Memory in autism: review and synthesis

Much research about memory in autism concerns the hypothesis that autism is similar to adult-onset amnesia. Initial support for the hypothesis came from post-mortem studies of individuals with autism showing abnormalities in the hippocampus and related brain structures, as well as behavioral studies finding contrasts between intact cued recall and impaired free recall and recognition in autism. The hypothesis was later brought into question by the finding of intact performance in individuals with autism on explicit memory tasks typically impaired in adult-onset amnesia. The present paper proposes a possible reconciliation of these contradictory findings, suggesting that there is selective damage to the limbic-prefrontal episodic memory system, sparing the limbic-only perceptual representation system, and the semantic memory system. This view is consistent with other evidence for early selective damage to other systems involving cooperation between the limbic system and the medial prefrontal cortex in autism.     

Memory function in normal aging.

We evaluated memory function in a group of 161 community-dwelling, cognitively normal individuals aged 62 to 100 years recruited as part of the Mayo Clinic Alzheimer's Disease Patient Registry. We used the Free and Cued Selective Reminding Test and the Rey Auditory Verbal Learning Test to evaluate two aspects of memory function thought to be sensitive to the effects of aging: learning (acquisition) and delayed recall (forgetting). The results were quite consistent and demonstrated that learning or acquisition performance declines uniformly with increasing age but is not related to education. Delayed recall or forgetting, however, remained relatively stable across age when adjusted for the amount of material initially learned. These findings are relevant for assessing normal memory function relative to the early impairments found in dementia and form a baseline against which memory performance can be assessed by the clinician. In particular, suspicion regarding a disorder of brain function affecting memory processes should be raised if learning performance declines more rapidly than expected or if delayed recall is impaired to any significant extent.     

Preserved hippocampus activation in normal aging as revealed by fMRI

The hippocampus is deteriorated in various pathologies such as Alzheimer's disease (AD) and such deterioration has been linked to memory impairment. By contrast, the structural and functional effects of normal aging on the hippocampus is a matter of debate, with some findings suggesting deterioration and others providing evidence of preservation. This constitutes a crucial question since many investigations on AD are based on the assumption that the deterioration of the hippocampus is the breaking point between normal and pathological aging. A growing number of fMRI studies specifically aimed at investigating hippocampal engagement in various cognitive tasks, notably memory tasks, but the results have been inconclusive. Here, we optimized the episodic face‐name paired‐associates task in order to test the functioning of the hippocampus in normal aging. Critically, we found no difference in the activation of the hippocampus between the young and a group of older participants. Analysis of individual patterns of activation substantiated this impression. Collectively, these findings provide evidence of preserved hippocampal functioning in normal aging. © 2010 Wiley‐Liss, Inc.     

A case of amnesia at an early age

A dissociation between short- and long-term memory (LTM) and between the episodic and the semantic component of LTM is reported in a young girl who became amnesic at the age of 6 after an episode of acute encephalopathy resulting in bilateral frontal, insular, thalamic, ponto-mesencephalic, hippocampal and temporal lesions, as documented by MRI. The girl became amnesic a few months after starting school. A follow-up investigation showed that she was able to learn to read, write and acquire number facts and procedures and to improve her semantic knowledge. Our results show that the features of adult amnesia can also be found in children and that new semantic knowledge can be acquired in spite of an anterograde memory deficit. This dissociation does not agree with theories viewing long- term declarative memory as a unitary process mediated by the hippocampal system, but supports recent hypotheses that the acquisition of semantic knowledge is independent from episodic memory processes, and takes place through spared cortical regions subjacent to the hippocampi (Vargha-Khadem et al., 1997).     

Preserved semantic learning in an amnesic patient

A case study is reported of an amnesic patient (KN), who displayed an ability to learn a substantial body of new visual and verbal semantic concepts, despite having a severe deficit in episodic memory. In two experiments, using an errorless learning paradigm, he was able to perform at a level close to that of his wife, who served as a control subject. When recall of material was retested after a delay of several months, during which time there were no further learning sessions, his retention was at least as good as, if not better, than that of his wife. This is taken as further evidence for the dissociation of semantic and episodic processes in amnesia. It also provides further evidence for the role of "errorless learning" in efficient acquisition of new facts in amnesia.     

Amnesia and the organization of the hippocampal system

Early hippocampal injury in humans has been found to result in a limited form of global anterograde amnesia. At issue is whether the limitation is qualitative, with the amnesia reflecting substantially greater impairment in episodic than in semantic memory, or only quantitative, with both episodic and semantic memory being partially and equivalently impaired. Evidence from neuroanatomical and lesion studies in animals suggests that the hippocampus and subhippocampal cortices form a hierarchically organized system, such that the greatest convergence of information (and, by implication, the richest amount of association) takes place within the hippocampus, located at the top of the hierarchy. On the one hand, this evidence is consistent with the view that selective hippocampal damage produces a differential impairment in context-rich episodic memory as compared with context-free semantic memory, because only the latter can be supported by the subhippocampal cortices. On the other hand, given the system's hierarchical form of organization, this dissociation of deficits is difficult to prove, because a quantitatively limited deficit will nearly always be a viable alternative. A final choice between the alternative views is therefore likely to depend less on further evidence gathered in brain-injured patients than on which view accounts for more of the data gathered from converging approaches to the problem. Hippocampus 1998;8:212–216. © 1998 Wiley-Liss, Inc.     

Memory for unfamiliar faces differentiates mild cognitive impairment from normal aging

Memory for unfamiliar faces has received little attention in the effort to identify neuropsychological measures that could differentiate mild cognitive impairment (MCI) from normal aging and/or predict conversion from MCI to dementia. We used the Wechsler Memory Scale–III Faces test to investigate facial memory in normal aging (n = 58), MCI (n = 74), and mild Alzheimer’s disease (n = 22). After adjustment for age, gender, and years of education, MCI patients demonstrated significantly poorer memory for unfamiliar faces than their healthy peers. Lower scores were also associated with worsening cognition and functional abilities but not an increased risk of dementia.     

Long-term memory following transient global amnesia: an investigation of episodic and semantic memory

BACKGROUND: Several studies noted persistence of memory impairment following an episode of transient global amnesia (TGA) with standard tests. AIM: To specify long-term memory impairments in a group of patients selected with stringent criteria. METHODS: Both retrograde and anterograde memory were investigated in 32 patients 13-67 months after a TGA episode with original tasks encompassing retrograde semantic memory (academic, public and personal knowledge), retrograde episodic memory (autobiographical events) and anterograde episodic memory. RESULTS: Patients had preserved academic and public knowledge. Pathological scores were obtained in personal verbal fluency for the two most recent periods, and patients produced less autobiographical events than controls. However, when they were provided time to detail, memories were as episodic as in controls regardless of their remoteness. Anterograde episodic tasks revealed a mild but significant impairment of the capacity of re-living the condition of encoding, i.e. the moment at which words were presented. CONCLUSIONS: Patients who have suffered from an episode of TGA manifest deficits of memory focused on the retrieval of both recent semantic information and episodic memories and especially the capacity of re-living. These deficits may not result from a deterioration of memory per se but rather from difficulties in accessing memories.     

Memory for the September 11, 2001, terrorist attacks one year later in patients with Alzheimer's disease, patients with mild cognitive impairment, and healthy older adults

Although there are many opportunities to study memory in patients with Alzheimer's disease (AD) in the laboratory, there are few opportunities to study memory for real world events in these patients. The September 11, 2001 terrorist attacks provided one such opportunity. Patients with AD, patients with mild cognitive impairment (MCI), and healthy older adults were given a telephone questionnaire in the initial weeks after the event, again three to four months later, and finally one year afterwards to evaluate their memory for the September 11, 2001 terrorist attacks. We were particularly interested in using the attacks as an opportunity to examine the decline of episodic memory in patients with AD, patients with MCI, and older adult controls over a period of months. We found that compared to healthy older adults, patients with AD and MCI showed impaired memory at the initial time point, more rapid forgetting from the initial to the three-month time point, and very similar changes in memory from the three-month to the one-year time point. We speculated that these findings were consistent with patients with AD and MCI showing initial impaired encoding and a more rapid rate of forgetting compared with healthy older adults, but that once the memories had been consolidated, their decay rate became similar to that of healthy older adults. Lastly, although memory distortions were common among all groups, they were greatest in the patients with AD.     

Encoding and the frontal lobes: a dissociation between retrograde and anterograde memories

Recent functional neuroimaging studies have suggested that different neural substrates within the frontal lobes are associated with memory encoding, retrieval and monitoring. If this is the case, then it should be possible to find frontal patients with selective deficits to these processes. However, most laboratory based memory tests (e.g. Wechsler Memory Scale) require a combination of all these processes making it hard to find clear dissociations between patients. Using tests of everyday memory, this study documents a clear dissociation between a frontal patient's (JB) impaired ability to retrieve events from the anterograde period relative to spared ability to retrieve events from the retrograde period. This is consistent with specific disruption to frontal mechanisms associated with encoding which disrupts the formation of new episodic memories. The defective mechanism may be related to more general aspects of cognitive processing (e.g. selection demands), but it is unlikely to reflect damage to working memory (as assessed by the n-back task) as there is a clear dissociation between spared performance on this task and impaired performance on a comparable episodic recognition memory task.     

Memory Reactivation during Learning Simultaneously Promotes Dentate Gyrus/CA2,3 Pattern Differentiation and CA1 Memory Integration

Events that overlap with previous experience may trigger reactivation of existing memories. However, such reactivation may have different representational consequences within the hippocampal circuit. Computational theories of hippocampal function suggest that dentate gyrus and CA_2,3 (DG/CA_2,3) are biased to differentiate highly similar memories, whereas CA₁ may integrate related events by representing them with overlapping neural codes. Here, we tested whether the formation of differentiated or integrated representations in hippocampal subfields depends on the strength of memory reactivation during learning. Human participants of both sexes learned associations (AB pairs, either face-shape or scene-shape), and then underwent fMRI scanning while they encoded overlapping associations (BC shape-object pairs). Both before and after learning, participants were also scanned while viewing indirectly related elements of the overlapping memories (A and C images) in isolation. We used multivariate pattern analyses to measure reactivation of initial pair memories (A items) during overlapping pair (BC) learning, as well as learning-related representational change for indirectly related memory elements in hippocampal subfields. When prior memories were strongly reactivated during overlapping pair encoding, DG/CA_2,3 and subiculum representations for indirectly related images (A and C) became less similar, consistent with pattern differentiation. Simultaneously, memory reactivation during new learning promoted integration in CA₁, where representations for indirectly related memory elements became more similar after learning. Furthermore, memory reactivation and subiculum representation predicted faster and more accurate inference (AC) decisions. These data show that reactivation of related memories during new learning leads to dissociable coding strategies in hippocampal subfields, in line with computational theories.SIGNIFICANCE STATEMENT The flexibility of episodic memory allows us to remember both the details that differentiate similar events and the commonalities among them. Here, we tested how reactivation of past experience during new learning promotes formation of neural representations that might serve these two memory functions. We found that memory reactivation during learning promoted formation of differentiated representations for overlapping memories in the dentate gyrus/CA_2,3 and subiculum subfields of the hippocampus, while simultaneously leading to the formation of integrated representations of related events in subfield CA₁. Furthermore, memory reactivation and subiculum representation predicted success when inferring indirect relationships among events. These findings indicate that memory reactivation is an important learning signal that influences how overlapping events are represented within the hippocampal circuit.     

Extensive temporally graded retrograde amnesia for personal-episodic facts in transient global amnesia

Abstract

Transient global amnesia (TGA) is characterized by an impairment of episodic memory resulting both in anterograde and retrograde amnesia. Few studies have assessed retrograde amnesia in TGA. Only Evans et al. (Journal of Neurology, Neurosurgery and Psychiatry 1993; 56: 1227-30) have distinguished between the episodic and semantic components of autobiographical memory, suggesting a disturbance of autobiographical incident recollection. A patient was tested during the acute phase of TGA with a sophisticated autobiographical event interview [derived from Kopelman et al. (Journal of Clinical and Experimental Neuropscyhology 1989; 11: 724-44) and Borrini et al. (Psychological Medicine 1989; 19: 215-24)], designed to replicate and extend this study of autobiographical memory. The autobiographical event interview disclosed an extensive disturbance in recalling memories with a temporal gradient, sparing earliest memories compared to more recent ones.     

Hippocampal Theta Oscillations Support Successful Associative Memory Formation

Models of memory formation posit that episodic memory formation depends critically on the hippocampus, which binds features of an event to its context. For this reason, the contrast between study items that are later recollected with their associative pair versus those for which no association is made fails should reveal electrophysiological patterns in the hippocampus selectively involved in associative memory encoding. Extensive data from studies in rodents support a model in which theta oscillations fulfill this role, but results in humans have not been as clear. Here, we used an associative recognition memory procedure to identify hippocampal correlates of successful associative memory encoding and retrieval in patients (10 females and 9 males) undergoing intracranial EEG monitoring. We identified a dissociation between 2–5 Hz and 5–9 Hz theta oscillations, by which power increases in 2–5 Hz oscillations were uniquely linked with successful associative memory in both the anterior and posterior hippocampus. These oscillations exhibited a significant phase reset that also predicted successful associative encoding and distinguished recollected from nonrecollected items at retrieval, as well as contributing to relatively greater reinstatement of encoding-related patterns for recollected versus nonrecollected items. Our results provide direct electrophysiological evidence that 2–5 Hz hippocampal theta oscillations preferentially support the formation of associative memories, although we also observed memory-related effects in the 5–9 Hz frequency range using measures such as phase reset and reinstatement of oscillatory activity.SIGNIFICANCE STATEMENT Models of episodic memory encoding predict that theta oscillations support the formation of interitem associations. We used an associative recognition task designed to elicit strong hippocampal activation to test this prediction in human neurosurgical patients implanted with intracranial electrodes. The findings suggest that 2–5 Hz theta oscillatory power and phase reset in the hippocampus are selectively associated with associative memory judgments. Furthermore, reinstatement of oscillatory patterns in the hippocampus was stronger for successful recollection. Collectively, the findings support a role for hippocampal theta oscillations in human associative memory.     

The nature and time-course of medial temporal lobe contributions to semantic retrieval: An fMRI study on verbal fluency

Recent investigations have shown that the medial temporal lobe (MTL), a region thought to be exclusive to episodic memory, can also influence performance on tests of semantic memory. The present study examined further the nature of MTL contributions to semantic memory tasks by tracking MTL activation as participants performed category fluency, a traditional test of semantic retrieval. For categories that were inherently autobiographical (e.g. names of friends), the MTLs were activated throughout the time period in which items were generated, consistent with the MTLs role in retrieving autobiographical memories. For categories that could not benefit from autobiographical or spatial/context information (e.g. governmental offices), the MTL was not implicated at any time point. For categories for which both prototypical and episodically-related information exists (e.g. kitchen utensils), there was more robust MTL activity for the open-ended, late generation periods compared with the more well-defined, early item generation time periods. We interpret these results as suggesting that early in the generation phase, responses are based on well-rehearsed prototypical knowledge whereas later performance relies more on open-ended strategies, such as deriving exemplars from personally relevant contextual information (e.g. imagining one's own kitchen). These findings and interpretation were consistent with the results of an initial, separate behavioral study (Expt 1), that used the distinctiveness of responses as a measure of open-endedness across the generation phase: Response distinctiveness corresponded to the predicted open-endedness of the various tasks at early and late phases. Overall, this is consistent with the view that as generation of semantic information becomes open-ended, it recruits processes from other domains, such as episodic memory, to support performance.     

Two further investigations of autobiographical memory in semantic dementia

A number of investigations in semantic dementia have documented better retrieval of recent personal events compared to those in the more distant past (Graham and Hodges, 1997). Westmacott et al. (2001) challenged this result, however, finding relative preservation of remote memories in a single case of semantic dementia when he was tested using family photographs. In Experiment 1, we tested two possible explanations for the discrepancy between the published papers: (a) that there is a significant effect of modality in autobiographical retrieval in semantic dementia (e.g., patients will show better, or even preserved, remote memory when tested on nonverbal, compared to verbal, tasks); and (b) that the distinct pattern seen between patients is attributable to the different methods adopted for scoring the episodic quality of the memories. A patient with semantic dementia, AM, produced autobiographical memories to both words and family photographs. These personal events were scored by two raters using the scoring method described by Westmacott et al. (2001) and that reported by Graham and Hodges (1997). It was found that AM showed similar levels of remote memory impairment regardless of whether the cue was verbal or nonverbal. In addition, significant effects of time were revealed in AM's performance on the verbal memory test, regardless of which method was used to score the memories. In Experiment 2, we investigated a related question: whether the relatively better retrieval of memories in semantic dementia could be due to over rehearsal of highly salient recent experiences? Four patients were tested on their ability to remember a recent event (either a trip to London or events from a Formula One Grand Prix race) using specially designed autobiographical questionnaires. It was found that all four were able to perform this task, although one patient showed evidence of some forgetting over three months, and another exhibited difficulty discriminating between two similar events. Together, the two experiments further confirm that patients with semantic dementia show a modality independent autobiographical memory deficit, with better retrieval of recent events.     

Normal aging modulates prefrontoparietal networks underlying multiple memory processes

A functional decline of brain regions underlying memory processing represents a hallmark of cognitive aging. Although a rich literature documents age‐related differences in several memory domains, the effect of aging on networks that underlie multiple memory processes has been relatively unexplored. Here we used functional magnetic resonance imaging during working memory and incidental episodic encoding memory to investigate patterns of age‐related differences in activity and functional covariance patterns common across multiple memory domains. Relative to younger subjects, older subjects showed increased activation in left dorso‐lateral prefrontal cortex along with decreased deactivation in the posterior cingulate. Older subjects showed greater functional covariance during both memory tasks in a set of regions that included a positive prefronto‐parietal‐occipital network as well as a negative network that spanned the default mode regions. These findings suggest that the memory process‐invariant recruitment of brain regions within prefronto‐parietal‐occipital network increases with aging. Our results are in line with the dedifferentiation hypothesis of neurocognitive aging, thereby suggesting a decreased specialization of the brain networks supporting different memory networks.