Multitarget Stereotactic Electrophysiological Recording and Stimulation for Tourette Syndrome

Official title

MultitArget STereotactic Electrophysiological Recording and Stimulation for Tourette Syndrome

Overview

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. Stimulation at the new target, 2. Stimulation at the CM, 3. Sham stimulation (does not actually stimulate). Finally, DBS will be continued at the optimal target for an additional three months to confirm its therapeutic impact. By analyzing the brain activity and comparing these conditions, the study will clarify the neural mechanisms underlying TS and learn which target works best to lower tics and improve overall quality of life for TS patients.

Interventions

• Device New Target DBS
  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.
• Device CM-DBS
  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.
• Device Sham Stimulation
  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.

Primary outcome measures

• Change in Yale Global Tic Severity Scale (YGTSS) Score [Time frame: administered at baseline, 1 month after each randomized stimulation period during the crossover phase, and 3 months after continuous optimal stimulation]

Secondary outcome measures (12)

• Change in Modified Rush Video Rating Scale (MRVRS) [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: administered at baseline, 1 month after each randomized stimulation period during the crossover phase, and 3 months after continuous optimal stimulation]
• Change in Hamilton Depression Scale (HAMD) score [Time frame: administered at baseline, 1 month after each randomized stimulation period during the crossover phase, and 3 months after continuous optimal stimulation]
• Change in Young Mania Rating Scale (YMRS) score [Time frame: administered at baseline, 1 month after each randomized stimulation period during the crossover phase, and 3 months after continuous optimal stimulation]
• Change in Columbia Suicide Severity Rating Scale (C-SSRS) [Time frame: administered at baseline, 1 month after each randomized stimulation period during the crossover phase, and 3 months after continuous optimal stimulation]
• Change in Mini-Mental State Examination (MMSE) score [Time frame: administered at baseline, 1 month after each randomized stimulation period during the crossover phase, and 3 months after continuous optimal stimulation]
• Change in Montreal Cognitive Assessment Beijing Version (MoCA) score [Time frame: administered at baseline, 1 month after each randomized stimulation period during the crossover phase, and 3 months after continuous optimal stimulation]
• change in Gilles de la Tourette Syndrome Quality of Life Scale (GTS-QOL) score [Time frame: administered at baseline, 1 month after each randomized stimulation period during the crossover phase, and 3 months after continuous optimal stimulation]
• Incidence of Treatment-Related Adverse Events [Time frame: administered at baseline, 1 month after each randomized stimulation period during the crossover phase, and 3 months after continuous optimal stimulation]

Eligibility criteria

Inclusion criteria

• 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.

Exclusion criteria

• 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).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Crossover

Masking

Double blind

Primary purpose

Treatment

Study locations

China · 1 center

• Beijing Tiantan Hospital, Capital Medical University — Beijing

Publications

• 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, M PMID 29340590
• 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
• 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
• 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
• 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
• 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
• 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
• 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

Identifiers

NCT: NCT06889480 · HX-B-2024057

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗