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During the 1980s and 1990s, much memory research focused on the differential role of the hippocampus in various forms of memory. My work on the distinction between explicit and implicit memory led me to become involved in several early neuroimaging studies that made use of cognitive paradigms to investigate the conditions in which hippocampal activity does and does not occur, and to address the theoretical implications of these findings. Here, I summarize two such projects and some of the personal backstory associated with them., (© 2024 Wiley Periodicals LLC.)

Flexible retrieval mechanisms that allow us to infer relationships across events may also lead to memory errors or distortion when details of one event are misattributed to the related event. Here, we tested how making successful inferences alters representation of overlapping events, leading to false memories. Participants encoded overlapping associations ('AB' and 'BC'), each of which was superimposed on different indoor and outdoor scenes that were pre-exposed prior to associative learning. Participants were subsequently tested on both the directly learned pairs ('AB' and 'BC') and inferred relationships across pairs ('AC'). We predicted that when people make a correct inference, features associated with overlapping events may become integrated in memory. To test this hypothesis, participants completed a final detailed retrieval test, in which they had to recall the scene associated with initially learned 'AB' pairs (or 'BC' pairs). We found that the outcome of inference decisions impacted the degree to which neural patterns elicited during detailed 'AB' retrieval reflected reinstatement of the scene associated with the overlapping 'BC' event. After successful inference, neural patterns in the anterior hippocampus, posterior medial prefrontal cortex, and our content-reinstatement region (left inferior temporal gyrus) were more similar to the overlapping, yet incorrect 'BC' context relative to after unsuccessful inference. Further, greater hippocampal activity during inference was associated with greater reinstatement of the incorrect, overlapping context in our content-reinstatement region, which in turn tracked contextual misattributions during detailed retrieval. These results suggest recombining memories during successful inference can lead to misattribution of contextual details across related events, resulting in false memories., (Copyright © 2021. Published by Elsevier Inc.)

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., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Prior functional magnetic resonance imaging (fMRI) studies indicate that a core network of brain regions, including the hippocampus, is jointly recruited during episodic memory, episodic simulation, and divergent creative thinking. Because fMRI data are correlational, it is unknown whether activity increases in the hippocampus, and the core network more broadly, play a causal role in episodic simulation and divergent thinking. Here we employed fMRI-guided transcranial magnetic stimulation (TMS) to assess whether temporary disruption of hippocampal brain networks impairs both episodic simulation and divergent thinking. For each of two TMS sessions, continuous θ-burst stimulation (cTBS) was applied to either a control site (vertex) or to a left angular gyrus target region. The target region was identified on the basis of a participant-specific resting-state functional connectivity analysis with a hippocampal seed region previously associated with memory, simulation, and divergent thinking. Following cTBS, participants underwent fMRI and performed a simulation, divergent thinking, and nonepisodic control task. cTBS to the target region reduced the number of episodic details produced for the simulation task and reduced idea production on divergent thinking. Performance in the control task did not statistically differ as a function of cTBS site. fMRI analyses revealed a selective and simultaneous reduction in hippocampal activity during episodic simulation and divergent thinking following cTBS to the angular gyrus versus vertex but not during the nonepisodic control task. Our findings provide evidence that hippocampal-targeted TMS can specifically modulate episodic simulation and divergent thinking, and suggest that the hippocampus is critical for these cognitive functions., Competing Interests: The authors declare no competing interest.

According to the constructive episodic simulation hypothesis, episodic simulation (i.e., imagining specific novel future episodes) draws on some of the same neurocognitive processes that support episodic memory (i.e., recalling specific past episodes). Episodic retrieval supports the ability to simulate future experiences by providing access to episodic details (e.g., the people and locations that comprise memories) that can be recombined in new ways. In the current functional neuroimaging study, we test this hypothesis by examining whether the hippocampus, a region implicated in the reinstatement of episodic information during memory, supports reinstatement of episodic information during simulation. Employing a multivoxel pattern similarity analysis, we interrogated the similarity between hippocampal neural patterns during memory and simulation at the level of individual event details. Our findings indicate that the hippocampus supports the reinstatement of detail-specific information from episodic memory during simulation, with the level of reinstatement contributing to the subjective experience of simulated details., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Episodic simulation - the mental construction of a possible future event - has been consistently associated with enhanced activity in a set of neural regions referred to as the core network. In the current functional neuroimaging study, we assessed whether members of the core network are differentially associated with the subjective experience of future events (i.e., vividness) versus the objective content comprising those events (i.e., the amount of episodic details). During scanning, participants imagined future events in response to object cues. On each trial, participants rated the subjective vividness associated with each future event. Participants completed a post-scan interview where they viewed each object cue from the scanner and verbally reported whatever they had thought about. For imagined events, we quantified the number of episodic or internal details in accordance with the Autobiographical Interview (i.e., who, what, when, and where details of each central event). To test whether core network regions are differentially associated with subjective experience or objective episodic content, imagined future events were sorted as a function of their rated vividness or the amount of episodic detail. Univariate analyses revealed that some regions of the core network were uniquely sensitive to the vividness of imagined future events, including the hippocampus (i.e., high > low vividness), whereas other regions, such as the lateral parietal cortex, were sensitive to the amount of episodic detail in the event (i.e., high > low episodic details). The present results indicate that members of the core network support distinct episodic simulation-related processes., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Imagining hypothetical events often entails the construction of a detailed mental simulation. Despite recent advances, debate still surrounds the fundamental constructive process underpinning simulations supported by the hippocampus. Palombo et al. (2016) report findings that suggest that scene construction drives hippocampal engagement during imagination. However, they fail to consider the findings of a previous study using an extremely similar manipulation that generated similar hippocampal findings, but was interpreted in terms of event specificity and relational processing (Addis et al. 2011). While we applaud the general approach taken by Palombo et al. in attempting to distinguish components of mental simulation, a comparison of these 2 papers has brought into sharp relief how the lack of a common theoretical framework can result in significant interpretative ambiguities. In this commentary, we attempt to identify and clarify these as yet unresolved conceptual issues that will require empirical and theoretical attention in future research.

Both the hippocampus and ventromedial prefrontal cortex (vmPFC) appear to be critical for episodic future simulation. Damage to either structure affects one's ability to remember the past and imagine the future, and both structures are commonly activated as part of a wider core network during future simulation. However, the precise role played by each of these structures and, indeed, the direction of information flow between them during episodic simulation, is still not well understood. In this study, we scanned participants using functional magnetic resonance imaging while they imagined future events in response to object cues. We then used dynamic causal modeling to examine effective connectivity between the left anterior hippocampus and vmPFC during the initial mental construction of the events. Our results show that while there is strong bidirectional intrinsic connectivity between these regions (i.e., irrespective of task conditions), only the hippocampus to vmPFC connection increases during the construction of episodic future events, suggesting that the hippocampus initiates event simulation in response to retrieval cues, driving activation in the vmPFC where episodic details may be further integrated., (© 2017 Wiley Periodicals, Inc.)

The hippocampus has been consistently associated with episodic simulation (i.e., the mental construction of a possible future episode). In a recent study, we identified an anterior-posterior temporal dissociation within the hippocampus during simulation. Specifically, transient simulation-related activity occurred in relatively posterior portions of the hippocampus and sustained activity occurred in anterior portions. In line with previous theoretical proposals of hippocampal function during simulation, the posterior hippocampal activity was interpreted as reflecting a transient retrieval process for the episodic details necessary to construct an episode. In contrast, the sustained anterior hippocampal activity was interpreted as reflecting the continual recruitment of encoding and/or relational processing associated with a simulation. In the present study, we provide a direct test of these interpretations by conducting a subsequent memory analysis of our previously published data to assess whether successful encoding during episodic simulation is associated with the anterior hippocampus. Analyses revealed a subsequent memory effect (i.e., later remembered > later forgotten simulations) in the anterior hippocampus. The subsequent memory effect was transient and not sustained. Taken together, the current findings provide further support for a component process model of hippocampal function during simulation. That is, unique regions of the hippocampus support dissociable processes during simulation, which include the transient retrieval of episodic information, the sustained binding of such information into a coherent episode, and the transient encoding of that episode for later retrieval., (© 2017 Wiley Periodicals, Inc.)

Neuroimaging data indicate that episodic memory (i.e., remembering specific past experiences) and episodic simulation (i.e., imagining specific future experiences) are associated with enhanced activity in a common set of neural regions, often referred to as the core network. This network comprises the hippocampus, parahippocampal cortex, lateral and medial parietal cortex, lateral temporal cortex, and medial prefrontal cortex. Evidence for a core network has been taken as support for the idea that episodic memory and episodic simulation are supported by common processes. Much remains to be learned about how specific core network regions contribute to specific aspects of episodic simulation. Prior neuroimaging studies of episodic memory indicate that certain regions within the core network are differentially sensitive to the amount of information recollected (e.g., the left lateral parietal cortex). In addition, certain core network regions dissociate as a function of their timecourse of engagement during episodic memory (e.g., transient activity in the posterior hippocampus and sustained activity in the left lateral parietal cortex). In the current study, we assessed whether similar dissociations could be observed during episodic simulation. We found that the left lateral parietal cortex modulates as a function of the amount of simulated details. Of particular interest, while the hippocampus was insensitive to the amount of simulated details, we observed a temporal dissociation within the hippocampus: transient activity occurred in relatively posterior portions of the hippocampus and sustained activity occurred in anterior portions. Because the posterior hippocampal and lateral parietal findings parallel those observed during episodic memory, the present results add to the evidence that episodic memory and episodic simulation are supported by common processes. Critically, the present study also provides evidence that regions within the core network support dissociable processes., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Age-related increases in reliance on gist-based processes can cause increased false recognition. Understanding the neural basis for this increase helps to elucidate a mechanism underlying this vulnerability in memory. We assessed age differences in gist-based false memory by increasing image set size at encoding, thereby increasing the rate of false alarms. False alarms during a recognition test elicited increased hippocampal activity for older adults as compared to younger adults for the small set sizes, whereas the age groups had similar hippocampal activation for items associated with larger set sizes. Interestingly, younger adults had stronger connectivity between the hippocampus and posterior temporal regions relative to older adults during false alarms for items associated with large versus small set sizes. With increased gist, younger adults might rely more on additional processes (e.g., semantic associations) during recognition than older adults. Parametric modulation revealed that younger adults had increased anterior cingulate activity than older adults with decreasing set size, perhaps indicating difficulty in using monitoring processes in error-prone situations., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Age-related declines in relational encoding are well documented. It remains unclear, however, whether such declines reflect dysfunction of (1) ventrolateral prefrontal cortex (VLPFC) and deficient generation of associations; and/or (2) hippocampal dysfunction and impoverished binding of associations. In order to separate VLPFC and hippocampal contributions to relational encoding, we manipulated the generative demands of the encoding task by varying the number of semantic associations between the to-be-encoded information (three words). Thus, trials with fewer semantic associations (lower-association trials) require more generative processing during encoding, relative to trials in which more semantic associations are provided for binding (higher-association trials). Parametric modulation analyses on successfully encoded items revealed that, unlike younger adults, older adults did not show an up-regulation of VLPFC activity during lower-association trials. In contrast, hippocampal activity in both older and younger adults was greater in higher- relative to lower-association trials. Moreover, recognition accuracy improved significantly in both groups with the provision of more semantic associations, indicating that both younger and older adults benefitted from this form of encoding support. Our findings suggest that left VLPFC dysfunction may underlie relational encoding deficits in older adults, but that when provided with associations to bind, hippocampal activity in older adults is comparable to young, consistent with their increased recognition accuracy under conditions of encoding support., (© 2013.)

Imagining future events and remembering past events rely on a common core network, but several regions within this network--including the hippocampus--show increased activity for imagining future events compared to remembering past events. It remains unclear whether this hippocampal activity reflects processes related to the demands of constructing details retrieved across disparate episodic memories into coherent imaginary events, encoding these events into memory, novelty detection, or some combination of these processes. We manipulated the degree of constructive processing by comparing activity associated with the initial construction of an imagined scenario with the re-construction of an imagined scenario (imagine vs. re-imagine). After accounting for effects of novelty and subsequent memory, we found that a region in the hippocampus was preferentially activated for newly constructed imagined events compared with re-imagined events. Our results suggest that the hippocampus may support several distinct but related processes that are critical for imagining future events, and they also indicate that a particular region within posterior hippocampus may uniquely contribute to the construction of imagined future events., (Copyright © 2013 Wiley Periodicals, Inc.)

Imagining or simulating future events has been shown to activate the anterior right hippocampus (RHC) more than remembering past events does. One fundamental difference between simulation and memory is that imagining future scenarios requires a more extensive constructive process than remembering past experiences does. Indeed, studies in which this constructive element is reduced or eliminated by "pre-imagining" events in a prior session do not report differential RHC activity during simulation. In this fMRI study, we examined the effects of repeatedly simulating an event on neural activity. During scanning, participants imagined 60 future events; each event was simulated three times. Activation in the RHC showed a significant linear decrease across repetitions, as did other neural regions typically associated with simulation. Importantly, such decreases in activation could not be explained by non-specific linear time-dependent effects, with no reductions in activity evident for the control task across similar time intervals. Moreover, the anterior RHC exhibited significant functional connectivity with the whole-brain network during the first, but not second and third simulations of future events. There was also evidence of a linear increase in activity across repetitions in right ventral precuneus, right posterior cingulate and left anterior prefrontal cortex, which may reflect source recognition and retrieval of internally generated contextual details. Overall, our findings demonstrate that repeatedly imagining future events has a decremental effect on activation of the hippocampus and many other regions engaged by the initial construction of the simulation, possibly reflecting the decreasing novelty of simulations across repetitions, and therefore is an important consideration in the design of future studies examining simulation.

Neuroimaging studies of episodic memory in young adults demonstrate greater functional neural activity in ventrolateral pFC and hippocampus during retrieval of relational information as compared with item information. We tested the hypothesis that healthy older adults--individuals who exhibit behavioral declines in relational memory--would show reduced specificity of ventrolateral prefrontal and hippocampal regions during relational retrieval. At study, participants viewed two nouns and were instructed to covertly generate a sentence that related the words. At retrieval, fMRIs were acquired during item and relational memory tasks. In the relational task, participants indicated whether the two words were previously seen together. In the item task, participants indicated whether both items of a pair were previously seen. In young adults, left posterior ventrolateral pFC and bilateral hippocampal activity was modulated by the extent to which the retrieval task elicited relational processing. In older adults, activity in these regions was equivalent for item and relational memory conditions, suggesting a reduction in ventrolateral pFC and hippocampal specificity with normal aging.

Recent studies have demonstrated that remembering past experiences and imagining future scenarios recruits a core network including the hippocampus. Even so, constructing future events engages the hippocampus more than remembering past events. This fMRI study examined whether increased hippocampal activity for future events includes both specific and general events. Participants constructed specific and general past and future events during fMRI scanning. We replicated previous findings of increased activity in the right anterior hippocampus when constructing future relative to past events, and when constructing specific relative to general events. Importantly, both effects were driven by a significant interaction between temporal direction and specificity, with specific future events resulting in more activity than other conditions, including general future events. No regions exhibited greater activity during the construction of past relative to future events, or general relative to specific events. These results suggest that the process of constructing a detailed representation of a novel and specific future event differentially engages the right anterior hippocampus compared with other forms of event simulation and recall. Future work is needed to disambiguate the role of encoding, novelty and detail recombination in engaging the right anterior hippocampus during simulation., (Copyright © 2010 Wiley-Liss, Inc.)

The role of the hippocampus in imagining the future has been of considerable interest. Preferential right hippocampal engagement is observed for imagined future events relative to remembered past events, and patients with hippocampal damage are impaired when imagining detailed future events. However, some patients with hippocampal damage are not impaired at imagining, suggesting that there are conditions in which the hippocampus may not be necessary for episodic simulation. Given the known hippocampal role in memory encoding, the hippocampal activity associated with imagining may reflect the encoding of simulations rather than event construction per se. The present functional (f)MRI study investigated this possibility. Participants imagined future events in response to person, place, and object cues. A postscan cued-recall test probing memory for detail sets classified future events as either successfully encoded or not. A contrast of successfully versus unsuccessfully encoded events revealed anterior and posterior right hippocampal clusters. When imagined events were successfully encoded, both anterior and posterior hippocampus showed common functional connectivity to a network including parahippocampal gyrus, medial parietal and cingulate cortex, and medial prefrontal cortex. However, when encoding was unsuccessful, only the anterior hippocampus, and not the posterior, exhibited this pattern of connectivity. These findings demonstrate that right hippocampal activity observed during future simulation may reflect the encoding of the simulations into memory. This function is not essential for constructing coherent scenarios and may explain why some patients with hippocampal damage are still able to imagine the future.

Human behavioral studies demonstrate that healthy aging is often accompanied by increases in memory distortions or errors. Here we used event-related fMRI to examine the neural basis of age-related memory distortions. We used the memory conjunction error paradigm, a laboratory procedure known to elicit high levels of memory errors. For older adults, right parahippocampal gyrus showed significantly greater activity during false than during accurate retrieval. We observed no regions in which activity was greater during false than during accurate retrieval for young adults. Young adults, however, showed significantly greater activity than old adults during accurate retrieval in right hippocampus. By contrast, older adults demonstrated greater activity than young adults during accurate retrieval in right inferior and middle prefrontal cortex. These data are consistent with the notion that age-related memory conjunction errors arise from dysfunction of hippocampal system mechanisms, rather than impairments in frontally mediated monitoring processes.

A rapidly growing number of studies indicate that imagining or simulating possible future events depends on much of the same neural machinery as does remembering past events. One especially striking finding is that the medial temporal lobe (MTL), which has long been linked to memory function, appears to be similarly engaged during future event simulation. This paper focuses on the role of two MTL regions--the hippocampus and parahippocampal cortex--in thinking about the future and building mental simulations.

Behavioral, lesion and neuroimaging evidence show striking commonalities between remembering past events and imagining future events. In a recent event-related fMRI study, we instructed participants to construct a past or future event in response to a cue. Once an event was in mind, participants made a button press, then generated details (elaboration) and rated them. The elaboration of past and future events recruited a common neural network. However, regions within this network may respond differentially to event characteristics, such as the amount of detail generated and temporal distance, depending on whether the event is in the past or future. To investigate this further, we conducted parametric modulation analyses, with temporal distance and detail as covariates, and focused on the medial temporal lobes and frontopolar cortex. The analysis of detail (independent of temporal distance) showed that the left posterior hippocampus was responsive to the amount of detail comprising both past and future events. In contrast, the left anterior hippocampus responded differentially to the amount of detail comprising future events, possibly reflecting the recombination of details into a novel future event. The analysis of temporal distance revealed that the increasing recency of past events correlated with activity in the right parahippocampus gyrus (Brodmann area (BA) 35/36), while activity in the bilateral hippocampus was significantly correlated with the increasing remoteness of future events. We propose that the hippocampal response to the distance of future events reflects the increasing disparateness of details likely included in remote future events, and the intensive relational processing required for integrating such details into a coherent episodic simulation of the future. These findings provide further support for the constructive episodic simulation hypothesis (Schacter and Addis (2007) Philos Trans R Soc Lond B Biol Sci 362:773-786) and highlight the involvement of the hippocampus in relational processing during elaboration of future events., ((c) 2007 Wiley-Liss, Inc.)

It has been well established that the hippocampal formation plays a critical role in the formation of memories. However, functional specialization within the hippocampus remains controversial. Using functional magnetic resonance imaging (fMRI) during a face-name associative encoding task, followed by a postscan recognition test for face memory and face-name pair memory, we investigated the roles of anterior and posterior hippocampal regions in successful encoding of associations and items. Whole-brain and region of interest (ROI) analyses revealed that the anterior hippocampal formation showed increased activation for subsequently remembered face-name associations compared with pairs that were forgotten. In contrast, the posterior hippocampal formation showed activation above baseline during attempted encoding of face-name pairs, but no evidence of differential activation based on subsequent memory. Furthermore, exploratory whole-brain analyses revealed that a parahippocampal region, most likely corresponding to perirhinal cortex, showed subsequent memory effects for faces. These data provide evidence for functional specialization within the hippocampal formation based on the associative nature of the stimuli and subsequent memory.

Background: Patients with schizophrenia have difficulty using contextual information to recall the source of information. Given the importance of the hippocampus and prefrontal cortex (PFC) in this type of memory, we hypothesized that this cognitive deficit stemmed from aberrant fronto-hippocampal activation during memory retrieval., Methods: Patients with schizophrenia (n = 16) and age-matched comparison subjects (n = 16) underwent functional magnetic resonance imaging while performing a verbal memory task that requires intact use of temporal context. Blood oxygen-level dependent (BOLD) signal during correct memory decisions was compared between the two groups with statistical parametric mapping., Results: Contrary to our hypotheses, patients with schizophrenia demonstrated nearly identical memory performance to that of the comparison subjects. Despite this, there were significant between-group BOLD signal differences, including a pattern of task-dependent hypofrontality or hyperfrontality. In addition, whereas the highest-performing subset of the comparison group demonstrated robust modulation of hippocampal activity, this pattern was not seen in the highest-performing patients with schizophrenia., Conclusions: Despite memory performance similar to that of comparison subjects, patients with schizophrenia activated different neural pathways to achieve this success. This might reflect underlying neuropathology in fronto-hippocampal circuitry, the use of an alternate cognitive strategy to accomplish task performance, or both.

Episodic memory function is known to decline in the course of normal aging; however, compensatory techniques can improve performance significantly in older persons. We investigated the effects of the memory enhancing technique of repetition encoding on brain activation using event-related functional magnetic resonance imaging (fMRI). Twelve healthy older adults without cognitive impairment were studied with fMRI during repetitive encoding of face-name pairs. During the first encoding trials of face-name pairs that were subsequently remembered correctly, activation of the hippocampus and multiple neocortical regions, including prefrontal, parietal and fusiform cortices, was observed. The second and third encoding trials resulted in continued activation in neocortical regions, but no task-related response within the hippocampus. Functional imaging of successful memory processes thus permits us to detect regionally specific responses in the aging brain. Our findings suggest that hippocampal function is preserved in normal aging and that repetition-based memory enhancing techniques may engage primarily neocortical attentional networks.

K.C. has been investigated extensively over some 20 years since a motorcycle accident left him with widespread brain damage that includes large bilateral hippocampal lesions, which caused a remarkable case of memory impairment. On standard testing, K.C.'s anterograde amnesia is as severe as that of any other case reported in the literature, including H.M. However, his ability to make use of knowledge and experiences from the time before his accident shows a sharp dissociation between semantic and episodic memory. A good deal of his general knowledge of the world, including knowledge about himself, is preserved, but he is incapable of recollecting any personally experienced events. In displaying such "episodic amnesia," which encompasses an entire lifetime of personal experiences, K.C. differs from many other amnesic cases. Here, we document for the first time the full extent of K.C.'s brain damage using MRI-based quantitative measurements. We then review the many investigations with K.C. that have contributed to our understanding not only of episodic and semantic memory but also to the development of other aspects of memory theory. These include the distinction between implicit and explicit memory, the prospect of new learning in amnesia, and the fate of recent and remote memory for autobiographical and public events, people, and spatial locations.

Recent studies have reported memory deficits and reduced hippocampal volumes in posttraumatic stress disorder (PTSD). The goal of the current research was to use functional neuroimaging and a validated explicit memory paradigm to examine hippocampal function in PTSD. We used positron emission tomography (PET) and a word-stem completion task to study regional cerebral blood flow (rCBF) in the hippocampus in 16 firefighters: 8 with PTSD (PTSD group) and 8 without PTSD (Control group). During PET scanning, participants viewed three-letter word stems on a computer screen and completed each stem with a word they had previously encoded either deeply (High Recall condition) or shallowly (Low Recall condition). Relative to the Control group, the PTSD group exhibited significantly smaller rCBF increases in the left hippocampus in the High vs Low Recall comparison. However, this finding reflected relatively elevated rCBF in the Low Recall condition in the PTSD group. Collapsing across High and Low Recall conditions, (1) the PTSD group had higher rCBF in bilateral hippocampus and left amygdala than the Control group, and (2) within the PTSD group, symptom severity was positively associated with rCBF in hippocampus and parahippocampal gyrus. The groups did not significantly differ with regard to accuracy scores on the word-stem completion task. The PTSD group had significantly smaller right (and a trend for smaller left) hippocampal volumes than the Control group. The results suggest an abnormal rCBF response in the hippocampus during explicit recollection of nonemotional material in firefighters with PTSD, and that this abnormal response appears to be driven by relatively elevated hippocampal rCBF in the comparison condition.

The ability to form associations between previously unrelated items of information, such as names and faces, is an essential aspect of episodic memory function. The neural substrate that determines success vs. failure in learning these associations remains to be elucidated. Using event-related functional MRI during the encoding of novel face-name associations, we found that successfully remembered face-name pairs showed significantly greater activation in the anterior hippocampal formation bilaterally and left inferior prefrontal cortex, compared to pairs that were forgotten. Functional connectivity analyses revealed significant correlated activity between the right and left hippocampus and neocortical regions during successful, but not attempted, encoding. These findings suggest that anterior regions of the hippocampal formation, in particular, are crucial for successful associative encoding and that the degree of coordination between hippocampal and neocortical activity may predict the likelihood of subsequent memory.

Background: Patients with schizophrenia demonstrate poor verbal memory, ascribed to impaired prefrontal and hippocampal function. Healthy adults can increase recall accuracy following encoding interventions, such as item repetition and the formation of semantic associations. We examined the effects of these interventions on both memory performance and retrieval-related hippocampal activity in healthy adults and patients with schizophrenia., Methods: Twelve patients with schizophrenia and twelve healthy control subjects participated. During study, subjects counted either the number of meanings or T-junctions in words seen only once or repeated four times. At test, O15-positron emission tomography scans were acquired while subjects completed word-stems with previously studied items., Results: Control subjects recalled more words overall, but both groups demonstrated similar performance benefits following deeper encoding. Both item repetition and the use of a semantic encoding task were associated with memory retrieval-related hippocampal recruitment in control but not schizophrenic participants. Patients with schizophrenia demonstrated greater activation of prefrontal cortical areas during word retrieval., Conclusions: Despite a lack of hippocampal recruitment, patients with schizophrenia showed intact modulation of memory performance following both encoding interventions. Impaired hippocampal recruitment, in concert with greater prefrontal activation, may reflect a specific deficit in conscious recollection in schizophrenia.

Repeated word presentation during learning and the use of a semantic encoding task both increase the accuracy of subsequent word retrieval. Previous neuroimaging studies have shown that successful word retrieval depends on the recruitment of the hippocampus, whereas the effort of retrieval is linked to activation of prefrontal cortex modules. We studied the effects of repetition (4x versus 1x presentation) and encoding task (semantic versus perceptual) on hippocampal and prefrontal cortex activation during word-stem cued recall using positron emission tomography. Repeated and semantic encoding resulted in increased recall accuracy, with word repetition showing a greater effect when using a semantic encoding task. The more successful retrieval of words presented repeatedly compared with words presented once was associated with activation of the left anterior hippocampus. The more successful retrieval of words encoded using a semantic compared with a perceptual task was associated with activation of the right posterior and, less significantly, the left anterior hippocampus. The greater benefit of repeated learning when using the semantic task was linked to activation of the right brainstem, in the region of the ventral tegmentum. Our results suggest that word repetition and semantic encoding increase recall accuracy during subsequent word retrieval via distinct hippocampal mechanisms and that ventral tegmentum activation is relevant for word retrieval after semantic encoding. These findings confirm the importance of hippocampal recruitment during word retrieval and provide novel evidence for a role of brainstem neurons in word retrieval after semantic encoding.

This article considers two recent lines of research concerned with the construction of imagined or simulated events that can provide insight into the relationship between memory and decision making. One line of research concerns episodic future thinking , which involves simulating episodes that might occur in one’s personal future, and the other concerns episodic counterfactual thinking , which involves simulating episodes that could have happened in one’s personal past. We first review neuroimaging studies that have examined the neural underpinnings of episodic future thinking and episodic counterfactual thinking. We argue that these studies have revealed that the two forms of episodic simulation engage a common core network including medial parietal, prefrontal, and temporal regions that also supports episodic memory. We also note that neuroimaging studies have documented neural differences between episodic future thinking and episodic counterfactual thinking, including differences in hippocampal responses. We next consider behavioral studies that have delineated both similarities and differences between the two kinds of episodic simulation. The evidence indicates that episodic future and counterfactual thinking are characterized by similarly reduced levels of specific detail compared with episodic memory, but that the effects of repeatedly imagining a possible experience have sharply contrasting effects on the perceived plausibility of those events during episodic future thinking versus episodic counterfactual thinking. Finally, we conclude by discussing the functional consequences of future and counterfactual simulations for decisions. [ABSTRACT FROM AUTHOR]

Recent research has demonstrated commonalities between remembering past events and imagining future events. Behavioral studies have revealed that remembering the past and imagining the future depend on shared cognitive processes, whereas neuropsychological and neuroimaging studies have shown that many of the same brain regions are involved in both remembering the past and imagining the future. Here, we review recent cognitive and neuroimaging studies that examine remembering the past and imagining the future in elderly adults. These studies document significant changes in elderly adults' capacities to imagine future events that are correlated with their memory deficits; most strikingly, older adults tend to remember the past and imagine the future with less episodic detail than younger adults. These findings are in line with the constructive episodic simulation hypothesis [Schacter and Addis: Phil Trans R Soc B 2007;362:773-786], which holds that past and future events draw on similar information and rely on similar underlying processes, and that episodic memory supports the construction of future events by extracting and recombining stored information into a simulation of a novel event. At the same time, however, recent data indicate that non-episodic factors also contribute to age-related changes in remembering the past and imagining the future. We conclude by considering a number of questions and challenges concerning the interpretation of age-related changes in remembering and imagining, as well as functional implications of this research for everyday concerns of older adults. [ABSTRACT FROM AUTHOR]

Abstract: When information is thematically related to previously studied information, gist-based processes contribute to false recognition. Using functional MRI, we examined the neural correlates of gist-based recognition as a function of increasing numbers of studied exemplars. Sixteen participants incidentally encoded small, medium, and large sets of pictures, and we compared the neural response at recognition using parametric modulation analyses. For hits, regions in middle occipital, middle temporal, and posterior parietal cortex linearly modulated their activity according to the number of related encoded items. For false alarms, visual, parietal, and hippocampal regions were modulated as a function of the encoded set size. The present results are consistent with prior work in that the neural regions supporting veridical memory also contribute to false memory for related information. The results also reveal that these regions respond to the degree of relatedness among similar items, and implicate perceptual and constructive processes in gist-based false memory. [Copyright &y& Elsevier]

This article focuses on the neural and cognitive processes that support imagining or simulating future events, a topic that has recently emerged in the forefront of cognitive neuroscience. We begin by considering concepts of simulation from a number of areas of psychology and cognitive neuroscience in order to place our use of the term in a broader context. We then review neuroimaging, neuropsychological, and cognitive studies that have examined future-event simulation and its relation to episodic memory. This research supports the idea that simulating possible future events depends on much of the same neural machinery, referred to here as a core network, as does remembering past events. After discussing several theoretical accounts of the data, we consider applications of work on episodic simulation for research concerning clinical populations suffering from anxiety or depression. Finally, we consider other aspects of future-oriented thinking that we think are related to episodic simulation, including planning, prediction, and remembering intentions. These processes together comprise what we have termed “the prospective brain,” whose primary function is to use past experiences to anticipate future events. [ABSTRACT FROM AUTHOR]

Thirty years of brain imaging research has converged to define the brain's default network—a novel and only recently appreciated brain system that participates in internal modes of cognition. Here we synthesize past observations to provide strong evidence that the default network is a specific, anatomically defined brain system preferentially active when individuals are not focused on the external environment. Analysis of connectional anatomy in the monkey supports the presence of an interconnected brain system. Providing insight into function, the default network is active when individuals are engaged in internally focused tasks including autobiographical memory retrieval, envisioning the future, and conceiving the perspectives of others. Probing the functional anatomy of the network in detail reveals that it is best understood as multiple interacting subsystems. The medial temporal lobe subsystem provides information from prior experiences in the form of memories and associations that are the building blocks of mental simulation. The medial prefrontal subsystem facilitates the flexible use of this information during the construction of self-relevant mental simulations. These two subsystems converge on important nodes of integration including the posterior cingulate cortex. The implications of these functional and anatomical observations are discussed in relation to possible adaptive roles of the default network for using past experiences to plan for the future, navigate social interactions, and maximize the utility of moments when we are not otherwise engaged by the external world. We conclude by discussing the relevance of the default network for understanding mental disorders including autism, schizophrenia, and Alzheimer's disease. [ABSTRACT FROM AUTHOR]

It has been debated whether the link between amygdala activity and subsequent memory is equally strong for positive and negative information. Moreover, it has been unclear whether amygdala activity at encoding corresponds with enhanced memory for all contextual aspects of the presentation of an emotional item, or whether amygdala activity primarily enhances memory for the emotional item itself. In the present functional magnetic resonance imaging study, participants encoded positive and negative stimuli while performing one of two tasks (judgment of animacy or commonness). Amygdala activity at encoding was related to subsequent memory for the positive and negative items but not to subsequent memory for the task performed. Amygdala activity showed no relationship to subsequent-memory performance for the neutral items. Regardless of the emotional content of the items, activity in the entorhinal cortex corresponded with subsequent memory for the item but not with memory for the task performed, whereas hippocampal activity corresponded with subsequent memory for the task performed. These results are the first to demonstrate that the amygdala can be equally engaged during the successful encoding of positive and negative items but that its activity does not facilitate the encoding of all contextual elements present during an encoding episode. The results further suggest that dissociations within the medial temporal lobe sometimes noted for nonemotional information (i.e., activity in the hippocampus proper leading to later memory for context, and activity in the entorhinal cortex leading to later memory for an item but not its context) also hold for emotional information. [ABSTRACT FROM AUTHOR]

Abstract: An essential feature of human memory is the capacity to assess confidence in one''s own memory performance, but the neural mechanisms underlying the process of determining confidence in memory performance have not yet been isolated. Using functional magnetic resonance imaging, we examined both the process of confidence assessment and the subjective level of high or low confidence expressed during this process. The comparison of confidence assessment to recognition showed greater relative activation during confidence assessment in medial and lateral parietal regions, which typically deactivate during cognitive tasks, previously described as part of the “default network”. Furthermore, comparisons of high versus low confidence judgments revealed modulation of neural activity in the hippocampus, cingulate and other limbic regions, previously described as the Circuit of Papez. Our findings suggest that activity in two distinct networks of brain regions contribute to the subjective experience of “knowing you know” through memory monitoring processes and signaling subjective confidence level for recognition memory. [Copyright &y& Elsevier]

The ability to bind information together, such as linking a name with a face or a car with a parking space, is a vital process in human episodic memory. To identify the neural bases for this binding process, we measured brain activity during a verbal associative encoding task using event-related functional MRI (fMRI), followed by an associative recognition test for the studied word pairs. Analysis of the encoding data sorted by the associative recognition accuracy allowed us to isolate regions involved in successfully creating associations. We found that encoding activity in bilateral anterior medial temporal lobe (MTL) regions was greater for successfully bound pairs, that is, those later recognized as intact, than for all other pairs. These findings provide evidence that the anterior medial temporal lobes support the successful binding of information in memory. [Copyright &y& Elsevier]

Human memory is not a literal reproduction of the past, but instead relies on constructive processes that are sometimes prone to error and distortion. Understanding of constructive memory has accelerated during recent years as a result of research that has linked together its cognitive and neural bases. This article focuses on three aspects of constructive memory that have been the target of recent research: (i) the idea that certain kinds of memory distortions reflect the operation of adaptive cognitive processes that contribute to the efficient functioning of memory; (ii) the role of a constructive memory system in imagining or simulating possible future events; and (iii) differences between true and false memories that have been revealed by functional neuroimaging techniques. The article delineates the theoretical implications of relevant research, and also considers some clinical and applied implications., Psychology

Imagining future scenarios involves recombining different elements of past experiences into a coherent event, a process broadly supported by the brain's default network. Prior work suggests that distinct brain regions may contribute to the inclusion of different simulation features. Here we examine how activity in these brain regions relates to the vividness of future simulations. Thirty-four healthy young adults imagined future events with familiar people and locations in a two-part study involving a repetition suppression paradigm. First, participants imagined events while their eyes were tracked during a behavioral session. Immediately after, participants imagined events during MRI scanning. The events to be imagined were manipulated such that some were identical to those imagined in the behavioral session while others involved new locations, new people, or both. In this way, we could examine how self-report ratings and eye movements predict brain activity during simulation along with specific simulation features. Vividness ratings were negatively correlated with eye movements, in contrast to an often-observed positive relationship with past recollection. Moreover, fewer eye movements predicted greater involvement of the hippocampus during simulation, an effect specific to location features. Our findings suggest that eye movements may facilitate scene construction for future thinking, lending support to frameworks that spatial information forms the foundation of episodic simulation. • The interplay between fixations and vividness during episodic processes is unclear. • A repetition suppression study on simulation was conducted with eye-tracking. • Fewer fixations predicted more vivid simulations. • Fixations predicted neural suppression, an effect driven by location features. • Eye movements may set the scene to initiate simulation. [ABSTRACT FROM AUTHOR]