TICS: Transcranial Magnetic Stimulation for Intervening in Children With Tourette's Syndrome (CIHR) (TICS-CIHR)

TICS: Transcranial Magnetic Stimulation for Intervening in Children With Tourette's Syndrome

Tourette's Syndrome (TS) is characterized by repetitive movements and vocalizations called tics. Due to the suffering caused by TS, children and adolescents often require treatment for their tics. The investigators' research focuses on developing novel repetitive transcranial magnetic stimulation (rTMS) interventions for child and adolescent neuropsychiatric disorders. In this project, the investigators will determine the effect of pairing 3 weeks of rTMS and HRT on tic severity and plasticity as indexed by supplementary motor area (SMA) y-aminobutyric acid (GABA) concentration and functional connectivity of the SMA to the primary motor cortex (M1) in children and adolescents with TS.

Children (N = 50, 6-18 years) with TS will be randomized to either a (1) rTMS+HRT arm, or (2) sham rTMS+HRT. Outcome measures will examine tic severity (primary), brain chemistry and function (secondary) at baseline and then at week 7. The investigators' proposed aims are:

(Aim 1) To determine the effect of paired rTMS and HRT on tic severity as measured by the Yale Global Tic Severity Scale (YGTSS) by comparing it to sham rTMS + HRT.

1-1: The investigators hypothesize that tic severity will decrease from baseline to post-treatment.

1-2: The investigators also hypothesize that the reduction in tic severity will be greater in the paired treatment group (rTMS+HRT > Sham rTMS+HRT).

(Aim 2) To determine the effect of paired rTMS and HRT on brain plasticity compared to sham rTMS + HRT.

2-1: The investigators hypothesize that patients treated with the paired rTMS and HRT will have a greater increase in GABA concentration comparted to sham and HRT.

2-2: The investigators also hypothesize that functional connectivity between the SMA and M1 will be greater with paired treatment (rTMS+HRT > Sham rTMS+HRT).

Study Overview

• Status: Recruiting
• Conditions: Tic Disorders
• Intervention / Treatment: Device: rTMS + CBIT; Behavioral: Sham rTMS + CBIT

Detailed Description

Tourette's Syndrome (TS) is characterized by repetitive movements and vocalizations called tics. Due to the suffering caused by TS, children and adolescents often require treatment for their tics. Tic severity predicts poor outcomes across physical, psychological, and cognitive domains in youth. Current treatments for TS remain limited in scope and efficacy. Atypical antipsychotics are often used and for many patients have an unacceptable side effect burden. Behavioral treatments, like habit reversal therapy (HRT), show promise and are safe, but are predicated on a certain level of brain maturation to execute.

The investigators' research focuses on developing novel repetitive transcranial magnetic stimulation (rTMS) interventions for child and adolescent neuropsychiatric disorders. Plasticity, precision, and pairing are key considerations in this process. In this project, the investigators will determine the effect of pairing 3 weeks of rTMS and HRT on tic severity and plasticity as indexed by supplementary motor area (SMA) y-aminobutyric acid (GABA) concentration and functional connectivity of the SMA to the primary motor cortex (M1) in children and adolescents with TS. The investigators will use functional magnetic resonance imaging (fMRI) and robot controlled rTMS to precisely target the SMA. The investigators believe this pairing will provide improved relief by inducing plasticity to retrain the brain to be better at suppressing tics at an earlier age than usually expected.

Children (N = 50, 6-18 years) with TS will be randomized to either a (1) rTMS+HRT arm, or (2) sham rTMS+HRT. Outcome measures will examine tic severity (primary), brain chemistry and function (secondary) at baseline and then at week 7. The investigators' proposed aims are:

(Aim 1) To determine the effect of paired rTMS and HRT on tic severity as measured by the Yale Global Tic Severity Scale (YGTSS) by comparing it to sham rTMS + HRT.

1-1: The investigators hypothesize that tic severity will decrease from baseline to post-treatment.

1-2: The investigators also hypothesize that the reduction in tic severity will be greater in the paired treatment group (rTMS+HRT > Sham rTMS+HRT).

(Aim 2) To determine the effect of paired rTMS and HRT on brain plasticity compared to sham rTMS + HRT.

2-1: The investigators hypothesize that patients treated with the paired rTMS and HRT will have a greater increase in GABA concentration comparted to sham and HRT.

2-2: The investigators also hypothesize that functional connectivity between the SMA and M1 will be greater with paired treatment (rTMS+HRT > Sham rTMS+HRT).

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Rose M Swansburg, MBT; Phone Number: 4039552784; Email: rose.swansburg@ucalgary.ca

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T3B 6A8
      • Recruiting
      • Alberta Children's Hospital
      • Contact: Frank P MacMaster, PhD; Phone Number: 403-955-2784; Email: fmacmast@ucalgary.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Diagnosis of Tourette's syndrome
2. IQ greater than 80
3. English fluency (to enable assent and consent).

Exclusion Criteria:

1. Diagnosis of mania or schizophrenia
2. Impediments to TMS or MRI.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: rTMS + CBIT; Repetitive transcranial magnetic stimulation (rTMS) and Comprehensive Behavioural Intervention for Tics (CBIT)	Device: rTMS + CBIT; Repetitive Transcranial Magnetic Stimulation (rTMS) parameters are: intensity 100% resting motor threshold (RMT), frequency 1Hz, duration = 30 minutes (1800 stimulations; 900 per side), target - the supplementary motor area (SMA). Treatments occur on weekdays (T - F) for four weeks (20 total). The Comprehensive Behavioral Intervention for Tics (CBIT) will be completed over eight sessions that will average 60 minutes in duration. First, participants will undergo awareness training. Participants will then be introduced to competing response training, which involves performing a voluntary behaviour designed to disrupt the execution of the tic. The eight sessions will occur on Mondays, once a week for six weeks and then on weeks 8 and 10.; Behavioral: Sham rTMS + CBIT; Sham rTMS (sham coil) will be paired with CBIT. Sham rTMS will be delivered over the same time-frame as above. CBIT will be identical to the above.
Active Comparator: Sham rTMS + CBIT; Sham repetitive transcranial magnetic stimulation (rTMS) and Comprehensive Behavioural Intervention for Tics (CBIT)	Behavioral: Sham rTMS + CBIT; Sham rTMS (sham coil) will be paired with CBIT. Sham rTMS will be delivered over the same time-frame as above. CBIT will be identical to the above.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Yale Global Tic Severity Scale Total Tic score (YGTSS)	30% reduction in Yale Global Tic Severity Scale Total Tic score (YGTSS) (~9 point reduction). A higher score on all scales suggests a more severe tics. The YGTSS provides two tic severity scores: Total Motor (0 to 25); Total Phonic (0 to 25) These are summed to form the Total Tic Severity Score (0 to 50). This is the measure for the primary outcome variable. There is also the separate Impairment Dimension Score (0 to 50). The total score is hence 0 to 100 (sum of Total Tic Severity Score and Impairment Dimension Score).	Baseline to week 7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Supplementary Motor Area (SMA) GABA concentration as measured by LCModel (Institutional Units)	10% increase in GABA concentration in the Supplementary Motor Area (SMA) as measured by LCModel (Institutional Units)	Baseline to week 7
Functional connectivity of the Supplementary Motor Area (SMA) and the dominant Primary Motor Cortex (M1)	Functional connectivity, as measured using SPM12, of the Supplementary Motor Area (SMA) and the dominant Primary Motor Cortex (M1).	Baseline to week 7

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Yale Global Tic Severity Scale Total Tic score (YGTSS) post CBIT	30% reduction in YGTSS (~9 point reduction) 30% reduction in Yale Global Tic Severity Scale Total Tic score (YGTSS) (~9 point reduction). A higher score on all scales suggests a more severe tics. The YGTSS provides two tic severity scores: Total Motor (0 to 25); Total Phonic (0 to 25) These are summed to form the Total Tic Severity Score (0 to 50). This is the measure for this outcome variable. There is also the separate Impairment Dimension Score (0 to 50). The total score is hence 0 to 100 (sum of Total Tic Severity Score and Impairment Dimension Score).	Baseline to week 11

Collaborators and Investigators

• Sponsor: University of Calgary
• Collaborators: Canadian Institutes of Health Research (CIHR)

Publications and helpful links

General Publications

• Kahl CK, Swansburg R, Kirton A, Pringsheim T, Wilcox G, Zewdie E, Harris A, Croarkin PE, Nettel-Aguirre A, Chenji S, MacMaster FP. 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. BMJ Open. 2021 Dec 24;11(12):e053156. doi: 10.1136/bmjopen-2021-053156.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2019
• Primary Completion (Anticipated): May 1, 2022
• Study Completion (Anticipated): November 1, 2022

Study Registration Dates

• First Submitted: February 11, 2019
• First Submitted That Met QC Criteria: February 14, 2019
• First Posted (Actual): February 19, 2019

Study Record Updates

• Last Update Posted (Actual): November 10, 2021
• Last Update Submitted That Met QC Criteria: November 2, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: Adolescent; MRI; Children; Transcranial magnetic stimulation; rTMS; Tourette's Syndrome; TMS; CBIT; Comprehensive Behavioral Intervention for Tics
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Basal Ganglia Diseases; Movement Disorders; Neurodegenerative Diseases; Heredodegenerative Disorders, Nervous System; Neurodevelopmental Disorders; Tourette Syndrome; Tic Disorders
• Other Study ID Numbers: REB18-0220

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Only de-identified data would be shared.
• IPD Sharing Time Frame: Study protocol, SAP, and ICF is open to be shared now. De-identified data will be shared after we submitted our main papers. This is estimated in 2025.
• IPD Sharing Access Criteria: Email for permission from PI of project.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No