This is an application for an Administrative Supplement award to an existing project, Using fMRI-guided TMS to increase central executive function in older adults. This award will provide our team with the support necessary to extend our existing EEG-TMS paradigm to patients with a prodromal form of Alzheimer?s Disease (AD) known as amnestic Mild Cognitive Impairment (MCI), and investigate the role of brain health factors in mediating the TMS-related memory performance benefits associated with communication between a network of frontoparietal brain regions in these populations. The main goal of the project is to address develop a novel approach to memory-based neurostimulation therapies. Neurostimulation affects multiple sites within a cortical network, but these global effects have not been used as targets for stimulation because of limited knowledge about what influence these localized sites have on global changes in brain state. To address this problem, we will use multimodal neuroimaging tools and network modeling approaches developed though the parent U01 project, to demonstrate how focal neurostimulation improves the efficacy of TMS for enhancing memory function. These goals will be addressed in the Administrative Supplement under our three specific aims.
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 Word Encoding task, a general task of memory performance. The ongoing work will provide an important tool for studying the dynamics of network connectivity of memory states in the aging brain, as well as new information on the effectiveness of brain stimulation technologies as a therapeutic approach for cognitive decline. The parent K01 project has made foundational advances towards these goals, as we have demonstrated the ability of to selectively modulate memory-related neural functions in healthy older adults and MCI. The project has proceeded successfully through Years 1-3, with multiple conference publications and prepared manuscripts, and the achievement of developmental goals in Clinical and Electrophysiology didactics. However, as outlined in the Budget Justification, the project has incurred a number of unanticipated costs, and in order to complete the project we request additional funds through this Supplement. The scientific goals and approach remain unchanged from the original proposal.
The ongoing research will test a novel neurostimulation approach that utilizes EEG-derived measures of brain connectivity to establish the critical site for stimulation, and demonstrate enhancement of memory function beyond a sham stimulation condition. This protocol will first be tested in a cohort of healthy older adults to optimize the neurostimulation approach, and then be applied in a cohort of MCI adults to evaluate the ability of network-guided neurostimulation to mitigate age-related memory deficits. These studies will provide important insights about the neural substrates of successful memory states, and will accelerate the discovery of potent non-invasive treatments to remediate cognitive decline in healthy and cognitively impaired older adults.
