Temporal Lobe Memory System Research Articles

Large-Scale Functional Brain Network Abnormalities in Alzheimer’s Disease: Insights from Functional Neuroimaging

Functional MRI (fMRI) studies of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) have begun to reveal abnormalities in large-scale memory and cognitive brain networks. Since the medial temporal lobe (MTL) memory system is a site of very early pathology in AD, a number of studies have focused on this region of the brain. Yet it is clear that other regions of the large-scale episodic memory network are affected early in the disease as well, and fMRI has begun to illuminate functional abnormalities in frontal, temporal, and parietal cortices as well in MCI and AD. Besides predictable hypoactivation of brain regions as they accrue pathology and undergo atrophy, there are also areas of hyperactivation in brain memory and cognitive circuits, possibly representing attempted compensatory activity. Recent fMRI data in MCI and AD are beginning to reveal relationships between abnormalities of functional activity in the MTL memory system and in functionally connected brain regions, such as the precuneus. Additional work with “resting state” fMRI data is illuminating functional-anatomic brain circuits and their disruption by disease. As this work continues to mature, it will likely contribute to our understanding of fundamental memory processes in the human brain and how these are perturbed in memory disorders. We hope these insights will translate into the incorporation of measures of task-related brain function into diagnostic assessment or therapeutic monitoring, which will hopefully one day be useful for demonstrating beneficial effects of treatments being tested in clinical trials.

Large-scale functional brain network abnormalities in Alzheimer's disease: insights from functional neuroimaging.

Functional MRI (fMRI) studies of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) have begun to reveal abnormalities in large-scale memory and cognitive brain networks. Since the medial temporal lobe (MTL) memory system is a site of very early pathology in AD, a number of studies have focused on this region of the brain. Yet it is clear that other regions of the large-scale episodic memory network are affected early in the disease as well, and fMRI has begun to illuminate functional abnormalities in frontal, temporal, and parietal cortices as well in MCI and AD. Besides predictable hypoactivation of brain regions as they accrue pathology and undergo atrophy, there are also areas of hyperactivation in brain memory and cognitive circuits, possibly representing attempted compensatory activity. Recent fMRI data in MCI and AD are beginning to reveal relationships between abnormalities of functional activity in the MTL memory system and in functionally connected brain regions, such as the precuneus. Additional work with “resting state” fMRI data is illuminating functional-anatomic brain circuits and their disruption by disease. As this work continues to mature, it will likely contribute to our understanding of fundamental memory processes in the human brain and how these are perturbed in memory disorders. We hope these insights will translate into the incorporation of measures of task-related brain function into diagnostic assessment or therapeutic monitoring, which will hopefully one day be useful for demonstrating beneficial effects of treatments being tested in clinical trials.

Social memory in mice: Disruption with an NMDA antagonist and attenuation with antipsychotic drugs

Social recognition reflects the ability of one animal to learn and remember the identity of another. Animal models of social learning and memory are pertinent to several different CNS diseases involving disruptions in cognition. Moreover, the increased understanding of the basic biology of memory increases the likelihood of discovery of memory-enhancing treatments in these human diseases. In the present study, we investigated the effects of the non-competitive NMDA antagonist ketamine on social recognition in mice across a broad dose range (5–30 mg/kg) and time-course (60 min–7 days). We also tested the ability of two antipsychotic drugs, haloperidol and olanzapine, to block the ketamine effect. Our results show that mice demonstrate social recognition over a several day period, with loss of recognition between 3–7 days. Ketamine disrupts social memory at doses which do not affect task performance. Chronic oral administration of haloperidol or olanzapine attenuates these ketamine-induced effects on social recognition, tending to normalize the memory behavior. The neural mechanisms of these actions are not known, although medial temporal lobe memory systems have been implicated.

Towards a functional organization of the medial temporal lobe memory system: role of the parahippocampal and medial entorhinal cortical areas.

Whereas substantial recent evidence has suggested to some that the medial entorhinal cortexá (MEC) plays a specialized role in spatial navigation, here we present evidence consistent with a broader role of the MEC in memory. A consideration of evidence on the anatomy and functional roles of medial temporal cortical areas and the hippocampus, and evidence from recordings from MEC neurons in rats performing a spatial memory task, suggest that the MEC may process information about both spatial and temporal context in support of episodic memory.

Role of Amygdala Connectivity in the Persistence of Emotional Memories Over Time: An Event-Related fMRI Investigation

According to the consolidation hypothesis, enhanced memory for emotional information reflects the modulatory effect of the amygdala on the medial temporal lobe (MTL) memory system during consolidation. Although there is evidence that amygdala-MTL connectivity enhances memory for emotional stimuli, it remains unclear whether this enhancement increases over time, as consolidation processes unfold. To investigate this, we used functional magnetic resonance imaging to measure encoding activity predicting memory for emotionally negative and neutral pictures after short (20-min) versus long (1-week) delays. Memory measures distinguished between vivid remembering (recollection) and feelings of knowing (familiarity). Consistent with the consolidation hypothesis, the persistence of recollection over time (long divided by short) was greater for emotional than neutral pictures. Activity in the amygdala predicted subsequent memory to a greater extent for emotional than neutral pictures. Although this advantage did not vary with delay, the contribution of amygdala-MTL connectivity to subsequent memory for emotional items increased over time. Moreover, both this increase in connectivity and amygdala activity itself were correlated with individual differences in recollection persistence for emotional but not neutral pictures. These results suggest that the amygdala and its connectivity with the MTL are critical to sustaining emotional memories over time, consistent with the consolidation hypothesis.

Activation of the human medial temporal lobes by stereoscopic depth cues

The perirhinal cortex (PER) is part of both the medial temporal lobe memory system (MTL) and the ventral visual stream (VVS). In the MTL, PER provides input to the hippocampal formation directly and via the entorhinal cortex (EC), whereas in the VVS, PER is considered to be at the top of the visual processing hierarchy of object information. Because of its position in both networks, PER presumably serves a role in memory and visual perception. PER's perceptual role is thought to be contingent upon the complexity of visual information, i.e., PER only becomes active in visual perception when many higher order visual cues are combined. Using high-resolution functional MRI (fMRI), we investigated the effect of varying the presence of binocular disparity, in complex visual object stimuli. Nineteen subjects were presented with movies of complex objects and a fixation cross, either with or without binocular disparity (referred to as stereo and mono condition respectively). Subjects were instructed to attentively watch the objects, but no instructions were given to memorize them. Group results showed increased activity in the MTL, among which is PER, when comparing the stereo over the mono condition (stereo > mono). Individual analysis showed dominant activation in the stereo > mono contrast in eleven out of nineteen subjects, whereas only three subjects showed dominance in the opposite contrast. We conclude that the MTL is differentially activated by the stereo and mono condition, such that activation is stronger when a complex visual object stimulus with disparity is presented.

Functional abnormalities of the medial temporal lobe memory system in mild cognitive impairment and Alzheimer's disease: Insights from functional MRI studies

Functional MRI (fMRI) studies of mild cognitive impairment (MCI) and Alzheimer's disease (AD) have begun to reveal abnormalities in memory circuit function in humans suffering from memory disorders. Since the medial temporal lobe (MTL) memory system is a site of very early pathology in AD, a number of studies, reviewed here, have focused on this region of the brain. By the time individuals are diagnosed clinically with AD dementia, the substantial memory impairments appear to be associated with not only MTL atrophy but also hypoactivation during memory task performance. Prior to dementia, when individuals are beginning to manifest signs and symptoms of memory impairment, the hippocampal formation and other components of the MTL memory system exhibit substantial functional abnormalities during memory task performance. It appears that, early in the course of MCI when memory deficits and hippocampal atrophy are less prominent, there may be hyperactivation of MTL circuits, possibly representing inefficient compensatory activity. Later in the course of MCI, when considerable memory deficits are present, MTL regions are no longer able to activate during attempted learning, as is the case in AD dementia. Recent fMRI data in MCI and AD are beginning to reveal relationships between abnormalities of functional activity in the MTL memory system and in functionally connected brain regions, such as the precuneus. As this work continues to mature, it will likely contribute to our understanding of fundamental memory processes in the human brain and how these are perturbed in memory disorders. We hope these insights will translate into the incorporation of measures of task-related brain function into diagnostic assessment or therapeutic monitoring, such as for use in clinical trials.

Accounting for change in declarative memory: A cognitive neuroscience perspective

The medial temporal lobe memory system matures relatively early and supports rudimentary declarative memory in young infants. There is considerable development, however, in the memory processes that underlie declarative memory performance during infancy. Here we consider age-related changes in encoding, retention, and retrieval in the context of current knowledge about the brain systems that may underlie these memory processes. While changes in infants’ encoding may be attributed to rapid myelination during the first year of life, improvements in long-term retention and flexible retrieval are likely due to the prolonged development of the dentate gyrus. Future studies combining measures of brain and behavior are critical in improving our understanding of how brain development drives memory development during infancy and early childhood.

Memory, perception, and the ventral visual‐perirhinal‐hippocampal stream: Thinking outside of the boxes

The prevailing paradigm in cognitive neuroscience assumes that the brain can be best understood as consisting of modules specialised for different psychological functions. Within the field of memory, we assume modules for different kinds of memory. The most influential version of this view posits a module called the "medial temporal lobe memory system" which operates in the service of "declarative memory." This system can be contrasted with a separate "perceptual representation system" in the ventral visual stream, which is critical for perceptual learning and memory, an example of nondeclarative function. Here we question this modular memory systems view and suggest that a better way to understand the ventral visual-perirhinal-hippocampal stream is as a hierarchically organised representational continuum. We suggest that in general, rather than trying to map psychological functions onto brain modules, we could benefit by instead attempting to understand the functions of brain regions in terms of the representations they contain, and the computations they perform.

Analysis of resurgent sodium-current expression in rat parahippocampal cortices and hippocampal formation

The resurgent Na + current ( I NaR) is a component of neuronal voltage-dependent Na + currents that is activated by repolarization and is believed to result from an atypical path of Na +-channel recovery from inactivation. So far, I NaR has only been identified in a small number of central neuronal populations in the cerebellum, diencephalon, and brainstem. The possible presence and roles of I NaR in neurons of the cerebral cortex and temporal-lobe memory system are still uncharacterized. In this study whole-cell, patch-clamp experiments were carried out in acute rat brain slices to investigate I NaR expression and properties in several neuronal populations of the parahippocampal region and hippocampal formation. Specifically, we examined pyramidal neurons of perirhinal cortex areas 36 and 35 (layers II and V); neurons of superficial and deep layers of medial entorhinal cortex (mEC); dentate gyrus (DG) granule cells; and pyramidal cells of the CA3 and CA1 hippocampal fields. I NaR was found to be thoroughly expressed in parahippocampal cortices. The most consistent and prominent I NaR expression was observed in mEC layer-II cells. A vast majority of areas 36 and 35 neurons (both in layers II and V) and mEC layer-III and -V neurons were also endowed with I NaR, although at lower amplitude levels. I NaR was expressed by ∼ 60% of DG granule cells and ∼ 35% of CA1 pyramidal cells of the ventral hippocampus, whereas it was never observed in CA3 neurons (both in the ventral and dorsal hippocampus) and CA1 neurons of the dorsal hippocampus. The biophysical properties of I NaR were very similar in all of the neuronal types in which the current was observed, with a peak in the current–voltage relationship at − 35/− 40 mV. Our results show that the parahippocampal region and part of the hippocampal formation are sites of major I NaR expression, and provide a new basis for further studies on the molecular correlates of I NaR.

Structural Plasticity: Rewiring the Brain

Experience may shape brain structure. Recent studies in which brain connections were traced in monkeys who had learnt a new skill or recovered from an injury suggest that extensive rewiring is possible, even in the adult brain.

Emotional memory in schizophrenia

Emotionally arousing scenes are better remembered than neutral ones. The biological basis of this emotional memory effect has been studied in lesion and neuro-imaging studies and depends upon an interaction between the amygdala and medial temporal lobe memory systems including the hippocampus. This study sought to investigate whether patients with schizophrenia had performance deficits on emotional memory tasks consistent with abnormal amygdala function. Patients with schizophrenia and matched control subjects were shown scenes with negative, positive and neutral emotional content. Subjects rated the slides according to how emotionally arousing they found them and then performed surprise memory tests at 10 min (recall) and 3 weeks (recall and recognition). Subjects with schizophrenia did not differ from control subjects in their ratings of the slides. However, patients showed a significant loss of the emotional enhancement of recognition memory for both negative and positive scenes. In addition, patients showed an overall deficit in recall memory, with a selective impairment in recall of the most arousing negative slides. These findings are consistent with the view that medial temporal lobe and in particular amygdala function is abnormal in schizophrenia.

Interaction between a verbal working memory network and the medial temporal lobe

The irrelevant speech effect illustrates that sounds that are irrelevant to a visually presented short-term memory task still interfere with neuronal function. In the present study we explore the functional and effective connectivity of such interference. The functional connectivity analysis suggested an interaction between the level of irrelevant speech and the correlation between in particular the left superior temporal region, associated with verbal working memory, and the left medial temporal lobe. Based on this psycho-physiological interaction, and to broaden the understanding of this result, we performed a network analysis, using a simple network model for verbal working memory, to analyze its interaction with the medial temporal lobe memory system. The results showed dissociations in terms of network interactions between frontal as well as parietal and temporal areas in relation to the medial temporal lobe. The results of the present study suggest that a transition from phonological loop processing towards an engagement of episodic processing might take place during the processing of interfering irrelevant sounds. We speculate that, in response to the irrelevant sounds, this reflects a dynamic shift in processing as suggested by a closer interaction between a verbal working memory system and the medial temporal lobe memory system.

The Placing Test: Preliminary Investigations of a Quick and Simple Memory Test Designed to be Sensitive to Pre-dementia Alzheimer's Disease but not to Normal Ageing

The medial temporal lobe (MTL) memory system is damaged early in Alzheimer's disease. Cognitive tests designed to help diagnose the disease must detect dysfunction in this system, but must also be insensitive to the cognitive slowing that characterizes normal ageing. On the assumption that the MTL system forms new memories by binding together the many informational aspects of events into units, The Placing Test was designed to index this function by measuring the ability to remember associations between faces and their locations. The influence of normal ageing was minimized by using procedures that compensate for the difficulties in learning and retrieval caused by the cognitive slowing of normal ageing. In two experiments The Placing Test was administered as part of a battery of neuropsychological tests to a group of healthy older people. In both studies, performance in The Placing Test correlated significantly with other measures of memory, but had weaker associations than standard memory measures with other types of cognitive function. The Placing Test appeared not to be biased by age, education or gender, although a larger sample is needed to verify this. A final study examined the performance of 16 patients with suspected Alzheimer's disease. These patients showed clear impairment in The Placing Test, with 81% scoring below the 5th percentile, despite the majority having normal MMSE scores. It is concluded that The Placing Test provides a quick, simple and sensitive measure of memory that has potential to be useful in routine diagnostic investigations for Alzheimer's disease. Elizabeth Anderson's work was supported by a Wellcome Trust Prize Studentship. All the staff at the OPTIMA project have provided considerable help and support during the course of this work. We would also like to thank the OPTIMA controls and patients who agreed to give up additional time to take part in this research. Dr. Julia Hornak very kindly provided photographs for the Missing Objects test. Thanks are also due to Anne Baker for her help in recruiting the additional subjects required for Study 1b from the Department of Experimental Psychology, Oxford University.

Perirhinal cortex and feature-ambiguous discriminations

Perirhinal cortex is often regarded as part of a medial temporal lobe (MTL) memory system, mediating memory selectively, and having little role in other functions such as perception (e.g., Squire and Zola-Morgan 1991; Buffalo et al. 1998, 1999; Squire et al. 2004). We and others have argued against this idea, suggesting instead that perirhinal cortex may have a role in perception (e.g., Buckley and Gaffan 1997; Murray and Bussey 1999; Buckley et al. 2001; Bussey and Saksida 2002). Evidence to support this view has come from recent work indicating that lesions of perirhinal cortex can impair the discrimination of visual stimuli. Perirhinal cortex is not, however, important for all types of visual discrimination (Buckley and Gaffan 1997; Hampton and Murray 2002), only for those requiring representations of complex conjunctions of features (Saksida and Bussey 1998; Murray and Bussey 1999; Buckley et al. 2001; Eacott et al. 2001; Bussey and Saksida 2002; Bussey et al. 2002, 2003). These discriminations possess a high degree of “feature ambiguity,” a property of visual discriminations that can emerge when features are a part of both rewarded and unrewarded stimuli (Bussey and Saksida 2002). In one such study (Bussey et al. 2003), we used complex featureambiguous “morphed” photographic stimuli to test this idea (Fig. 1). Monkeys were first trained on a pairwise discrimination of unmorphed photographs (e.g., images 1 and 40 in Fig.1). This was followed by the critical performance test session, in which the monkeys were presented with three pairs of stimuli: the trained pair, and two pairs in which the photographs had been morphed together to different degrees, thus creating three levels of perceptual difficulty. It was found that monkeys with perirhinal cortex lesions were impaired on the perceptually difficult, but not the perceptually easy, pairs (Fig. 2). This impairment was specific to complex, high feature-ambiguity discriminations: The lesions did not affect difficult color or size discriminations, indicating that the impairment was not due simply to the difficulty of the discriminations. Levy et al. (2005) investigated visual discrimination ability in amnesic patients using similar stimulus materials to those used in our monkey study. In their report, these authors challenge our previously published results, and call for a reanalysis of our previously published data, suggesting that an impairment in new learning may explain the poor performance in our monkeys with perirhinal cortex damage. Specifically they ask: “In the case of the study with blended images, it was suggested that learning was required during initial discrimination learning but not during the 32 test trials with blended images. Accordingly, it was suggested that impaired performance during the trials with blended images reflected impaired visual perception, not an impairment in learning and memory. This interpretation was based on an analysis of variance that indicated that no further learning occurred across the 32 trials (the 32 trials were partitioned into eight four-trial blocks). There was also no group x trial-block interaction. Yet, one wonders how monkeys performed on the first one or two blocks of the test trials with blended images. Did generalization fail altogether? One also wonders whether the impaired performance during these test trials could reflect to some degree the fact that control monkeys improved more during the test trials than the monkeys with perirhinal lesions. Did no learning occur at all? Accordingly, it

Perirhinal cortical contributions to object perception

The traditional theory of the medial temporal lobe (MTL) memory system asserts that the primate MTL (hippocampus, perirhinal, entorhinal and parahippocampal cortices) is exclusively involved in consolidating declarative memories. However, several recent reports have directly challenged this dogma by arguing that MTL structures also contribute to perception. Controversy remains as many of the behavioural tasks used have confounded memory with perception. We review the evidence here and highlight new studies in humans and macaques that indicate a perceptual role for MTL in the absence of such confounds. We argue that the challenge to MTL memory system theory is substantiated and that the implications are considerable, namely that most psychologists and neuroscientists have held a fundamentally flawed view of how memory is implemented in the brain.

Individual differences in generalization and imitation: what is the role of brain development?

Jones and Herbert describe research on deferred imitation and how this research reflects on the development of explicit memory in infancy. The article raises several interesting questions about how the medial temporal lobe memory system develops. In this commentary, I discuss some of the additional theoretical and empirical questions that are raised by the target article, and propose ways that these questions could be addressed in future research. Copyright © 2006 John Wiley & Sons, Ltd.

No effect of hippocampal lesions on perirhinal cortex-dependent feature-ambiguous visual discriminations

Previous studies have shown that perirhinal cortex lesions in monkeys impair visual discriminations with a high degree of "feature ambiguity," a property of visual discriminations that can emerge when features are a part of both rewarded and unrewarded stimuli. The effects of damage to the hippocampus on these perirhinal-dependent feature-ambiguous tasks are, however, unknown. Prominent theories of medial temporal lobe function predict similar effects of perirhinal cortex and hippocampal lesions on cognitive tasks. In contrast, our hypothesis is that perirhinal cortex, and not the hippocampus, is important for nonspatial complex feature-ambiguous discriminations. We sought to distinguish between these competing theories in a straightforward way, by testing rhesus monkeys with hippocampal lesions on the same feature-ambiguous tasks shown previously to depend on perirhinal cortex. It was found that hippocampal lesions had no effects on any of these tasks. The findings support the perceptual-mnemonic/feature conjunction model of perirhinal cortex function, and provide further evidence for heterogeneity of function within the putative medial temporal lobe memory system.

Interictal Slow-Wave Focus in Left Medial Temporal Lobe during Bilateral Electroconvulsive Therapy

The interictal state between two electroconvulsive therapy (ECT) sessions is clinically characterised by possible cognitive adverse effects like mild amnestic syndrome. ECT-induced mnestic deficits can persist for several weeks after ECT. Electrophysiologically, slowing of brain electrical activity in the interictal state has often been reported. Especially, for bilateral ECT a correlation between enhanced left frontotemporal theta activity and retrograde amnesia has been demonstrated. This study focuses on the topographic distribution of cortical slow-wave oscillations during the interictal state of a bilateral ECT cycle. Twelve patients with major depression have been investigated with 32-channel resting EEG 24 h after the 6th ECT session. As controls, 8 major depressive patients were investigated prior to antidepressive treatment. The generating sources of slow-wave activity are estimated within the theta frequency band with low-resolution brain electromagnetic tomography. Source analysis revealed a distinct pattern of theta activity in the depth of the left temporal lobe (fusiform and parahippocampal gyri, Brodmann areas 37 and 36, respectively; p< 0.05) during the interictal state. This finding suggests a dysfunction of the left medial temporal lobe memory system during the interictal state of a bilateral ECT cycle. It will further be discussed whether it is possible to obtain information about activity of deep brain structures like the hippocampal formation from scalp-recorded signals.

Towards an explicit account of implicit learning

The human brain supports acquisition mechanisms that can extract structural regularities implicitly from experience without the induction of an explicit model. Reber defined the process by which an individual comes to respond appropriately to the statistical structure of the input ensemble as implicit learning. He argued that the capacity to generalize to new input is based on the acquisition of abstract representations that reflect underlying structural regularities in the acquisition input. We focus this review of the implicit learning literature on studies published during 2004 and 2005. We will not review studies of repetition priming ('implicit memory'). Instead we focus on two commonly used experimental paradigms: the serial reaction time task and artificial grammar learning. Previous comprehensive reviews can be found in Seger's 1994 article and the Handbook of Implicit Learning. Emerging themes include the interaction between implicit and explicit processes, the role of the medial temporal lobe, developmental aspects of implicit learning, age-dependence, the role of sleep and consolidation. The attempts to characterize the interaction between implicit and explicit learning are promising although not well understood. The same can be said about the role of sleep and consolidation. Despite the fact that lesion studies have relatively consistently suggested that the medial temporal lobe memory system is not necessary for implicit learning, a number of functional magnetic resonance studies have reported medial temporal lobe activation in implicit learning. This issue merits further research. Finally, the clinical relevance of implicit learning remains to be determined.