Transcranial Temporal Interference Stimulation (tTIS) To Modulate Essential Tremor (TremorTIS)

Transcranial Temporal Interference Stimulation (tTIS) To Modulate Essential Tremor: A Single-Center, Proof-of-Concept Study (TremorTIS (Pilot))

The goal of this proof-of-concept study is to examine the effects of a relatively new, non-invasive electrical current-based technique, transcranial temporal interference stimulation (tTIS), in patients with Essential Tremor (ET). TTIS is delivered via a Digitimer Ltd. stimulator, the "DS5 Isolated Bipolar Constant Current Stimulator." The method enables targeting deep cerebral structures to selectively modulate neurons. The structure of interest in the present study is the ventralis intermedius (VIM) of the thalamus, which plays a key role in tremor generation in people with essential tremor. Therefore, techniques targeting the VIM nucleus can potentially improve the tremor and the quality of life in the long term, as is the case with MRI-guided high-intensity focused ultrasound (MRgHIFU). Despite its efficiency, MRgHIFU can lead to side effects that could benefit from improved predictive modeling. In our proof-of-concept study, the investigators aim to examine whether tTIS of the VIM nucleus can alter tremor characteristics and, therefore, mimic the effects of MRgHIFU. This work would pave the way for future clinical trials to design prediction tools for MRgHIFU if the investigators can demonstrate the positive impact of tTIS.

Study Overview

• Status: Not yet recruiting
• Conditions: Essential Tremor
• Intervention / Treatment: Device: Transcranial temporal interference stimulation; Other: Tremor monitoring through Inertial Measurement Units (IMUs)

Detailed Description

Essential tremor (ET) represents one of the most common movement disorders worldwide, with an estimated prevalence of 1 % across all ages, increasing with age. Despite being considered a benign disease, it can nevertheless lead to significant functional impairment. Several drugs, such as beta-blockers, can be used to alleviate the tremor, but they may not be enough to improve the quality of life, and they can cause significant side effects.

The etiology and pathophysiology of ET are not yet fully understood. One pathophysiological hypothesis for ET is a deficiency in cerebellar GABAergic transmission, leading to abnormal oscillatory activity that interferes with motor function. This abnormal oscillatory activity converges on the thalamus, specifically in the ventralis intermedius (VIM) nucleus. Various surgical or disruptive medical techniques can target this nucleus in case of a drug-resistant tremor or drug intolerance.

One such technique is MRI-guided, high-intensity focused ultrasound thalamotomy (MRgHIFU), which results in a long-lasting, significant reduction of tremor in most cases. Despite the MRgHIFU's millimetric precision, the VIM is not directly visible on peri-operative MRI scans. MRgHIFU thalamotomy can also lead to side effects, such as modifications of sensations (paresthesia), speech difficulties (dysarthria), imbalance (ataxia), or even motor deficits (hemiparesis). Therefore, more accurate tools are needed to predict the effects of MRgHIFU.

One promising technique that could help clinicians predict the effects of MRgHIFU is transcranial temporal interference stimulation. This non-invasive neuromodulation technique uses two pairs of scalp electrodes, which deliver two slightly different high-frequency currents (e.g., f1 = 2.00 kHz; f2 = 2.01 kHz). Frequencies in the kHz range are too high to induce an effect on neurons and nerves. Still, due to their difference Δf = f2-f1, they both interfere in the depth of the brain to create a so-called amplitude-modulated envelope with a beat frequency falling in the physiological range (e.g., Δf = 10 Hz). This allows neuromodulation of deep structures-the VIM in this study-and avoids stimulation of the cortical structures at the same time. The investigators will use the Digitimer Ltd. "DS5 Isolated Bipolar Constant Current Stimulator" to deliver tTIS.

The goal of the proposed proof-of-concept study is to examine the effects of tTIS on tremor modulation in essential tremor patients who are candidates for MRgHIFU thermoablation of the VIM, and to compare the impact of tTIS with the "true" effect of tremor reduction after MRgHIFU. The primary outcome will be the change in tremor amplitude (in mm), as measured by Inertial Measurement Units (IMUs) comprising an accelerometer, a gyroscope, and a magnetometer. The secondary outcomes will be other quantitative tremor parameters, such as the frequency, angular and linear acceleration, and power, as well as safety outcomes.

• Study Type: Interventional
• Enrollment (Estimated): 6
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Christian Lüscher, Full Professor; Phone Number: +41 22 379 54 44; Email: christian.luscher@unige.ch
• Study Contact Backup: Name: Vanessa Fleury, Privat Docent; Phone Number: +41 22 372 83 37; Email: vanessa.fleurynissen@hug.ch

Study Locations

• Switzerland
  • Geneva, Switzerland, 1205
    • University of Geneva (UNIGE)
    • Contact: Christian Lüscher, Full Professor; Phone Number: +41 22 379 54 44; Email: christian.luscher@unige.ch
    • Contact: Vanessa Fleury, Privat Docent; Phone Number: +41 22 372 83 37; Email: vanessa.fleurynissen@hug.ch
    • Principal Investigator: Vanessa Fleury, Privat Docent
    • Sub-Investigator: Shahan Momjian, Associate Professor
    • Sub-Investigator: Alma Lingenberg, Medical Doctor

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria (for both arms):

• Informed Consent signed by the subject;
• Age ≥ 18 years;
• Diagnosis of Essential Tremor (ET) based on the proposed criteria by the Movement Disorders Society;
• Candidate for MRgHIFU thalamotomy

Exclusion Criteria (for both arms):

• Unable to provide informed consent;
• Severe sensory or cognitive impairment or musculoskeletal dysfunction that prohibits understanding instructions or performing the experimental tasks.

Only for patients undergoing the tTIS protocol (experimental arm):

• Severe neuropsychiatric (e.g., major depression, severe dementia, psychosis) or unstable systemic diseases (e.g., severe progressive and unstable cancer, life-threatening infectious disease);
• Inability to follow or non-compliance with the procedures of the study;

• Contraindications for non-invasive brain stimulation:

  • Electronic or ferromagnetic medical implants or devices
  • History of seizures

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental arm: tTIS stimulation protocol; In this arm, patients with essential tremor who are candidates for MRgHIFU will undergo the tTIS stimulation protocol before MRgHIFU. The tremor changes will be monitored using Inertial Measurement Units (IMUs) during the tTIS, as well as after tTIS and MRgHIFU.	Device: Transcranial temporal interference stimulation; We will deliver transcranial temporal interference stimulation (tTIS) via the DS5 stimulator (Digitimer Ltd.) in patients with essential tremor who are candidates for MRgHIFU to examine its ability to modulate the tremor amplitude.; Other: Tremor monitoring through Inertial Measurement Units (IMUs); Essential tremor patients candidates for MRgFUS, whether undergoing the tTIS protocol (experimental arm) or acting as controls (control arm), will undergo a tremor quantification through Inertial Measurement Units (IMUs) before, during, and after the stimulation (for the experimental arm), as well as before and after MRgHIFU (both arms).
Other: Control arm: Tremor Monitoring; In this arm, essential tremor patients who are candidates for MRgHIFU will undergo only tremor monitoring using Inertial Measurement Units (IMUs) before and after MRgHIFU.	Other: Tremor monitoring through Inertial Measurement Units (IMUs); Essential tremor patients candidates for MRgFUS, whether undergoing the tTIS protocol (experimental arm) or acting as controls (control arm), will undergo a tremor quantification through Inertial Measurement Units (IMUs) before, during, and after the stimulation (for the experimental arm), as well as before and after MRgHIFU (both arms).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tremor amplitude	Tremor amplitude, measured in mm in the 3 axes, using an Inertial Measurement Unit (IMU) secured on the dorsum of both hands of the essential tremor patient.	From enrollment to day 1 (D1) after MRgHIFU

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tremor peak frequency	Peak (dominant) frequency of the tremor in Hz	From enrollment to day 1 (D1) post-MRgHIFU
Frequency Width Half Maximum (FWHM)	Frequency Width Half Maximum (FWHM) in Hz, i.e., the frequency bandwidth where the power spectrum's value is at least half of its maximum value	From enrollment to day 1 (D1) post-MRgHIFU
Tremor Stability Index (TSI)	Tremor Stability Index (TSI), i.e., the interquartile range of the change in frequency (Δf), indicating the cycle-to-cycle variations of tremor	From enrollment to day 1 (D1) post-MRgHIFU
Power of the tremor	Power band spectrum, measured in dB, derived from the three-dimensional data of the IMU	From enrollment to day 1 (D1) post-MRgHIFU
Half-Width Power (HWP)	Half-Width Power (HWP), .i.e., the power referring to the frequency bandwidth where the power spectrum remains at least half of its maximum, calculated as the area under the spectral curve between two vertical straight lines intersecting the rising and falling edge of the peak at half of the peak power (full-width half maximum), in the main frequency band of interest	From enrollment to day 1 (D1) post-MRgHIFU
Linear acceleration of tremor	Linear acceleration in 3 dimensions (measured in m/s^2 through the accelerometer component of the IMU)	From enrollment to day 1 (D1) post-MRgHIFU
Angular velocity of tremor	Angular velocity in 3 axes, measured in degrees per second (°/s), through the gyroscope component	From enrollment to day 1 (D1) post-MRgHIFU
Incidence of Device-Emergent (Serious) Adverse Events [Safety]	Only for the experimental arm (tTIS protocol): safety will be assessed through the number of (severe) adverse events (SAEs/AEs) possibly, probably, or definitely related to the study device.	From enrollment to day 1 (D1) post-stimulation

Collaborators and Investigators

• Sponsor: University Hospital, Geneva
• Collaborators: Wyss Center for Bio and Neuroengineering; University of Geneva, Switzerland
• Investigators: Principal Investigator: Christian Lüscher, Full Professor, Department of Basic Neuroscience, University of Geneva

Study record dates

Study Major Dates

• Study Start (Estimated): May 26, 2026
• Primary Completion (Estimated): April 30, 2027
• Study Completion (Estimated): May 1, 2027

Study Registration Dates

• First Submitted: December 17, 2025
• First Submitted That Met QC Criteria: April 8, 2026
• First Posted (Actual): April 15, 2026

Study Record Updates

• Last Update Posted (Actual): May 1, 2026
• Last Update Submitted That Met QC Criteria: April 27, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Neuromodulation; Essential Tremor; Transcranial temporal interference stimulation; Nucleus ventralis intermedius
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Essential Tremor
• Other Study ID Numbers: BASEC 2025-D0091

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

De-identified individual participant data, including demographic data, clinical characteristics, and quantitative tremor assessment data, will be shared.

Data will be available upon reasonable request to the corresponding author after publication of the primary results, in accordance with ethical approval and applicable data protection regulations.

• IPD Sharing Time Frame: After publication of the primary results, upon reasonable request.

Drug and device information, study documents

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