Multitarget Stereotactic Electrophysiological Recording and Stimulation for Tourette Syndrome

NCT06889480 | Recruiting DMC

• 1 other identifier: HX-B-2024057
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical trial is to investigate the neural mechanisms underlying Tourette syndrome (TS) and see if personalized deep brain stimulation (DBS) can help reduce tics in TS patients and improve related issues like anxiety, attention problems, and obsessive-compulsive behaviors. In this study, researchers will use stereoelectroencephalography (SEEG) and electrocorticography (ECoG) to record brain activity in key areas involved in movement and emotion, including the nucleus accumbens (NAc), anterior limb of the internal capsule (ALIC), insular cortex, anterior cingulate cortex (ACC), central medial thalamic nucleus (CM), globus pallidus internus (GPi), and motor cortex (M1). They will test stimulation in these areas to evaluate acute therapeutic effect for each target and to identify a new effective new target. Later, participants will receive DBS treatment under three different conditions, each for 1 month to identify the optimal target:

1. 1.Stimulation at the new target,
2. 2.Stimulation at the CM,
3. 3.Sham stimulation (does not actually stimulate).

Conditions

Tourette Syndrome; Deep Brain Stimulation

Keywords

Tourette syndrome; Electrophysiology; Tics; Psychiatric Comorbidities; Deep Brain Stimulation; Biomarker

Outcome Measures

Primary Outcomes (1)

• Change in Yale Global Tic Severity Scale (YGTSS) Score

  The YGTSS is a 10-item semi-structured clinician-rating instrument that evaluates motor and phonic symptoms' number, frequency, intensity, complexity, and interference. The items about the tic ratings are scored on two subscales: motor tics and phonic tics. Behaviors are rated on a 6-point scale. The Total Tic Severity Score ranges from 0-50, with a higher score indicating a higher severity of symptoms.

  administered at baseline, 1 month after each randomized stimulation period during the crossover phase, and 3 months after continuous optimal stimulation

Secondary Outcomes (12)

• Change in Modified Rush Video Rating Scale (MRVRS)

  administered at baseline, 1 month after each randomized stimulation period during the crossover phase, and 3 months after continuous optimal stimulation

• Change in Premonitory Urge Scale (PUTS) Score

  administered at baseline, 1 month after each randomized stimulation period during the crossover phase, and 3 months after continuous optimal stimulation

• Change in Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score

  administered at baseline, 1 month after each randomized stimulation period during the crossover phase, and 3 months after continuous optimal stimulation

• Change in Conners' Adult ADHD Rating Scale (CAARS) score

  administered at baseline, 1 month after each randomized stimulation period during the crossover phase, and 3 months after continuous optimal stimulation

• Change in Hamilton Anxiety Scale (HAMA) Score

  administered at baseline, 1 month after each randomized stimulation period during the crossover phase, and 3 months after continuous optimal stimulation

Other Outcomes (1)

• New Stimulation Target Identification

  administered at baseline, 1 month after each randomized stimulation period during the crossover phase, and 3 months after continuous optimal stimulation

Study Arms (3)

New Target DBS

EXPERIMENTAL

Participants in this arm will receive active deep brain stimulation targeted to a novel brain region. The new target is identified through electrophysiological brain mapping and 24-hour stimulation. Stimulation parameters (frequency, voltage, pulse width) will be individually optimized based on mapping results.

Device: New Target DBS

CM-DBS

ACTIVE COMPARATOR

Participants in this arm will receive active deep brain stimulation at the central medial thalamic nucleus (CM), a well-established target for TS treatment. Stimulation settings are determined during electrophysiological brain mapping and 24-hour stimulation. This arm serves as the active comparator, enabling the evaluation of relative efficacy and safety between the conventional CM target and the new target intervention.

Device: CM-DBS

Sham Stimulation

SHAM COMPARATOR

Participants in this arm will undergo identical surgical procedures and follow-up assessments as in the active stimulation arms but will receive sham (inactive) stimulation. This arm is designed to control for placebo effects and ensure that any observed improvements in TS symptoms are attributable to the active interventions.

Device: Sham Stimulation

Interventions

New Target DBS DEVICE

Participants in this arm will receive active DBS targeting a novel brain region identified via electrophysiological brain mapping. A DBS electrode will be implanted at the new target, and stimulation parameters (including frequency, voltage, and pulse width) are individually optimized based on mapping and 24-hour testing. The procedure is performed using a robotic system for precise electrode placement, and the device is provided by Beijing PINS Medical Co., Ltd.

New Target DBS

CM-DBS DEVICE

This intervention involves active DBS at the central medial thalamic nucleus (CM) -a widely used target in TS treatment. A DBS electrode is implanted at the CM target, with stimulation settings determined through electrophysiological brain mapping and subsequent 24-hour stimulation. This arm serves as an active comparator, with stimulation administered during a 1-month period in the crossover phase. The same device and robotic-assisted implantation are used to ensure consistency and precision.

CM-DBS

Sham Stimulation DEVICE

Participants assigned to the sham stimulation arm undergo the identical surgical procedure and electrode implantation as those in the active arms. However, during the stimulation periods, the device is programmed to deliver no active stimulation. This sham intervention is designed to control for placebo effects and ensure that any observed improvements in TS symptoms are attributable to the active DBS interventions.

Sham Stimulation

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Age between 18 and 60 years.
• Diagnosis of Tourette Syndrome according to DSM-V criteria, defined as:
• i. The presence of multiple motor tics and at least one vocal tic at some point (not necessarily simultaneous).
• ii. Tics that have persisted for more than 1 year from their onset.
• iii. Onset of tics occurring before the age of 18.
• iv. The disorder is not attributable to the physiological effects of a substance or another medical condition.
• A Yale Global Tic Severity Scale (YGTSS) total score greater than 35 (on a scale of 0-50) for at least 1 year, with a motor tic score of ≥15, and tics being the primary cause of disability.
• Inadequate response to conservative treatments (standard pharmacological and behavioral therapy).
• Disease duration of more than 1 year.
• Any coexisting medical, neurological, or psychiatric disorders have been treated and remain stable for at least 6 months.
• A stable psychosocial environment.
• Neuropsychological evaluation demonstrating that the candidate can tolerate the surgical procedure, postoperative follow-up, and potential adverse events.
• The participant, or his/her legal representative, is able to provide written informed consent.

You may not qualify if:

• Presence of suicidal risk, defined as a score of ≥3 on the suicide-related items of the Hamilton Depression Rating Scale (HAMD).
• History of drug or alcohol dependence within the past 6 months.
• Abnormal brain structure as indicated by CT or MRI scans.
• Presence of any condition that could lead to surgical failure or interfere with postoperative management.
• Diagnosis of factitious disorder, malingering, or psychogenic tics.
• Contraindications to neurosurgical procedures (e.g., history of cerebral infarction, hydrocephalus, cerebral atrophy, or post-stroke sequelae).
• Contraindications for CT/MRI scanning (e.g., claustrophobia).
• Pregnancy or lactation, or a positive pregnancy test prior to randomization.
• Contraindications to general anesthesia (e.g., severe arrhythmia, severe anemia, hepatic or renal dysfunction).
• Expected survival of less than 12 months.
• Participation in other interventional clinical studies that may influence outcome assessments.
• Any other condition that, in the investigator's judgment, renders the candidate unsuitable for participation or poses a significant risk (e.g., inability to understand study procedures or poor adherence).

Sponsors & Collaborators

• Beijing Tiantan Hospital: lead

Study Sites (1)

Beijing Tiantan Hospital, Capital Medical University

Beijing, Beijing Municipality, 100070, China

RECRUITING

Related Publications (23)

• Martinez-Ramirez D, Jimenez-Shahed J, Leckman JF, Porta M, Servello D, Meng FG, Kuhn J, Huys D, Baldermann JC, Foltynie T, Hariz MI, Joyce EM, Zrinzo L, Kefalopoulou Z, Silburn P, Coyne T, Mogilner AY, Pourfar MH, Khandhar SM, Auyeung M, Ostrem JL, Visser-Vandewalle V, Welter ML, Mallet L, Karachi C, Houeto JL, Klassen BT, Ackermans L, Kaido T, Temel Y, Gross RE, Walker HC, Lozano AM, Walter BL, Mari Z, Anderson WS, Changizi BK, Moro E, Zauber SE, Schrock LE, Zhang JG, Hu W, Rizer K, Monari EH, Foote KD, Malaty IA, Deeb W, Gunduz A, Okun MS. Efficacy and Safety of Deep Brain Stimulation in Tourette Syndrome: The International Tourette Syndrome Deep Brain Stimulation Public Database and Registry. JAMA Neurol. 2018 Mar 1;75(3):353-359. doi: 10.1001/jamaneurol.2017.4317.

  PMID: 29340590 BACKGROUND

• Muller-Vahl KR, Szejko N, Saryyeva A, Schrader C, Krueger D, Horn A, Kuhn AA, Krauss JK. Randomized double-blind sham-controlled trial of thalamic versus GPi stimulation in patients with severe medically refractory Gilles de la Tourette syndrome. Brain Stimul. 2021 May-Jun;14(3):662-675. doi: 10.1016/j.brs.2021.04.004. Epub 2021 Apr 18.

  PMID: 33857664 BACKGROUND

• Schuller T, Gruendler TOJ, Smith EE, Baldermann JC, Kohl S, Fischer AG, Visser-Vandewalle V, Ullsperger M, Kuhn J, Huys D. Performance monitoring in obsessive-compulsive disorder: Insights from internal capsule/nucleus accumbens deep brain stimulation. Neuroimage Clin. 2021;31:102746. doi: 10.1016/j.nicl.2021.102746. Epub 2021 Jun 29.

  PMID: 34229156 BACKGROUND

• Xiong B, Li B, Wen R, Gao Y, Gong F, Li D, Xu Y, Deng H, Xiao L, Yin S, Zhang W, Lozano AM, Wang W. Use of differential stimulation of the nucleus accumbens and anterior limb of the internal capsule to improve outcomes of obsessive-compulsive disorder. J Neurosurg. 2023 May 26;139(5):1376-1385. doi: 10.3171/2023.4.JNS221824. Print 2023 Nov 1.

  PMID: 37243560 BACKGROUND

• McGovern RA, Sheth SA. Role of the dorsal anterior cingulate cortex in obsessive-compulsive disorder: converging evidence from cognitive neuroscience and psychiatric neurosurgery. J Neurosurg. 2017 Jan;126(1):132-147. doi: 10.3171/2016.1.JNS15601. Epub 2016 Apr 1.

  PMID: 27035167 BACKGROUND

• O'Neill J, Piacentini JC, Peterson BS. Cingulate role in Tourette syndrome. Handb Clin Neurol. 2019;166:165-221. doi: 10.1016/B978-0-444-64196-0.00011-X.

  PMID: 31731911 BACKGROUND

• Jackson SR, Sigurdsson HP, Dyke K, Condon M, Jackson GM. The role of the cingulate cortex in the generation of motor tics and the experience of the premonitory urge-to-tic in Tourette syndrome. J Neuropsychol. 2021 Sep;15(3):340-362. doi: 10.1111/jnp.12242. Epub 2021 Mar 27.

  PMID: 33774919 BACKGROUND

• Jackson SR, Loayza J, Crighton M, Sigurdsson HP, Dyke K, Jackson GM. The role of the insula in the generation of motor tics and the experience of the premonitory urge-to-tic in Tourette syndrome. Cortex. 2020 May;126:119-133. doi: 10.1016/j.cortex.2019.12.021. Epub 2020 Jan 22.

  PMID: 32070809 BACKGROUND

• Neumann WJ, Huebl J, Brucke C, Lofredi R, Horn A, Saryyeva A, Muller-Vahl K, Krauss JK, Kuhn AA. Pallidal and thalamic neural oscillatory patterns in tourette's syndrome. Ann Neurol. 2018 Oct;84(4):505-514. doi: 10.1002/ana.25311. Epub 2018 Oct 4.

  PMID: 30112767 BACKGROUND

• Gunduz A, Okun MS. A Review and Update on Tourette Syndrome: Where Is the Field Headed? Curr Neurol Neurosci Rep. 2016 Apr;16(4):37. doi: 10.1007/s11910-016-0633-x.

  PMID: 26936259 BACKGROUND

• Cagle JN, Okun MS, Opri E, Cernera S, Molina R, Foote KD, Gunduz A. Differentiating tic electrophysiology from voluntary movement in the human thalamocortical circuit. J Neurol Neurosurg Psychiatry. 2020 May;91(5):533-539. doi: 10.1136/jnnp-2019-321973. Epub 2020 Mar 5.

  PMID: 32139653 BACKGROUND

• Bohlhalter S, Goldfine A, Matteson S, Garraux G, Hanakawa T, Kansaku K, Wurzman R, Hallett M. Neural correlates of tic generation in Tourette syndrome: an event-related functional MRI study. Brain. 2006 Aug;129(Pt 8):2029-37. doi: 10.1093/brain/awl050. Epub 2006 Mar 6.

  PMID: 16520330 BACKGROUND

• Wang Z, Maia TV, Marsh R, Colibazzi T, Gerber A, Peterson BS. The neural circuits that generate tics in Tourette's syndrome. Am J Psychiatry. 2011 Dec;168(12):1326-37. doi: 10.1176/appi.ajp.2011.09111692. Epub 2011 Sep 28.

  PMID: 21955933 BACKGROUND

• Johnson KA, Duffley G, Foltynie T, Hariz M, Zrinzo L, Joyce EM, Akram H, Servello D, Galbiati TF, Bona A, Porta M, Meng FG, Leentjens AFG, Gunduz A, Hu W, Foote KD, Okun MS, Butson CR. Basal Ganglia Pathways Associated With Therapeutic Pallidal Deep Brain Stimulation for Tourette Syndrome. Biol Psychiatry Cogn Neurosci Neuroimaging. 2021 Oct;6(10):961-972. doi: 10.1016/j.bpsc.2020.11.005. Epub 2020 Nov 24.

  PMID: 33536144 BACKGROUND

• Johnson KA, Fletcher PT, Servello D, Bona A, Porta M, Ostrem JL, Bardinet E, Welter ML, Lozano AM, Baldermann JC, Kuhn J, Huys D, Foltynie T, Hariz M, Joyce EM, Zrinzo L, Kefalopoulou Z, Zhang JG, Meng FG, Zhang C, Ling Z, Xu X, Yu X, Smeets AY, Ackermans L, Visser-Vandewalle V, Mogilner AY, Pourfar MH, Almeida L, Gunduz A, Hu W, Foote KD, Okun MS, Butson CR. Image-based analysis and long-term clinical outcomes of deep brain stimulation for Tourette syndrome: a multisite study. J Neurol Neurosurg Psychiatry. 2019 Oct;90(10):1078-1090. doi: 10.1136/jnnp-2019-320379. Epub 2019 May 25.

  PMID: 31129620 BACKGROUND

• Frey J, Malaty IA. Tourette Syndrome Treatment Updates: a Review and Discussion of the Current and Upcoming Literature. Curr Neurol Neurosci Rep. 2022 Feb;22(2):123-142. doi: 10.1007/s11910-022-01177-8. Epub 2022 Feb 2.

  PMID: 35107785 BACKGROUND

• Gao Y, Wang S, Wang A, Fan S, Ge Y, Wang H, Gao D, Wang J, Mao Z, Zhao H, Zhang H, Shi L, Liu H, Zhu G, Yang A, Bai Y, Zhang X, Liu C, Wang Q, Li R, Liang K, Brown KG, Cui Z, Han C, Zhang J, Meng F. Comparison of children and adults in deep brain stimulation for Tourette Syndrome: a large-scale multicenter study of 102 cases with long-term follow-up. BMC Med. 2024 May 30;22(1):218. doi: 10.1186/s12916-024-03432-w.

  PMID: 38816877 BACKGROUND

• Schrock LE, Mink JW, Woods DW, Porta M, Servello D, Visser-Vandewalle V, Silburn PA, Foltynie T, Walker HC, Shahed-Jimenez J, Savica R, Klassen BT, Machado AG, Foote KD, Zhang JG, Hu W, Ackermans L, Temel Y, Mari Z, Changizi BK, Lozano A, Auyeung M, Kaido T, Agid Y, Welter ML, Khandhar SM, Mogilner AY, Pourfar MH, Walter BL, Juncos JL, Gross RE, Kuhn J, Leckman JF, Neimat JA, Okun MS; Tourette Syndrome Association International Deep Brain Stimulation (DBS) Database and Registry Study Group. Tourette syndrome deep brain stimulation: a review and updated recommendations. Mov Disord. 2015 Apr;30(4):448-71. doi: 10.1002/mds.26094. Epub 2014 Dec 5.

  PMID: 25476818 BACKGROUND

• Baldermann JC, Schuller T, Huys D, Becker I, Timmermann L, Jessen F, Visser-Vandewalle V, Kuhn J. Deep Brain Stimulation for Tourette-Syndrome: A Systematic Review and Meta-Analysis. Brain Stimul. 2016 Mar-Apr;9(2):296-304. doi: 10.1016/j.brs.2015.11.005. Epub 2015 Dec 29.

  PMID: 26827109 BACKGROUND

• Jafari F, Abbasi P, Rahmati M, Hodhodi T, Kazeminia M. Systematic Review and Meta-Analysis of Tourette Syndrome Prevalence; 1986 to 2022. Pediatr Neurol. 2022 Dec;137:6-16. doi: 10.1016/j.pediatrneurol.2022.08.010. Epub 2022 Sep 5.

  PMID: 36182698 BACKGROUND

• Liu ZS, Cui YH, Sun D, Lu Q, Jiang YW, Jiang L, Wang JQ, Luo R, Fang F, Zhou SZ, Wang Y, Cai FC, Lin Q, Xiong L, Zheng Y, Qin J. Current Status, Diagnosis, and Treatment Recommendation for Tic Disorders in China. Front Psychiatry. 2020 Aug 13;11:774. doi: 10.3389/fpsyt.2020.00774. eCollection 2020.

  PMID: 32903695 BACKGROUND

• Hirschtritt ME, Lee PC, Pauls DL, Dion Y, Grados MA, Illmann C, King RA, Sandor P, McMahon WM, Lyon GJ, Cath DC, Kurlan R, Robertson MM, Osiecki L, Scharf JM, Mathews CA; Tourette Syndrome Association International Consortium for Genetics. Lifetime prevalence, age of risk, and genetic relationships of comorbid psychiatric disorders in Tourette syndrome. JAMA Psychiatry. 2015 Apr;72(4):325-33. doi: 10.1001/jamapsychiatry.2014.2650.

  PMID: 25671412 BACKGROUND

• Johnson KA, Worbe Y, Foote KD, Butson CR, Gunduz A, Okun MS. Tourette syndrome: clinical features, pathophysiology, and treatment. Lancet Neurol. 2023 Feb;22(2):147-158. doi: 10.1016/S1474-4422(22)00303-9. Epub 2022 Oct 28.

  PMID: 36354027 BACKGROUND

MeSH Terms

Conditions

Tourette Syndrome; Tics

Condition Hierarchy (Ancestors)

Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tic Disorders; Movement Disorders; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Neurodevelopmental Disorders; Mental Disorders; Dyskinesias; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Jianguo Zhang, M.D., Ph.D.

  Beijing Tiantan Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Hutao Xie, M.D., Ph.D.

CONTACT

+8618756921517; xieht0123@163.com

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Masking Details: Participants are blinded to the stimulation condition (i.e., whether they receive new target stimulation, CM-DBS, or sham stimulation), and the outcomes assessors are also blinded to the intervention assignments. However, due to the nature of the procedure, care providers and investigators are not masked.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of Department of Functional Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

Model Details: This study employs a randomized crossover design. In the initial phase, each participant is randomly assigned to receive one of three different stimulation interventions - new target stimulation, CM-DBS, and sham stimulation - each for one month in a randomized order. Following this phase, the best target stimulation and short-term efficacy parameters are individually re-optimized for an additional three months to evaluate long-term efficacy. This design allows each participant to serve as their own control, thereby reducing inter-subject variability and improving the precision of treatment comparisons. Outcome measures, including tic severity and standard neuropsychiatric assessments, are administered at baseline, 1 month after each randomized stimulation period during the crossover phase, and 3 months after continuous optimal stimulation.

Study Record Dates

• First Submitted: March 16, 2025
• First Posted: March 21, 2025
• Study Start: October 1, 2024
• Primary Completion: March 1, 2026
• Study Completion: March 1, 2026
• Last Updated: May 22, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)