Teen and Adult Tic TMS Study

This project investigates safety, tolerability, and efficacy signals of accelerated continuous theta burst stimulation (cTBS), a form of inhibitory repetitive transcranial magnetic stimulation (rTMS), for patients with Tourette Syndrome and chronic tic disorders (CTD). It integrates resting-state functional MRI (fMRI) to assess changes in brain circuits and neurophysiology. CTD are neurodevelopmental disorders marked by motor and/or vocal tics, associated with dysfunction in cortico-striato-thalamo-cortical (CSTC) networks, particularly the supplementary motor area (SMA), primary motor cortex (M1), and connected regions. While low-frequency rTMS has shown preliminary benefits in pediatric populations, circuit-targeted approaches remain relatively unexplored in children, adolescents and adults, leaving no consensus about optimal applications.

Participants will be randomized to receive 50 sessions of 1800 pulses of cTBS rTMS over two weeks, with five sessions/day targeting the SMA or M1. Assessments will include the Yale Global Tic Severity Scale (YGTSS) and MRI.

Aim 1 Determine if cTBS to the M1 can reduce CTD symptoms and normalize abnormal network connectivity within the Somato-Cognitive Action Network (SCAN).

Aim 2 Determine if cTBS to the SMA can reduce symptoms of CTD and normalize abnormal network connectivity within the Action Mode Network (AMN).

For Aims 1 and 2, the investigators propose to test a protocol of accelerated inhibitory continuous theta burst stimulation (cTBS) targeting areas of tic-related hyperactivity as identified by functional MRI. Participants will be randomized by computerized list to either receive rTMS directed at the SMA or rTMS directed toward the M1. The investigators will examine data on tolerability, adverse events and early efficacy signals that could inform future, larger scale controlled trials for this indication in adolescents and young adults.

TMS: Our protocol consists of five treatments of inhibitory continuous TBS (cTBS) with the target intensity less than 100% to the SMA or M1 Thumb (as determined by random assignment) lasting five minutes delivered over the course of 10 days (2 weeks) for a total of 50 treatments.

For Aim 3, the investigators will utilize repeated brain MRI imaging pre- and post-TMS treatment within persons with CTD to gauge direction of effects. The investigators plan to observe functional network activity in presumed tic-related neural circuits in youth with CTD pre- and post-treatment. A within-person design also highlights a personalized approach to circuit-based therapeutics that can be explored for individual differences in neural and clinical responses.

MR Imaging Protocol: MRI scanning including T1-weighted anatomical and rs-fMRI will take place on a GE Discovery MR750 3 Tesla scanner. For the rs-fMRI scan, patients will be asked to undergo at least 2x 7 minute scans with eyes open and were observed by an MR technician to ensure wakefulness. All T1 and fMRI scans will be preprocessed using the fMRIprep, a standardized preprocessing pipeline which utilizes tools from the widely-used MRI processing software packages AFNI, ANTs, FreeSurfer, and FSL. T1 scans will be corrected for intensity nonuniformity, skull-stripped, and segmented for registration purposes, then resampled into MNI space. fMRI scans will be slice-time corrected and resampled back to their native space with headmotion correction, then registered and resampled to both T1 space and MNI space. Data analysis will be performed in AFNI, including denoising of fMRI data using nuisance regressors generated by fMRIprep including 12 motion parameters as well as CSF and white matter signals. The resulting residual signal will then be utilized to generate RSFC matrices from the Fisher transformed correlation to generate normalized Z statistics.