Targeted Interventions in Tourette's using Advanced Neuroimaging and Stimulation (TITANS): study protocol for a double-blind, randomised controlled trial of transcranial magnetic stimulation (TMS) to the supplementary motor area in children with Tourette's syndrome

Cynthia K Kahl, Rose Swansburg, Adam Kirton, Tamara Pringsheim, Gabrielle Wilcox, Ephrem Zewdie, Ashley Harris, Paul E Croarkin, Alberto Nettel-Aguirre, Sneha Chenji, Frank P MacMaster, Cynthia K Kahl, Rose Swansburg, Adam Kirton, Tamara Pringsheim, Gabrielle Wilcox, Ephrem Zewdie, Ashley Harris, Paul E Croarkin, Alberto Nettel-Aguirre, Sneha Chenji, Frank P MacMaster

Abstract

Introduction: Tourette's syndrome (TS) affects approximately 1% of children. This study will determine the efficacy and safety of paired comprehensive behavioural intervention for tics (CBIT) plus repetitive transcranial magnetic stimulation (rTMS) treatment in children with Tourette's syndrome. We hypothesise that CBIT and active rTMS to the supplementary motor area (SMA) will (1) decrease tic severity, and (2) be associated with changes indicative of enhanced neuroplasticity (eg, changes in in vivo metabolite concentrations and TMS neurophysiology measures).

Methods and analysis: This study will recruit 50 youth with TS, aged 6-18 for a phase II, double-blind, block randomised, sham-controlled trial comparing active rTMS plus CBIT to sham rTMS plus CBIT in a 1:1 ratio. The CBIT protocol is eight sessions over 10 weeks, once a week for 6 weeks and then biweekly. The rTMS protocol is 20 sessions of functional MRI-guided, low-frequency (1 Hz) rTMS targeted to the bilateral SMA over 5 weeks (weeks 2-6). MRI, clinical and motor assessments and neurophysiological evaluations including motor mapping will be performed 1 week before CBIT start, 1 week after rTMS treatment and 1 week after CBIT completion. The primary outcome measure is Tourette's symptom change from baseline to post-CBIT treatment, as measured by the Yale Global Tic Severity Scale. Secondary outcomes include changes in imaging, neurophysiological and behavioural markers.

Ethics and dissemination: Ethical approval by the Conjoint Health Research Ethics Board (REB18-0220). The results of this study will be published in peer-reviewed scientific journals, on ClinicalTrials.gov and shared with the Tourette and OCD Alberta Network. The results will also be disseminated through the Alberta Addictions and Mental Health Research Hub.

Trial registration: NCT03844919.

Keywords: child & adolescent psychiatry; developmental neurology & neurodisability; paediatric neurology; protocols & guidelines.

Conflict of interest statement

Competing interests: FM, CKK, RS, AK, TP, GW, EZ, AH, AN-A and SC have no conflicts of interest. PEC has received research grant support from the National Institute of Mental Health, Brain and Behavior Research Foundation and Pfizer. He has received equipment support from Neuonetics and received supplies and genotyping services from Assurex Health for investigator-initiated studies. He is the primary investigator for a multicentre study funded by Neuronetics and a site primary investigator for a study funded by NeoSync. PEC is a consultant for Procter & Gamble Company and Myriad Neuroscience.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
TITANS trial timeline. Outline of participant progression through the TITANS trial. At baseline (week 0) and post-treatments (weeks 7 and 11), participants undergo MRI, a battery of clinical assessments, symptom monitoring (Yale Global Tic Severity Scale and Modified Rush Video Rating Scale), transcranial magnetic stimulation (TMS) neurophysiology measures, motor assessment (Purdue Pegboard Task), and TMS motor mapping. Treatment consists of active or sham repetitive TMS (rTMS) for 5 weeks overlapped with simultaneous Comprehensive Behavioural Intervention for Tics (CBIT) therapy for 10 weeks. CBIT occurs on Mondays, weekly for the first 6 weeks then bi-weekly for a total of eight therapy sessions. rTMS treatment occurs 4 days a week (Tuesday to Friday) for 5 weeks (weeks 2–6). Symptom monitoring occurs every Friday (weekly). TMS tolerability is recorded with each TMS neurophysiology and motor mapping session, and weekly for rTMS sessions. Follow-up (Tourette’s and mental health symptoms) occurs at week 36.
Figure 2
Figure 2
Study flow diagram. Consolidated Standards of Reporting Trials diagram showing the flow of participants through each stage of the TITANS clinical trial: phase II single centre, randomised, parallel group, double-blind sham controlled rTMS trial in children with moderate-to-severe Tourette’s syndrome. CBIT, comprehensive intervention for tics; HRT, habit reversal therapy; rTMS, repetitive; TMS, transcranial magnetic stimulation; YGTSS, Yale Global Tic Severity Scale.

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