Larry R. Squire, Ph.D. - US grants

The overall objective of the proposed work is to understand the structure and organization of normal memory and its neurological foundations. We are studying the amnesic effects of electroconvulsive therapy (ECT), the noted patient N.A., and have recently established a population of Korsakoff patients. In addition we are studying memory as it is affected by normal aging, and by certain psychotropic drugs. A related goal of the research is to specify the risks of ECT to memory, and to define those current parameters associated with least memory loss.

The proposed programs has three main objectives: 1) to understand the organization and neurological foundations of human memory; 2) to understand the ways in which memory impairment can occur and also the best ways to measure memory impairment; and 3) to specify the effects of electroconvulsive therapy on memory. Nineteen separate projects are proposed in six specific areas: 1) characterizing the neuroanatomical and neuropsychological manifestations of memory impairment; 2) anterograde amnesia: the nature of impaired memory; 3) preserved learning in amnesia; 4) retrograde amnesia: memory for remote events; 5) electroconvulsive therapy and memory impairment: clinical studies; and 6) experimental amnesia in the mouse: electroconvulsive shock. The subject populations are memory-impaired patients with neurological injury or disease, patients with circumscribed vascular lesions of frontal cortex, psychiatric patients prescribed ECT, and control subjects for these groups including depressed inpatients not receiving ECT, alcoholics, and healthy subjects. The 19 proposed projects include a quantitative neuroradiological evaluation (CT scan) of patients with Korsakoff's syndrome and two control groups; a series of studies on a newly established population of patients with frontal lobe injury designed to illuminate the contribution of the frontal lobes to normal memory functions; a test of the hypothesis that human amnesia disproportionately affects spatial memory; a test of the idea that amnesic patients can learn and retain novel associations in a normal fashion, although the knowledge can be expressed only implicitly (i.e., unconsciously); a search for the limits of preserved learning capacity in amnesia using tests of adaptation level and other judgment tasks; a study of the status of retrograde amnesia in non-Korsakoff amnesic patients; a study of transient global amnesia, which is an incompletely understood neurological syndrome; and studies of the objective and subjective memory impairment associated with electroconvulsive therapy. Overall, this work should answer questions about how memory is organized in the brain, about how to quantify and classify memory impairment, and about the risks of ECT to memory.

The proposed programs has three main objectives: 1) to understand the organization and neurological foundations of human memory; 2) to understand the ways in which memory impairment can occur and also the best ways to measure memory impairment; and 3) to specify the effects of electroconvulsive therapy on memory. Nineteen separate projects are proposed in six specific areas: 1) characterizing the neuroanatomical and neuropsychological manifestations of memory impairment; 2) anterograde amnesia: the nature of impaired memory; 3) preserved learning in amnesia; 4) retrograde amnesia: memory for remote events; 5) electroconvulsive therapy and memory impairment: clinical studies; and 6) experimental amnesia in the mouse: electroconvulsive shock. The subject populations are memory-impaired patients with neurological injury or disease, patients with circumscribed vascular lesions of frontal cortex, psychiatric patients prescribed ECT, and control subjects for these groups including depressed inpatients not receiving ECT, alcoholics, and healthy subjects. The 19 proposed projects include a quantitative neuroradiological evaluation (CT scan) of patients with Korsakoff's syndrome and two control groups; a series of studies on a newly established population of patients with frontal lobe injury designed to illuminate the contribution of the frontal lobes to normal memory functions; a test of the hypothesis that human amnesia disproportionately affects spatial memory; a test of the idea that amnesic patients can learn and retain novel associations in a normal fashion, although the knowledge can be expressed only implicitly (i.e., unconsciously); a search for the limits of preserved learning capacity in amnesia using tests of adaptation level and other judgment tasks; a study of the status of retrograde amnesia in non-Korsakoff amnesic patients; a study of transient global amnesia, which is an incompletely understood neurological syndrome; and studies of the objective and subjective memory impairment associated with electroconvulsive therapy. Overall, this work should answer questions about how memory is organized in the brain, about how to quantify and classify memory impairment, and about the risks of ECT to memory.

The proposed programs has three main objectives: 1) to understand the organization and neurological foundations of human memory; 2) to understand the ways in which memory impairment can occur and also the best ways to measure memory impairment; and 3) to specify the effects of electroconvulsive therapy on memory. Nineteen separate projects are proposed in six specific areas: 1) characterizing the neuroanatomical and neuropsychological manifestations of memory impairment; 2) anterograde amnesia: the nature of impaired memory; 3) preserved learning in amnesia; 4) retrograde amnesia: memory for remote events; 5) electroconvulsive therapy and memory impairment: clinical studies; and 6) experimental amnesia in the mouse: electroconvulsive shock. The subject populations are memory-impaired patients with neurological injury or disease, patients with circumscribed vascular lesions of frontal cortex, psychiatric patients prescribed ECT, and control subjects for these groups including depressed inpatients not receiving ECT, alcoholics, and healthy subjects. The 19 proposed projects include a quantitative neuroradiological evaluation (CT scan) of patients with Korsakoff's syndrome and two control groups; a series of studies on a newly established population of patients with frontal lobe injury designed to illuminate the contribution of the frontal lobes to normal memory functions; a test of the hypothesis that human amnesia disproportionately affects spatial memory; a test of the idea that amnesic patients can learn and retain novel associations in a normal fashion, although the knowledge can be expressed only implicitly (i.e., unconsciously); a search for the limits of preserved learning capacity in amnesia using tests of adaptation level and other judgment tasks; a study of the status of retrograde amnesia in non-Korsakoff amnesic patients; a study of transient global amnesia, which is an incompletely understood neurological syndrome; and studies of the objective and subjective memory impairment associated with electroconvulsive therapy. Overall, this work should answer questions about how memory is organized in the brain, about how to quantify and classify memory impairment, and about the risks of ECT to memory.

The proposed programs has three main objectives: 1) to understand the organization and neurological foundations of human memory; 2) to understand the ways in which memory impairment can occur and also the best ways to measure memory impairment; and 3) to specify the effects of electroconvulsive therapy on memory. Nineteen separate projects are proposed in six specific areas: 1) characterizing the neuroanatomical and neuropsychological manifestations of memory impairment; 2) anterograde amnesia: the nature of impaired memory; 3) preserved learning in amnesia; 4) retrograde amnesia: memory for remote events; 5) electroconvulsive therapy and memory impairment: clinical studies; and 6) experimental amnesia in the mouse: electroconvulsive shock. The subject populations are memory-impaired patients with neurological injury or disease, patients with circumscribed vascular lesions of frontal cortex, psychiatric patients prescribed ECT, and control subjects for these groups including depressed inpatients not receiving ECT, alcoholics, and healthy subjects. The 19 proposed projects include a quantitative neuroradiological evaluation (CT scan) of patients with Korsakoff's syndrome and two control groups; a series of studies on a newly established population of patients with frontal lobe injury designed to illuminate the contribution of the frontal lobes to normal memory functions; a test of the hypothesis that human amnesia disproportionately affects spatial memory; a test of the idea that amnesic patients can learn and retain novel associations in a normal fashion, although the knowledge can be expressed only implicitly (i.e., unconsciously); a search for the limits of preserved learning capacity in amnesia using tests of adaptation level and other judgment tasks; a study of the status of retrograde amnesia in non-Korsakoff amnesic patients; a study of transient global amnesia, which is an incompletely understood neurological syndrome; and studies of the objective and subjective memory impairment associated with electroconvulsive therapy. Overall, this work should answer questions about how memory is organized in the brain, about how to quantify and classify memory impairment, and about the risks of ECT to memory.

DESCRIPTION (provided by applicant): Studies are proposed to improve understanding of the structure, organization, and function of mammalian memory systems and the nature of memory disorders. The work is organized as 6 separate topics: 1) the organization of declarative memory; the hippocampus; 2) the organization of declarative memory; the medial temporal lobe; 3) memory, awareness, and measures of eye movements; 4) conjoint fMRI studies and lesion studies; 5) classical eyeblink conditioning; 6) studies with rodents, which will complement the studies in humans. Salient among the proposed plans is a novel direction of research for this laboratory to determine to what extent and how eye movements (e.g., as one scans a recently encountered scene) might reveal experience-dependent effects. What kind of declarative or non-declarative memory is indexed by eye movements? Also salient among the proposed plans is a program of study of the rat hippocampus, perirhinal cortex, and postrhinal cortex (and also the caudate nucleus), which is intended to address a number of longstanding issues that arise from the tradition of human neuropsychological studies. Studies are proposed of discrimination learning, remote spatial memory, and visual recognition memory, which are intended to address a number of long-standing issues. Another salient part of the proposed plans are studies intended to improve the interpretational power of fMRI, which on its own provides correlation data. Specifically, fMRI studies of hippocampus and medial temporal lobe are proposed in which the identical experimental design used in fMRI will also be used (outside the scanner) with amnesic study patients who have damage limited to the hippocampal region. A key component of the work is the availability of amnesic study patients, whose lesions have been described in considerable anatomical and quantitative detail. Up to 7 patients are available whose damage is limited to the hippocampal region, and 2 others (E.P. and G.P.) are of interest because they have large medial temporal lobe lesions and virtually no capacity for declarative memory. A second key component of the work is the close conceptual relationship between the rodent program and the work with humans.

Neuroscience has made enormous progress during the past half century as new tools and technological advances have made it possible to ask increasingly specific questions about the structure and function of neurons, synapses, proteins, and genes. Progress has been slower in understanding the organization and function of circuits, networks, and brain systems. And in that context, it is sometimes overlooked how important it is to have an account of cognition itself ? perception, attention, memory, language, and the organization of action. One wants to understand its components and to understand how the components of cognition can be related to brain substrates. The work proposed herein addresses a fundamental issue about how the brain has organized its memory functions. The issue is whether short-term and long-term memory are indeed distinct entities, such that short-term memory is independent of the hippocampus (and related structures); or whether an exception to that principle exists in the case of spatial cognition. It is a deep and fundamental matter. Do the hippocampus and related structures have online, computational functions? Or are these structures in fact needed only when short-term memory capacity has been exceeded. To evaluate these two perspectives, five studies are proposed in individuals with hippocampal lesions (or larger lesions that include related structures) using navigation in open space, virtual reality, as well as a test of spatial imagining. Parallel work on path integration is proposed for rats with selective lesions of the hippocampal, entorhinal, or parietal cortex. Understanding the relationship between memory and spatial cognition is fundamental to understanding how the brain has organized its memory functions.

Project Summary/Abstract Studies are proposed to improve understanding of the structure and organization of declarative memory and the function of the hippocampus and related medial temporal lobe structures. In particular, the studies will test two contrasting views of hippocampal function, one that emphasizes memory and one that emphasizes spatial cognition. The work involves 8 separate studies, organized as two related topics: A. Memory and spatial cognition; B. Autobiographical memory and construction of episodes. A salient aspect of the proposed work is the continuing opportunity to study memory-impaired patients with bilateral hippocampal lesions or larger medial temporal lobe lesions that are well characterized in terms of quantitative neuroanatomy. Topic A attempts to reconcile two traditions of work on the hippocampus, one emphasizing memory and memory impairment and the other focusing on spatial navigation and spatial cognition. Topic B grows out of the recent explosion of interest in autobiographical memory, future imagining, scene construction, and the broad topic of mental time travel. A1 and A2 will study navigation and map reading ability in hippocampal patients and healthy volunteers in conditions where the burden on memory is minimal. A3 will test the ability of hippocampal patients to make horizontal shifts in perspective in extra-personal space. A4 will test the ability of hippocampal patients to accomplish shifts in perspective from overhead views to ground-level views of an environment. B1 will examine autobiographical memory and future imagining in hippocampal patients in conditions when minimal prompts are provided, following one of the protocols that have been used in this kind of work. B2 will explore these same abilities in hippocampal patients using extensive probing, following the main alternative protocol that has been used. A number of novel methods will be brought to the analysis of narrative constructions, including the unique opportunity to exchange data with another laboratory (full transcripts) in order to explore why laboratories have obtained different results when analyzing autobiographical narratives. B3 will use fMRI to ask whether hippocampal activity during the recollection of episodes correlates with particular aspects of narrative content, including the amount of spatial detail in the narratives. A second study asks in individuals with hippocampal lesions what other structures support recollection of episodic detail and whether activity in these structures correlates with aspects of narrative content. B4 involves a prospective, naturalistic, study of the capacity of hippocampal patients to construct episodic recollections about a structured event in which they participate. The proposed studies involve brain structures known to be important for declarative memory and for understanding memory impairment as it occurs in a number of psychiatric conditions. The work should provide new tests, improved understanding of the conditions that affect memory, and better insights about the ways that declarative memory is affected in mental disorders.