Short-Term Memory Depends on Dissociable Medial Temporal Lobe Regions in Amnestic Mild Cognitive Impairment.
ABSTRACT: Short-term memory (STM) has generally been thought to be independent of the medial temporal lobe (MTL) in contrast to long-term memory (LTM). Prodromal Alzheimer's disease (AD) is a condition in which the MTL is a major early focus of pathology and LTM is thought disproportionately affected relative to STM. However, recent studies have suggested a role for the MTL in STM, particularly hippocampus, when binding of different elements is required. Other work has suggested involvement of extrahippocampal MTL structures, particularly in STM tasks that involve item-level memory. We examined STM for individual objects, locations, and object-location conjunctions in amnestic mild cognitive impairment (MCI), often associated with prodromal AD. Relative to age-matched, cognitively normal controls, MCI patients not only displayed impairment on object-location conjunctions but were similarly impaired for non-bound objects and locations. Moreover, across all participants, these conditions displayed dissociable correlations of cortical thinning along the long axis of the MTL and associated cortical nodes of anterior and posterior MTL networks. These findings support the role of the MTL in visual STM tasks and the division of labor of MTL in support of different types of memory representations, overlapping with findings in LTM.
Project description:The medial temporal lobe (MTL), a set of heavily interconnected structures including the hippocampus and underlying entorhinal, perirhinal and parahippocampal cortex, is traditionally believed to be part of a unitary system dedicated to declarative memory. Recent studies, however, demonstrated perceptual impairments in amnesic individuals with MTL damage, with hippocampal lesions causing scene discrimination deficits, and perirhinal lesions causing object and face discrimination deficits. The degree of impairment on these tasks was influenced by the need to process complex conjunctions of features: discriminations requiring the integration of multiple visual features caused deficits, whereas discriminations that could be solved on the basis of a single feature did not. Here, we address these issues with functional neuroimaging in healthy participants as they performed a version of the oddity discrimination task used previously in patients. Three different types of stimuli (faces, scenes, novel objects) were presented from either identical or different viewpoints. Consistent with studies in patients, we observed increased perirhinal activity when participants distinguished between faces and objects presented from different, compared to identical, viewpoints. The posterior hippocampus, by contrast, showed an effect of viewpoint for both faces and scenes. These findings provide convergent evidence that the MTL is involved in processes beyond long-term declarative memory and suggest a critical role for these structures in integrating complex features of faces, objects, and scenes into view-invariant, abstract representations.
Project description:BACKGROUND:Deficits in short-term memory (STM) binding are a distinguishing feature of preclinical stages leading to Alzheimer's disease (AD). However, the neuroanatomical correlates of conjunctive STM binding are largely unexplored. Here we examine the possible association between the volumes of hippocampi, parahippocampal gyri, and grey matter within the subcortical structures - all found to have foci that seemingly correlate with basic daily living activities in AD patients - with cognitive tests related to conjunctive STM binding. MATERIALS AND METHODS:Hippocampal, thalamic, parahippocampal and corpus striatum volumes were semi-automatically quantified in brain magnetic resonance images from 25 cognitively normal people and 21 patients with Mild Cognitive Impairment (MCI) at high risk of AD progression, who undertook a battery of cognitive tests and the short-term memory binding test. Associations were assessed using linear regression models and group differences were assessed using the Mann-Whitney U test. RESULTS:Hippocampal and parahippocampal gyrus volumes differed between MCI and control groups. Although the grey matter volume in the globus pallidus (r = -0.71, p < 0.001) and parahippocampal gyry (r = -0.63, p < 0.05) correlated with a STM binding task in the MCI group, only the former remained associated with STM binding deficits in MCI patients, after correcting for age, gender and years of education (? = -0.56,P = 0.042) although with borderline significance. CONCLUSIONS:Loss of hippocampal volume plays no role in the processing of STM binding. Structures within the basal ganglia, namely the globus pallidus, could be part of the extrahippocampal network supporting binding. Replication of this study in large samples is now needed.
Project description:Long-term episodic memory deficits in Alzheimer's disease (AD) are well characterised but, until recently, short-term memory (STM) function has attracted far less attention. We employed a recently-developed, delayed reproduction task which requires participants to reproduce precisely the remembered location of items they had seen only seconds previously. This paradigm provides not only a continuous measure of localization error in memory, but also an index of relational binding by determining the frequency with which an object is misplaced to the location of one of the other items held in memory. Such binding errors in STM have previously been found on this task to be sensitive to medial temporal lobe (MTL) damage in focal lesion cases. Twenty individuals with pathological mutations in presenilin 1 or amyloid precursor protein genes for familial Alzheimer's disease (FAD) were tested together with 62 healthy controls. Participants were assessed using the delayed reproduction memory task, a standard neuropsychological battery and structural MRI. Overall, FAD mutation carriers were worse than controls for object identity as well as in gross localization memory performance. Moreover, they showed greater misbinding of object identity and location than healthy controls. Thus they would often mislocalize a correctly-identified item to the location of one of the other items held in memory. Significantly, asymptomatic gene carriers - who performed similarly to healthy controls on standard neuropsychological tests - had a specific impairment in object-location binding, despite intact memory for object identity and location. Consistent with the hypothesis that the hippocampus is critically involved in relational binding regardless of memory duration, decreased hippocampal volume across FAD participants was significantly associated with deficits in object-location binding but not with recall precision for object identity or localization. Object-location binding may therefore provide a sensitive cognitive biomarker for MTL dysfunction in a range of diseases including AD.
Project description:Behavioral research has yielded conflicting results regarding the architecture of short-term memory (STM). Whereas a consensus has emerged that within STM a single chunk within the focus of attention (FA) has a privileged status, it is unclear whether further distinctions exist. One proposal is that outside of FA, memory is all of one sort with a continuous progression from STM to long-term memory (LTM). On the other hand, sharp performance drop-offs when STM is loaded with more than 4±1 items suggest distinctions between STM and LTM. We use functional magnetic resonance imaging (fMRI) to adjudicate between these theories. A neural triple dissociation provided evidence for a 3-state model of memory. Critically, prefrontal cortex was selectively enhanced to retrieval from activated portions of LTM whereas the hippocampus was associated with retrieval of items within putative 4±1 capacity limits. We hypothesize that the associative properties of the hippocampus serve to inter-relate information actively maintained in STM which not only promotes strong STM, but also lays the foundations for subsequent LTM. By contrast, information not actively maintained in mind requires top-down retrieval processes mediated by the prefrontal cortex. These data provide key insights into the architecture of STM and its relationship to LTM.
Project description:Accumulating evidence suggests a critical role for epigenetic regulations in long term memory (LTM) formation. Among them, post-translational modifications of proteins, as histone acetylation, are an important regulator of chromatin remodelling and gene transcription. While the implication of histone acetylation in memory consolidation is widely accepted, less is known about its role in memory reconsolidation i.e. during memory restabilization after its reactivation. In the present study, we investigated the role of histone acetylation during the initial consolidation and the reconsolidation of spatial memory, using a weak massed learning procedure in the Morris water maze paradigm in mice. Usually a weak learning is sufficient for short term memory (STM) formation, but insufficient to upgrade STM to LTM. We found that promoting histone acetylation through intra-hippocampal infusion of a class I selective histone deacetylase (HDAC) inhibitor immediately after a subthreshold spatial learning improved LTM but not STM retention. More importantly, inhibiting HDAC activity after the reactivation of a weak memory promoted specifically LTM reconsolidation without affecting post-reactivation STM. These findings argue in favour of an important role for histone acetylation in memory consolidation, and more particularly during the reconsolidation of spatial memory in mice.
Project description:Previous neuropsychological findings have implicated medial temporal lobe (MTL) structures in retaining object-location relations over the course of short delays, but MTL effects have not always been reported in neuroimaging investigations with similar short-term memory requirements. Here, we used event-related functional magnetic resonance imaging to test the hypothesis that the hippocampus and related MTL structures support accurate retention of relational memory representations, even across short delays. On every trial, four objects were presented, each in one of nine possible locations of a three-dimensional grid. Participants were to mentally rotate the grid and then maintain the rotated representation in anticipation of a test stimulus: a rendering of the grid, rotated 90 degrees from the original viewpoint. The test stimulus was either a "match" display, in which object-location relations were intact, or a "mismatch" display, in which one object occupied a new, previously unfilled location (mismatch position), or two objects had swapped locations (mismatch swap). Encoding phase activation in anterior and posterior regions of the left hippocampus, and in bilateral perirhinal cortex, predicted subsequent accuracy on the short-term memory decision, as did bilateral posterior hippocampal activity after the test stimulus. Notably, activation in these posterior hippocampal regions was also sensitive to the degree to which object-location bindings were preserved in the test stimulus; activation was greatest for match displays, followed by mismatch-position displays, and finally mismatch-swap displays. These results indicate that the hippocampus and related MTL structures contribute to successful encoding and retrieval of relational information in visual short-term memory.
Project description:Critical to perceiving an object is the ability to bind its constituent features into a cohesive representation, yet the manner by which the visual system integrates object features to yield a unified percept remains unknown. Here, we present a novel application of multivoxel pattern analysis of neuroimaging data that allows a direct investigation of whether neural representations integrate object features into a whole that is different from the sum of its parts. We found that patterns of activity throughout the ventral visual stream (VVS), extending anteriorly into the perirhinal cortex (PRC), discriminated between the same features combined into different objects. Despite this sensitivity to the unique conjunctions of features comprising objects, activity in regions of the VVS, again extending into the PRC, was invariant to the viewpoints from which the conjunctions were presented. These results suggest that the manner in which our visual system processes complex objects depends on the explicit coding of the conjunctions of features comprising them.
Project description:The induction, formation and maintenance of memory represent dynamic processes modulated by multiple factors including the circadian clock and sleep. Chronic sleep restriction has become common in modern society due to occupational and social demands. Given the impact of cognitive impairments associated with sleep deprivation, there is a vital need for a simple animal model in which to study the interactions between chronic sleep deprivation and memory. We used the marine mollusk Aplysia californica, with its simple nervous system, nocturnal sleep pattern and well-characterized learning paradigms, to assess the effects of two chronic sleep restriction paradigms on short-term (STM) and long-term (LTM) associative memory. The effects of sleep deprivation on memory were evaluated using the operant learning paradigm, learning that food is inedible, in which the animal associates a specific netted seaweed with failed swallowing attempts. We found that two nights of 6h sleep deprivation occurring during the first or last half of the night inhibited both STM and LTM. Moreover, the impairment in STM persisted for more than 24h. A milder, prolonged sleep deprivation paradigm consisting of 3 consecutive nights of 4h sleep deprivation also blocked STM, but had no effect on LTM. These experiments highlight differences in the sensitivity of STM and LTM to chronic sleep deprivation. Moreover, these results establish Aplysia as a valid model for studying the interactions between chronic sleep deprivation and associative memory paving the way for future studies delineating the mechanisms through which sleep restriction affects memory formation.
Project description:The Atkinson-Shiffrin modal model forms the foundation of our understanding of human memory. It consists of three stores (Sensory Memory (SM), also called iconic memory, Short-Term Memory (STM), and Long-Term Memory (LTM)), each tuned to a different time-scale. Since its inception, the STM and LTM components of the modal model have undergone significant modifications, while SM has remained largely unchanged, representing a large capacity system funneling information into STM. In the laboratory, visual memory is usually tested by presenting a brief static stimulus and, after a delay, asking observers to report some aspect of the stimulus. However, under ecological viewing conditions, our visual system receives a continuous stream of inputs, which is segmented into distinct spatio-temporal segments, called events. Events are further segmented into event-segments. Here we show that SM is not an unspecific general funnel to STM but is allocated exclusively to the current event-segment. We used a Multiple-Object Tracking (MOT) paradigm in which observers were presented with disks moving in different directions, along bi-linear trajectories, i.e., linear trajectories, with a single deviation in direction at the mid-point of each trajectory. The synchronized deviation of all of the trajectories produced an event stimulus consisting of two event-segments. Observers reported the pre-deviation or the post-deviation directions of the trajectories. By analyzing observers' responses in partial- and full-report conditions, we investigated the involvement of SM for the two event-segments. The hallmarks of SM hold only for the current event segment. As the large capacity SM stores only items involved in the current event-segment, the need for event-tagging in SM is eliminated, speeding up processing in active vision. By characterizing how memory systems are interfaced with ecological events, this new model extends the Atkinson-Shiffrin model by specifying how events are stored in the first stage of multi-store memory systems.
Project description:There is a surge of studies confirming that old age spares the ability to bind in visual working memory (VWM) multiple features within singular object representations. Furthermore, it has been suggested that such ability may also be independent of the cultural background of the assessed individual. However, this evidence has been gathered with tasks that use arbitrary bindings of unfamiliar features. Whether age spares memory binding functions when the memoranda are features of everyday life objects remains less well explored. The present study investigated the influence of age, memory delay, and education, on conjunctive binding functions responsible for representing everyday items in VWM. We asked 32 healthy young and 41 healthy older adults to perform a memory binding task. During the task, participants saw visual arrays of objects, colours, or coloured objects presented for 6 s. Immediately after they were asked either to select the objects or the colours that were presented during the study display from larger sets of objects or colours, or to recombine them by selecting from such sets the objects and their corresponding colours. This procedure was repeated immediately after but this time providing a 30 s unfiled delay. We manipulated familiarity by presenting congruent and incongruent object-colour pairings. The results showed that the ability to bind intrinsic features in VWM does not decline with age even when these features belong to everyday items and form novel or well-known associations. Such preserved memory binding abilities held across memory delays. The impact of feature congruency on item-recognition appears to be greater in older than in younger adults. This suggests that long-term memory (LTM) supports binding functions carried out in VWM for familiar everyday items and older adults still benefit from this LTM support. We have expanded the evidence supporting the lack of age effects on VWM binding functions to new feature and object domains (i.e., everyday items). We have confirmed that education does not negatively impact on such ability at old age. Such results have important implications for the selection of culturally unbiased tests to screen for abnormal ageing trajectories.