More than just summed neuronal activity: how multiple cell types shape the BOLD response

Abstract

Functional neuroimaging techniques are widely applied to investigations of human cognition and disease. The most commonly used among these is blood oxygen level-dependent (BOLD) functional magnetic resonance imaging. The BOLD signal occurs because neural activity induces an increase in local blood supply to support the increased metabolism that occurs during activity. This supply usually outmatches demand, resulting in an increase in oxygenated blood in an active brain region, and a corresponding decrease in deoxygenated blood, which generates the BOLD signal. Hence, the BOLD response is shaped by an integration of local oxygen use, through metabolism, and supply, in the blood. To understand what information is carried in BOLD signals, we must understand how several cell types in the brain-local excitatory neurons, inhibitory neurons, astrocytes and vascular cells (pericytes, vascular smooth muscle and endothelial cells), and their modulation by ascending projection neurons-contribute to both metabolism and haemodynamic changes. Here, we review the contributions of each cell type to the regulation of cerebral blood flow and metabolism, and discuss situations where a simplified interpretation of the BOLD response as reporting local excitatory activity may misrepresent important biological phenomena, for example with regards to arousal states, ageing and neurological disease. This article is part of the theme issue 'Key relationships between non-invasive functional neuroimaging and the underlying neuronal activity'.

Keywords: BOLD fMRI; astrocyte; endothelial propagation; interneuron; neurometabolic coupling; neurovascular coupling.

Figure 1.

Multicellular contributions to neurovascular coupling. Activation of excitatory neurons in the brain is believed to initiate the neurovascular signals that cause increases in cerebral blood flow (CBF). However, inhibitory interneuron activity almost invariably occurs in parallel with excitatory activity and signals from these interneurons appear to be the stronger regulators of CBF. The neural activity also stimulates astrocytes, which can regulate capillary diameter and modulate overall changes in CBF. Ascending projection systems can further tune the locally generated vasoactive signals, or may directly modulate the vasculature. Once the vascular pericytes or endothelial cells have sensed vasoactive signals from the surrounding tissue, these signals propagate through the endothelium to contractile pericytes and smooth muscle cells on upstream vessels and their branches, which may not themselves feed active tissue. VSMCs, vascular smooth muscle cells. Created with BioRender.com.