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.

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.

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.

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.

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.

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.

Reminders activate the prefrontal-medial temporal cortex and attenuate forgetting of event memory.

Replicas of an aspect of an experienced event can serve as effective reminders, yet little is known about the neural basis of such reminding effects. Here we examined the neural activity underlying the memory-enhancing effect of reminders 1 week after encoding of naturalistic film clip events. We used fMRI to determine differences in network activity associated with recently reactivated memories relative to comparably aged, non-reactivated memories. Reminders were effective in facilitating overall retrieval of memory for film clips, in an all-or-none fashion. Prefrontal cortex and hippocampus were activated during both reminders and retrieval. Peak activation in ventro-lateral prefrontal cortex (vPFC) preceded peak activation in the right hippocampus during the reminders. For film clips that were successfully retrieved after 7 days, pre-retrieval reminders did not enhance the quality of the retrieved memory or the number of details retrieved, nor did they more strongly engage regions of the recollection network than did successful retrieval of a non-reminded film clip. These results suggest that reminders prior to retrieval are an effective means of boosting retrieval of otherwise inaccessible episodic events, and that the inability to recall certain events after a delay of a week largely reflects a retrieval deficit, rather than a storage deficit for this information. The results extend other evidence that vPFC drives activation of the hippocampus to facilitate memory retrieval and scene construction, and show that this facilitation also occurs when reminder cues precede successful retrieval attempts. The time course of vPFC-hippocampal activity during the reminder suggests that reminders may first engage schematic information meditated by vPFC followed by a recollection process mediated by the hippocampus.

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.

Age-related differences in the impact of mind-wandering and visual distraction on performance in a go/no-go task.

Optimal performance in many tasks requires minimizing the impact of both visual distraction and mind-wandering. Yet, so far, these two types of distraction have been studied in isolation and it remains unclear whether they act in similar or dissociable ways across age groups. Here, we studied the impact of visual distraction and mind-wandering on performance in a go/no-go task in young and older adults. Older adults reported higher task focus than young, which was associated with a specific age-related reduction in mind-wandering, rather than to thoughts triggered by the task. Older adults exhibited fewer no-go errors, higher mean reaction time (RT) and reduced RT variability compared to young adults. In contrast, visual distraction was associated with a disproportionate effect in older versus young adults on go accuracy, mean RT, and RT variability. Decreasing task focus was similarly associated with reduced go- and no-go accuracy and increased RT variability across age groups. In summary, our results suggest that whereas older adults are disproportionately affected by visual distraction compared to young, they exhibit a reduction in mind-wandering frequency. Moreover, the impact of decreasing task focus on task performance is similar across age groups. Our results suggest a dissociation of the impact of visual distraction and mind-wandering as a function of age. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Differential effects of mind-wandering and visual distraction on age-related changes in neuro-electric brain activity and variability.

Optimal performance in many tasks requires minimizing the impact of both visual distractors in the environment and distracting internal thoughts (i.e., mind-wandering). Prior research has indicated that older adults are disproportionately affected by the presence of visual distractors compared to young adults, but are not excessively affected by distracting thoughts. Yet an explanation for these dissociable effects remains elusive. In the current study, we assessed age-related differences in event-related potentials and neural variability associated with internal distraction and visual distractors in a go/no-go task. Compared to young adults, older adults showed an increased visual distraction cost in mean reaction time (RT) and RT variability but a reduction in internal distraction frequency and a reduced internal distraction cost on go accuracy and RT variability. Visual distraction and internal distraction were associated with opposite patterns of behavioral and neural effects. Behaviorally, across age groups, internal distraction was associated with more no-go errors whereas visual distraction was associated with reduced no-go errors. Across groups, internal distraction was associated with decreased P3 amplitude, whereas visual distraction was associated with increased P3 amplitude. In addition, internal distraction was associated with an increase in neural variability (more so in young versus older adults), while visual distraction was associated with a reduction in variability in young adults only. We suggest that the opposing effects of the two distractor types on behavioral and neural measures occur because visual distraction is associated with increased attentional resources devoted to the task to overcome visual interference whereas internal distraction is associated with decreased attentional resources devoted to the task. Moreover, older adults exhibited reduced flexibility of neural variability as a function of both distractor types, which may correspond to a diminished ability to up-regulate attention in the face of visual distraction and a diminished shift in attention away from the task during internal distraction.

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.

Holding On to the Past: Older Adults Show Lingering Neural Activation of No-Longer-Relevant Items in Working Memory.

Goal-relevant information can be maintained in working memory over a brief delay interval to guide an upcoming decision. There is also evidence suggesting the existence of a complementary process: namely, the ability to suppress information that is no longer relevant to ongoing task goals. Moreover, this ability to suppress or inhibit irrelevant information appears to decline with age. In this study, we compared younger and older adults undergoing fMRI on a working memory task designed to address whether the modulation of neural representations of relevant and no-longer-relevant items during a delay interval is related to age and overall task performance. Following from the theoretical predictions of the inhibitory deficit hypothesis of aging, we hypothesized that older adults would show higher activation of no-longer-relevant items during a retention delay compared to young adults and that higher activation of these no-longer-relevant items would predict worse recognition memory accuracy for relevant items. Our results support this prediction and more generally demonstrate the importance of goal-driven modulation of neural activity in successful working memory maintenance. Furthermore, we showed that the largest age differences in the regulation of category-specific pattern activity during working memory maintenance were seen throughout the medial temporal lobe and prominently in the hippocampus, further establishing the importance of "long-term memory" retrieval mechanisms in the context of high-load working memory tasks that place large demands on attentional selection mechanisms.

Frontostriatal functional connectivity supports reward-enhanced memory in older adults.

Both younger and older adults prioritize reward-associated stimuli in memory, but there has been little research on possible age differences in the neural mechanisms mediating this effect. In the present study, we examine neural activation and functional connectivity in healthy younger and older adults to test the hypothesis that older adults would engage prefrontal regions to a greater extent in the service of reward-enhanced memory. While undergoing MRI, target stimuli were presented after high- or low-reward cues. The cues indicated the reward value for successfully recognizing the stimulus on a memory test 24 hours later. We replicated prior findings that both older and younger adults had better memory for high- compared to low-reward stimuli. Critically, in older but not younger adults, this enhanced subsequent memory for high-reward items was supported by greater connectivity between the caudate and bilateral inferior frontal gyrus. The findings add to the growing literature on motivation-cognition interactions in healthy aging and provide novel findings of the neural underpinnings of reward-motivated encoding.

Creative, internally-directed cognition is associated with reduced BOLD variability.

In a range of externally-directed tasks, intra-individual variability of fMRI BOLD signal has been shown to be a stronger predictor of cognitive performance than mean BOLD signal. BOLD variability's strong association with cognitive performance is hypothesised to be due to it capturing the dynamic range of neural systems. Although increased BOLD variability is also speculated to play a role in internally-directed thought, particularly when creative and flexible cognition is required, there is a relative lack of research exploring whether BOLD variability is related to internally-directed cognition. Thus, we investigated the relationship between BOLD variability and a key component of creativity - divergent thinking - in various tasks that required participants to think flexibly. We also determined whether any associations between BOLD variability and creativity overlapped with, or differed, from associations between mean BOLD signal and creativity. First, we performed task Partial Least Squares (PLS) analyses that compared BOLD signal (either mean or variability) during two future imagination conditions that differed in the amount of cognitive flexibility required: a Congruent condition in which autobiographical details (people, places, objects) comprising an imagined event belonged to the same social sphere (e.g., university) and an Incongruent condition in which details belonged to different social spheres and required greater cognitive flexibility to integrate. Results indicated that the Incongruent condition was associated with a widespread reduction in both BOLD variability and mean signal (relative to the Congruent condition), but in largely non-overlapping regions. Next, we used behavioral PLS to determine whether individual differences in performance on future simulation tasks as well as the Alternate Uses Task relates to BOLD variability and mean BOLD signal. Better performance on these tasks was predominantly associated with increases in mean BOLD signal and decreases in BOLD variability, in a range of disparate brain regions. Together, the results suggest that, unlike tasks requiring externally-directed cognition, superior performance on tasks requiring creative internal mentation is associated with less (not more) variability.

Resting State BOLD Variability of the Posterior Medial Temporal Lobe Correlates with Cognitive Performance in Older Adults with and without Risk for Cognitive Decline.

Local brain signal variability [SD of the BOLD signal (SDBOLD]] correlates with age and cognitive performance, and recently differentiated Alzheimer's disease (AD) patients from healthy controls. However, it is unknown whether changes to SDBOLD precede diagnosis of AD or mild cognitive impairment. We compared ostensibly healthy older adult humans who scored below the recommended threshold on the Montreal cognitive assessment (MoCA) and who showed reduced medial temporal lobe (MTL) volume in a previous study ("at-risk" group, n = 20), with healthy older adults who scored within the normal range on the MoCA ("control" group, n = 20). Using multivariate partial least-squares analysis we assessed the correlations between SDBOLD and age, MoCA score, global fractional anisotropy, global mean diffusivity, and four cognitive factors. Greater SDBOLD in the MTL and occipital cortex positively correlated with performance on cognitive control/speed tasks but negatively correlated with memory scores in the control group. These relations were weaker in the at-risk group. A post hoc analysis assessed associations between MTL volumes and SDBOLD in both groups. This revealed a negative correlation, most robust in the at-risk group, between MTL SDBOLD and MTL subregion volumetry, particularly the entorhinal and parahippocampal regions. Together, these results suggest that the association between SDBOLD and cognition differs between the at-risk and control groups, which may be because of lower MTL volumes in the at-risk group. Our data indicate relations between MTL SDBOLD and cognition may be helpful in understanding brain differences in individuals who may be at risk for further cognitive decline.

Meta-analytic and functional connectivity evidence from functional magnetic resonance imaging for an anterior to posterior gradient of function along the hippocampal axis.

There is considerable evidence from non-human animal studies that the anterior and posterior regions of the hippocampus have different anatomical connections and support different behavioural functions. Although there are some recent human studies using functional magnetic resonance imaging (fMRI) that have addressed this idea directly in the memory and spatial processing domains and provided support for it, there has been no broader meta-analysis of the fMRI literature to determine if there is consistent evidence for functional dissociations in anterior and posterior hippocampus across all of the different cognitive domains in which the hippocampus participates. The purpose of this review is to address this gap in our knowledge using three approaches. One approach involved PubMed searches to identify relevant fMRI papers reporting hippocampal activation during episodic encoding and retrieval, semantic retrieval, working memory, spatial navigation, simulation/scene construction, transitive inference, and social cognition tasks. The second was to use a large meta-analytic database (neurosynth) to find text terms and coactivation maps associated with the anterior and posterior hippocampal regions identified in the literature search. The third approach was to contrast the resting-state functional connectivity of the anterior and posterior hippocampal regions using a publicly available database that includes a large sample of adults. These three approaches provided converging evidence that not only are cognitive processes differently distributed along the hippocampal axis, but there also are distinct areas coactivated and functionally connected with the anterior and posterior segments. This anterior/posterior distinction involving multiple cognitive domains is consistent with the animal literature and provides strong support from fMRI for the idea of functional dissociations across the long axis of the hippocampus.