Saturday, May 17, 2025
5/17/2025
Cognitive and Neural Correlates of TMS Motor Intracortical Inhibition in Schizophrenia - Project Summary: This K01 application is designed to prepare the applicant to become a successful, independent investigator combining state of the art neuroimaging methods and transcranial magnetic stimulation (TMS) to elucidate the neural circuits that underlie specific signs and symptoms of schizophrenia (Sz), and using repetitive TMS as an intervention to attempt to normalize circuit function. To achieve this career objective, I have worked with my mentoring/advisory committee to develop a plan to receive training in: (1) TMS application, data analysis and how to design TMS studies, (2) clinical trial study design and implementation, and (3) cognitive neuroscience including circuitry of specific cognitive domains and cognitive impairment(s) in Sz. The short interval intracortical inhibition (SICI) is a biomarker of cortical excitability that can be easily obtained with non-invasive paired-pulse TMS. Intracortical inhibition is consistently reduced in prior studies of Sz (indicated by higher SICI scores in Sz). The overall goal of the proposed K01 research is to evaluate the broader significance and clinical impact of reduced SICI in Sz, and evaluate whether repetitive TMS can enhance SICI in Sz. The proposed research is important because it will help determine whether SICI may serve as a meaningful target for future intervention studies and clinical trials. The specific aims are to: (1) determine the specificity of relationships between SICI and different cognitive domains in Sz; (2) determine the relationship between SICI and brain functional communication in Sz; and (3) perform a pilot mechanistic repetitive TMS clinical trial targeting motor cortex of Sz patients to evaluate whether repetitive TMS can enhance SICI in Sz. Aim 1 will combine use of paired-pulse TMS (to measure SICI) and in-depth cognitive assessment to test the hypothesis that reduced inhibition (indexed by higher SICI score) in Sz will be associated with poorer motor inhibition (Stop-Signal) task performance, and will generalize to spatial working memory performance, which is thought to be sensitive to the same type of excitatory/inhibitory signaling imbalance that is assayed by SICI. Aim 2 will combine use of paired-pulse TMS (to measure SICI) and resting functional magnetic resonance imaging (fMRI) to test the hypothesis that reduced inhibition (indexed by higher SICI score) in Sz is associated with lower resting connectivity between the anterior insula and both the motor cortex and the dorsolateral-prefrontal cortex. Aim 3 will use inhibitory 1Hz repetitive TMS applied to motor cortex of a sample of participants with Sz (N=17 active TMS, N=17 sham TMS) to evaluate whether five sessions of active repetitive TMS can enhance SICI in Sz relative to sham stimulation. The proposed research combines several quantitative approaches/assessments (cognitive assessment, fMRI, paired-pulse TMS, and repetitive TMS) to better understand the underlying neurophysiology of Sz and its relationship to cognitive impairments, with the translational aim of developing better treatments and innovative treatment targets for Sz.
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