Decreased fMRI activity in the hippocampus of patients with schizophrenia compared to healthy control participants,tested on a wayfinding task in a virtual town

Intact episodic memory requires the ability to make associations between the contextual features of an event, referred to as contextual binding. Binding processes combine different contextual elements into a complete memory representation. It has been proposed that binding errors during the encoding process are responsible for the episodic memory impairments reported in schizophrenia. Since the hippocampus is critical for contextual binding and episodic memory, it was hypothesized that patients with schizophrenia would show a deficit in information processing in the hippocampus, measured with functional magnetic resonance imaging (fMRI). In the current experiment, 21 patients with schizophrenia and 22 healthy control participants were scanned while being tested on navigating in a virtual town (i.e. find the grocery store from the school), a task that was shown to be critically dependent on the hippocampus. Between-group comparisons revealed significantly less activation among patients relative to controls in the left middle frontal gyrus, and right and left hippocampi. We propose that the context and the content are not appropriately linked, therefore affecting the formation of a cognitive map representation in the patient group and eliciting a contextual binding deficit.     

An animal model of amnesia that uses Receiver Operating Characteristics (ROC) analysis to distinguish recollection from familiarity deficits in recognition memory

Here we review our development of an animal model of episodic memory and amnesia that employs a signal detection analyses to characterize recognition memory performance in rats. This approach aims to distinguish episodic recollection of studied items from mere familiarity for recently experienced stimuli, and then to examine the neural basis of these memory processes. Our findings on intact animals indicate that it is possible to distinguish independent components of recognition that are associated with features of recollection and familiarity in humans. Furthermore, we have found that damage limited to the hippocampus results in a selective deficit in recollection and not familiarity. Also, aging and prefrontal damage result in a similar pattern of impaired recollection and spared familiarity. However, whereas the recollection deficit following hippocampal damage can be attributed to the forgetting of studied materials, the impairment following prefrontal damage is due to false alarms, likely reflecting a deficit in source monitoring.     

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.     

Amnesia and the organization of the hippocampal system

Early hippocampal injury in humans has been found to result in a limited form of global anterograde amnesia. At issue is whether the limitation is qualitative, with the amnesia reflecting substantially greater impairment in episodic than in semantic memory, or only quantitative, with both episodic and semantic memory being partially and equivalently impaired. Evidence from neuroanatomical and lesion studies in animals suggests that the hippocampus and subhippocampal cortices form a hierarchically organized system, such that the greatest convergence of information (and, by implication, the richest amount of association) takes place within the hippocampus, located at the top of the hierarchy. On the one hand, this evidence is consistent with the view that selective hippocampal damage produces a differential impairment in context-rich episodic memory as compared with context-free semantic memory, because only the latter can be supported by the subhippocampal cortices. On the other hand, given the system's hierarchical form of organization, this dissociation of deficits is difficult to prove, because a quantitatively limited deficit will nearly always be a viable alternative. A final choice between the alternative views is therefore likely to depend less on further evidence gathered in brain-injured patients than on which view accounts for more of the data gathered from converging approaches to the problem. Hippocampus 1998;8:212–216. © 1998 Wiley-Liss, Inc.     

A Consequence of Failed Sequential Learning: A Computational Account of Developmental Amnesia

Developmental amnesia, featured with severely impaired episodic memory and almost normal semantic memory, has been discovered to occur in children with hippocampal atrophy. Such amnesia seems to challenge the understanding that early loss of episodic memory may impede cognitive development and result in severe mental retardation. While the underlying mechanism is still unclear, no computational model has been reported to simulate developmental amnesia. A cognitive and computational system is presented, for the first time, to simulate the unique characteristics of the amnesia: impaired episodic recall, spared recognition, and spared semantic learning. The lesioned sequential/spatial learning ability of the hippocampus is suggested to be able to cause severe impairment of episodic recall, but affect neither recognition ability nor semantic learning. Semantic learning is generally thought to largely associate with the consolidation of episodic memory, a process in which sequential activation of episodic memory may not be necessary. Semantic learning through memory consolidation featured with random activation of stored experiences is performed, and the acquired knowledge is demonstrated to have the flexibility that is one of the key characteristics of semantic memory.     

Age-Related Increases in Posterior Hippocampal Granularity Are Associated with Remote Detailed Episodic Memory in Development

Episodic memory is critical to human functioning. In adults, episodic memory involves a distributed neural circuit in which the hippocampus plays a central role. As episodic memory abilities continue to develop across childhood and into adolescence, studying episodic memory maturation can provide insight into the development and construction of these hippocampal networks, and ultimately clues to their function in adulthood. While past developmental studies have shown that the hippocampus helps to support memory in middle childhood and adolescence, the extent to which ongoing maturation within the hippocampus contributes to developmental change in episodic memory abilities remains unclear. In contrast, slower maturing regions, such as the PFC, have been suggested to be the neurobiological locus of memory improvements into adolescence. However, it is also possible that the methods used to detect hippocampal development during middle childhood and adolescence are not sensitive enough. Here, we examine how temporal covariance (or differentiation) in voxel representations within anterior and posterior hippocampus change with age to support the development of detailed recollection in male and female developing humans. We find age-related increases in the distinctiveness of temporal activation profiles in the posterior, but not anterior, hippocampus. Second, we show that this measure of granularity, when present during postencoding rest periods, correlates with the recall of detailed memories of preceding stimuli several weeks postencoding, suggesting that granularity may promote memory stabilization.SIGNIFICANCE STATEMENT Studying hippocampal maturation can provide insight into episodic memory development, as well as clues to episodic functioning in adulthood. Past work has shown evidence both for and against hippocampal contributions to age-related improvements in memory performance, but has relied heavily on univariate approaches (averaging activity across hippocampal voxels), which may not be sensitive to nuanced developmental change. Here we use a novel approach, examining time signatures in individual hippocampal voxels to reveal regionally specific (anterior vs posterior hippocampus) differences in the distinctiveness (granularity) of temporal activation profiles across development. Importantly, posterior hippocampus granularity during windows of putative memory stabilization was associated with long-term memory specificity. This suggests that the posterior hippocampus gradually builds the capacity to support detailed episodic recall.     

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.     

Associations evoked during memory encoding recruit the context-network

An extensive cortical network consisting of structures in the medial temporal lobe (hippocampus and parahippocampal cortex), lateral parietal cortex, retrosplenial cortex, and medial prefrontal cortex has recently attracted attention in cognitive neuroscience research, linking the network to both episodic memory and spatial processing. It has been suggested that its function may be best characterized as supporting the processing of contextual associations (context network). In this study, we explored whether the role of this network in contextual processing extends to associations that are evoked in a spontaneous manner. In a novel memory encoding task, participants indicated whether they encoded pictures (objects and novel faces) based on an evoked association or based on a perceptual feature. Memory encoding with subjective associations enhanced memory formation relative to feature-based encoding, and this effect was more pronounced for rapidly evoked associations. Functional magnetic resonance imaging during encoding yielded significant activations in all regions of the context network, i.e., medial prefrontal cortex, lateral parietal cortex, retrosplenial cortex, and posterior medial temporal lobe for the associative vs. feature-based comparisons. The low number of misses did not permit the analysis of a subsequent memory contrast. Our data suggest that the context network, which includes the posterior hippocampus and parahippocampal cortex, might support the linkage of external stimuli to long-term memory representations.     

The relationship between level of processing and hippocampal–cortical functional connectivity during episodic memory formation in humans

New episodic memory traces represent a record of the ongoing neocortical processing engaged during memory formation (encoding). Thus, during encoding, deep (semantic) processing typically establishes more distinctive and retrievable memory traces than does shallow (perceptual) processing, as assessed by later episodic memory tests. By contrast, the hippocampus appears to play a processing‐independent role in encoding, because hippocampal lesions impair encoding regardless of level of processing. Here, we clarified the neural relationship between processing and encoding by examining hippocampal–cortical connectivity during deep and shallow encoding. Participants studied words during functional magnetic resonance imaging and freely recalled these words after distraction. Deep study processing led to better recall than shallow study processing. For both levels of processing, successful encoding elicited activations of bilateral hippocampus and left prefrontal cortex, and increased functional connectivity between left hippocampus and bilateral medial prefrontal, cingulate and extrastriate cortices. Successful encoding during deep processing was additionally associated with increased functional connectivity between left hippocampus and bilateral ventrolateral prefrontal cortex and right temporoparietal junction. In the shallow encoding condition, on the other hand, pronounced functional connectivity increases were observed between the right hippocampus and the frontoparietal attention network activated during shallow study processing. Our results further specify how the hippocampus coordinates recording of ongoing neocortical activity into long‐term memory, and begin to provide a neural explanation for the typical advantage of deep over shallow study processing for later episodic memory. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc.     

Deeper processing is beneficial during episodic memory encoding for adults with Williams syndrome

Previous research exploring declarative memory in Williams syndrome (WS) has revealed impairment in the processing of episodic information accompanied by a relative strength in semantic ability. The aim of the current study was to extend this literature by examining how relatively spared semantic memory may support episodic remembering. Using a level of processing paradigm, older adults with WS (aged 35–61 years) were compared to typical adults of the same chronological age and typically developing children matched for verbal ability. In the study phase, pictures were encoded using either a deep (decide if a picture belongs to a particular category) or shallow (perceptual based processing) memory strategy. Behavioural indices (reaction time and accuracy) at retrieval were suggestive of an overall difficulty in episodic memory for WS adults. Interestingly, however, semantic support was evident with a greater recall of items encoded with deep compared to shallow processing, indicative of an ability to employ semantic encoding strategies to maximise the strength of the memory trace created. Unlike individuals with autism who find semantic elaboration strategies problematic, the pattern of findings reported here suggests in those domains that are relatively impaired in WS, support can be recruited from relatively spared cognitive processes.     

Preserved visual recognition memory in an amnesic patient with hippocampal lesions

There is ongoing debate about whether performance on tests of recognition memory can remain preserved after hippocampal damage. In the present study, we report F.R.G., a patient who became severely amnesic following herpes simplex encephalitis. Although F.R.G. failed all tests involving recall and verbal recognition, she obtained normal performance on a wide number of tests evaluating visual recognition memory (14 of 18 different tests). Her performance was independent of various factors, such as test difficulty, duration of exposure to the stimuli, or delay separating encoding and recognition. F.R.G. also achieved normal performance on two tasks requiring that she associate pairs of visual stimuli. In addition, she demonstrated spared feeling of knowing, suggesting that her performance on recognition tests was explicit and likely to rely on familiarity. Brain imaging (MRI) revealed bilateral lesions of the hippocampus and lesions of the left parahippocampal gyrus, while the right parahippocampal gyrus remained relatively spared. The results of this study support the view that recognition memory can be preserved despite severe hippocampal damage and that familiarity is a distinct memory process that can be dissociated from recollection.     

Iconic Decay in Schizophrenia

Working memory impairment is considered a core deficit in schizophrenia, but the precise nature of this deficit has not been determined. Multiple lines of evidence implicate deficits at the encoding stage. During encoding, information is held in a precategorical sensory store termed iconic memory, a literal image of the stimulus with high capacity but rapid decay. Pathologically increased iconic decay could reduce the number of items that can be transferred into working memory before the information is lost and could thus contribute to the working memory deficit seen in the illness. The current study used a partial report procedure to test the hypothesis that patients with schizophrenia (n = 37) display faster iconic memory decay than matched healthy control participants (n = 28). Six letters, arranged in a circle, were presented for 50 ms. Following a variable delay of 0–1000 ms, a central arrow cue indicated the item to be reported. In both patients and control subjects, recall accuracy decreased with increasing cue delay, reflecting decay of the iconic representation of the stimulus array. Patients displayed impaired memory performance across all cue delays, consistent with an impairment in working memory, but the rate of iconic memory decay did not differ between patients and controls. This provides clear evidence against faster loss of iconic memory representations in schizophrenia, ruling out iconic decay as an underlying source of the working memory impairment in this population. Thus, iconic decay rate can be added to a growing list of unimpaired cognitive building blocks in schizophrenia.     

Using virtual reality to characterize episodic memory profiles in amnestic mild cognitive impairment and Alzheimer's disease: influence of active and passive encoding

Most neuropsychological assessments of episodic memory bear little similarity to the events that patients actually experience as memories in daily life. The first aim of this study was to use a virtual environment to characterize episodic memory profiles in an ecological fashion, which includes memory for central and perceptual details, spatiotemporal contextual elements, and binding. This study included subjects from three different populations: healthy older adults, patients with amnestic mild cognitive impairment (aMCI) and patients with early to moderate Alzheimer's disease (AD). Second, we sought to determine whether environmental factors that can affect encoding (active vs. passive exploration) influence memory performance in pathological aging. Third, we benchmarked the results of our virtual reality episodic memory test against a classical memory test and a subjective daily memory complaint scale. Here, the participants were successively immersed in two virtual environments; the first, as the driver of a virtual car (active exploration) and the second, as the passenger of that car (passive exploration). Subjects were instructed to encode all elements of the environment as well as the associated spatiotemporal contexts. Following each immersion, we assessed the patient's recall and recognition of central information (i.e., the elements of the environment), contextual information (i.e., temporal, egocentric and allocentric spatial information) and lastly, the quality of binding. We found that the AD patients' performances were inferior to that of the aMCI and even more to that of the healthy aged groups, in line with the progression of hippocampal atrophy reported in the literature. Spatial allocentric memory assessments were found to be particularly useful for distinguishing aMCI patients from healthy older adults. Active exploration yielded enhanced recall of central and allocentric spatial information, as well as binding in all groups. This led aMCI patients to achieve better performance scores on immediate temporal memory tasks. Finally, the patients' daily memory complaints were more highly correlated with the performances on the virtual test than with their performances on the classical memory test. Taken together, these results highlight specific cognitive differences found between these three populations that may provide additional insight into the early diagnosis and rehabilitation of pathological aging. In particular, neuropsychological studies would benefit to use virtual tests and a multi-component approach to assess episodic memory, and encourage active encoding of information in patients suffering from mild or severe age-related memory impairment. The beneficial effect of active encoding on episodic memory in aMCI and early to moderate AD is discussed in the context of relatively preserved frontal and motor brain functions implicated in self-referential effects and procedural abilities.     

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.     

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 lesions that abolish spatial maze performance spare object recognition memory at delays of up to 48 hours

The hippocampus is widely considered to be a critical component of a medial temporal lobe memory system, necessary for normal performance on tests of declarative memory. Object recognition memory is thought to be a classic test of declarative memory function. However, previous tests of the effects of hippocampal lesions on object recognition memory have not always supported this view. One possible reason for this inconsistency is that previously reported effects of hippocampal lesions on object recognition memory tasks may have stemmed not from a deficit in object recognition memory per se, but as a result of spatial and contextual confounds in the task. Thus, in the present study, we used a spontaneous object recognition test in a modified apparatus designed to minimize spatial and contextual factors. A group of rats with complete excitotoxic lesions of the hippocampus and a group of control rats were tested on this modified spontaneous object recognition task with retention delays of up to 48 h. These rats were also tested on a spatial nonmatching-to-place task. Spatial memory performance was abolished following hippocampal lesions, whereas performance on the recognition memory task was intact at all delays tested.     

Is the hippocampus necessary for visual and verbal binding in working memory?

A series of experiments test the recent claim that the hippocampus is necessary for the binding of features in working memory. Some potential limitations of studies underlying this claim are discussed, and an attempt is made to further test the hypothesis by studying a case of developmental amnesia whose extensively investigated pathology appears to be principally limited to the hippocampus, and who shows the expected deficit in episodic long-term memory. One series of experiments studied the short-term visual binding of color and shape under conditions ranging from simple presentation of colored objects through the more demanding task of combining the features when separated in space, or in time. A second set of experiments studied the capacity to use sentence structure to bind words into chunks in short-term verbal memory. Hippocampal pathology did not lead to a decrement on any of these tasks, suggesting that the hippocampus is not essential for short-term binding in working memory.     

Increased inhibition and enhancement of memory retrieval are associated with reduced hippocampal volume

Putative control of encoding and retrieval processes have been linked to communication between the lateral prefrontal cortex (LPFC) and the hippocampus. Moreover, correlations between the LPFC (e.g., MFG) and hippocampus have predicted individuals' ability to inhibit memory retrieval. Anatomically, differences in volume of the hippocampus have been related to changes in long-term episodic memories. Although the relationship between these ideas is clear, few studies have examined the association of how anatomy may affect the role of control over brain regions involved in distint memory processes. The current study sought to examine hippocampal volume and its relationship to LPFC control over the hippocampus. Using an automated cortical/subcortical segmentation technique (FIRST) on brain imaging gata from the Think/No-Think task, we show that hippocampal volume is associated to changes in both enhancement and inhibitory processes of memory retrival.     

Spatial deficits in an amnesic patient with hippocampal damage: questioning the multiple trace theory

Mediotemporal lobe structures are involved in both spatial processing and long-term memory. Patient M.R. suffers from amnesia, due to bilateral hippocampal lesion and temporoparietal atrophy following carbon monoxide poisoning. We compared his performance in immediate spatial memory tasks with the performance of ten healthy matched participants. Using an immediate reproduction of path, we observed a dissociation between his performance in three allocentric tasks and in five egocentric-updating tasks. His performance was always impaired on tasks requiring the use of an egocentric-updating representation but remained preserved on allocentric tasks. These results fit with the hypothesis that the hippocampus plays a role in spatial memory, but they also suggest that allocentric deficits previously observed in amnesia might actually reflect deficits in egocentric-updating processes. Furthermore, the co-occurrence of deficits in episodic long-term memory and short-term egocentric-updating representation without any short-term allocentric deficit suggests a new link between the mnemonic and navigational roles of the hippocampus. The Cognitive Map theory, the Multiple Trace theory, as well as further models linking spatial and nonspatial functions of the hippocampus are discussed.     

Reduced parahippocampal connectivity produces schizophrenia-like memory deficits in simulated neural circuits with reduced parahippocampal connectivity

CONTEXT: Episodic memory impairments are well characterized in schizophrenia, but their neural origin is unclear. OBJECTIVE: To determine whether the episodic memory impairments in schizophrenia may originate from reduced parahippocampal connectivity. DESIGN: Experimental in silico model. SETTING: Department of Psychology, University of Amsterdam, Amsterdam, the Netherlands. INTERVENTIONS: A new, in silico medial temporal lobe model that simulates normal performance on a variety of episodic memory tasks was devised. The effects of reducing parahippocampal connectivity in the model (from perirhinal and parahippocampal cortex to entorhinal cortex and from entorhinal cortex to hippocampus) were evaluated and compared with findings in schizophrenic patients. Alternative in silico neuropathologies, increased noise and loss of hippocampal neurons, were also evaluated. RESULTS: In the model, parahippocampal processing subserves integration of different cortical inputs to the hippocampus and feature extraction during recall. Reduced connectivity in this area resulted in a pattern of deficits that closely mimicked the impairments in schizophrenia, including a mild recognition impairment and a more severe impairment in free recall. Furthermore, the schizophrenic model was not differentially sensitive to interference, also consistent with behavioral data. Notably, neither increased noise levels nor a reduction of hippocampal nodes in the model reproduced this characteristic memory profile. CONCLUSIONS: Taken together, these findings highlight the importance of parahippocampal neuropathology in schizophrenia, demonstrating that reduced connectivity in this region may underlie episodic memory problems associated with the disorder.