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Early stages of Alzheimer's disease (AD) are associated with volume reductions in specific subregions of the medial temporal lobe (MTL). Using a manual segmentation method-the Olsen-Amaral-Palombo (OAP) protocol-previous work in healthy older adults showed that reductions in grey matter volumes in MTL subregions were associated with lower scores on the Montreal Cognitive Assessment (MoCA), suggesting atrophy may occur prior to diagnosis of mild cognitive impairment, a condition that often progresses to AD. However, current "gold standard" manual segmentation methods are labour intensive and time consuming. Here, we examined the utility of Automatic Segmentation of Hippocampal Subfields (ASHS) to detect volumetric differences in MTL subregions of healthy older adults who varied in cognitive status as determined by the MoCA. We trained ASHS on the OAP protocol to create the ASHS-OAP atlas and then examined how well automated segmentation replicated manual segmentation. Volumetric measures obtained from the ASHS-OAP atlas were also contrasted against those from the ASHS-PMC atlas, a widely used atlas provided by the ASHS team. The pattern of volumetric results was similar between the ASHS-OAP atlas and manual segmentation for anterolateral entorhinal cortex and perirhinal cortex, suggesting that ASHS-OAP is a viable alternative to current manual segmentation methods for detecting group differences based on cognitive status. Although ASHS-OAP and ASHS-PMC produced varying volumes for most regions of interest, they both identified early signs of neurodegeneration in CA2/CA3/DG and identified marginal differences in entorhinal cortex. Our findings highlight the utility of automated segmentation methods but still underscore the need for a unified and harmonized MTL segmentation atlas.

The psychological states of hunger and satiety play an important role in regulating human food intake. Several lines of evidence suggest that these states rely upon declarative learning and memory processes, which are based primarily in the medial temporal lobes (MTL). The MTL, and particularly the hippocampus, is unusual in that it is especially vulnerable to insult. Consequently, we examine here the impact on hunger and satiety of conditions that: (1) are central to ingestive behaviour and where there is evidence of MTL pathology (i.e., habitual consumption of a Western-style diet, obesity, and anorexia nervosa); and (2) where there is overwhelming evidence of MTL pathology, but where ingestive behaviour is not thought central (i.e., temporal lobe epilepsy and post-traumatic stress disorder). While for some of these conditions the evidence base is currently limited, the general conclusion is that MTL impairment is linked, sometimes strongly, to dysfunctional hunger and satiety. This focus on the MTL, and declarative learning and memory processes, has implications for the development of alternative treatment approaches for the regulation of appetite.

INTRODUCTION: Virtually all people with Down syndrome (DS) develop neuropathology associated with Alzheimers disease (AD). Atrophy of the hippocampus and entorhinal cortex (EC), as well as elevated plasma concentrations of neurofilament light chain (NfL) protein, are markers of neurodegeneration associated with late-onset AD. We hypothesized that hippocampus and EC gray matter loss and increased plasma NfL concentrations are associated with memory in adults with DS. METHODS: T1-weighted structural magnetic resonance imaging (MRI) data were collected from 101 participants with DS. Hippocampus and EC volume, as well as EC subregional cortical thickness, were derived. In a subset of participants, plasma NfL concentrations and modified Cued Recall Test scores were obtained. Partial correlation and mediation were used to test relationships between medial temporal lobe (MTL) atrophy, plasma NfL, and episodic memory. RESULTS: Hippocampus volume, left anterolateral EC (alEC) thickness, and plasma NfL were correlated with each other and were associated with memory. Plasma NfL mediated the relationship between left alEC thickness and memory as well as hippocampus volume and memory. DISCUSSION: The relationship between MTL gray matter and memory is mediated by plasma NfL levels, suggesting a link between neurodegenerative processes underlying axonal injury and frank gray matter loss in key structures supporting episodic memory in people with DS.

Grid cells in the entorhinal cortex demonstrate spatially periodic firing, thought to provide a spatial map on behaviorally relevant length scales. Whether such periodicity exists for behaviorally relevant time scales in the human brain remains unclear. We investigate neuronal firing during a temporally continuous experience by presenting 14 neurosurgical patients with a video while recording neuronal activity from multiple brain regions. We report on neurons that modulate their activity in a periodic manner across different time scales-from seconds to many minutes, most prevalently in the entorhinal cortex. These neurons remap their dominant periodicity to shorter time scales during a subsequent recognition memory task. When the video is presented at two different speeds, a significant percentage of these temporally periodic cells (TPCs) maintain their time scales, suggesting a degree of invariance. The TPCs temporal periodicity might complement the spatial periodicity of grid cells and together provide scalable spatiotemporal metrics for human experience.

IntroductionWe tested whether Alzheimer's disease (AD) pathology predicts memory deficits in non-demented older adults through its effects on medial temporal lobe (MTL) subregional volume.MethodsThirty-two, non-demented older adults with cerebrospinal fluid (CSF) (amyloid-beta [Aβ]42/Aβ40, phosphorylated tau [p-tau]181, total tau [t-tau]), positron emission tomography (PET; 18F-florbetapir), high-resolution structural magnetic resonance imaging (MRI), and neuropsychological assessment were analyzed. We examined relationships between biomarkers and a highly granular measure of memory consolidation, retroactive interference (RI).ResultsBiomarkers of AD pathology were related to RI. Dentate gyrus (DG) and CA3 volume were uniquely associated with RI, whereas CA1 and BA35 volume were related to both RI and overall memory recall. AD pathology was associated with reduced BA35, CA1, and subiculum volume. DG volume and Aβ were independently associated with RI, whereas CA1 volume mediated the relationship between AD pathology and RI.DiscussionIntegrity of distinct hippocampal subfields demonstrate differential relationships with pathology and memory function, indicating specificity in vulnerability and contribution to different memory processes.

BackgroundEducation is believed to contribute positively to brain structure and function, as well as to cognitive reserve. One of the brain regions most impacted by education is the medial temporal lobe (MTL), a region that houses the hippocampus, which has an important role in learning processes and in consolidation of memories, and is also known to undergo neurogenesis in adulthood. We aimed to investigate the influence of education on the absolute cell numbers of the MTL (comprised by the hippocampal formation, amygdala, and parahippocampal gyrus) of men without cognitive impairment.MethodsThe Isotropic Fractionator technique was used to allow the anisotropic brain tissue to be transformed into an isotropic suspension of nuclei, and therefore assess the absolute cell composition of the MTL. We dissected twenty-six brains from men aged 47 to 64 years, with either low or high education.ResultsA significant difference between groups was observed in brain mass, but not in MTL mass. No significant difference was found between groups in the number of total cells, number of neurons, and number of non-neuronal cells. Regression analysis showed that the total number of cells, number of neurons, and number of non-neuronal cells in MTL were not affected by education.ConclusionsThe results indicate a resilience of the absolute cellular composition of the MTL of typical men to low schooling, suggesting that the cellularity of brain regions is not affected by formal education.

Brain atrophy is associated with degenerative neuropathologies and the clinical status of dementia. Whether dementia is associated with atrophy independent of neuropathologies is not known. In this study, we examined the pattern of atrophy associated with dementia while accounting for the most common dementia-related neuropathologies. We used data from National Alzheimer's Coordinating Center (n = 129) and Alzheimer's Disease Neuroimaging Initiative (n = 47) participants with suitable in vivo 3D-T1w MRI and autopsy data. We determined dementia status at the visit closest to MRI. We examined the following dichotomized neuropathological variables: Alzheimer's disease neuropathology, hippocampal sclerosis, Lewy bodies, cerebral amyloid angiopathy and atherosclerosis. Voxel-based morphometry identified areas associated with dementia after accounting for neuropathologies. Identified regions of interest were further analysed. We used multiple linear regression models adjusted for neuropathologies and demographic variables. We also examined models with dementia and Clinical Dementia Rating sum of the boxes as the outcome and explored the potential mediating effect of medial temporal lobe structure volumes on the relationship between pathology and cognition. We found strong associations for dementia with volumes of the hippocampus, amygdala and parahippocampus (semi-partial correlations ≥ 0.28, P < 0.0001 for all regions in National Alzheimer's Coordinating Center; semi-partial correlations ≥ 0.35, P ≤ 0.01 for hippocampus and parahippocampus in Alzheimer's Disease Neuroimaging Initiative). Dementia status accounted for more unique variance in atrophy in these structures (∼8%) compared with neuropathological variables; the only exception was hippocampal sclerosis which accounted for more variance in hippocampal atrophy (10%). We also found that the volumes of the medial temporal lobe structures contributed towards explaining the variance in Clinical Dementia Rating sum of the boxes (ranging from 5% to 9%) independent of neuropathologies and partially mediated the association between Alzheimer's disease neuropathology and cognition. Even after accounting for the most common neuropathologies, dementia still had among the strongest associations with atrophy of medial temporal lobe structures. This suggests that atrophy of the medial temporal lobe is most related to the clinical status of dementia rather than Alzheimer's disease or other neuropathologies, with the potential exception of hippocampal sclerosis.

IntroductionAlthough subjective cognitive decline (SCD) may be an early risk marker of Alzheimer's Disease (AD), research on SCD among Hispanics/Latinos/as/x (henceforth Latinos/as) living in the U.S. is lacking. We investigated if the cross-sectional relationship of self-reported SCD with objective cognition varies as a function of ethnic background (Latinos/as versus Non-Hispanic Whites [NHWs]). Secondary analyses conducted solely within the Latino/a group investigated if informant reported SCD is associated with objective cognition and whether self-reported SCD is related to markers of brain health in a sub-sample of Latinos/as with available MRI data.MethodsEighty-three participants (≥60 years of age) without dementia (35 Latinos/as; 48 NHWs) completed the Mattis Dementia Rating Scale (MDRS) and the Subjective Cognitive Decline-Questionnaire (SCD-Q). Additionally, 22 Latino/a informants completed the informant-version of the SCD-Q. Hierarchical regression models investigated if ethnicity moderates the association of MDRS and SCD-Q scores after adjusting for demographics and depressive symptoms. Correlational analyses within the Latino/a group investigated self- and informant-reported associations of SCD-Q scores with objective cognition, and associations of self-reported SCD-Q scores with medial temporal lobe volume and thickness.ResultsLatinos/as had lower education and MDRS scores than NHWs. Higher SCD-Q scores were associated with lower MDRS scores only in Latinos/as. Within the Latino/a group, self, but not informant reported SCD was related to objective cognition. Medium to large effect sizes were found whereby higher self-reported SCD was associated with lower entorhinal cortex thickness and left hippocampal volume in Latinos/as.ConclusionsThe association of SCD and concurrent objectively measured global cognition varied by ethnic background and was only significant in Latinos/as. Self-reported SCD may be an indicator of cognitive and brain health in Latinos/as without dementia, prompting clinicians to monitor cognition. Future studies should explore if SCD predicts objective cognitive decline in diverse groups of Latinos/as living in the U.S.

Recent work has conceptualized the brain as a network comprised of groups of sub-networks or modules. "Flexibility" of brain network(s) indexes the dynamic reconfiguration of comprising modules. Using novel techniques from dynamic network neuroscience applied to high-resolution resting-state functional magnetic resonance imaging (fMRI), the present study investigated the effects of an aerobic exercise intervention on the dynamic rearrangement of modular community structure-a measure of neural flexibility-within the medial temporal lobe (MTL) network. The MTL is one of the earliest brain regions impacted by Alzheimer's disease. It is also a major site of neuroplasticity that is sensitive to the effects of exercise. In a two-group non-randomized, repeated measures and matched control design with 34 healthy older adults, we observed an exercise-related increase in flexibility within the MTL network. Furthermore, MTL network flexibility mediated the beneficial effect aerobic exercise had on mnemonic flexibility, as measured by the ability to generalize past learning to novel task demands. Our results suggest that exercise exerts a rehabilitative and protective effect on MTL function, resulting in dynamically evolving networks of regions that interact in complex communication patterns. These reconfigurations may underlie exercise-induced improvements on cognitive measures of generalization, which are sensitive to subtle changes in the MTL.

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.

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.

A growing body of research indicates that the medial temporal lobe (MTL) is essential not only for long-term episodic memory but also for visual working memory (VWM). In particular, recent work has shown that the MTL is especially important for VWM when complex, high-resolution binding is required. However, all of these studies tested VWM for multiple items which invites the possibility that working memory capacity was exceeded and patient impairments instead reflected deficits in long-term memory. Thus, the precise conditions under which the MTL is critical for VWM and the type of working memory processes that are affected by MTL damage are not yet clear. To address these issues, we examined the effects of MTL damage on VWM for a single item (i.e., a square that contained color, location, and orientation information) using confidence-based receiver operating characteristic methods to assess VWM discriminability and to separate perceiving- and sensing-based memory judgments. This approach was motivated by dual-process theories of cognition that posit distinct subprocesses underlie performance across perception, working memory, and long-term memory. The results indicated that MTL patients were significantly impaired in VWM for a single item. Interestingly, the patients were not impaired at making accurate high-confidence judgments that a change had occurred (i.e., perceiving), rather they were impaired at making low-confidence judgments that they sensed whether or not there had been a change in the absence of identifying the exact change. These results demonstrate that the MTL is critical in supporting working memory even for a single item, and that it contributes selectively to sensing-based discriminations.

Although a memory systems view of the medial temporal lobe (MTL) has been widely influential in understanding how memory processes are implemented, a large body of work across humans and animals has converged on the idea that the MTL can support various other decisions, beyond those involving memory. Specifically, recent work suggests that perception of and memory for visual representations may interact in order to support ongoing cognition. However, given considerations involving lesion profiles in neuropsychological investigations and the correlational nature of fMRI, the precise nature of representations supported by the MTL are not well understood in humans. In the present investigation, three patients with highly specific lesions to MTL were administered a task that taxed perceptual and mnemonic judgments with highly similar face stimuli. A striking double dissociation was observed such that I.R., a patient with a cyst localized to right posterior PRc, displayed a significant impairment in perceptual discriminations, whereas patient A.N., an individual with a lesion in right posterior parahippocampal cortex and the tail of the right hippocampus, and S.D., an individual with bilateral hippocampal damage, did not display impaired performance on the perceptual task. A.N. and S.D. did, however, show impairments in memory performance, whereas patient I.R. did not. These results causally implicate right PRc in successful perceptual oddity judgments, however they suggest that representations supported by PRc are not necessary for correct mnemonic judgments, even in situations of high featural overlap.

The posteromedial cortex (PMC) and medial temporal lobes (MTL) are two brain regions particularly vulnerable in Alzheimer's disease (AD). We have reviewed the spatiotemporal patterns of amyloid-β and tau accumulation, local MTL functional alterations and MTL-PMC network reconfiguration, and propose a model to relate these elements to each other. Functional and structural MTL-PMC disconnection happen concomitant with amyloid-β plaques and neurofibrillary tau accumulation within these same regions. Ongoing disconnection is accompanied by dysfunctional intrinsic local MTL circuit hyperexcitability, which exacerbates across distinct clinical stages of AD. Our overarching model proposes a sequence of events relating the spatiotemporal patterns of amyloid-β and tau accumulation to MTL-PMC disconnection and local MTL hyperexcitability. We hypothesize that cortical PMC amyloid-β pathology induces long-range information processing deficits through functional and structural MTL-PMC dysconnectivity at early disease stages, which in turn drives local MTL circuit hyperexcitability. Intrinsic local MTL circuit hyperexcitability subsequently accelerates local age-related tau deposition, facilitating tau spread from the MTL to the PMC, eventually resulting in extensive structural degeneration of white and grey matter as the disease advances. We hope that the present model may inform future longitudinal studies needed to test the proposed sequence of events.

Participants with stimulating and recording electrodes implanted within the brain for clinical evaluation and treatment provide a rare opportunity to unravel the neuronal correlates of human memory, as well as offer potential for modulation of behavior. Recent intracranial stimulation studies of memory have been inconsistent in methodologies employed and reported conclusions, which renders generalizations and construction of a framework impossible. In an effort to unify future study efforts and enable larger meta-analyses we propose in this mini-review a set of guidelines to consider when pursuing intracranial stimulation studies of human declarative memory and summarize details reported by previous relevant studies. We present technical and safety issues to consider when undertaking such studies and a checklist for researchers and clinicians to use for guidance when reporting results, including targeting, placement, and localization of electrodes, behavioral task design, stimulation and electrophysiological recording methods, details of participants, and statistical analyses. We hope that, as research in invasive stimulation of human declarative memory further progresses, these reporting guidelines will aid in setting standards for multicenter studies, in comparison of findings across studies, and in study replications.

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 statementRemembering 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.

The theta rhythm-a slow (6-12 Hz) oscillatory component of the local field potential-plays a critical role in spatial navigation and memory by coordinating the activity of neuronal ensembles within the medial temporal lobe (MTL). Although theta has been extensively studied in freely moving rodents, its presence in humans has been elusive and primarily investigated in stationary subjects. Here we used a unique clinical opportunity to examine theta within the human MTL during untethered, real-world ambulatory movement. We recorded intracranial electroencephalographic activity from participants chronically implanted with the wireless NeuroPace responsive neurostimulator (RNS) and tracked their motion with sub-millimeter precision. Our data revealed that movement-related theta oscillations indeed exist in humans, such that theta power is significantly higher during movement than immobility. Unlike in rodents, however, theta occurs in short bouts, with average durations of ∼400 ms, which are more prevalent during fast versus slow movements. In a rare opportunity to study a congenitally blind participant, we found that both the prevalence and duration of theta bouts were increased relative to the sighted participants. These results provide critical support for conserved neurobiological characteristics of theta oscillations during ambulatory spatial navigation, while highlighting some fundamental differences across species in these oscillations between humans and rodents.

The hippocampus is critical for episodic memory, and synaptic changes induced by long-term potentiation (LTP) are thought to underlie memory formation. In rodents, hippocampal LTP may be induced through electrical stimulation of the perforant path. To test whether similar techniques could improve episodic memory in humans, we implemented a microstimulation technique that allowed delivery of low-current electrical stimulation via 100 μm-diameter microelectrodes. As thirteen neurosurgical patients performed a person recognition task, microstimulation was applied in a theta-burst pattern, shown to optimally induce LTP. Microstimulation in the right entorhinal area during learning significantly improved subsequent memory specificity for novel portraits; participants were able both to recognize previously-viewed photos and reject similar lures. These results suggest that microstimulation with physiologic level currents-a radical departure from commonly used deep brain stimulation protocols-is sufficient to modulate human behavior and provides an avenue for refined interrogation of the circuits involved in human memory.

The hippocampus is critical for episodic memory, and synaptic changes induced by long-term potentiation (LTP) are thought to underlie memory formation. In rodents, hippocampal LTP may be induced through electrical stimulation of the perforant path. To test whether similar techniques could improve episodic memory in humans, we implemented a microstimulation technique that allowed delivery of low-current electrical stimulation via 100 μm-diameter microelectrodes. As thirteen neurosurgical patients performed a person recognition task, microstimulation was applied in a theta-burst pattern, shown to optimally induce LTP. Microstimulation in the right entorhinal area during learning significantly improved subsequent memory specificity for novel portraits; participants were able both to recognize previously-viewed photos and reject similar lures. These results suggest that microstimulation with physiologic level currents-a radical departure from commonly used deep brain stimulation protocols-is sufficient to modulate human behavior and provides an avenue for refined interrogation of the circuits involved in human memory.

IntroductionSubjective cognitive decline (SCD) is a risk factor for mild cognitive impairment (MCI) and Alzheimer's disease (AD). Although sleep has been shown to be altered in MCI and AD, little is known about sleep in SCD.MethodsSeventy cognitively normal community-dwelling participants were classified as SCD (32) or controls (38) using the Subjective Cognitive Decline Questionnaire. Sleep was assessed using actigraphy and diaries. FreeSurfer was used for performing medial temporal lobes (MTLs) and brain cortical parcellation of 3T magnetic resonance images. Multiple regression models were used to assess the presence of sleep, MTL, or regional cortical differences between groups.ResultsObjective sleep was disrupted in SCD participants, which showed increased nighttime wakefulness and reduced sleep efficiency. No group differences emerged in subjective sleep or magnetic resonance imaging outcomes.DiscussionObjective sleep resulted disrupted in community-dwelling SCD, without any subjective sleep or cortical change. Sleep assessment/intervention in SCD might help prevent/delay AD onset.

Since the earliest attempts to characterize the "receptive fields" of neurons, a central aim of many neuroscience experiments is to elucidate the information that is represented in various regions of the brain. Recent studies suggest that, in the service of memory, information is represented in the medial temporal lobe in a conjunctive or associative form with the contextual aspects of the experience being the primary factor or highest level of the conjunctive hierarchy. A critical question is whether the information that has been observed in these studies reflects notions such as a cognitive representation of context or whether the information reflects the low-level sensory differences between stimuli. We performed two functional magnetic resonance imaging experiments to address this question and we found that associative representations observed between context and item (and order) in the human brain can be highly influenced by low-level sensory differences between stimuli. Our results place clear constraints on the experimental design of studies that aim to investigate the representation of contexts and items during performance of associative memory tasks. Moreover, our results raise interesting theoretical questions regarding the disambiguation of memory-related representations from processing-related representations.

Since the earliest attempts to characterize the "receptive fields" of neurons, a central aim of many neuroscience experiments is to elucidate the information that is represented in various regions of the brain. Recent studies suggest that, in the service of memory, information is represented in the medial temporal lobe in a conjunctive or associative form with the contextual aspects of the experience being the primary factor or highest level of the conjunctive hierarchy. A critical question is whether the information that has been observed in these studies reflects notions such as a cognitive representation of context or whether the information reflects the low-level sensory differences between stimuli. We performed two functional magnetic resonance imaging experiments to address this question and we found that associative representations observed between context and item (and order) in the human brain can be highly influenced by low-level sensory differences between stimuli. Our results place clear constraints on the experimental design of studies that aim to investigate the representation of contexts and items during performance of associative memory tasks. Moreover, our results raise interesting theoretical questions regarding the disambiguation of memory-related representations from processing-related representations.

This study examines how individuals differentiate recent-single-exposure-based familiarity from pre-existing familiarity. If these are two distinct cognitive processes, are they supported by the same neural bases? This study examines how recent-single-exposure-based familiarity and multiple-previous-exposure-based familiarity are supported and represented in the brain using functional MRI. In a novel approach, we first behaviorally show that subjects can divide retrieval of items in pre-existing memory into judgments of recollection and familiarity. Then, using functional magnetic resonance imaging, we examine the differences in blood oxygen level dependent activity and regional connectivity during judgments of recent-single-exposure-based and pre-existing familiarity. Judgments of these two types of familiarity showed distinct regions of activation in a whole-brain analysis, in medial temporal lobe (MTL) substructures, and in MTL substructure functional-correlations with other brain regions. Specifically, within the MTL, perirhinal cortex showed increased activation during recent-single-exposure-based familiarity while parahippocampal cortex showed increased activation during judgments of pre-existing familiarity. We find that recent-single-exposure-based and pre-existing familiarity are represented as distinct neural processes in the brain; this is supported by differing patterns of brain activation and regional correlations. This spatially distinct regional brain involvement suggests that the two separate experiences of familiarity, recent-exposure-based familiarity and pre-existing familiarity, may be cognitively distinct.

Maintaining similar memories in a distinct and nonoverlapping manner, known as pattern separation, is an important mnemonic process. The medial temporal lobe, especially the hippocampus, has been implicated in this crucial memory function. The present study thus examines whether it is possible to modulate pattern separation using bilateral transcranial direct current stimulation (tDCS) over the temporal lobes. Specifically, in this study, pattern separation was assessed using the Mnemonic Similarity Task following 15-min offline bilateral temporal lobe tDCS (left cathode and right anode or left anode and right cathode) or sham stimulation. In the Mnemonic Similarity Task, participants studied a series of sequentially presented visual objects. In the subsequent recognition memory test, participants viewed a series of sequentially presented objects that could be old images from study, novel foils, or lures that were visually similar to the studied images. Participants reported whether these images were exactly the same as, similar to, or different from the studied images. Following both active tDCS conditions, participants were less likely to identify lures as 'similar' compared with the sham condition, indicating a reduction in pattern separation resulting from temporal lobe tDCS. In contrast, no significant difference in overall accuracy was found for participants' discrimination of old and new images. Together, these results suggest that temporal lobe tDCS can selectively modulate the pattern separation function without changing participants' baseline recognition memory performance.

It is well established that the medial temporal lobe (MTL), including the hippocampus, is essential for long-term memory. In addition, recent studies suggest that the MTL may also support visual working memory (VWM), but the conditions under which the MTL plays a critical role are not yet clear. To address this issue, we used a color change detection paradigm to examine the effects of MTL damage on VWM by analyzing the receiver operating characteristics of patients with MTL damage and healthy age- and education-matched controls. Compared to controls, patients with MTL damage demonstrated significant reductions in VWM accuracy. Importantly, the patients were not impaired at making accurate high-confidence judgments that a change had occurred; however, they were impaired when making low-confidence responses indicating that they sensed whether or not there had been a visual change. Moreover, these impairments were observed under conditions that emphasized the retrieval of complex bindings or the retrieval of high-resolution bindings. That is, patients with MTL damage exhibited VWM impairments when they were required to remember either a larger number of low-resolution bindings (i.e., set size of 5 and obvious color changes) or a smaller number of high-resolution bindings (i.e., set size of 3 and subtle color changes). The results indicate that only some VWM processes are dependent on the MTL, and are consistent with the proposal that the MTL plays a critical role in forming complex, high-resolution bindings.

Maintaining similar memories in a distinct and nonoverlapping manner, known as pattern separation, is an important mnemonic process. The medial temporal lobe, especially the hippocampus, has been implicated in this crucial memory function. The present study thus examines whether it is possible to modulate pattern separation using bilateral transcranial direct current stimulation (tDCS) over the temporal lobes. Specifically, in this study, pattern separation was assessed using the Mnemonic Similarity Task following 15-min offline bilateral temporal lobe tDCS (left cathode and right anode or left anode and right cathode) or sham stimulation. In the Mnemonic Similarity Task, participants studied a series of sequentially presented visual objects. In the subsequent recognition memory test, participants viewed a series of sequentially presented objects that could be old images from study, novel foils, or lures that were visually similar to the studied images. Participants reported whether these images were exactly the same as, similar to, or different from the studied images. Following both active tDCS conditions, participants were less likely to identify lures as 'similar' compared with the sham condition, indicating a reduction in pattern separation resulting from temporal lobe tDCS. In contrast, no significant difference in overall accuracy was found for participants' discrimination of old and new images. Together, these results suggest that temporal lobe tDCS can selectively modulate the pattern separation function without changing participants' baseline recognition memory performance.

Many aspects of the complex relationship between working memory (WM) and long-term memory (LTM) remain unclear. Here, we manipulated task demands on a brief delayed-recognition paradigm to reveal behavioral and neural dissociations between these systems. Variations from a Baseline task included 3 challenges: increased delay duration, distraction during maintenance, and more closely matched memory probes, which were presented in behavioral experiments and during functional magnetic resonance imaging. Each of the challenges resulted in a significant decline in WM accuracy, and interestingly, a concurrent improvement in incidental LTM. Neural data revealed that, in task blocks, when participants anticipated, and then experienced, increased demands, they engaged medial temporal lobe (MTL) regions more during both the encoding and delay periods. Overall, these results indicate that distinct memory systems are recruited based on anticipated demands of a memory task, and MTL involvement underlies the observed dissociation between WM and LTM performance.

Attention and memory are intricately linked, but how attention modulates brain areas that subserve memory, such as the hippocampus, is unknown. We hypothesized that attention may stabilize patterns of activity in human hippocampus, resulting in distinct but reliable activity patterns for different attentional states. To test this prediction, we utilized high-resolution functional magnetic resonance imaging and a novel "art gallery" task. On each trial, participants viewed a room containing a painting, and searched a stream of rooms for a painting from the same artist (art state) or a room with the same layout (room state). Bottom-up stimulation was the same in both tasks, enabling the isolation of neural effects related to top-down attention. Multivariate analyses revealed greater pattern similarity in all hippocampal subfields for trials from the same, compared with different, attentional state. This stability was greater for the room than art state, was unrelated to univariate activity, and, in CA2/CA3/DG, was correlated with behavior. Attention therefore induces representational stability in the human hippocampus, resulting in distinct activity patterns for different attentional states. Modulation of hippocampal representational stability highlights the far-reaching influence of attention outside of sensory systems.

Attention influences what is later remembered, but little is known about how this occurs in the brain. We hypothesized that behavioral goals modulate the attentional state of the hippocampus to prioritize goal-relevant aspects of experience for encoding. Participants viewed rooms with paintings, attending to room layouts or painting styles on different trials during high-resolution functional MRI. We identified template activity patterns in each hippocampal subfield that corresponded to the attentional state induced by each task. Participants then incidentally encoded new rooms with art while attending to the layout or painting style, and memory was subsequently tested. We found that when task-relevant information was better remembered, the hippocampus was more likely to have been in the correct attentional state during encoding. This effect was specific to the hippocampus, and not found in medial temporal lobe cortex, category-selective areas of the visual system, or elsewhere in the brain. These findings provide mechanistic insight into how attention transforms percepts into memories.

Ego-disturbances have been a topic in schizophrenia research since the earliest clinical descriptions of the disorder. Manifesting as a feeling that one's "self," "ego," or "I" is disintegrating or that the border between one's self and the external world is dissolving, "ego-disintegration" or "dissolution" is also an important feature of the psychedelic experience, such as is produced by psilocybin (a compound found in "magic mushrooms"). Fifteen healthy subjects took part in this placebo-controlled study. Twelve-minute functional MRI scans were acquired on two occasions: subjects received an intravenous infusion of saline on one occasion (placebo) and 2 mg psilocybin on the other. Twenty-two visual analogue scale ratings were completed soon after scanning and the first principal component of these, dominated by items referring to "ego-dissolution", was used as a primary measure of interest in subsequent analyses. Employing methods of connectivity analysis and graph theory, an association was found between psilocybin-induced ego-dissolution and decreased functional connectivity between the medial temporal lobe and high-level cortical regions. Ego-dissolution was also associated with a "disintegration" of the salience network and reduced interhemispheric communication. Addressing baseline brain dynamics as a predictor of drug-response, individuals with lower diversity of executive network nodes were more likely to experience ego-dissolution under psilocybin. These results implicate MTL-cortical decoupling, decreased salience network integrity, and reduced inter-hemispheric communication in psilocybin-induced ego disturbance and suggest that the maintenance of "self"or "ego," as a perceptual phenomenon, may rest on the normal functioning of these systems.

We proposed a diffeomorphometry-based statistical pipeline to study the regional shape change rates of the bilateral hippocampus, amygdala, and ventricle in mild cognitive impairment (MCI) and Alzheimer's disease (AD) compared with healthy controls (HC), using sequential magnetic resonance imaging (MRI) scans of 713 subjects (3,123 scans in total). The subgroup shape atrophy rates of the bilateral hippocampus and amygdala, as well as the expansion rates of the bilateral ventricles, for a majority of vertices were found to follow the order of AD>MCI>HC. The bilateral hippocampus and the left amygdala were subsegmented into multiple functionally meaningful subregions with the help of high-field MRI scans. The largest group differences in localized shape atrophy rates on the hippocampus were found to occur in CA1, followed by subiculum, CA2, and finally CA3/dentate gyrus, which is consistent with the neurofibrillary tangle accumulation trajectory. Highly nonuniform group differences were detected on the amygdala; vertices on the core amygdala (basolateral and lateral nucleus) revealed much larger atrophy rates, whereas those on the noncore amygdala (mainly centromedial) displayed similar or even smaller atrophy rates in AD relative to HC. The temporal horns of the ventricles were observed to have the largest localized ventricular expansion rate differences; with the AD group showing larger localized expansion rates on the anterior horn and the body part of the ventricles as well. Significant correlations were observed between the localized shape change rates of each of these six structures and the cognitive deterioration rates as quantified by the Alzheimer's Disease Assessment Scale-Cognitive Behavior Section increase rate and the Mini Mental State Examination decrease rate.

We proposed a diffeomorphometry-based statistical pipeline to study the regional shape change rates of the bilateral hippocampus, amygdala, and ventricle in mild cognitive impairment (MCI) and Alzheimer's disease (AD) compared with healthy controls (HC), using sequential magnetic resonance imaging (MRI) scans of 713 subjects (3,123 scans in total). The subgroup shape atrophy rates of the bilateral hippocampus and amygdala, as well as the expansion rates of the bilateral ventricles, for a majority of vertices were found to follow the order of AD>MCI>HC. The bilateral hippocampus and the left amygdala were subsegmented into multiple functionally meaningful subregions with the help of high-field MRI scans. The largest group differences in localized shape atrophy rates on the hippocampus were found to occur in CA1, followed by subiculum, CA2, and finally CA3/dentate gyrus, which is consistent with the neurofibrillary tangle accumulation trajectory. Highly nonuniform group differences were detected on the amygdala; vertices on the core amygdala (basolateral and lateral nucleus) revealed much larger atrophy rates, whereas those on the noncore amygdala (mainly centromedial) displayed similar or even smaller atrophy rates in AD relative to HC. The temporal horns of the ventricles were observed to have the largest localized ventricular expansion rate differences; with the AD group showing larger localized expansion rates on the anterior horn and the body part of the ventricles as well. Significant correlations were observed between the localized shape change rates of each of these six structures and the cognitive deterioration rates as quantified by the Alzheimer's Disease Assessment Scale-Cognitive Behavior Section increase rate and the Mini Mental State Examination decrease rate.

ObjectiveAn increasing number of human in vivo magnetic resonance imaging (MRI) studies have focused on examining the structure and function of the subfields of the hippocampal formation (the dentate gyrus, CA fields 1-3, and the subiculum) and subregions of the parahippocampal gyrus (entorhinal, perirhinal, and parahippocampal cortices). The ability to interpret the results of such studies and to relate them to each other would be improved if a common standard existed for labeling hippocampal subfields and parahippocampal subregions. Currently, research groups label different subsets of structures and use different rules, landmarks, and cues to define their anatomical extents. This paper characterizes, both qualitatively and quantitatively, the variability in the existing manual segmentation protocols for labeling hippocampal and parahippocampal substructures in MRI, with the goal of guiding subsequent work on developing a harmonized substructure segmentation protocol.MethodMRI scans of a single healthy adult human subject were acquired both at 3 T and 7 T. Representatives from 21 research groups applied their respective manual segmentation protocols to the MRI modalities of their choice. The resulting set of 21 segmentations was analyzed in a common anatomical space to quantify similarity and identify areas of agreement.ResultsThe differences between the 21 protocols include the region within which segmentation is performed, the set of anatomical labels used, and the extents of specific anatomical labels. The greatest overall disagreement among the protocols is at the CA1/subiculum boundary, and disagreement across all structures is greatest in the anterior portion of the hippocampal formation relative to the body and tail.ConclusionsThe combined examination of the 21 protocols in the same dataset suggests possible strategies towards developing a harmonized subfield segmentation protocol and facilitates comparison between published studies.

BackgroundThis study aimed to have international experts converge on a harmonized definition of whole hippocampus boundaries and segmentation procedures, to define standard operating procedures for magnetic resonance (MR)-based manual hippocampal segmentation.MethodsThe panel received a questionnaire regarding whole hippocampus boundaries and segmentation procedures. Quantitative information was supplied to allow evidence-based answers. A recursive and anonymous Delphi procedure was used to achieve convergence. Significance of agreement among panelists was assessed by exact probability on Fisher's and binomial tests.ResultsAgreement was significant on the inclusion of alveus/fimbria (P = .021), whole hippocampal tail (P = .013), medial border of the body according to visible morphology (P = .0006), and on this combined set of features (P = .001). This definition captures 100% of hippocampal tissue, 100% of Alzheimer's disease-related atrophy, and demonstrated good reliability on preliminary intrarater (0.98) and inter-rater (0.94) estimates.DiscussionConsensus was achieved among international experts with respect to hippocampal segmentation using MR resulting in a harmonized segmentation protocol.

Declarative memory (DM) impairments are reported in schizophrenia and in unaffected biological relatives of patients. However, the neural correlates of successful and unsuccessful encoding, mediated by the medial temporal lobe (MTL) memory system, and the influence of disease-related genetic liability remain under explored. This study employed an event-related functional MRI paradigm to compare activations for successfully and unsuccessfully encoded associative face-name stimuli between 26 schizophrenia patients (mean age: 33, 19m/7f), 30 controls (mean age: 29, 24m/6f), and 14 unaffected relatives of patients (mean age: 40, 5m/9f). Compared to controls or unaffected relatives, patients showed hyper-activations in ventral visual stream and temporo-parietal cortical association areas when contrasting successfully encoded events to fixation. Follow-up hippocampal regions-of-interest analysis revealed schizophrenia-related hyper-activations in the right anterior hippocampus during successful encoding; contrasting successful versus unsuccessful events produced schizophrenia-related hypo-activations in the left anterior hippocampus. Similar hippocampal hypo-activations were observed in unaffected relatives during successful versus unsuccessful encoding. Post hoc analyses of hippocampal volume showed reductions in patients, but not in unaffected relatives compared to controls. Findings suggest that DM encoding deficits are attributable to both disease-specific and genetic liability factors that impact different components of the MTL memory system. Hyper-activations in temporo-occipital and parietal regions observed only in patients suggest the influence of disease-related factors. Regional hyper- and hypo-activations attributable to successful encoding occurring in both patients and unaffected relatives suggest the influence of schizophrenia-related genetic liability factors.

IntroductionThe medial temporal lobe supports integrating the “what,” “where,” and “when” of an experience into a unified memory. However, it remains unclear how representations of these contextual features are neurally encoded and distributed across medial temporal lobe subregions.MethodsThis study conducted functional magnetic resonance imaging of the medial temporal lobe, while participants retrieved pair, spatial, and temporal source memories. Multivoxel classifiers were trained to distinguish between retrieval conditions before and after correction for mean signal and response times, to more thoroughly characterize the multivoxel signal associated with memory context.ResultsActivity in perirhinal and parahippocampal cortex dissociated between memory for associated items and memory for their spatiotemporal context, and hippocampal activity was linked to memory for spatial context. However, perirhinal and hippocampal classifiers were, respectively, driven by effects of mean signal amplitude and task difficulty, whereas the parahippocampal classifier survived correction for these effects.ConclusionThese findings demonstrate dissociable coding mechanisms for episodic memory context across the medial temporal lobe, and further highlight a critical distinction between multivoxel representations driven by spatially distributed activity patterns, and those driven by the regional signal.

Rare autosomal dominant mutations result in familial Alzheimer's disease (FAD) with a relatively consistent age of onset within families. This provides an estimate of years until disease onset (relative age) in mutation carriers. Increased AD risk has been associated with differences in functional magnetic resonance imaging (fMRI) activity during memory tasks, but most of these studies have focused on possession of apolipoprotein E allele 4 (APOE4), a risk factor, but not causative variant, of late-onset AD. Evaluation of fMRI activity in presymptomatic FAD mutation carriers versus noncarriers provides insight into preclinical changes in those who will certainly develop AD in a prescribed period of time. Adults from FAD mutation-carrying families (nine mutation carriers, eight noncarriers) underwent fMRI scanning while performing a memory task. We examined fMRI signal differences between carriers and noncarriers, and how signal related to fMRI task performance within mutation status group, controlling for relative age and education. Mutation noncarriers had greater retrieval period activity than carriers in several AD-relevant regions, including the left hippocampus. Better performing noncarriers showed greater encoding period activity including in the parahippocampal gyrus. Poorer performing carriers showed greater retrieval period signal, including in the frontal and temporal lobes, suggesting underlying pathological processes.

Rare autosomal dominant mutations result in familial Alzheimer's disease (FAD) with a relatively consistent age of onset within families. This provides an estimate of years until disease onset (relative age) in mutation carriers. Increased AD risk has been associated with differences in functional magnetic resonance imaging (fMRI) activity during memory tasks, but most of these studies have focused on possession of apolipoprotein E allele 4 (APOE4), a risk factor, but not causative variant, of late-onset AD. Evaluation of fMRI activity in presymptomatic FAD mutation carriers versus noncarriers provides insight into preclinical changes in those who will certainly develop AD in a prescribed period of time. Adults from FAD mutation-carrying families (nine mutation carriers, eight noncarriers) underwent fMRI scanning while performing a memory task. We examined fMRI signal differences between carriers and noncarriers, and how signal related to fMRI task performance within mutation status group, controlling for relative age and education. Mutation noncarriers had greater retrieval period activity than carriers in several AD-relevant regions, including the left hippocampus. Better performing noncarriers showed greater encoding period activity including in the parahippocampal gyrus. Poorer performing carriers showed greater retrieval period signal, including in the frontal and temporal lobes, suggesting underlying pathological processes.

Memory formation is known to be critically dependent upon the medial temporal lobe (MTL). Despite this well-characterized role, it remains unclear whether and how MTL encoding processes are affected by top-down goal states. Here, we examined the manner in which task demands at encoding affect MTL activity and its relation to subsequent memory performance. Participants were scanned using high-resolution neuroimaging of the MTL while engaging in two incidental encoding tasks: one that directed participants' attention to stimulus distinctiveness, and the other requiring evaluation of similarities across stimuli. We hypothesized that attending to distinctiveness would lead to the formation of more detailed memories and would more effectively engage the hippocampal circuit than attending to similarity. In line with our hypotheses, higher rates of subsequent recollection were observed for stimuli studied under the Distinctiveness than Similarity task. Critically, within the hippocampus, CA1 and the subiculum demonstrated an interaction between memory performance and task such that a significant subsequent memory effect was found only when task goals required attention to stimulus distinctiveness. To this end, robust engagement of the hippocampal circuit may underlie the observed behavioral benefits of attending to distinctiveness. Taken together, these findings advance understanding of the effects of top-down intentional information on successful memory formation across subregions of the MTL.

Memory formation is known to be critically dependent upon the medial temporal lobe (MTL). Despite this well-characterized role, it remains unclear whether and how MTL encoding processes are affected by top-down goal states. Here, we examined the manner in which task demands at encoding affect MTL activity and its relation to subsequent memory performance. Participants were scanned using high-resolution neuroimaging of the MTL while engaging in two incidental encoding tasks: one that directed participants' attention to stimulus distinctiveness, and the other requiring evaluation of similarities across stimuli. We hypothesized that attending to distinctiveness would lead to the formation of more detailed memories and would more effectively engage the hippocampal circuit than attending to similarity. In line with our hypotheses, higher rates of subsequent recollection were observed for stimuli studied under the Distinctiveness than Similarity task. Critically, within the hippocampus, CA1 and the subiculum demonstrated an interaction between memory performance and task such that a significant subsequent memory effect was found only when task goals required attention to stimulus distinctiveness. To this end, robust engagement of the hippocampal circuit may underlie the observed behavioral benefits of attending to distinctiveness. Taken together, these findings advance understanding of the effects of top-down intentional information on successful memory formation across subregions of the MTL.

Healthy aging is marked by declines in a variety of cognitive and motor abilities. A better understanding of the aging brain may aid in elucidating the neural substrates of these behavioral effects. Investigations of resting state functional brain connectivity have provided insights into pathology, and to some degree, healthy aging. Given the role of the cerebellum in both motor and cognitive behaviors, as well as its known volumetric declines with age, investigating cerebellar networks may shed light on the neural bases of age-related functional declines. We mapped the resting state networks of the lobules of the right hemisphere and the vermis of the cerebellum in a group of healthy older adults and compared them to those of young adults. We report disrupted cortico-cerebellar resting state network connectivity in older adults. These results remain even when controlling for cerebellar volume, signal-to-noise ratio, and signal-to-fluctuation noise ratio. Specifically, there was consistent disruption of cerebellar connectivity with both the striatum and the medial temporal lobe. Associations between connectivity strength and both sensorimotor and cognitive task performance indicate that cerebellar engagement with the default mode network and striatal pathways is associated with better performance for older adults. These results extend our understanding of the resting state networks of the aging brain to include cortico-cerebellar networks, and indicate that age differences in network connectivity strength are important for behavior.

Three studies examined amnesic H.M.'s use of words, phrases, and propositions on the Test of Language Competence (TLC). In Study 1, H.M. used 19 lexical categories (e.g., common nouns, verbs) and one syntactic category (noun phrases) with the same relative frequency as memory-normal controls, he used no lexical or syntactic category with less-than-normal frequency, and he used proper names (e.g., Melanie) and coordinative conjunctions (e.g., and) with reliably greater-than-normal frequency. In Study 2, H.M. overused proper names relative to controls when answering episodic memory questions about childhood experiences in speech and writing, replicating and extending Study 1 results for proper names. Based on detailed analyses of the use (and misuse) of coordinating conjunctions on the TLC, Study 3 developed a syntax-level "compensation hypothesis" for explaining why H.M. overused coordinating conjunctions relative to controls in Study 1. Present results suggested that (a) frontal mechanisms for retrieving word-, phrase-, and propositional-categories are intact in H.M., unlike in category-specific aphasia, (b) using his intact retrieval mechanisms, H.M. has developed a never-previously-observed proposition-level free association strategy to compensate for the hippocampal region damage that has impaired his mechanisms for encoding novel linguistic structures, and (c) H.M.'s overuse of proper names warrants further research.

Medial temporal atrophy is a well-established marker for Alzheimer’s disease (AD). However, due to normal variation in the size of medial temporal structures and variability in how radiologists interpret images, the use of clinical reads in establishing the presence of pathological atrophy is imprecise. A limitation of studies of magnetic resonance imaging (MRI) measures in AD is diagnostic uncertainty as it can be unknown if pre- or early-symptomatic subjects go on to develop AD and most subjects do not undergo autopsy verification of the diagnosis. In persons with or at-risk for AD due to fully-penetrant autosomal dominant mutations in the PSEN1 and APP genes, the diagnosis or future development of AD can be predicted with essentially 100% accuracy. We used this predictability to assess the ability of radiologists to detect hippocampal atrophy (HA) in persons destined to develop AD. Coronal T1-weighted MRI scans of 39 persons demented from (n = 4) or at-risk for inheriting (n = 35) PSEN1 or APP mutations were independently assessed by two radiologists and the presence or absence of HA determined. Of the 39 subjects, 26 were FAD mutation carriers. Fifteen of 28 asymptomatic at-risk persons were FAD mutation carriers and four of these were rated as having atrophy for a sensitivity of 27% and a specificity of 85%. Among seven mildly affected yet non-demented subjects, atrophy was detected in three and in the four demented subjects HA was identified in two. Our results suggest that radiologists’ ability to detect HA in persons in whom the diagnosis of incipient AD is certain is sub-optimal and quantitative MRI techniques or other biological markers of the disease are needed.

A substantial and growing body of evidence from cognitive neuroscience supports the concept of multiple memory systems (MMS). However, the existence of multiple systems has been questioned by theorists who instead propose that dissociations can be accounted for within a single memory system. We present convergent evidence from neuroimaging and neuro psycho logical studies of category learning in favor of the existence of MMS for category learning and declarative knowledge. Whereas single-system theorists have argued that their approach is more parsimonious because it only postulates a single form of memory representation, we show that the MMS approach is superior in its ability to account for a broad range of data from psychology and neuroscience. (c) 2007 Elsevier Ltd. All rights reserved.