Closed-loop TMS for Tremor

Plain-language summary

This study investigates the potential of phase-locked transcranial magnetic stimulation (TMS) as a non-invasive intervention for tremor in patients with Essential Tremor (ET) and Parkinson's Disease (PD). Tremor is a prevalent symptom that significantly impacts physical function and social participation. ET affects approximately 1% of the global population and worsens with age, while PD tremor is often less responsive to conventional dopaminergic therapy. Current treatments, including oral medications (propranolol, primidone), anticholinergics, and deep brain stimulation (DBS), are either limited by efficacy, side effects, or invasiveness. These challenges highlight the need for alternative, less invasive therapeutic options. The rationale for the study is based on the principle of phase-dependent neural modulation. Just as a swing's amplitude can be increased or decreased depending on when it is pushed, neural oscillations underlying tremor can theoretically be suppressed by precisely timed stimulation. Previous studies have shown that TMS over the motor cortex at tremor frequency (\~5 Hz) produces modest improvements in PD rest tremor. This study aims to enhance these effects by targeting amplitude-suppressing phases in the tremor cycle, potentially leading to greater and cumulative tremor reduction. The study has two components: Study 1 (Primary Objective): Determine whether phase-locked TMS can acutely reduce tremor. Participants (20 ET, 20 PD) will undergo two visits where tremor is recorded via inertial measurement units (IMUs) and surface EMG. TMS will be delivered over the motor cortex at or below active motor threshold, synchronized to the participant's tremor phase. The primary outcome is the change in tremor power during stimulation compared to no stimulation, measured objectively via IMU signals. Study 2 (Secondary Objective): Examine whether stimulation at the maximal tremor-suppressing phase, identified in Study 1, produces a larger reduction in tremor amplitude than stimulation at the minimal suppressing phase or sham stimulation. This will involve three additional sessions per participant, randomized for order, with outcomes assessed via IMU tremor power and participant-reported measures including the Quality of Life in Essential Tremor Questionnaire (QUEST), TETRAS, and Unified Parkinson's Disease Rating Scale (UPDRS). Study Design and Procedures: The design is a within-subject crossover. Participants may withhold tremor medications during visits to reduce confounding effects. EMG electrodes and IMU sensors will record tremor, while a figure-of-eight TMS coil will deliver phase-locked pulses. Phase-specific stimulation trains are applied for 3 seconds at intervals, with randomized order across multiple blocks. Study sessions last under two hours, including setup and post-stimulation recordings. Participants are recruited via self-referral or through DeNDRoN, screened for eligibility, and provide informed consent. Inclusion criteria require symptomatic ET or PD tremor, age ≥18, and ability to consent. Exclusion criteria include epilepsy, psychiatric illness, metal implants, pacemakers, or other conditions contraindicating TMS. Participants may withdraw at any time without penalty. Safety Measures: TMS and IMU recordings are low-risk, with potential minor effects including scalp tapping sensations, muscle twitches, or mild headaches, which are managed through monitoring and coil adjustment. Serious adverse events are defined, and procedures for reporting and auditing are established in accordance with UK regulations and Good Clinical Practice. Data Analysis: Tremor power will be quantified from IMU recordings using spectral analysis. Statistical comparisons between stimulation conditions and baseline will be conducted using paired t-tests or Wilcoxon tests. The study will employ validated software for randomization and analysis (SPSS, Matlab). Data will be pseudo-anonymized, securely stored, and archived for long-term research use. Ethical Considerations: The study follows the Declaration of Helsinki, Good Clinical Practice, and institutional approvals. Participants' privacy and data protection are ensured under GDPR standards. There are no commercial conflicts of interest, and participants are reimbursed for travel expenses. In summary, this research aims to evaluate the efficacy of phase-locked TMS as a non-invasive, targeted interventionfor tremor in ET and PD. By systematically stimulating the motor cortex at tremor-specific phases, the study seeks to establish a foundation for future minimally invasive treatments that could complement or replace existing pharmacological and surgical options.

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