Episodic autobiographical memory in amnestic mild cognitive impairment: What are the neural correlates?

Autobiographical memory in amnestic Mild Cognitive Impairment (aMCI) is characterized by impaired retrieval of episodic memories, but relatively preserved personal semantic knowledge. This study aimed to identify (via FDG‐PET) the neural substrates of impaired episodic specificity of autobiographical memories in 35 aMCI patients compared with 24 healthy elderly controls. Significant correlations between regional cerebral activity and the proportion of episodic details in autobiographical memories from two life periods were found in specific regions of an autobiographical brain network. In aMCI patients, more than in controls, specifically episodic memories from early adulthood were associated with metabolic activity in the cuneus and in parietal regions. We hypothesized that variable retrieval of episodic autobiographical memories in our aMCI patients would be related to their variable capacity to reactivate specific sensory‐perceptual and contextual details of early adulthood events linked to reduced (occipito‐parietal) visual imagery and less efficient (parietal) attentional processes. For recent memories (last year), a correlation emerged between the proportion of episodic details and activity in lateral temporal regions and the temporo‐parietal junction. Accordingly, variable episodic memory for recent events may be related to the efficiency of controlled search through general events likely to provide cues for the retrieval of episodic details and to the ability to establish a self perspective favouring recollection. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.     

Hippocampal formation alterations differently contribute to autobiographic memory deficits in mild cognitive impairment and Alzheimer's disease

Autobiographical memory (AM) is part of declarative memory and includes both semantic and episodic aspects. AM deficits are among the major complaints of patients with Alzheimer's disease (AD) even in early or preclinical stages. Previous MRI studies in AD patients have showed that deficits in semantic and episodic AM are associated with hippocampal alterations. However, the question which specific hippocampal subfields and adjacent extrahippocampal structures contribute to deficits of AM in individuals with mild cognitive impairment (MCI) and AD patients has not been investigated so far. Hundred and seven participants (38 AD patients, 38 MCI individuals and 31 healthy controls [HC]) underwent MRI at 3 Tesla. AM was assessed with a semi‐structured interview (E‐AGI). FreeSurfer 5.3 was used for hippocampal parcellation. Semantic and episodic AM scores were related to the volume of 5 hippocampal subfields and cortical thickness in the parahippocampal and entorhinal cortex. Both semantic and episodic AM deficits were associated with bilateral hippocampal alterations. These associations referred mainly to CA1, CA2‐3, presubiculum, and subiculum atrophy. Episodic, but not semantic AM loss was associated with cortical thickness reduction of the bilateral parahippocampal and enthorinal cortex. In MCI individuals, episodic, but not semantic AM deficits were associated with alterations of the CA1, presubiculum and subiculum. Our findings support the crucial role of CA1, presubiculum, and subiculum in episodic memory. The present results implicate that in MCI individuals, semantic and episodic AM deficits are subserved by distinct neuronal systems.     

Characterizing the role of the hippocampus during episodic simulation and encoding

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.     

Exploring the roles of the executive and short-term feature-binding functions in retrieval of retrograde autobiographical memories in severe traumatic brain injury

Conway’s autobiographical memory (AM) model postulates that memories are not stored in a crystallised form in long-term memory but are reconstructed at time of retrieval via executive and binding processes, to create a temporary multimodal representation from different AM knowledge. Traumatic brain injury (TBI) impairs AM recollection. However, no study has yet considered the distinct roles of executive and short-term feature-binding functions in the retrieval deficits of retrograde AMs after TBI. Examining a group of 33 TBI patients and 33 controls, our study addresses these roles through a first-ever exploration of the links between performance on an AM verbal fluency evaluation that distinguishes four levels of representation, from semantic to episodic (lifetime periods, general events, specific events, specific details of a specific event), and three executive functions (shifting, inhibition and updating) and two short-term feature-binding functions (short-term formation and maintenance of multimodal representations). The results showed that TBI patients were impaired compared to controls in the retrieval of both semantic and episodic retrograde AM representations, but especially for the most episodic level of AM, in the three executive functions and the short-term maintenance of multimodal representations. Regression analyses indicated that the executive predictors (mainly updating) mediated a large proportion (over 70%) of TBI-related deficit on the retrieval of lifetime periods, general events and specific events, in contrast with the main impairment on generation of specific details which were only mildly (just 12%) predicted by the short-term maintenance of multimodal representations. Additional analyses in a subgroup of patients point to episodic memory abilities and time since injury in predicting the retrieval of specific events and details. In summary, the present study mainly emphasizes that the executive deficits in TBI are involved in the disruption of the first levels of AM generative processes that give access to the multiple episodic details recollection.     

Hippocampal hemispheric and long‐axis differentiation of stimulus content during episodic memory encoding and retrieval: An activation likelihood estimation meta‐analysis

While there is ample evidence that the hippocampus is functionally heterogeneous along its longitudinal axis, there is still no consensus regarding its exact organization. Whereas spatial memory tasks frequently engage the posterior hippocampus, the regions engaged during episodic memory are more varying and may depend on the specific nature of the stimuli. Here, we investigate the effect of stimulus content on the location of hippocampal recruitment during episodic memory encoding and retrieval of pictorial and verbal material with a meta‐analysis approach, using activation likelihood estimation and restricting the analysis to the hippocampus. Verbal material was associated with left‐lateralized anterior activation, compared to pictorial material that recruited a more posterior aspect of the hippocampus, primarily within the right hemisphere. This effect held for encoding of both single items and item–item associations but was less clear during retrieval. The findings lend further support to a functional subdivision of the hippocampus along its longitudinal axis and indicate that the content of episodic memories is one factor that determines the location of hippocampal recruitment. © 2015 Wiley Periodicals, Inc.     

Hippocampal morphology and autobiographic memory in mild cognitive impairment and Alzheimer's disease

Autobiographical memory (AM) comprises memories of one's own past that are characterized by a sense of subjective time and autonoetic awareness. AM deficits are among the major complaints of patients with Alzheimer's disease (AD) even in early or preclinical stages. However, little is known on the association between cerebral alterations and AM in mild cognitive impairment (MCI) and AD. In the current study, patients with AD or MCI and healthy controls underwent high-resolution magnetic resonance imaging (MRI) and neuropsychological testing including semi-structured assessment of semantic and episodic AM of distinct lifetime periods. In MRI analysis, FSL-FIRST was used to automatically ascertain volume and shape of the hippocampal formation. Episodic, but not semantic AM loss was associated with morphological changes of the hippocampus, primarily involving the left hemisphere. According to shape analyses, these associations referred to regionally specific rather than global atrophy of the hippocampus. Our study demonstrates that loss of episodic AM early in the course of AD is associated with regionally confined hippocampal atrophy, thus supporting the multiple trace theory for the role of the hippocampus in episodic AM. Our findings are not only relevant for the understanding of memory function, but may also contribute to facilitating the early diagnosis of AD.     

Reminders activate the prefrontal‐medial temporal cortex and attenuate forgetting of event memory

Replicas of an aspect of an experienced event can serve as effective reminders, yet little is known about the neural basis of such reminding effects. Here we examined the neural activity underlying the memory‐enhancing effect of reminders 1 week after encoding of naturalistic film clip events. We used fMRI to determine differences in network activity associated with recently reactivated memories relative to comparably aged, non‐reactivated memories. Reminders were effective in facilitating overall retrieval of memory for film clips, in an all‐or‐none fashion. Prefrontal cortex and hippocampus were activated during both reminders and retrieval. Peak activation in ventro‐lateral prefrontal cortex (vPFC) preceded peak activation in the right hippocampus during the reminders. For film clips that were successfully retrieved after 7 days, pre‐retrieval reminders did not enhance the quality of the retrieved memory or the number of details retrieved, nor did they more strongly engage regions of the recollection network than did successful retrieval of a non‐reminded film clip. These results suggest that reminders prior to retrieval are an effective means of boosting retrieval of otherwise inaccessible episodic events, and that the inability to recall certain events after a delay of a week largely reflects a retrieval deficit, rather than a storage deficit for this information. The results extend other evidence that vPFC drives activation of the hippocampus to facilitate memory retrieval and scene construction, and show that this facilitation also occurs when reminder cues precede successful retrieval attempts. The time course of vPFC‐hippocampal activity during the reminder suggests that reminders may first engage schematic information meditated by vPFC followed by a recollection process mediated by the hippocampus.     

Reduced specificity of autobiographical memory and aging: Do the executive and feature binding functions of working memory have a role?

Autobiographical memory (AM) is built up from various kinds of knowledge, from general to specific, via generative processes. Aging seems to particularly affect the episodic autobiographical information while preserving information that is more semantic. However, the mechanism of this deficit has not yet been thoroughly tested in relation to working memory. This study is designed to investigate, in a group of 100 subjects, the relationships between age, accessibility to different levels of AM specificity, and two main components of working memory: the central executive and the episodic buffer. We used a new task composed of four embedded verbal autobiographical fluencies (VAF) - from low to highest specificity levels - exploring lifetime periods, general events, specific events, and details, plus tasks exploring free recall of episodic AM and updating, shifting, inhibition, and feature binding in working memory. The results demonstrate that age-related difficulties increase with level of specificity of autobiographical knowledge, i.e., from semantic to episodic aspects. Moreover, regression analyses mainly show that increase in age-related deficit with level of specificity of AM is largely mediated by performance on executive functions (updating and inhibition) and to a lesser extent feature binding in working memory. The results confirm in episodic AM the executive/working memory aging hypothesis, and for the first time highlight the role of episodic buffer in associating the various different details of specific events that elicit the conscious recollection.     

Dissociating the “retrieval success” regions of the brain: Effects of retrieval delay

There is abundant evidence that the hippocampal formation critically supports episodic memory retrieval, the remembering of episodes including contextual details. Yet, a group of other brain regions has also been consistently implicated in successful episodic retrieval. This retrieval success network (RSN) includes the posterior midline region, medial prefrontal cortex (mPFC), and posterior parietal cortex (PPC). Despite these consistent findings, the functional roles of the RSN regions remain poorly understood. Given that vivid remembering leads to high-confidence retrieval decisions, it is unclear whether activity in these regions reflects episodic long-term memory, or is merely associated with retrieval confidence. In order to distinguish between these alternatives, we manipulated study-test delays within the context of a continuous recognition task during fMRI-scanning. The design was based on previous evidence indicating that retrieval at short delays is easier leading to high-evidence mnemonic decisions, whereas retrieval at longer delays is more difficult but also more hippocampus-dependent. Confirming previous findings, we found that retrieval decisions at short delays were more accurate and faster, and that the hippocampus showed greater activity at longer delays. Within the other RSN regions, we found three distinct activation patterns as a function of delay. Similar to the hippocampus, the retrosplenial cortex showed increased activity as a function of retrieval delay. Dorsal PPC and the precuneus showed decreased activity. Finally, the posterior cingulate, medial PFC and ventral PPC showed a V-shaped pattern. These findings support the idea that dorsal PPC and the precuneus are involved in decision-related retrieval processes rather than successful remembering.     

Development of memory for spatial context: Hippocampal and cortical contributions

The goal of the present study was to examine age-related differences in hippocampal and cortical contribution to episodic retrieval of spatial context in 3 age groups. Children ages 8–9 and 10–11 years old, and adults ages 18–25 (N=48) encoded black and white line drawings appearing either on the right side or the left side of a screen. Functional magnetic resonance imaging (fMRI) data were acquired while participants attempted to recall where each studied drawing had originally appeared. Correct recall of spatial source indicated successful episodic retrieval of spatial context. Activity in head and body of the hippocampus was associated with episodic retrieval in adults, but not in children. In children, individual differences in hippocampal activation for recognition predicted rates of correct spatial recall. Developmental differences were also found in regions in posterior parietal cortex, anterior prefrontal cortex, and insula. Overall, these results support the view that the development of episodic memory is supported by functional changes in the hippocampus as well as cortical regions.     

Effortful retrieval reduces hippocampal activity and impairs incidental encoding

Functional imaging studies frequently report that the hippocampus is engaged by successful episodic memory retrieval. However, considering that concurrent encoding of the background environment occurs during retrieval and influences medial temporal lobe activity, it is plausible that hippocampal encoding functions are reduced with increased attentional engagement during effortful retrieval. Expanding upon evidence that retrieval efforts suppress activity in hippocampal regions implicated in encoding, this study examines the influence of retrieval effort on encoding performance and the interactive effects of encoding and retrieval on hippocampal and neocortical activity. Functional magnetic resonance imaging was conducted while subjects performed a word recognition task with incidental picture encoding. Both lower memory strength and increased search duration were associated with encoding failure and reduced hippocampal and default network activity. Activity in the anterior hippocampus tracked encoding, which was more strongly deactivated when incidental encoding was unsuccessful. These findings highlight potential contributions from background encoding processes to hippocampal activations during neuroimaging studies of episodic memory retrieval. © 2013 Wiley Periodicals, Inc.     

Hippocampal activation during episodic and semantic memory retrieval: comparing category production and category cued recall

Whether or not the hippocampus participates in semantic memory retrieval has been the focus of much debate in the literature. However, few neuroimaging studies have directly compared hippocampal activation during semantic and episodic retrieval tasks that are well matched in all respects other than the source of the retrieved information. In Experiment 1, we compared hippocampal fMRI activation during a classic semantic memory task, category production, and an episodic version of the same task, category cued recall. Left hippocampal activation was observed in both episodic and semantic conditions, although other regions of the brain clearly distinguished the two tasks. Interestingly, participants reported using retrieval strategies during the semantic retrieval task that relied on autobiographical and spatial information; for example, visualizing themselves in their kitchen while producing items for the category kitchen utensils. In Experiment 2, we considered whether the use of these spatial and autobiographical retrieval strategies could have accounted for the hippocampal activation observed in Experiment 1. Categories were presented that elicited one of three retrieval strategy types, autobiographical and spatial, autobiographical and nonspatial, and neither autobiographical nor spatial. Once again, similar hippocampal activation was observed for all three category types, regardless of the inclusion of spatial or autobiographical content. We conclude that the distinction between semantic and episodic memory is more complex than classic memory models suggest.     

Gamma oscillations during episodic memory processing provide evidence for functional specialization in the longitudinal axis of the human hippocampus

The question of whether the anterior and posterior hippocampus serve different or complementary functional roles during episodic memory processing has been motivated by noteworthy findings in rodent experiments and from noninvasive studies in humans. Researchers have synthesized these data to postulate several models of functional specialization, However, the issue has not been explored in detail using direct brain recordings. We recently published evidence that theta power increases during episodic memory encoding occur in the posterior hippocampus in humans. In our current investigation we analyzed an expanded data set of 32 epilepsy patients undergoing stereo EEG seizure mapping surgery with electrodes precisely targeted to the anterior and posterior hippocampus simultaneously who performed an episodic memory task. Using a repeated measures design, we looked for an interaction between encoding versus retrieval differences in gamma oscillatory power and anterior versus posterior hippocampal location. Our findings are consistent with a recently articulated model (the HERNET model) favoring posterior hippocampal activation during retrieval related processing. We also tested for encoding versus retrieval differences in the preferred gamma frequency band (high versus low gamma oscillations) motivated by published rodent data.     

Reliving lifelong episodic autobiographical memories via the hippocampus: a correlative resting PET study in healthy middle-aged subjects

We aimed at identifying the cerebral structures whose synaptic function subserves the recollection of lifetime's episodic autobiographical memory (AM) via autonoetic consciousness. Twelve healthy middle-aged subjects (mean age: 59 years +/- 2.5) underwent a specially designed cognitive test to assess the ability to relive richly detailed episodic autobiographical memories from five time periods using the Remember/Know procedure. We computed an index of episodicity (number of Remember responses justified by the recall of specific events and details) and an index of retrieval spontaneity, and additionally an index of semanticized memories (number of Know responses). The regional cerebral blood flow (rCBF) was measured in the resting state, with H(2)O(15) as part of an activation PET study. The indexes were correlated with blood flow using volumes of interest in frontotemporal regions, including hippocampus and voxel-wise analyses in SPM. With both analyses, significant correlations were mainly found between the index of episodicity and rCBF in the medial temporal lobe, including hippocampus, across the five time periods (unlike the index of semanticized memories) and between the spontaneity index and rCBF in the prefrontal areas. These results highlight, in healthy subjects, the distinct role of these two structures in AM retrieval and support the view that the hippocampus is needed for reexperiencing detailed episodic memories no matter how old they are.     

Event conjunction: How the hippocampus integrates episodic memories across event boundaries

Our lives are a continuous stream of experience. Our episodic memories on the other hand have a definitive beginning, middle, and end. Theories of event segmentation suggest that salient changes in our environment produce event boundaries which partition the past from the present and, as a result, produce discretized memories. However, event boundaries cannot completely discretize two memories; any shared conceptual link will lead to the rapid integration of these memories. Here, we present a new framework inspired by electrophysiological research that resolves this apparent contradiction. At its heart, the framework proposes that hippocampal theta‐gamma coupling maintains a highly abstract model of an ongoing event and serves to encode this model as an episodic memory. When a second but related event begins, this theta‐gamma model is rapidly reconstructed within the hippocampus where new details of the second event can be appended to the existing event model. The event conjunction framework is the first electrophysiological explanation of how event memories can be formed at, and integrated across, event boundaries.     

Neuropsychological correlates of hippocampal and rhinal cortex volumes in patients with mesial temporal sclerosis

Considerable progress has been made toward understanding the function of the primate rhinal cortex, comprising the entorhinal (ErC) and perirhinal (PrC) cortices. However, translating animal models to human memory has been limited by the technological problems associated with characterizing neural structures in vivo. Functional correlates of hippocampal and rhinal cortex volume changes were examined in a sample of 61 temporal lobe epilepsy patients with mesial temporal sclerosis (MTS; 33 left, 28 right). Patients were administered the Wechsler Adult Intelligence Scale (revised or third edition), the Wechsler Memory Scale (revised or third edition), and a spatial maze task. Neuropsychological data, together with rhinal cortex and hippocampal volumes, collected in our earlier study (O'Brien CE, Bowden SC, Whelan G, Cook MJ, unpublished observations), were analyzed using multiple regression. The only significant predictor of verbal memory function was the difference score between the volume of left hippocampus and the left PrC. Spatial maze scores were predicted by the bilateral sum of ErC volume. The difference score between the left hippocampus and left PrC volumes was the most powerful predictor of verbal episodic memory. Right hippocampal volume was not a significant predictor of nonverbal episodic memory. Verbal and nonverbal semantic memory were not significantly predicted by any combination of rhinal cortex structures. This quantitative study suggests a lateralized or material-specific memory function for the left hippocampus and left PrC, in contrast to the bilateral role of the ErC. The left hippocampus and left PrC appear to act on verbal memory function through an opposing relationship. Finally, differentiation between hippocampal and subhippocampal components in terms of episodic and semantic memory, respectively, could not be supported by the current data.     

Regional analysis of hippocampal activation during memory encoding and retrieval: fMRI study

Investigators have recently begun to examine the differential role of subregions of the hippocampus in episodic memory. Two distinct models have gained prominence in the field. One model, outlined by Moser and Moser (Hippocampus 1998;8:608-619), based mainly on animal studies, has proposed that episodic memory is subserved by the posterior two-thirds of the hippocampus alone. A second model, derived by Lepage et al. (Hippocampus 1998;8:313-322) from their review of 52 PET studies, has suggested that the anterior hippocampus is activated by memory encoding while the posterior hippocampus is activated by memory retrieval. Functional magnetic resonance imaging (fMRI) studies have tended to show limited activation in the anteriormost regions of the hippocampus, providing support for the Moser and Moser model. A potential confounding factor in these fMRI studies, however, is that susceptibility artifact may differentially reduce signal in the anterior versus the posterior hippocampus. In the present study, we examined activation differences between hippocampal subregions during encoding and retrieval of words and interpreted our findings within the context of these two models. We also examined the extent to which susceptibility artifact affects the analysis and interpretation of hippocampal activation by demonstrating its differential effect on the anterior versus the posterior hippocampus. Both voxel-by-voxel and region-of-interest analyses were conducted, allowing us to quantify differences between the anterior and posterior aspects of the hippocampus. We detected significant hippocampal activation in both the encoding and retrieval conditions. Our data do not provide evidence for regional anatomic differences in activation between encoding and retrieval. The data do suggest that, even after accounting for susceptibility artifact, both encoding and retrieval of verbal stimuli activate the middle and posterior hippocampus more strongly than the anterior hippocampus. Finally, this study is the first to quantify the effects of susceptibility-induced signal loss on hippocampal activation and suggests that this artifact has significantly biased the interpretation of earlier fMRI studies.     

Patterns of autobiographical memory loss in medial-temporal lobe amnesic patients

The issue of whether the hippocampus and related structures in the medial-temporal lobe (MTL) play a temporary or permanent role in autobiographical episodic memory remains unresolved. One long-standing belief is that autobiographical memory (AM), like semantic memory, is initially dependent on the MTL but ultimately can be retained and recovered independently of it. However, evidence that hippocampal amnesia results in severe loss of episodic memory for a lifetime of personally experienced events suggests otherwise. To test the opposing views, we conducted detailed investigations of autobiographical episodic memory in people with amnesia resulting from MTL lesions of varying extent. By combining precise quantification of MTL and neocortical volumes with sensitive measures of recollection of one's personal past, we show that the severity of episodic, but not semantic, AM loss is best accounted for by the degree of hippocampal damage and less likely related to additional neocortical compromise.     

Segregating cognitive functions within hippocampal formation: A quantitative meta‐analysis on spatial navigation and episodic memory

The most important cognitive domains where hippocampal formation is crucially involved are navigation and memory. Some evidence suggests that different hippocampal subregions mediate these domains. However, a quantitative meta‐analysis on neuroimaging studies of spatial navigation versus memory is lacking. By means of activation likelihood estimation (ALE), we investigate concurrence of brain regions activated during spatial navigation encoding and retrieval as well as during episodic memory encoding and retrieval tasks in humans. During encoding in spatial navigation, activity was located in more posterior regions of the hippocampal formation, whereas episodic memory encoding was located in more anterior regions. Retrieval in spatial navigation was more strongly lateralized to the right compared to episodic memory retrieval. Within studies on spatial navigation retrieval, immediate recall was located more posterior and delayed recall more anterior. Overlap between concurrence of activation in spatial navigation and episodic memory was rather limited in comparison to uniquely involved regions. This argues in favor of two distinct networks, one for spatial navigation the other for episodic memory within the hippocampal formation. Hum Brain Mapp 35:1129–1142, 2014. © 2013 Wiley Periodicals, Inc.