Separating vascular and neuronal effects of age on fMRI BOLD signals

Abstract

Accurate identification of brain function is necessary to understand the neurobiology of cognitive ageing, and thereby promote well-being across the lifespan. A common tool used to investigate neurocognitive ageing is functional magnetic resonance imaging (fMRI). However, although fMRI data are often interpreted in terms of neuronal activity, the blood oxygenation level-dependent (BOLD) signal measured by fMRI includes contributions of both vascular and neuronal factors, which change differentially with age. While some studies investigate vascular ageing factors, the results of these studies are not well known within the field of neurocognitive ageing and therefore vascular confounds in neurocognitive fMRI studies are common. Despite over 10 000 BOLD-fMRI papers on ageing, fewer than 20 have applied techniques to correct for vascular effects. However, neurovascular ageing is not only a confound in fMRI, but an important feature in its own right, to be assessed alongside measures of neuronal ageing. We review current approaches to dissociate neuronal and vascular components of BOLD-fMRI of regional activity and functional connectivity. We highlight emerging evidence that vascular mechanisms in the brain do not simply control blood flow to support the metabolic needs of neurons, but form complex neurovascular interactions that influence neuronal function in health and disease. This article is part of the theme issue ‘Key relationships between non-invasive functional neuroimaging and the underlying neuronal activity’.

Brain functional network integrity sustains cognitive function despite atrophy in presymptomatic genetic frontotemporal dementia

“…The inclusion of study site as a covariate of no interest 61 and the nature of our multivariate approach to identify shared signals between brain and behavioral data reduce residual effects of scanner variance 38,62 . Future studies may use alternative brain measures that reflect differences in cortical surface and thickness estimates, 63,64 or which infer neural connectivity directly from neurophysiology or from the separation of neurovascular from neuronal contributors to blood oxygen level–dependent (BOLD) fMRI variance, 18,65 given the confounding effects of age, drug, or disease on neurovascular signals 66,67 …”

Brain functional network integrity sustains cognitive function despite atrophy in presymptomatic genetic frontotemporal dementia

“…The inclusion of study site as a covariate of no interest [61] and the nature of our multivariate approach to identify shared signals between brain and behavioural data reduce residual effects of scanner variance [38,62]. Future studies may use alternative brain measures that reflect differences in cortical surface and thickness estimates [63,64], or which infer neural connectivity directly from neurophysiology or from the separation of neurovascular from neuronal contributors to BOLD fMRI variance [18,65], given the confounding effects of age, drug or disease on neurovascular signals [66,67].…”

Functional connectivity changes in cerebral small vessel disease - a systematic review of the resting-state MRI literature

“…As a measure of synchronous brain activity, the interpretation of BOLD-derived functional connectivity is contingent upon an understanding of the relation between neuronal activity and local blood flow. This neurovascular coupling, however, is known to be altered in normal ageing as well as the presence of ischaemic disease [ 102 , 182 , 183 ], and attributing differences in BOLD-derived measures of connectivity to either vascular or neuronal factors is therefore challenging [ 184 ]. More specifically, white matter lesions of presumed vascular origin are known to be associated with subcortical hypoperfusion [ 185 ], possibly reflecting observed rarefaction of the microcirculation in a mouse genetic model of CSVD [ 186 ].…”