Mechanisms Mediating Functional Hyperemia in the Brain

Abstract

Neuronal activity within the brain evokes local increases in blood flow, a response termed functional hyperemia. This response ensures that active neurons receive sufficient oxygen and nutrients to maintain tissue function and health. In this review, we discuss the functions of functional hyperemia, the types of vessels that generate the response, and the signaling mechanisms that mediate neurovascular coupling, the communication between neurons and blood vessels. Neurovascular coupling signaling is mediated primarily by the vasoactive metabolites of arachidonic acid (AA), by nitric oxide, and by K+. While much is known about these pathways, many contentious issues remain. We highlight two controversies, the role of glial cell Ca2+ signaling in mediating neurovascular coupling and the importance of capillaries in generating functional hyperemia. We propose signaling pathways that resolve these controversies. In this scheme, capillary dilations are generated by Ca2+ increases in astrocyte endfeet, leading to production of AA metabolites. In contrast, arteriole dilations are generated by Ca2+ increases in neurons, resulting in production of nitric oxide and AA metabolites. Arachidonic acid from neurons also diffuses into astrocyte endfeet where it is converted into additional vasoactive metabolites. While this scheme resolves several discrepancies in the field, many unresolved challenges remain and are discussed in the final section of the review.

Near‐Infrared Spectroscopy Reveals Brain Hypoxia and Cerebrovascular Dysregulation in Primary Biliary Cholangitis

“…The endothelial signaling pathways to neurons and astrocytes have increasingly been recognized as key regulators of NVC within the brain . In MS patients, similar to our findings in cholestatic mice, blocking activated immune cells within the circulation from adhering to CECs increases task‐induced cortical blood flow (i.e., NVC), suggesting that immune cell–CEC adhesive interactions lead to neurovascular uncoupling.…”

“…This balance is achieved through highly sensitive mechanisms of blood flow regulation such as neurovascular coupling (NVC), cerebrovascular reactivity, and cerebral autoregulation. NVC is characterized by a robust increase in local blood flow in response to neuronal activity, referred to as “functional hyperemia.” NVC is primarily mediated through vasoactive signaling molecules such as arachidonic acid and nitric oxide, as well as K + and pH, and relies on the intricate interplay between cerebral endothelial cells (CECs), glial cells, pericytes, vascular smooth muscle cells, and neurons . Functional hyperemia forms the basis of the blood oxygen level–dependent signal in functional MRI and the O 2 Hb and HHb signals in fNIRS, which are commonly used as indirect measures of local brain activity.…”

“…Therefore, NIRS can be used to quantify cortical tissue oxygen saturation (StO 2 ), which reflects changing metabolic rate and perfusion . Furthermore, functional NIRS (fNIRS) can be used to probe brain activity in a similar fashion to functional MRI, by assuming that the measured changes in blood perfusion and oxygenation are due to functional hyperemia, i.e., hemodynamic changes caused by neural activity . It is important, however, to note that due to the biophysical properties of light transmission in tissue, NIRS is limited to approximately 3 cm depth penetration and is therefore unable to measure deep brain structures.…”

The present and future use of functional near‐infrared spectroscopy (fNIRS) for cognitive neuroscience

“…When a brain area is active and involved in the execution of a certain task, the brain's metabolic demand for oxygen and glucose increases, leading to an oversupply in regional cerebral blood flow (CBF) to meet the increased metabolic demand of the brain. The increase in CBF in response to an increase in neuronal activity is called functional hyperemia and is mediated by several neurovascular coupling mechanisms, such as changes in capillary diameter and vasoactive metabolites . Hence, the oversupply in regional CBF produces an increase in HbO 2 and a decrease in HbR concentrations; these are estimated by changes in light attenuation that can be measured by fNIRS.…”

“…The increase in CBF in response to an increase in neuronal activity is called functional hyperemia and is mediated by several neurovascular coupling 41 mechanisms, such as changes in capillary diameter and vasoactive metabolites. 42 Hence, the oversupply in regional CBF produces an increase in HbO 2 and a decrease in HbR concentrations; these are estimated by changes in light attenuation that can be measured by fNIRS. In addition to absorption, the NIR light is also scattered when it travels through the biological tissue.…”