The roadmap for estimation of cell-type-specific neuronal activity from non-invasive measurements

Abstract

The computational properties of the human brain arise from an intricate interplay between billions of neurons connected in complex networks. However, our ability to study these networks in healthy human brain is limited by the necessity to use non-invasive technologies. This is in contrast to animal models where a rich, detailed view of cellular-level brain function with cell-type-specific molecular identity has become available due to recent advances in microscopic optical imaging and genetics. Thus, a central challenge facing neuroscience today is leveraging these mechanistic insights from animal studies to accurately draw physiological inferences from non-invasive signals in humans. On the essential path towards this goal is the development of a detailed ‘bottom-up’ forward model bridging neuronal activity at the level of cell-type-specific populations to non-invasive imaging signals. The general idea is that specific neuronal cell types have identifiable signatures in the way they drive changes in cerebral blood flow, cerebral metabolic rate of O 2 (measurable with quantitative functional Magnetic Resonance Imaging), and electrical currents/potentials (measurable with magneto/electroencephalography). This forward model would then provide the ‘ground truth’ for the development of new tools for tackling the inverse problem—estimation of neuronal activity from multimodal non-invasive imaging data. This article is part of the themed issue ‘Interpreting BOLD: a dialogue between cognitive and cellular neuroscience’.

Interpreting BOLD: towards a dialogue between cognitive and cellular neuroscience

“…This relationship between the BOLD signal and neuronal activity is extensively discussed in previous reviews [1][2] and other papers in this issue [3][4][5]. Box 1 provides an introduction to the origin of the BOLD signal.…”

“…Release of neurotransmitters such as glutamate induces dilation of cerebral blood vessels by triggering the release of vasoactive signalling molecules from both neurons and glia (LeCrux and Hamel, and Uhlirova et al in this issue; [3,4,7]). Much is now known about these signalling pathways, but their variability across brain areas and circuits is likely to lead to differences in neurovascular coupling properties and therefore also to variations in the relationship between BOLD and neuronal activity across different brain regions and experimental conditions (discussed below).…”

“…Vascular responses propagate outward from their site of initiation [22,23], which means that late BOLD responses are less spatially localized to the initial site of neuronal activity than the first few seconds of the positive BOLD response (discussed below, and by Uhlirova et al [4] in this issue and in [24]). …”

“…Classically blood flow was thought to be regulated solely by rings of smooth muscle on penetrating arterioles, but recent work has suggested that capillary blood flow can also be regulated by virtue of the contraction and relaxation of pericytes [49,50]. While these findings are somewhat disputed [51,52], this is primarily due to differences in the definitions of capillaries, arterioles, smooth muscle cells and pericytes (see [53] and Uhlirova et al [4] in this issue). In fact, the studies broadly agree that cerebral blood vessels from large to small calibre (down to 4 mm) and even up to four branches from diving arterioles can be regulated by neuronal activity [50,52] due to the relaxation of vascular mural cells which express contractile proteins, including those that have a 'bump on a log' morphology and processes extending along and around the blood vessels [52,54].…”

“…In fact, the studies broadly agree that cerebral blood vessels from large to small calibre (down to 4 mm) and even up to four branches from diving arterioles can be regulated by neuronal activity [50,52] due to the relaxation of vascular mural cells which express contractile proteins, including those that have a 'bump on a log' morphology and processes extending along and around the blood vessels [52,54]. Current evidence suggests that pericytes on capillary regions at branching orders more than four from penetrating arterioles are less contractile and therefore less likely to actively contribute to neurovascular coupling ( [52]; Uhlirova et al [4] in this issue). Capillary-level blood flow regulation explains how individual cortical columns can be mapped from the haemodynamic response (e.g.…”