Motor and Non-Motor Effects of Low-Intensity Focused Ultrasound (LIFU) as a Neuromodulation Tool in Essential Tremor (LIFU-ET)

March 16, 2026 updated by: University of Sao Paulo General Hospital

Motor and Non-Motor Effects of Low-Intensity Focused Ultrasound (LIFU) as a Neuromodulation Tool in Movement Disorders: A Randomized, Double-Blind, Sham-Controlled, Crossover Clinical Trial in Essential Tremor

This study investigates the motor and non-motor effects of Low-Intensity Focused Ultrasound (LIFU) as a non-invasive neuromodulation technique in patients with essential tremor (ET) and refractory tremor. LIFU is a non-thermal, non-ablative form of transcranial focused ultrasound that modulates neural activity through mechanical mechanisms, including direct effects on neuronal membranes, alterations in membrane excitability, and modulation of synaptic transmission. Unlike high-intensity focused ultrasound (HIFU), which produces tissue ablation, LIFU induces reversible effects with a favorable safety profile, making it a promising candidate for non-invasive neuromodulation in movement disorders.

In this randomized, double-blind, sham-controlled, crossover trial, 20 patients with ET and refractory tremor will receive active LIFU targeting the ventral intermediate nucleus (VIM) of the thalamus and sham stimulation in separate sessions, separated by a washout period of at least 12 weeks. Clinical assessments using standardized and validated neurological scales will be performed before and after each session to evaluate changes in motor symptoms, tremor severity, quality of life, and non-motor features.

The primary outcome is the change in the Fahn-Tolosa-Marín Tremor Rating Scale (FTMTRS) and the Essential Tremor Rating Assessment Scale (TETRAS©). Secondary outcomes include the Patient Global Impression of Change (PGIC) and monitoring of adverse events.

This study is being conducted at the Movement Disorders Center of Hospital das Clínicas, University of São Paulo (HC-FMUSP), São Paulo, Brazil, and has been approved by the institutional ethics committee (CAPPesq; approval number 7.406.027).

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

Background: The most common cause of tremor is essential tremor (ET), a disorder characterized by action tremor that predominantly affects the upper limbs. It has a prevalence of approximately 1-2% in the general population, with increasing frequency with age. Pharmacological therapy is the mainstay of treatment, with propranolol and primidone considered first-line medications. Other drugs that may be used include topiramate, gabapentin, and alprazolam. Approximately 50% of patients do not achieve adequate symptom control with medications, either due to tremor severity or intolerance to adverse drug effects. Some refractory cases may benefit from bilateral deep brain stimulation (DBS) of the thalamus or unilateral thalamotomy, which can also be performed using magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU). Although effective, these approaches are invasive or ablative, which may limit their applicability. Low-Intensity Focused Ultrasound (LIFU) offers a non-invasive, non-ablative alternative capable of modulating deep brain circuits transcranially with millimeter precision without causing permanent tissue damage. The ventral intermediate nucleus (VIM) of the thalamus is a well-established target for tremor reduction and has been validated in both DBS and HIFU thalamotomy studies. Study Design: Prospective, randomized, double-blind, sham-controlled, crossover clinical trial. Participants: Twenty adult patients with refractory essential tremor and clinically relevant tremor despite optimized pharmacological treatment will be included. Intervention: Each participant undergoes two study sessions (active LIFU and sham LIFU), assigned in random order and separated by a washout period of at least 12 weeks. The sequence is determined using computer-generated randomization (Randomizer.com) and is blinded to both participants and clinical assessors. LIFU Procedure: Stimulation is delivered using the NeuroFUS PRO device (Brainbox Ltd., Cardiff, UK), consisting of a 64 mm single-element focused ultrasound transducer coupled to the scalp using degassed aqueous ultrasound gel (Aquaflex, Parker Laboratories, USA). Targeting is performed using the Brainsight neuronavigation system (Rogue Research Inc., Montreal, Canada) based on each participant's individual MRI. The acoustic target is the ventral intermediate nucleus (VIM) of the thalamus, contralateral to the most affected side. Patient-specific acoustic simulations are performed prior to the procedure using MATLAB R2022a and the BRIC TUS Simulation Tools, incorporating individual MRI and CT data to model skull acoustic properties and adjust focal depth and trajectory. Stimulation Parameters: Transducer frequency: 500 kHz; pulse width: 5 ms; pulse repetition frequency (PRF): 10 Hz; duty cycle: 5%; maximum spatial-peak pulse-average intensity (ISPPA): 30 W/cm². The protocol consists of two applications of 10 minutes each, separated by a 20-minute interval. Each application includes 10 cycles of 30 seconds ON and 30 seconds OFF. Sham Condition: In the sham condition, the transducer is positioned identically to the active condition. The ultrasound generator is activated but delivers no acoustic energy to the brain. Auditory and physical sensations associated with the procedure are replicated to maintain participant blinding. Clinical Assessment: Validated neurological scales are administered immediately before and immediately after each stimulation session by a blinded evaluator following standardized assessment protocols. The scales include the Fahn-Tolosa-Marín Tremor Rating Scale (FTMTRS), the Essential Tremor Rating Assessment Scale (TETRAS©), and the Patient Global Impression of Change (PGIC). Adverse events are also monitored after each session. A follow-up clinical reassessment is performed one month after each intervention.

Study Type

Interventional

Enrollment (Estimated)

20

Phase

  • Phase 2
  • Phase 1

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

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:

  1. Diagnosis of essencial Tremor.
  2. Presence of clinically relevant tremor despite optimized pharmacological treatment.3. Age 18-80 years.4. Ability and willingness to provide written informed consent.5. Availability to attend all scheduled study visits at HC-FMUSP.6. Availability of a brain MRI suitable for neuronavigation planning

Exclusion Criteria:

- 1. Dementia syndrome or severe cognitive impairment precluding informed consent or reliable clinical assessment.

2. Uncontrolled psychiatric disorders.3. Alcohol or illicit substance dependence.4. Use of stimulants or medications that lower seizure threshold.5. History of epileptic seizures within the last 6 months.6. Hospitalization or surgery within the last 6 months.7. Presence of implanted metallic or electronic devices in the cranium or spine that are contraindicated for focused ultrasound procedures (e.g., deep brain stimulator, cochlear implant, cardiac pacemaker, metal plates or wires).8. History of brain surgery or traumatic brain injury.9. Skull defects, craniotomy, or significant calvarial irregularities that preclude safe ultrasound delivery.10. Pregnancy or breastfeeding.11. Social impossibility of follow-up attendance.

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: Crossover Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Active LIFU
Participants receive transcranial Low-Intensity Focused Ultrasound (LIFU) targeting the ventral intermediate nucleus (VIM) of the thalamus, contralateral to the most affected side, delivered via the NeuroFUS PRO device (Brainbox Ltd., UK) with the following parameters: 500 kHz frequency, 5 ms pulse width, 10 Hz PRF, 5% duty cycle, ISPPA 30 W/cm². Each session consists of two 10-minute sonication blocks separated by a 20-minute interval, guided by individual MRI-based neuronavigation (Brainsight, Rogue Research).
Device: Low-Intensity Focused Ultrasound (LIFU) - NeuroFUS PRO
Non-invasive transcranial neuromodulation using a focused ultrasound transducer (NeuroFUS PRO, Brainbox Ltd., UK) operating at 500 kHz. Pulsed ultrasound is delivered in two 10-minute applications separated by a 20-minute interval, targeting the VIM of the thalamus under MRI-based neuronavigation. Parameters: 5 ms pulse width, 10 Hz PRF, 5% duty cycle, ISPPA 30 W/cm².
Other Names:
  • TUS
  • LIFU
  • tFUS
  • pulsed low-intensity focused ultrasound transcranial focused ultrasound
Device: Low-Intensity Focused Ultrasound (LIFU) - NeuroFUS PRO
Non-invasive transcranial neuromodulation using a focused ultrasound transducer (NeuroFUS PRO, Brainbox Ltd., UK) operating at 500 kHz. Pulsed ultrasound is delivered in two 10-minute applications separated by a 20-minute interval, targeting the VIM of the thalamus under MRI-based neuronavigation. Parameters: 5 ms pulse width, 10 Hz PRF, 5% duty cycle, ISPPA 30 W/cm²
Other Names:
  • TUS
  • LIFU
  • transcranial focused ultrasound
  • tFUS
  • LIFUP
  • pulsed low-intensity focused ultrasound
Sham Comparator: Sham LIFU
Participants undergo an identical procedure including transducer positioning, neuronavigation guidance, and full session duration, but no ultrasound energy is delivered to the brain. The sham condition replicates the auditory and tactile sensations of the active condition to maintain participant blinding.
Device: Low-Intensity Focused Ultrasound (LIFU) - NeuroFUS PRO
Non-invasive transcranial neuromodulation using a focused ultrasound transducer (NeuroFUS PRO, Brainbox Ltd., UK) operating at 500 kHz. Pulsed ultrasound is delivered in two 10-minute applications separated by a 20-minute interval, targeting the VIM of the thalamus under MRI-based neuronavigation. Parameters: 5 ms pulse width, 10 Hz PRF, 5% duty cycle, ISPPA 30 W/cm².
Other Names:
  • TUS
  • LIFU
  • tFUS
  • pulsed low-intensity focused ultrasound transcranial focused ultrasound
Device: Low-Intensity Focused Ultrasound (LIFU) - NeuroFUS PRO
Non-invasive transcranial neuromodulation using a focused ultrasound transducer (NeuroFUS PRO, Brainbox Ltd., UK) operating at 500 kHz. Pulsed ultrasound is delivered in two 10-minute applications separated by a 20-minute interval, targeting the VIM of the thalamus under MRI-based neuronavigation. Parameters: 5 ms pulse width, 10 Hz PRF, 5% duty cycle, ISPPA 30 W/cm²
Other Names:
  • TUS
  • LIFU
  • transcranial focused ultrasound
  • tFUS
  • LIFUP
  • pulsed low-intensity focused ultrasound

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in the Fahn-Tolosa-Marín Tremor Rating Scale (FTMTRS) and the Essential Tremor Rating Assessment Scale (TETRAS©).
Time Frame: Baseline (immediately pre-stimulation) and immediately after the LIFU/sham session, at Week 0 (Phase 1) and Week 12 (Phase 2); and at 4 weeks post-stimulation (Week 4 and Week 16)

Fahn-Tolosa-Marín (FTM) Tremor Rating Scale Total Score is a validated scale assessing tremor severity, including tremor amplitude, functional disability, and impact on activities of daily living across multiple body regions. The total score ranges from 0 to 144, with higher scores indicating greater tremor severity.

Essential Tremor Rating Assessment Scale (TETRAS) Total Score is a validated scale designed specifically for Essential Tremor, assessing tremor severity and functional disability. Higher scores indicate greater tremor severity. The total score ranges from 0 to 112, with with higher scores indicating greater tremor severity.
Baseline (immediately pre-stimulation) and immediately after the LIFU/sham session, at Week 0 (Phase 1) and Week 12 (Phase 2); and at 4 weeks post-stimulation (Week 4 and Week 16)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Application of the Patient Global Impression of Change (PGIC) and assessment of the number and type of adverse events
Time Frame: In post-stimulation and 4 weeks post-stimulation at each phase
Application of the Patient Global Impression of Change to assess the participant's overall perception of improvement or worsening of tremor symptoms following the intervention and assessment of the number and type of adverse events occurring during the study period to evaluate the safety of the intervention.
In post-stimulation and 4 weeks post-stimulation at each phase

Collaborators and Investigators

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

Sponsor

University of Sao Paulo General Hospital

Investigators

  • Principal Investigator: Rubens Gisbert Cury, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - Movement Disorders Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

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 (Estimated)

March 17, 2026

Primary Completion (Estimated)

May 10, 2028

Study Completion (Estimated)

December 10, 2028

Study Registration Dates

First Submitted

March 16, 2026

First Submitted That Met QC Criteria

March 16, 2026

First Posted (Actual)

March 19, 2026

Study Record Updates

Last Update Posted (Actual)

March 19, 2026

Last Update Submitted That Met QC Criteria

March 16, 2026

Last Verified

March 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CAAE 63579822.3.0000.0068
  • 7.406.027 (Other Identifier: CAPPesq)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

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.

Clinical Trials on Essential Tremor (ET)

Clinical Trials on Low-Intensity Focused Ultrasound (LIFU) - NeuroFUS PRO

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Armenia

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe