Project Summary/Abstract (1) Our work is directed towards understanding the structure, organization, and anatomy of human memory. We study neurological patients who have circumscribed memory impairment as the result of brain injury or disease that has damaged the hippocampus bilaterally. We also study healthy volunteers using the technique of functional magnetic resonance imaging (fMRI). This work is continuing to reveal useful and important information about the organization of memory and the brain systems that support memory. In this work, I collaborate with Christine Smith, Ph.D. at the VA (Research Health Science Specialist), who in 2016 obtained independent VA funding. I also collaborate with Robert Clark, Ph.D. (VA investigator) in his program of work on memory in rodents. Memory is a precious mental faculty. Lost or diminished memory, as occurs in neurological disease, leads to a loss of self, a loss of one’s life history, and a loss of the ability to have enduring contact with other human beings. Memory problems are common in VA neurological and psychiatric patients. Modest difficulties with memory are of course well-documented as a universal feature of normal aging, and more severe memory problems are a prominent early sign of Alzheimer’s disease. Our work is intended to learn how memory is affected by these conditions, how the brain accomplishes learning and memory, and what brain structures are important. Our neuropsychological work has provided new tests, the possibility of better and earlier diagnosis, improved understanding of the conditions that affect memory, and established a clearer path to the development of interventions for treating and ultimately preventing diseases that affect memory. During the past 10 years, our work has been reported in 95 publications, (53 peer-reviewed journal articles, 20 books or book chapters, 18 invited reviews, and four other pieces). We explored a number of issues that are prominent in current discussions about the organization of memory. We investigated how eye movements can be experience-dependent (e.g., different depending on whether a scene is novel or recently presented); the key distinction between conscious and unconscious memory systems; the function of the hippocampus with respect to the constructs of recollection and familiarity; the brain-based distinction between short-term (working) memory and long-term memory; the role of the hippocampus and related medial temporal lobe structures in recollecting the recent past, the remote past, and in imagining the future; the special status of face recognition with respect to hippocampal function; the possible role of medial temporal lobe structures in certain perceptual functions; and the role of these structures in navigation, scene construction, and spatial cognition. Over my career, my work has been cited 48,000 times and continues to be cited about 2000 times/year. My h-index is 108. Current work proceeds on several fronts. First, we are carrying out a number of studies supported by the VA to illuminate the ways that eye movements can reflect memory. For example, individuals scan a scene differently depending on whether the scene is familiar or novel. They make fewer fixations and sample fewer regions when viewing a familiar (as opposed to novel) scene. What kind of memory effects are these? Do these eye movement effects simply provide another example of conscious, declarative memory? Or, are they more automatic, and independent of awareness that a scene is novel or familiar? Are they hippocampus- dependent or independent? Do they honor or contradict the dominant view that conscious memory is hippocampus-dependent? In other NIH-supported work we are exploring memory and spatial cognition, and autobiographical memory. We are attempting to reconcile two traditions of work that emphasize the role of the hippocampus in memory vs. its role in the ability to mentally construct scenes and navigate. Squire - 1

Project Narrative The proposed work aims to understand the organization and function of the brain systems that support human memory and to illuminate the nature of memory disorders. We are studying individuals with memory impairment due to brain injury, and we are studying healthy volunteers using functional magnetic resonance imaging (fMRI). The neuropathology has been thoroughly documented quantitatively with MRI. Memory problems are commonly reported in conjunction with neurological and psychiatric illness and are a significant issue in veterans’ health. Improved knowledge about how memory works, and about how memory fails after injury or disease, lays a foundation for the development of interventions to help diagnose, treat, and prevent the diseases that affect memory, including Alzheimer’s disease. Better knowledge about how memory works, and how to measure it, also provides a foundation for improved assessment of memory impairment, which is increasingly significant in Veterans returning from combat and in aging Veterans.