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

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.

Inclusion criteria

• 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

Exclusion criteria

• 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.