Cerebral Blood Flow

Question 1

Arterial blood supply: draw and explain the blood supply to the brain, identify perfusion fields for the main cerebral arteries and explain the neurological deficits that result following disruption

Answer 1

Demands of the Brain

• 2% of body weight
• 10-20% of cardiac output
• 20% of body oxygen consumption
• 66% of liver glucose

Because of this, the brain is very vulnerable if its blood supply is impaired

Blood Supply to the Brain
TWO sources:

1. Internal Carotid Arteries (front)
2. Vertebral Arteries (back)

• These give rise to an important network of cerebral arteries called the Circle of Willis
• You get cerebral arteries coming off the circle

Arteries to the Brain and Meninges

1. External Carotid - supplies the face
2. Internal Carotid - makes its way up into the skull to supply the cerebral hemispheres
3. The vertebral arteries branch off the subclavian arteries and make their way through transverse foramina in the cervical vertebrae and through the foramen magnum into the brain

Arteries of the Brain (Inferior View)

• The ventral view of the brain in humans is this view from underneath - this is because you consider what the ventral surface of the brain is like for four-legged animals
• The two arteries are the bottom are the vertebral arteries
• The vertebral arteries join together to form the basilar artery
• The basilar artery bifurcates to form the posterior cerebral arteries
• The vertebral arteries and basilar artery start moving anteriorly before they bifurcate into posterior cerebral arteries
• The internal carotid arteries travel superiorly
• and then head outwards (laterally) to form
• the middle cerebral arteries that emerge through the fissure between the frontal, parietal and temporal lobes
• The internal carotids also branch to form the anterior cerebral arteries that go up in between the two medial surfaces of the hemispheres and they follow the corpus callosum backwards about 2/3 of the way
• This arrangement of arteries is made into a circle by TWO posterior communicating arteries and ONE anterior communicating artery
• It is a circle so that if one side gets occluded there is still another route for blood to travel

Question 2

Venous drainage: recognise the pattern of venous drainage of the brain

Answer 2

There is a huge system of large veins that drain the cerebral hemispheres via the jugular system

• Cerebral veins
• Venous sinuses
• Dura mater
• Internal jugular vein

Dural Venous Sinuses

• Running along the top is the superior sagittal sinus, which is housed between the two folds of dura (folded dura matter opens up and forms the sinuses)
• This is also the point at which the CSF is drained back into the venous system
• Running along the bottom of the dural fold is the inferior sagittal sinus
• These sinuses run backward to form a big space filled with blood called the
• CONFLUENCE OF THE SINUSES (where all the sinuses come together)
• A bleed at the confluence of sinuses can be pretty bad

Difference between dura in the skull and in the vertebral column:

• Vertebral column has a SINGLE LAYER of dura with fat between the bone and the dura
• In the skull there are TWO LAYERS of dura that are mostly stuck together
• TWO layers of dura in the skull:

1. Periosteal
2. Meningeal

• These two layers peel apart in some places and are filled with venous blood
• A fold of dura extends between the medial surfaces of the two hemispheres called the FALX CEREBRI
• The peeling apart of the two layers of dura at the top of the falx cerebri forms the superior sagittal sinus
• Within this gap in the dural layers you find arachnoid granulation - these are burst of subarachnoid space that protrude into the superior sagittal sinus
• CSF leaks through holes in the arachnoid membrane and enter the superior sagittal sinus
• Extradural haemorrhages have a rapid onset because it is usually due to the rupture of a meningeal ARTERY

Question 3

Cerebrovascular pathology: define the following terms: cerebral ischaemia, cerebral infarction, cerebral thrombosis, cerebral embolism and cerebral haemorrhage; define “stroke” and “transient ischaemic attack” and list the main risk factors for these conditions; compare the effects of a cerebrovascular accident in the cerebral cortex with one in the brainstem

Answer 3

Cerebrovascular accident 

Stroke

• Definition: 
Rapidly developing focal disturbance of brain function of presumed 
vascular origin lasting more than 24 hours 

• These are 85% due to infarction and 15% due to haemorrhage 


Infarction

• Degenerative changes that occur in tissue following occlusion of an artery (loss of oxygen and nutrients)

Transient Ischaemic Attack (TIA)

• In this case, it is the death of brain tissue following the occlusion of an artery
• Temporary blockage that could be a sign of future stroke
• If the vessels are restored you don’t have a structural deficit

Cerebral Ischaemia

• Lack of sufficient blood supply to nervous tissue resulting in permanent damage if blood flow is not restored quickly
• Due to hypoxia/anoxia

Causes of Occlusions

1. Thrombosis: Formation of a blood clot (thrombus)
2. Embolism: Plugging of small vessel by material carried from larger vessel e.g. thrombi from the heart or atherosclerotic debris from the internal carotid, breaks away and goes up in the smaller vessels (could be air or fat)

The more proximal the occlusion is in the artery, the more devastating the result

Epidemiology

• 3rd commonest cause of death
• 100,000 deaths in the UK per annum
• 50% of survivors are permanently disabled
• 70% show an obvious neurological deficit
• Risk Factors: Age, Hypertension, Cardiac disease Smoking, Diabetes mellitus

Question 4

Outline perfusion fields of the brain and their relation to stroke and hemorrhagic stroke

Answer 4

(from lateral view - attached)

• The middle cerebral artery extends laterally and emerges through the lateral fissure between the frontal and temporal lobes
• It supplies the front 2/3 of the lateral part of the hemisphere
• The posterior cerebral artery supplies the medial and lateral parts of the posterior part of the hemisphere
• The anterior cerebral artery supplies the medial part of the hemisphere (to the parietal – occipital lobes (although it is anterior- more likely to be affiliated with the leg)
• Posterior cerebral artery supplies the lateral and medial third
• There is a characteristic set of symptoms depending on which artery is occluded

Disturbance of the Anterior Cerebral Artery

1. Paralysis of the contralateral LEG more so than the arm
2. This is because the motor homunculus shows that the part of the motor
3. cortex that controls the leg is more medial to the part controlling the arm
4. Disturbance of intellect, executive function and judgement (abulia - absence of willpower)
5. Loss of appropriate social behaviour (overly-agressive, hypersexual)

Disturbance of the Middle Cerebral Artery

CLASSIC STROKE

1. Contralateral hemiplegia - more the contralateral ARMS than the legs

Because the lesion is more lateral - this is where the part of the motor cortex controlling the arms is found

1. Contralateral hemisensory deficits
2. Hemianopia
3. Aphasia (Left sided) - can’t speak

Left-sided lesion of the middle cerebral artery will result in aphasia because the language centres are more on the left side of the brain than the right

NOTE: Broca’s Area - involved in speech
Wernicke’s Area - involved in understanding language

Disturbance of the Posterior Cerebral Artery

1. Posterior cerebral artery supplies the occipital lobe where you find the primary visual cortex
2. This leads to visual defects:
   
   1. Homonymous hemianopia
   2. Visual agnosia Not being able to recognise things that you see
   3. Prosopagnosia inability to recognise familiar faces

Lacunar Infarcts

• A stroke often causes small holes to appear in brain tissue
• These holes are called lacunae
• Bits of brain tissue die and these gaps appear
• They appear in deep structures as a result of small vessel occlusion
• Because there are so many of these small vessels throughout the brain, the symptoms experienced are totally dependent on the anatomical location of the vessel that has been occluded
• Hypertension can cause lacunar infarcts

Haemorrhagic Stroke

1. Extradural
   
   • Trauma
   • IMMEDIATE effects
   • may injure middle meningeal artery – pressure on the brain – death because of raised intracranial pressure – neurosurgical emergency
   • Make holes – remove o piece of skull, locate the bleeder and correct it
2. Subdural
   
   • Trauma
   • DELAYED effects
   • slow, venous, lower pressure bleed, may be difficult to pick up
3. Subarachnoid
   
   • Usually caused by RUPTURED ANEURYSMS
   • Usually treated by platinum wire placed by radiologists to stop it from rupturing
4. Intracerebral
   
   • Spontaneous hypertensive rupture of small vessels

Question 5

Intra-cranial haemorrhage: explain the possible consequences of subdural or epidural haemorrhage

Answer 5

Extradural Haematoma

• High pressure arterial supply to the brain leads to the splitting of some of the arteries that are running in the meninges themselves (between the dura and the skull)
• This leads to compression of the skull underneath
• The periosteal dura is stuck to the skull so it is only a potential space that is there, which can be filled by blood in an extradural haemorrhage

Subdural Haemorrhage

• Tend to be SLOWER
• It is caused by the rupture of VEINS in the skull - as this is at much lower pressure the onset of symptoms is much slower
• Because of the slow onset of symptoms, patients may initially think that they are ok and then experience symptoms a few hours later

Question 6

Outline oxygen and glucose supply to the brain

Answer 6

BLOOD FLOW TO THE BRAIN

Oxygen Supply

• The brain is a highly metabolically active organ, therefore requires a high blood supply (16% of cardiac output = 55ml/100g tissue/min)
• Whenever blood flow to the brain is reduced by more than 50%, insufficient O2 is delivered and function is increasingly impaired (leading to ischaemia + infarct)
• If total CBF is interrupted for as little as 4secs, unconsciousness will result
• After a few minutes, irreversible damage occurs to the brain

Glucose supply

• It is imperative that brain cells + neurons receive sufficient glucose for metabolism as the brain cannot synthesize or utilise any other source of energy (although ketones can be metabolized to a very limited extent)
• If the supply of glucose to the brain is interrupted, or the blood glucose concentration is low (hypoglycaemia), brain function is impaired
• If the glucose concentration falls below 2mM it can result in unconsciousness > coma > death

Question 7

Cerebral blood flow: explain the importance of cerebral blood flow regulation, list the neural and humoral factors involved in regulation

Answer 7

CEREBRAL BLOOD FLOW REGULATION

Cerebral blood flow

Because of the constant need for oxygen and glucose, there must be an efficient regulatory system in operation. Cerebral blood flow is regulated:

• Systemically (mechanisms which affect the total CBF)
• Locally (mechanisms which relate activity or requirement in specific brain regions to altered localised blood flow)

Total Cerebral Blood Flow is Autoregulated

• Autoregulation occurs within a relatively wide breadth of the arterial blood pressure from 60 - 160 mm Hg
• One Factor: MYOGENIC (response to stretch)
  
  • The smooth muscle lining the arteries can stretch in response to blood flow
  • An increase in pressure on the vessel wall will result in a myogenic response that leads to contraction of the smooth muscle - this decreases cerebral blood flow
  • This myogenic response occurs when there is a change in blood pressure in the body
• Also, the local delivery of oxygen to brain tissue is related to the needs of that tissue by local autoregulation

Regulation of Cerebral Blood Flow

1. Neural
2. Chemical control

Neural Control

Sympathetic Nerve Stimulation

• Sympathetic innervation of the main cerebral arteries can cause vasoconstriction - this only happens when the arterial blood pressure is HIGH

Parasympathetic (facial nerve) Stimulation

• We don’t normally associate the parasympathetic nervous system with vasculature
• However, facial nerve fibres are innervated by parasympathetic fibres - this causes a slight vasodilation

Central Cortical Neurones

• The neurones within the brain itself can release neurotransmitters such as catecholamines that cause vasoconstriction

Dopaminergic Neurones
• Produce vasoconstriction
• They are important in regulating differential blood flow to areas of the brain that are more active

Dopaminergic Neurones

• NOTE: Capillaries in the brain have PERICYTES around them, which are contractile
• Pericytes are a type of brain macrophage
• They have a variety of functions e.g. immune function, transport properties, contractile
• Dopaminergic neurones innervate the smooth muscle surrounding arterioles and the pericytes around the capillaries
• When the dopaminergic neurones are active, they can cause the contraction of pericytes to decrease the blood flow to a particular area thus diverting blood to other, more active areas of the brain
• Dopamine may cause contraction of pericytes via aminergic and serotoninergic receptors

Chemical control: when cells are metabolically active, there is a localised release of chemical factors which have localised effects on blood flow (e.g. lactic acid > local vasodilation). These chemical factors include:

• pH - when cells are active they will produce lactic acid - the H+ ions in the lactic acid will cause a drop in pH and cause vasodilation in that area
• K+ is released at one stage of the action potential and acts as a vasodilator
• CO2 is indirectly associated with vasodilation

1. CO2 (indirectly) > vasodilation
2. pH (H+, lactic acid, etc) > vasodilation
3. nitric oxide > vasodilation
4. K+ > vasodilation
5. Adenosine > vasodilation
6. Anoxia > vasodilation
7. Others include kinins, prostaglandins, histamine, endothelins

Question 8

Explain the regulatory mechanisms in response to changes in blood pressure and carbon dioxide tension

Answer 8

Effect of pCO2 on cerebral blood flow. There is a sinusoidal relationship between increased carbon dioxide and cerebral blood flow (via a local autoregulatory effect).

Cerebral Arterial Vasodilation by CO2

• H+ ions DO NOT cross the BBB
• However, H+ ions can be generated within the brain (on the other side of the BBB)
• CO2 can move through the BBB
• In the smooth muscle cells and neural tissue, CO2 and H2O in the presence of carbonic anhydrase leads to the formation of bicarbonate and H+
• So this H+ that is produced acts as a vasodilator Vasodilation mediated by Nitric Oxide

Vasodilation mediated by Nitric Oxide

NO stimulates guanylyl cyclase which converts GTP to cGMP which then causes vasodilation

Question 9

Blood brain barrier: define the blood brain barrier (structure, function,mechanism) and explain its significance

Answer 9

Functions of the BBB

1. Protects the brain tissue from certain toxins and circulating transmitters like catecholamines
2. It also protects the brain from wide variations in ion concentrations

Structure of the BBB (image)

• The endothelial cells that line the capillaries in the brain, unlike in the rest of the body, have VERY TIGHT JUNCTIONS - the capillaries are non-fenestrated
• These tight junctions mean that a lot of molecules can’t pass readily through the BBB
• In addition, these capillaries are surrounded by pericytes that have end-feet that run along the capillary wall
• When the pericytes contract, they make it more likely for molecules to escape the capillary
• So it is mainly the tight junctions between endothelial cells that form the BBB but the pericytes are also involved

More on the BBB

• Some molecules - lipophilic molecules - cross the BBB relatively easily (e.g. alcohol and anaesthetics)
• Only certain hydrophilic substances are allowed through the BBB by means of specific transport mechanisms including:

1. Water via aquaporin channels
2. Glucose via GLUT1 proteins
3. Amino acids via 3 different transporters
4. Electrolytes via specific transporter systems

• Circumventricular organs have fenestrated capillaries and therefore they lie outside the BBB
  
  • So molecules can readily pass from the blood to the CSF/ECF
  • Circumventricular organs include:
  1. Median eminence region of the hypothalamus
  2. Subfornical organ (SFO)
  3. Organum vasculosum of the lamina terminalis (OVLT)

Question 10

Outline the formation and composition of the CSF

Answer 10

Formation of CSF

• Formed by the CHOROID PLEXUS
• Capillaries surrounded by ependymal cells (tight junctions)
• Ependymal cells secrete molecules into the ventricles to make the CSF - this is why the
• CSF is different to blood
• Path of CSF:
  
  • Lateral Ventricles
  • 3rd Ventricle (via interventricular foramina)
  • Cerebral Aqueduct
  • 4th Ventricle
  • Subarachnoid Space (via medial and lateral apertures)
• VolumeofCSF=80-150mL
• Volume of CSF formed per day = 450 mL/day
• Function of CSF:
  
  • Protection (chemical and physical)
  • Nutrition of neurones
  • Transport of molecules

Composition of Plasma compared to CSF (mM/L)

LOWER in the CSF:

1. K+
2. Calcium
3. Amino Acids
4. Bicarbonate

HIGHER in the CSF:

1. Magnesium
2. Chloride
3. OSMOLARITY IS THE SAME

The pH of the CSF is slightly more ACIDIC