Transcranial Ultrasound Stimulation for Tourette Syndrome

This is a phase 1 clinical trial investigating the use of low-energy Transcranial Ultrasound Stimulation (TUS) to treat Tourette Syndrome (TS).

Objectives and Background. TS is a neurodevelopmental condition marked by motor and vocal tics that often resist standard pharmacological or behavioral treatments. Current neuromodulation options like Deep Brain Stimulation (DBS) are invasive, while non-invasive methods like TMS lack the precision to reach deep brain structures.

The study aims to:

1. Evaluate tolerability: Assess TUS safety in older adolescents and adults with TS.
2. Test efficacy: Compare TUS at the intralaminar thalamic nuclei (CM/Pf/Voi) and the supplementary motor area (SMA) against a sham treatment to see if it reduces tic frequency and severity.
3. Optimize protocols: Determine if dual-target or multiple-session stimulation is more effective than single-target or single-session protocols.

TUS uses low energy, pulsed, focused ultrasound to induce transient neuromodulatory responses lasting up to 60 minutes. TUS can precisely target deep structures like the thalamus.

Study Methods

• Design: A phase 1, double-blind, crossover trial.

• Participants: 20 individuals (ages 16+) with a diagnosis of TS and significant tic severity (YGTSS score > 22 or sub-score > 15).

• Procedure: Participants receive four different modalities over four separate weeks, with 7-day washouts:

• TUS of the CM/Pf/Voi only.

• TUS of the SMA only.

• Combined TUS of both targets.

• Sham TUS.

• Evaluation: The primary endpoint is the percent change on the Rush Video-Based Tic Rating Scale (RVBTRS). Secondary measures include the Yale Global Tic Severity Scale (YGTSS) and the Premonitory Urges for Tics Scale (PUTS).

Because TUS requires extreme precision to hit deep brain targets, every participant undergoes a comprehensive imaging protocol using a 3T GE UHP scanner.

• Mapping the Targets: We use Diffusion Tensor Imaging (DTI) and Tractography to locate the specific "wiring" of the individual's brain. This allows to find:

• The CM/Pf/Voi (Centromedian-parafascicular complex) in the thalamus.

• The SMA (Supplementary Motor Area) in the cortex.

• Precision Imaging: High-resolution 1 mm-isotropic T1-weighted, T2-weighted, and Zero Echo Time (ZTE) images are used. ZTE is particularly important as it helps the BabelBrain software account for the thickness and density of the skull, which can deflect ultrasound waves.

• Real-Time Tracking: During the actual stimulation, the team uses a Brainsight neuro-navigation system. This acts like a GPS, using the patient's MRI "map" to ensure the ultrasound transducer is perfectly aligned with the target.

Innovation This is the first human study to apply TUS to TS patients. By targeting both deep and cortical regions independently or simultaneously, the researchers aim to modulate the "network-level" connectivity implicated in tic generation.

Technical Ultrasound Parameters The study uses a custom 128-element phased-array transducer (Sonic Concepts H317) to deliver TUS.

• Core Settings:

• Frequency: 250 kHz.

• Intensity: spatial-peak pulse-average intensity (ISPPA) of 10 W/cm2

• Targeting & Safety:

• BabelBrain Software: Calculates real-time acoustic simulations to correct for bone aberrations and ensure the Mechanical Index (MI) stays below 1.9 and thermal rise remains under 2°C.

• Electronic Steering: Allows the focal spot to be moved without physically repositioning the device, enabling coverage of large areas like the SMA or deep structures like the CM/Pf/Voi complex.

• Biological Protocols:

• Inhibitory: pulse repetition frequency (PRF), 10% duty cycle, lasting 120 seconds.

• Excitatory: "theta burst" PRF, 10% duty cycle, lasting 80 seconds. Clinical Assessment Criteria

The trial employs three main scales to capture both objective tic data and subjective patient experiences:

1. Rush Video-Based Tic Rating Scale (RVBTRS):

• The Primary Measure: This is the only validated tool that provides an objective assessment by analyzing 10-minute video recordings.
• Method: Two blinded evaluators count tics and rate their severity across two views: a close-up (head/shoulders) and a full-body frontal view.
• Focus: It specifically measures the patient's ability to actively inhibit tics during the recording.

2. Yale Global Tic Severity Scale (YGTSS):

• The Gold Standard: A clinician-rated interview that assesses symptoms over the prior 7-10 days.
• Scoring: It rates motor and phonic tics separately on five dimensions: number, frequency, intensity, complexity, and interference.
• Baseline Requirement: To participate in the trial, patients must have a total tic severity score of at least 22 (or a sub-score of 15).

3. Premonitory Urges for Tics Scale (PUTS):

• Self-Report: A 9-item questionnaire where patients rate the intensity of pre-tic sensations (like pressure, itchiness, or tension) on a scale of 1 to 4.
• Interpretation: Scores range from 9 to 36; higher scores reflect more distressing urges.