Haemodynamic response

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The canonical haemodynamic response function (HRF). The spike indicates a brief intense period of neuron stimulation, which requires increased blood and nutrient flow. As the needs of the neuronal activity are met, blood flow returns to homeostatic levels.

In

neurovascular coupling.[1]

Vascular anatomy overview

In order to understand how blood is delivered to cranial tissues, it is important to understand the vascular anatomy of the space itself. Large cerebral arteries in the brain split into smaller

blood brain barrier (BBB). Endothelial cells, smooth muscle, neurons, astrocytes, and pericytes work together in the brain order to maintain the BBB while still delivering nutrients to tissues and adjusting blood flow in the intracranial space to maintain homeostasis. As they work as a functional neurovascular unit, alterations in their interactions at the cellular level can impair HR in the brain and lead to deviations in normal nervous function.[2]

Mechanisms

Various cell types play a role in HR, including astrocytes, smooth muscle cells, endothelial cells of blood vessels, and pericytes. These cells control whether the vessels are constricted or dilated, which dictates the amount of oxygen and glucose that is able to reach the neuronal tissue.

Brain blood vasculature as a function of blood flow. Red arrows show vascular pruning, while white arrowheads indicate vessel widening in response to increased blood flow.[3]

Astrocytes

Astrocytes are unique in that they are intermediaries that lie between blood vessels and neurons. They are able to communicate with other astrocytes via

glutamate, and perform various other functions to maintain chemical and electrical homeostasis
in the neuronal environment.

Constriction has been shown in vitro to occur when NE is placed in the synapse and is taken up by astrocyte receptors. NE uptake leads to an increase in intracellular astrocyte

metabotropic glutamate receptors (mGluR) also increase intracellular Ca2+ to produce constriction.[4]

Smooth muscle

Dilation occurs when

cyclic GMP (cGMP) levels in the smooth muscle cells, inducing a signaling cascade that results in the activation of cGMP-dependent protein kinase (PKG) and an ultimate decrease in smooth muscle Ca2+ concentration.[5]
This leads to a decrease in muscle contraction and a subsequent dilation of the blood vessel. Whether the vessels are constricted or dilated dictates the amount of oxygen and glucose that is able to reach the neuronal tissue.

Pericytes

A principal function of pericytes is to interact with astrocytes, smooth muscle cells, and other intracranial cells to form the blood brain barrier and to modulate the size of blood vessels to ensure proper delivery and distribution of oxygen and nutrients to neuronal tissues. Pericytes have both cholinergic (α2) and adrenergic (β2) receptors. Stimulation of the latter leads to vessel relaxation, while stimulation of the cholinergic receptors leads to contraction.

Paracrine activity and oxygen availability have been shown to also modulate pericyte activity. The peptides

CO2 concentrations cause relaxation. This suggests that pericytes may have the ability to dilate blood vessels when oxygen is in demand and constrict them when it is in surplus, modifying the rate of blood flow to tissues depending on their metabolic activity.[6]

Complications

The haemodynamic response is rapid delivery of blood to active neuronal tissue. Complications in this response arise in acute coronary syndromes and

pulmonary arterial hypertension. These complications lead to a change in the regulation of blood flow to the brain, and in turn the amount of glucose and oxygen that is supplied to neurons, which may have serious effects not only on the functioning of the nervous system, but functioning of all bodily systems.[7]

Acute coronary syndrome

Acute infections, such as

atherosclerotic plaques. The most common symptom that prompts diagnosis is chest pain, associated with nausea and sweating. Treatment usually includes aspirin, Clopidogrel, nitroglycerin, and if chest pain persists morphine. Recent study suggests that acute respiratory tract infection can act as a trigger for ACS. This in turn has major prothrombotic and haemodynamic effects.[7]

These effects result from

hypoxia. When neuronal tissue is deprived of adequate oxygen, the haemodynamic response has less of an effect at active neuronal tissue. All of these disturbances increase the likelihood of ACS, due to coronary plaque rupture and thrombosis. Overall, ACS results from the damage of coronaries by atherosclerosis, so primary prevention of ACS is to prevent atherosclerosis by controlling risk factors. This includes eating healthy, exercising regularly, and controlling cholesterol levels.[7]

Pulmonary arterial hypertension

Pulmonary hypertension (PAH) is disease of small pulmonary arteries that is usually caused by more than one mechanism. This includes

cyclic AMP (cAMP), which inhibits the growth of smooth-muscle cells.[8]

Overall, pulmonary arterial tension and acute coronary syndromes are few of the many diseases that lead to hypoxia of neuronal tissue, which in turns deteriorates the haemodynamic response and leads to neuronal death. Prolonged hypoxia induces neuronal death via apoptosis. With a dysfunctional haemodynamic response, active neuronal tissue due to membrane depolarization lacks the necessary energy to propagate signals, as a result of blood flow hindrance. This affects many functions in the body, and may lead to severe symptoms.

Reduced haemodynamic response diseases

Alzheimer's disease

In this disease, there is a build of the amyloid beta protein in the brain. This ultimately leads to a reduction in the haemodynamic response and less blood flow in the brain. This reduced cerebral blood flow not only kills neuronal cells because of shortages in oxygen and glucose but it also reduces the brain's ability to remove amyloid beta. In a healthy brain, these protein fragments are broken down and eliminated. In Alzheimer's disease, the fragments accumulate to form hard, insoluble plaques which reduce blood flow. Two proteins are involved in this accumulation of amyloid beta: serum response factor or SRF and myocardin.[9] Together, these 2 proteins determine whether smooth muscle of blood vessels contract. SRF and myocardin are more active in the brains of people with Alzheimer's disease. When these proteins are active, they turn on SREBP2 which inhibits LRP-1. LRP-1 helps the brain remove amyloid beta. Therefore, when SRF and myocardin are active, there is a buildup in amyloid beta protein which ultimately leads to less blood flow in the brain because of contracted blood vessels.[10]

Ischemia

A decrease in circulation in the brain vasculature due to stroke or injury can lead to a condition known as ischemia. In general, decrease in blood flow to the brain can be a result of thrombosis causing a partial or full blockage of blood vessels, hypotension in systemic circulation (and consequently the brain), or cardiac arrest. This decrease in blood flow in the cerebral vascular system can result in a buildup of metabolic wastes generated by neurons and glial cells and a decrease in oxygen and glucose delivery to them. As a result, cellular energy failure, depolarization of neuronal and glial membranes, edema, and excess neurotransmitter and calcium ion release can occur.[11] This ultimately ends with cell death, as cells succumb to a lack of nutrients to power their metabolism and to a toxic brain environment, full of free radicals and excess ions that damage normal cell organelle function.

Clinical use

Changes in brain activity are closely coupled with changes in blood flow in those areas, and knowing this has proved useful in mapping brain functions in humans. The measurement of haemodynamic response, in a clinical setting, can be used to create images of the brain in which especially active and inactive regions are shown as distinct from one another. This can be a useful tool in diagnosing neural disease or in pre-surgical planning.

PET scan
are the most common techniques that use haemodynamic response to map brain function. Physicians use these imaging techniques to examine the anatomy of the brain, to determine which specific parts of the brain are handling certain high order functions, to assess the effects of degenerative diseases, and even to plan surgical treatments of the brain.

Functional magnetic resonance imaging

oxyhemoglobin) interferes with the magnetic resonance (MR) signal less and this leads to an improved MR signal in that area of increased neuronal activity. However, Paramagnetic blood (deoxyhemoglobin) makes the local magnetic field inhomogenous. This has the effect of dephasing the signal emitted in this domain, causing destructive interference in the observed MR signal. Therefore, greater amounts of deoxyhemoglobin lead to less signal. Neuronal activity ultimately leads to an increase in local MR signaling corresponding to a decrease in the concentration of deoxyhemoglobin.[14]

This sample fMRI shows how there are certain areas of activation during stimulation

If fMRI can be used to detect the regular flow of blood in a healthy brain, it can also be used to detect the problems with a brain that has undergone degenerative diseases. Functional MRI, using haemodynamic response, can help assess the effects of stroke and other degenerative diseases such as Alzheimer's disease on brain function. Another way fMRI could be used is in the planning of surgery of the brain. Surgeons can use fMRI to detect blood flow of the most active areas of the brain and the areas involved in critical functions like thought, speech, movement, etc. In this way, brain procedures are less dangerous because there is a brain mapping that shows which areas are vital to a person's life. Haemodynamic response is vital to fMRI and clinical use because through the study of blood flow we are able to examine the anatomy of the brain and effectively plan out procedures of the brain and link together the causes of degenerative brain disease.[15]

Resting state fMRI enables the evaluation of the interaction of brain regions, when not performing a specific task.[16] This is also used to show the default mode network.

PET scan

PET scan or

Positron emission tomography scan is also used alongside fMRI for brain imaging. PET scan can detect active brain areas either haemodynamically or metabolically through glucose intake. They allow one to observe blood flow or metabolism in any part of the brain. The areas that are activated by increased blood flow and/or increased glucose intake are visualized in increased signal in the PET image.[17]

Before a PET scan begins, the patient will be injected with a small dose of a radioactive medicine tagged to a

radiotracer collide with electrons in the brain. As a radiotracer is broken down, more positrons are made and there will be an increased signal in the PET scan.[18]

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External links

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