Intact memory for irrelevant information impairs perception in amnesia

Memory and perception have long been considered separate cognitive processes, and amnesia resulting from medial temporal lobe (MTL) damage is thought to reflect damage to a dedicated memory system. Recent work has questioned these views, suggesting that amnesia can result from impoverished perceptual representations in the MTL, causing an increased susceptibility to interference. Using a perceptual matching task for which fMRI implicated a specific MTL structure, the perirhinal cortex, we show that amnesics with MTL damage including the perirhinal cortex, but not those with damage limited to the hippocampus, were vulnerable to object-based perceptual interference. Importantly, when we controlled such interference, their performance recovered to normal levels. These findings challenge prevailing conceptions of amnesia, suggesting that effects of damage to specific MTL regions are better understood not in terms of damage to a dedicated declarative memory system, but in terms of impoverished representations of the stimuli those regions maintain.     

Intact performance on feature-ambiguous discriminations in rats with lesions of the perirhinal cortex

We developed a behavioral paradigm for the rat that made it possible to separate the evaluation of memory functions from the evaluation of perceptual functions. Animals were given extensive training on an automated two-choice discrimination task and then maintained their memory performance at a high level while interpolated probe trials tested visual perceptual ability. The probe trials systematically varied the degree of feature ambiguity between the stimuli, such that perceptual functions could be tested across 14 different levels of difficulty. As feature ambiguity increased, performance declined in an orderly, monotonic manner (from 87% correct to chance, 50% correct). Bilateral lesions of the perirhinal cortex fully spared the capacity to make feature-ambiguous discriminations and the performance of lesioned and intact animals was indistinguishable at every difficulty level. In contrast, the perirhinal lesions did impair recognition memory. The findings suggest that the perirhinal cortex is important for memory and not for perceptual functions.     

Consolidation of passive avoidance learning is associated with transient increases of polysialylated neurons in layer II of the rat medial temporal cortex

Within the rat medial temporal lobe, transient modulations of neural cell adhesion molecule (NCAM) polysialylation have been observed to follow spatial learning. These have been attributed to neuroplastic events associated with the processing of information destined for long term memory consolidation. To determine if similar events are associated with avoidance learning, we investigated change in polysialylated cell number in the entorhinal, perirhinal, and piriform cortex, following acquisition of a passive avoidance task in the rat. Direct quantification of polysialylated neurons in layer II of these cortical regions revealed a significant increase in polysialylated cell frequency at 12 h following passive avoidance training. Unlike spatial learning, the increased expression of polysialylated neurons persisted for up to 24-48 h following training. In the more dorsal aspect of the perirhinal/entorhinal cortex, this increase was found to be specific to learning, as it was not observed in animals rendered amnesic with scopolamine. By contrast, change in polysialylated cell frequency in the ventral aspect of the medial temporal lobe was only partially reduced by amnesic doses of scopolamine. The persisting activation of NCAM polysialylation in the more dorsal aspects of the perirhinal and entorhinal cortex is suggested to reflect the need for more extensive synaptic alterations, as compared to those required for the consolidation of spatial learning. Moreover, the neuroplastic modulations observed in the more ventral regions of the entorhinal and perirhinal cortex appear to be a unique aspect of avoidance conditioning that reflects the activation of alternative learning strategies associated with motivational and/or contextual parameters of the task.     

The medial temporal lobe supports conceptual implicit memory

The medial temporal lobe (MTL) is generally thought to be critical for explicit, but not implicit, memory. Here, we demonstrate that the perirhinal cortex (PRc), within the MTL, plays a role in conceptually-driven implicit memory. Amnesic patients with MTL lesions that converged on the left PRc exhibited deficits on two conceptual implicit tasks (i.e., exemplar generation and semantic decision). A separate functional magnetic resonance imaging (fMRI) study in healthy subjects indicated that PRc activation during encoding of words was predictive of subsequent exemplar generation. Moreover, across subjects, the magnitude of the fMRI and behavioral conceptual priming effects were directly related. Additionally, the PRc region implicated in the fMRI study was the same region of maximal lesion overlap in the patients with impaired conceptual priming. These patient and imaging results converge to suggest that the PRc plays a critical role in conceptual implicit memory, and possibly conceptual processing in general.     

Multisynaptic Inputs from the Medial Temporal Lobe to V4 in Macaques

Retrograde transsynaptic transport of rabies virus was employed to undertake the top-down projections from the medial temporal lobe (MTL) to visual area V4 of the occipitotemporal visual pathway in Japanese monkeys (Macaca fuscata). On day 3 after rabies injections into V4, neuronal labeling was observed prominently in the temporal lobe areas that have direct connections with V4, including area TF of the parahippocampal cortex. Furthermore, conspicuous neuron labeling appeared disynaptically in area TH of the parahippocampal cortex, and areas 35 and 36 of the perirhinal cortex. The labeled neurons were located predominantly in deep layers. On day 4 after the rabies injections, labeled neurons were found in the hippocampal formation, along with massive labeling in the parahippocampal and perirhinal cortices. In the hippocampal formation, the densest neuron labeling was seen in layer 5 of the entorhinal cortex, and a small but certain number of neurons were labeled in other regions, such as the subicular complex and CA1 and CA3 of the hippocampus proper. The present results indicate that V4 receives major input from the hippocampus proper via the entorhinal cortex, as well as “short-cut” pathways that bypass the entorhinal cortex. These multisynaptic pathways may define an anatomical basis for hippocampal-cortical interactions involving lower visual areas. The multisynaptic input from the MTL to V4 is likely to provide mnemonic information about object recognition that is accomplished through the occipitotemporal pathway.     

Modulation of activity in human visual area V1 during memory masking

Neurons in the primary visual cortex, V1, are specialized for the processing of elemental features of the visual stimulus, such as orientation and spatial frequency. Recent fMRI evidence suggest that V1 neurons are also recruited in visual perceptual memory; a number of studies using multi-voxel pattern analysis have successfully decoded stimulus-specific information from V1 activity patterns during the delay phase in memory tasks. However, consistent fMRI signal modulations reflecting the memory process have not yet been demonstrated. Here, we report evidence, from three subjects, that the low V1 BOLD activity during retention of low-level visual features is caused by competing interactions between neural populations coding for different values along the spectrum of the dimension remembered. We applied a memory masking paradigm in which the memory representation of a masker stimulus interferes with a delayed spatial frequency discrimination task when its frequency differs from the discriminanda with ±1 octave and found that impaired behavioral performance due to masking is reflected in weaker V1 BOLD signals. This cross-channel inhibition in V1 only occurs with retinotopic overlap between the masker and the sample stimulus of the discrimination task. The results suggest that memory for spatial frequency is a local process in the retinotopically organized visual cortex.     

Shaping of object representations in the human medial temporal lobe based on temporal regularities

Regularities are gradually represented in cortex after extensive experience [1], and yet they can influence behavior after minimal exposure [2, 3]. What kind of representations support such rapid statistical learning? The medial temporal lobe (MTL) can represent information from even a single experience [4], making it a good candidate system for assisting in initial learning about regularities. We combined anatomical segmentation of the MTL, high-resolution fMRI, and multivariate pattern analysis to identify representations of objects in cortical and hippocampal areas of human MTL, assessing how these representations were shaped by exposure to regularities. Subjects viewed a continuous visual stream containing hidden temporal relationships-pairs of objects that reliably appeared nearby in time. We compared the pattern of blood oxygen level-dependent activity evoked by each object before and after this exposure, and found that perirhinal cortex, parahippocampal cortex, subiculum, CA1, and CA2/CA3/dentate gyrus (CA2/3/DG) encoded regularities by increasing the representational similarity of their constituent objects. Most regions exhibited bidirectional associative shaping, whereas CA2/3/DG represented regularities in a forward-looking predictive manner. These findings suggest that object representations in MTL come to mirror the temporal structure of the environment, supporting rapid and incidental statistical learning.     

Object memory and perception in the medial temporal lobe: an alternative approach

The medial temporal lobe (MTL) includes several structures--the hippocampus, and the adjacent perirhinal, entorhinal and parahippocampal cortices--that have been associated with memory for at least the past 50 years. These components of the putative 'MTL memory system' are thought to operate together in the service of declarative memory--memory for facts and events--having little or no role in other functions such as perception. Object perception, however, is thought to be independent of the MTL, and instead is usually considered to be the domain of the ventral visual stream (VVS) or 'what' pathway. This 'textbook' view fits squarely into the prevailing paradigm of anatomical modularisation of psychological function in the brain. Recent studies, however, question this view, indicating that first, the MTL is functionally heterogeneous, and second, structures in the MTL might have a role in perception. Furthermore, the specific contributions of the individual structures within the MTL are being elucidated. These new findings indicate that it might no longer be useful to assume a strict functional dissociation between the MTL and the VVS, and that psychological functions might not be modularised in the way usually assumed. We propose an alternative approach to understanding the functions of these brain regions in terms of what computations they perform, and what representations they contain.     

One-trial visual recognition in cats: the role of the rhinal cortex

Visual recognition memory in primates is mediated at least in part by the perirhinal and entorhinal (i.e., rhinal) cortices. To examine the role of these structures in cats' visual recognition memory, we performed combined electrolytic rhinal (perirhinal and entorhinal) lesions in a group of cats trained in visual delayed matching-to-sample with trial-unique objects in the modified Wisconsin General Testing Apparatus. Sham-operated and intact cats were used as control groups. Cats with rhinal lesions did not differ from the control sham-operated and unoperated groups in initial learning of the rules of the task; difference between experimental and control groups under conditions of minimum 5-sec delay was nonsignificant as well. However, significant difference between experimental and control groups was revealed under conditions of testing with 10-sec delay. This finding suggests a disorder in the visual recognition memory.     

Medial temporal lobe projections to the retrosplenial cortex of the macaque monkey

The projections to the retrosplenial cortex (areas 29 and 30) from the hippocampal formation, the entorhinal cortex, perirhinal cortex, and amygdala were examined in two species of macaque monkey by tracking the anterograde transport of amino acids. Hippocampal projections arose from the subiculum and presubiculum to terminate principally in area 29. Label was found in layer I and layer III(IV), the former seemingly reflecting both fibers of passage and termination. While the rostral subiculum mainly projects to the ventral retrosplenial cortex, mid and caudal levels of the subiculum have denser projections to both the caudal and dorsal retrosplenial cortex. Appreciable projections to dorsal area 30 [layer III(IV)] were only seen following an extensive injection involving both the caudal subiculum and presubiculum. This same case provided the only example of a light projection from the hippocampal formation to posterior cingulate area 23 (layer III). Anterograde label from the entorhinal cortex injections was typically concentrated in layer I of 29a-c, though the very caudal entorhinal cortex appeared to provide more widespread retrosplenial projections. In this study, neither the amygdala nor the perirhinal cortex were found to have appreciable projections to the retrosplenial cortex, although injections in either medial temporal region revealed efferent fibers that pass very close or even within this cortical area. Finally, light projections to area 30V, which is adjacent to the calcarine sulcus, were seen in those cases with rostral subiculum and entorhinal injections. The results reveal a particular affinity between the hippocampal formation and the retrosplenial cortex, and so distinguish areas 29 and 30 from area 23 within the posterior cingulate region. The findings also suggest further functional differences within retrosplenial subregions as area 29 received the large majority of efferents from the subiculum. ? 2012 Wiley Periodicals, Inc.     

Visual short-term memory compared in rhesus monkeys and humans

Change detection is a popular task to study visual short-term memory (STM) in humans [1-4]. Much of this work suggests that STM has a fixed capacity of 4 ± 1 items [1-6]. Here we report the first comparison of change-detection memory between humans and a species closely related to humans, the rhesus monkey. Monkeys and humans were tested in nearly identical procedures with overlapping display sizes. Although the monkeys' STM was well fit by a one-item fixed-capacity memory model, other monkey memory tests with four-item lists have shown performance impossible to obtain with a one-item capacity [7]. We suggest that this contradiction can be resolved using a continuous-resource approach more closely tied to the neural basis of memory [8, 9]. In this view, items have a noisy memory representation whose noise level depends on display size as a result of the distributed allocation of a continuous resource. In accord with this theory, we show that performance depends on the perceptual distance between items before and after the change, and d' depends on display size in an approximately power-law fashion. Our results open the door to combining the power of psychophysics, computation, and physiology to better understand the neural basis of STM.     

Expression of long-term depression underlies visual recognition memory

The modifications occurring in the brain during learning and memory are still poorly understood but may involve long-lasting changes in synaptic transmission (synaptic plasticity). In perirhinal cortex, a lasting decrement in neuronal responsiveness is associated with visual familiarity discrimination, leading to the hypothesis that long-term depression (LTD)-like synaptic plasticity may underlie recognition memory. LTD relies on internalization of AMPA receptors (AMPARs) through interaction between their GluR2 subunits and AP2, the clathrin adaptor protein required for endocytosis. We demonstrate that a peptide that blocks interactions between GluR2 and AP2 blocks LTD in perirhinal cortex in vitro. Viral transduction of this peptide in perirhinal cortex produced striking deficits in visual recognition memory. Furthermore, there was a deficit of LTD in perirhinal cortex slices from virally transduced, recognition memory-deficient animals. These results suggest that internalization of AMPA receptors, a process critical for the expression of LTD in perirhinal cortex, underlies visual recognition memory.     

Sound facilitates visual learning

Numerous studies show that practice can result in performance improvements on low-level visual perceptual tasks [1-5]. However, such learning is characteristically difficult and slow, requiring many days of training [6-8]. Here, we show that a multisensory audiovisual training procedure facilitates visual learning and results in significantly faster learning than unisensory visual training. We trained one group of subjects with an audiovisual motion-detection task and a second group with a visual motion-detection task, and compared performance on trials containing only visual signals across ten days of training. Whereas observers in both groups showed improvements of visual sensitivity with training, subjects trained with multisensory stimuli showed significantly more learning both within and across training sessions. These benefits of multisensory training are particularly surprising given that the learning of visual motion stimuli is generally thought to be mediated by low-level visual brain areas [6, 9, 10]. Although crossmodal interactions are ubiquitous in human perceptual processing [11-13], the contribution of crossmodal information to perceptual learning has not been studied previously. Our results show that multisensory interactions can be exploited to yield more efficient learning of sensory information and suggest that multisensory training programs would be most effective for the acquisition of new skills.     

Transient and cumulative memory impairments induced by GSM 1.8 GHz cell phone signal in a mouse model

This study was designed to investigate the transient and cumulative impairments in spatial and non-spatial memory of C57Bl/6J mice exposed to GSM 1.8 GHz signal for 90 min daily by a typical cellular (mobile) phone at a specific absorption rate value of 0.11 W/kg. Free-moving male mice 2 months old were irradiated in two experimental protocols, lasting for 66 and for 148 days respectively. Each protocol used three groups of animals (n = 8 each for exposed, sham exposed and controls) in combination with two behavioural paradigms, the object recognition task and the object location task sequentially applied at different time points. One-way analysis of variance revealed statistically significant impairments of both types of memory gradually accumulating, with more pronounced effects on the spatial memory. The impairments persisted even 2 weeks after interruption of the 8 weeks daily exposure, whereas the memory of mice as detected by both tasks showed a full recovery approximately 1 month later. Intermittent every other day exposure for 1 month had no effect on both types of memory. The data suggest that visual information processing mechanisms in hippocampus, perirhinal and entorhinal cortex are gradually malfunctioning upon long-term daily exposure, a phenotype that persists for at least 2 weeks after interruption of radiation, returning to normal memory performance levels 4 weeks later. It is postulated that cellular repair mechanisms are operating to eliminate the memory affecting molecules. The overall contribution of several possible mechanisms to the observed cumulative and transient impairments in spatial and non-spatial memory is discussed.     

A model of the ventral visual system based on temporal stability and local memory

The cerebral cortex is a remarkably homogeneous structure suggesting a rather generic computational machinery. Indeed, under a variety of conditions, functions attributed to specialized areas can be supported by other regions. However, a host of studies have laid out an ever more detailed map of functional cortical areas. This leaves us with the puzzle of whether different cortical areas are intrinsically specialized, or whether they differ mostly by their position in the processing hierarchy and their inputs but apply the same computational principles. Here we show that the computational principle of optimal stability of sensory representations combined with local memory gives rise to a hierarchy of processing stages resembling the ventral visual pathway when it is exposed to continuous natural stimuli. Early processing stages show receptive fields similar to those observed in the primary visual cortex. Subsequent stages are selective for increasingly complex configurations of local features, as observed in higher visual areas. The last stage of the model displays place fields as observed in entorhinal cortex and hippocampus. The results suggest that functionally heterogeneous cortical areas can be generated by only a few computational principles and highlight the importance of the variability of the input signals in forming functional specialization.     

Backward signal from medial temporal lobe in neural circuit reorganization of primate inferotemporal cortex

Neuropsychological theories proposed a critical role of the interaction between the medial temporal lobe and neocortex in the formation of long-term memory for facts and events, which has often been tested by learning of a series of paired words or figures in humans. We identify neural mechanisms of this long-term memory formation process by single-unit recording and molecular biological methods in an animal model of visual pair-association task in monkeys. In our previous studies, we found a group of neurons that manifested selective responses to both of the paired associates (pair-coding neuron) in the anterior inferior temporal (IT) cortex. It provides strong evidence that single IT neurons acquire the response-selectivity through associative learning, and suggests that the reorganized neural circuits for the pair-coding neurons serve as the memory engram of the pair-association learning. In this article, we investigated further mechanisms of the neural circuit reorganization. First, we tested the role of the backward connections from the medial temporal lobe to IT cortex. lbotenic acid was injected unilaterally into the entorhinal and perirhinal cortex which provided massive backward projections ipsilaterally to IT cortex. We found that the limbic lesion disrupted the associative code of the IT neurons between the paired associates, without impairing the visual response to each stimulus. Second, we ask why the limbic-neocortical interactions are so important. We hypothesize that limbic neurons would undergo rapid modification of synaptic connectivity and provide backward signals that guide reorganization of neocortical neural circuits. We then investigated the molecular basis of such rapid synaptic modifiability by detecting the expression of immediate-early genes. We found strong expression of zif268 during the learning of a new set of paired associates, most intensively in area 36 of the perirhinal cortex. All these results with visual pair-association task support our hypothesis, and demonstrate that the ‘consolidation’ process, which was first proposed on the basis of clinico-psychological evidence, can now be examined in the primate with neurophysiolocical and molecular biological approaches.     

Against memory systems

The medial temporal lobe is indispensable for normal memory processing in both human and non-human primates, as is shown by the fact that large lesions in it produce a severe impairment in the acquisition of new memories. The widely accepted inference from this observation is that the medial temporal cortex, including the hippocampal, entorhinal and perirhinal cortex, contains a memory system or multiple memory systems, which are specialized for the acquisition and storage of memories. Nevertheless, there are some strong arguments against this idea: medial temporal lesions produce amnesia by disconnecting the entire temporal cortex from neuromodulatory afferents arising in the brainstem and basal forebrain, not by removing cortex; the temporal cortex is essential for perception as well as for memory; and response properties of temporal cortical neurons make it impossible that some kinds of memory trace could be stored in the temporal lobe. All cortex is plastic, and it is possible that the same rules of plasticity apply to all cortical areas; therefore, memory traces are stored in widespread cortical areas rather than in a specialized memory system restricted to the temporal lobe. Among these areas, the prefrontal cortex has an important role in learning and memory, but is best understood as an area with no specialization of function.     

A Comprehensive Protocol for Manual Segmentation of the Medial Temporal Lobe Structures

The present paper describes a comprehensive protocol for manual tracing of the set of brain regions comprising the medial temporal lobe (MTL): amygdala, hippocampus, and the associated parahippocampal regions (perirhinal, entorhinal, and parahippocampal proper). Unlike most other tracing protocols available, typically focusing on certain MTL areas (e.g., amygdala and/or hippocampus), the integrative perspective adopted by the present tracing guidelines allows for clear localization of all MTL subregions. By integrating information from a variety of sources, including extant tracing protocols separately targeting various MTL structures, histological reports, and brain atlases, and with the complement of illustrative visual materials, the present protocol provides an accurate, intuitive, and convenient guide for understanding the MTL anatomy. The need for such tracing guidelines is also emphasized by illustrating possible differences between automatic and manual segmentation protocols. This knowledge can be applied toward research involving not only structural MRI investigations but also structural-functional colocalization and fMRI signal extraction from anatomically defined ROIs, in healthy and clinical groups alike.     

Human hippocampal neurons predict how well word pairs will be remembered

What is the neuronal basis for whether an experience is recalled or forgotten? In contrast to recognition, recall is difficult to study in nonhuman primates and rarely is accessible at the single neuron level in humans. We recorded 128 medial temporal lobe (MTL) neurons in patients implanted with intracranial microelectrodes while they encoded and recalled word paired associates. Neurons in the amygdala, entorhinal cortex, and hippocampus showed altered activity during encoding (9%), recall (22%), and both task phases (23%). The responses of hippocampal neurons during encoding predicted whether or not subjects later remembered the pairs successfully. Entorhinal cortex neuronal activity during retrieval was correlated with recall success. These data provide support at the single neuron level for MTL contributions to encoding and retrieval, while also suggesting there may be differences in the level of contribution of MTL regions to these memory processes.