Regulation and Pathology of the Cerebral Circulation Flashcards
What are the 2 main sections of cerebral circulation?
- Anterior Cerebral Circulation
- Posterior Cerebral Circulation
* The two separate circulations are connected via communicating arteries
Which arteries supply the anterior cerebral circulation?
Mainly the Internal Carotid Arteries (which are branches of the common carotid artery)
Which arteries supply the posterior cerebral circulation?
Mainly the Vertebral Arteries which fuse to form a singular Basillar Artery (supplies the brainstem)
Which arteries connect the anterior and posterior cerebral circulations?
The two separate circulations are connected by the Posterior Communicating Arteries
Where do the posterior communicating arteries come from?
They arise from the Circle Of Willis which is a ring of arteries situated at the cranial end of the brainstem to ensure continuous blood supply to the brain should any arteries become occluded or dissected
What are the three major blood vessels of the brain?
- Anterior Cerebral Artery
- Middle Cerebral Artery
- Posterior Cerebral Artery
What does the Anterior Cerebral Artery do?
It arises from the internal carotid artery and extends upwards and forwards to supply the frontal lobes of the brain
What does the Middle Cerebral Artery do?
The largest branch to arise from the internal carotid artery. It supplies a portion of the frontal lobes along with the lateral surfaces of the temporal and parietal lobes
What does the Posterior Cerebral Artery do?
This artery usually arises from the Basilar Artery (but some individuals show anatomical variation in which it arises from the internal carotid)
It supplies the temporal and occipital lobes
Why is blood supply to the brain special?
Blood flow around the peripheral circulation is constantly changing in response to stimuli, however the blood flow in the brain remains relatively constant
-It is regulated locally in the brain (rather than by receptors situated around the body) to ensure that neurones are supplied with adequate vital nutrients so as to maintain optimal neural activity
Is the sympathetic nervous system involved?
The sympathetic nervous system plays a huge role in the regulation of systemic blood pressure through the likes of Baroceptors, however in the brain the Sympathetic nervous system has VERY LITTLE EFFECT because there is hardly any sympathetic innervation of cerebral blood vessels
-So the autonomic nervous system only has a global protective effect on cerebral blood flow, NOT a local one
How do neurohormonal systems alter blood flow to the brain?
Neurohormonal systems in the body such as the RAAS system or Natriuretic Peptides can cause large fluctuations in blood flow resulting in chronic hyper or hypotension
BUT
Unless these disturbances in blood pressure are extreme, blood flow within the brain can generally be maintained within normal limits
What happens if blood flow in the brain is disturbed?
If the mechanisms controlling local cerebral blood flow are disturbed, neuronal hypoxia, cell death, stroke and cognitive decline are all a possibility.
Neuronal cells in the brain have incredibly high metabolic rates and so need a constant blood supply, without which neuronal cells will die very quickly
How many capillaries are there in the human brain?
100 million capillaries in the human brain
This equates to 400 miles of vasculature
How far is each neurone from a capillary?
No neurone is more than 30-40um from a capillary
All neurones are in very close proximity to a capillary meaning they are effectively supplied by their own dedicated capillary-MICROVESSEL
Can cerebral neurones store energy?
No, cerebral neurones cannot store energy. This means that they must be supplied with a constant flow of blood in order to maintain oxygen levels and glucose levels that are coupled to their level of activity
How does PET/Functional MRI work?
Neurones need a constant supply of blood as they can’t store energy. Functional MRI and PET scanning uses this a basis for imaging as it can detect the uptake of oxygen from blood to neurone effectively using it as a quantitative analysis of neurone activity
How much oxygen does the brain use during normal intellectual functioning?
35ml/min/kg
Does the brain have a high metabolic rate?
YES-the brain only weighs 2% of entire body weight, however it is supplied with 20% of total cardiac output.
This is because it has a very high metabolic rate (brain is always functioning and neurones cannot store energry) so it needs a lot of blood to meet oxygen and glucose requirements
What mechanisms control cerebral blood supply?
- Metabolic factors - a specialised form of Functional Hyperaemia
- Cerebrovascular Autoregulation
- Endothelial Cell Function
- Effect of the blood-brain barrier
What is an astrocyte?
An astroycyte is a star-shaped glial cell. Gliacl cells are supportive and insulating cells localised around neurons.
Astrocytes are only located in the central nervous system
Where are astrocytes in the CNS?
The astrocytes are interposed between neurones and blood vessels, and they have processes called ‘End-feet’ that make contacts with capillaries
How many processes do astrocytes have?
Usually around 50
What is a Neurovascular Unit?
The functional collective consisting of neurones, astrocytes and microvessels
What do astrocytes do?
Despite supporting and insulating neurons, astrocytes transmit chemical signals from neurones to the microvessels to cause the microvessels to constrict or dilate in the context of neural activity
What is the function of astrocytes generally known as?
NEUROVASCULAR COUPLING
What neurotransmitter is released from neurones that acts on astrocytes?
Glutamate-the chief excitatory neurotransmitter
What astrocyte receptors are responsive to Glutamate?
NMDA and mGluRs
What does glutamate stimulation of astrocytes do?
It causes calcium spikes in astrocytes
What does calcium spikes do?
the Calcium spikes in astrocytes as a result of Glutamate stimulation from neurones causes the release of Vasodilator or Vasoconstrictor agents from Astrocyte End Feet which then act on the capillaries/microvessels
How is Nitric Oxide used in the brain?
It is used as a vasodilator
Where is NO released from?
Both neurones and endothelial cells
When do endothelial cells release NO?
In response to ACh release from cholinergic neurones (parasympathetic)
What is released from neurones simultaneously with NO?
NO is co-released with Neuropeptide Y (NPY) which is a powerful vasoconstrictor to maintain a balance
When can constant cerebral blood flow no longer be maintained?
Chronically increased systemic blood pressure above >160mmHg overwhelms the cerebral regulatory mechanisms
Why would cerebral vessels become occluded and shut down?
- Deposition of atherosclerotic plaques
2. Increase in wall thickness by inflammatory processes and oxidative stress=hypertrophic remodelling of smooth muscle
What is the problem with vessel remodelling in the brain?
Vessel remodelling causes disruption to the blood brain barrier which means the vessel becomes leaky allowing toxic products to reach the cerebral parenchyma
What happens if there is reduced cerebral blood flow?
Cerebral blood flow no longer matches neural activity.
If PO2 of the brain falls below 20mmHg ischaemia sets in.
Ischaemia causes neuronal cells to die resulting in stroke
How many strokes occur each year?
150,000
It is the leading causes of severe disability and the 3rd cause of mortality
How does age affect stroke risk?
The risk of stroke doubles every decade after the age of 55
Therapeutics for Ischaemic stroke:
- Thrombolysis with tPA
- limited efficacy due to short window, lack of responsiveness and haemorrhagic complications - NEUROPROTECTION
- trials are currently challenging drugs that interfere with the ischaemic cascade to minimise subsequent neurodegeneration
- so far have showed no clinical use
What is the sequence of main events in the ischaemia cascade?
- Loss of o2 hypoxia/anoxia and lack of energy supply results in co2/lactic acid build up
- the build up of hydrogen ions causes the dilation of vessels to try and restore blood flow - Failure of membrane ion pumps e.g Na/K ATPase results in oedema and failure of glutamate reuptake mechanisms
- Disrupted neural membranes fire off random action potentials
- The random action potentials cause release and build up of glutamate resulting in over-stimulation of glutamate receptors-resulting in excitotoxicity
- Calcium influx into neurones activates intracellular enzyme systems (lipases and proteases) which begins to induce neurodegeneration
- Breakdown of cellular structure and free radical production
- Apoptosis and necrosis
What cells make up the blood brain barrier?
Endothelial cells (which form tight junctions), PERICYTES and astrocytes
What are pericytes?
Pericytes are cells that regulate the passage of substances between the lumen of microvessels and the brain’s interstitial space
When are pericytes and astrocytes damaged?
These cells are damaged by inflammatory cytokines that are produced in many diseases that affect the central nervous system such as Stroke, Alzheimer’s, ALS and AIDs
What happens when pericytes and astrocytes are damaged?
The blood-brain barrier becomes leaky which causes changes to vascular tone and allows toxic agents to cross into the cerebral parenchyma causing neurodegeneration
In healthy conditions, what do pericytes do to the Blood-Brain Barrier?
They release signals to the brain endothelial cells which helps to maintain blood-brain barrier integrity and pericytes secure normal perfusion and vasoregulation
What happens when pericytes are lost?
Microvessels lose their vasoreactivity and REGRESS. This means the microvessels are no longer in such close proximity to neurons so hypoxia ensues
-Hypoxia further damages the cells of the microvessel causing the blood-brain barrier to breakdown resulting in the leakage of toxic by-products into the cerebral parenchyma
What is white matter?
White matter makes up 50% of the brains volume and is responsible for transmitting signals from one region of the cerebrum to another, between the cerebrum and also to lower brain centres
-White matter is effectively used to TRANSMIT SIGNALS
What does white matter consist of?
Glial cells, axons (myelinated and unmyelinated) and blood vessels
What happens if blood flow to white matter is restricted?
White matter is VERY SENSITIVE to hypoxia, it becomes injured in MOST strokes.
-White matter damage contributes extensively to the clinical deficits seen in brain injury
Why is white matter so sensitive?
White matter is predominantly used for signal transmission, and this relies upon maintained structural integrity and stable electrical function. These functions become damaged in hypoxia so the entire function of white matter is effected
At what ages can white matter damage occur?
White matter damage occurs at different ages throughout life for different reasons.
- Periventricular Leukomalacia in neonates occurs due to hypoxia during birth and can lead to cerebral palsy
- Stroke and cardiac events in adults can cause brain hypoxia
- Alzheimer’s disease and vascular dementia in the elderly (alzheimer’s deposits toxic agents (amyloid) that causes neurodegeneration) (vascular dementia causes hypoxia via hypoperfusion)
What are oligodendrocytes?
The cells that form myelin around cerebral neurons
What is important about oligodendroyctes?
It is the oligodendrocytes in white matter that are the MOST SENSITIVE TO HYPOXIA
Why is white matter damage important in the elderly?
White matter damage plays a significant role in cognitive decline and the development of Alzheimer’s
What is periventricular leukomalacia?
Damage to the white matter surrounding the ventricles that occurs in neonates due to hypoxia during birth.
Immature and fully differentiated oligodendrocytes are lost and so cannot form myelin in white matter
-This means signals cannot be transmitted and so can cause cerebral palsy
What does periventricular leukomalacia do?
It often causes neonatal death, however 5-10% of surviving premature infants will develop cerebral palsy which affects muscle movement and control. Cerebral palsy can also cause intellectual deficits and visual impairments
What is one of the most unique features about the brain and its circulation?
It lies within a rigid structure-THE CRANIUM, and because of this expansion cannot occur so any increase in arterial inflow must be accompanied with a comparable venous outflow
Does blood volume in the brain vary?
NO-other tissues show large variability in blood and extracellular volume but this is not possible in the brain due to rigidity of the cranium, so blood and fluid volume remains very constant
What is the rate of cerebral blood flow?
55ml/min/100g of brain tissue
What is the mean pressure of cerebral arterial blood flow?
77mmHg
Are local or neural factors more important in controlling cerebral blood flow?
LOCAL factors are more important
What neural factors affect the cerebral blood supply?
Cerebral vessels receive innervation from cervical sympathetic fibres but this innervation is VERY WEAK and virtually negligible.
There are no known sympathetic vasodilator fibres to vessels but some does come from parasympathetic innervation from the facial nerve
How is regional cerebral flow different from general?
General cerebral blood flow is constant, however regional cortical blood flow is associated with variations in neural activity
What are cerebral vessels very sensitive to?
They are very sensitive to CARBON DIOXIDE TENSION
-as neural activity increases, oxygen is used up and respiration produces carbon dioxide
What does increased co2 levels indicate?
CO2 is produced when oxygen is used up in respiration, so increased co2 levels indicates increased levels of neural activity. The increased neural activity requires more blood to restore the oxygen already used up, so increased co2 is effectively an indicator that more blood flow is needed
What happens upon inhalation of 7% co2?
Experimental studies showed that inhalation of 7% co2 results in a 2-fold increment in vessel dilation and cerebral blood flow
What does co2 do to cerebral vessels?
Co2 lowers the pH of Perivascular cells and also smooth muscle cells (due to diffusion)
-The lowered pH inhibits contraction of smooth muscle cells causing it to relax and thus DILATE
Co2 can inflict MARKED VASODILATION
Can elevated blood H+ cause vasodilation?
No, because H+ ions cannot diffuse through the endothelial blood brain barrier. H+ can only cause vasodilation if its levels are elevated in cerebrospinal fluid which has already crossed the BBB
How does adenosine affect cerebral blood flow?
When oxygen is used up or electrical stimulation of the brain occurs, adenosine is produced.
Adenosine produces cAMP which activates PKA which initiates vasorelaxation by relaxation of vascular smooth muscle
How does K+ ions affect cerebral blood flow?
Neural activity increases levels of perivascular K+
-This results in vasodilation via specific cascades but only amounts to an initial increase in cerebral blood flow because the increase in K+ is not sustained throughout neural activity
So what is functional hyperaemia?
Changes in metabolism that direct blood to areas of the brain that are metabollically active and require more substrate
What is cerebral autoregulation?
The encompassing term for the maintenance of constant cerebral blood flow and PRESSURE
- Mechanisms:
1. Metabolic
2. Myogenic i.e endothelium and smooth muscle detect increases or decreases in pressure-probably stretch senses and there is argument that the autonomic nervous system must play a role-for example the change in blood flow seen upon standing, but then denervated animals still show autoregulation-SO THIS MECHANISM IS YET TO BE FULLY ESTABLISHED
3. The endothelium releases NO and NPY for vasodilation and vasoconstriction
Between what systemic pressures does autoregulation work?
60-160mmHg
Below what systemic pressure does autoregulation no longer work?
<50mmHg
What happens to the brain when systemic pressure exceeds >160mmHg and autoregulation fails?
Endothelial cells are damaged so the blood-brain barrier becomes more permeable and the cerebral parenchyma becomes oedematous. Toxic agents are also able to permeate the parenchyma
What else abolished autoregulation?
Hypercapnoea and potent vasodilators.
Hypercapnoeic abolition of autoregulation is the reason COPD patients get headaches-because intracranial pressure rises
