🖇 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:

Tight junctions between endothelial cells of capillaries
No fenestrations (unlike capillaries elsewhere in body)
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

Physiology