Neocortical connectivity during episodic memory formation

During the formation of new episodic memories, a rich array of perceptual information is bound together for long-term storage. However, the brain mechanisms by which sensory representations (such as colors, objects, or individuals) are selected for episodic encoding are currently unknown. We describe a functional magnetic resonance imaging experiment in which participants encoded the association between two classes of visual stimuli that elicit selective responses in the extrastriate visual cortex (faces and houses). Using connectivity analyses, we show that correlation in the hemodynamic signal between face- and place-sensitive voxels and the left dorsolateral prefrontal cortex is a reliable predictor of successful face-house binding. These data support the view that during episodic encoding, "top-down" control signals originating in the prefrontal cortex help determine which perceptual information is fated to be bound into the new episodic memory trace.     

The neural substrates of memory suppression: a FMRI exploration of directed forgetting

The directed forgetting paradigm is frequently used to determine the ability to voluntarily suppress information. However, little is known about brain areas associated with information to forget. The present study used functional magnetic resonance imaging to determine brain activity during the encoding and retrieval phases of an item-method directed forgetting recognition task with neutral verbal material in order to apprehend all processing stages that information to forget and to remember undergoes. We hypothesized that regions supporting few selective processes, namely recollection and familiarity memory processes, working memory, inhibitory and selection processes should be differentially activated during the processing of to-be-remembered and to-be-forgotten items. Successful encoding and retrieval of items to remember engaged the entorhinal cortex, the hippocampus, the anterior medial prefrontal cortex, the left inferior parietal cortex, the posterior cingulate cortex and the precuneus; this set of regions is well known to support deep and associative encoding and retrieval processes in episodic memory. For items to forget, encoding was associated with higher activation in the right middle frontal and posterior parietal cortex, regions known to intervene in attentional control. Items to forget but nevertheless correctly recognized at retrieval yielded activation in the dorsomedial thalamus, associated with familiarity-based memory processes and in the posterior intraparietal sulcus and the anterior cingulate cortex, involved in attentional processes.     

Memory for events and their spatial context: models and experiments

The computational role of the hippocampus in memory has been characterized as: (i) an index to disparate neocortical storage sites; (ii) a time-limited store supporting neocortical long-term memory; and (iii) a content-addressable associative memory. These ideas are reviewed and related to several general aspects of episodic memory, including the differences between episodic, recognition and semantic memory, and whether hippocampal lesions differentially affect recent or remote memories. Some outstanding questions remain, such as: what characterizes episodic retrieval as opposed to other forms of read-out from memory; what triggers the storage of an event memory; and what are the neural mechanisms involved? To address these questions a neural-level model of the medial temporal and parietal roles in retrieval of the spatial context of an event is presented. This model combines the idea that retrieval of the rich context of real-life events is a central characteristic of episodic memory, and the idea that medial temporal allocentric representations are used in long-term storage while parietal egocentric representations are used to imagine, manipulate and re-experience the products of retrieval. The model is consistent with the known neural representation of spatial information in the brain, and provides an explanation for the involvement of Papez''s circuit in both the representation of heading direction and in the recollection of episodic information. Two experiments relating to the model are briefly described. A functional neuroimaging study of memory for the spatial context of life-like events in virtual reality provides support for the model''s functional localization. A neuropsychological experiment suggests that the hippocampus does store an allocentric representation of spatial locations.     

Age-Related Changes in the Functional Network Underlying Specific and General Autobiographical Memory Retrieval: A Pivotal Role for the Anterior Cingulate Cortex

Age-related changes in autobiographical memory (AM) recall are characterized by a decline in episodic details, while semantic aspects are spared. This deleterious effect is supposed to be mediated by an inefficient recruitment of executive processes during AM retrieval. To date, contrasting evidence has been reported on the neural underpinning of this decline, and none of the previous studies has directly compared the episodic and semantic aspects of AM in elderly. We asked 20 young and 17 older participants to recall specific and general autobiographical events (i.e., episodic and semantic AM) elicited by personalized cues while recording their brain activity by means of fMRI. At the behavioral level, we confirmed that the richness of episodic AM retrieval is specifically impoverished in aging and that this decline is related to the reduction of executive functions. At the neural level, in both age groups, we showed the recruitment of a large network during episodic AM retrieval encompassing prefrontal, cortical midline and posterior regions, and medial temporal structures, including the hippocampus. This network was very similar, but less extended, during semantic AM retrieval. Nevertheless, a greater activity was evidenced in the dorsal anterior cingulate cortex (dACC) during episodic, compared to semantic AM retrieval in young participants, and a reversed pattern in the elderly. Moreover, activity in dACC during episodic AM retrieval was correlated with inhibition and richness of memories in both groups. Our findings shed light on the direct link between episodic AM retrieval, executive control, and their decline in aging, proposing a possible neuronal signature. They also suggest that increased activity in dACC during semantic AM retrieval in the elderly could be seen as a compensatory mechanism underpinning successful AM performance observed in aging. These results are discussed in the framework of recently proposed models of neural reorganization in aging.     

The BDNF Val66Met Polymorphism Has Opposite Effects on Memory Circuits of Multiple Sclerosis Patients and Controls

Episodic memory deficits are frequent symptoms in Multiple Sclerosis and have been associated with dysfunctions of the hippocampus, a key region for learning. However, it is unclear whether genetic factors that influence neural plasticity modulate episodic memory in MS. We thus studied how the Brain Derived Neurotrophic Factor Val⁶⁶Met genotype, a common polymorphism influencing the hippocampal function in healthy controls, impacted on brain networks underlying episodic memory in patients with Multiple Sclerosis. Functional magnetic resonance imaging was used to assess how the Brain Derived Neurotrophic Factor Val⁶⁶Met polymorphism modulated brain regional activity and functional connectivity in 26 cognitively unimpaired Multiple Sclerosis patients and 25 age- and education-matched healthy controls while performing an episodic memory task that included encoding and retrieving visual scenes. We found a highly significant group by genotype interaction in the left posterior hippocampus, bilateral parahippocampus, and left posterior cingulate cortex. In particular, Multiple Sclerosis patients homozygous for the Val⁶⁶ allele, relative to Met⁶⁶ carriers, showed greater brain responses during both encoding and retrieval while the opposite was true for healthy controls. Furthermore, a robust group by genotype by task interaction was detected for the functional connectivity between the left posterior hippocampus and the ipsilateral posterior cingulate cortex. Here, greater hippocampus-posterior cingulate cortex connectivity was observed in Multiple Sclerosis Met⁶⁶ carriers relative to Val⁶⁶ homozygous during retrieval (but not encoding) while, again, the reverse was true for healthy controls. The Val⁶⁶Met polymorphism has opposite effects on hippocampal circuitry underlying episodic memory in Multiple Sclerosis patients and healthy controls. Enhancing the knowledge of how genetic factors influence cognitive functions may improve the clinical management of memory deficits in patients with Multiple Sclerosis.     

The nose smells what the eye sees: crossmodal visual facilitation of human olfactory perception

Human olfactory perception is notoriously unreliable, but shows substantial benefits from visual cues, suggesting important crossmodal integration between these primary sensory modalities. We used event-related fMRI to determine the underlying neural mechanisms of olfactory-visual integration in the human brain. Subjects participated in an olfactory detection task, whereby odors and pictures were delivered separately or together. By manipulating the degree of semantic correspondence between odor-picture pairs, we show a perceptual olfactory facilitation for semantically congruent (versus incongruent) trials. This behavioral advantage was associated with enhanced neural activity in anterior hippocampus and rostromedial orbitofrontal cortex. We suggest these findings can be interpreted as indicating that human hippocampus mediates reactivation of crossmodal semantic associations, even in the absence of explicit memory processing.     

Cortical contributions to olfaction: plasticity and perception

In most sensory systems, the sensory cortex is the place where sensation approaches perception. As described in this review, olfaction is no different. The olfactory system includes both primary and higher order cortical regions. These cortical structures perform computations that take highly analytical afferent input and synthesize it into configural odor objects. Cortical plasticity plays an important role in this synthesis and may underlie olfactory perceptual learning. Olfactory cortex is also involved in odor memory and association of odors with multimodal input and contexts. Finally, the olfactory cortex serves as an important sensory gate, modulating information throughput based on recent experience and behavioral state.     

Hippocampus Is Place of Interaction between Unconscious and Conscious Memories

Recent evidence suggests that humans can form and later retrieve new semantic relations unconsciously by way of hippocampus—the key structure also recruited for conscious relational (episodic) memory. If the hippocampus subserves both conscious and unconscious relational encoding/retrieval, one would expect the hippocampus to be place of unconscious-conscious interactions during memory retrieval. We tested this hypothesis in an fMRI experiment probing the interaction between the unconscious and conscious retrieval of face-associated information. For the establishment of unconscious relational memories, we presented subliminal (masked) combinations of unfamiliar faces and written occupations (“actor” or “politician”). At test, we presented the former subliminal faces, but now supraliminally, as cues for the reactivation of the unconsciously associated occupations. We hypothesized that unconscious reactivation of the associated occupation—actor or politician—would facilitate or inhibit the subsequent conscious retrieval of a celebrity’s occupation, which was also actor or politician. Depending on whether the reactivated unconscious occupation was congruent or incongruent to the celebrity’s occupation, we expected either quicker or delayed conscious retrieval process. Conscious retrieval was quicker in the congruent relative to a neutral baseline condition but not delayed in the incongruent condition. fMRI data collected during subliminal face-occupation encoding confirmed previous evidence that the hippocampus was interacting with neocortical storage sites of semantic knowledge to support relational encoding. fMRI data collected at test revealed that the facilitated conscious retrieval was paralleled by deactivations in the hippocampus and neocortical storage sites of semantic knowledge. We assume that the unconscious reactivation has pre-activated overlapping relational representations in the hippocampus reducing the neural effort for conscious retrieval. This finding supports the notion of synergistic interactions between conscious and unconscious relational memories in a common, cohesive hippocampal-neocortical memory space.     

Breast cancer affects both the hippocampus volume and the episodic autobiographical memory retrieval

Background

Neuroimaging studies show the hippocampus is a crucial node in the neural network supporting episodic autobiographical memory retrieval. Stress-related psychiatric disorders, namely Major Depression and Post Traumatic Stress Disorder (PTSD), are related to reduced hippocampus volume. However, this is not the case for remitted breast cancer patients with co-morbid stress-related psychiatric disorders. This exception may be due to the fact that, consequently to the cancer experience as such, this population might already be characterized by a reduced hippocampus with an episodic autobiographical memory deficit.

Methodology

We scanned, with a 3T Siemens TRIO, 16 patients who had lived through a “standard experience of breast cancer” (breast cancer and a standard treatment in remission since 18 month) in the absence of any associated stress-related psychiatric or neurological disorder and 21 matched controls. We then assessed their episodic autobiographical memory retrieval ability.

Principal Findings

Remitted breast cancer patients had both a significantly smaller hippocampus and a significant deficit in episodic autobiographical memory retrieval. The hippocampus atrophy was characterized by a smaller posterior hippocampus. The posterior hippocampus volume was intimately related to the ability to retrieve negative memories and to the past experience of breast cancer or not.

Conclusions/Significance

These results provide two main findings: (1) we identify a new population with a specific reduction in posterior hippocampus volume that is independent of any psychiatric or neurological pathology; (2) we show the intimate relation of the posterior hippocampus to the ability to retrieve episodic autobiographical memories. These are significant findings as it is the first demonstration that indicates considerable long-term effects of living through the experience of breast cancer and shows very specific hippocampal atrophy with a functional deficit without any presence of psychiatric pathology.     

An unexpected sequence of events: mismatch detection in the human hippocampus

The ability to identify and react to novelty within the environment is fundamental to survival. Computational models emphasize the potential role of the hippocampus in novelty detection, its unique anatomical circuitry making it ideally suited to act as a comparator between past and present experience. The hippocampus, therefore, is viewed to detect associative mismatches between what is expected based on retrieval of past experience and current sensory input. However, direct evidence that the human hippocampus performs such operations is lacking. We explored brain responses to novel sequences of objects using functional magnetic resonance imaging (fMRI), while subjects performed an incidental target detection task. Our results demonstrate that hippocampal activation was maximal when prior predictions concerning which object would appear next in a sequence were violated by sensory reality. In so doing, we establish the biological reality of associative match-mismatch computations within the human hippocampus, a process widely held to play a cardinal role in novelty detection. Our results also suggest that the hippocampus may generate predictions about how future events will unfold, and critically detect when these expectancies are violated, even when task demands do not require it. The present study also offers broader insights into the nature of essential computations carried out by the hippocampus, which may also underpin its unique contribution to episodic memory.     

Amnesia and neglect: beyond the Delay-Brion system and the Hebb synapse.

Hippocampal damage in people causes impairments of episodic memory, but in rats it causes impairments of spatial learning. Experiments in macaque monkeys show that these two kinds of impairment are functionally similar to each other. After any lesion that interrupts the Delay-Brion system (hippocampus, fornix, mamillary bodies and anterior thalamus) monkeys are impaired in scene-specific memory, where an event takes place against a background that is specific to that event. Scene-specific memory in the monkey corresponds to human episodic memory, which is the memory of a unique event set in a particular scene, as opposed to scene-independent human knowledge, which is abstracted from many different scenes. However, interruption of the Delay-Brion system is not sufficient to explain all of the memory impairments that are seen in amnesic patients. To explain amnesia the specialized function of the hippocampus in scene memory needs to be considered alongside the other, qualitatively different functional specializations of other memory systems of the temporal lobe, including the perirhinal cortex and the amygdala. In all these specialized areas, however, including the hippocampus, there is no fundamental distinction between memory systems and perceptual systems. In explaining memory disorders in amnesia it is also important to consider them alongside the memory disorders of neglect patients. Neglect patients fail to represent in memory the side of the world that is contralateral to the current fixation point, in both short- and long-term memory retrieval. Neglect was produced experimentally by unilateral visual disconnection in the monkey, confirming the idea that visual memory retrieval is retinotopically organized; patients with unilateral medial temporal-lobe removals showed lateralized memory impairments for half-scenes in the visual hemifield contralateral to the removal. Thus, in scene-memory retrieval the Delay-Brion system contributes to the retrieval of visual memories into the retinotopically organized visual cortex. This scene memory interpretation of hippocampal function needs to be contrasted with the cognitive-map hypothesis. The cognitive-map model of hippocampal function shares some common assumptions with the Hebb-synapse model of association formation, and the Hebb-synapse model can be rejected on the basis of recent evidence that monkeys can form direct associations in memory between temporally discontiguous events. Our general conclusion is that the primate brain encompasses widespread and powerful memory mechanisms which will continue to be poorly understood if theory and experimentation continue to concentrate too much, as they have in the past, on the hippocampus and the Hebb synapse.     

记忆水平依赖的海马-前额叶神经节律交互

海马(HPC)和前额叶皮层(PFC)的协同作用是记忆加工过程的关键,其相互作用对学习和记忆功能至关重要.大量证据表明,情景记忆的形成、巩固与检索依赖于特征神经节律在PFC和HPC脑区间的同步作用,这些节律包括theta节律、gamma节律和sharp wave ripples (SWRs)节律等.在精神类疾病中患者往往伴随出现学习记忆功能障碍,基于人类和动物的脑电研究均发现以上3种神经节律在HPC和PFC之间的同步性下降,可能作为反映精神病理下认知功能障碍的重要指标.本文从HPC-PFC网络中的神经节律研究出发,总结了theta节律、gamma节律和SWRs节律在两脑区间的协调交互模式在情景记忆中的作用,以及精神分裂症和抑郁症状态下HPC-PFC通路上神经节律的异常表现及其潜在损伤机制,为今后精神疾病的快速诊断提供客观依据.     

The neural basis of episodic memory: evidence from functional neuroimaging

We review some of our recent research using functional neuroimaging to investigate neural activity supporting the encoding and retrieval of episodic memories, that is, memories for unique events. Findings from studies of encoding indicate that, at the cortical level, the regions responsible for the effective encoding of a stimulus event as an episodic memory include some of the regions that are also engaged to process the event 'online'. Thus, it appears that there is no single cortical site or circuit responsible for episodic encoding. The results of retrieval studies indicate that successful recollection of episodic information is associated with activation of lateral parietal cortex, along with more variable patterns of activity in dorsolateral and anterior prefrontal cortex. Whereas parietal regions may play a part in the representation of retrieved information, prefrontal areas appear to support processes that act on the products of retrieval to align behaviour with the demands of the retrieval task.     

Enhanced odor discrimination and impaired olfactory memory by spatially controlled switch of AMPA receptors

Genetic perturbations of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPARs) are widely used to dissect molecular mechanisms of sensory coding, learning, and memory. In this study, we investigated the role of Ca²⁺-permeable AMPARs in olfactory behavior. AMPAR modification was obtained by depletion of the GluR-B subunit or expression of unedited GluR-B(Q), both leading to increased Ca²⁺ permeability of AMPARs. Mice with this functional AMPAR switch, specifically in forebrain, showed enhanced olfactory discrimination and more rapid learning in a go/no-go operant conditioning task. Olfactory memory, however, was dramatically impaired. GluR-B depletion in forebrain was ectopically variable (“mosaic”) among individuals and strongly correlated with decreased olfactory memory in hippocampus and cortex. Accordingly, memory was rescued by transgenic GluR-B expression restricted to piriform cortex and hippocampus, while enhanced odor discrimination was independent of both GluR-B variability and transgenic GluR-B expression. Thus, correlated differences in behavior and levels of GluR-B expression allowed a mechanistic and spatial dissection of olfactory learning, discrimination, and memory capabilities.     

A reduction in hippocampal GABAA receptor α5 subunits disrupts the memory for location of objects in mice

The memory for location of objects, which binds information about objects to discrete positions or spatial contexts of occurrence, is a form of episodic memory particularly sensitive to hippocampal damage. Its early decline is symptomatic for elderly dementia. Substances that selectively reduce α5‐GABA_A receptor function are currently developed as potential cognition enhancers for Alzheimer's syndrome and other dementia, consistent with genetic studies implicating these receptors that are highly expressed in hippocampus in learning performance. Here we explored the consequences of reduced GABA_Aα5‐subunit contents, as occurring in α5(H105R) knock‐in mice, on the memory for location of objects. This required the behavioral characterization of α5(H105R) and wild‐type animals in various tasks examining learning and memory retrieval strategies for objects, locations, contexts and their combinations. In mutants, decreased amounts of α5‐subunits and retained long‐term potentiation in hippocampus were confirmed. They exhibited hyperactivity with conserved circadian rhythm in familiar actimeters, and normal exploration and emotional reactivity in novel places, allocentric spatial guidance, and motor pattern learning acquisition, inhibition and flexibility in T‐ and eight‐arm mazes. Processing of object, position and context memories and object‐guided response learning were spared. Genotype difference in object‐in‐place memory retrieval and in encoding and response learning strategies for object–location combinations manifested as a bias favoring object‐based recognition and guidance strategies over spatial processing of objects in the mutants. These findings identify in α5(H105R) mice a behavioral–cognitive phenotype affecting basal locomotion and the memory for location of objects indicative of hippocampal dysfunction resulting from moderately decreased α5‐subunit contents.     

Theories of episodic memory

Theories of episodic memory need to specify the encoding (representing), storage, and retrieval processes that underlie this form of memory and indicate the brain regions that mediate these processes and how they do so. Representation and re-representation (retrieval) of the spatiotemporally linked series of scenes, which constitute an episode, are probably mediated primarily by those parts of the posterior neocortex that process perceptual and semantic information. However, some role of the frontal neocortex and medial temporal lobes in representing aspects of context and high-level visual object information at encoding and retrieval cannot currently be excluded. Nevertheless, it is widely believed that the frontal neocortex is mainly involved in coordinating episodic encoding and retrieval and that the medial temporal lobes store aspects of episodic information. Establishing where storage is located is very difficult and disagreement remains about the role of the posterior neocortex in episodic memory storage. One view is that this region stores all aspects of episodic memory ab initio for as long as memory lasts. This is compatible with evidence that the amygdala, basal forebrain, and midbrain modulate neocortical storage. Another view is that the posterior neocortex only gradually develops the ability to store some aspects of episodic information as a function of rehearsal over time and that this information is initially stored by the medial temporal lobes. A third view is that the posterior neocortex never stores these aspects of episodic information because the medial temporal lobes store them for as long as memory lasts in an increasingly redundant fashion. The last two views both postulate that the medial temporal lobes initially store contextual markers that serve to cohere featural information stored in the neocortex. Lesion and functional neuroimaging evidence still does not clearly distinguish between these views. Whether the feeling that an episodic memory is familiar depends on retrieving an association between a retrieved episode and this feeling, or by an attribution triggered by a priming process, is unclear. Evidence about whether the hippocampus and medial temporal lobe cortices play different roles in episodic memory is conflicting. Identifying similarities and differences between episodic memory and both semantic memory and priming will require careful componential analysis of episodic memory.     

The dynamics of hippocampal activation during encoding of overlapping sequences

Sequence disambiguation, the process by which overlapping sequences are kept separate, has been proposed to underlie a wide range of memory capacities supported by the hippocampus, including episodic memory and spatial navigation. We used functional magnetic resonance imaging (fMRI) to explore the dynamic pattern of hippocampal activation during the encoding of sequences of faces. Activation in right posterior hippocampus, only during the encoding of overlapping sequences but not nonoverlapping sequences, was found to correlate robustly with a subject-specific behavioral index of sequence learning. Moreover, our data indicate that hippocampal activation in response to elements common to both sequences in the overlapping sequence pair, may be particularly important for accurate sequence encoding and retrieval. Together, these findings support the conclusion that the human hippocampus is involved in the earliest stage of sequence disambiguation, when memory representations are in the process of being created, and provide empirical support for contemporary computational models of hippocampal function.     

Effects of the BDNF Val66Met Polymorphism and Met Allele Load on Declarative Memory Related Neural Networks

It has been suggested that the BDNF Val66Met polymorphism modulates episodic memory performance via effects on hippocampal neural circuitry. However, fMRI studies have yielded inconsistent results in this respect. Moreover, very few studies have examined the effect of met allele load on activation of memory circuitry. In the present study, we carried out a comprehensive analysis of the effects of the BDNF polymorphism on brain responses during episodic memory encoding and retrieval, including an investigation of the effect of met allele load on memory related activation in the medial temporal lobe. In contrast to previous studies, we found no evidence for an effect of BDNF genotype or met load during episodic memory encoding. Met allele carriers showed increased activation during successful retrieval in right hippocampus but this was contrast-specific and unaffected by met allele load. These results suggest that the BDNF Val66Met polymorphism does not, as previously claimed, exert an observable effect on neural systems underlying encoding of new information into episodic memory but may exert a subtle effect on the efficiency with which such information can be retrieved.     

A unified model of spatial and episodic memory

Medial temporal lobe structures including the hippocampus are implicated by separate investigations in both episodic memory and spatial function. We show that a single recurrent attractor network can store both the discrete memories that characterize episodic memory and the continuous representations that characterize physical space. Combining both types of representation in a single network is actually necessary if objects and where they are located in space must be stored. We thus show that episodic memory and spatial theories of medial temporal lobe function can be combined in a unified model.     

Item, context and relational episodic encoding in humans

Recent functional imaging work supports the view that item and relational memory depend upon distinct encoding operations within the medial temporal lobe. Specifically, emerging findings demonstrate that the level of engagement of perirhinal cortex predicts later memory for individual items, whereas the level of hippocampal processing correlates with later relational memory, or recovery of additional episodic details. Furthermore, recent functional magnetic resonance imaging evidence in humans suggests that medial temporal lobe cortical input structures, the perirhinal and posterior parahippocampal cortices, differentially participate in the encoding of objects and their context, providing domain-specific input to the hippocampus. Taken together, these data help to construct a working model of how distinct medial temporal lobe structures participate in episodic memory formation with domain-general relational binding mechanisms supported by the hippocampus and provide emerging evidence for domain-specificity within the perirhinal and parahippocampal cortices.