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.     

Functional neuroanatomy of the autobiographical memory

Autobiographical memory refers to events and information about personal life and the self. Within autobiographical memory, many authors make a difference between episodic and semantic components. Study of retrograde amnesia gives information about memory consolidation. According to the "standard model" of consolidation, the medial temporal lobe plays a time-limited role in retrieval memory. Functional neuroanatomy studies of autobiographical memory are very few and many are recent. These studies concern which brain regions are involved in the autobiographical retrieval, episodic or semantic autobiographical memory and consolidation process. Results show that autobiographical retrieval depends on specific brain regions like frontal cortex. Concerning memory consolidation, findings are most consistent with the idea that hippocampal complex is involved in both recent and remote memories.     

Recognition memory: what are the roles of the perirhinal cortex and hippocampus?

The hallmark of medial temporal lobe amnesia is a loss of episodic memory such that patients fail to remember new events that are set in an autobiographical context (an episode). A further symptom is a loss of recognition memory. The relationship between these two features has recently become contentious. Here, we focus on the central issue in this dispute--the relative contributions of the hippocampus and the perirhinal cortex to recognition memory. A resolution is vital not only for uncovering the neural substrates of these key aspects of memory, but also for understanding the processes disrupted in medial temporal lobe amnesia and the validity of animal models of this syndrome.     

Dissociations in cognitive memory: the syndrome of developmental amnesia

The dearth of studies on amnesia in children has led to the assumption that when damage to the medial temporal lobe system occurs early in life, the compensatory capacity of the immature brain rescues memory functions. An alternative view is that such damage so interferes with the development of learning and memory that it results not in selective cognitive impairments but in general mental retardation. Data will be presented to counter both of these arguments. Results obtained from a series of 11 amnesic patients with a history of hypoxic ischaemic damage sustained perinatally or during childhood indicate that regardless of age at onset of hippocampal pathology, there is a pronounced dissociation between episodic memory, which is severely impaired, and semantic memory, which is relatively preserved. A second dissociation is characterized by markedly impaired recall and relatively spared recognition leading to a distinction between recollection-based versus familiarity-based judgements. These findings are discussed in terms of the locus and extent of neuropathology associated with hypoxic ischaemic damage, the neural basis of 'remembering' versus 'knowing', and a hierarchical model of cognitive memory.     

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

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

Successful recollection of remote autobiographical memories by amnesic patients with medial temporal lobe lesions

Current views about the organization of human memory make strikingly different predictions about the integrity of remote autobiographical memory following damage to the medial temporal lobe. We have carried out a detailed analysis of narrative content in memory-impaired patients for whom neuropsychological and neuroanatomical information is available. All eight patients were able to recall detailed memories from their early lives. The recollections of the patients and the recollections of 25 matched controls contained the same number of details (+/-5%) and were also similar by several other measures. The results support the view that autobiographical memories eventually become independent of the medial temporal lobe as time passes after learning. A number of other considerations suggest that the neocortex ultimately supports the capacity for recollecting remote autobiographical memory.     

The organization of recent and remote memories

A fundamental question in memory research is how our brains can form enduring memories. In humans, memories of everyday life depend initially on the medial temporal lobe system, including the hippocampus. As these memories mature, they are thought to become increasingly dependent on other brain regions such as the cortex. Little is understood about how new memories in the hippocampus are transformed into remote memories in cortical networks. However, recent studies have begun to shed light on how remote memories are organized in the cortex, and the molecular and cellular events that underlie their consolidation.     

Interactions between attention and memory

Attention and memory cannot operate without each other. In this review, we discuss two lines of recent evidence that support this interdependence. First, memory has a limited capacity, and thus attention determines what will be encoded. Division of attention during encoding prevents the formation of conscious memories, although the role of attention in formation of unconscious memories is more complex. Such memories can be encoded even when there is another concurrent task, but the stimuli that are to be encoded must be selected from among other competing stimuli. Second, memory from past experience guides what should be attended. Brain areas that are important for memory, such as the hippocampus and medial temporal lobe structures, are recruited in attention tasks, and memory directly affects frontal-parietal networks involved in spatial orienting. Thus, exploring the interactions between attention and memory can provide new insights into these fundamental topics of cognitive neuroscience.     

Hierarchical organization of cognitive memory.

This paper addresses the question of the organization of memory processes within the medial temporal lobe. Evidence obtained in patients with late-onset amnesia resulting from medial temporal pathology has given rise to two opposing interpretations of the effects of such damage on long-term cognitive memory. One view is that cognitive memory, including memory for both facts and events, is served in a unitary manner by the hippocampus and its surrounding cortices; the other is that the basic function affected in amnesia is event memory, the memory for factual material often showing substantial preservation. Recent findings in patients with amnesia resulting from relatively selective hippocampal damage sustained early in life suggest a possible reconciliation of the two views. The new findings suggest that the hippocampus may be especially important for event as opposed to fact memory, with the surrounding cortical areas contributing to both. Evidence from neuroanatomical and neurobehavioural studies in monkeys is presented in support of this proposal.     

A unified model of spatial and episodic memory

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

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.     

Single-trial learning of novel stimuli by individual neurons of the human hippocampus-amygdala complex

The ability to distinguish novel from familiar stimuli allows nervous systems to rapidly encode significant events following even a single exposure to a stimulus. This detection of novelty is necessary for many types of learning. Neurons in the medial temporal lobe (MTL) are critically involved in the acquisition of long-term declarative memories. During a learning task, we recorded from individual MTL neurons in vivo using microwire electrodes implanted in human epilepsy surgery patients. We report here the discovery of two classes of neurons in the hippocampus and amygdala that exhibit single-trial learning: novelty and familiarity detectors, which show a selective increase in firing for new and old stimuli, respectively. The neurons retain memory for the stimulus for 24 hr. Thus, neurons in the MTL contain information sufficient for reliable novelty-familiarity discrimination and also show rapid plasticity as a result of single-trial learning.     

The cognitive neuroscience of remote episodic, semantic and spatial memory

The processes and mechanisms implicated in retention and retrieval of memories as they age is an enduring problem in cognitive neuroscience. Research from lesion and functional neuroimaging studies on remote episodic, semantic and spatial memory in humans is crucial for evaluating three theories of hippocampal and/or medial temporal lobe-neocortical interaction in memory retention and retrieval: cognitive map theory, standard consolidation theory and multiple trace theory. Each theory makes different predictions regarding first, the severity and extent of retrograde amnesia following lesions to some or all of the structures mentioned; second, the extent of activation of these structures to retrieval of memory across time; and third, the type of memory being retrieved. Each of these theories has strengths and weaknesses, and there are various unresolved issues. We propose a unified account based on multiple trace theory. This theory states that the hippocampus is needed for re-experiencing detailed episodic and spatial memories no matter how old they are, and that it contributes to the formation and assimilation of semantic memories and schematic spatial maps.     

The loss of episodic memories in retrograde amnesia: single-case and group studies

Retrograde amnesia in neurological disorders is a perplexing and fascinating research topic. The severity of retrograde amnesia is not well correlated with that of anterograde amnesia, and there can be disproportionate impairments of either. Within retrograde amnesia, there are various dissociations which have been claimed-for example, between the more autobiographical (episodic) and more semantic components of memory. However, the associations of different types of retrograde amnesia are also important, and clarification of these issues is confounded by the fact that retrograde amnesia seems to be particularly vulnerable to psychogenic factors. Large frontal and temporal lobe lesions have been postulated as critical in producing retrograde amnesia. Theories of retrograde amnesia have encompassed storage versus access disruption, physiological processes of 'consolidation', the progressive transformation of episodic memories into a more 'semantic' form, and multiple-trace theory. Single-case investigations, group studies and various forms of neuroimaging can all contribute to the resolution of these controversies.     

Episodic memory on the path to Alzheimer's disease

This review is focused on specific circuits of the medial temporal lobe that have become better understood in recent years for their computational properties contributing to episodic memory and to memory impairment associated with aging and other risk for AD. The layer II neurons in the entorhinal cortex and their targets in the dentate gyrus and CA3 region of hippocampus comprise a system that rapidly encodes representations that are distinct from prior memories. Frank neuron loss in the entorhinal cortex is specific for AD, and related structural and functional changes across the network comprised of the entorhinal cortex and the dentate/CA3 regions hold promise for predicting progression on the path to AD.     

Sequence learning: what's the hippocampus to do?

The medial temporal lobe is crucial for some forms of memory, but its role in implicit learning has remained in question. A brain imaging study by Schendan et al., in this issue of Neuron, provides direct evidence of medial temporal lobe activation during implicit learning of motor sequences.     

Item, context and relational episodic encoding in humans

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

Suppression of neurotoxic lesion-induced seizure activity: evidence for a permanent role for the hippocampus in contextual memory

Damage to the hippocampus (HPC) using the excitotoxin N-methyl-D-aspartate (NMDA) can cause retrograde amnesia for contextual fear memory. This amnesia is typically attributed to loss of cells in the HPC. However, NMDA is also known to cause intense neuronal discharge (seizure activity) during the hours that follow its injection. These seizures may have detrimental effects on retrieval of memories. Here we evaluate the possibility that retrograde amnesia is due to NMDA-induced seizure activity or cell damage per se. To assess the effects of NMDA induced activity on contextual memory, we developed a lesion technique that utilizes the neurotoxic effects of NMDA while at the same time suppressing possible associated seizure activity. NMDA and tetrodotoxin (TTX), a sodium channel blocker, are simultaneously infused into the rat HPC, resulting in extensive bilateral damage to the HPC. TTX, co-infused with NMDA, suppresses propagation of seizure activity. Rats received pairings of a novel context with foot shock, after which they received NMDA-induced, TTX+NMDA-induced, or no damage to the HPC at a recent (24 hours) or remote (5 weeks) time point. After recovery, the rats were placed into the shock context and freezing was scored as an index of fear memory. Rats with an intact HPC exhibited robust memory for the aversive context at both time points, whereas rats that received NMDA or NMDA+TTX lesions showed a significant reduction in learned fear of equal magnitude at both the recent and remote time points. Therefore, it is unlikely that observed retrograde amnesia in contextual fear conditioning are due to disruption of non-HPC networks by propagated seizure activity. Moreover, the memory deficit observed at both time points offers additional evidence supporting the proposition that the HPC has a continuing role in maintaining contextual memories.     

Developmental Changes in Memory-Related Linguistic Skills and Their Relationship to Episodic Recall in Children

This longitudinal study of nine children examined two issues concerning infantile amnesia: the time at which memories for events experienced before the age of 3–4 years disappear from consciousness and whether this timing of memory loss is related to the development of specific aspects of episodic and autobiographical memory. This study followed children from infancy to early childhood and examined the central role of three verbal–cognitive milestones related to autobiographical memory: the age at which children begin to report autobiographical memories using the past tense (Milestone 1); the age at which they begin to verbally acknowledge past events (Milestone 2); and the age at which they begin to spontaneously use memory-related verbs (Milestone 3). As expected, memories of events that occurred before 3–4 years of age were affected by infantile amnesia. Achievement of these milestones followed almost the same developmental progression: Milestone 1 (1 year; 10 months (1;10) to 3 years; 4 months (3;4)) was followed by Milestones 2 (3;1 to 4;0) and 3 (3;5 to 4;4). Milestone 2 was typically related to the onset of infantile amnesia, whereas Milestone 1 occurred during the period for which the children became amnesic as they aged. These data suggest that linguistic meta-cognitive awareness of personal memory is the key feature in infantile amnesia.     

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.