Evidence supporting a time-limited hippocampal role in retrieving autobiographical memories.

The necessity of the human hippocampus for remote autobiographical recall remains fiercely debated. The standard model of consolidation predicts a time-limited role for the hippocampus, but the competing multiple trace/trace transformation theories posit indefinite involvement. Lesion evidence remains inconclusive, and the inferences one can draw from functional MRI (fMRI) have been limited by reliance on covert (silent) recall, which obscures dynamic, moment-to-moment content of retrieved memories. Here, we capitalized on advances in fMRI denoising to employ overtly spoken recall. Forty participants retrieved recent and remote memories, describing each for approximately 2 min. Details associated with each memory were identified and modeled in the fMRI time-series data using a variant of the Autobiographical Interview procedure, and activity associated with the recall of recent and remote memories was then compared. Posterior hippocampal regions exhibited temporally graded activity patterns (recent events > remote events), as did several regions of frontal and parietal cortex. Consistent with predictions of the standard model, recall-related hippocampal activity differed from a non-autobiographical control task only for recent, and not remote, events. Task-based connectivity between posterior hippocampal regions and others associated with mental scene construction also exhibited a temporal gradient, with greater connectivity accompanying the recall of recent events. These findings support predictions of the standard model of consolidation and demonstrate the potential benefits of overt recall in neuroimaging experiments.

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.

A Role for the Anterior Hippocampus in Autobiographical Memory Construction Regardless of Temporal Distance.

Mounting evidence suggests distinct functional contributions of the anterior and posterior hippocampus to autobiographical memory retrieval, but how these subregions function under different retrieval demands as memories age is not yet understood. Specifically, autobiographical memory retrieval is not a homogeneous process; rather, it is thought to consist of the following multiple stages: an early stage of memory construction and a later stage of detailed elaboration, which may differently engage the hippocampus over time. In the present study, we analyzed data from 40 participants (23 female/17 male) who constructed and overtly elaborated on recent and remote memories in response to picture cues in the fMRI scanner. We previously reported a temporal gradient in the posterior hippocampus during the elaboration period of autobiographical retrieval, with posterior hippocampal activation observed for recent but not remote time points. Here, we consider the previously unanalyzed construction stage of retrieval, where participants searched for and selected a memory. We found no evidence of a temporal gradient during memory construction, instead observing strong anterior hippocampus activity regardless of memory remoteness. Our findings suggest a unique contribution of the anterior hippocampus to the construction process of autobiographical retrieval over time. These findings highlight that retrieval processes, which have yet to be integrated with current models of systems consolidation, offer novel insights into hippocampal subregion function over time.SIGNIFICANCE STATEMENTHippocampal contributions to autobiographical memory retrieval may depend on several distinct factors including memory age and the retrieval process engaged. We previously found that the contribution of the posterior hippocampus to detailed elaborative retrieval diminishes as memories age, with no reliable activation of the anterior hippocampus over time. Here, we report that consideration of the earlier "construction" period of retrieval, where participants search for and retrieve general aspects of the memory, yielded significant anterior hippocampus activation regardless of memory age. These results provide evidence for a unique contribution of the anterior hippocampus to the constructive process of autobiographical retrieval over time and suggest that component processes of retrieval should be integrated into models of systems consolidation.

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.

Dynamic Content Reactivation Supports Naturalistic Autobiographical Recall in Humans.

Humans can vividly recall and re-experience events from their past, and these are commonly referred to as episodic or autobiographical memories. fMRI experiments reliably associate autobiographical event recall with activity in a network of "default" or "core" brain regions. However, as prior studies have relied on covert (silent) recall procedures, current understanding may be hampered by methodological limitations that obscure dynamic effects supporting moment-to-moment content retrieval. Here, fMRI participants (N = 40) overtly (verbally) recalled memories for ∼2 min periods. The content of spoken descriptions was categorized using a variant of the Autobiographical Interview (AI) procedure (Levine et al., 2002) and temporally re-aligned with BOLD data so activity accompanying the recall of different details could be measured. Replicating prior work, sustained effects associated with autobiographical recall periods (which are insensitive to the moment-to-moment content of retrieval) fell primarily within canonical default network regions. Spoken descriptions were rich in episodic details, frequently focusing on physical entities, their ongoing activities, and their appearances. Critically, neural activity associated with recalling specific details (e.g., those related to people or places) was transient, broadly distributed, and grounded in category-selective cortex (e.g., regions related to social cognition or scene processing). Thus, although a single network may generally support the process of vivid event reconstruction, the structures required to provide detail-related information shift in a predictable manner that respects domain-level representations across the cortex.SIGNIFICANCE STATEMENT Humans can vividly recall memories of autobiographical episodes, a process thought to involve the reconstruction of numerous distinct event details. Yet how the brain represents a complex episode as it unfolds over time remains unclear and appears inconsistent across experimental traditions. One hurdle is the use of covert (silent) in-scanner recall to study autobiographical memory, which prevents experimenter knowledge of what information is being retrieved, and when, throughout the remembering process. In this experiment, participants overtly described autobiographical memories while undergoing fMRI. Activity associated with the recall and description of specific details was transient, broadly distributed, and grounded in category-selective cortex. Thus, it appears that as events unfold mentally, structures are dynamically reactivated to support vivid recollection.

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.

The stability of visual perspective and vividness during mental time travel.

When remembering or imagining, people can experience an event from their own eyes, or as an outside observer, with differing levels of vividness. The perspective from, and vividness with, which a person remembers or imagines has been related to numerous individual difference characteristics. These findings require that phenomenology during mental time travel be trait-like-that people consistently experience similar perspectives and levels of vividness. This assumption remains untested. Across two studies (combined N = 295), we examined the stability of visual perspective and vividness across multiple trials and timepoints. Perspective and vividness showed weak within-session stability when reported across just a few trials but showed strong within-session stability when sufficient trials were collected. Importantly, both visual perspective and vividness demonstrated good-to-excellent across-session stability across different delay intervals (two days to six weeks). Overall, our results suggest that people dependably experience similar visual phenomenology across occurrences of mental time travel.

A Posterior-Anterior Distinction between Scene Perception and Scene Construction in Human Medial Parietal Cortex.

Human retrosplenial complex (RSC), located in medial parietal cortex, has been implicated in numerous cognitive functions, including scene perception, spatial navigation, and autobiographical memory retrieval. Recently, a posterior-anterior distinction within RSC was proposed, such that posterior aspects process scene-related visual information (constituting a medial place area [MPA]), whereas anterior aspects process information that is vividly retrieved from memory, thereby supporting remembering and potentially navigation. Here, we tested this proposed distinction in a single group of participants (both male and female) using fMRI with both perceptual and mnemonic tasks. After completing a resting-state scan, participants performed a task that required constructing scenes from memory and completed a scene selectivity localizer task. We tested directly perceptual and mnemonic responses in MPA and an anterior, connectivity-defined region (CON), which showed strong functional connectivity with anterior parahippocampal place area. A double dissociation was observed, such that CON was more strongly activated during scene construction than was MPA, whereas MPA was more perceptually responsive than CON. Further, peak responses from the scene construction task were anterior to perceptual peaks in all but 1 participant and hemisphere. Finally, through analyses of the posterior-anterior response profiles, we identify the fundus of the parieto-occipital sulcus as a potential location for the crossover from perceptual to mnemonic representations and highlight a potential left-hemisphere advantage for mnemonic representations. Collectively, our results support a distinction between posterior and anterior aspects of the RSC, suggesting that more specific functional-anatomic terms should be used in its place in future work.SIGNIFICANCE STATEMENT The retrosplenial complex (RSC) has been implicated in vision, spatial cognition, and memory. We previously speculated on a potential posterior-anterior distinction within RSC for scene perception and memory-based scene construction/navigation. Here, we tested this distinction through a combination of resting-state, perceptual, and mnemonic task data. Consistent with our predictions, we demonstrate that perceptual responses peak consistently posterior of those elicited by memory-based scene construction within the broader RSC. Further, we highlight (1) the fundus of the parieto-occipital sulcus as a landmark for the transition between these representations, (2) the anterior bank of parieto-occipital sulcus as the point of maximal separation between these representations, and (3) identify a potential hemispheric asymmetry in mnemonic representations. These data support functional dissociations within RSC.

Brain networks, dimensionality, and global signal averaging in resting-state fMRI: Hierarchical network structure results in low-dimensional spatiotemporal dynamics.

One of the most controversial practices in resting-state fMRI functional connectivity studies is whether or not to regress out the global average brain signal (GS) during artifact removal. Some groups have argued that it is absolutely essential to regress out the GS in order to fully remove head motion, respiration, and other global imaging artifacts. Others have argued that removing the GS distorts the resulting correlation matrices and inappropriately alters the results of group comparisons and relationships to behavior. At the core of this argument is the assessment of dimensionality in terms of the number of brain networks with uncorrelated time series. If the dimensionality is high, then the distortions due to GS removal could be effectively negligible. In the current paper, we examine the dimensionality of resting-state fMRI data using principal component analyses (PCA) and network clustering analyses. In two independent datasets (Set 1: N = 62, Set 2: N = 32), scree plots of the eigenvalues level off at or prior to 10 principal components, with prominent elbows at 3 and 7 components. While network clustering analyses have previously demonstrated that numerous networks can be distinguished with high thresholding of the voxel-wise correlation matrices, lower thresholding reveals a lower-dimensional hierarchical structure, with the first prominent branch at 2 networks (corresponding to the previously described "task-positive"/"task-negative" distinction) and further stable subdivisions at 4, 7 and 17. Since inter-correlated time series within these larger branches do not cancel to zero when averaged, the hierarchical nature of the correlation structure results in low effective dimensionality. Consistent with this, partial correlation analyses revealed that network-specific variance remains present in the GS at each level of the hierarchy, accounting for at least 14-18% of the overall GS variance in each dataset. These results demonstrate that GS regression is expected to remove substantial portions of network-specific brain signals along with artifacts, not simply whole-brain signals corresponding to arousal levels. We highlight alternative means of controlling for residual global artifacts when not removing the GS.

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.

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.

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.

Scene construction and autobiographical memory retrieval in autism spectrum disorder.

Individuals with autism spectrum disorder (ASD) frequently exhibit difficulties in retrieving autobiographical memories (AMs) of specific events from their life. Such memory deficits are frequently attributed to underlying disruptions in self-referential or social cognition processes. This makes intuitive sense as these are hallmarks of ASD. However, an emerging literature suggests that parallel deficits also exist in ASD individuals' ability to reconstruct the rich spatial contexts in which events occur. This is a capacity known as scene construction, and in typically developing individuals is considered a core process in retrieving AMs. In this review, we discuss evidence of difficulties with scene construction in ASD, drawing upon experiments that involve AM retrieval, other forms of mental time travel, and spatial navigation. We also highlight aspects of extant data that cannot be accounted for using purely social explanations of memory deficits in ASD. We conclude by identifying key questions raised by our framework and suggest how they might be addressed in future research.

Specifying 'where' and 'what' is critical for testing hippocampal contributions to memory retrieval.

Tallman and colleagues' review of consolidation studies found that the length of the delay between 'recent' and 'remote' events is an influential determinant of detecting temporally graded hippocampal activity. Here, we discuss two additional factors - separate analysis of distinct regions within the hippocampus and the use of overt recall methods - that should be considered when testing competing theories of hippocampal contributions to memory.