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

Официальное название

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

Обзор

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).

Подробное описание

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.

Вмешательства

• Устройство 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.
• Устройство 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

Первичные конечные точки

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

Вторичные конечные точки (1)

• Application of the Patient Global Impression of Change (PGIC) and assessment of the number and type of adverse events [Срок оценки: In post-stimulation and 4 weeks post-stimulation at each phase]

Критерии участия

Критерии включения

• 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

Критерии исключения

\- 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Перекрёстный дизайн

Маскирование

Двойное слепое

Основная цель

Лечение

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Публикации

• 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
• 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
• 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
• 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
• 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
• 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 PMID 27557301
• 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

Идентификаторы

NCT: NCT07484152 · CAAE 63579822.3.0000.0068 · 7.406.027

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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