The brain is enclosed within a rigid bony skull, of fixed volume
Fluid is incompressible
Therefore, any ↑
in volume of intracranial contents will cause a large
↑
in pressure
Blood-Brain Barrier
Refers to the barrier to diffusion from the plasma into the ECF compartment of the brain for many substances that pass freely into the interstitium of other tissues
These substances include charged and polar molecules and macromolecules
Control of ICP
Monro-Kellie Doctrine
Monro-Kellie Doctrine states that
The brain is enclosed within a rigid bony skull, of fixed volume
Fluid is incompressible
Therefore, any ↑
in volume of intracranial contents will cause a large
↑
in pressure
Intracranial Contents
Brain
85%
CSF
10%
Blood
5%
Brain volume would not vary unless there is pathology (eg oedema, haemorrhage, etc
CSF volume total 150ml, of which 75ml is in cranium and 75ml is in spinal canal. CSF volume in cranium could increase if there is hydrocephalus
Cerebral blood volume corresponds to cerebral blood flow, which is controlled by several factors (see next section)
ICP Buffering
When intracranial volume rises, initially the intracranial pressure is buffered by the
translocation of CSF from the cranium into the spinal canal
Once this buffering mechanism is exhausted, the ICP will rise rapidly
Cerebral Blood Flow & O2 Consumption
Cerebral O2 Consumption
3 - 3.5ml O2/100g/min
Total 50ml O2/min
Brain is only 1400g, but uses 20% of
O2
Control of Cerebral Blood Flow
CBF = CPP/CVR
CPP = MAP - (JVP or ICP) *whichever is higher
CVR controlled by:
Metabolic autoregulation
Pressure autoregulation
Chemical factors (CO2, O2)
Nervous system (systemic BP homeostasis)
Metabolic Autoregulation
Linear relationship between O2 consumption and blood flow
Pressure Autoregulation
CBF maintained constant between MAP of 50 –
150mmHg
Lower inflection point –
maximal vasodilation
Upper inflection point –
high pressure overcomes vasoconstriction
paCO2 vs CBF
↑
CBF by 4% for every ↑
paCO2 of 1mmHg between paCO2 of 20 –
80mmHg
Lower inflection point –
limited by hypoxaemia →
vasodilatation
Upper inflection point –
maximal vasodilatation
paO2 vs CBF
Fairly flat until pO2 drops below 50mmHg
This relationship is due to shape of oxygen-Hb dissociation curve
If you plot CBF vs O2 content instead, it reveals a more linear relationship
Blood-Brain Barrier
Definition
Refers to the barrier to diffusion from the plasma into the ECF compartment of the brain for many substances that pass freely into the interstitium of other tissues
These substances include charged and polar molecules and macromolecules
Components
Physical
Endothelial cells
Tight junctions between endothelial cells in the cerebral capillaries
Cell membrane of endothelial cells has lower water permeabiliity than most other cells due to absence of fenestrations.
Basement membrane
Astrocyte pedicles (foot processes)
Chemical
Enzymatic degradation in endothelial cells of certain substances
MAO and dopa decarboxylase prevent entry of some amines
AChE prevents passage of neurotransmitter ACh
What can cross?
Passive diffusion/osmosis
Resp gases (CO2, O2) →
alter pH, stimulation of resp centre
Lipid soluble substances, MW <
30kDa
Water (though transfer is significantly lower than in most other capillaries)
Active/facilitated transport by specific transporter mechanisms
Glucose (GLUT-1 transporter)
Amino acids
Electrolytes must be able to cross but may not occur rapidly, via specific ion channels
Na+, K+, Ca2+, HCO3-, Mg2+, Cl-
Hormones, eg insulin, thyroxine
Brain is protected from potentially toxic substances while metabolic substances have free access
What can't cross?
Large, polar molecules
Proteins, eg immunoglobulins
Urea
Cells, eg leukocytes
Bilirubin (neurotoxic)
Functions of the BBB
Maintain constancy of environment of neurons in CNS
Constancy of ionic concentrations of K+, Ca2+, Mg2+, H+
are critical for normal neural transmission.
Minor fluctuation can cause big consequences
Protects brain from endogenous and exogenous toxins
Protects against bloodborne pathogens →
encephalitis
Protects against autoimmune attack, eg multiple sclerosis
Prevent escape of neurotransmitters into general circulation
Circumventricular Organs
Areas surrounding the 3rd and 4th ventricles that are outside the BBB:
Post pituitary (secrete hormones)
Chemoreceptor trigger zone (area postrema), stimulated by chemicals that can't cross BBB
Subfornical organ (respond to Ang II →
thirst)
Organum vasculosum of the lamina terminalis (OVLT) osmoreceptor
Pineal gland (secretes melatonin)
Functions of these areas require access to the general circulation for neuroendocrine reasons
Overlying the circumventricular organs is the Blood-CSF Barrier
Clinical Implications
Anaesthetic drugs
Some drugs can cross BBB to cause their clinical effect eg propofol or side effect, eg atropine (tertiary amine)
Others are excluded, eg glycopyrrolate (quaternary amine) has no CNS side effects
Dopamine and serotonin cannot enter but precursors L-dopa and 5-HT can
BBB immature in neonate
Drugs such as morphine, can penetrate faster
Unconjugated bilirubin (neurotoxin) can enter brain →
kernicterus
BBB breaks down in areas of inflammation/infection, eg meningitis
Tumours develop new blood vx that don't have tight junctions
BBB may be temporarily disrupted by sudden marked increase in BP or injection of hypertonic fluid
Cerebrospinal Fluid
Functions
Protects the brain from trauma by cushioning it (water bath effect)
Buffer rise in ICP by translocation to the extracranial subarachnoid space
Return of interstitial proteins to the circulation (no lymph vx)
Production & Turnover
Total volume 150ml
Daily production 500-600ml
Formed by :
Choroid plexus (>
67%)
Directly from ependyma of the walls of the ventricles (<
33%)
Flows through Foramina of Magendie and Luschka into subarachnoid space of brain and spinal cord
Absorbed by:
Arachnoid villi (90%)
Directly by cerebral venules (10%)
Blood-CSF Barrier
Barrier to diffusion of most polar molecules from blood into CSF
Due to tight junctions between the epithelial cells of the choroid plexus
Functions to maintain a constant composition of the CSF
