Dissociating the past from the present in the activity of place cells

It has been proposed that declarative memories can be dependent on both an episodic and a semantic memory system. While the semantic system deals with factual information devoid of reference to its acquisition, the episodic system, characterized by mental time travel, deals with the unique past experience in which an event took place. Episodic memory is characteristically hippocampus-dependent. Place cells are recorded from the hippocampus of rodents and their firing reflects many of the key characteristics of episodic memory. For example, they encode information about "what" happens "where," as well as temporal information. However, when these features are expressed during an animal's behavior, the neuronal activity could merely be categorizing the present situation and could therefore reflect semantic memory rather than episodic memory. We propose that mental time travel is the key feature of episodic memory and that it should take a form, in the awake animal, similar to the replay of behavioral patterns of activity that has been observed in hippocampus during sleep. Using tasks designed to evoke episodic memory, one should be able to see memory reactivation of behaviorally relevant sequences of activity in the awake animal while recording from hippocampus and other cortical structures.     

Validation of computerized episodic memory measures in a diverse clinical sample referred for neuropsychological assessment

Objective: To examine the convergent and discriminant validity of two brief computerized episodic memory measures in a large, diverse clinical sample of adults undergoing neuropsychological assessment. Method: Computerized measures of word and face memory were administered to 233 adults (age 30 and over) who also completed comprehensive neuropsychological testing. Results: Moderate correlations were observed between the computerized memory tests and a wide range of traditional neuropsychological measures of episodic memory (e.g. word-list learning, story recall, face recognition, design recall). Select measures of visuomotor processing speed and language were also related to performance on the computerized tasks. In contrast, the computerized memory tests showed weak correlations with tests in other cognitive domains (i.e. visuospatial skills, attention/working memory, executive function, motor dexterity, academic skills) and self-report screening measures of mood and anxiety. Similar to traditional measures of episodic memory, the computerized memory measures were sensitive to effects of age and gender. Conclusions: Computerized measures of word and face memory showed good convergent and discriminant validity in this diverse clinical sample supporting the construct validity of these measures. This indicates that it may be feasible to measure memory function in clinical settings using brief, well-designed computerized memory measures.     

Episodic memory--from brain to mind

Neuronal mechanisms of episodic memory, the conscious recollection of autobiographical events, are largely unknown because electrophysiological studies in humans are conducted only in exceptional circumstances. Unit recording studies in animals are thus crucial for understanding the neurophysiological substrate that enables people to remember their individual past. Two features of episodic memory--autonoetic consciousness, the self-aware ability to "travel through time", and one-trial learning, the acquisition of information in one occurrence of the event--raise important questions about the validity of animal models and the ability of unit recording studies to capture essential aspects of memory for episodes. We argue that autonoetic experience is a feature of human consciousness rather than an obligatory aspect of memory for episodes, and that episodic memory is reconstructive and thus its key features can be modeled in animal behavioral tasks that do not involve either autonoetic consciousness or one-trial learning. We propose that the most powerful strategy for investigating neurophysiological mechanisms of episodic memory entails recording unit activity in brain areas homologous to those required for episodic memory in humans (e.g., hippocampus and prefrontal cortex) as animals perform tasks with explicitly defined episodic-like aspects. Within this framework, empirical data suggest that the basic structure of episodic memory is a temporally extended representation that distinguishes the beginning from the end of an event. Future research is needed to fully understand how neural encodings of context, sequences of items/events, and goals are integrated within mnemonic representations of autobiographical events.     

The effect of retrieval cues on post-retrieval monitoring in episodic memory: an electrophysiological study

The aim of the present experiment was to examine whether episodic retrieval and 'post-retrieval' monitoring are affected by the nature of the cue that guides a search of memory. We recorded event-related brain potentials (ERPs) from young healthy adult participants while they tried to recall studied words (e.g. 'MOTHER') with the aid of word-stem (e.g. 'MOT') and word-fragment (e.g. 'M-TH--') retrieval cues. Analyses of the behavioural data showed that while it was far more difficult to generate completions per se for the fragments, the levels of conscious, or 'explicit', recall obtained with each type of cue were statistically identical. ERP analyses focussed upon differences in neural activity evoked by each type of cue (termed 'old/new' ERP effects) during successful versus unsuccessful retrieval. The stem and fragment old/new ERP effects were remarkably similar in their time course and magnitude, and also in their scalp distribution, which changed over time as multiple neuronal populations, and hence multiple cognitive operations, became activated. These behavioural and ERP findings suggest that the cognitive operations reflected by old/new effects in cued recall tasks may be insensitive to changes in the retrieval strategy, or effort, that participants apply to monitor the episodic status of retrieved information. The findings are discussed in relation to previous ERP and functional imaging studies that have investigated task-specific features of retrieval and post-retrieval processing in episodic memory.     

Implications of animal object memory research for human amnesia

Damage to structures in the human medial temporal lobe causes severe memory impairment. Animal object recognition tests gained prominence from attempts to model ‘global’ human medial temporal lobe amnesia, such as that observed in patient HM. These tasks, such as delayed nonmatching-to-sample and spontaneous object recognition, for assessing object memory in non-human primates and rodents have proved invaluable as animal models of specific aspects of human declarative memory processes. This paper reviews research in non-human primates and rats using object recognition memory tasks to assess the neurobiological bases of amnesia. A survey of this research reveals several important implications for our understanding of the anatomical basis of memory and the medial temporal lobe amnesic syndrome. First, research with monkeys and rats reveals that the contributions of medial temporal lobe structures such as the hippocampus and perirhinal cortex to memory processes are dissociable, with particular structures contributing to specific tasks on the basis of the specific type of information that a structure is optimized to process. Second, the literature suggests that cognitive tasks requiring integration of different types of information, such as in the case of complex, multimodal declarative memory, will recruit structures of the medial temporal lobe in an interactive manner. The heterogeneity of function within the medial temporal lobe, as well as the multimodal and complex nature of human declarative memory, implies that animal tests of object recognition memory, once believed to be comprehensive models for the study of human global amnesia, model just one important facet of human declarative memory. Finally, in light of the research reviewed here, it is apparent that the specific nature of amnesia observed in an individual with medial temporal lobe damage will depend on the particular medial temporal lobe regions affected and their specific representational capacities.     

抑郁症和早期阿尔茨海默病的记忆和执行功能

目的 研究抑郁症和早期阿尔茨海默病(AD)的神经心理学特征,试图运用神经心理学评估对两者进行鉴别。方法 对32例单相抑郁症、38例早期AD和34例对照进行WHO-UCLA词语学习、词语流畅、复杂图形和逻辑记忆的评估。结果 早期AD组神经心理学测验得分最低,抑郁症组次之,对照组最高,3组之间有显著性差异(P<0.01);抑郁症组仅表现为词语学习和逻辑记忆的自由回忆以及语义流畅的损害(P<0.05),而早期AD组表现为全面的认知功能损害(P<0.01);逐步判别分析提示,复杂图形延迟自由回忆、词语学习长时延迟自由回忆和语义流畅是区分抑郁症组和早期AD组的重要指标。结论 抑郁症和早期AD认知功能损害的特征不同,长时延迟自由回忆、再认和语义流畅能够区分早期AD和抑郁症。     

Sex differences in the effect of acute tryptophan depletion on declarative episodic memory: a pooled analysis of nine studies

Acute tryptophan depletion (ATD) studies have shown that serotonin plays a role in learning and memory processes. In this study, we performed a pooled analysis of nine ATD studies in order to examine the nature of the memory-impairing effects of ATD and mediating factors, such as gender, age and vulnerability for disease in which disturbed serotonin was hypothesized to play a role. All studies that were used in this pooled analysis assessed declarative episodic memory using a verbal learning task paradigm. Immediate recall, delayed recall, and delayed recognition scores were examined. A total of 211 participants were included in the analysis. The analysis revealed that ATD impaired not only delayed recall, but also immediate recall. The ATD-induced impairments were larger in females than in males. Furthermore, ATD did not interact with any other serotonergic vulnerability and age. This suggests that the only factor that actually has the properties of a serotonergic vulnerability factor for declarative memory performance is female gender. The findings provide further support for a critical role of serotonin in declarative episodic memory.     

Hippocampal place cells, context, and episodic memory

Although most observers agree that the hippocampus has a critical role in learning and memory, there remains considerable debate about the precise functional contribution of the hippocampus to these processes. Two of the most influential accounts hold that the primary function of the hippocampus is to generate cognitive maps and to mediate episodic memory processes. The well-documented spatial firing patterns (place fields) of hippocampal neurons in rodents, along with the spatial learning impairments observed with hippocampal damage support the cognitive mapping hypothesis. The amnesia for personally experienced events seen in humans with hippocampal damage and the data of animal models, which show severe memory deficits associated with hippocampal lesions, support the episodic memory account. Although an extensive literature supports each of these hypotheses, a specific contribution of place cells to episodic memory has not been clearly demonstrated. Recent data from our laboratory, together with previous findings, indicate that hippocampal place fields and neuronal responses to task-relevant stimuli are highly sensitive to the context, even when the contexts are defined by abstract task demands rather than the spatial geometry of the environment. On the basis of these findings, it is proposed that place fields reflect a more general context processing function of the hippocampus. Hippocampal context representations could serve to differentiate contexts and prime the relevant memories and behaviors. Since episodic memories, by definition, include information about the time and place where the episode occurred, contextual information is a necessary prerequisite for any episodic memory. Thus, place fields contribute importantly to episodic memory as part of the needed context representations. Additionally, recent findings indicate that hippocampal neurons differentiate contexts at progressively finer levels of detail, suggesting a hierarchical coding scheme which, if combined with temporal information, could provide a means of differentiating memory episodes.     

Computational models of the hippocampal region: implications for prediction of risk for Alzheimer's disease in non-demented elderly

We have pursued an interdisciplinary research program to develop novel behavioral assessment tools for evaluating specific memory impairments following damage to the medial temporal lobe, including the hippocampus and associated structures that show pathology early in the course of Alzheimer's disease (AD). Our approach uses computational models to identify the functional consequences of hippocampal-region damage, leading to testable predictions in both rodents and humans. Our modeling argues that hippocampal-region dysfunction may selectively impair the ability to generalize when familiar information is presented in novel recombinations. Previous research has shown that specific reductions in hippocampal volume in non-demented elderly individuals correlate with future development of AD. In two previous studies, we tested non-demented elderly with and without mild hippocampal atrophy (HA) on stimulus-response learning tasks. Individuals with and without HA could learn the initial information, but the HA group was selectively impaired on transfer tests where familiar features and objects were recombined. This suggests that such generalization deficits may be behavioral markers of HA, and an early indicator of risk for subsequent cognitive decline. Converging support for the relevance of these tasks to aging and Alzheimer's disease comes from our recent fMRI studies of individuals with mild cognitive impairment (MCI). Activity in the hippocampus declines with progressive training on these tasks, suggesting that the hippocampus is important for learning new stimulus representations that support subsequent transfer. Individuals with HA may be able to learn, but in a more hippocampal-independent fashion that does not support later transfer. Ultimately, this line of research could lead to a novel battery of behavioral tests sensitive to very mild hippocampal atrophy and risk for decline to AD, allowing early diagnosis and also allowing researchers to test new Alzheimer's drugs that target individuals in the earliest stages of the disease - before significant cognitive decline. A new mouse version of one of our tasks shows promise for translating these paradigms into rodents, allowing for future studies of therapeutic interventions in transgenic mouse models of AD.     

Oestrogen replacement therapy may improve memory functioning in the absence of APOE epsilon4

There is currently intense controversy regarding the use of hormone replacement therapy (HRT) in postmenopausal women, in relation to its therapeutic efficacy in Alzheimer's disease (AD). It has been suggested that the benefits of HRT may be modified by apolipoprotein E (APOE) genotype (the major genetic risk factor for AD). Here we report the findings of the first study designed to systematically explore the interaction of (a) oestrogen replacement therapy (ERT) and (b) possession of an epsilon4 allele of APOE on specific elements of episodic learning and memory that are commonly used indices of age-related cognitive decline. This data represents a cross-sectional analysis of the interaction of ERT and APOE genotype on learning and memory in a cohort of 181 healthy postmenopausal women [ERT users (n = 101, mean age 65.40 +/- 6.34); ERT non-users (n = 80, mean age 67.03 +/- 6.80)] residing in Perth, Western Australia. The highest level of learning (trials 2-5; P < 0.05) and memory (e.g. total number of items recalled; P < 0.05) performance was observed in women taking ERT who were not carriers of the APOE epsilon4 allele. APOEepsilon4 carriers receiving ERT performed no better on episodic memory testing than APOE epsilon4 carriers who were not receiving ERT. These cognitive differences related to genetic profile, were noted on both recall and recognition (P = 0.005) tests of memory. The findings have significance for evaluating whether and when ERT may be clinically indicated. Specifically, ERT may benefit the cognitive functioning of women not carrying the APOE epsilon4 allele.     

Sex differences in episodic memory among children with intractable epilepsy

This study investigated whether children with epilepsy exhibit sex differences in episodic memory. Fifty-one children and adolescents (26 boys and 25 girls) with intractable epilepsy were administered two verbal-auditory tasks (learning and recall of a word list and story recall) and two visual tasks (design recall and face recognition). Girls exhibited an advantage on the delayed recall of stories and on the learning phase of the word list task. No significant differences were observed on the delayed recall of words or the visual tasks. These results identify a particular risk for cognitive impairment in boys that could have an important impact on their academic performance.     

Hand gestures support word learning in patients with hippocampal amnesia

Co‐speech hand gesture facilitates learning and memory, yet the cognitive and neural mechanisms supporting this remain unclear. One possibility is that motor information in gesture may engage procedural memory representations. Alternatively, iconic information from gesture may contribute to declarative memory representations mediated by the hippocampus. To investigate these alternatives, we examined gesture's effects on word learning in patients with hippocampal damage and declarative memory impairment, with intact procedural memory, and in healthy and in brain‐damaged comparison groups. Participants learned novel label‐object pairings while producing gesture, observing gesture, or observing without gesture. After a delay, recall and object identification were assessed. Unsurprisingly, amnesic patients were unable to recall the labels at test. However, they correctly identified objects at above chance levels, but only if they produced a gesture at encoding. Comparison groups performed well above chance at both recall and object identification regardless of gesture. These findings suggest that gesture production may support word learning by engaging nondeclarative (procedural) memory.     

Visual-Spatial Memory and Recall Test (V-SMART): validity and reliability*

Abstract

Objective: Nonverbal memory decline is a concern associated with aging. Visuospatial memory tests often do not distinguish between learning, recall, or retrieval, yet such distinctions may help clarify the nature of memory difficulties. Further, many visuospatial tests rely on abilities not directly related to memory (e.g. graphomotor skill). The present study examined the feasibility and initial psychometric evidence of the Visual-Spatial Memory and Recall Test (V-SMART). Method: Ninety-nine adults (71% women) were recruited from two sources: undergraduate students (n = 37) and healthy older adults (n = 62). Volunteers completed a brief battery of cognitive tests. Results: Internal consistency and interrater reliability were strong. Principal Components Analysis supported the hypothesized learning and recall structure, and correlations with other memory tests supported external validity of the V-SMART as a visuospatial learning measure. Correlations with recall scores were less compelling yet likely reflected the intact recall among this generally healthy sample. Conclusions: These preliminary findings support the V-SMART as a visuospatial memory test. Evidence for validity was acceptable for learning indices; further examination of recall measures is needed.     

The case for episodic memory in animals

The conscious recollection of unique personal experiences in terms of their details (what), their locale (where) and temporal occurrence (when) is known as episodic memory and is thought to require a ‘self-concept’, autonoetic awareness/conciousness, and the ability to subjectively sense time. It has long been held that episodic memory is unique to humans, because it was accepted that animals lack a ‘self-concept’, ‘autonoetic awareness’, and the ability to ‘subjectively sense time’. These assumptions are now being questioned by behavioral evidence showing that various animal species indeed show behavioral manifestations of different features of episodic memory such as, e.g. ‘metacognition’, ‘conscious recollection’ of past events, ‘temporal order memory’, ‘mental time travel’ and have the capacity to remember personal experiences in terms of what happened, where and when. The aim of this review is to provide a comprehensive overview on the current progress in attempts to model different prerequisites and features of human episodic memory in animals and to identify possible neural substrates of animal episodic memory. The literature covered includes behavioral and physiological studies performed with different animal species, such as non-human primates, rodents, dolphins and birds. The search for episodic memory in animals has forced researchers to define objective behavioral criteria by which different features of episodic memory can be operationalized experimentally and assessed in both animals and humans. This is especially important because the current definition of episodic memory in terms of mentalistic constructs such as ‘self’, ‘autonoetic awareness/consciousness’, and ‘subjectively sensed time’, not only hinders animal research on the neurobiology of episodic memory but also research with healthy human subjects as well as neuropsychiatric patients with impaired language or in children with less-developed verbal abilities.     

Overlap in the functional neural systems involved in semantic and episodic memory retrieval

Neuroimaging and neuropsychological data suggest that episodic and semantic memory may be mediated by distinct neural systems. However, an alternative perspective is that episodic and semantic memory represent different modes of processing within a single declarative memory system. To examine whether the multiple or the unitary system view better represents the data we conducted a network analysis using multivariate partial least squares (PLS ) activation analysis followed by covariance structural equation modeling (SEM) of positron emission tomography data obtained while healthy adults performed episodic and semantic verbal retrieval tasks. It is argued that if performance of episodic and semantic retrieval tasks are mediated by different memory systems, then there should differences in both regional activations and interregional correlations related to each type of retrieval task, respectively. The PLS results identified brain regions that were differentially active during episodic retrieval versus semantic retrieval. Regions that showed maximal differences in regional activity between episodic retrieval tasks were used to construct separate functional models for episodic and semantic retrieval. Omnibus tests of these functional models failed to find a significant difference across tasks for both functional models. The pattern of path coefficients for the episodic retrieval model were not different across tasks, nor were the path coefficients for the semantic retrieval model. The SEM results suggest that the same memory network/system was engaged across tasks, given the similarities in path coefficients. Therefore, activation differences between episodic and semantic retrieval may ref lect variation along a continuum of processing during task performance within the context of a single memory system.     

Competition among multiple memory systems: converging evidence from animal and human brain studies

Research of the neurobiological bases of learning and memory suggest that these processes are not unitary in nature, but rather that relatively independent neural systems appear to mediate different types of memory. Neurobiological studies, for instance, have identified separable cognitive or "declarative" and stimulus-response "habit" memory systems that rely upon the medial temporal lobe (e.g. hippocampus) and basal ganglia (e.g. caudate-putamen), respectively. Evidence indicates that multiple memory systems are activated simultaneously and in parallel in various learning tasks, and recent findings suggest that these systems may interact. One form of interaction between medial temporal lobe and basal ganglia memory systems appears competitive in nature, and has been revealed in non-human animal studies in which damage to a given memory system results in enhanced learning. Recent human neuroimaging research has also provided evidence in favor of competition between memory systems. Thus, converging evidence across species supports the hypothesis of interactive multiple memory systems in the mammalian brain. Potential neurobiological mechanisms mediating such interactions include direct anatomical projections between the medial temporal lobe and basal ganglia, indirect neuromodulatory influences of other brain structures (e.g. basolateral amygdala) and activity of neocortical brain regions involved in top-down response selection.     

Schizophrenia patients demonstrate a dissociation on declarative and non-declarative memory tests

Declarative memory refers to the recall and recognition of factual information. In contrast, non-declarative memory entails a facilitation of memory based on prior exposure and is typically assessed with priming and perceptual-motor sequencing tasks. In this study, schizophrenia patients were compared to normal comparison subjects on two computerized memory tasks: the Word-stem Priming Test (n=30) and the Pattern Sequence Learning Test (n=20). Word-stem Priming includes recall, recognition (declarative) and priming (non-declarative) components of memory. The schizophrenia patients demonstrated an impaired performance on recall of words with relative improvement during the recognition portion of the test. Furthermore, they performed normally on the priming portion of the test. Thus, on tests of declarative memory, the patients had retrieval deficits with intact performance on the non-declarative memory component. The Pattern Sequence Learning Test utilizes a serial reaction time paradigm to assess non-declarative memory. The schizophrenia patients' serial reaction time was significantly slower than that of comparison subjects. However, the patients' rate of acquisition was not different from the normal comparison group. The data suggest that patients with schizophrenia process more slowly than normal, but have an intact non-declarative memory. The schizophrenia patients' dissociation on declarative vs. non-declarative memory tests is discussed in terms of possible underlying structural impairment.     

The appetitively motivated "cognitive" holeboard: a family of complex spatial discrimination tasks for assessing learning and memory

Spatial learning and memory tasks have captured a solid position in neuroscience research. A variety of holeboard-type tasks are suitable for investigating the effects of a broad range of experimental manipulations on spatial learning and memory in a broad range of species, including fish, rodents, cats, pigs, tupaias, and humans. We summarize the concepts and procedures underlying tests of spatial discrimination learning, with special emphasis on holeboard-type tasks and task-specific characteristics. Holeboard-type tasks enable a broad range of mnemonic and cognitive variables to be measured in parallel, including cognitive processes such as habituation processes, spatial working and reference memory, and search strategies, but also non-cognitive variables, such as exploration, anxiety-related behavior, and stereotypies. These tasks are sensitive to a large number of naturally occurring differences (e.g. strain differences and age effects) and to the effects of non-genetic (e.g. specific brain lesions, stress, treatment with cognition impairers or cognition enhancers) and genetic experimental manipulations.In conclusion, holeboard-type tasks provide powerful tools to investigate multiple aspects of spatial orientation behavior in the same experimental setup. Cross-species comparison of holeboard performance shows the potential for translational studies.     

The hippocampus and declarative memory: cognitive mechanisms and neural codes.

It is widely accepted that the hippocampus and related brain areas mediate declarative (or explicit) memory in humans. However, little is known about the fundamental cognitive mechanisms of hippocampal dependent memory or about the nature of hippocampal neural representations that underlie properties of declarative memory. Here, it is proposed that the hippocampus plays a critical role, when distinct personal experiences must be encoded in relation to one another and linked within an organization that supports flexible, inferential memory expression. This set of fundamental cognitive mechanisms is consistent with key properties of declarative memory as observed in humans. Furthermore, emerging evidence from recordings of hippocampal neural activity shows that hippocampal networks encode episodic memories as sequences of events and the places, where they occur. In addition, hippocampal neuronal networks encode events and places that are common across related episodes. This combination of coding properties suggests that the hippocampus contributes to declarative memory by mediating the construction of a "memory space" composed of a network of linked episodic representations.