PROJECT SUMMARY This is an application for a K01 award to Dr. Simon Davis, an Assistant Professor and cognitive neuroscientist at the Duke Institute of Brain Sciences, a scientific institute that supports researchers bridging basic science and translational applications. Dr. Davis is establishing himself as a young investigator in both basic and translational research of age-related disorders of cognition. This K01 award will provide Dr. Davis with the support necessary to accomplish the following goals: (1) become an expert in Cognitive Electrophysiology (EEG) and Clinical Research, with a focus on Alzheimer’s Disease (AD), (2) gain practical expertise in electrophysiological approaches to hemispheric communication during memory, (3) integrate novel brain stimulation and EEG techniques in both basic and translational studies, and (4) develop novel brain stimulation protocols to enhance attentional control and memory in normative and demented elderly populations. To achieve these goals, Dr. Davis, who has a background on the neural mechanisms of episodic and semantic memory, has assembled a mentoring team comprised of his primary mentor, Dr. Marty G. Woldorff, a senior cognitive neuroscientist with extensive experience in electrophysiological studies of attentional and cognitive control, and co-mentor Dr. Richard O’Brien, Chair of the Neurology Department at Duke, who has extensive experience conducting multimethodological investigations of aging and neurodegenerative disease, including AD and amnestic Mild Cognitive Impairment (MCI-AD), the population examined in the current proposal. This proposal is focused on the gap in understanding of bilateral brain interactions and their role in helping normative and clinical elderly populations maintain cognitive health. Dr. Davis’ research will focus on investigating this neural mechanism of these interactions and promoting them with a precise application of TMS, in order to test the hypothesis that excitatory interactions between the hemispheres can provide positive outcomes for patients with pre-clinical AD (amnestic Mild Cognitive Impairment or MCI-AD). In Aim 1, Dr. Davis will establish the spatial specificity of bilateral brain mechanisms with combination of behavior and high- resolution structural neuroimaging in cortical sites known to be active during memory encoding. In Aim 2, Dr. Davis will establish the underlying dynamics of interhemispheric frontal communication using a novel combination of single-sided TMS, rTMS entraining conditions, and electroencephalography (EEG) to establish the coordinated activity between the hemispheres; Lastly, in Aim 3, Dr. Davis will use the rTMS entraining parameters delineated in Aim 2 to promote specific cross-hemispheric communication, applied to participants performing a Picture Encoding task, a general task of memory performance. The outcome of these studies will allow Dr. Davis to evaluate the strength of this brain stimulation protocol in alleviating age-related and dementia-related cognitive decline. This research will enable development of novel treatment protocols for dementia in elderly cohorts, and form the basis of a longitudinal study in neurodegenerative disease that will be proposed in an R01 grant application before the termination of the K award.

Project Narrative / Public Health Statement: Improved understanding of the bilateral brain interactions underlying cognitive health in normative and demented populations of older adults is critical to effective medical and therapeutic management of age-related cognitive decline and may clarify the underlying mechanisms for cognition across the lifespan.