Summary: Randy Buckner is interested in determining brain systems that support human memory and how these systems change during progressive dementia associated with Alzheimer’s disease.

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Dr. Buckner is Professor of Psychology at Harvard University, where he is affiliated with the Center for Brain Science and faculty of the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital/Harvard Medical School. He received his B.A. degree in psychology and his M.A. and Ph.D. degrees in psychology and neuroscience from Washington University under the direction of Steven Petersen. He trained with Bruce Rosen as a postdoctoral fellow and then Instructor of Radiology at Harvard Medical School, where he developed and applied functional MRI methods to study human memory. As an Assistant and Associate Professor at Washington University in St. Louis his work expanded to include studies of aging and Alzheimer’s disease. Among his awards are the Wiley Young Investigator Award from the Organization of Human Brain Mapping, the Young Investigator Award from the Cognitive Neuroscience Society, and the 2007 Troland Research Award from the National Academy of Sciences.

Howard Hughes Medical Institute, December 05, 2007 – Human memory arises from complementary brain systems that are modified by experience. Certain memory systems support conscious recollection of prior episodes, such as the memory for a recently encountered face or a tune on the radio. Other memory systems operate below our awareness and facilitate implicit forms of learning, such as motor skill acquisition and priming of a response through repeated exposure. Our research program explores how these multiple forms of memory arise in the human brain and how they change during healthy aging and aging associated with dementia. To undertake these explorations, we conduct behavioral and functional brain imaging studies while human participants perform memory tasks. A series of interrelated questions drive our research.

How are memories formed? Functional brain imaging studies demonstrate that regions of frontal cortex, near those classically associated with language function, are active during memory formation. We are pursuing the hypothesis that frontal cortex supplies a critical input to medial temporal brain regions during memory formation. To explore this idea, our laboratory is studying the degree to which appropriate frontal and medial temporal participation can predict memorization by using functional brain imaging procedures that measure neural activity on a second-by-second basis. For example, one study showed that medial temporal lobe areas near those damaged in amnesia influence the successful formation of memories. This study also showed that specific frontal regions contribute to the process of memory formation. Brain activity in left frontal cortex was significantly higher, on average, for those words that were remembered as compared to those words that were forgotten. Broadly applying these procedures in the context of experimental manipulations that influence memory formation allows us to study which specific regions (or interactions among regions) contribute to memory formation. (Grants from the National Institutes of Health and James S. McDonnell Foundation provided support for these projects.)

One related issue is how we memorize different kinds of information, e.g., how the brain memorizes an unfamiliar face as opposed to a tune on the radio. A series of our recent studies suggest that frontal and medial temporal regions participate in memory formation in a domain-specific manner. For example, the right frontal cortex becomes active while memorizing nonverbal materials, such as a face or a picture of an object, while the left frontal cortex becomes active while memorizing words. These findings are consistent with predictions from patients with lateralized brain lesions.

Our laboratory is pursuing an in-depth study of these apparently domain-specific frontal regions. Of particular interest is the possibility that, for many material types and study strategies, multiple distinct domain-specific frontal regions are recruited. For example, when memorizing objects that can be named (a picture of a chair), brain activity increases in both left (verbal) and right (nonverbal) frontal regions. Several studies indicate that, to the degree multiple regions are appropriately recruited, memory performance will improve. We are now exploring whether subjects can be trained to recruit multiple domain-specific frontal regions during study as a means to boost memory performance. Such aids may be especially important for developing compensatory strategies in older adults whose frontal and medial temporal resources diminish.

How does repeating (practicing) a particular behavior promote learning? How does the transition from unskilled task performance, which proceeds slowly and requires considerable effort, change to rapid, effortless performance in a skilled task state? Evidence suggests that there may be two kinds of mechanisms: those that tune specific neural responses to make behaviors more efficient, and those that link stimuli and motor responses more directly by shifting responses to entirely separate brain pathways in the skilled state. We have been exploring to what degree these separate mechanisms contribute to human learning. The procedure has been to image the brain during different points of learning and to compare pathways active during initial and overlearned task performance. Our longer-term objective is to track these pathways continuously during the transition from naive to skilled performance. (A grant from the National Institutes of Health provides partial support for this project.)

How can we retrieve the stored attributes, or “echo,” of a memory? We all know that we can remember sounds and visual images from the past. However, it is largely a mystery how the human brain revives and represents these memories during retrieval. We are examining one possible solution to this issue by testing whether human visual processing areas become active when individuals remember visually based memories, and whether auditory processing areas become active when sounds from the past are remembered.

Initial studies indicate that sensory-specific regions are reactivated during memorization. In one study, subjects studied either pictures (an image of a dog) or sounds (a bird singing). Brain activity was then imaged while subjects retrieved individual items that had been either studied as pictures or sounds, using cues that were neither pictures nor sounds. Results showed visual cortex activity increases during picture recall and auditory cortex activity increases during sound recall. Frontal regions were also concurrently activated with the sensory-specific regions of visual and auditory cortex. These results collectively suggest that, during recollection, frontal regions modulate posterior sensory-specific regions to reinstate a memory.

Why does memory function break down? Fifty percent of adults over the age of 85 experience some form of dementia such as Alzheimer’s disease, which often begins with memory lapses and progresses to severe cognitive and behavioral dysfunction. The growing understanding of healthy brain anatomy and function provides a foundation for exploring why certain older adults experience memory decline. We are pursuing this question by imaging older adults at the earliest stages of dementia and examining both structural and functional changes that correlate with memory impairment. The focus of these studies is motivated by the finding that cognitive performance often abruptly declines after many years of stability in older adults, reflecting what may be a discontinuous pathological progression in aging. The specific clinical question is whether we can predict the course of progressive dementia by tracking functional-anatomic changes in the circuits normally responsible for impaired higher-level functions. If we can identify the earliest signs of this “cliff” before noted cognitive decline has occurred, clinicians will be better positioned to administer treatment or therapy appropriately as interventions are developed. The basic research has provided us with sensitive methods to measure appropriate frontal and medial temporal involvement during memory function. A major future direction of our research is to apply these procedures—and derivatives of them—with the explicit goals of understanding and predicting progressive dementia. (Grants from the National Institutes of Health and the Alzheimer’s Association provided support for this project.)

A new study has shown that a skin patch can prime the 1) ___ system to fend off traveler’s diarrhea. 2) ___ that contaminate food and water in developing countries cause roughly 17 million cases of diarrhea each year, many in visitors to those countries. To test a 3) ___ against a strain of Escherichia coli responsible for a large fraction of these bouts, researchers enlisted U.S. volunteers who were planning travel to Mexico or Guatemala. Shortly before each traveler’s departure, the scientists mildly abraded a small area of each person’s skin and then applied a patch. One-third got the vaccine; the others received an 4) ___ patch. During roughly 2 weeks of travel, 170 participants kept diaries of their health. Five percent of those getting the vaccine patch and 21% of those getting the 5) ___ reported a moderate or severe case of diarrhea on their trips, reports Gregory M. Glenn of Iomai Corp. in Gaithersburg, Md., which makes the vaccine. The patch contains a 6) ___ made by E. coli. In many people, exposure through the skin appears to be enough to induce an immune response without causing disease. According to Glenn, this is an area where there have been few breakthroughs in past years. (meeting of the American Society of Tropical Medicine and Hygiene, week of Dec 1, 2007)

ANSWERS: 1) immune; 2) Bacteria; 3) vaccine; 4) inert; 5) placebo; 6) toxin