Hippocampal complex and retrieval of recent and very remote autobiographical memories: evidence from functional magnetic resonance imaging in neurologically intact people.

It has been argued that the role of the hippocampus in memory is time-limited: during a period of memory consolidation, other brain regions such as the neocortex are said to acquire the ability to support memory retention and retrieval on their own. An alternative view is that retention and retrieval of memory for autobiographical episodes depend on the hippocampal complex, regardless of the age of the memory. We examined the participation of the hippocampal complex in a functional magnetic resonance imaging (fMRI) study in which participants were asked to recollect autobiographical events that occurred either within the last 4 years or more than 20 years ago. We found equivalent levels of hippocampal activation in both conditions in all participants (N = 10). In addition, activation in neocortical regions did not differ as a function of the age of the memory, even though most of the recent memories recalled were less than 2 years old and the remote memories more than 35 years old. The results support the notion that the hippocampal complex participates in retention and recovery of even very old autobiographical memories, and place boundary conditions on theories of memory consolidation.     

Patterns of hippocampal–neocortical interactions in the retrieval of episodic autobiographical memories across the entire life‐span of aged adults

We previously demonstrated that episodic autobiographical memories (EAMs) rely on a network of brain regions comprising the medial temporal lobe (MTL) and distributed neocortical regions regardless of their remoteness. The findings supported the model of memory consolidation, which proposes a permanent role of MTL during EAM retrieval (multiple‐trace theory or MTT) rather than a temporary role (standard model). Our present aim was to expand the results by examining the interactions between the MTL and neocortical regions (or MTL–neocortical links) during EAM retrieval with varying retention intervals. We used an experimental paradigm specially designed to engage aged participants in the recollection of EAMs, extracted from five different time‐periods, covering their whole life‐span, in order to examine correlations between activation in the MTL and neocortical regions. The nature of the memories was checked at debriefing by means of behavioral measures to control the degree of episodicity and properties of memories. Targeted correlational analyses carried out on the MTL, frontal, lateral temporal, and posterior regions revealed strong links between the MTL and neocortex during the retrieval of both recent and remote EAMs, challenging the standard model of memory consolidation and supporting MTT instead. Further confirmation was given by results showing that activation in the left and right hippocampi significantly correlated during the retrieval of both recent and remote memories. Correlations among extra‐MTL neocortical regions also emerged for all time‐periods, confirming the critical role of the prefrontal, temporal (lateral temporal cortex and temporal pole), precuneus, and posterior cingulate regions in EAM retrieval. Overall, this paper emphasizes the role of a bilateral network of MTL and neocortical areas whose activation correlate during the recollection of rich phenomenological recent and remote EAMs. © 2009 Wiley‐Liss, Inc.     

Smell your memories: Positive effect of odor exposure on recent and remote autobiographical memories in Alzheimer’s disease

Introduction: There is a burgeoning interest in the effects of odor exposure on autobiographical memory in Alzheimer’s disease (AD). We pursued this line of research by assessing the effect of odor exposure on the retrieval of recent and remote memories in AD.

Method: Twenty-six patients with mild AD and 28 controls were tested in two conditions: with and without odor exposure. In each condition, participants were invited to retrieve two childhood memories, two adulthood memories, and two recent memories.

Results: Analysis showed that AD patients produced a higher number of and more specific childhood memories, adulthood memories, and recent memories after odor exposure than without odor.

Discussion: These findings demonstrate how odor exposure may alleviate anterograde and retrograde amnesia, at least when considering the ability of patients with mild AD to retrieve few recent or remote memories.     

Selective perforant-pathway atrophy in Huntington disease: MRI analysis of hippocampal subfields

Introduction

While individuals with Huntington disease (HD) show memory impairment that indicates hippocampal dysfunction, the available literature does not consistently identify structural evidence for involvement of the whole hippocampus but rather suggests that hippocampal atrophy may be confined to certain hippocampal subregions.

Methods

We processed T1-weighted MRI from IMAGE-HD study using FreeSurfer 7.0 and compared the volumes of the hippocampal subfields among 36 early motor symptomatic (symp-HD), 40 pre-symptomatic (pre-HD), and 36 healthy control individuals across three timepoints over 36 months.

Results

Mixed-model analyses revealed significantly lower subfield volumes in symp-HD, compared with pre-HD and control groups, in the subicular regions of the perforant-pathway: presubiculum, subiculum, dentate gyrus, tail, and right molecular layer. These adjoining subfields aggregated into a single principal component, which demonstrated an accelerated rate of atrophy in the symp-HD. Volumes between pre-HD and controls did not show any significant difference. In the combined HD groups, CAG repeat length and disease burden score were associated with presubiculum, molecular layer, tail, and perforant-pathway subfield volumes. Hippocampal left tail and perforant-pathway subfields were associated with motor onset in the pre-HD group.

Conclusions

Hippocampal subfields atrophy in early symptomatic HD affects key regions of the perforant-pathway, which may implicate the distinctive memory impairment at this stage of illness. Their volumetric associations with genetic and clinical markers suggest the selective susceptibility of these subfields to mutant Huntingtin and disease progression.     

When I relive a positive me: Vivid autobiographical memories facilitate autonoetic brain activation and enhance mood

Autobiographical memory is vital for our well‐being and therefore used in therapeutic interventions. However, not much is known about the (neural) processes by which reliving memories can have beneficial effects. This study investigates what brain activation patterns and memory characteristics facilitate the effectiveness of reliving positive autobiographical memories for mood and sense of self. Particularly, the role of vividness and autonoetic consciousness is studied. Participants (N = 47) with a wide range of trait self‐esteem relived neutral and positive memories while their bold responses, experienced vividness of the memory, mood, and state self‐esteem were recorded. More vivid memories related to better mood and activation in amygdala, hippocampus and insula, indicative of increased awareness of oneself (i.e., prereflective aspect of autonoetic consciousness). Lower vividness was associated with increased activation in the occipital lobe, PCC, and precuneus, indicative of a more distant mode of reliving. While individuals with lower trait self‐esteem increased in state self‐esteem, they showed less deactivation of the lateral occipital cortex during positive memories. In sum, the vividness of the memory seemingly distinguished a more immersed and more distant manner of memory reliving. In particular, when reliving positive memories higher vividness facilitated increased prereflective autonoetic consciousness, which likely is instrumental in boosting mood.     

As time goes by: hippocampal connectivity changes with remoteness of autobiographical memory retrieval

The hippocampus is crucial for episodic autobiographical memory retrieval. Functional neuroimaging evidence suggests that it is similarly engaged in recent and remote retrieval when memories are matched on vividness and personal importance. Far fewer studies have investigated the nature of hippocampal-neocortical coactivation in relation to memory remoteness. The purpose of this study was to examine hippocampal activity and functional connectivity as a function of memory age. Unlike most studies of autobiographical memory, we included autobiographical memories formed in the days and weeks before scanning, in addition to truly remote memories on the order of months and years. Like previous studies, we found that the hippocampus was active bilaterally regardless of memory age, with anterior activity increasing up to 1 yr and then decreasing, and with posterior activity being less sensitive to memory age. More importantly, hippocampal functional connectivity varied with memory age. Retrieving recent memories (≤1 yr) showed a late coactivation of the hippocampus and areas of the autobiographical memory network, whereas retrieving remote memories (10 yrs) showed an early negative coactivation of the hippocampus and left inferior frontal gyrus followed by a positive coactivation with anterior cingulate. This finding may reflect that the hippocampus is more strongly integrated with the autobiographical memory network for recent than for remote memories, and that more effort is required to recover remote memories.     

Variations in electrophysiological properties of hippocampal neurons in different subfields

Intracellular recording were made from hippocampal pyramidal cells (HPCs) in subregions CAla, b, c, CA2 and CA3a, b of the guinea pig hippocampal slice. There were significant differences in the mode of spike discharge at various sites. Most neurons in CA1b and CA3b fired single spikes spontaneously, or during intracellular depolarizing current pulses. HPCs in the CA1a and c, as well as CA2 and CA3a subregions usually had a burst mode of discharge under the same conditions. Basic differences in neuronal properties presumably underlie these varieties of behavior between or within various regions. Specification of the site or subregion of recording is important especially in those experiments where the mode of spike discharge or membrane events in HPCs are important variables.     

Intrinsic connectivity of hippocampal subfields in normal elderly and mild cognitive impairment patients

Hippocampal connectivity has been widely described but connectivity specificities of hippocampal subfields and their changes in early AD are poorly known. The aim of this study was to highlight hippocampal subfield networks in healthy elderly (HE) and their changes in amnestic patients with mild cognitive impairment (aMCI). Thirty‐six HE and 27 aMCI patients underwent resting‐state functional MRI scans. Specific intrinsic connectivity of bilateral CA1, SUB (subiculum), and CA2/3/4/DG was identified in HE (using seeds derived from manually delineation on high‐resolution scans) and compared between HE and aMCI. Compared to the other subfields, CA1 was more strongly connected to the amygdala and occipital regions, CA2/3/4/DG to the left anterior cingulate cortex, temporal, and occipital regions, and SUB to the angular, precuneus, putamen, posterior cingulate, and frontal regions. aMCI patients showed reduced connectivity within the SUB network (with frontal and posterior cingulate regions). Our study highlighted for the first time three specific and distinct hippocampal subfield functional networks in HE, and their alterations in aMCI. These findings are important to understand AD specificities in both cognitive deficits and lesion topography, given the role of functional connectivity in these processes. Hum Brain Mapp 38:4922–4932, 2017. © 2017 Wiley Periodicals, Inc.     

Brains creating stories of selves: the neural basis of autobiographical reasoning

Personal identity critically depends on the creation of stories about the self and one’s life. The present study investigates the neural substrates of autobiographical reasoning, a process central to the construction of such narratives. During functional magnetic resonance imaging scanning, participants approached a set of personally significant memories in two different ways: in some trials, they remembered the concrete content of the events (autobiographical remembering), whereas in other trials they reflected on the broader meaning and implications of their memories (autobiographical reasoning). Relative to remembering, autobiographical reasoning recruited a left-lateralized network involved in conceptual processing [including the dorsal medial prefrontal cortex (MPFC), inferior frontal gyrus, middle temporal gyrus and angular gyrus]. The ventral MPFC—an area that may function to generate personal/affective meaning—was not consistently engaged during autobiographical reasoning across participants but, interestingly, the activity of this region was modulated by individual differences in interest and willingness to engage in self-reflection. These findings support the notion that autobiographical reasoning and the construction of personal narratives go beyond mere remembering in that they require deriving meaning and value from past experiences.     

Effects of age and Alzheimer's disease on hippocampal subfields

Growing interest has developed in hippocampal subfield volumetry over the past few years and an increasing number of studies use the automatic segmentation algorithm implemented in FreeSurfer. However, this approach has not been validated on standard resolution T1‐weighted magnetic resonance (MR) as used in most studies. We aimed at comparing hippocampal subfield segmentation using FreeSurfer on standard T1‐weighted images versus manual delineation on dedicated high‐resolution hippocampal scans. Hippocampal subfields were segmented in 133 individuals including 98 cognitively normal controls aged 19–84 years, 17 mild cognitive impairment and 18 Alzheimer's disease (AD) patients using both methods. Intraclass correlation coefficients (ICC) and Bland–Altman plots were computed to assess the consistency between both methods, and the effects of age and diagnosis were assessed from both measures. Low to moderate ICC (0.31–0.74) were found for the subiculum and other subfields as well as for the whole hippocampus, and the correlations were very low for cornu ammonis (CA)1 (<0.1). FreeSurfer CA1 volume estimates were found to be much lower than those obtained from manual segmentation, and this bias was proportional to the volume of this structure so that no effect of age or AD could be detected on FreeSurfer CA1 volumes. This study points to the differences in the anatomic definition of the subfields between FreeSurfer and manual delineation, especially for CA1, and provides clue for improvement of this automatic technique for potential clinical application on standard T1‐weighted MR. Hum Brain Mapp 36:463–474, 2015. © 2014 Wiley Periodicals, Inc.     

Episodic autobiographical memory is associated with variation in the size of hippocampal subregions

Striking individual differences exist in the human capacity to recollect past events, yet, little is known about the neural correlates of such individual differences. Studies investigating hippocampal volume in relation to individual differences in laboratory measures of episodic memory in young adults suggest that whole hippocampal volume is unrelated (or even negatively associated) with episodic memory. However, anatomical and functional specialization across hippocampal subregions suggests that individual differences in episodic memory may be linked to particular hippocampal subregions, as opposed to whole hippocampal volume. Given that the DG/CA_2/3 circuitry is thought to be especially critical for supporting episodic memory in humans, we predicted that the volume of this region would be associated with individual variability in episodic memory. This prediction was supported using high‐resolution MRI of the hippocampal subfields and measures of real‐world (autobiographical) episodic memory. In addition to the association with DG/CA_2/3, we further observed a relationship between episodic autobiographical memory and subiculum volume, whereas no association was observed with CA₁ or with whole hippocampal volume. These findings provide insight into the possible neural substrates that mediate individual differences in real‐world episodic remembering in humans.     

EEG and fMRI evidence for autobiographical memory reactivation in empathy

Empathy relies on the ability to mirror and to explicitly infer others'' inner states. Theoretical accounts suggest that memories play a role in empathy, but direct evidence of reactivation of autobiographical memories (AM) in empathy is yet to be shown. We addressed this question in two experiments. In Experiment 1, electrophysiological activity (EEG) was recorded from 28 participants. Participants performed an empathy task in which targets for empathy were depicted in contexts for which participants either did or did not have an AM, followed by a task that explicitly required memory retrieval of the AM and non‐AM contexts. The retrieval task was implemented to extract the neural fingerprints of AM and non‐AM contexts, which were then used to probe data from the empathy task. An EEG pattern classifier was trained and tested across tasks and showed evidence for AM reactivation when participants were preparing their judgement in the empathy task. Participants self‐reported higher empathy for people depicted in situations they had experienced themselves as compared to situations they had not experienced. A second independent fMRI experiment replicated this behavioural finding and showed increased activation for AM compared to non‐AM in the brain networks underlying empathy: precuneus, posterior parietal cortex, superior and inferior parietal lobule, and superior frontal gyrus. Together, our study reports behavioural, electrophysiological, and fMRI evidence that robustly supports AM reactivation in empathy.     

Context-dependent modulation of hippocampal and cortical recruitment during remote spatial memory retrieval

According to systems consolidation, as hippocampal-dependent memories mature over time, they become additionally (or exclusively) dependent on extra-hippocampal structures. We assessed the recruitment of hippocampal and cortical structures on remote memory retrieval in a performance-degradation resistant (PDR; no performance degradation with time) versus performance-degradation prone (PDP; performance degraded with time) context. Using a water-maze task in two contexts with a hidden platform and three control conditions (home cage, visible platform with or without access to distal cues), we compared neuronal activation (c-Fos imaging) patterns in the dorsal hippocampus and the medial prefrontal cortex (mPFC) after the retrieval of recent (5 days) versus remote (25 days) spatial memory. In the PDR context, the hippocampus exhibited greater c-Fos protein expression on remote than recent memory retrieval, be it in the visible or hidden platform group. In the PDP context, hippocampal activation increased at the remote time point and only in the hidden platform group. In the anterior cingulate cortex, c-Fos expression was greater for remote than for recent memory retrieval and only in the PDR context. The necessity of the mPFC for remote memory retrieval in the PDR context was confirmed using region-specific lidocaine inactivation, which had no impact on recent memory. Conversely, inactivation of the dorsal hippocampus impaired both recent and remote memory in the PDR context, and only recent memory in the PDP context, in which remote memory performance was degraded. While confirming that neuronal circuits supporting spatial memory consolidation are reorganized in a time-dependent manner, our findings further indicate that mPFC and hippocampus recruitment (i) depends on the content and perhaps the strength of the memory and (ii) may be influenced by the environmental conditions (e.g., cue saliency, complexity) in which memories are initially formed and subsequently recalled.     

Modeling longitudinal changes in hippocampal subfields and relations with memory from early- to mid-childhood

The hippocampus has been suggested to show protracted postnatal developmental growth across childhood. Most previous studies during this developmental period have been cross-sectional in nature and have focused on age-related differences in either hippocampal subregions or subfields, but not both, potentially missing localized changes. This study capitalized on a latent structural equation modeling approach to examine the longitudinal development of hippocampal subfields (cornu ammonis (CA) 2-4/dentate gyrus (DG), CA1, subiculum) in both the head and the body of the hippocampus, separately, in 165 typically developing 4- to 8-year-old children. Our findings document differential development of subfields within hippocampal head and body. Specifically, within hippocampal head, CA1 volume increased between 4−5 years and within hippocampal body, CA2-4/DG and subiculum volume increased between 5−6 years. Additionally, changes in CA1 volume in the head and changes in subiculum in the body between 4−5 years related to improvements in memory between 4−5 years. These findings demonstrate the protracted development of subfields in vivo during early- to mid-childhood, illustrate the importance of considering subfields separately in the head and body of the hippocampus, document co-occurring development of brain and behavior, and highlight the strength of longitudinal data and latent modeling when examining brain development.     

FreeSurfer-based segmentation of hippocampal subfields: A review of methods and applications,with a novel quality control procedure for ENIGMA studies and other collaborative efforts

Structural hippocampal abnormalities are common in many neurological and psychiatric disorders, and variation in hippocampal measures is related to cognitive performance and other complex phenotypes such as stress sensitivity. Hippocampal subregions are increasingly studied, as automated algorithms have become available for mapping and volume quantification. In the context of the Enhancing Neuro Imaging Genetics through Meta Analysis Consortium, several Disease Working Groups are using the FreeSurfer software to analyze hippocampal subregion (subfield) volumes in patients with neurological and psychiatric conditions along with data from matched controls. In this overview, we explain the algorithm's principles, summarize measurement reliability studies, and demonstrate two additional aspects (subfield autocorrelation and volume/reliability correlation) with illustrative data. We then explain the rationale for a standardized hippocampal subfield segmentation quality control (QC) procedure for improved pipeline harmonization. To guide researchers to make optimal use of the algorithm, we discuss how global size and age effects can be modeled, how QC steps can be incorporated and how subfields may be aggregated into composite volumes. This discussion is based on a synopsis of 162 published neuroimaging studies (01/2013–12/2019) that applied the FreeSurfer hippocampal subfield segmentation in a broad range of domains including cognition and healthy aging, brain development and neurodegeneration, affective disorders, psychosis, stress regulation, neurotoxicity, epilepsy, inflammatory disease, childhood adversity and posttraumatic stress disorder, and candidate and whole genome (epi-)genetics. Finally, we highlight points where FreeSurfer-based hippocampal subfield studies may be optimized.     

In vivo mapping of hippocampal subfields in mesial temporal lobe epilepsy: Relation to histopathology

A particularly popular automated magnetic resonance imaging (MRI) hippocampal subfield mapping technique is the one described by Van Leemput et al. (2009: Hippocampus 19:549–557) that is currently distributed with FreeSurfer software. This method assesses the probabilistic locations of subfields based on a priori knowledge of subfield topology determined from high‐field MRI. Many studies have applied this technique to conventionally acquired T1‐weighted MRI data. In the present study, we investigated the relationship between this technique applied to conventional T1‐weighted MRI data acquired at 3 T and postsurgical hippocampal histology in patients with medically intractable mesial temporal lobe epilepsy (mTLE) and hippocampal sclerosis (HS). Patients with mTLE (n = 82) exhibited significant volume loss of ipsilateral CA1, CA2‐3, CA4‐dentate gyrus (DG), subiculum, and fimbria relative to controls (n = 81). Histopathological analysis indicated that the most significant neuronal loss was observed in CA1, then CA4 and CA3, and more subtle neuronal loss in CA2, consistent with classical HS. Neuronal density of CA1 significantly correlated with MRI‐determined volume of CA1, and increasingly so with CA2‐3 and CA4–DG. Patients with increased HS based on histopathology had greater volume loss of the ipsilateral hippocampal regions on MRI. We conclude by suggesting that whilst time efficient and fully reproducible when applied to conventional single acquisition sequences, the use of the automated subfield technique described here may necessitate the application to multiacquisition high‐resolution MR sequences for accurate delineation of hippocampal subfields. Hum Brain Mapp 35:4718–4728, 2014. © 2014 Wiley Periodicals, Inc .     

Functional neuroimaging of sex differences in autobiographical memory recall

Autobiographical memory (AM) is episodic memory for personally experienced events. The brain areas underlying AM retrieval are known to include several prefrontal cortical and medial temporal lobe regions. Sex differences in AM recall have been reported in several behavioral studies, but the functional anatomical correlates underlying such differences remain unclear. This study used fMRI to compare the neural correlates of AM recall between healthy male and female participants (n = 20 per group). AM recall in response to positive, negative, and neutral cue words was compared to a semantic memory task involving the generation of examples from a category using emotionally valenced cues. Behaviorally, females recalled more negative and fewer positive AMs compared with males, while ratings of arousal, vividness, and memory age did not differ significantly between sexes. Males and females also did not differ significantly in their performance on control tasks. Neurophysiologically, females showed increased hemodynamic activity compared to males in the dorsolateral prefrontal cortex (DLPFC), dorsal anterior insula, and precuneus while recalling specific AMs (all valences combined); increased activity in the DLPFC, transverse temporal gyrus, and precuneus while recalling positive AMs; and increased activity in the anterior cingulate cortex, precuneus, amygdala, and temporopolar cortex when recalling negative AMs. When comparing positive to negative AMs directly, males and females differed in their BOLD responses in the hippocampus and DLPFC. We propose that the differential hemodynamic changes may reflect sex‐specific cognitive strategies during recall of AMs irrespective of the phenomenological properties of those memories. Hum Brain Mapp 34:3320–3332, 2013. © 2012 Wiley Periodicals, Inc.     

Complete or partial hippocampal damage produces equivalent retrograde amnesia for remote contextual fear memories

We examined the effects of partial or complete damage to the hippocampus on long-term retention of a Pavlovian conditioned fear response to context. Rats received a single contextual fear-conditioning episode and 1 week, 3 months or 6 months later they received sham, partial (dorsal) or complete NMDA-induced damage of the hippocampus. During a retention test conducted 2 weeks after surgery, the control rats exhibited high levels of freezing in the context, although their level of freezing was significantly lower with longer retention intervals. Rats with complete hippocampal damage displayed very little freezing in the context at each learning-surgery interval. Partial hippocampal damage caused a smaller but consistent deficit in conditioned responding, especially at longer learning-surgery intervals. Neither group of hippocampus-damaged rats showed less retrograde amnesia for more remote memories. We found that the severity of retrograde amnesia for contextual fear conditioning following hippocampal damage is related to the extent of the damage and that there is consistent and severe retrograde amnesia for even remote contextual fear memories. These findings support the idea that the hippocampal formation has an essential and long-lasting, possibly permanent, role in memory for contexts.