The biological role of local and global fMRI BOLD signal variability in human brain organization.

Variability drives the organization and behavior of complex systems, including the human brain. Understanding the variability of brain signals is thus necessary to broaden our window into brain function and behavior. Few empirical investigations of macroscale brain signal variability have yet been undertaken, given the difficulty in separating biological sources of variance from artefactual noise. Here, we characterize the temporal variability of the most predominant macroscale brain signal, the fMRI BOLD signal, and systematically investigate its statistical, topographical and neurobiological properties. We contrast fMRI acquisition protocols, and integrate across histology, microstructure, transcriptomics, neurotransmitter receptor and metabolic data, fMRI static connectivity, and empirical and simulated magnetoencephalography data. We show that BOLD signal variability represents a spatially heterogeneous, central property of multi-scale multi-modal brain organization, distinct from noise. Our work establishes the biological relevance of BOLD signal variability and provides a lens on brain stochasticity across spatial and temporal scales.

Relation of resting brain signal variability to cognitive and socioemotional measures in an adult lifespan sample.

Temporal variability of the fMRI-derived blood-oxygen-level-dependent (BOLD) signal during cognitive tasks shows important associations with individual differences in age and performance. Less is known about relations between spontaneous BOLD variability measured at rest and relatively stable cognitive measures, such as IQ or socioemotional function. Here, we examined associations among resting BOLD variability, cognitive/socioemotional scores from the NIH Toolbox and optimal time of day for alertness (chronotype) in a sample of 157 adults from 20 to 86 years of age. To investigate individual differences in these associations independently of age, we regressed age out from both behavioral and BOLD variability scores. We hypothesized that greater BOLD variability would be related to higher fluid cognition scores, more positive scores on socioemotional scales and a morningness chronotype. Consistent with this idea, we found positive correlations between resting BOLD variability, positive socioemotional scores (e.g. self-efficacy) and morning chronotype, as well as negative correlations between variability and negative emotional scores (e.g. loneliness). Unexpectedly, we found negative correlations between BOLD variability and fluid cognition. These results suggest that greater resting brain signal variability facilitates optimal socioemotional function and characterizes those with morning-type circadian rhythms, but individuals with greater fluid cognition may be more likely to show less temporal variability in spontaneous measures of BOLD activity.

Women's Brain Health: Midlife Ovarian Removal Affects Associative Memory.

Women with early bilateral salpingo-oophorectomy (BSO; removal of ovaries and fallopian tubes) have greater Alzheimer's disease (AD) risk than women in spontaneous/natural menopause (SM), but early biomarkers of this risk are not well-characterized. Considering associative memory deficits may presage preclinical AD, we wondered if one of the earliest changes might be in associative memory and whether younger women with BSO had changes similar to those observed in SM. Women with BSO (with and without 17ß-estradiol replacement therapy (ERT)), their age-matched premenopausal controls (AMC), and older women in SM completed a functional magnetic resonance imaging face-name associative memory task shown to predict early AD. Brain activation during encoding was compared between groups: AMC (n=25), BSO no ERT (BSO; n=15), BSO+ERT (n=16), and SM without hormone therapy (n=16). Region-of-interest analyses revealed AMC did not contribute to functional group differences. BSO+ERT had higher hippocampal activation than BSO and SM. This hippocampal activation correlated positively with urinary metabolite levels of 17ß-estradiol. Multivariate partial least squares analyses showed BSO+ERT had a different network-level activation pattern than BSO and SM. Thus, despite being approximately 10 years younger, women with BSO without ERT had similar brain function to those with SM, suggesting early 17ß-estradiol loss may lead to an altered functional brain phenotype which could influence late-life AD risk, making face-name encoding a potential biomarker for midlife women with increased AD risk. Despite similarities in activation, BSO and SM groups showed opposite within-hippocampus connectivity, suggesting menopause type is an important consideration when assessing brain function.

Reduced modulation of BOLD variability as a function of cognitive load in healthy aging.

BOLD variability, which measures moment-to-moment fluctuations in brain signal, is sensitive to age differences in cognitive performance. However, the effect of aging on BOLD variability in the context of different cognitive demands is still unclear. The current study examined how aging affects brain variability across cognitive loads and the contribution of BOLD variability to working memory abilities. Participants (N = 149, ages 20‒86) completed an fMRI n-back paradigm with 3 loads and 10-minute resting state scan. We found that BOLD variability was greater during rest compared to task and decreased even further as n-back load increased. Older age was associated with smaller load-related modulations of BOLD variability in default mode and fronto-parietal control networks. Increased variability in default mode, fronto-parietal control, and limbic regions and decreased variability in sensori-motor regions during the n-back task was associated with better working memory performance, regardless of age. Our findings suggest that working memory reductions in older ages are related to failure of core cognitive control and default mode regions to modulate dynamic range of activity in the face of increased demands.

Dataset of functional connectivity during cognitive control for an adult lifespan sample.

We provide functional connectivity matrices generated during functional magnetic resonance imaging (fMRI) during different tasks of cognitive control in healthy aging adults. These data can be used to replicate the primary results from the related manuscript: Reconfiguration and dedifferentiation of functional networks during cognitive control across the adult lifespan (Rieck et al., 2021). One-hundred-forty-four participants (ages 20-86) were scanned on a Siemens 3T MRI scanner while they were completing tasks to measure functional activity during inhibition, initiation, shifting, and working memory. Estimates of functional connectivity (quantified with timeseries correlations) between different brain regions were computed using three different brain atlases: Schaefer 100 parcel 17 network atlas (Schaefer et al., 2018; Yeo et al., 2011), Power 229 node 10 network atlas (Power et al., 2011), and Schaefer 200 parcel 17 network atlas (Schaefer et al., 2018; Yeo et al., 2011). The resulting functional connectivity correlation matrices are provided as text files with this article. Cov-STATIS (Abdi et al., 2012; a multi-table multivariate statistical technique; https://github.com/HerveAbdi/DistatisR) was used to examine similarity between functional connectivity during the different domains of cognitive control. The effect of aging on these functional connectivity patterns was also examined by computing measures of "task differentiation" and "network segregation." This dataset also provides supplemental analyses from the related manuscript (Rieck et al., 2021) to replicate the primary age findings with additional brain atlases. Cognitive neuroscience researchers can benefit from these data by further investigating the age effects on functional connectivity during tasks of cognitive control, in addition to examining the impact of different brain atlases on functional connectivity estimates. These data can also be used for the development of other multi-table and network-based statistical methods in functional neuroimaging.

Contributions of Brain Function and Structure to Three Different Domains of Cognitive Control in Normal Aging.

Cognitive control involves the flexible allocation of mental resources during goal-directed behavior and comprises three correlated but distinct domains-inhibition, shifting, and working memory. The work of Don Stuss and others has demonstrated that frontal and parietal cortices are crucial to cognitive control, particularly in normal aging, which is characterized by reduced control mechanisms. However, the structure-function relationships specific to each domain and subsequent impact on performance are not well understood. In the current study, we examined both age and individual differences in functional activity associated with core domains of cognitive control in relation to fronto-parietal structure and task performance. Participants (n = 140, aged 20-86 years) completed three fMRI tasks: go/no-go (inhibition), task switching (shifting), and n-back (working memory), in addition to structural and diffusion imaging. All three tasks engaged a common set of fronto-parietal regions; however, the contributions of age, brain structure, and task performance to functional activity were unique to each domain. Aging was associated with differences in functional activity for all tasks, largely in regions outside common fronto-parietal control regions. Shifting and inhibition showed greater contributions of structure to overall decreases in brain activity, suggesting that more intact fronto-parietal structure may serve as a scaffold for efficient functional response. Working memory showed no contribution of structure to functional activity but had strong effects of age and task performance. Together, these results provide a comprehensive and novel examination of the joint contributions of aging, performance, and brain structure to functional activity across multiple domains of cognitive control.

Reconfiguration and dedifferentiation of functional networks during cognitive control across the adult lifespan.

Healthy aging is accompanied by reduced cognitive control and widespread alterations in the underlying brain networks; but the extent to which large-scale functional networks in older age show reduced specificity across different domains of cognitive control is unclear. Here we use cov-STATIS (a multi-table multivariate technique) to examine similarity of functional connectivity during different domains of cognitive control-inhibition, initiation, shifting, and working memory-across the adult lifespan. We report two major findings: (1) Functional connectivity patterns during initiation, inhibition, and shifting were more similar in older ages, particularly for control and default networks, a pattern consistent with dedifferentiation of the neural correlates associated with cognitive control; and (2) Networks exhibited age-related reconfiguration such that frontal, default, and dorsal attention networks were more integrated whereas sub-networks of somato-motor system were more segregated in older age. Together these findings offer new evidence for dedifferentiation and reconfiguration of functional connectivity underlying different aspects of cognitive control in normal aging.

Influence of sample size and analytic approach on stability and interpretation of brain-behavior correlations in task-related fMRI data.

Limited statistical power due to small sample sizes is a problem in fMRI research. Most of the work to date has examined the impact of sample size on task-related activation, with less attention paid to the influence of sample size on brain-behavior correlations, especially in actual experimental fMRI data. We addressed this issue using two large data sets (a working memory task, N = 171, and a relational processing task, N = 865) and both univariate and multivariate approaches to voxel-wise correlations. We created subsamples of different sizes and calculated correlations between task-related activity at each voxel and task performance. Across both data sets the magnitude of the brain-behavior correlations decreased and similarity across spatial maps increased with larger sample sizes. The multivariate technique identified more extensive correlated areas and more similarity across spatial maps, suggesting that a multivariate approach would provide a consistent advantage over univariate approaches in the stability of brain-behavior correlations. In addition, the multivariate analyses showed that a sample size of roughly 80 or more participants would be needed for stable estimates of correlation magnitude in these data sets. Importantly, a number of additional factors would likely influence the choice of sample size for assessing such correlations in any given experiment, including the cognitive task of interest and the amount of data collected per participant. Our results provide novel experimental evidence in two independent data sets that the sample size commonly used in fMRI studies of 20-30 participants is very unlikely to be sufficient for obtaining reproducible brain-behavior correlations, regardless of analytic approach.

Functional Connectivity within and beyond the Face Network Is Related to Reduced Discrimination of Degraded Faces in Young and Older Adults.

Degrading face stimuli reduces face discrimination in both young and older adults, but the brain correlates of this decline in performance are not fully understood. We used functional magnetic resonance imaging to examine the effects of degraded face stimuli on face and nonface brain networks and tested whether these changes would predict the linear declines seen in performance. We found decreased activity in the face network (FN) and a decrease in the similarity of functional connectivity (FC) in the FN across conditions as degradation increased but no effect of age. FC in whole-brain networks also changed with increasing degradation, including increasing FC between the visual network and cognitive control networks. Older adults showed reduced modulation of this whole-brain FC pattern. The strongest predictors of within-participant decline in accuracy were changes in whole-brain network FC and FC similarity of the FN. There was no influence of age on these brain-behavior relations. These results suggest that a systems-level approach beyond the FN is required to understand the brain correlates of performance decline when faces are obscured with noise. In addition, the association between brain and behavior changes was maintained into older age, despite the dampened FC response to face degradation seen in older adults.

White Matter Microstructure Predicts Focal and Broad Functional Brain Dedifferentiation in Normal Aging.

Ventral visual cortex exhibits highly organized and selective patterns of functional activity associated with visual processing. However, this specialization decreases in normal aging, with functional responses to different visual stimuli becoming more similar with age, a phenomenon termed "dedifferentiation." The current study tested the hypothesis that age-related degradation of the inferior longitudinal fasciculus (ILF), a white matter pathway involved in visual perception, could account for dedifferentiation of both localized and distributed brain activity in ventral visual cortex. Participants included 281 adults, ages 20-89 years, from the Dallas Lifespan Brain Study who underwent diffusion-weighted imaging to measure white matter diffusivity, as well as fMRI to measure functional selectivity to viewing photographs from different categories (e.g., faces, houses). In general, decreased ILF anisotropy significantly predicted both focal and broad functional dedifferentiation. Specifically, there was a localized effect of structure on function, such that decreased anisotropy in a smaller mid-fusiform region of ILF predicted less selective (i.e., more dedifferentiated) response to viewing faces in a proximal face-responsive region of fusiform. On the other hand, the whole ILF predicted less selective response across broader ventral visual cortex for viewing animate (e.g., human faces, animals) versus inanimate (e.g., houses, chairs) images. This structure-function relationship became weaker with age and was no longer significant after the age of 70 years. These findings indicate that decreased white matter anisotropy is associated with maladaptive differences in proximal brain function and is an important variable to consider when interpreting age differences in functional selectivity.

Joint contributions of cortical morphometry and white matter microstructure in healthy brain aging: A partial least squares correlation analysis.

Cortical atrophy and degraded axonal health have been shown to coincide during normal aging; however, few studies have examined these measures together. To lend insight into both the regional specificity and the relative timecourse of structural degradation of these tissue compartments across the adult lifespan, we analyzed gray matter (GM) morphometry (cortical thickness, surface area, volume) and estimates of white matter (WM) microstructure (fractional anisotropy, mean diffusivity) using traditional univariate and more robust multivariate techniques to examine age associations in 186 healthy adults aged 20-94 years old. Univariate analysis of each tissue type revealed that negative age associations were largest in frontal GM and WM tissue and weaker in temporal, cingulate, and occipital regions, representative of not only an anterior-to-posterior gradient, but also a medial-to-lateral gradient. Multivariate partial least squares correlation (PLSC) found the greatest covariance between GM and WM was driven by the relationship between WM metrics in the anterior corpus callosum and projections of the genu, anterior cingulum, and fornix; and with GM thickness in parietal and frontal regions. Surface area was far less susceptible to age effects and displayed less covariance with WM metrics, while regional volume covariance patterns largely mirrored those of cortical thickness. Results support a retrogenesis-like model of aging, revealing a coupled relationship between frontal and parietal GM and the underlying WM, which evidence the most protracted development and the most vulnerability during healthy aging.

Dynamic range in BOLD modulation: lifespan aging trajectories and association with performance.

Alteration of dynamic range of modulation to cognitive difficulty has been proposed as a salient predictor of cognitive aging. Here, we examine in 171 adults (aged 20-94 years) the effects of age on dynamic modulation of blood oxygenation-level dependent activation to difficulty in parametrically increasing working memory (WM) load (0-, 2-, 3-, and 4-back conditions). First, we examined parametric increases and decreases in activation to increasing WM load (positive modulation effect and negative modulation effect). Second, we examined the effect of age on modulation to difficulty (WM load) to identify regions that differed with age as difficulty increased (age-related positive and negative modulation effects). Weakened modulation to difficulty with age was found in both the positive modulation (middle frontal, superior/inferior parietal) and negative modulation effect (deactivated) regions (insula, cingulate, medial superior frontal, fusiform, and parahippocampal gyri, hippocampus, and lateral occipital cortex). Age-related alterations to positive modulation emerged later in the lifespan than negative modulation. Furthermore, these effects were significantly coupled in that greater upmodulation was associated with lesser downmodulation. Importantly, greater fronto-parietal upmodulation to difficulty and greater downmodulation of deactivated regions were associated with better task accuracy and upmodulation with better WM span measured outside the scanner. These findings suggest that greater dynamic range of modulation of activation to cognitive challenge is in service of current task performance, as well as generalizing to cognitive ability beyond the scanner task, lending support to its utility as a marker of successful cognitive aging.

Functional magnetic resonance imaging data of incremental increases in visuo-spatial difficulty in an adult lifespan sample.

These data provide coordinates generated from a large healthy adult lifespan sample undergoing functional Magnetic Resonance Imaging (fMRI) while completing a spatial judgment task with varying levels of difficulty, as well as a control categorical condition. The data presented here include the average blood-oxygen-dependent (BOLD) response to the spatial judgment vs. the control task, as well as the BOLD response to incremental increasing difficulty; see also "Age-related Reduction of BOLD Modulation to Cognitive Difficulty Predicts Poorer Task Accuracy and Poorer Fluid Reasoning Ability" (Rieck et al., 2017) [1].

Age-related reduction of BOLD modulation to cognitive difficulty predicts poorer task accuracy and poorer fluid reasoning ability.

Aging is associated with reduced resources needed to perform difficult cognitive tasks, but the neural underpinnings are not well understood, especially as there is scant evidence linking functional brain differences to aging cognition. Therefore, the current study examined modulation of fMRI activation from easier to harder spatial distance judgments across a large lifespan sample (N=161; ages 20-94) to identify when in the lifespan modulation to difficulty begins to show deficits and if age-related modulation predicts cognition. Analyses revealed two sets of regions in which modulation increased with difficulty due to either more activation (positive modulation) or more deactivation (negative modulation) to difficulty. These two networks evidenced differential aging trajectories: a right-lateralized fronto-parietal network that decreased in modulation to difficulty between middle- and older-age, and a network of regions in ventromedial prefrontal cortex, posterior cingulate, left angular and middle frontal gyri that showed decreased modulation at the transition from younger to middle-age. Critically, older adults who maintained negative modulation to difficulty showed higher task accuracy. Further, individuals who showed greater coupling between positive and negative modulation performed better on a fluid reasoning task. Age-related preservation of coupled modulation in both cognitive control regions and regions typically associated with default network may be a salient marker of how the brain adapts to maintain cognitive function as we age.

The effect of beta-amyloid on face processing in young and old adults: A multivariate analysis of the BOLD signal.

The recent ability to measure in vivo beta-amyloid (Aß), a marker of Alzheimer's disease (AD), has led to an increased focus on the significance of Aß deposition in clinically normal adults. Evidence suggests that healthy adults with elevated cortical Aß show differences in neural activity associated with memory encoding-specifically encoding of face stimuli. Here, we examined if Aß deposition in clinically normal adults was related to differences in neural activity in ventral visual cortex during face viewing. Our sample included 23 high-Aß older adults, 23 demographically matched low-Aß older adults, and 16 young adults. Participants underwent cognitive testing, Aß positron emission tomography imaging with (18) F-Florbetapir, and functional magnetic resonance imaging to measure neural activity while participants passively viewed photographs of faces. Using barycentric discriminant analysis-a between-groups classification technique-we found that patterns of neural activity in the left fusiform gyrus, a region highly responsive to faces, distinguished Aß status of participants. Older adults with elevated Aß were characterized by decreased activity in left fusiform compared to Aß-negative older adults. Further, we found that the degree to which older adults expressed decreased fusiform activity was related to worse performance on tasks of processing speed. Our results provide unique evidence that, in addition to previously studied memory and default regions, decreased neural activity in a region important for face perception was associated with elevated Aß and may be an early manifestation of AD.