Repetitive Transcranial Magnetic Stimulation (rTMS) is a noninvasive brain stimulation technique capable of modulating activity in the targeted brain region and its connected brain circuits beyond the duration of the stimulation itself. rTMS is utilized in neuroscience research to investigate brain function during human cognition and behavior, and to understand brain pathophysiology in neuropsychiatric diseases. In patients with Alzheimer's disease (AD) rTMS-driven approaches are being explored as early diagnostic biomarkers, markers of disease progression, and potential therapeutic intervention. However, while there is great promise in these techniques, the variability of the neuromodulatory effects of rTMS and its sources are ill-defined, especially for AD and related dementias. This knowledge gap represents a fundamental limitation for both the interpretation of rTMS results and the design of future studies. For example, it is challenging to calculate or assess the sample size for a study, and one cannot optimize rTMS parameters for an individual without knowing whether individual differences in rTMS response are reproducible. In addition, one cannot assume that rTMS protocols tested in motor cortex will produce similar neuromodulatory effects when administered to other brain regions. We propose to assess the test-retest reliability of the neuromodulatory effects of rTMS in well- cahracterized patients with AD dementia. Mechanisms of cortical plasticity will be explored by assessing the modulation of cortical reactivity induced by a specific rTMS protocol known as intermittent theta burst stimulation (iTBS). The comparison of the motor responses induced by single-pulse TMS before and following iTBS provides a noninvasive measure of the mechanisms of cortical plasticity in humans. We will investigate the efficacy and reliability of this technique first in the motor cortex, where it is best understood, and then apply it to the parietal cortex, which is more directly affected by AD-associated pathology. Our pilot studies demonstrate the feasibility of our approach and provide supportive evidence for our hypothesis that the mechanisms of plasticity are abnormal in AD and rTMS measures offer reliable and valuable biomarkers. All subjects will undergo extensive baseline assessment, including detailed exam, neuropsychological measures, structural and resting-state functional-connectivity MRI, computational modeling, laboratory and genetic testing, and EEG to identify predictors of inter-subject variability in response to rTMS. All data will be placed in a secure repository and made publicly accessible to other investigators This study will define the reproducibility of the neuromodulatory effects of rTMS, quantifying the intrinsic variability of the method within and across individuals, across modes of assessment (electromyography versus electroencephalography) and brain regions (motor versus parietal). These results will serve as a foundation to guide the planning, development and interpretation of all future studies utilizing rTMS to modulate brain function in both healthy aging and dementia.

Public Health Relevance

Repetitive Transcranial Magnetic Stimulation (rTMS) is a noninvasive brain stimulation method increasingly being used in basic, translational, and clinical research, as well as for therapeutic applications in a variety of neurologic and psychiatric diseases. For Alzheimer's disease, rTMS measures can serve as a marker of in-vivo neuroplasticity, and represents a potential future target for intervention. However, a critical impediment to greater utility and efficacy is a lack of knowledge of the reproducibility of the neuromodulatory effects of rTMS. We aim to address this knowledge gap with a series of experiments combining rTMS with electromyography and electroencephalography to characterize the magnitude and reliability of rTMS effects across sessions and cortical sites. This information is critical for calculation of sample size in studies, interpretation of results, identification of predictors to response to rTMS, and optimization of stimulation protocols for use in future clinical trials of Alzheimer's disease.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Mcmullen, David
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Beth Israel Deaconess Medical Center
United States
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