Peter J. Bayley

The neuroscience of remote memory

Recently, there has been renewed interest in the organization and neurobiology of remote memory, and the pace of work in this area has accelerated. Yet the recent literature does not suggest that a consensus is developing, and there is disagreement about both facts and their interpretation. This article undertakes a comprehensive review of the three kinds of evidence that have been most prominent in recent discussion: studies of retrograde amnesia in memory-impaired patients who have well-characterized lesions, neuroimaging of healthy volunteers, and work with experimental animals including lesion studies, imaging and mouse genetics. The available evidence tells a coherent story and leads to some straightforward conclusions about the neuroscience of remote memory.

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 Neuroanatomy of Remote Memory

In humans and experimental animals, damage to the hippocampus or related medial temporal lobe structures severely impairs the formation of new memory but typically spares very remote memory. Questions remain about the importance of these structures for the storage and retrieval of remote autobiographical memory. We carried out a detailed volumetric analysis of structural brain images from eight memory-impaired patients. Five of the patients had damage limited mainly to the medial temporal lobe. These patients performed normally on tests of remote autobiographical memory. Three patients had medial temporal lobe damage plus significant additional damage to neocortex, and these patients were severely impaired. These findings account for previously reported differences in the recollective ability of memory-impaired patients and demonstrate that the ability to recollect remote autobiographical events depends not on the medial temporal lobe but on widely distributed neocortical areas, especially the frontal, lateral temporal, and occipital lobes.

Robust habit learning in the absence of awareness and independent of the medial temporal lobe.

Habit memory is thought to involve slowly acquired associations between stimuli and responses and to depend on the basal ganglia. Habit memory has been well studied in experimental animals but is poorly understood in humans because of their strong tendency to acquire information as conscious (declarative) knowledge. Here we show that humans have a robust capacity for gradual trial-and-error learning that operates outside awareness for what is learned and independently of the medial temporal lobe. We tested two patients with large medial temporal lobe lesions and no capacity for declarative memory. Both patients gradually acquired a standard eight-pair object discrimination task over many weeks but at the start of each session could not describe the task, the instructions or the objects. The acquired knowledge was rigidly organized, and performance collapsed when the task format was altered.

Medial Temporal Lobe Amnesia: Gradual Acquisition of Factual Information by Nondeclarative Memory

Most amnesic patients with damage to the medial temporal lobe retain some capacity to learn new information about facts and events. In many cases, the learning appears to depend on a residual ability to acquire conscious (declarative) knowledge. We have studied the capacity for semantic (fact) learning in the profoundly amnesic patient E.P., who has extensive damage limited primarily to the medial temporal lobe. E.P. was presented with factual information (novel three-word sentences) during 24 study sessions across 12 weeks. E.P. performed much more poorly than controls but demonstrated unmistakable improvement across the sessions, achieving after 12 weeks a score of 18.8% correct on a cued-recall test and 64.6% correct on a two-alternative, forced-choice test. Unlike controls, E.P.s learning was not accompanied by conscious knowledge about which answers were correct. He assigned the same confidence ratings to his correct answers as his incorrect answers. Moreover, on the forced-choice test his response times were identical for correct and incorrect responses. Furthermore, unlike controls, he could not respond correctly when the second word in each sentence was replaced by a synonym. Thus, what E.P. learned was rigidly organized, unavailable as conscious knowledge, and in all respects exhibited the characteristics of nondeclarative memory. Thus, factual information, which is ordinarily learned as declarative (conscious) knowledge and with the participation of the medial temporal lobe, can be acquired as nondeclarative memory, albeit very gradually and in a form that is outside of awareness and that is not represented as factual knowledge. We suggest that E.P.s learning depended on a process akin to perceptual learning and occurred directly within neocortex.

Improving dementia care: The role of screening and detection of cognitive impairment

The value of screening for cognitive impairment, including dementia and Alzheimers disease, has been debated for decades. Recent research on causes of and treatments for cognitive impairment has converged to challenge previous thinking about screening for cognitive impairment. Consequently, changes have occurred in health care policies and priorities, including the establishment of the annual wellness visit, which requires detection of any cognitive impairment for Medicare enrollees. In response to these changes, the Alzheimers Foundation of America and the Alzheimers Drug Discovery Foundation convened a workgroup to review evidence for screening implementation and to evaluate the implications of routine dementia detection for health care redesign. The primary domains reviewed were consideration of the benefits, harms, and impact of cognitive screening on health care quality. In conference, the workgroup developed 10 recommendations for realizing the national policy goals of early detection as the first step in improving clinical care and ensuring proactive, patient‐centered management of dementia.

Choline acetyltransferase activity and cognitive domain scores of Alzheimer’s patients☆

Choline acetyltransferase activity and cognitive domain scores of Alzheimers patients. Item scores from the Mattis Dementia Rating Scale (MDRS) and the Mini-Mental State Examination (MMSE) from 389 patients with probable Alzheimers disease were submitted to principal component analysis with orthogonal rotation. The optimal solution identified four factors that reflected the cognitive domains of attention/registration, verbal fluency/reasoning, graphomotor/praxis and recent memory. A subgroup of patients was identified for whom both the MDRS and the MMSE had been administered within the 12 months before death. Scores were assigned to these patients for the four factors. These cognitive-domain scores were then correlated with postmortem choline acetyltransferase (ChAT) activity in the medial frontal cortex, inferior parietal cortex, and hippocampus. ChAT activity in both the medial frontal and the inferior parietal cortex significantly correlated with scores on the graphomotor/praxis factor. Medial frontal ChAT also correlated significantly with the attention/registration scores. Hippocampal ChAT correlated significantly only with recent memory scores. These results are consistent with current animal research regarding the effect of selective cholinergic lesions on behavior.

The Fate of Old Memories after Medial Temporal Lobe Damage

Damage to the hippocampal region and related medial temporal lobe structures (perirhinal, entorhinal, and parahippocampal cortices) impairs new learning (anterograde amnesia) as well as memory for information that was acquired before the damage occurred (retrograde amnesia). We assessed retrograde amnesia with the Autobiographical Memory Interview (AMI) and with a news events test in six patients with damage limited primarily to the hippocampal region (H group) and two patients with large medial temporal lobe lesions (MTL group). On the news event test, the H group exhibited temporally limited retrograde amnesia covering ∼5 years. On the same test, the MTL group exhibited an extensive retrograde amnesia covering decades. Nevertheless, performance was relatively spared for very remote time periods. On the AMI, all patients had intact remote autobiographical memory. Because our patients with hippocampal lesions, as well as our patients with large MTL lesions, performed normally on the AMI, patients who perform poorly on the same test presumably have damage beyond the hippocampus and related structures in the medial temporal lobe. The findings emphasize the difference in the extent of retrograde amnesia associated with hippocampal lesions and large MTL lesions.

Detailed recollection of remote autobiographical memory after damage to the medial temporal lobe

Previous findings of intact remote autobiographical memory in patients with medial temporal lobe damage have been questioned on the grounds that the narrative recollections were impoverished and fact-like and that the methods were not sufficiently sensitive to detect an impairment. We adopted a newer method, the Autobiographical Interview [Levine B, Svoboda E, Hay JF, Winocur G, Moscovitch M (2002) Psychol Aging 17:677–689], which uses extensive probing to elicit an average of 50 or more details per memory (in contrast to the ≈20 details per memory elicited with previous methods). We found that autobiographical recollection was impaired in patients with medial temporal lobe damage when memories were drawn from the recent past but fully intact when memories were drawn from the remote past. Impaired remote autobiographical memory, which has sometimes been reported with this and other tests, is likely caused by significant damage outside the medial temporal lobe.

Spatial memory and the human hippocampus

The hippocampus and adjacent medial temporal lobe structures are known to support declarative memory, but there is not consensus about what memory functions the hippocampus might support that are distinct from the functions of the adjacent cortex. One idea is that the hippocampus is specifically important for allocentric spatial memory, e.g., the hippocampus is especially needed to remember object locations when there is a shift in viewpoint between study and test. We tested this proposal in two experiments. Patients with damage limited to the hippocampus were given memory tests for object locations in a virtual environment. In the first experiment, participants studied locations of a variable number of images (one to five) and tried to remember the image locations from either the same viewpoint as during study (shift of 0°) or a different viewpoint (shift of 55°, 85°, or 140°). In each viewpoint condition (shifts of 0°, 55°, 85°, and 140°), patients performed normally when remembering one or two image locations. Further, performance declined to a similar degree in each viewpoint condition as patients tried to remember increasing numbers of image locations. In the second experiment, participants tried to remember four images after viewpoint shifts of 0°, 55°, 85°, or 140°. Patients were mildly impaired at all conditions (shifts of 0°, 55°, 85°, and 140°), and the impairment was no greater when viewpoint shifted. We conclude that damage to the hippocampus does not selectively impair viewpoint-independent spatial memory. Rather, hippocampal damage impairs memory as the memory load increases.