Excessive left anterior hippocampal and caudate activation in schizophrenia underlie cognitive underperformance in a virtual navigation task.

We used a virtual navigation paradigm in a city environment to assess neuroanatomical correlates of cognitive deficits in schizophrenia spectrum disorders (SSD). We studied a total of N = 36 subjects: 18 with SSD and 18 matched unaffected controls. Participants completed 10 rapid, single-trial navigation tasks within the virtual city while undergoing functional magnetic resonance imaging (fMRI). All trials tested ability to find different targets seen earlier, during the passive viewing of a path around different city blocks. SSD patients had difficulty finding previously-encountered targets, were less likely to find novel shortcuts to targets, and more likely to attempt retracing of the path observed during passive viewing. Based on a priori region-of-interest analyses, SSD participants had hyperactivation of the left hippocampus when passively viewing turns, hyperactivation of the left caudate when finding targets, and hypoactivation of a focal area of the dorsolateral prefrontal cortex when targets were initially shown during passive viewing. We propose that these brain-behaviour relations may bias or reinforce stimulus-response navigation approaches in SSD and underlie impaired performance when allocentric spatial memory is required, such as when forming efficient shortcuts. This pattern may extend to more general cognitive impairments in SSD that could be used to design remediation strategies.

Age-related Differences in Response Inhibition Are Mediated by Frontoparietal White Matter but Not Functional Activity.

Healthy older adults often exhibit lower performance but increased functional recruitment of the frontoparietal control network during cognitive control tasks. According to the cortical disconnection hypothesis, age-related changes in the microstructural integrity of white matter may disrupt inter-regional neuronal communication, which in turn can impair behavioral performance. Here, we use fMRI and diffusion-weighted imaging to determine whether age-related differences in white matter microstructure contribute to frontoparietal over-recruitment and behavioral performance during a response inhibition (go/no-go) task in an adult life span sample (n = 145). Older and female participants were slower (go RTs) than younger and male participants, respectively. However, participants across all ages were equally accurate on the no-go trials, suggesting some participants may slow down on go trials to achieve high accuracy on no-go trials. Across the life span, functional recruitment of the frontoparietal network within the left and right hemispheres did not vary as a function of age, nor was it related to white matter fractional anisotropy (FA). In fact, only frontal FA and go RTs jointly mediated the association between age and no-go accuracy. Our results therefore suggest that frontal white matter cortical "disconnection" is an underlying driver of age-related differences in cognitive control, and white matter FA may not fully explain functional task-related activation in the frontoparietal network during the go/no-go task. Our findings add to the literature by demonstrating that white matter may be more important for certain cognitive processes in aging than task-related functional activation.

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.

Disturbed sleep is associated with reduced verbal episodic memory and entorhinal cortex volume in younger middle-aged women with risk-reducing early ovarian removal.

Introduction: Women with early ovarian removal (<48 years) have an elevated risk for both late-life Alzheimer's disease (AD) and insomnia, a modifiable risk factor. In early midlife, they also show reduced verbal episodic memory and hippocampal volume. Whether these reductions correlate with a sleep phenotype consistent with insomnia risk remains unexplored. Methods: We recruited thirty-one younger middleaged women with risk-reducing early bilateral salpingo-oophorectomy (BSO), fifteen of whom were taking estradiol-based hormone replacement therapy (BSO+ERT) and sixteen who were not (BSO). Fourteen age-matched premenopausal (AMC) and seventeen spontaneously peri-postmenopausal (SM) women who were ~10y older and not taking ERT were also enrolled. Overnight polysomnography recordings were collected at participants' home across multiple nights (M=2.38 SEM=0.19), along with subjective sleep quality and hot flash ratings. In addition to group comparisons on sleep measures, associations with verbal episodic memory and medial temporal lobe volume were assessed. Results: Increased sleep latency and decreased sleep efficiency were observed on polysomnography recordings of those not taking ERT, consistent with insomnia symptoms. This phenotype was also observed in the older women in SM, implicating ovarian hormone loss. Further, sleep latency was associated with more forgetting on the paragraph recall task, previously shown to be altered in women with early BSO. Both increased sleep latency and reduced sleep efficiency were associated with smaller anterolateral entorhinal cortex volume. Discussion: Together, these findings confirm an association between ovarian hormone loss and insomnia symptoms, and importantly, identify an younger onset age in women with early ovarian removal, which may contribute to poorer cognitive and brain outcomes in these women.

A neural mechanism of cognitive reserve: The case of bilingualism.

Cognitive Reserve (CR) refers to the preservation of cognitive function in the face of age- or disease-related neuroanatomical decline. While bilingualism has been shown to contribute to CR, the extent to which, and what particular aspect of, second language experience contributes to CR are debated, and the underlying neural mechanism(s) unknown. Intrinsic functional connectivity reflects experience-dependent neuroplasticity that occurs across timescales ranging from minutes to decades, and may be a neural mechanism underlying CR. To test this hypothesis, we used voxel-based morphometry and resting-state functional connectivity analyses of MRI data to compare structural and functional brain integrity between monolingual and bilingual older adults, matched on cognitive performance, and across levels of second language proficiency measured as a continuous variable. Bilingualism, and degree of second language proficiency specifically, were associated with lower gray matter integrity in a hub of the default mode network - a region that is particularly vulnerable to decline in aging and dementia - but preserved intrinsic functional network organization. Bilingualism moderated the association between neuroanatomical differences and cognitive decline, such that lower gray matter integrity was associated with lower executive function in monolinguals, but not bilinguals. Intrinsic functional network integrity predicted executive function when controlling for group differences in gray matter integrity and language status. Our findings confirm that lifelong bilingualism is a CR factor, as bilingual older adults performed just as well as their monolingual peers on tasks of executive function, despite showing signs of more advanced neuroanatomical aging, and that this is a consequence of preserved intrinsic functional network organization.

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.

Differential involvement of the anterior and posterior hippocampus, parahippocampus, and retrosplenial cortex in making precise judgments of spatial distance and object size for remotely acquired memories of environments and objects.

The hippocampus is known to support processing of precise spatial information in recently learned environments. It is less clear, but crucial for theories of systems consolidation, to know whether it also supports processing of precise spatial information in familiar environments learned long ago and whether such precision extends to objects and numbers. In this fMRI study, we asked participants to make progressively more refined spatial distance judgments among well-known Toronto landmarks (whether landmark A is closer to landmark B or C) to examine hippocampal involvement. We also tested whether the hippocampus was similarly engaged in estimating magnitude regarding sizes of familiar animals and numbers. We found that the hippocampus was only engaged in spatial judgment. Activation was greater and lasted longer in the posterior than anterior hippocampus, which instead showed greater modulation as discrimination between spatial distances became more fine grained. These findings suggest that the anterior and posterior hippocampus have different functions which are influenced differently by estimation of differential distance. Similarly, parahippocampal-place-area and retrosplenial cortex were involved only in the spatial condition. By contrast, activation of the intraparietal sulcus was modulated by precision in all conditions. Therefore, our study supports the idea that the hippocampus and related structures are implicated in retrieving and operating even on remote spatial memories whenever precision is required, as posted by some theories of systems consolidation.

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.

Spatial cognition is associated with levels of phosphorylated-tau and ß-amyloid in clinically normal older adults.

Spatial cognition is associated with Alzheimer's disease (AD) biomarkers in the symptomatic stages of the disease. We investigated whether cerebrospinal fluid (CSF) biomarkers (phosphorylated-tau [p-tau] and ß-amyloid) are associated with poorer spatial cognition in clinically normal older adults. Participants were 1875 clinically normal adults (age 67.8 [8.5] years) from the European Prevention of Alzheimer's Dementia Consortium. Mixed effect models assessed the cross-sectional association between p-tau181, ß-amyloid1-42 (Aß1-42) and p-tau181/Aß1-42 ratio and spatial cognition measured using semi-automated Supermarket Task and the 4 Mountains Task. Levels of p-tau181, Aß1-42, and p-tau181/Aß1-42 ratio were significantly associated with spatial cognition scores on both tasks. The p-tau181/Aß1-42 ratio showed the largest effect sizes (ß = -0.04/0.05, p < 0.001). Lower entorhinal cortical volume was associated with poorer outcomes on both tasks (ß = 0.06, p < 0.002) and accounted for 18%-22% of the direct association between p-tau181 and spatial cognition scores. In conclusion, degeneration of the entorhinal cortex mediates a significant proportion of the association between p-tau181 and spatial assessments in cognitively normal adults. Future studies should focus on increasing the sensitivity of digital spatial assessments.

Connectivity between default mode and frontoparietal networks mediates the association between global amyloid-ß and episodic memory.

Βeta-amyloid (Aß) is a neurotoxic protein that deposits early in the pathogenesis of preclinical Alzheimer's disease. We aimed to identify network connectivity that may alter the negative effect of Aß on cognition. Following assessment of memory performance, resting-state fMRI, and mean cortical PET-Aß, a total of 364 older adults (286 with clinical dementia rating [CDR-0], 59 with CDR-0.5 and 19 with CDR-1, mean age: 74.0 ± 6.4 years) from the OASIS-3 sample were included in the analysis. Across all participants, a partial least squares regression showed that lower connectivity between posterior medial default mode and frontoparietal networks, higher within-default mode, and higher visual-motor connectivity predict better episodic memory. These connectivities partially mediate the effect of Aß on episodic memory. These results suggest that connectivity strength between the precuneus cortex and the superior frontal gyri may alter the negative effect of Aß on episodic memory. In contrast, education was associated with different functional connectivity patterns. In conclusion, functional characteristics of specific brain networks may help identify amyloid-positive individuals with a higher likelihood of memory decline, with implications for AD clinical trials.

Recollection and prior knowledge recruit the left angular gyrus during recognition.

The human angular gyrus (AG) is implicated in recollection, or the ability to retrieve detailed memory content from a specific episode. A separate line of research examining the neural bases of more general mnemonic representations, extracted over multiple episodes, also highlights the AG as a core region of interest. To reconcile these separate views of AG function, the present fMRI experiment used a Remember-Know paradigm with famous (prior knowledge) and non-famous (no prior knowledge) faces to test whether AG activity could be modulated by both task-specific recollection and general prior knowledge within the same individuals. Increased BOLD activity in the left AG was observed during both recollection in the absence of prior knowledge (recollected > non-recollected or correctly rejected non-famous faces) and when prior knowledge was accessed in the absence of experiment-specific recollection (famous > non-famous correct rejections). This pattern was most prominent for the left AG as compared to the broader inferior parietal lobe. Recollection-related responses in the left AG increased with encoding duration and prior knowledge, despite prior knowledge being incidental to the recognition decision. Overall, the left AG appears sensitive to both task-specific recollection and the incidental access of general prior knowledge, thus broadening our notions of the kinds of mnemonic representations that drive activity in this region.

Transcranial magnetic stimulation to the angular gyrus modulates the temporal dynamics of the hippocampus and entorhinal cortex.

Transcranial magnetic stimulation (TMS) delivered to the angular gyrus (AG) affects hippocampal function and associated behaviors (Thakral PP, Madore KP, Kalinowski SE, Schacter DL. Modulation of hippocampal brain networks produces changes in episodic simulation and divergent thinking. 2020a. Proc Natl Acad Sci U S A. 117:12729-12740). Here, we examine if functional magnetic resonance imaging (fMRI)-guided TMS disrupts the gradient organization of temporal signal properties, known as the temporal organization, in the hippocampus (HPC) and entorhinal cortex (ERC). For each of 2 TMS sessions, TMS was applied to either a control site (vertex) or to a left AG target region (N = 18; 14 females). Behavioral measures were then administered, and resting-state scans were acquired. Temporal dynamics were measured by tracking change in the fMRI signal (i) "within" single voxels over time, termed single-voxel autocorrelation and (ii) "between" different voxels over time, termed intervoxel similarity. TMS reduced AG connectivity with the hippocampal target and induced more rapid shifting of activity in single voxels between successive time points, lowering the single-voxel autocorrelation, within the left anteromedial HPC and posteromedial ERC. Intervoxel similarity was only marginally affected by TMS. Our findings suggest that hippocampal-targeted TMS disrupts the functional properties of the target site along the anterior/posterior axis. Further studies should examine the consequences of altering the temporal dynamics of these medial temporal areas to the successful processing of episodic information under task demand.

Are older adults susceptible to visual distraction when targets and distractors are spatially separated?

Older adults show preserved memory for previously distracting information due to reduced inhibitory control. In some previous studies, targets and distractors overlap both temporally and spatially. We investigated whether age differences in attentional orienting and disengagement affect recognition memory when targets and distractors are spatially separated at encoding. In Experiments 1 and 2, eye movements were recorded while participants completed an incidental encoding task under covert (i.e., restricted viewing) and overt (i.e., free-viewing) conditions, respectively. The encoding task consisted of pairs of target and distractor item-color stimuli presented in separate visual hemifields. Prior to stimulus onset, a central cue indicated the location of the upcoming target. Participants were subsequently tested on their recognition of the items, their location, and the associated color. In Experiment 3, targets were validly cued on 75% of the encoding trials; on invalid trials, participants had to disengage their attention from the distractor and reorient to the target. Associative memory for colors was reduced among older adults across all experiments, though their location memory was only reduced in Experiment 1. In Experiment 2, older and younger adults directed a similar proportion of fixations toward targets and distractors. Explicit recognition of distractors did not differ between age groups in any of the experiments. However, older adults were slower to correctly recognize distractors than false alarm to novel items in Experiment 2, suggesting some implicit memory for distraction. Together, these results demonstrate that older adults may only be vulnerable to encoding visual distraction when viewing behavior is unconstrained.

Scene memory and hippocampal volume in middle-aged women with early hormone loss.

The present study explored whether early midlife bilateral salpingo-oophorectomy (BSO), a female-specific risk factor for dementia, is associated with reduced medial temporal lobe structure and function. Younger middle-aged women with the BRCA1/2 mutation and a BSO prior to spontaneous menopause (SM) were recruited. We determined the performance of women with BSO not taking estradiol-based hormone therapy (n = 18) on a task measuring object and scene recognition and quantified medial temporal lobe subregion volumes using manually segmented high-resolution T2-weighted MRI scans. Comparisons were made to those with BSO taking estradiol-based hormone therapy (n = 20), age-matched premenopausal controls (n = 28), and older women in SM not taking hormone therapy matched for duration of hormone deprivation (n = 17). Reduced hippocampal integrity specific to the BSO group not taking hormone therapy was observed, reflected by significantly smaller dentate gyrus/CA2/CA3 volumes and lower scene recognition memory performance. These findings show that hippocampal subfield volume may be useful for identifying early midlife changes in women at elevated risk for dementia.

Exploration of salient risk factors involved in mild cognitive impairment.

Mild cognitive impairment (MCI) is a prevalent and complex condition among older adults that often progresses into Alzheimer's disease (AD). Although MCI affects individuals differently, there are specific indicators of risk commonly associated with the development of MCI. The present study explored the prevalence of seven established MCI risk categories within a large sample of older adults with and without MCI. We explored trends across the different diagnostic groups and extracted the most salient risk factors related to MCI using partial least squares. Neuropsychological risk categories showed the largest differences across groups, with the cognitively unimpaired groups outperforming the MCI groups on all measures. Apolipoprotein E4 (ApoE4) carriers were significantly more common among the more severe MCI group, whereas ApoE4 non-carriers were more common in the healthy controls. Participants with subjective and objective cognitive impairment were trending towards AD-like cerebral spinal fluid (CSF) biomarker levels. Increased age, being male and having fewer years of education were identified as important risk factors of MCI. Higher CSF tau levels were correlated with ApoE4 carrier status, age and a decrease in the ability to carry out daily activities across all diagnostic groups. Amyloid beta1-42 CSF concentration was positively correlated with cognitive and memory performance and non-ApoE4 carrier status regardless of diagnostic status. Unlike previous research, poor cardiovascular health or being female had no relation to MCI. Altogether, the results highlighted risk factors that were specific to persons with MCI, findings that will inform future research in healthy aging, MCI and AD.

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.

Influence of target-distractor neural similarity on working memory performance in older and younger adults.

According to the inhibitory deficit hypothesis, older adults often fail to selectively inhibit distractors and attend to relevant information in working memory, leading to poorer memory of target items but better recall of irrelevant distractors compared to younger adults. Here, we explored how neural similarity of activity patterns between relevant and irrelevant stimulus categories impacts memory performance. We found evidence that older adults may benefit from failing to inhibit distractors that are similar to targets, perhaps because sustained neural activation of distractors partially supports maintenance of targets when they share neural resources, allowing for better subsequent recognition of studied target items. We also found increased category-specific multivoxel pattern activity in medial temporal regions in younger compared to older adults as category similarity increased. We propose that this reduced category-specific activation in medial temporal regions in older adults may reflect more blended representations of all the information available in working memory.

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.

Bilingualism contributes to reserve and working memory efficiency: Evidence from structural and functional neuroimaging.

This study compared brain and behavioral outcomes for monolingual and bilingual older adults who reported no cognitive or memory problems on three types of memory that typically decline in older age, namely, working memory (measured by n-back), item, and associative recognition. The results showed that bilinguals were faster on the two-back working memory task than monolinguals but used a set of frontostriatal regions less than monolinguals. There was no group difference on an item/associative recognition task. In brain structure, gray matter volume and white matter integrity (fractional anisotropy) were generally lower in bilinguals than in monolinguals, but bilinguals had better white matter integrity than monolinguals in the bilateral superior corona radiata and better gray matter density in the left inferior temporal gyrus. These regions may help preserve bilinguals' executive functions despite generally more significant atrophy throughout the brain than monolinguals in that these structures contribute to efficient communication between executive frontal regions and subcortical motor regions, and perceptual pathways. Reliable negative correlations between brain structure and age were only observed in bilinguals, and to the extent that bilinguals (but not monolinguals) had better brain structure, their performance was enhanced. Collectively, the findings provide evidence for reserve in bilingual older adults.

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.