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

NCT07484152 | Not Yet Recruiting Phase 1

• 2 other identifiers: CAAE 63579822.3.0000.00687.406.027
• Study Type: interventional
• Target: 20
• Locations: 0 countries
• Sites: N/A

Brief Summary

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).

Conditions

Essential Tremor (ET)

Keywords

essential tremor

Outcome Measures

Primary Outcomes (1)

• Change in the Fahn-Tolosa-Marín Tremor Rating Scale (FTMTRS) and the Essential Tremor Rating Assessment Scale (TETRAS©).

  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 Outcomes (1)

• Application of the Patient Global Impression of Change (PGIC) and assessment of the number and type of adverse events

  In post-stimulation and 4 weeks post-stimulation at each phase

Study Arms (2)

Active LIFU

EXPERIMENTAL

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

Sham LIFU

SHAM COMPARATOR

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

Interventions

Low-Intensity Focused Ultrasound (LIFU) - NeuroFUS PRO DEVICE

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.

Also known as: LIFU, pulsed low-intensity focused ultrasound transcranial focused ultrasound, tFUS, TUS

Active LIFU

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of essencial Tremor.
• 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

You may not qualify if:

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

Sponsors & Collaborators

• University of Sao Paulo General Hospital: lead

Related Publications (7)

• Vuong MQ, Sreenivasan V, Lee S, Quinn B, Keung MS, Grundy M, Ayala Castaneda J, Baek H, McKeown MJ. Low-intensity transcranial ultrasound effects on the ventral intermediate nucleus and zona incerta in Parkinson's disease tremor. Brain Stimul. 2026 Jan-Feb;19(1):103025. doi: 10.1016/j.brs.2026.103025. Epub 2026 Jan 8.

  PMID: 41519465 BACKGROUND

• Sharabi S, Daniels D, Last D, Guez D, Zivli Z, Castel D, Levy Y, Volovick A, Grinfeld J, Rachmilevich I, Amar T, Mardor Y, Harnof S. Non-thermal focused ultrasound induced reversible reduction of essential tremor in a rat model. Brain Stimul. 2019 Jan-Feb;12(1):1-8. doi: 10.1016/j.brs.2018.08.014. Epub 2018 Aug 27.

  PMID: 30181107 BACKGROUND

• Legon W, Adams S, Bansal P, Patel PD, Hobbs L, Ai L, Mueller JK, Meekins G, Gillick BT. A retrospective qualitative report of symptoms and safety from transcranial focused ultrasound for neuromodulation in humans. Sci Rep. 2020 Mar 27;10(1):5573. doi: 10.1038/s41598-020-62265-8.

  PMID: 32221350 BACKGROUND

• Fomenko A, Neudorfer C, Dallapiazza RF, Kalia SK, Lozano AM. Low-intensity ultrasound neuromodulation: An overview of mechanisms and emerging human applications. Brain Stimul. 2018 Nov-Dec;11(6):1209-1217. doi: 10.1016/j.brs.2018.08.013. Epub 2018 Aug 23.

  PMID: 30166265 BACKGROUND

• Meng Y, Hynynen K, Lipsman N. Applications of focused ultrasound in the brain: from thermoablation to drug delivery. Nat Rev Neurol. 2021 Jan;17(1):7-22. doi: 10.1038/s41582-020-00418-z. Epub 2020 Oct 26.

  PMID: 33106619 BACKGROUND

• Elias WJ, Lipsman N, Ondo WG, Ghanouni P, Kim YG, Lee W, Schwartz M, Hynynen K, Lozano AM, Shah BB, Huss D, Dallapiazza RF, Gwinn R, Witt J, Ro S, Eisenberg HM, Fishman PS, Gandhi D, Halpern CH, Chuang R, Butts Pauly K, Tierney TS, Hayes MT, Cosgrove GR, Yamaguchi T, Abe K, Taira T, Chang JW. A Randomized Trial of Focused Ultrasound Thalamotomy for Essential Tremor. N Engl J Med. 2016 Aug 25;375(8):730-9. doi: 10.1056/NEJMoa1600159.

  PMID: 27557301 BACKGROUND

• Shah C, Jackson GR, Sarwar AI, Mandava P, Jamal F. Treatment Patterns in Essential Tremor: A Retrospective Analysis. Tremor Other Hyperkinet Mov (N Y). 2022 Mar 23;12:10. doi: 10.5334/tohm.682. eCollection 2022.

  PMID: 35415009 BACKGROUND

MeSH Terms

Conditions

Essential Tremor

Condition Hierarchy (Ancestors)

Movement Disorders; Central Nervous System Diseases; Nervous System Diseases

Study Officials

• Rubens Gisbert Cury

  Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - Movement Disorders Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Rubens Gisbert Cury

CONTACT

+55 11 2661-7877; rubens_cury@usp.br

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Masking Details: Participants are blinded to the stimulation condition (active vs. sham). Clinical outcome assessments are performed by a neurologist blinded to the assigned condition. The researcher delivering stimulation is aware of the allocation (single-blind for the operator). Sham condition replicates auditory and tactile sensations of the active condition.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Each participant receives both active LIFU and sham LIFU in a randomized order, separated by an 12-week washout period. The crossover design allows each participant to serve as their own control (20 active vs. 20 sham comparisons).

Study Record Dates

• First Submitted: March 16, 2026
• First Posted: March 19, 2026
• Study Start: March 17, 2026
• Primary Completion (Estimated): May 10, 2028
• Study Completion (Estimated): December 10, 2028
• Last Updated: March 19, 2026

Record last verified: 2026-03