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Although the medial temporal lobe (MTL) is traditionally considered a region dedicated to long-term memory, recent neuroimaging and intracranial recording evidence suggests that the MTL also contributes to certain aspects of visual short-term memory (VSTM), such as the quality or precision of retained VSTM content. This study aims to further investigate the MTL's role in VSTM precision through the application of transcranial direct current stimulation (tDCS) and functional magnetic resonance imaging (fMRI). Participants underwent 1.5 mA offline tDCS over bilateral temporal lobes using left cathodal and right anodal electrodes, administered for either 20 min (active) or 0.5 min within a 20-min window (sham), in a counterbalanced design. As the electrical current passes through midbrain structures with this bilateral stimulation montage, prior behavioral and modeling evidence suggests that this tDCS protocol can modulate MTL functions. To confirm this and examine its impacts on VSTM, participants completed a VSTM color recall task immediately following tDCS, while undergoing a 20-min fMRI scan and a subsequent 7.5-min resting-state scan, during which they focused on a fixation cross. Behavioral results indicated that this tDCS protocol decreased VSTM precision without significantly affecting overall recall success. Furthermore, psychophysiological interaction analysis revealed that tDCS over the temporal lobe modulated hippocampal-occipital functional connectivity during the VSTM task, despite no main effect on fMRI BOLD activity. Notably, this modulation was also observed during resting-state fMRI 15-20 min post-tDCS, with the magnitude of the effect correlating with participants' behavioral changes in VSTM precision across active and control conditions. Combined, these findings suggest that tDCS over the temporal lobe can modulate the intrinsic functional connectivity between the MTL and visual sensory areas, thereby affecting VSTM precision., (© 2024 The Author(s). Hippocampus published by Wiley Periodicals LLC.)

The wide array of cognitive functions associated with the hippocampus is supported through interactions with the cerebral cortex. However, most of the direct cortical input to the hippocampus originates in the entorhinal cortex, forming the hippocampal-entorhinal system. In humans, the role of the entorhinal cortex in mediating hippocampal-cortical interactions remains unknown. In this study, we used precision neuroimaging to examine the distributed cortical anatomy associated with the human hippocampal-entorhinal system. Consistent with animal anatomy, our results associate different subregions of the entorhinal cortex with different parts of the hippocampus long axis. Furthermore, we find that the entorhinal cortex comprises three band-like zones that are associated with functionally distinct cortical networks. Importantly, the entorhinal cortex bands traverse the proposed human homologs of rodent lateral and medial entorhinal cortices. Finally, we show that the entorhinal cortex is a major convergence area of distributed cortical processing and that the topography of cortical networks associated with the anterior medial temporal lobe mirrors the macroscale structure of high-order cortical processing., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Despite the need for successful navigation, humans vary greatly in their ability to navigate, and these individual differences may relate to variation in brain structure. While prior research provides support for a correlation between hippocampal volume and navigation ability in both navigation experts and in older individuals, this relationship is under scrutiny for healthy, young adults. We assessed 99 healthy young adults' ability to navigate in a virtual, desktop maze and correlated their performance with total hippocampal gray matter volume. For a subset of these individuals, we further segmented the medial temporal lobe-including regions of the hippocampus-into anatomically-distinct subregions to uniquely examine the association between volumes of hippocampal subfields and navigation. Given the need to distinguish between similar-looking maze hallways and partially overlapping routes, young adults with stronger pattern separation ability may perform better in this task. Thus, we theorized that successful navigation would positively correlate with hippocampal CA3 and dentate gyrus (DG) subfield volumes due to these regions' role in pattern separation. CA1 and entorhinal cortex (ERC) are both associated with rodent spatial memory, too, suggesting a possible relationship between their volumes and navigation performance. Consistent with our hypotheses, we observed a positive relationship between volumes of hippocampal subfields and wayfinding accuracy, while ERC and parahippocampal cortex volumes correlated with navigation efficiency. However, when analyzing total hippocampal volume, a nuanced interpretation is warranted. We found evidence of Simpson's Paradox, where total hippocampal volume and navigation accuracy displayed no correlation in males, a negative correlation in females, yet a positive correlation when considering the full sample of males and females combined. Furthermore, no significant relationship was observed between total hippocampal volume and path efficiency. Given these findings, we urge caution in interpreting the results because these associations differ by analysis techniques (including voxel-based morphometry), after sex stratification, and with anterior and posterior hippocampal subdivisions. Overall, this study enhances our understanding of the relationship between brain volume and navigation ability for young adults but also emphasizes the need for methodological consistency across studies with respect to boundary definitions, neuroimaging techniques, statistical methods, and factors that give rise to individual differences., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

It has been hypothesized that differential processing occurs along the longitudinal (anterior-posterior) axis of the hippocampus. One hypothesis is that spatial memory (during both encoding and retrieval) is associated with the posterior hippocampus. An alternative hypothesis is that memory encoding (either spatial or nonspatial) is associated with the anterior hippocampus and memory retrieval is associated with the posterior hippocampus. Of importance, during spatial memory encoding, the spatial-posterior hypothesis predicts posterior hippocampal involvement, whereas the encoding-retrieval hypothesis predicts anterior hippocampal involvement. To distinguish between these hypotheses, we conducted a coordinate-based fMRI activation likelihood estimation (ALE) meta-analysis of 26 studies (with a total of 435 participants) that reported hippocampal activity during spatial memory encoding and/or spatial memory retrieval. Both spatial memory encoding and spatial memory retrieval produced extensive activity along the longitudinal axis of the hippocampus as well as the entorhinal cortex, the perirhinal cortex, and the parahippocampal cortex. Critically, the contrast of spatial memory encoding and spatial memory retrieval produced activations in both the anterior hippocampus and the posterior hippocampus. That spatial memory encoding produced activity in both the anterior and posterior hippocampus can be taken to reject strict forms of the spatial-posterior hypothesis, which stipulates that all forms of spatial memory produce activity in the posterior hippocampus, and the encoding-retrieval hypothesis, which stipulates that all forms of encoding versus retrieval produce activity in only the anterior hippocampus. Our results indicate that spatial memory encoding can involve the anterior hippocampus and the posterior hippocampus., (© 2024 Wiley Periodicals LLC.)

The traditional memory-systems view is that explicit (conscious) long-term memory is associated with the hippocampus and implicit (nonconscious) memory is associated with non-hippocampal brain regions. This special issue of Cognitive Neuroscience focuses on whether the hippocampus is associated with implicit memory. An empirical fMRI paper by Miller, Kennard, Gowland, Antoniades, and Rosenthal (this issue) evaluated recognition memory performance of autobiographical amnesia patients with bilateral damage to hippocampal sub-region CA3 and found they had greater than chance recognition memory performance for spatial sequence learning, spatial item learning-same location, and non-spatial item learning, but chance performance for non-spatial sequence learning and spatial item learning-different location. These results are at odds with the view that the hippocampus is generally involved in sequence learning and complex event recognition. A discussion paper by Steinkrauss and Slotnick (this issue) considered whether fMRI studies have provided evidence that the hippocampus is associated with implicit memory. It was argued that all previous studies have been confounded by explicit memory, attentional states, stimuli, or novelty. This discussion paper is followed by commentaries from Hannula (this issue), Henke and Ruch (this issue), Rosenthal (this issue), Spaak (this issue), Thakral et al. (this issue), and Züst (this issue). The articles in this special issue illustrate that the association between the hippocampus and implicit memory is under active investigation and debate. It is hoped that the evidence and discourse in this issue will provide directions for future research.

Prior univariate functional magnetic resonance imaging (fMRI) studies in humans suggest that the anteromedial subicular complex of the hippocampus is a hub for scene-based cognition. However, it is possible that univariate approaches were not sufficiently sensitive to detect scene-related activity in other subfields that have been implicated in spatial processing (e.g., CA1). Further, as connectivity-based functional gradients in the hippocampus do not respect classical subfield boundary definitions, category selectivity may be distributed across anatomical subfields. Region-of-interest approaches, therefore, may limit our ability to observe category selectivity across discrete subfield boundaries. To address these issues, we applied searchlight multivariate pattern analysis to 7T fMRI data of healthy adults who undertook a simultaneous visual odd-one-out discrimination task for scene and non-scene (including face) visual stimuli, hypothesising that scene classification would be possible in multiple hippocampal regions within, but not constrained to, anteromedial subicular complex and CA1. Indeed, we found that the scene-selective searchlight map overlapped not only with anteromedial subicular complex (distal subiculum, pre/para subiculum), but also inferior CA1, alongside posteromedial (including retrosplenial) and parahippocampal cortices. Probabilistic overlap maps revealed gradients of scene category selectivity, with the strongest overlap located in the medial hippocampus, converging with searchlight findings. This was contrasted with gradients of face category selectivity, which had stronger overlap in more lateral hippocampus, supporting ideas of parallel processing streams for these two categories. Our work helps to map the scene, in contrast to, face processing networks within, and connected to, the human hippocampus., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The hippocampus, critical for learning and memory, undergoes substantial changes early in life. Investigating the developmental trajectory of hippocampal structure and function requires an accurate method for segmenting this region from anatomical MRI scans. Although manual segmentation is regarded as the "gold standard" approach, it is laborious and subjective. This has fueled the pursuit of automated segmentation methods in adults. However, little is known about the reliability of these automated protocols in infants, particularly when anatomical scan quality is degraded by head motion or the use of shorter and quieter infant-friendly sequences. During a task-based fMRI protocol, we collected quiet T1-weighted anatomical scans from 42 sessions with awake infants aged 4-23 months. Two expert tracers first segmented the hippocampus in both hemispheres manually. The resulting inter-rater reliability (IRR) was only moderate, reflecting the difficulty of infant segmentation. We then used four protocols to predict these manual segmentations: average adult template, average infant template, FreeSurfer software, and Automated Segmentation of Hippocampal Subfields (ASHS) software. ASHS generated the most reliable hippocampal segmentations in infants, exceeding the manual IRR of experts. Automated methods thus provide robust hippocampal segmentations of noisy T1-weighted infant scans, opening new possibilities for interrogating early hippocampal development., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

As we learn, dynamic memory processes build structured knowledge across our experiences. Such knowledge enables the formation of internal models of the world that we use to plan, make decisions, and act. Recent theorizing posits that mnemonic mechanisms of differentiation and integration - which at one level may seem to be at odds - both contribute to the emergence of structured knowledge. We tested this possibility using fMRI as human participants learned to navigate within local and global virtual environments over the course of 3 days. Pattern similarity analyses on entorhinal cortical and hippocampal patterns revealed evidence that differentiation and integration work concurrently to build local and global environmental representations, and that variability in integration relates to differences in navigation efficiency. These results offer new insights into the neural machinery and the underlying mechanisms that translate experiences into structured knowledge that allows us to navigate to achieve goals., Competing Interests: CF, JJ, SW, HC, AW No competing interests declared, (© 2023, Fernandez et al.)

The hippocampus has a well-established role in spatial and episodic memory but a broader function has been proposed including aspects of perception and relational processing. Neural bases of sound analysis have been described in the pathway to auditory cortex, but wider networks supporting auditory cognition are still being established. We review what is known about the role of the hippocampus in processing auditory information, and how the hippocampus itself is shaped by sound. In examining imaging, recording, and lesion studies in species from rodents to humans, we uncover a hierarchy of hippocampal responses to sound including during passive exposure, active listening, and the learning of associations between sounds and other stimuli. We describe how the hippocampus' connectivity and computational architecture allow it to track and manipulate auditory information - whether in the form of speech, music, or environmental, emotional, or phantom sounds. Functional and structural correlates of auditory experience are also identified. The extent of auditory-hippocampal interactions is consistent with the view that the hippocampus makes broad contributions to perception and cognition, beyond spatial and episodic memory. More deeply understanding these interactions may unlock applications including entraining hippocampal rhythms to support cognition, and intervening in links between hearing loss and dementia., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The use of multi-modal approaches, particularly in conjunction with multivariate analytic techniques, can enrich models of cognition, brain function, and how they change with age. Recently, multivariate approaches have been applied to the study of eye movements in a manner akin to that of neural activity (i.e., pattern similarity ). Here, we review the literature regarding multi-modal and/or multivariate approaches, with specific reference to the use of eyetracking to characterize age-related changes in memory. By applying multi-modal and multivariate approaches to the study of aging, research has shown that aging is characterized by moment-to-moment alterations in the amount and pattern of visual exploration, and by extension, alterations in the activity and function of the hippocampus and broader medial temporal lobe (MTL). These methodological advances suggest that age-related declines in the integrity of the memory system has consequences for oculomotor behavior in the moment, in a reciprocal fashion. Age-related changes in hippocampal and MTL structure and function may lead to an increase in, and change in the patterns of, visual exploration in an effort to upregulate the encoding of information. However, such visual exploration patterns may be non-optimal and actually reduce the amount and/or type of incoming information that is bound into a lasting memory representation. This research indicates that age-related cognitive impairments are considerably broader in scope than previously realized.

The neural correlates of subjective cognitive decline (SCD; i.e., without objectifiable deficit) remain to be elucidated. Possible causes of SCD include early neurodegeneration related to Alzheimer's disease or functional and structural changes related to sub-clinical depression. We investigated the relationship between episodic memory performance or memory complaints and structural or functional magnetic resonance imaging (MRI) measures in participants with SCD (n=18) but without psychiatric disorders and healthy controls (n=31). In SCD, memory complaints were not associated with memory performance but with sub-clinical depression and executive functions. SCD-associated memory complaints correlated with higher amygdala and parahippocampal gyrus (specifically subiculum) gray matter density. In controls, but not in SCD, mesiotemporal gray matter density and superior frontal gyrus functional connectivity predicted memory performance. In contrast, in SCD, only a trend toward a correlation between memory performance and gray matter density in the parietooccipital lobes was observed. In our memory-clinic sample of SCD, we did not observe incipient neurodegeneration (limited to structural and functional MRI) but rather sub-clinical depression underlying subjective cognitive complaints., (Copyright © 2021. Published by Elsevier Inc.)

Objectives: The goal of the present study was to identify the role of the medial temporal lobe (MTL) in the detection and later processing of novelty., Methods: Twenty-one epilepsy patients with unilateral MTL resection (10 left-sided; 11 right-sided) and 26 matched healthy controls performed an adapted visual novelty oddball task. In this task two streams of stimuli were presented on the left and right of fixation while the patients' electroencephalogram was measured. The participants had to respond to infrequent target stimuli, while ignoring frequent standard, and infrequent novel stimuli that were presented to the left or right, appearing either contra- or ipsilateral to the patients' resections., Results: Novelty detection, as indexed by the N2 ERP component elicited by novels, was reduced by the MTL resections, as evidenced by a smaller N2 for patients than healthy controls. Later processing of novels, as indexed by the novelty P3 ERP component, was reduced for novels presented contra- versus ipsilateral to the resected side. Moreover, at a frontal electrode site, the N2-P3 complex showed reduced novelty processing in patients with MTL resections compared to healthy controls. The ERP differences were specific for the novel stimuli, as target processing, as indexed by the P3b, was unaffected in the patients: No P3b differences were found between targets presented ipsi- or contralaterally to the resected side, nor between patients and healthy controls., Conclusions: The current results suggest that MTL structures play a role in novelty processing. In contrast, target processing was unaffected by MTL resections., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The hippocampus is essential for human memory. 1 The protracted maturation of memory capacities from infancy through early childhood 2-4 is thus often attributed to hippocampal immaturity. 5-7 The hippocampus of human infants has been characterized in terms of anatomy, 8 , 9 to test the hypothesis that the infant hippocampus supports statistical learning. 10 Hippocampal activity increased with exposure to visual sequences of objects when the temporal order contained regularities to be learned, compared to when the order was random. Despite the hippocampus doubling in anatomical volume across infancy, learning-related functional activity bore no relationship to age. This suggests that the hippocampus is recruited for statistical learning at the youngest ages in our sample, around 3 months. Within the hippocampus, statistical learning was clearer in anterior than posterior divisions. This is consistent with the theory that statistical learning occurs in the monosynaptic pathway, , which is more strongly represented in the anterior hippocampus. 11 Here, we use recently developed methods for task-based fMRI in awake human infants 12 raising the possibility that the infant hippocampus participates in statistical learning before it forms durable memories. Beyond the hippocampus, the medial prefrontal cortex showed statistical learning, consistent with its role in adult memory integration 13-15 Hippocampal activity increased with exposure to visual sequences of objects when the temporal order contained regularities to be learned, compared to when the order was random. Despite the hippocampus doubling in anatomical volume across infancy, learning-related functional activity bore no relationship to age. This suggests that the hippocampus is recruited for statistical learning at the youngest ages in our sample, around 3 months. Within the hippocampus, statistical learning was clearer in anterior than posterior divisions. This is consistent with the theory that statistical learning occurs in the monosynaptic pathway, 16 These results suggest that the hippocampus supports the vital ability of infants to extract the structure of their environment through experience.17 , 18 The monosynaptic pathway develops earlier than the trisynaptic pathway, which is linked to episodic memory, 19 , 20 raising the possibility that the infant hippocampus participates in statistical learning before it forms durable memories. Beyond the hippocampus, the medial prefrontal cortex showed statistical learning, consistent with its role in adult memory integration 21 and generalization. 22 These results suggest that the hippocampus supports the vital ability of infants to extract the structure of their environment through experience., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The Traveling Salesman Problem (TSP) is an optimization problem in which the subject attempts to find the shortest possible route that passes through a set of fixed locations exactly once. The TSP is used in cognitive and behavioral research to study problem solving and spatial navigation. While the TSP has been studied in some depth from this perspective, the biological mechanisms underlying the behavior have not yet been explored. The hippocampus is a structure in the brain that is known to be involved in tasks that require spatial memory. Because the TSP requires spatial problem solving, we designed the current study to determine whether the hippocampus is required to find efficient solutions to the TSP, and if so, what role the hippocampus serves. Rats were pretrained on the TSP, which involved learning to retrieve bait from targets in a variety of spatial configurations. Matched for performance, rats were then divided into two groups, receiving either a hippocampal lesion or a control sham surgery. After recovering from surgery, the rats were tested on eight new configurations. A variety of behavioral measures were recorded, including distance travelled, number of revisits, memory span, and latency. The results showed that the sham group outperformed the lesion group on most of these measures. Based on the behavioral data and histological tissue analysis of each group, we determined that the hippocampus is involved in successful performance in the TSP, particularly regarding memory for which targets have already been visited., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The rodent ventral and primate anterior hippocampus have been implicated in approach-avoidance (AA) conflict processing. It is unclear, however, whether this structure contributes to AA conflict detection and/or resolution, and if its involvement extends to conditions of AA conflict devoid of spatial/contextual information. To investigate this, neurologically healthy human participants first learned to approach or avoid single novel visual objects with the goal of maximizing earned points. Approaching led to point gain and loss for positive and negative objects, respectively, whereas avoidance had no impact on score. Pairs of these objects, each possessing nonconflicting (positive-positive/negative-negative) or conflicting (positive-negative) valences, were then presented during functional magnetic resonance imaging. Participants either made an AA decision to score points (Decision task), indicated whether the objects had identical or differing valences (Memory task), or followed a visual instruction to approach or avoid (Action task). Converging multivariate and univariate results revealed that within the medial temporal lobe, perirhinal cortex, rather than the anterior hippocampus, was predominantly associated with object-based AA conflict resolution. We suggest the anterior hippocampus may not contribute equally to all learned AA conflict scenarios and that stimulus information type may be a critical and overlooked determinant of the neural mechanisms underlying AA conflict behavior., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Accumulating evidence suggests that the hippocampus plays a critical role in the creative and flexible use of language at the sentence or discourse level. Yet it is currently unclear whether the hippocampus also supports language use at the level of single words. A recent study by Hilverman et al. (2017) found that amnesic patients with hippocampal damage use less imageable words when describing autobiographical episodes compared to healthy controls, but this deficit was attributed to patients' deficits in episodic memory rather than impairments in linguistic functions of the hippocampus per se. Yet, in addition to affecting word use by way of its role in memory, the hippocampus could also impact language use more directly. The current study aimed to test this hypothesis by investigating the status of imageable word use in amnesia during two different types of language production tasks. In Experiment 1, participants constructed narratives about events depicted in visually presented pictures (picture narratives). In Experiment 2, participants constructed verbal narratives about remembered events from the past or simulated events in the future (past/future narratives). Across all types of narratives, patients produced words that were rated as having similar levels of imageability compared to controls. Importantly, this was the case both in patients' picture narratives, which did not require generating details from episodic memory and were matched to those of controls with respect to narrative content, and in patients' narratives about past/future events, which required generating details from memory and which were reduced in narrative content compared to those of controls. These results distinguish between the quantity and quality of individual linguistic details produced in amnesia during narrative construction, and suggest that the use of imageable linguistic representations does not depend on intact episodic memory and can be supported by regions outside the hippocampus., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The organization of temporal information is critical for the encoding and retrieval of episodic memories. In the rodent hippocampus and entorhinal cortex, evidence accumulated over the last decade suggests that populations of "time cells" in the hippocampus encode temporal information. We identify time cells in humans using intracranial microelectrode recordings obtained from 27 human epilepsy patients who performed an episodic memory task. We show that time cell activity predicts the temporal organization of retrieved memory items. We also uncover evidence of ramping cell activity in humans, which represents a complementary type of temporal information. These findings establish a cellular mechanism for the representation of temporal information in the human brain needed to form episodic memories., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Neuromodulatory regions that detect salience, such as amygdala and ventral tegmental area (VTA), have distinct effects on memory. Yet, questions remain about how these modulatory regions target subregions across the hippocampus and medial temporal lobe (MTL) cortex. Here, we sought to characterize how VTA and amygdala subregions (i.e., basolateral amygdala and central-medial amygdala) interact with hippocampus head, body, and tail, as well as cortical MTL areas of perirhinal cortex and parahippocampal cortex in a task-free state. To quantify these interactions, we used high-resolution resting state fMRI and characterized pair-wise, partial correlations across regions-of-interest. We found that basolateral amygdala showed greater functional coupling with hippocampus head, hippocampus tail, and perirhinal cortex when compared to either VTA or central-medial amygdala. Furthermore, the VTA showed greater functional coupling with hippocampus tail when compared to central-medial amygdala. There were no significant differences in functional coupling with hippocampus body and parahippocampal cortex. These results support a framework by which neuromodulatory regions do not indiscriminately influence all MTL subregions equally, but rather bias information processing to discrete MTL targets. These findings provide a more specified model of the intrinsic properties of systems underlying MTL neuromodulation. This emphasizes the need to consider heterogeneity both across and within neuromodulatory systems to better understand affective memory., (© 2020 Wiley Periodicals, Inc.)

Interoceptive deficits are associated with medial temporal lobe (MTL) lesions, and especially the hippocampus, which may relate to interoception's reliance upon predictive coding and hence on mnemonic processes. Here, we develop a new task to assess interoceptive predictions and assess their dependence upon MTL memory systems. Healthy participants were asked to imagine and predict what they would feel like across nine interoceptive situations. Later, each situation was physically experienced, and participants reported what they actually felt. An index of predictive congruence was derived and correlated with a neuropsychological measure of hippocampal dependent learning and memory (HDLM), finding that more accurate predictions were associated with better HDLM (Cohen's d = 0.5). We suggest the MTL, and in particular the hippocampus, generates contextually appropriate episodic memories, providing a predictive framework for interpreting afferent bodily neurohormonal signals. The loss of this capacity may account for the profound interoceptive deficits observed following MTL lesions., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Repeated stimuli elicit attenuated responses in visual cortex relative to novel stimuli. This adaptation can be considered as a form of rapid learning and a signature of perceptual memory. Adaptation occurs not only when a stimulus is repeated immediately, but also when there is a lag in terms of time and other intervening stimuli before the repetition. But how does the visual system keep track of which stimuli are repeated, especially after long delays and many intervening stimuli? We hypothesized that the hippocampus and medial temporal lobe (MTL) support long-lag adaptation, given that this memory system can learn from single experiences, maintain information over delays, and send feedback to visual cortex. We tested this hypothesis with fMRI in an amnesic patient, LSJ, who has encephalitic damage to the MTL resulting in extensive bilateral lesions including complete hippocampal loss. We measured adaptation at varying time lags between repetitions in functionally localized visual areas that were intact in LSJ. We observed that these areas track information over a few minutes even when the hippocampus and extended parts of the MTL are unavailable. LSJ and controls were identical when attention was directed away from the repeating stimuli: adaptation occurred for lags up to three minutes, but not six minutes. However, when attention was directed toward stimuli, controls now showed an adaptation effect at six minutes but LSJ did not. These findings suggest that visual cortex can support one-shot perceptual memories lasting for several minutes but that the hippocampus and surrounding MTL structures are necessary for adaptation in visual cortex after longer delays when stimuli are task-relevant., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Reports on social cognition in patients with developmental amnesia resulting from bilateral hippocampal lesions are rare, although the link between social cognition and temporal lobe structures is well established. We present the case of a 23-year-old male epilepsy patient, BM, with developmental amnesia due to perinatal cerebral hypoxia. The patient was examined with neuroimaging and neuropsychological methods and compared to IQ-matched patients with epilepsy to control for effects of epilepsy. In addition, we used a test battery that evaluates emotion recognition and theory of mind to study his social cognition abilities. Structural high-resolution magnetic resonance imaging showed bilateral hippocampal atrophy. The comparison to controls showed that, in addition to the well-documented memory disorders in developmental amnesia, BM showed remarkable deficits in 9 out of 17 social cognitive tasks assessing emotion recognition and theory of mind. In contrast, BM's performance on tasks of executive functions was largely preserved. The relevance of deficits in social cognition for patients with developmental amnesia is discussed.

The role of the hippocampus in P300 has long been debated. Here, we present a theoretical framework that elucidates hippocampal contributions to scalp P300 based on intracranial and lesion research combined with emerging evidence on the role of the hippocampus in rapid statistical learning, memory, and novelty processing. The P300 has been divided in two subcomponents: a fronto-central P3a related to novelty and distractor processing, and a parietal P3b related to target detection. Interest in a role for hippocampus in scalp P300 was sparked by P3-like ERPs measured intracranially in human hippocampus. Subsequent medial temporal lobe lesion studies show intact scalp P3b, indicating that the hippocampus is not critical for P3b. This contrasts with the scalp P3a, which was significantly diminished in human patients with lesions in the posterior hippocampus. This suggests a differential role for hippocampus in P3a and P3b. Our framework purports that the hippocampus plays a central role in distractor processing that leads to P3a generation in cortical regions. We also propose that the hippocampus is involved at the end of the cognitive episode for both P3a and P3b implementing contextual updating. P3-like ERPs measured in hippocampus may reflect input signals from cortical regions implementing updates based on the outcome of cognitive processes underlying scalp P3, enabling a model update of the environment facilitated by the hippocampus. Overall, this framework proposes an active role for the hippocampus in novelty processing leading up to P3a generation, followed by contextual updating of the outcome of both scalp P3a and P3b., (© 2019 Society for Psychophysiological Research.)

Experimental findings show the ubiquitous presence of graded responses and tuning curves in the neocortex, particularly in visual areas [1-15]. Among these, inferotemporal-cortex (IT) neurons respond to complex visual stimuli, but differences in the neurons' responses can be used to distinguish the stimuli eliciting the responses [8, 9, 16-18]. The IT projects directly to the medial temporal lobe (MTL) [19], where neurons respond selectively to different pictures of specific persons and even to their written and spoken names [20-22]. However, it is not clear whether this is done through a graded coding, as in the neocortex, or a truly invariant code, in which the response-eliciting stimuli cannot be distinguished from each other. To address this issue, we recorded single neurons during the repeated presentation of different stimuli (pictures and written and spoken names) corresponding to the same persons. Using statistical tests and a decoding approach, we found that only in a minority of cases can the different pictures of a given person be distinguished from the neurons' responses and that in a larger proportion of cases, the responses to the pictures were different to the ones to the written and spoken names. We argue that MTL neurons tend to lack a representation of sensory features (particularly within a sensory modality), which can be advantageous for the memory function attributed to this area [23-25], and that a full representation of memories is given by a combination of mostly invariant coding in the MTL with a representation of sensory features in the neocortex., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

We review evidence from an extensive single case study in an individual (NB) who underwent a rare left-sided anterior temporal-lobe resection with sparing of the hippocampus. Our study aimed to determine whether memory functions of perirhinal cortex, which was largely removed in the resection, can be impaired against a background of preserved hippocampus-dependent memory processing. This research was guided by the proposal that item-based familiarity assessment relies on contributions of perirhinal cortex, and that the hippocampus plays a unique role in the relational binding of items to episodic contexts, which is critical for recollection. Seven sets of findings have emerged from our research on NB (synthesized from five primary research articles), and from follow-up work in other patients: (i) Familiarity impairments can be selective and be revealed with multiple methods; (ii) selective familiarity and selective recollection impairments can be double dissociated; (iii) selective familiarity impairments show material specificity; (iv) selective familiarity impairments extend to assessment of cumulative lifetime experience; (v) selective familiarity impairments are sensitive to degree of feature overlap between object concepts; (vi) selective familiarity impairments are associated with preserved task-related fMRI signals in the hippocampus; (vii) selective familiarity impairments can be observed in other lesion cases. Despite our main focus on the dual-process framework, we also discuss implications for the functional organization of the medial temporal lobes in broader terms. We argue that our findings shed light on this organization even if the functional specialization of different medial temporal structures is ultimately not fully captured with reference to the cognitive distinction between familiarity and recollection., Competing Interests: Declaration of competing interest None., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)

Why do we sometimes easily retrieve memories, but other times appear to forget them? We often look to our external environment for retrieval cues, but another way to optimize memory retrieval is to be in a mental state, or mode, that prioritizes access to our internal representation of the world. Such a 'retrieval mode' was proposed by Endel Tulving (1983), who considered it a neurocognitive state in which one keeps the goal of memory retrieval in mind. Building on Tulving's proposal, we review converging evidence from multiple lines of research that emphasize the importance of internal states in the instantiation of retrieval modes that optimize successful remembering. We identify three key factors that contribute to a retrieval mode by modulating either the likelihood or the content of retrieval: (1) an intention to remember or forget (either in the present or the future), (2) attentional selection of goal-relevant memories and suppression of distractors, and (3) fluctuating levels of acetylcholine in the hippocampus. We discuss empirical evidence that these internal states individually influence memory retrieval and propose how they may interact synergistically. Characterizing these dynamic internal factors is an important key for unlocking our understanding of the organization and accessibility of our memories., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

It is debated whether the amygdala is critical for the emotional modulation of attention. While some studies show reduced attentional benefits for emotional stimuli in amygdala-damaged patients, others report preserved emotional effects. Various factors may account for these discrepant findings, including the temporal onset of the lesion, the completeness and severity of tissue damage, or the extent of neural plasticity and compensatory mechanisms, among others. Here, we investigated a rare patient with focal acute destruction of bilateral amygdala and adjacent hippocampal structures after late-onset herpetic encephalitis in adulthood. We compared her performance in two classic visual attention paradigms with that of healthy controls. First, we tested for any emotional advantage during an attentional blink task. Whereas controls showed better report of fearful and happy than neutral faces on trials with short lags between targets, the patient showed no emotional advantage, but also globally reduced report rates for all faces. Second, to ensure that memory disturbance due to hippocampal damage would not interfere with report performance, we also used a visual search task with either emotionally or visually salient face targets. Although the patient still exhibited efficient guided search for visually salient, non-emotional faces, her search slopes for emotional versus neutral faces showed no comparable benefit. In both tasks, however, changes in the patient predominated for happy more than fear stimuli, despite her normal explicit recognition of happy expressions. Our results provide new support for a causal role of the amygdala in emotional facilitation of visual attention, especially under conditions of increasing task-demands, and not limited to negative information. In addition, our data suggest that such deficits may not be amenable to plasticity and compensation, perhaps due to sudden and late-onset damage occurring in adulthood., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The hippocampus displays a complex organization and function that is perturbed in many neuropathologies. Histological work revealed a complex arrangement of subfields along the medial-lateral and the ventral-dorsal dimension, which contrasts with the anterior-posterior functional differentiation. The variety of maps has raised the need for an integrative multimodal view. We applied connectivity-based parcellation to 1) intrinsic connectivity 2) task-based connectivity, and 3) structural covariance, as complementary windows into structural and functional differentiation of the hippocampus. Strikingly, while functional properties (i.e., intrinsic and task-based) revealed similar partitions dominated by an anterior-posterior organization, structural covariance exhibited a hybrid pattern reflecting both functional and cytoarchitectonic subdivision. Capitalizing on the consistency of functional parcellations, we defined robust functional maps at different levels of partitions, which are openly available for the scientific community. Our functional maps demonstrated a head-body and tail partition, subdivided along the anterior-posterior and medial-lateral axis. Behavioral profiling of these fine partitions based on activation data indicated an emotion-cognition gradient along the anterior-posterior axis and additionally suggested a self-world-centric gradient supporting the role of the hippocampus in the construction of abstract representations for spatial navigation and episodic memory., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The hippocampus is the canonical memory system in the brain and is not typically considered part of the visual system. Yet, it sits atop the ventral visual stream and has been implicated in certain aspects of vision. Here I review the place of the hippocampal memory system in vision science. After a brief primer on the local circuity, external connectivity, and computational functions of the hippocampus, I explore what can be learned from each field about the other. I first present four areas of vision science (scene perception, imagery, eye movements, attention) that challenge our current understanding of the hippocampus in terms of its role in episodic memory. In the reverse direction, I leverage this understanding to inform vision science in other ways, presenting a working hypothesis about a unique form of visual representation. This spatiotemporal similarity hypothesis states that the hippocampus represents objects according to whether they co-occur in space and/or time, and not whether they look alike, as elsewhere in the visual system. This tuning may reflect hippocampal mechanisms of pattern separation, relational binding, and statistical learning, allowing the hippocampus to generate visual expectations to facilitate search and recognition., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Temporal lobe epilepsy has been usually associated with progressive brain atrophy due to neuronal cell loss. However, recent animal models demonstrated a dual effect of epileptic seizures with initial enhancement of hippocampal neurogenesis followed by abnormal astrocyte proliferation and neurogenesis depletion in the chronic stage. Our aim was to test for the hypothesized bidirectional pattern of epilepsy-associated brain remodeling in the context of the presence and absence of mesial temporal lobe sclerosis. We acquired MRIs from a large cohort of mesial temporal lobe epilepsy patients with or without hippocampus sclerosis on radiological examination. The statistical analysis tested explicitly for common and differential brain patterns between the two patients' cohorts and healthy controls within the computational anatomy framework of voxel-based morphometry. The main effect of disease was associated with continuous hippocampus volume loss ipsilateral to the seizure onset zone in both temporal lobe epilepsy cohorts. The post hoc simple effects tests demonstrated bilateral hippocampus volume increase in the early epilepsy stages in patients without hippocampus sclerosis. Early age of onset and longer disease duration correlated with volume decrease in the ipsilateral hippocampus. Our findings of seizure-induced hippocampal remodeling are associated with specific patterns of mesial temporal lobe atrophy that are modulated by individual clinical phenotype features. Directionality of hippocampus volume changes strongly depends on the chronicity of disease. Specific anatomy differences represent a snapshot within a progressive continuum of seizure-induced structural remodeling.

Hippocampal episodic memory is fundamentally relational, comprising links between events and the spatiotemporal contexts in which they occurred. Such relations are also important over shorter timescales, during online perception. For example, how do we assess the relative spatial positions of objects, their temporal order, or the relationship between their features? Here, we investigate the role of the hippocampus in online relational processing by manipulating attention to different kinds of relations. While undergoing fMRI, participants viewed two images in rapid succession on each trial and performed one of three relational tasks, judging the images' relative: spatial positions, temporal onsets, or sizes. Additionally, they sometimes judged whether one image was tilted, irrespective of the other. This served as a baseline item task with no demands on relational processing. The hippocampus showed reliable deactivation when participants attended to relational vs. item information. Attention to temporal relations was associated with the most robust deactivation. One interpretation of such deactivation is that it reflects hippocampal disengagement. If true, there should be reduced information content and noisier activity patterns for the temporal vs. other tasks. Instead, multivariate pattern analysis revealed more stable hippocampal representations in the temporal task. This increased pattern similarity was not simply a reflection of lower univariate activity. Thus, the hippocampus differentiates between relational and item processing even during online perception, and its representations of temporal relations are particularly robust. These findings suggest that the relational computations of the hippocampus extend beyond long-term memory, enabling rapid extraction of relational information in perception., (© 2019 Wiley Periodicals, Inc.)

Purpose: Type IIB focal cortical dysplasia (FCD) is an important cause of drug-resistant epilepsy. However, balloon cells located in the medial temporal lobe have been seldom reported. We aimed to discuss the clinical and pathological features of Type IIB FCD with balloon cells in the medial temporal lobe (MTLE-FCDIIB) and the differential diagnosis with other types of mesial temporal lobe epilepsy., Methods: Three MTLE-FCDIIB cases were enrolled from Peking Union Medical College Hospital. Clinical and neuroimaging data were analyzed and histology features observed on hematoxylin-eosin (H&E) staining and immunochemical staining, including vimentin, nestin, S-100, CD34, neuronal nuclei antigen (Neun), glial fibrillary acidic protein (GFAP), neurofilament heavy chain (SMI32), were discussed., Results: All cases involved drug-resistant epilepsy patients with childhood onset. The semiology of the epileptic seizure was a highly frequent partial seizure with or without generalized tonic-clonic seizures. Magnetic resonance imaging showed hyper-intensity in the medial temporal lobe without atrophy, different from mesial temporal sclerosis. Histological examination indicated the presence of balloon cells in the white matter of the para-hippocampal gyrus, subiculum, and cornu ammonis with cortical disorganization, and SMI32 positive dysmorphic neurons in the gray matter. Balloon cells were immunohistochemically stained with vimentin and nestin. Granular cell dispersion and pyramidal cell loss were not found., Conclusions: The presence of balloon cells in the medial temporal lobe is observed in a rare subgroup of FCD, named MTLE-FCDIIB. It has distinct clinical manifestations, neuroimaging features, pathological changes, and prognosis, which should be differentiated from mesial temporal lobe sclerosis and mesial temporal lobe tumors. Our findings enable more accurate diagnosis of mesial temporal lobe epilepsy., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Immediately repeated meaningful pictures in a continuous recognition task induce a positive frontal potential at about 200-300 ms, which appears to emanate from the medial temporal lobe (MTL) centered on the hippocampus, as concluded from inverse solutions, coherence measurements, and depth electrode recordings in humans. In this study, we tested patients with unilateral MTL lesions due to stroke to verify the provenance of this signal and its association with the spacing effect (SE)-the improved learning of material encountered in spaced rather than massed presentation. We found that unilateral left or right MTL lesions abolished the early frontal MTL-mediated signal but not the spacing effect. We conclude that the SE does not depend on MTL integrity. We suggest that the early frontal signal at 200-300 ms after immediate picture repetition may serve as a direct biomarker of MTL integrity that may be useful in the early stages of diseases like Alzheimer's., (© 2018 Wiley Periodicals, Inc.)

Mesial temporal lobe epilepsy (TLE) is a common neurological disorder affecting the hippocampus and surrounding medial temporal lobe (MTL). Although prior studies have analyzed whole-brain network distortions in TLE patients, the functional network architecture of the MTL at the subregion level has not been examined. In this study, we utilized high-resolution 7T T2-weighted magnetic resonance imaging (MRI) and resting-state BOLD-fMRI to characterize volumetric asymmetry and functional network asymmetry of MTL subregions in unilateral medically refractory TLE patients and healthy controls. We subdivided the TLE group into mesial temporal sclerosis patients (TLE-MTS) and MRI-negative nonlesional patients (TLE-NL). Using an automated multi-atlas segmentation pipeline, we delineated 10 MTL subregions per hemisphere for each subject. We found significantly different patterns of volumetric asymmetry between the two groups, with TLE-MTS exhibiting volumetric asymmetry corresponding to decreased volumes ipsilaterally in all hippocampal subfields, and TLE-NL exhibiting no significant volumetric asymmetries other than a mild decrease in whole-hippocampal volume ipsilaterally. We also found significantly different patterns of functional network asymmetry in the CA1 subfield and whole hippocampus, with TLE-NL patients exhibiting asymmetry corresponding to increased connectivity ipsilaterally and TLE-MTS patients exhibiting asymmetry corresponding to decreased connectivity ipsilaterally. Our findings provide initial evidence that functional neuroimaging-based network properties within the MTL can distinguish between TLE subtypes. High-resolution MRI has potential to improve localization of underlying brain network disruptions in TLE patients who are candidates for surgical resection., (© 2019 Wiley Periodicals, Inc.)

Neurons in the temporal cortex signal object familiarity by modulating their spiking activity as the object is repeatedly experienced. However, the neural mechanisms underlying this "repetition effect" and its functional significance remain unknown. We investigated this process in a goal-directed object recognition task in which rats were required to recognize familiar and novel objects. Single-unit spiking activity and local field potential were recorded from the hippocampus and perirhinal cortex (PER) as rats performed the task. Repetition effects were detected in both the hippocampus and PER. However, phase-locking to the theta rhythm was strengthened with object repetitions in the hippocampus but not in the PER, whereas stronger phase-locking was observed with gamma rhythm in the PER but not in the hippocampus. Our findings suggest that the repetition effect occurs in sync with different rhythmic oscillations across different regions and may underlie neural "pruning" of noise that facilitates object recognition., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

The hippocampus plays an indispensable role in episodic memory, particularly during the consolidation process. However, its precise role in retrieval of episodic memory is still ambiguous. In this study, we investigated the correlation of hippocampal morphometry and the performance in an autobiographical memory task in 27 healthy controls and 24 patients suffering from Alzheimer's disease (AD). Most importantly, correlations were defined separately and comparatively for memory contents with different retrieval frequency in the past. In healthy subjects, memory performance for seldom retrieved autobiographical events was significantly associated with gray matter density in the bilateral hippocampus, whereas this correlation was not present for events with high retrieval frequency. This pattern of findings confirms that retrieval frequency plays a critical role in the consolidation of episodic autobiographical memories, thereby making them more independent of the hippocampal system. In AD patients, on the other hand, successful memory retrieval appeared to be related to hippocampal morphometry irrespective of the contents' retrieval frequency, comprising events with high retrieval frequency, too. The observed differences between patients and control subjects suggest that AD-related neurodegeneration not only impairs the function, but also decreases the functional specialization of the hippocampal memory system, which, thus, may be considered as marker for AD.

We explored the relationship between memory performance and conscious knowledge (or awareness) of what has been learned in memory-impaired patients with hippocampal lesions or larger medial temporal lesions. Participants viewed familiar scenes or familiar scenes where a change had been introduced. Patients identified many fewer of the changes than controls. Across all of the scenes, controls preferentially directed their gaze toward the regions that had been changed whenever they had what we term robust knowledge about the change: They could identify that a change occurred, report what had changed, and indicate where the change occurred. Preferential looking did not occur when they were unaware of the change or had only partial knowledge about it. The patients, overall, did not direct their gaze toward the regions that had been changed, but on the few occasions when they had robust knowledge about the change they (like controls) did exhibit this effect. Patients did not exhibit this effect when they were unaware of the change or had partial knowledge. The findings support the idea that awareness of what has been learned is a key feature of hippocampus-dependent memory., Competing Interests: The authors declare no conflict of interest.

Arterial spin labeling (ASL) provides absolute quantification of resting tissue cerebral blood flow (CBF) as an entirely noninvasive approach with good reproducibility. As a result of neurovascular coupling, ASL provides a useful marker of resting neuronal activity. Recent ASL studies in individuals at clinical high risk of psychosis (CHR) have reported increased resting hippocampal perfusion compared with healthy controls. Schizotypy refers to the presence of subclinical psychotic-like experiences in healthy individuals and represents a robust framework to study neurobiological mechanisms involved in the extended psychosis phenotype while avoiding potentially confounding effects of antipsychotic medications or disease comorbidity. Here we applied pseudo-continuous ASL to examine differences in resting CBF in 21 subjects with high positive schizotypy (HS) relative to 22 subjects with low positive schizotypy (LS), as determined by the Oxford and Liverpool Inventory of Feelings and Experiences. Based on preclinical evidence that hippocampal hyperactivity leads to increased activity in mesostriatal dopamine projections, CBF in hippocampus, midbrain, and striatum was assessed. Participants with HS showed higher CBF of the right hippocampus compared to those with LS (p = .031, family-wise error corrected). No differences were detected in the striatum or midbrain. The association between increased hippocampal CBF and HS supports the notion that hippocampal hyperactivity might be a central characteristic of the extended psychosis phenotype, while hyperactivity in subcortical dopamine pathways may only emerge at a higher intensity of psychotic experiences., (© 2018 Wiley Periodicals, Inc.)

Objectives: Hippocampal hyperactivation marks preclinical dementia pathophysiology, potentially due to differences in the connectivity of specific medial temporal lobe structures. Our aims were to characterize the resting-state functional connectivity of medial temporal lobe sub-structures in older adults, and evaluate whether specific substructural (rather than global) functional connectivity relates to memory function., Methods: In 15 adults (mean age: 69 years), we evaluated the resting state functional connectivity of medial temporal lobe substructures: dentate/Cornu Ammonis (CA) 4, CA1, CA2/3, subiculum, the molecular layer, entorhinal cortex, and parahippocampus. We used 7-Tesla susceptibility weighted imaging and magnetization-prepared rapid gradient echo sequences to segment substructures of the hippocampus, which were used as structural seeds for examining functional connectivity in a resting BOLD sequence. We then assessed correlations between functional connectivity with memory performance (short and long delay free recall on the California Verbal Learning Test [CVLT])., Results: All the seed regions had significant connectivity within the temporal lobe (including the fusiform, temporal, and lingual gyri). The left CA1 was the only seed with significant functional connectivity to the amygdala. The left entorhinal cortex was the only seed to have significant functional connectivity with frontal cortex (anterior cingulate and superior frontal gyrus). Only higher left dentate-left lingual connectivity was associated with poorer CVLT performance (Spearman r = -0.81, p = 0.0003, Benjamini-Hochberg false discovery rate: 0.01) after multiple comparison correction., Conclusions: Rather than global hyper-connectivity of the medial temporal lobe, left dentate-lingual connectivity may provide a specific assay of medial temporal lobe hyper-connectivity relevant to memory in aging., (Copyright © 2018 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

The medial temporal lobe (MTL) is widely implicated in supporting episodic memory and navigation, but its precise functional role in organizing memory across time and space remains elusive. Here we examine the specific cognitive processes implemented by MTL structures (hippocampus and entorhinal cortex) to organize memory by using electrical brain stimulation, leveraging its ability to establish causal links between brain regions and features of behavior. We studied neurosurgical patients of both sexes who performed spatial-navigation and verbal-episodic memory tasks while brain stimulation was applied in various regions during learning. During the verbal memory task, stimulation in the MTL disrupted the temporal organization of encoded memories such that items learned with stimulation tended to be recalled in a more randomized order. During the spatial task, MTL stimulation impaired subjects' abilities to remember items located far away from boundaries. These stimulation effects were specific to the MTL. Our findings thus provide the first causal demonstration in humans of the specific memory processes that are performed by the MTL to encode when and where events occurred. SIGNIFICANCE STATEMENT Numerous studies have implicated the medial temporal lobe (MTL) in encoding spatial and temporal memories, but they have not been able to causally demonstrate the nature of the cognitive processes by which this occurs in real-time. Electrical brain stimulation is able to demonstrate causal links between a brain region and a given function with high temporal precision. By examining behavior in a memory task as subjects received MTL stimulation, we provide the first causal evidence demonstrating the role of the MTL in organizing the spatial and temporal aspects of episodic memory., (Copyright © 2018 the authors 0270-6474/18/384471-11$15.00/0.)

Individuals with chronic temporal lobe epilepsy (TLE) experience episodic memory deficits that may be progressive in nature. These memory decrements have been shown to increase with the extent of hippocampal damage, a hallmark feature of TLE. Pattern separation, a neural computational mechanism thought to play a role in episodic memory formation, has been shown to be negatively affected by aging and in individuals with known hippocampal dysfunction. Despite the link between poor pattern separation performance and episodic memory deficits, behavioral pattern separation has not been examined in patients with TLE. We examined pattern separation performance in a group of 22 patients with medically-refractory TLE and 20 healthy adults, using a task hypothesized to measure spatial pattern separation with graded levels of spatial interference. We found that individuals with TLE showed less efficient spatial pattern separation performance relative to healthy adults. Poorer spatial pattern separation performance in TLE was associated with poorer visuospatial memory, but only under high interference conditions. In addition, left hippocampal atrophy was associated with poor performance in the high interference condition in TLE. These data suggest that episodic memory impairments in patients with chronic, refractory TLE may be partially due to less efficient pattern separation, which likely reflects their underlying hippocampal dysfunction., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

This meta-analysis summarizes research examining whether deficits in verbal learning are related to bilateral hippocampal volume reductions in patients with or at risk for schizophrenia and in healthy controls. 17 studies with 755 patients with schizophrenia (SCZ), 232 Genetic High Risk (GHR) subjects and 914 healthy controls (HC) were included. Pooled correlation coefficients were calculated between hemisphere (left, right or total) and type of recall (immediate or delayed) for each diagnostic group individually (SCZ, GHR and HC). In SCZ, left and right hippocampal volume positively correlated with immediate (r=0.256, 0.230) and delayed (r=0.132, 0.231) verbal recall. There was also a correlation between total hippocampal volume and delayed recall (r=0.233). None of these correlations were significant in healthy controls. There was however, a positive correlation between left hippocampal volume and immediate recall in the GHR group (r=0.356). The results suggest that hippocampal volume affects immediate and delayed verbal learning capacity in schizophrenia and provides further evidence of hippocampal dysfunction in the pathophysiology of schizophrenia., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Increasing evidence suggests that the human hippocampus contributes to a range of different behaviors, including episodic memory, language, short-term memory, and navigation. A novel theoretical framework, the Precision and Binding Model, accounts for these phenomenon by describing a role for the hippocampus in high-resolution, complex binding. Other theories like Cognitive Map Theory, in contrast, predict a specific role for the hippocampus in allocentric navigation, while Declarative Memory Theory predicts a specific role in delay-dependent conscious memory. Navigation provides a unique venue for testing these predictions, with past results from research with humans providing inconsistent findings regarding the role of the human hippocampus in spatial navigation. Here, we tested five patients with lesions primarily restricted to the hippocampus and those extending out into the surrounding medial temporal lobe cortex on a virtual water maze task. Consistent with the Precision and Binding Model, we found partially intact allocentric memory in all patients, with impairments in the spatial precision of their searches for a hidden target. We found similar impairments at both immediate and delayed testing. Our findings are consistent with the Precision and Binding Model of hippocampal function, arguing for its role across domains in high-resolution, complex binding., Significance Statement: Remembering goal locations in one's environment is a critical skill for survival. How this information is represented in the brain is still not fully understood, but is believed to rely in some capacity on structures in the medial temporal lobe. Contradictory findings from studies of both humans and animals have been difficult to reconcile with regard to the role of the MTL, specifically the hippocampus. By assessing impairments observed during navigation to a goal in patients with medial temporal lobe damage we can better understand the role these structures play in such behavior. Utilizing virtual reality and novel analysis techniques, we have more precisely assessed the impact that medial temporal lobe damage has on spatial memory and navigation., (© 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.)

Brain stimulation is increasingly viewed as an effective approach to treat neuropsychiatric disease. The brain's organization in distributed networks suggests that the activity of a remote brain structure could be modulated by stimulating cortical areas that strongly connect to the target. Most connections between cerebral areas are asymmetric, and a better understanding of the relative direction of information flow along connections could improve the targeting of stimulation to influence deep brain structures. The hippocampus and amygdala, two deep-situated structures that are crucial to memory and emotions, respectively, have been implicated in multiple neurological and psychiatric disorders. We explored the directed connectivity between the hippocampus and amygdala and the cerebral cortex in patients implanted with intracranial electrodes using corticocortical evoked potentials (CCEPs) evoked by single-pulse electrical stimulation. The hippocampus and amygdala were connected with most of the cortical mantle, either directly or indirectly, with the inferior temporal cortex being most directly connected. Because CCEPs assess the directionality of connections, we could determine that incoming connections from cortex to hippocampus were more direct than outgoing connections from hippocampus to cortex. We found a similar, although smaller, tendency for connections between the amygdala and cortex. Our results support the roles of the hippocampus and amygdala to be integrators of widespread cortical influence. These results can inform the targeting of noninvasive neurostimulation to influence hippocampus and amygdala function.

Background: Cannabis exposure, particularly heavy cannabis use, has been associated with neuroanatomical alterations in regions rich with cannabinoid receptors such as the hippocampus in some but not in other (mainly cross-sectional) studies. However, it remains unclear whether continued heavy cannabis use alters hippocampal volume, and whether an earlier age of onset and/or a higher dosage exacerbate these changes., Methods: Twenty heavy cannabis users (mean age 21 years, range 18-24 years) and 23 matched non-cannabis using healthy controls were submitted to a comprehensive psychological assessment and magnetic resonance imaging scan at baseline and at follow-up (average of 39 months post-baseline; standard deviation=2.4). Cannabis users started smoking around 16 years and smoked on average five days per week. A novel aspect of the current study is that hippocampal volume estimates were obtained from manual tracing the hippocampus on T1-weighted anatomical magnetic resonance imaging scans, using a previously validated protocol., Results: Compared to controls, cannabis users did not show hippocampal volume alterations at either baseline or follow-up. Hippocampal volumes increased over time in both cannabis users and controls, following similar trajectories of increase. Cannabis dose and age of onset of cannabis use did not affect hippocampal volumes., Conclusions: Continued heavy cannabis use did not affect hippocampal neuroanatomical changes in early adulthood. This contrasts with prior evidence on alterations in this region in samples of older adult cannabis users. In young adults using cannabis at this level, cannabis use may not be heavy enough to affect hippocampal neuroanatomy.

Recent "representational" accounts suggest a key role for the hippocampus in complex scene perception. Due to limitations in scanner field strength, however, the functional neuroanatomy of hippocampal-dependent scene perception is unknown. Here, we applied 7 T high-resolution functional magnetic resonance imaging (fMRI) alongside a perceptual oddity task, modified from nonhuman primate studies. This task requires subjects to discriminate highly similar scenes, faces, or objects from multiple viewpoints, and has revealed selective impairments during scene discrimination following hippocampal lesions. Region-of-interest analyses identified a preferential response in the subiculum subfield of the hippocampus during scene, but not face or object, discriminations. Notably, this effect was in the anteromedial subiculum and was not modulated by whether scenes were subsequently remembered or forgotten. These results highlight the value of ultra-high-field fMRI in generating more refined, anatomically informed, functional accounts of hippocampal contributions to cognition, and a unique role for the human subiculum in discrimination of complex scenes from different viewpoints. SIGNIFICANCE STATEMENT There is increasing evidence that the human hippocampus supports functions beyond just episodic memory, with human lesion studies suggesting a contribution to the perceptual processing of navigationally relevant, complex scenes. While the hippocampus itself contains several small, functionally distinct subfields, examining the role of these in scene processing has been previously limited by scanner field strength. By applying ultra-high-resolution 7 T fMRI, we delineated the functional contribution of individual hippocampal subfields during a perceptual discrimination task for scenes, faces, and objects. This demonstrated that the discrimination of scenes, relative to faces and objects, recruits the anterior subicular region of the hippocampus, regardless of whether scenes were subsequently remembered or forgotten., (Copyright © 2017 Hodgetts et al.)

Objective: The purpose of this study was to compare the diagnostic efficacies of an automated volumetric assessment tool and visual assessment in the evaluation of medial temporal lobar atrophy in mild-to-moderate Alzheimer disease (AD)., Materials and Methods: This retrospective study included 30 patients with mild-to-moderate AD and 25 age-matched healthy control subjects undergoing MRI with a 3D fast spoiled gradient recalled-echo sequence at 3 T. The images were processed with fully automated volumetric analysis software. To assess medial temporal lobe (MTL) atrophy, two MTL indexes, which took into account the volumes of the hippocampus and the inferior lateral ventricle, were calculated with the automated volumetric assessment software. In addition, two neuroradiologists assessed MTL atrophy visually using the Scheltens scale. ROC curve analysis was used to compare the diagnostic performances of the two methods. The weighted kappa statistic was used to assess the intrarater and interrater reliability of visual inspection., Results: The automated volumetric assessment tool had moderate sensitivity (63.3%) and high specificity (100%) in differentiating patients with mild-to-moderate AD from control subjects. Visual inspection showed sensitivity of 63.3% and specificity of 92.0%. The diagnostic performance was not significantly different between the two methods (p = 0.536-0.906). Intraobserver reliability for visual inspection was 0.858 and 0.902 for the two reviewers, and interobserver reliability was 0.692-0.780., Conclusion: Both the automated volumetric assessment tool and visual inspection can be used to evaluate MTL atrophy and differentiate patients with AD from healthy individuals with good diagnostic accuracy. Thus, the automated tool can be a useful and efficient adjunct in clinical practice for evaluating MTL atrophy in the diagnosis of AD.

A growing literature suggests that the hippocampus is critical for the rapid extraction of regularities from the environment. Although this fits with the known role of the hippocampus in rapid learning, it seems at odds with the idea that the hippocampus specializes in memorizing individual episodes. In particular, the Complementary Learning Systems theory argues that there is a computational trade-off between learning the specifics of individual experiences and regularities that hold across those experiences. We asked whether it is possible for the hippocampus to handle both statistical learning and memorization of individual episodes. We exposed a neural network model that instantiates known properties of hippocampal projections and subfields to sequences of items with temporal regularities. We found that the monosynaptic pathway-the pathway connecting entorhinal cortex directly to region CA1-was able to support statistical learning, while the trisynaptic pathway-connecting entorhinal cortex to CA1 through dentate gyrus and CA3-learned individual episodes, with apparent representations of regularities resulting from associative reactivation through recurrence. Thus, in paradigms involving rapid learning, the computational trade-off between learning episodes and regularities may be handled by separate anatomical pathways within the hippocampus itself.This article is part of the themed issue 'New frontiers for statistical learning in the cognitive sciences'., (© 2016 The Author(s).)

Surprisingly little is known about how the brain combines spatial elements to form a coherent percept. Regions that may underlie this process include the hippocampus (HC) and parahippocampal place area (PPA), regions central to spatial perception but whose role in spatial coherency has not been explored. Participants were scanned with functional MRI while they judged whether Escher-like scenes were possible or impossible. Univariate analyses revealed differential HC and PPA involvement, with greater HC activity during spatial incoherency detection and more PPA activity during spatial coherency detection. Recognition and eye-tracking data ruled out long- or short-term memory confounds. Multivariate statistics demonstrated spatial coherency-dependent functional connectivity for the HC, but not PPA, with greater HC connectivity to various brain regions including lateral occipital complex during spatial incoherency detection. We suggest the PPA is preferentially involved during the perception of spatially coherent scenes, whereas the HC binds distinct features to create coherent representations. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)