Joanna L. Hutchison

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.

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.

A BOLD Perspective on Age-Related Neurometabolic-Flow Coupling and Neural Efficiency Changes in Human Visual Cortex.

Age-related performance declines in visual tasks have been attributed to reductions in processing efficiency. The neural basis of these declines has been explored by comparing the blood-oxygen-level-dependent (BOLD) index of neural activity in older and younger adults during visual task performance. However, neural activity is one of many factors that change with age and lead to BOLD signal differences. We investigated the origin of age-related BOLD changes by comparing blood flow and oxygen metabolic constituents of BOLD signal. Subjects periodically viewed flickering annuli and pressed a button when detecting luminance changes in a central fixation cross. Using magnetic resonance dual-echo arterial spin labeling and CO2 ingestion, we observed age-equivalent (i.e., similar in older and younger groups) fractional cerebral blood flow (ΔCBF) in the presence of age-related increases in fractional cerebral metabolic rate of oxygen (ΔCMRO2). Reductions in ΔCBF responsiveness to increased ΔCMRO2 in elderly led to paradoxical age-related BOLD decreases. Age-related ΔCBF/ΔCMRO2 ratio decreases were associated with reaction times, suggesting that age-related slowing resulted from less efficient neural activity. We hypothesized that reduced vascular responsiveness to neural metabolic demand would lead to a reduction in ΔCBF/ΔCMRO2. A simulation of BOLD relative to ΔCMRO2 for lower and higher neurometabolic-flow coupling ratios (approximating those for old and young, respectively) indicated less BOLD signal change in old than young in relatively lower CMRO2 ranges, as well as greater BOLD signal change in young compared to old in relatively higher CMRO2 ranges. These results suggest that age-comparative studies relying on BOLD signal might be misinterpreted, as age-related BOLD changes do not merely reflect neural activity changes. Age-related declines in neurometabolic-flow coupling might lead to neural efficiency reductions that can adversely affect visual task performance.

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. In the current work, we propose that impairment of the cholinergic system in Gulf War Illness patients (GWIPs) leads to behavioral and neural deficits of the central executive of working memory. A large sample of GWIPs and matched control participants underwent functional MRI during a varied-load working memory task. Compared with matched control participants, GWIPs showed a greater decline in performance as working memory demand increased. Functional imaging results 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 working memory performance. Behavioral data suggest that working memory executive strategies are impaired in GWIPs. Functional data further support this hypothesis and suggest that GWIPs use less effective strategies during high-demand working memory.

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.

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.

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.

The Relationship Between M in "Calibrated fMRI" and the Physiologic Modulators of fMRI.

The “calibrated fMRI” technique requires a hypercapnia calibration experiment in order to estimate the factor “M”. It is desirable to be able to obtain the M value without the need of a gas challenge calibration. According to the analytical expression of M, it is a function of several baseline physiologic parameters, such as baseline venous oxygenation and CBF, both of which have recently been shown to be significant modulators of fMRI signal. Here we studied the relationship among hypercapnia-calibrated M, baseline venous oxygenation and CBF, and assessed the possibility of estimating M from the baseline physiologic parameters. It was found that baseline venous oxygenation and CBF are highly correlated (R2=0.77, P<0.0001) across subjects. However, the hypercapnia-calibrated M was not correlated with baseline venous oxygenation or CBF. The hypercapnia-calibrated M was not correlated with an estimation of M based on analytical expression either. The lack of correlation may be explained by the counteracting effect of venous oxygenation and CBF on the M factor, such that the actual M value of an individual may be mostly dependent on other parameters such as hematocrit. Potential biases in hypercapnia-based M estimation were also discussed in the context of possible reduction of CMRO2 during hypercapnia.

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

ABSTRACT 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. HighlightsIntact neural‐vascular communication may play a central role in cognitive performance.Patients with Multiple Sclerosis (MS) are known to have white‐matter damage and impaired cognitive performance.Hemodynamic response function (HRF) shapes of healthy individuals were compared to those of MS patients.Spline interpolation (minimizing shape assumptions) revealed group differences in both HRF amplitude and time‐to‐peak (TTP).Faster performance predicted faster HRF TTP, implicating vasodilatory speed in the physiology underlying cognitive speed.

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.