Altered linear coupling between stimulus-evoked blood flow and oxygen metabolism in the aging human brain.

Neural-vascular coupling (NVC) is the process by which oxygen and nutrients are delivered to metabolically active neurons by blood vessels. Murine models of NVC disruption have revealed its critical role in healthy neural function. We hypothesized that, in humans, aging exerts detrimental effects upon the integrity of the neural-glial-vascular system that underlies NVC. To test this hypothesis, calibrated functional magnetic resonance imaging (cfMRI) was used to characterize age-related changes in cerebral blood flow (CBF) and oxygen metabolism during visual cortex stimulation. Thirty-three younger and 27 older participants underwent cfMRI scanning during both an attention-controlled visual stimulation task and a hypercapnia paradigm used to calibrate the blood-oxygen-level-dependent signal. Measurement of stimulus-evoked blood flow and oxygen metabolism permitted calculation of the NVC ratio to assess the integrity of neural-vascular communication. Consistent with our hypothesis, we observed monotonic NVC ratio increases with increasing visual stimulation frequency in younger adults but not in older adults. Age-related changes in stimulus-evoked cerebrovascular and neurometabolic signal could not fully explain this disruption; increases in stimulus-evoked neurometabolic activity elicited corresponding increases in stimulus-evoked CBF in younger but not in older adults. These results implicate age-related, demand-dependent failures of the neural-glial-vascular structures that comprise the NVC system.

Preserved canonicality of the BOLD hemodynamic response reflects healthy cognition: Insights into the healthy brain through the window of Multiple Sclerosis.

The hemodynamic response function (HRF), a model of brain blood-flow changes in response to neural activity, reflects communication between neurons and the vasculature that supplies these neurons in part by means of glial cell intermediaries (e.g., astrocytes). Intact neural-vascular communication might play a central role in optimal cognitive performance. This hypothesis can be tested by comparing healthy individuals to those with known white-matter damage and impaired performance, as seen in Multiple Sclerosis (MS). Glial cell intermediaries facilitate the ability of neurons to adequately convey metabolic needs to cerebral vasculature for sufficient oxygen and nutrient perfusion. In this study, we isolated measurements of the HRF that could quantify the extent to which white-matter affects neural-vascular coupling and cognitive performance. HRFs were modeled from multiple brain regions during multiple cognitive tasks using piecewise cubic spline functions, an approach that minimized assumptions regarding HRF shape that may not be valid for diseased populations, and were characterized using two shape metrics (peak amplitude and time-to-peak). Peak amplitude was reduced, and time-to-peak was longer, in MS patients relative to healthy controls. Faster time-to-peak was predicted by faster reaction time, suggesting an important role for vasodilatory speed in the physiology underlying processing speed. These results support the hypothesis that intact neural-glial-vascular communication underlies optimal neural and cognitive functioning.

Calibrated imaging reveals altered grey matter metabolism related to white matter microstructure and symptom severity in multiple sclerosis.

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. Hum Brain Mapp 38:5375-5390, 2017. © 2017 Wiley Periodicals, Inc.

Ear Advantage for Musical Location and Relative Pitch: Effects of Musical Training and Attention.

Trained musicians have been found to exhibit a right-ear advantage for high tones and a left-ear advantage for low tones. We investigated whether this right/high, left/low pattern of musical processing advantage exists in listeners who had varying levels of musical experience, and whether such a pattern might be modulated by attentional strategy. A dichotic listening paradigm was used in which different melodic sequences were presented to each ear, and listeners attended to (a) the left ear or the right ear or (b) the higher pitched tones or the lower pitched tones. Listeners judged whether tone-to-tone transitions within each melodic sequence moved upward or downward in pitch. Only musically experienced listeners could adequately judge the direction of successive pitch transitions when attending to a specific ear; however, all listeners could judge the direction of successive pitch transitions within a high-tone stream or a low-tone stream. Overall, listeners exhibited greater accuracy when attending to relatively higher pitches, but there was no evidence to support a right/high, left/low bias. Results were consistent with effects of attentional strategy rather than an ear advantage for high or low tones. Implications for a potential performer/audience paradox in listening space are considered.

Depressive thoughts limit working memory capacity in dysphoria.

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.

Neural mechanisms of age-related slowing: the ΔCBF/ΔCMRO2 ratio mediates age-differences in BOLD signal and human performance.

The precise mechanisms that give rise to the blood-oxygen-level-dependent (BOLD) activation differences that accompany age-related cognitive slowing remain fundamentally unknown. We sought to isolate the origin of age-related BOLD changes by comparing blood-flow and oxygen-metabolic constituents of the BOLD response using dual-echo arterial spin labeling during visual stimulation and CO2 ingestion. We hypothesized, and our results confirmed, that age-related changes in the ratio of fractional cerebral blood flow to fractional cerebral metabolic rate of oxygen consumption (ΔCBF/ΔCMRO2) lead to the BOLD changes that are observed in older adults. ΔCBF/ΔCMRO2 was also significantly related to performance, suggesting that age-related cognitive slowing results from neural cell assemblies that operate less efficiently, requiring greater oxygen metabolism that is not matched by blood-flow changes relative to younger adults. Age-related changes in ΔCBF/ΔCMRO2 are sufficient to explain variations in BOLD responding and performance cited throughout the literature, assuming no bias based on physiological baseline CMRO2.

The enduring effects of depressive thoughts on working memory.

BACKGROUND: Depressive thoughts are known to persist in persons with depressed mood leading to rumination and exacerbation of depressive symptoms. What has not yet been examined is whether this persistence of depressive thoughts can lead to impairment of working memory (WM). METHODS: We assessed whether receiving a WM task featuring depressive cues could bias performance on a subsequent, non-depressive WM task for dysphoric individuals (DIs) compared to non-DIs. RESULTS: DIs showed significantly attenuated performance on the WM task with depressive cues compared to non-DIs. Further, when DIs were given the WM task with depressive cues first, they showed deficits on a second WM task without depressive cues, compared to DIs given the non-depressive WM task first and non-DIs in either condition. LIMITATIONS: Unselected recruitment procedures did not permit balanced sample sizes in each group. Future research is needed to assess whether these results extend to a clinically depressed sample and whether WM deficits are the consequence of depressed mood, or a risk factor for the development and maintenance of depressed mood. CONCLUSIONS: Results suggest that, for DIs, the influence of depressive cues on performance transfers to subsequent tasks in which these cues are no longer present. These results support the hypothesis that when depressive thoughts are part of depressed persons' conscious experience, cognitive deficits arise. Further, these results suggest an ecologically-relevant mechanism by which day-to-day cognitive deficits in depression can develop.

Cognitive Slowing in Gulf War Illness Predicts Executive Network Hyperconnectivity: Study in a Population-Representative Sample.

Cognitive slowing is a prevalent symptom observed in Gulf War Illness (GWI). The present study assessed the extent to which functional connectivity between dorsolateral prefrontal cortex (DLPFC) and other task-relevant brain regions was predictive of GWI-related cognitive slowing. GWI patients (n = 54) and healthy veteran controls (n = 29) were assessed on performance of a processing speed task (the Digit Symbol Substitution Task; DSST) while undergoing functional magnetic resonance imaging (fMRI). GWI patients were slower on the DSST relative to controls. Bilateral DLPFC connectivity with task-relevant nodes was altered in GWI patients compared to healthy controls during DSST performance. Moreover, hyperconnectivity in these networks predicted GWI-related increases in reaction time on the DSST, whereas hypoconnectivity did not. These results suggest that GWI-related cognitive slowing reflects reduced efficiency in cortical networks.

Multiple sclerosis-related white matter microstructural change alters the BOLD hemodynamic response.

Multiple sclerosis (MS) results in inflammatory damage to white matter microstructure. Prior research using blood-oxygen-level dependent (BOLD) imaging indicates MS-related alterations to brain function. What is currently unknown is the extent to which white matter microstructural damage influences BOLD signal in MS. Here we assessed changes in parameters of the BOLD hemodynamic response function (HRF) in patients with relapsing-remitting MS compared to healthy controls. We also used diffusion tensor imaging to assess whether MS-related changes to the BOLD-HRF were affected by changes in white matter microstructural integrity. Our results showed MS-related reductions in BOLD-HRF peak amplitude. These MS-related amplitude decreases were influenced by individual differences in white matter microstructural integrity. Other MS-related factors including altered reaction time, limited spatial extent of BOLD activity, elevated lesion burden, or lesion proximity to regions of interest were not mediators of group differences in BOLD-HRF amplitude. Results are discussed in terms of functional hyperemic mechanisms and implications for analysis of BOLD signal differences.

Asynchrony in executive networks predicts cognitive slowing in multiple sclerosis.

OBJECTIVE: Cognitive slowing is a core neuropsychological symptom of Multiple Sclerosis (MS). We aimed to assess the extent to which cognitive slowing in MS was predicted by changes in dorsolateral prefrontal networks. METHOD: We assessed patients with relapsing-remitting MS and healthy controls (HCs) on measures of processing speed. Participants underwent a functional MRI while performing a processing speed task to allow assessment of task-based connectivity. RESULTS: Patients were slower than HCs on the processing speed tasks. Patients showed attenuated connectivity between right and left dorsolateral prefrontal cortex (DLPFC) and task-relevant brain regions compared to HCs during processing speed task performance. Patients' connectivity with DLPFC in these group-disparate networks accounted for significant variability in their performance on processing speed measures administered both in and out of the imaging environment. Specifically, patients who had stronger functional connections with DLPFC in group-disparate networks performed faster than patients with weaker connections with DLPFC in group-disparate networks. CONCLUSION: Results suggest that MS-related cognitive slowing can be accounted for by systemic alterations in executive functional networks.

The efficiency of fMRI region of interest analysis methods for detecting group differences.

BACKGROUND: Using a standard space brain template is an efficient way of determining region-of-interest (ROI) boundaries for functional magnetic resonance imaging (fMRI) data analyses. However, ROIs based on landmarks on subject-specific (i.e., native space) brain surfaces are anatomically accurate and probably best reflect the regional blood oxygen level dependent (BOLD) response for the individual. Unfortunately, accurate native space ROIs are often time-intensive to delineate even when using automated methods. NEW METHOD: We compared analyses of group differences when using standard versus native space ROIs using both volume and surface-based analyses. Collegiate and military-veteran participants completed a button press task and a digit-symbol verification task during fMRI acquisition. Data were analyzed within ROIs representing left and right motor and prefrontal cortices, in native and standard space. Volume and surface-based analysis results were also compared using both functional (i.e., percent signal change) and structural (i.e., voxel or node count) approaches. RESULTS AND COMPARISON WITH EXISTING METHOD(S): Results suggest that transformation into standard space can affect the outcome of structural and functional analyses (inflating/minimizing differences, based on cortical geography), and these transformations can affect conclusions regarding group differences with volumetric data. CONCLUSIONS: Caution is advised when applying standard space ROIs to volumetric fMRI data. However, volumetric analyses show group differences and are appropriate in circumstances when time is limited. Surface-based analyses using functional ROIs generated the greatest group differences and were less susceptible to differences between native and standard space. We conclude that surface-based analyses are preferable with adequate time and computing resources.

Central Executive Dysfunction and Deferred Prefrontal Processing in Veterans with Gulf War Illness.

Gulf War Illness is associated with toxic exposure to cholinergic disruptive chemicals. The cholinergic system has been shown to mediate the central executive of working memory (WM). The current work proposes that impairment of the cholinergic system in Gulf War Illness patients (GWIPs) leads to behavioral and neural deficits of the central executive of WM. A large sample of GWIPs and matched controls (MCs) underwent functional magnetic resonance imaging during a varied-load working memory task. Compared to MCs, GWIPs showed a greater decline in performance as WM-demand increased. Functional imaging suggested that GWIPs evinced separate processing strategies, deferring prefrontal cortex activity from encoding to retrieval for high demand conditions. Greater activity during high-demand encoding predicted greater WM performance. Behavioral data suggest that WM executive strategies are impaired in GWIPs. Functional data further support this hypothesis and suggest that GWIPs utilize less effective strategies during high-demand WM.

Auditory memory distortion for spoken prose.

Observers often remember a scene as containing information that was not presented but that would have likely been located just beyond the observed boundaries of the scene. This effect is called boundary extension (BE; e.g., Intraub & Richardson, 1989). Previous studies have observed BE in memory for visual and haptic stimuli, and the present experiments examined whether BE occurred in memory for auditory stimuli (prose, music). Experiments 1 and 2 varied the amount of auditory content to be remembered. BE was not observed, but when auditory targets contained more content, boundary restriction (BR) occurred. Experiment 3 presented auditory stimuli with less content and BR also occurred. In Experiment 4, white noise was added to stimuli with less content to equalize the durations of auditory stimuli, and BR still occurred. Experiments 5 and 6 presented trained stories and popular music, and BR still occurred. This latter finding ruled out the hypothesis that the lack of BE in Experiments 1-4 reflected a lack of familiarity with the stimuli. Overall, memory for auditory content exhibited BR rather than BE, and this pattern was stronger if auditory stimuli contained more content. Implications for the understanding of general perceptual processing and directions for future research are discussed.

Boundary extension: findings and theories.

A view of a scene is often remembered as containing information that might have been present just beyond the actual boundaries of that view, and this is referred to as boundary extension. Characteristics of the view (e.g., scene or nonscene; close-up or wide-angle; whether objects are cropped, static, or in motion, emotionally neutral or emotionally charged), display (e.g., aperture shape and size; target duration; retention interval; whether probes of memory involve magnification/minification or change in physical distance), and observer (e.g., allocation of attention; age; planned fixation, gaze direction, and eye movements; monocular or binocular viewing; prior exposure; neurological correlates) that influence boundary extension are reviewed. Proposed mechanisms of boundary extension (perceptual, memory, or motion schema; extension-normalization; attentional selection; errors in source monitoring) are discussed, and possible relationships of boundary extension to other cognitive processes (e.g., representational momentum; remembered distance and remembered size; amodal completion; transsaccadic memory) are briefly addressed.