Ultrasound Neuromodulation in Essential Tremor (UNMET)

March 4, 2026 updated by: University of California, San Francisco
This study is being done to test whether low-intensity focused ultrasound (LIFU) (low energy sound waves) cause temporary changes in brain activity and behavior when directed at particular parts of the brain. By targeting LIFU to the parts of the brain thought to be responsible for essential tremor (ET), and measuring any associated improvement in tremor, the investigators hope to show that LIFU can be a useful tool for studying the brain circuits responsible for tremor and other brain disorders.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Hypothesis

Precisely targeted low-intensity focused ultrasound (LIFU) modulation of the dentatorubrothalamic tract (DRTT) results in transient improvement of essential tremor (ET). DRTT LIFU neuromodulation produces functional connectivity changes that mirror brain network changes after MR-guided high-intensity focused ultrasound (HIFU) thalamotomy.

Aims

  1. To determine the optimal stimulation parameters for DRTT LIFU neuromodulation: the investigators will record wrist accelerometer signals while systematically varying pulse repetition frequency, duty cycle, and acoustic intensity.
  2. To map network effects of DRTT LIFU neuromodulation: the investigators will record resting state fMRI (rs-fMRI) immediately after DRTT LIFU neuromodulation with the parameters most effective at reducing tremor in each patient.

Design

This is a within-subject repeated-measures interventional study designed to determine the set of LIFU stimulation parameters that are maximally effective at producing a temporary tremor reduction when applied to the DRTT - the white matter circuit in the brain in which abnormal activity causes essential tremor.

The investigators will recruit patients from the established MR-guided high-intensity focused ultrasound (HIFU) ET program at UCSF (which treats 6-9 patients/month). Due to the logistical complexity of performing MRI in patients with MR-conditional pacemakers (need for device and patient monitoring), patients with pacemakers will be excluded from enrollment. Study inclusion criteria will otherwise be similar to those for the HIFU procedure itself, namely medically refractory tremor that is expected to improve with HIFU thalamotomy without contraindications to MRI or inability to stop anticoagulation. As part of their routine pre-procedure evaluation these patients receive a dedicated head CT for calculation of skull density ratio (SDR) and a 3T brain MRI that includes high resolution diffusion imaging for tractography to identify the DRTT, as well as specialized anatomic scans (including proton density (PD) and white matter nulled T1 (wm-null T1) sequences to define adjacent thalamic anatomy.

Study participants will undergo a single LIFU session lasting 3-4 hours, generally in the 1-2 days prior to their HIFU treatment. The investigators will perform LIFU stimulation using a commercially available, portable, neuronavigated focused ultrasound system (NeuroFUS PRO, BrainBox, Cardiff, UK) and will target LIFU stimulation using the same image-guided protocol used for the patient's subsequent HIFU treatment. Wrist-based accelerometers (MP160 + TSD109A; BIOPAC Systems, Inc.) will be used to provide a quantitative behavioral readout of the LIFU effect. The investigators will use power spectrum density analysis of accelerometer signals to quantify the severity of tremor before and after LIFU and HIFU sonications. To evaluate the effect of DRTT LIFU on tremor severity and the contribution of the different acoustic parameters tested, the investigators will perform individual- and group-level statistical analyses on the quantified tremor power in the characteristic ET range of 4-12 Hz. The hair on the participant's head will be shave at the start of the session to facilitate the passage of the ultrasound energy (an existing requirement of the subsequent HIFU treatment).

The transient nature of LIFU tremor reduction (on the order of 10-20 minutes) will facilitate high-throughput parameter screening through repeated sonications within the same session (up to 25, depending on patient response). Stimulation protocols consisting of 5 seconds of active stimulation followed by 10 seconds of no stimulation repeated four times (total 60 s) will be delivered using a range of sample parameters. Stimulation parameters will be shuffled in each session to control for carryover effects at the group level. After each 60-s stimulation, there will be a 3 minute inter-stimulation period, during which tremor severity will be monitored every 60 seconds through quantitative accelerometer recordings. If a change in tremor severity greater than 50% is found in the post-LIFU period compared to the pre-LIFU baseline, the investigators will wait until tremor returns to a level comparable to baseline before proceeding with additional stimulations. The entire LIFU stimulation session will last approximately 100 minutes, sufficient to screen up to 25 stimulation protocols (1 min sonication + 3 min wait per protocol) depending on tremor response.

At the end of the session, the investigators will identify the stimulation parameters that produced the largest tremor suppression compared to the respective pre-LIFU baseline. They will then deliver a sham (off-target or defocused) sonication using these maximally effective parameters to control for nonspecific sensory and auditory effects evoked by the ultrasound stimulation. Following this, the investigators will perform a final active sonication targeting the DRTT with the maximally effective parameters, this final stimulation will be immediately followed by a brief (~20-30 minute) MRI scan to measure the effects of LIFU on brain functional connectivity derived from rs-fMRI.

Patients will then proceed with their scheduled HIFU treatment, which will include similar intra-procedure wrist-base accelerometer measurements to document behavioral effects of HIFU on ET, as well as post treatment MRI to evaluate for post-treatment complications and to measure the effects of HIFU on brain functional connectivity as assessed with rs-fMRI.

Study Type

Interventional

Enrollment (Estimated)

60

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Patients with medically refractory tremor scheduled to undergo MR-guided high-intensity focused ultrasound (HIFU) thalamotomy to treat their tremor at UCSF.

Exclusion Criteria:

  • Due to the logistical complexity of performing MRI in patients with MR-conditional pacemakers (need for device and patient monitoring), patients with pacemakers will be excluded from enrollment. All other patients undergoing HIFU thalamotomy for tremor will be eligible for enrollment.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Single Group Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: To determine the most effective stimulation parameters for DRTT LIFU neuromodulation.
Investigators will record wrist accelerometer signals while participants maintain standardized postures that maximally elicit their tremor before, during, and after delivering LIFU stimulation.
Device: Focused ultrasound neuromodulation
Each ultrasound stimulation protocol will last for 60 seconds, consisting of 4 pulse trains of 5 seconds duration separated by 10 second intervals without stimulation. Across successive stimulation protocols (up to 25/patient) investigators will systematically vary pulse repetition frequency, duty cycle, and acoustic intensity to determine how these parameters contribute to the behavioral effect (transient tremor reduction) in each patient. Parameters will be shuffled to control for group-level carry over effects and will include sham (unfocused or off-target stimulation) conditions to control for non-specific auditory confounds.
Device: Focused Ultrasound Neuromodulation - Sham Control
Each ultrasound stimulation protocol will last for 60 seconds, consisting of 4 pulse trains of 5 seconds duration separated by 10 second intervals without stimulation. Across successive stimulation protocols (up to 25/patient) investigators will systematically vary pulse repetition frequency, duty cycle, and acoustic intensity to determine how these parameters contribute to the behavioral effect (transient tremor reduction). Parameters will be shuffled to control for group-level carry over effects. A defocusing lens will be in place during the session to test the difference between focused and unfoucused ultrasound while controlling for non-specific auditory and somatosensory confounds.
Sham Comparator: Defocusing lens
This arm will be exactly the same as that of the active arm with the exception that a defocusing lens will be fitted to the ultrasound device which will cause the ultrasound energy to be dispersed rather than directed at the target structure.
Device: Focused Ultrasound Neuromodulation - Sham Control
Each ultrasound stimulation protocol will last for 60 seconds, consisting of 4 pulse trains of 5 seconds duration separated by 10 second intervals without stimulation. Across successive stimulation protocols (up to 25/patient) investigators will systematically vary pulse repetition frequency, duty cycle, and acoustic intensity to determine how these parameters contribute to the behavioral effect (transient tremor reduction). Parameters will be shuffled to control for group-level carry over effects. A defocusing lens will be in place during the session to test the difference between focused and unfoucused ultrasound while controlling for non-specific auditory and somatosensory confounds.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Reduction in tremor
Time Frame: For 3 minutes immediately after the application of each sonication protocol
The investigators will screen ultrasound parameters through repeated sonications within the same session (up to 25, depending on patient response) to determine which parameter set is most effective at reducing tremor in each participant as measured by wrist accelerometers (reduction in tremor power from baseline in the characteristic ET range of 4-12 Hz). Stimulation protocols will consist of 5 seconds of active stimulation followed by 10 seconds of no stimulation repeated four times (total 60 s). After each 60-s stimulation, there will be a delay of 3 minutes, during which the investigators will monitor tremor severity every 60 seconds through quantitative accelerometer recordings. If a change in tremor severity greater than 50% is found in the post-LIFU period compared to the pre-LIFU baseline, the investigators will wait until tremor returns to a level comparable to baseline before proceeding with additional stimulations.
For 3 minutes immediately after the application of each sonication protocol

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Increases or decreases in functional connectivity of brain networks
Time Frame: 20-30 minute MRI scan at the end of the 3-4 hour experimental session
The investigators will record resting state fMRI (rs-fMRI) immediately after DRTT LIFU neuromodulation with the parameters most effective at reducing tremor in each patient. The investigators hypothesize that LIFU neuromodulation will result in systematic changes in functional connectivity in motor-related brain networks between pre-LIFU (baseline) imaging and immediate post-LIFU imaging. These changes will additionally be compared to those observed between baseline imaging and post-HIFU imaging.
20-30 minute MRI scan at the end of the 3-4 hour experimental session

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of California, San Francisco

Collaborators

Focused Ultrasound Foundation

Investigators

  • Principal Investigator: Leo Sugrue, MD, PhD, University of California, San Francisco

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 1, 2024

Primary Completion (Estimated)

March 1, 2027

Study Completion (Estimated)

March 1, 2027

Study Registration Dates

First Submitted

September 20, 2024

First Submitted That Met QC Criteria

September 20, 2024

First Posted (Actual)

September 24, 2024

Study Record Updates

Last Update Posted (Actual)

March 6, 2026

Last Update Submitted That Met QC Criteria

March 4, 2026

Last Verified

March 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • P0573974

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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