Parallel hippocampal-parietal circuits for self- and goal-oriented processing.

The hippocampus is critically important for a diverse range of cognitive processes, such as episodic memory, prospective memory, affective processing, and spatial navigation. Using individual-specific precision functional mapping of resting-state functional MRI data, we found the anterior hippocampus (head and body) to be preferentially functionally connected to the default mode network (DMN), as expected. The hippocampal tail, however, was strongly preferentially functionally connected to the parietal memory network (PMN), which supports goal-oriented cognition and stimulus recognition. This anterior-posterior dichotomy of resting-state functional connectivity was well-matched by differences in task deactivations and anatomical segmentations of the hippocampus. Task deactivations were localized to the hippocampal head and body (DMN), relatively sparing the tail (PMN). The functional dichotomization of the hippocampus into anterior DMN-connected and posterior PMN-connected parcels suggests parallel but distinct circuits between the hippocampus and medial parietal cortex for self- versus goal-oriented processing.

Individualized Functional Subnetworks Connect Human Striatum and Frontal Cortex.

The striatum and cerebral cortex are interconnected via multiple recurrent loops that play a major role in many neuropsychiatric conditions. Primate corticostriatal connections can be precisely mapped using invasive tract-tracing. However, noninvasive human research has not mapped these connections with anatomical precision, limited in part by the practice of averaging neuroimaging data across individuals. Here we utilized highly sampled resting-state functional connectivity MRI for individual-specific precision functional mapping (PFM) of corticostriatal connections. We identified ten individual-specific subnetworks linking cortex-predominately frontal cortex-to striatum, most of which converged with nonhuman primate tract-tracing work. These included separable connections between nucleus accumbens core/shell and orbitofrontal/medial frontal gyrus; between anterior striatum and dorsomedial prefrontal cortex; between dorsal caudate and lateral prefrontal cortex; and between middle/posterior putamen and supplementary motor/primary motor cortex. Two subnetworks that did not converge with nonhuman primates were connected to cortical regions associated with human language function. Thus, precision subnetworks identify detailed, individual-specific, neurobiologically plausible corticostriatal connectivity that includes human-specific language networks.

Default-mode network streams for coupling to language and control systems.

The human brain is organized into large-scale networks identifiable using resting-state functional connectivity (RSFC). These functional networks correspond with broad cognitive domains; for example, the Default-mode network (DMN) is engaged during internally oriented cognition. However, functional networks may contain hierarchical substructures corresponding with more specific cognitive functions. Here, we used individual-specific precision RSFC to test whether network substructures could be identified in 10 healthy human brains. Across all subjects and networks, individualized network subdivisions were more valid-more internally homogeneous and better matching spatial patterns of task activation-than canonical networks. These measures of validity were maximized at a hierarchical scale that contained ∼83 subnetworks across the brain. At this scale, nine DMN subnetworks exhibited topographical similarity across subjects, suggesting that this approach identifies homologous neurobiological circuits across individuals. Some DMN subnetworks matched known features of brain organization corresponding with cognitive functions. Other subnetworks represented separate streams by which DMN couples with other canonical large-scale networks, including language and control networks. Together, this work provides a detailed organizational framework for studying the DMN in individual humans.

Individual-specific functional connectivity of the amygdala: A substrate for precision psychiatry.

The amygdala is central to the pathophysiology of many psychiatric illnesses. An imprecise understanding of how the amygdala fits into the larger network organization of the human brain, however, limits our ability to create models of dysfunction in individual patients to guide personalized treatment. Therefore, we investigated the position of the amygdala and its functional subdivisions within the network organization of the brain in 10 highly sampled individuals (5 h of fMRI data per person). We characterized three functional subdivisions within the amygdala of each individual. We discovered that one subdivision is preferentially correlated with the default mode network; a second is preferentially correlated with the dorsal attention and fronto-parietal networks; and third subdivision does not have any networks to which it is preferentially correlated relative to the other two subdivisions. All three subdivisions are positively correlated with ventral attention and somatomotor networks and negatively correlated with salience and cingulo-opercular networks. These observations were replicated in an independent group dataset of 120 individuals. We also found substantial across-subject variation in the distribution and magnitude of amygdala functional connectivity with the cerebral cortex that related to individual differences in the stereotactic locations both of amygdala subdivisions and of cortical functional brain networks. Finally, using lag analyses, we found consistent temporal ordering of fMRI signals in the cortex relative to amygdala subdivisions. Altogether, this work provides a detailed framework of amygdala-cortical interactions that can be used as a foundation for models relating aberrations in amygdala connectivity to psychiatric symptoms in individual patients.

Altered white matter microstructural organization in posttraumatic stress disorder across 3047 adults: results from the PGC-ENIGMA PTSD consortium.

A growing number of studies have examined alterations in white matter organization in people with posttraumatic stress disorder (PTSD) using diffusion MRI (dMRI), but the results have been mixed which may be partially due to relatively small sample sizes among studies. Altered structural connectivity may be both a neurobiological vulnerability for, and a result of, PTSD. In an effort to find reliable effects, we present a multi-cohort analysis of dMRI metrics across 3047 individuals from 28 cohorts currently participating in the PGC-ENIGMA PTSD working group (a joint partnership between the Psychiatric Genomics Consortium and the Enhancing NeuroImaging Genetics through Meta-Analysis consortium). Comparing regional white matter metrics across the full brain in 1426 individuals with PTSD and 1621 controls (2174 males/873 females) between ages 18-83, 92% of whom were trauma-exposed, we report associations between PTSD and disrupted white matter organization measured by lower fractional anisotropy (FA) in the tapetum region of the corpus callosum (Cohen's d = -0.11, p = 0.0055). The tapetum connects the left and right hippocampus, for which structure and function have been consistently implicated in PTSD. Results were consistent even after accounting for the effects of multiple potentially confounding variables: childhood trauma exposure, comorbid depression, history of traumatic brain injury, current alcohol abuse or dependence, and current use of psychotropic medications. Our results show that PTSD may be associated with alterations in the broader hippocampal network.

Trait-like variants in human functional brain networks.

Resting-state functional magnetic resonance imaging (fMRI) has provided converging descriptions of group-level functional brain organization. Recent work has revealed that functional networks identified in individuals contain local features that differ from the group-level description. We define these features as network variants. Building on these studies, we ask whether distributions of network variants reflect stable, trait-like differences in brain organization. Across several datasets of highly-sampled individuals we show that 1) variants are highly stable within individuals, 2) variants are found in characteristic locations and associate with characteristic functional networks across large groups, 3) task-evoked signals in variants demonstrate a link to functional variation, and 4) individuals cluster into subgroups on the basis of variant characteristics that are related to differences in behavior. These results suggest that distributions of network variants may reflect stable, trait-like, functionally relevant individual differences in functional brain organization.

Cortisol as a Biomarker of Alcohol Use in Combat Veterans: A Literature Review and Framework for Future Research.

Objective: Alcohol use and alcohol use disorders (AUDs) are an increasing concern among veterans, particularly those from recent conflicts in Iraq and Afghanistan. The study of biomarkers in alcohol use and AUD has moved to enhancing the understanding of the development and maintenance of AUDs, as well as investigating its association with clinical severity and potential predictors of treatment response. Cortisol, a glucocorticoid known as a stress hormone, has been linked with both stress and trauma, as well as increased alcohol suppression effects. Method/Results: The present review summarizes existing literature and presents suggestions for future research to evaluate whether cortisol may be a possible biomarker of alcohol use disorder risk in combat veterans. Specifically, aspects of combat deployments and high levels of PTSD, coupled with the stress of reintegration may dysregulate cortisol and increase risk to AUD. There may also be bidirectional impacts, such that alcohol is used as a coping mechanism and can dysregulate hypothalamic pituitary adrenal (HPA) axis functioning and cortisol. Conclusions: In the context of this framework, cortisol may serve as a biomarker for the development of AUD, as well as a biomarker of risk or relapse. This review ends with both theoretical and clinical implications, as well as directions for future research.

MRI-based measures of intracortical myelin are sensitive to a history of TBI and are associated with functional connectivity.

Traumatic brain injuries (TBIs) induce persistent behavioral and cognitive deficits via diffuse axonal injury. Axonal injuries are often examined in vivo using diffusion MRI, which identifies damaged and demyelinated regions in deep white matter. However, TBI patients can exhibit impairment in the absence of diffusion-measured abnormalities, suggesting that axonal injury and demyelination may occur outside the deep white matter. Importantly, myelinated axons are also present within the cortex. Cortical myelination cannot be measured using diffusion imaging, but can be mapped in-vivo using the T1-w/T2-w ratio method. Here, we conducted the first work examining effects of TBI on intracortical myelin in living humans by applying myelin mapping to 46 US Military Veterans with a history of TBI. We observed that myelin maps could be created in TBI patients that matched known distributions of cortical myelin. After controlling for age and presence of blast injury, the number of lifetime TBIs was associated with reductions in the T1-w/T2-w ratio across the cortex, most significantly in a highly-myelinated lateral occipital region corresponding with the human MT+ complex. Further, the T1-w/T2-w ratio in this MT+ region predicted resting-state functional connectivity of that region. By contrast, a history of blast TBI did not affect the T1-w/T2-w ratio in either a diffuse or focal pattern. These findings suggest that intracortical myelin, as measured using the T1-w/T2-w ratio, may be a TBI biomarker that is anatomically complementary to diffusion MRI. Thus, myelin mapping could potentially be combined with diffusion imaging to improve MRI-based diagnostic tools for TBI.

High-fidelity mapping of repetition-related changes in the parietal memory network.

fMRI studies of human memory have identified a "parietal memory network" (PMN) that displays distinct responses to novel and familiar stimuli, typically deactivating during initial encoding but robustly activating during retrieval. The small size of PMN regions, combined with their proximity to the neighboring default mode network, makes a targeted assessment of their responses in highly sampled subjects important for understanding information processing within the network. Here, we describe an experiment in which participants made semantic decisions about repeatedly-presented stimuli, assessing PMN BOLD responses as items transitioned from experimentally novel to repeated. Data are from the highly-sampled subjects in the Midnight Scan Club dataset, enabling a characterization of BOLD responses at both the group and single-subject level. Across all analyses, PMN regions deactivated in response to novel stimuli and displayed changes in BOLD activity across presentations, but did not significantly activate to repeated items. Results support only a portion of initially hypothesized effects, in particular suggesting that novelty-related deactivations may be less susceptible to attentional/task manipulations than are repetition-related activations within the network. This in turn suggests that novelty and familiarity may be processed as separable entities within the PMN.

BOLD Activity During Correct-Answer Feedback in Cued Recall Predicts Subsequent Retrieval Performance: An fMRI Investigation Using a Partial Trial Design.

Receiving correct answer feedback following a retrieval attempt has proven to be a highly effective means of learning new information, yet the mechanisms behind its efficacy remain poorly understood. Here, fMRI was used to examine how BOLD activity measured during a period of feedback could predict subsequent memory (SM) performance on a final test. Twenty-five human subjects studied pairs of associated words, and were then asked to covertly recall target words in response to provided cues. Correct answer feedback was provided immediately after covert retrieval attempts. A partial trial design enabled separate modeling of activity related to retrieval and to feedback processing. During initial study, typical SM effects were observed across the whole brain. During feedback following a failed recall attempt, activity in only a subset of these regions predicted final test performance. These regions fell within the default mode network (DMN) and demonstrated negative SM effects, such that greater deactivation was associated with successful recall. No "task-positive" regions demonstrated SM effects in this contrast. The obtained results are consistent with a growing literature that associates DMN deactivation with successful learning in multiple task contexts, likely reflecting differences in the allocation of attentional resources during encoding.

Are There Multiple Kinds of Episodic Memory? An fMRI Investigation Comparing Autobiographical and Recognition Memory Tasks.

What brain regions underlie retrieval from episodic memory? The bulk of research addressing this question with fMRI has relied upon recognition memory for materials encoded within the laboratory. Another, less dominant tradition has used autobiographical methods, whereby people recall events from their lifetime, often after being cued with words or pictures. The current study addresses how the neural substrates of successful memory retrieval differed as a function of the targeted memory when the experimental parameters were held constant in the two conditions (except for instructions). Human participants studied a set of scenes and then took two types of memory test while undergoing fMRI scanning. In one condition (the picture memory test), participants reported for each scene (32 studied, 64 nonstudied) whether it was recollected from the prior study episode. In a second condition (the life memory test), participants reported for each scene (32 studied, 64 nonstudied) whether it reminded them of a specific event from their preexperimental lifetime. An examination of successful retrieval (yes responses) for recently studied scenes for the two test types revealed pronounced differences; that is, autobiographical retrieval instantiated with the life memory test preferentially activated the default mode network, whereas hits in the picture memory test preferentially engaged the parietal memory network as well as portions of the frontoparietal control network. When experimental cueing parameters are held constant, the neural underpinnings of successful memory retrieval differ when remembering life events and recently learned events.SIGNIFICANCE STATEMENT Episodic memory is often discussed as a solitary construct. However, experimental traditions examining episodic memory use very different approaches, and these are rarely compared to one another. When the neural correlates associated with each approach have been directly contrasted, results have varied considerably and at times contradicted each other. The present experiment was designed to match the two primary approaches to studying episodic memory in an unparalleled manner. Results suggest a clear separation of systems supporting memory as it is typically tested in the laboratory and memory as assessed under autobiographical retrieval conditions. These data provide neurobiological evidence that episodic memory is not a single construct, challenging the degree to which different experimental traditions are studying the same construct.

Learning Efficiency: Identifying Individual Differences in Learning Rate and Retention in Healthy Adults.

People differ in how quickly they learn information and how long they remember it, yet individual differences in learning abilities within healthy adults have been relatively neglected. In two studies, we examined the relation between learning rate and subsequent retention using a new foreign-language paired-associates task (the learning-efficiency task), which was designed to eliminate ceiling effects that often accompany standardized tests of learning and memory in healthy adults. A key finding was that quicker learners were also more durable learners (i.e., exhibited better retention across a delay), despite studying the material for less time. Additionally, measures of learning and memory from this task were reliable in Study 1 ( N = 281) across 30 hr and Study 2 ( N = 92; follow-up n = 46) across 3 years. We conclude that people vary in how efficiently they learn, and we describe a reliable and valid method for assessing learning efficiency within healthy adults.

Dorsal Anterior Cingulate, Medial Superior Frontal Cortex, and Anterior Insula Show Performance Reporting-Related Late Task Control Signals.

The cingulo-opercular network (including the dorsal anterior cingulate and bilateral anterior insula) shows 3 distinct task-control signals across a wide variety of tasks, including trial-related signals that appear to come online at or near the end of the trial. Previous work suggests that there are separable responses in this network for errors and ambiguity, implicating multiple types of processing units within these regions. Using a unique paradigm, we directly show that these separable responses withhold activity to the end of the trial, in the service of reporting performance back into the task set. Participants performed a slow reveal task where images were presented behind a black mask which was gradually degraded, and they pressed a button when they could recognize the object that was being revealed. A behavioral pilot was used to identify ambiguous stimuli. We found interactive effects of accuracy and ambiguity, which suggests that these regions are computing and utilizing information, at one time, about both types of performance indices. Importantly, we showed a relationship between cingulo-opercular activity and behavioral performance, suggesting a role for these regions in performance reporting, per se. We discuss these results in the context of task control.

On the Stability of BOLD fMRI Correlations.

Measurement of correlations between brain regions (functional connectivity) using blood oxygen level dependent (BOLD) fMRI has proven to be a powerful tool for studying the functional organization of the brain. Recently, dynamic functional connectivity has emerged as a major topic in the resting-state BOLD fMRI literature. Here, using simulations and multiple sets of empirical observations, we confirm that imposed task states can alter the correlation structure of BOLD activity. However, we find that observations of "dynamic" BOLD correlations during the resting state are largely explained by sampling variability. Beyond sampling variability, the largest part of observed "dynamics" during rest is attributable to head motion. An additional component of dynamic variability during rest is attributable to fluctuating sleep state. Thus, aside from the preceding explanatory factors, a single correlation structure-as opposed to a sequence of distinct correlation structures-may adequately describe the resting state as measured by BOLD fMRI. These results suggest that resting-state BOLD correlations do not primarily reflect moment-to-moment changes in cognitive content. Rather, resting-state BOLD correlations may predominantly reflect processes concerned with the maintenance of the long-term stability of the brain's functional organization.

Individual-specific features of brain systems identified with resting state functional correlations.

Recent work has made important advances in describing the large-scale systems-level organization of human cortex by analyzing functional magnetic resonance imaging (fMRI) data averaged across groups of subjects. However, new findings have emerged suggesting that individuals' cortical systems are topologically complex, containing small but reliable features that cannot be observed in group-averaged datasets, due in part to variability in the position of such features along the cortical sheet. This previous work has reported only specific examples of these individual-specific system features; to date, such features have not been comprehensively described. Here we used fMRI to identify cortical system features in individual subjects within three large cross-subject datasets and one highly sampled within-subject dataset. We observed system features that have not been previously characterized, but 1) were reliably detected across many scanning sessions within a single individual, and 2) could be matched across many individuals. In total, we identified forty-three system features that did not match group-average systems, but that replicated across three independent datasets. We described the size and spatial distribution of each non-group feature. We further observed that some individuals were missing specific system features, suggesting individual differences in the system membership of cortical regions. Finally, we found that individual-specific system features could be used to increase subject-to-subject similarity. Together, this work identifies individual-specific features of human brain systems, thus providing a catalog of previously unobserved brain system features and laying the foundation for detailed examinations of brain connectivity in individuals.

The Contextual Association Network Activates More for Remembered than for Imagined Events.

The human capacities to remember events from the past and imagine events in the future rely on highly overlapping neural substrates. Neuroimaging studies have revealed brain regions that are more active for imagined events than remembered events, but the reverse pattern has not been shown consistently. Given that remembered events tend to be associated with more contextual information ( Johnson et al. 1988), one might expect a set of regions to demonstrate greater activity for remembered events. Specifically, regions sensitive to the strength of contextual associations might be hypothesized to show greater activity for remembered events. The present experiment tests this hypothesis. fMRI was used to identify brain regions within the contextual association network ( Bar and Aminoff 2003); regions within this network were then examined to see whether they showed differential activity during remembering and imagining. Bilateral regions within the parahippocampal cortex and retrosplenial complex responded more strongly to remembered past events, supporting work that suggests these events have more contextual information associated with them. Follow-up voxel-wise analysis demonstrated the specificity of these results, as did re-analysis of previous experimental datasets. These results suggest that a key differentiating feature of remembering and imagining is the strength of contextual associations.

Default Mode Network Activity Predicts Early Memory Decline in Healthy Young Adults Aged 18-31.

Functional magnetic resonance imaging (fMRI) research conducted in healthy young adults is typically done with the assumption that this sample is largely homogeneous. However, studies from cognitive psychology suggest that long-term memory and attentional control begin to diminish in the third decade of life. Here, 100 participants between the ages of 18 and 31 learned Lithuanian translations of English words in an individual differences study using fMRI. Long-term memory ability was operationalized for each participant by deriving a memory score from 3 convergent measures. Age of participant predicted memory score in this cohort. In addition, degree of deactivation during initial encoding in a set of regions occurring largely in the default mode network (DMN) predicted both age and memory score. The current study demonstrates that early memory decline may partially be accounted for by failure to modulate activity in the DMN.

Spatial and temporal characteristics of error-related activity in the human brain.

A number of studies have focused on the role of specific brain regions, such as the dorsal anterior cingulate cortex during trials on which participants make errors, whereas others have implicated a host of more widely distributed regions in the human brain. Previous work has proposed that there are multiple cognitive control networks, raising the question of whether error-related activity can be found in each of these networks. Thus, to examine error-related activity broadly, we conducted a meta-analysis consisting of 12 tasks that included both error and correct trials. These tasks varied by stimulus input (visual, auditory), response output (button press, speech), stimulus category (words, pictures), and task type (e.g., recognition memory, mental rotation). We identified 41 brain regions that showed a differential fMRI BOLD response to error and correct trials across a majority of tasks. These regions displayed three unique response profiles: (1) fast, (2) prolonged, and (3) a delayed response to errors, as well as a more canonical response to correct trials. These regions were found mostly in several control networks, each network predominantly displaying one response profile. The one exception to this "one network, one response profile" observation is the frontoparietal network, which showed prolonged response profiles (all in the right hemisphere), and fast profiles (all but one in the left hemisphere). We suggest that, in the place of a single localized error mechanism, these findings point to a large-scale set of error-related regions across multiple systems that likely subserve different functions.

Parcellating an individual subject's cortical and subcortical brain structures using snowball sampling of resting-state correlations.

We describe methods for parcellating an individual subject's cortical and subcortical brain structures using resting-state functional correlations (RSFCs). Inspired by approaches from social network analysis, we first describe the application of snowball sampling on RSFC data (RSFC-Snowballing) to identify the centers of cortical areas, subdivisions of subcortical nuclei, and the cerebellum. RSFC-Snowballing parcellation is then compared with parcellation derived from identifying locations where RSFC maps exhibit abrupt transitions (RSFC-Boundary Mapping). RSFC-Snowballing and RSFC-Boundary Mapping largely complement one another, but also provide unique parcellation information; together, the methods identify independent entities with distinct functional correlations across many cortical and subcortical locations in the brain. RSFC parcellation is relatively reliable within a subject scanned across multiple days, and while the locations of many area centers and boundaries appear to exhibit considerable overlap across subjects, there is also cross-subject variability-reinforcing the motivation to parcellate brains at the level of individuals. Finally, examination of a large meta-analysis of task-evoked functional magnetic resonance imaging data reveals that area centers defined by task-evoked activity exhibit correspondence with area centers defined by RSFC-Snowballing. This observation provides important evidence for the ability of RSFC to parcellate broad expanses of an individual's brain into functionally meaningful units.

Neural signatures of test-potentiated learning in parietal cortex.

Testing, or retrieval practice, is beneficial for long-term memory both directly, by enhancing performance on tested information, and indirectly, by facilitating learning from subsequent encounters with the information. Although a wealth of behavioral research has examined the "testing effect," neuroimaging has provided little insight regarding the potential mechanisms that underlie the benefits of retrieval practice. Here, fMRI was used to examine the effects of retrieval practice on later study trials. Human subjects studied pairs of associated words, which were then tested, restudied, or neither tested nor restudied. All pairs were then studied once more in expectation of a final test. We asked how this Final Study episode was affected by prior history (whether the pair had been previously tested, restudied, or neither). The data revealed striking similarities between responses in lateral parietal cortex in the present study and those in a host of studies explicitly tapping recognition memory processes. Moreover, activity in lateral parietal cortex during Final Study was correlated with a behavioral index of test-potentiated learning. We conclude that retrieval practice may enhance learning by promoting the recruitment of retrieval mechanisms during subsequent study opportunities.