Tourette Syndrome Deep Brain Stimulation

The Human Thalamocortical Network in Tourette Syndrome

The purpose of this study is to evaluate the effectiveness and safety of deep brain stimulation (DBS) as a possible new treatment for Tourette Syndrome (TS).

This investigation will (1) test the hypothesis that centromedian (CM) continuous brain stimulation will be an effective, safe method for the treatment of tics in medication refractory TS, (2) will define the intra-operative and post-operative physiological changes, and (3) will test the hypothesis that responsive brain stimulation (RBS) will provide an alternative to chronic DBS in TS.

Study Overview

• Status: Active, not recruiting
• Conditions: Tourette Syndrome
• Intervention / Treatment: Device: DBS System; Device: DBS System (RBS Setting)

Detailed Description

Normal clinical care for TS includes cognitive behavior therapy, medication, supportive psychotherapy, and/or a combination of the two. To meet entry criteria for this study, you must have already tried these methods and they did not help your symptoms. DBS is considered experimental for the treatment of TS and would not be done as normal clinical care.

Participation in this study will require extensive pre-surgical screening to determine eligibility for DBS surgery, a DBS surgical procedure, and regular follow-ups. Subjects will be seen monthly post surgery for 6 months. After 6 months, data will be assessed and RBS may be offered as a stimulation setting. If so, the stimulator settings will be changed from chronic to responsive. If not, the subject will continue to receive chronic DBS stimulation. Subsequent visits will be scheduled every 6 months until a total of 24 months of study participation.

At the end of the initial 24-month study period, subjects will have the choice of 1) continuing active stimulation at the current setting, 2) continuing stimulation but searching for a new setting, 3) discontinuing stimulation (turning the device off), 4) having the device removed. If the subject continues to receive active stimulation, they will be followed by the PI and seen at yearly intervals until the DBS system is commercially available, FDA approved for the treatment of TS, or unavailable for patient use.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32607
      • University of Florida

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Must be 21+ years of age
• Diagnosis of Tourette Syndrome (TS) in accordance to the Diagnostic and Statistical Manual of Mental DIsorders (DSM-V) criteria
• Yale Global Tic Severity Scale (YGTSS) must be ≥35/50 for at least 12 months; Motor Tic subscore must be ≥15
• TS must be causing incapacitation with severe distress, self-injurious behavior, and/or quality of life disruption
• TS must be medication refractory. Criteria to determine if medication refractory is the exact criteria stated by Mink et. al TSA DBS Guidelines published in 2006: Subjects must have been treated by a psychiatrist or neurologist experienced in TS with therapeutic doses of either 1-4 mg/day of haloperidol or 2-8 mg/day of pimozide, risperidone (1-3 mg/day), and aripiprazole (2.5-5 mg/day). Must be at minimum a single trial with an alpha-2 adrenergic agonist (0.1-0.3 mg/day)
• Clinically relevant depression must be pharmacologically treated and deemed stable
• Must have been stabilized for 1 month on TS medication without a dose change prior to surgical intervention. If medication trials resulted in discontinuation of TS medications, the subject must be stabilized for 3 months off TS medicines
• Must be willing to keep TS related medications stable and unchanged throughout the trial
• Must have been offered habit reversal therapy/cognitive behavioral intervention therapy (HRT) if subject did not have it prior to enrollment. (Subjects not required to participate in HRT but it will be highly encouraged, and must be completed prior to start of this study's protocol. Those who improve significantly will be excluded from receiving DBS surgery)
• If tic is focal or addressable by botulinum toxin treatment, the study neurologist will offer to administer a trial of botulinum toxin prior to consideration of surgical therapy. (If the subject chooses not to have the treatment, they cannot participate in the study. If the patient responds satisfactorily and their quality of life significantly improves, they will be excluded)

Exclusion Criteria:

• Any previous neurological intervention including DBS or ablative brain lesions, any metal in the head, and any type of implanted stimulator
• Untreated or unstable anxiety, depression, bipolar disorder, or other Axis I psychiatric disorder
• Presence of psychotic features
• Significant psychosocial factors that can cause increased risk
• The presence of only simple motor tics, a movement disorder other than TS, or medication related movement disorders from TS medications
• Severe medical co-morbidity including cardiovascular disorder, lung disorder, kidney disease, chronic neurological disease, hematological disease, or frailty that impacts tolerability of the surgery as judged by the screening physicians
• Abnormal brain magnetic resonance imaging (MRI) scan, including severe atrophy, hydrocephalus, stroke, structural lesions, demyelinating lesions, or infectious lesions that would potentially confound the outcome or safety of the surgery as judged by the study neurosurgeon
• Dementia or cognitive dysfunction that will place the subject at risk for worsening cognition, and/or may impact the ability to cooperate with tasks involved in the study
• Any attempt or intent of suicide in the last 6 months
• Significant substance abuse or dependence within the last 6 months
• Multiple failed medication treatments of inadequate dose or duration
• History of noncompliance with previous medical and psychosocial treatment efforts
• Severe head banging tics
• Women of child-bearing potential who are pregnant or planning pregnancy (urine pregnancy test required)
• Positive urine drug screen for illicit substances (urine drug screen required)
• History of multiple surgical procedures with poor outcomes
• Unexplained gaps in medical history
• Pending lawsuits or other legal action

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Deep Brain Stimulation (DBS); Subjects' DBS surgical intervention requires implantation of a DBS system: two CM thalamic leads (one in each brain hemisphere), two ECOG strip leads (one in each brain hemisphere), and two neurostimulators implanted in the chest. The ECOG strip lead is implanted into the brain to provide an interface through which stimulation can be delivered or activity of the brain can be monitored by the device, or observed by a clinician using a programmer. Neurostimulator and leads system includes a programmer, which includes a wand and telemetry interface, and a patient remote control to check battery status and whether the device is on or off. The programmer is used to set up the device, including setup of stimulation and recording, as well as to retrieve data for subsequent review.

Device: DBS System; The DBS system includes an implantable neurostimulator, CM thalamic leads, and Electrocorticography (ECOG) strips. The DBS system will be set to provide continuous stimulation for the 6 months following surgery. Subjects will be seen monthly for evaluation as a part of normal clinical care for DBS. At 6 months, the investigators will determine whether or not the subject is a candidate for responsive brain stimulation (RBS). Qualifying subjects will have the option to have their settings changed in order to participate in the RBS stimulation intervention. Subjects who do not qualify or do not participate will continue to receive this intervention for the duration of the study. These subjects will been seen every 6 months for evaluation as part of normal clinical care for DBS.; Other Names: Neurostimulator: Medtronic Activa PC+S Device Model 37604; CM thalamic leads: Medtronic Leads Model 3387; ECOG strip leads: The Resume II Medtronic Model 3587A; Device: DBS System (RBS Setting); The DBS system includes an implantable neurostimulator, CM thalamic leads, and Electrocorticography (ECOG) strips. Six months post-surgery, the DBS system will be set to provide responsive stimulation for the duration of the study. Subjects will be seen every 6 months for evaluation as a part of normal clinical care for DBS. Data gathered from the subject during the first 6 months will be used to determine if this intervention is applicable for each individual subject. Subjects who do not qualify will continue to receive the other study intervention.; Other Names: Neurostimulator: Medtronic Activa PC+S Device Model 37604; CM thalamic leads: Medtronic Leads Model 3387; ECOG strip leads: The Resume II Medtronic Model 3587A

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction in total tics on the Yale Global Tic Severity Scale (YGTSS) after 6 months as an effect of centromedian (CM) continuous DBS stimulation	The YGTSS is a 10-item semi-structured clinician-rating instrument that provides an evaluation of the number, frequency, intensity, complexity, and interference of motor and phonic symptoms. The items pertaining to the tic ratings are scored on two subscales: motor tics and phonic tics. Behaviors are rated on a 6-point scale. A higher score indicates a higher severity of symptoms.	Baseline to 6 months post-surgery
Correlation between increase in gamma oscillations and improvement in TS symptomatology	The investigators will collect real time, local field potentials (LFP) that are time synchronized with clinical behavior, from the CM region, pre-motor, and motor cortex in order to study the thalamocortical interactions and determine if there is a correlation between increases in gamma oscillations and improvement in Tourette Syndrome (TS) symptomology.	Date of surgery until 24 months post-surgery
Responsive brain stimulation (RBS) as an effective alternative to continuous DBS stimulation	Scores on the YGTSS during continuous stimulation will be compared to scores on the YGTSS during RBS. The YGTSS is a 10-item semi-structured clinician-rating instrument that provides an evaluation of the number, frequency, intensity, complexity, and interference of motor and phonic symptoms. The items pertaining to the tic ratings are scored on two subscales: motor tics and phonic tics. Behaviors are rated on a 6-point scale. A higher score indicates a higher severity of symptoms.	Baseline until 24 months post-surgery
Reduction in total tics on the YGTSS after 24 months as an effect of centromedian (CM) continuous DBS stimulation	The YGTSS is a 10-item semi-structured clinician-rating instrument that provides an evaluation of the number, frequency, intensity, complexity, and interference of motor and phonic symptoms. The items pertaining to the tic ratings are scored on two subscales: motor tics and phonic tics. Behaviors are rated on a 6-point scale. A higher score indicates a higher severity of symptoms.	Baseline to 24 months post-surgery

Collaborators and Investigators

• Sponsor: University of Florida
• Collaborators: National Institutes of Health (NIH); National Science Foundation; Medtronic
• Investigators: Principal Investigator: Michael Okun, MD, University of Florida

Publications and helpful links

General Publications

• Cagle JN, Okun MS, Cernera S, Eisinger RS, Opri E, Bowers D, Ward H, Foote KD, Gunduz A. Embedded Human Closed-Loop Deep Brain Stimulation for Tourette Syndrome: A Nonrandomized Controlled Trial. JAMA Neurol. 2022 Oct 1;79(10):1064-1068. doi: 10.1001/jamaneurol.2022.2741.

Helpful Links

• UF Center for Movement Disorders & Neurorestoration

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2014
• Primary Completion (Estimated): June 30, 2023
• Study Completion (Estimated): June 30, 2023

Study Registration Dates

• First Submitted: February 3, 2014
• First Submitted That Met QC Criteria: February 4, 2014
• First Posted (Estimated): February 6, 2014

Study Record Updates

• Last Update Posted (Actual): June 15, 2023
• Last Update Submitted That Met QC Criteria: June 13, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: deep brain stimulation; TS; DBS; tourette syndrome; tourette; tourette's
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Disease; Genetic Diseases, Inborn; Basal Ganglia Diseases; Movement Disorders; Neurodegenerative Diseases; Heredodegenerative Disorders, Nervous System; Neurodevelopmental Disorders; Tic Disorders; Syndrome; Tourette Syndrome
• Other Study ID Numbers: IRB201300850 -A-N; KL2TR001429 (U.S. NIH Grant/Contract); 1553482 (Other Grant/Funding Number: NATIONAL SCIENCE FOUNDATION); OCR20343 (Other Identifier: UF OnCore)

Drug and device information, study documents

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