 pairs of major arteries:
• • 2 Anterior Cerebral Arteries
  • 2 Middle Cerebral Arteries
  • 2 Posterior Cerebral Arteries

🚨 Functional End Arteries (Exam Point)

• Anatomical anastomoses exist between cerebral arteries
• However, these anastomoses are NOT sufficient to prevent occlusion or infarction
• Therefore, cerebral arteries are described as functional end arteries (Exam Point)
• Although anatomical connections exist, they are not materially functional enough to prevent damage from blockage
• Vessels are considered functionally terminal despite anatomical fusions

📌 Vascular Distribution Pattern

• No crossing between right and left hemispheric circulation
• No material communication between right and left brain circulation
• If substance injected into one hemisphere → distributes only to that hemisphere
• Lateral isolation occurs because pressures within Circle of Willis are typically equal
• No pressure difference to drive movement across midline

🖇 II. The Blood-Brain Barrier (BBB)

📌 Definition & Function

• Specialized barrier regulating exchange between:
• • Blood
  • Cerebrospinal Fluid (CSF)
  • Brain tissue

🚨 Structure of the BBB (Exam Point)

Three main structural features around capillaries:

1. Tight junctions between endothelial cells of capillaries
2. No fenestrations (unlike capillaries elsewhere in body)
3. Thick basement membrane + Astrocyte end-feet covering the capillary

📌 Substances That Pass Freely Through BBB

• Substances necessary for brain metabolism
• Water
• Gases (O₂ and CO₂)
• Lipid-soluble substances with high partition coefficients
• Free Steroid Hormones (Exam Point):
• • Only steroid hormones not bound to proteins can pass
  • Crucial for regulatory mechanisms
  • Enables long-loop feedback for brain to monitor systemic hormone levels

🟠 Substances That Are Restricted (Do Not Pass Normally)

• Proteins (do not cross at all)
• Protein hormones
• Bacteria
• Bile pigments
• Penicillin (under normal conditions)
• Dopamine (Exam Point)
• Serotonin (Exam Point)

🟣 Clinical Applications: Circumventing the BBB

Parkinsonism Treatment:

• Dopamine (required for treatment) does not cross BBB
• L-Dopa (Levodopa) is administered instead
• L-Dopa can cross the barrier
• Converted to Dopamine within the brain

Serotonin Administration:

• Serotonin cannot cross BBB
• 5-Hydroxytryptophan is administered
• Can cross BBB and be converted to Serotonin in brain

BBB Permeability in Infection:

• During inflammation or infection (meningitis, encephalitis)
• Barrier becomes dysfunctional or more permeable
• Allows Penicillin to cross and treat bacterial infection

🚨 Glucose Transport (Exam Point)

Primary Energy Source:

• Glucose is the primary source of energy for the brain (Exam Point)

Transport Mechanism:

• Glucose transport uses GLUT-1 transporter
• GLUT-1 is Insulin-Independent (Exam Point)

GLUT-4 Exception:

• Only brain region using insulin-dependent GLUT-4 transporter: satiety center

Mechanism of Satiety Center:

• Insulin levels rise after a meal (post-prandial)
• Increased insulin activates GLUT-4 in satiety center
• Signals that body has been fed (post-meal glucose)
• Activation helps shut down feeding center

Clinical Relevance:

• If entire brain were insulin-dependent
• Type 1 Diabetes (absent insulin) would render brain dysfunctional

📌 Functions of the BBB

• Maintains brain homeostasis
• Stabilizes concentration of substances
• Maintains optimal pH
• Prevents waste products and toxins from reaching brain

🟣 Clinical Note: Hemolytic Disease of the Newborn (Kernicterus)

BBB Immaturity:

• BBB in newborns (especially premature infants) not fully mature
• Incomplete development in infants under 1-2 years old

Pathophysiology:

• Severe hyperbilirubinemia (e.g., Rh incompatibility)
• Maternal antibodies attack fetal red blood cells
• Unbound bilirubin can cross immature barrier
• Bilirubin reaches brain → causes kernicterus damage

Clinical Management:

• Infants with high bilirubin monitored closely
• Bilirubin measured every 12-14 hours

🟣 Clinical Note: Diagnostic Use of BBB Breakdown

Principle:

• BBB compromised in areas affected by:
• • Infection
  • Inflammation
  • Tumors
• Breach allows normally restricted substances to enter brain tissue

Diagnostic Procedure:

• Inject substance that normally cannot cross BBB
• Example: Albumin bound to radio-iodine
• If radioactivity detected via imaging in specific area
• Indicates barrier is defective
• Localizes site of tumor or inflammation

🖇 III. Circumventricular Organs (CVOs) (Exam Point)

📌 Definition & Location

• Specialized structures located around 3rd and 4th ventricles
• Structurally lack the BBB
• Act as "openings" or "windows" between blood circulation and CNS

📌 Purpose

• Allow brain to:
• • Sense substances in systemic circulation blocked by BBB
  • Secrete substances directly into circulation

🚨 Functions: Sensory and Secretory (Exam Point)

1. Sensory Function (Sensing Blood-borne Chemicals):

• Allows brain to sense chemicals in circulation

Examples of Sensory Function:

• Sensing HCG (pregnancy hormone)
• Sensing Interleukins (protein released during inflammation/tissue breakdown) → triggers fever response
• Sensing toxins absorbed from stomach → triggers vomiting reflex
• Sensing Angiotensin II (protein) → regulates blood pressure (affects vasomotor center)

2. Secretory Function (Secreting into Circulation):

• Allows brain/CNS structures to release hormones or substances into circulation

Examples of Secretory Function:

• Releasing hormones formed in hypothalamus
• Pineal gland (a CVO) secretes melatonin (hormone/protein that cannot cross BBB)
• Releasing waste products for detoxification (associated with defecation sensation)

🚨 Regulatory Roles Achieved via CVOs (Exam Point)

• Regulation of defecation sensation
• Blood pressure regulation
• Fever production
• Coagulation regulation

🖇 IV. Cerebral Metabolism and Energy Use

🚨 Oxygen Consumption (Exam Point)

• Brain consumes approximately 50 ml of O₂ per minute (Exam Point)
• Represents 20% of total body resting oxygen consumption (Exam Point)
• 100 grams of brain tissue consume approximately 3.5 ml of O₂ per minute

🚨 Sensitivity to Hypoxia (Exam Point)

• Brain is highly sensitive to hypoxia (Exam Point)

Timeline of Hypoxic Damage:

• Loss of O₂ for 5 seconds → causes unconsciousness
• Loss of O₂ for 3-5 minutes → death of neuronal cell bodies throughout cortex and brain

🚨 Energy Source (Exam Point)

• Glucose is the main source of energy (Exam Point)
• Confirmed by Respiratory Quotient (RQ) of brain tissue = 1

Alternative Energy:

• In starvation or low glucose states
• Brain can use Amino Acids for energy

📌 Detoxification

• Brain uptakes lactate from blood
• Used for detoxification of Ammonia

🖇 V. Cerebral Blood Flow (CBF)

🚨 Brain Weight and Cardiac Output (Exam Point)

• Brain weight: approximately 1.4 kg (1400 grams)
• Represents 2% of body weight
• Receives 15% of total Cardiac Output (Exam Point)

🚨 Total CBF Volume (Exam Point)

• Total cerebral blood flow: 700-750 ml per minute (Exam Point)
• Regional flow: approximately 50 ml per 100 grams of brain tissue per minute

📌 Distribution of CBF

Gray Matter vs White Matter:

• CBF is not uniform
• Gray matter receives approximately 3 times the blood flow of white matter
• Due to higher metabolic activity in gray matter

Specific Flow Rates:

• Gray matter: 69 ml/100g/min
• White matter: 420 ml/100g/min

Highest Blood Flow:

• Inferior colliculi (part of auditory pathway) has highest blood flow

🚨 Total CBF vs. Activity (Exam Point)

• Total amount of CBF (750 ml/min) remains constant (Exam Point)
• Constant regardless of:
• • Mental activity level
  • Physical activity
  • Sleep
  • Stressful exams

What Changes:

• Regional or local distribution changes
• Blood redirected to most active areas
• Examples: visual cortex, Broca's area, motor areas
• Active areas receive more flow at expense of less active regions

🖇 VI. Regulation of Cerebral Blood Flow

📌 A. Factors Affecting Flow (Hemodynamics)

1. Effective Perfusion Pressure:

• CBF is directly proportional to effective perfusion pressure
• Perfusion pressure = (P arterial) - (P venous or Intracranial Tension)

2. Viscosity:

• CBF is inversely proportional to blood viscosity
• Higher viscosity increases resistance

3. Intracranial Tension (ICT) (Exam Point):

Monro-Kellie Doctrine:

• Combined volume inside rigid skull must remain constant:
• • Brain tissue
  • CSF
  • Blood/blood vessels
• Brain and CSF are largely incompressible
• If ICT increases (swelling, hemorrhage) → blood vessels compressed → reduces CBF

🚨 B. Clinical Note: Cushing's Reflex (CNS Ischemic Response) (Exam Point)

Mechanism:

• High ICT (brain hemorrhage, edema) compresses vessels
• Compression reduces CBF → causes brain ischemia
• Ischemic brain triggers vasomotor center
• Dramatically increases systemic blood pressure
• Rise in systemic pressure increases effective perfusion pressure
• Attempts to overcome compression and force blood back into brain

Cushing's Triad:

• High blood pressure triggers baroreceptors
• Causes reflex bradycardia (slow heart rate)
• Brain hemorrhage is the ONLY hemorrhage where hypertension and bradycardia observed together (Exam Point)
• Hypoventilation/irregular respiration also part of response

Normal ICT:

• Normal ICT = 10 mmHg

📌 C. Chemical Regulation (Metabolic Control)

General Chemical Regulators:

• CBF highly sensitive to:
• • Metabolites (Potassium, Adenosine)
  • Acidosis
  • Hypoxia
• Act as powerful vasodilators
• Drive regional redistribution of blood flow during activity

🚨 Carbon Dioxide (CO₂) - Most Significant Regulator (Exam Point)

• CO₂ is most significant chemical regulator of CBF (Exam Point)

Mechanism:

• CO₂ crosses into brain tissue
• Reacts with water → forms carbonic acid
• Dissociates into bicarbonate + hydrogen ions (H⁺)
• Resulting local acidosis (increase in H⁺) is strongest effector
• Causes marked vasodilation

🚨 D. Autoregulation (Intrinsic Control) (Exam Point)

Definition:

• Autoregulation ensures total CBF remains constant
• Despite fluctuations in systemic blood pressure

Range of Autoregulation (Exam Point):

• Stability maintained between Mean Arterial Pressure (MAP) of 65 mmHg and 140 mmHg (Exam Point)

Outside Autoregulation Range:

• If MAP falls below 65 mmHg → CBF drops → leads to ischemia
• If MAP rises above 140 mmHg → danger to cerebral vasculature

Mechanisms of Autoregulation:

1. Metabolic Theory:

• Blood pressure drops (flow slows)
• Metabolites accumulate (inadequate washout)
• Metabolites cause vasodilation
• Compensates for low pressure

2. Myogenic Theory:

• Cerebral arteries respond to stretch
• Pressure increases → vessels stretched → reflexive vasoconstriction
• Pressure decreases → vessels relax → vasodilation

🚨 E. Sympathetic Nervous System (Exam Point)

General Effect:

• Sympathetic nervous system causes vasoconstriction

Effect Under Normal Pressure:

• Under normal conditions (65-140 mmHg)
• Sympathetic system has minimal net effect on total CBF

Key Role in Hypertension (Exam Point):

• Importance emerges when MAP exceeds 140 mmHg
• In severe hypertension:
• • Sympathetic system induces strong vasoconstriction
  • Prevents excessive flow
  • Protects cerebral vasculature from damage
  • Also plays role in decreasing edema

📌 F. Neurovascular Coupling (Functional Hyperemia/Activity Hyperemia)

Definition:

• Mechanism linking neuronal activity to local blood flow changes
• Responsible for regional distribution of CBF

Mechanism:

• Highly active neurons release Glutamate
• Glutamate influx stimulates Calcium (Ca²⁺) entry into Astrocytes
• Activated Astrocytes release potent vasodilating substances:
• • Nitric Oxide (NO)
  • Eicosanoids
• Ensures most active areas receive localized increases in CBF

🖇 VII. Cerebrospinal Fluid (CSF)

🚨 Formation Site (Exam Point)

• CSF formed mainly (50-70%) by Choroid Plexus (Exam Point)
• Located in the ventricles
• Smaller amount produced by capillaries lining ventricles

📌 Structure of Choroid Plexus

• Unlike BBB, Choroid Plexus capillaries are fenestrated
• Highly vascularized
• Allows continuous filtration and secretion of CSF

📌 Circulation Pathway

• CSF moves through ventricles
• Exits 4th ventricle through:
• • Foramina of Luschka
  • Foramen of Magendie
• Flows into subarachnoid space and central canal

🚨 Volume and Turnover (Exam Point)

• Total CSF Volume: 150 ml (Exam Point)
• Production Rate: 0.5 ml per minute (Exam Point)
• Total Daily Production: 550 ml per day (Exam Point)
• Turnover Rate: CSF completely renewed 3-4 times daily (Exam Point)

🚨 Absorption (Outflow) (Exam Point)

• Primary drainage pathway: Arachnoid Villi (Exam Point)
• Some drainage also occurs through capillaries

🚨 Composition Compared to Plasma (Exam Point)

CSF resembles interstitial fluid (ISF) of brain

CSF Concentrations LOWER than Plasma:

• pH: Lower (more acidic) than plasma
• • Due to high metabolic activity producing CO₂ → acidosis
• Protein: Significantly lower
• • Proteins do not cross BBB
• Glucose: Lower
• • Constantly consumed as fuel
• Potassium: Lower than plasma

CSF Concentrations HIGHER than Plasma:

• CO₂: Higher (due to metabolism)

📌 Functions of CSF

1. Mechanical Protection (Cushioning):

• Acts as protective buffer
• Absorbs shocks and impacts
• Prevents injury (e.g., without CSF, activities like boxing would be dangerous)

2. Buoyancy:

• Brain suspended and floats in CSF
• Effectively reduces brain weight
• Prevents strain and tension on nerves and structures
• Would otherwise cause constant headaches

3. Exchange Medium:

• Brings necessary materials:
• • Nutrients
  • Hormones
  • Drugs
• Removes waste products

🟣 Clinical Note: CSF Volume/Pressure Changes

• CSF volume or pressure can increase in certain conditions
• Effect on clinical outcome mostly determined by:
• • Resultant compression (tension) on surrounding structures
  • As governed by Monro-Kellie Doctrine