Functional magnetic resonance imaging (fMRI) has been used to infer age-differences in neural activity from the hemodynamic response function (HRF) that characterizes the blood-oxygen-level-dependent (BOLD) signal over time. BOLD literature in healthy aging lacks consensus in age-related HRF changes, the nature of those changes, and their implications for measurement of age differences in brain function. Between-study discrepancies could be due to small sample sizes, analysis techniques, and/or physiologic mechanisms. We hypothesize that, with large sample sizes and minimal analysis assumptions, age-related changes in HRF parameters could reflect alterations in one or more components of the neural-vascular coupling system. To assess HRF changes in healthy aging, we analyzed the large population-derived dataset from the Cambridge Center for Aging and Neuroscience (CamCAN) study (Shafto et al., 2014). During scanning, 74 younger (18–30 years of age) and 173 older participants (54–74 years of age) viewed two checkerboards to the left and right of a central fixation point, simultaneously heard a binaural tone, and responded via right index finger button-press. To assess differences in the shape of the HRF between younger and older groups, HRFs were estimated using FMRIB’s Linear Optimal Basis Sets (FLOBS) to minimize a priori shape assumptions. Group mean HRFs were different between younger and older groups in auditory, visual, and motor cortices. Specifically, we observed increased time-to-peak and decreased peak amplitude in older compared to younger adults in auditory, visual, and motor cortices. Changes in the shape and timing of the HRF in healthy aging, in the absence of performance differences, support our hypothesis of age-related changes in the neural-vascular coupling system beyond neural activity alone. More precise interpretations of HRF age-differences can be formulated once these physiologic factors are disentangled and measured separately.

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The present and future research efforts in cognitive neuroscience and psychophysiology rely on the measurement, understanding, and interpretation of blood oxygenation level‐dependent (BOLD) functional magnetic resonance imaging (fMRI) to effectively investigate brain function. Aging and age‐associated pathophysiological processes change the structural and functional integrity of the cerebrovasculature which can significantly alter how the BOLD signal is recorded and interpreted. In order to gain an improved understanding of the benefits, drawbacks, and methodological implications for BOLD fMRI in the context of cognitive neuroscience, it is crucial to understand the cellular and molecular mechanism of age‐related vascular pathologies. This review discusses the multifaceted effects of aging and the contributions of age‐related pathologies on structural and functional integrity of the cerebral microcirculation as they has been investigated in animal models of aging, including age‐related alterations in neurovascular coupling responses, cellular and molecular mechanisms involved in microvascular damage, vascular rarefaction, blood–brain barrier disruption, senescence, humoral deficiencies as they relate to, and potentially introduce confounding factors in the interpretation of BOLD fMRI.

Dysphoria is associated with persistence of attention on mood-congruent information. Longer time attending to mood-congruent information for dysphoric individuals (DIs) detracts from goal-relevant information processing and should reduce working memory (WM) capacity. Study 1 showed that DIs and non-DIs have similar WM capacities. Study 2 embedded depressive information into a WM task. Compared to non-DIs, DIs showed significantly reduced WM capacity for goal-relevant information in this task. Study 3 replicated results from Studies 1 and 2, and further showed that DIs had a significantly greater association between processing speed and recall on the depressively modified WM task compared to non-DIs. The presence of inter-task depressive information leads to DI-related decreased WM capacity. Results suggest dysphoria-related WM capacity deficits when depressive thoughts are present. WM capacity deficits in the presence of depressive thoughts are a plausible mechanism to explain day-to-day memory and concentration difficulties associated with depressed mood.

Multiple sclerosis (MS) involves damage to white matter microstructures. This damage has been related to grey matter function as measured by standard, physiologically-nonspecific neuroimaging indices (i.e., blood-oxygen-level dependent signal [BOLD]). Here, we used calibrated functional magnetic resonance imaging and diffusion tensor imaging to examine the extent to which specific, evoked grey matter physiological processes were associated with white matter diffusion in MS. Evoked changes in BOLD, cerebral blood flow (CBF), and oxygen metabolism (CMRO2) were measured in visual cortex. Individual differences in the diffusion tensor measure, radial diffusivity, within occipital tracts were strongly associated with MS patients’ BOLD and CMRO2. However, these relationships were in opposite directions, complicating the interpretation of the relationship between BOLD and white matter microstructural damage in MS. CMRO2 was strongly associated with individual differences in patients’ fatigue and neurological disability, suggesting that alterations to evoked oxygen metabolic processes may be taken as a marker for primary symptoms of MS. This work demonstrates the first application of calibrated and diffusion imaging together and details the first application of calibrated functional MRI in a neurological population. Results lend support for neuroenergetic hypotheses of MS pathophysiology and provide an initial demonstration of the utility of evoked oxygen metabolism signals for neurology research.