Neal J. Cohen - US grants

This research will explore the mechanisms of memory supporting the ability of people to remember the details of their experiences. Previous research has indicated that there are different memory systems in the brain that support different types or forms of memory. Considerable recent research has been directed at attempting to characterize these systems.

One form of memory that has been identified, "declarative" or "relational" memory, is associated with the operation of a particular brain system, the hippocampal system. This system is thought to be critical for remembering one's experiences by enabling memory for the relations among the elements of the events, situations, or scenes encountered in daily life (or in the laboratory). This form of memory maintains information about what people and/or what objects were part of a given experience, in what context they were encountered, where they were located with respect to the scene and to each other, who did what to whom in that experience, and so forth.

This research will take advantage of a new research approach and a set of converging methods to examine the specialization of different memory systems for different aspects of memory processing, operating simultaneously. In doing so, it will provide a test of the idea that the hippocampal system is specialized to support relational memory processing, and it will provide a more detailed characterization of the nature of this relational form of memory.

The research will use an eye-movement-based methodology to assess memory for items and memory for relations among items, both in normal control subjects and in amnesic patients with profound memory deficits following hippocampal system damage. The research methodology will allow this assessment to take place separately and simultaneously. It is expected that amnesic patients will be selectively impaired on measures of memory for relations among items, across a range of different types of relations, while simultaneously being intact on measures of memory for (repetition of) individual items. Additional studies will assess brain activation during memory performance of normal human subjects using functional neuroimaging methods. It is expected that activity of the hippocampal system will be associated selectively with measures of memory for relations among items, again across a range of different types of relations, while activity of other brain systems will be associated with measures of memory for (repetition of) individual items.

Taken together, such results will provide critical information about the nature of relational memory, its dependence on the hippocampal system, and its impairment in amnesia. By furthering understanding of how we form and maintain memory for relations among items, this work will provide insight into that form of memory most critical for the ability to remember our experiences and to learn relational information. Such insight holds enormous promise for guiding the teaching of any domain of knowledge involving fundamentally relational material, from structural relations to the relations among high-level concepts.

DESCRIPTION (provided by applicant): The proposed work employs a multidisciplinary approach to empirically test the idea that the hippocampus is involved in, and amnesia is a deficit in, relational memory processing. This form of memory processing is thought to support memory for all manner of relationships among perceptually distinct objects, permitting remembering of the constituent elements of the events, situations, or scenes encountered in daily life or in the laboratory. Based on results from preliminary work that combines eye movement studies, functional magnetic resonance imaging (fMRI) studies, and studies of amnesic patients with severe memory disorders, we propose a series of 11 studies that sample memory for the repetition of items and memory for the relations among items (relational memory). These studies manipulate the amount and type of information to be remembered, the nature of the task demands, the modality of presentation of the stimuli, and the context in which the information is to be remembered. The specific hypotheses to be tested in the present project are that amnesic patients are selectively impaired on tasks that require relational memory processing, that hippocampal activity is associated selectively with relational memory processing, and that non-relational forms of memory are associated with brain systems other than the hippocampus. These experiments constitute a strong test of the claimed link between relational memory processing, amnesia, and hippocampal function. They should also serve to further clarify the nature of relational memory processing.

DESCRIPTION (provided by applicant): The overall goal of the proposed research is to enhance our understanding of the relational nature of declarative memory, its dependence on the hippocampus and associated medial temporal-lobe (MTL) structures, and its role in supporting various aspects of human performance. The proposed work combines neuropsychological, eye movement, ERP, and fMRI studies, in a converging methods approach, to address a set of specific theory-driven claims and data-inspired questions about the nature, scope, and time course of relational memory processing. It also tests critical ideas about differential roles played by hippocampus vs other MTL memory structures. There are six specific aims: (1) To show that the hippocampus is centrally involved in relational memory binding of all manner of relations, including spatial, non-spatial co-occurrence, and temporal-sequential relations, above and beyond memory for the items themselves;(2) To show that although it plays a critical role in supporting conscious recollection and may participate in the detection or processing of novelty, the hippocampus supports relational memory, independent of conscious recollection, and even when item novelty is controlled for;(3) To show that the hippocampus is centrally involved in memory for relations among perceptually distinct objects, but not among features within objects;(4) To show that although it is involved in the formation of memory for all manner of relations, the hippocampus is necessary (only) for memory for arbitrary, accidental relations, not for non-arbitrary, derivable relations;(5) To show that the hippocampus is critical for relational memory even at the shortest lags or delays, i.e., even on the timescale of working memory;and (6) To examine the time course of aspects of relational memory processing. The memory system mediated by the hippocampus supports the particular form of memory that underlies remembering of the events and demands of everyday life, and, at the same time, the particular form of memory that is especially vulnerable to memory dysfunction in amnesia, in Alzheimer's disease, and even in the course of normal aging. Moreover, the hippocampus has been implicated not only in these instances of memory loss, but also in schizophrenia and depression. A better understanding of this critical system will have great significance.

This project combines neuropsychological, neuroimaging, and eye tracking approaches in order to study the functional interactions of PFC and the hippocampus in supporting richly conditional behavior in humans. The experiments test our hypothesis that the hippocampus is critically involved in relational memory representations whereas PFC is involved in more abstract context-guided associative rules. Neuropsychological studies will provide evidence about the necessity of PFC and MTL regions in relational memory and context-dependent associations, and neuroimaging studies will provide evidence about the nature and timing of functional interactions between these regions. For each study, performance assessments will include not only explicit behavioral judgments but also eye movement-based assessment of memory, pioneered in our laboratory. This approach affords sensitive, implicit nr>easures of the strength of relational and context-dependent representations, based on preferential viewing patterns, as they change dynamically during each trial and across learning and retention. Experiments start with a "base" task in common with all the other empirical projects of the Center, and then graduate to more elaborate variants that systematically manipulate the amount and complexity of relational information or the complexity and abstractness of the context-dependent associative rules to be learned, in order to better determine the dependency of each of these aspects of memory on PFC, hippocampus, and their functional interactions, and further, on the directionality of their interactions.

DESCRIPTION (provided by applicant): The progress that we made during the initial funding period (The Hippocampus and Relational (Declarative) Memory) has had a tremendous impact on the field of memory research in general, and it is now widely accepted that relational memory is a primary function of the hippocampus. This renewal application seeks to discover how the hippocampus, a brain structure unequivocally necessary for feats of long-term memory, plays a crucial role in the construction and use of memory in real-time. Because hippocampal pathology has been implicated in many brain disorders, including amnesia, schizophrenia, Alzheimer's disease and the autism spectrum, our efforts to extend the functional description of the hippocampus beyond the traditional purview of long-term memory are necessary for understanding the pathological mechanisms of these diseases and for developing accurate assays for their diagnosis and treatment. The proposed studies build upon the strides we have made during the initial award period in showing how the hippocampus participates in expressions of memory that occur on very short timescales (i.e., seconds). The current studies will push further, and will seek to determine the role of the hippocampus in truly on-line memory processing, with no retention delay. Furthermore, we will show how the hippocampus is directly and immediately linked to various behavioral expressions of memory; that is, how the moment-to-moment ramifications of hippocampal processing are used to control in real-time our interactions with the information in the environment. Our studies will employ sophisticated behavioral methods, such as eye-tracking, in conjunction with both functional neuroimaging studies in healthy individuals and with neuropsychological studies of amnesic patients with circumscribed hippocampal damage. We will therefore be uniquely able to determine both how the hippocampus normally interacts with the rest of the brain during on-line processing, and how these transactions are disrupted when the functional integrity of the hippocampus is compromised. Studying hippocampal processing at this network/systems level is directly relevant to understanding neuropathological disorders, which are widely characterized as disrupting brain function at a network level.

This National Science Foundation Research Traineeship award to the University of Illinois at Urbana-Champaign will address the next frontier in biotechnology: to engineer, and then decipher and harness, the living three-dimensional brain. The program will provide doctoral students with the skills and knowledge base to develop and utilize miniature brain machinery in an effort to understand and regulate brain activities. To achieve the goals of developing cross-disciplinary researchers, trainees will learn diverse fundamentals in biology, mathematics, engineering, and cognitive science, relevant to miniature brain machinery. The training grant anticipates providing a unique and comprehensive training opportunity for sixty (60) PhD students, including thirty four (34) funded trainees. Trainees will be recruited from neuroscience, cell and developmental biology, molecular and integrative physiology, chemistry, chemical and biomolecular engineering, bioengineering, electrical and computer engineering, and psychology. The training program will foster a culture of innovation and translational research, and will produce a new generation of scientists and engineers prepared to tackle major problems in brain studies that can improve the quality of human life.

The research and training program will bridge two dominant, non-overlapping brain research paradigms: i) cognitive and behavioral studies, focused principally on understanding of adaptation, decision-making, psychology, and learning of an individual using bioimaging and computational tools vs. ii) cell and tissue studies, focused on activities of multiple neuronal cells by altering their internal and external microenvironments comprised of biomolecules, extracellular matrix, and external stimuli. The goal of this NRT training program is to unite these two dominant paradigms in brain science studies and bridge the expertise of cell and molecular biologists, physiologists, chemists, nano/micro technologists, and cognitive neuroscientists. This training program prepares students for studies that enable control over the networks producing behavior and thus to study causal relations. The overarching goal of the program is to provide students with an interdisciplinary curriculum grounded in problem-based learning and an immersive research experience that blends techniques from multiple disciplines. A second goal is to increase the participation of women, underrepresented minorities, and students with disabilities in neuroscience, life sciences, chemical sciences, and engineering fields. A third goal is to train students in communication skills with the public. Evaluative studies conducted throughout this research traineeship project will explore the dynamics and efficacy of interdisciplinary collaboration by students in this program. Project outcomes will be a demonstrated, evaluated model for transformative graduate training that is effective in developing broadly trained professionals.

The NSF Research Traineeship (NRT) Program is designed to encourage the development and implementation of bold, new potentially transformative models for STEM graduate education training. The Traineeship Track is dedicated to effective training of STEM graduate students in high priority interdisciplinary research areas, through comprehensive traineeship models that are innovative, evidence-based, and aligned with changing workforce and research needs.

Abstract Adults with traumatic brain injury (TBI) have deficits in flexible and goal-directed behavior and these impairments have been linked to negative outcomes and poor community reintegration and independence. The frontal lobes, and their putative functions of executive control and working memory, have figured prominently, and nearly exclusively, in mechanistic accounts of flexible and adaptive behavior and in understanding the underlying nature of behavioral dysfunction in individuals with TBI. Yet, interventions designed to target the frontal lobes have not yielded significant improvements in behavior or independence in the community. We propose that the frontal lobes may be the wrong, or not the only, mechanism of impairment leading to inflexible and maladaptive behavior in TBI. We aim to show that flexible and goal-directed behavior depends critically on the operation of the hippocampal relational memory system and is a key mechanism in the observed behavioral dysfunction and poor outcomes in individuals with TBI. The proposed program of research represents a novel direction in the study of traumatic brain injury with substantial basic science and clinical translational significance. The proposal is organized around four AIMS: (1) To characterize disruptions in the integrity of the structure of the hippocampal system and their impact on relational memory in individuals with traumatic brain injury. (2) To characterize the impact of relational memory impairments on flexible and goal- directed behavior in individuals with traumatic brain injury. (3) To investigate the impact of disruption of the hippocampal system and relational memory on the larger network of structures participating in flexible and goal-directed behavior in individuals with traumatic brain injury. (4) To determine the relationship between impairment in relational memory and community integration and independence in individuals with traumatic brain injury. This proposal is unique in the field and uniquely promising for understanding the nature of behavioral dysfunction in TBI and, ultimately, improving rehabilitation intervention outcomes. Indeed, the proposed work lays the critical foundation for the identification of objective and diagnostic biomarkers for behavioral dysfunction following TBI and for the development of new rehabilitative targets. Linking behavioral dysfunction in TBI to the hippocampal relational memory system will also inform the characterization of a number of other neurological (e.g., stroke, TBI, Alzheimer's disease), psychiatric (e.g., schizophrenia, depression), and developmental (e.g., autism) conditions that affect hippocampal relational memory and where deficits in flexible and goal-directed behavior are also hallmark.