Lawrence Gregory Appelbaum, Ph.D. - US grants

? DESCRIPTION (provided by applicant): Cognitive decline and dementia have become important public health issues in our time as medical science has increased lifespan and our society becomes progressively older. A great deal of the cognitive decline due to aging can be explained by decline in working memory (WM), a mental function central to cognition in which aging deficits appear almost universally. Attempts to use WM training to increase WM ability in older adults has had some success, but the transfer of performance enhancements caused by this training to other cognitive skills is controversial. Another intervention that shows much promise is noninvasive stimulation of cerebral cortex using transcranial magnetic stimulation (TMS), which has been shown to increase performance in many cognitive tasks. In previous work we developed a paradigm using fMRI-guided TMS in which we identified a cortical network sensitive to the effects of sleep deprivation and to WM and targeted it with TMS, almost completely remediating the deficits in WM performance caused by the sleep deprivation, and whose effects outlasted TMS stimulation by at least a day. We then applied this paradigm to healthy young and older adults, to assess the effects of aging on WM. Stimulation to the left lateral occipital complex, a region involved in the maintenance of visual information, enhanced WM performance in both young and older groups. Here we propose to use our fMRI-guided TMS enhancement paradigm to stimulate dorsolateral prefrontal cortex (DLPFC), a region involved not only in the maintenance of items in WM, but also in their manipulation, in order to create WM performance enhancements that will be long lasting and that will transfer to other cognitive tasks as well. This will be achieved through three studies. In the first we will stimulat both old and young healthy adults while they perform different WM tasks that will increasingly engage DLPFC in order to demonstrate enhancement of WM performance that is greater in the older adults. In the second and third studies, older adults will receive active or sham TMS over two weeks of daily sessions while they perform the WM tasks. In the second study, we hope to demonstrate that the cumulative effect of multiple TMS sessions, in tandem with the synergistic effects of simultaneous TMS + WM training, create WM performance enhancements greater than those found with WM training alone, whose effects are long-lasting, continuing a month following the course of TMS sessions. In the third, we will investigate whether the WM enhancements generated by the two- weeks of TMS sessions will generalize to other cognitive tasks. Success of these studies will provide proof in principle for long-lasting, transferable effects of TMS in remediating WM and more general cognitive deficits due to aging, and point to a possible non-invasive brain stimulation therapy for cognitive decline in healthy aging and in dementia.

Project Summary 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 fMRI-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. To achieve these goals, we have developed a plan to expand our existing project and augmented our scientific team to add Dr. Richard O?Brien, Chair of the Neurology Department at Duke, and Dr. Jeffrey Browndyke, who both have extensive experience conducting multimethodological investigations of aging and neurodegenerative disease, including AD and MCI, the population examined in the current proposal. The focus on focal neurostimulation at only a single site represents a fundamental gap in the approach of 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 two specific aims. First, we will use network-guided TMS to optimize memory success based in the frontoparietal network (FPN) in a new group of MCI patients. We will implement a new form of TMS targeting that involves modeling of the global network to understand how the controllability of a stimulation site evokes changes in widespread brain networks. Second, we will identify structural and functional factors affecting the efficacy of individualized network-guided TMS to ameliorate deficits in MCI. By creating a multimodal model of neural deficits related to MCI, we will adjust network-guided TMS to demonstrate how the MCI brain might compensate for these neural deficits. The parent U01 project has made foundational advances towards these goals, as we have demonstrated the ability of to selectively enhance and reduce working memory performance in healthy older adults. In the current Administrative Supplement we will extend this paradigm to a group of MCI participants in order to test the hypothesis that excitatory rTMS to the working memory network can provide positive outcomes for patients with pre-clinical AD. The proposed work will provide an important tool for studying the stability and controllability 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.