Closed-loop TMS for Tremor

Background and Rationale Tremor is a common and often debilitating neurological symptom that can profoundly impact daily function, social participation, and quality of life. The most frequent causes are Essential Tremor (ET) and Parkinson's Disease (PD)tremor. ET is the most common adult movement disorder, affecting approximately 1% of the global population, with prevalence increasing with age. It is typically characterized by postural and kinetic tremor, most commonly affecting the upper limbs, but can also involve the head, voice, and other body regions. ET often leads to difficulties with fine motor tasks such as writing, eating, or handling objects, causing both physical limitations and social embarrassment. Pharmacological management primarily relies on propranolol and primidone, which have the strongest evidence for reducing upper-limb tremor. However, around 50% of patients eventually discontinue these medications due to either limited efficacy or intolerable side effects, leaving a substantial proportion of individuals with untreated or inadequately treated tremor. For severe and refractory cases, deep brain stimulation (DBS) targeting the thalamus can be highly effective. Despite this, DBS is invasive, expensive, and associated with risks of morbidity and side effects, including speech and balance disturbances, infection, or hardware complications. Moreover, its effectiveness can diminish over time, highlighting the need for alternative therapies.

Tremor in PD presents additional challenges. While dopaminergic therapy effectively alleviates cardinal symptoms such as rigidity and bradykinesia, tremor is often less responsive. Some PD tremors may also be unresponsive to Levodopa or other dopaminergic drugs, and anticholinergic therapy, though sometimes beneficial in younger patients, carries risks of confusion and cognitive side effects in older adults. β-blockers, effective in ET, have not shown consistent benefit in PD tremor. DBS of the subthalamic nucleus or globus pallidus can reduce tremor, but again carries procedural risks and long-term efficacy concerns. Taken together, these limitations underscore the urgent need for non-invasive neuromodulatory approaches that can safely and effectively reduce tremor amplitude in both ET and PD populations.

The proposed research investigates transcranial magnetic stimulation (TMS) as a non-invasive neuromodulation strategy to reduce tremor. TMS uses rapidly changing magnetic fields to induce small electric currents in cortical neurons. When applied over the primary motor cortex, TMS can modulate neural oscillations responsible for tremor. A key innovation in this study is phase-specific, phase-locked TMS, which leverages the oscillatory nature of tremor. Neural oscillations, like a swinging pendulum, have phases that correspond to positions within a repetitive cycle. Delivering stimulation at certain phases can either amplify or suppress the oscillation. Prior studies demonstrate that TMS delivered at tremor frequency (~5 Hz) can produce modest reductions in Parkinsonian rest tremor, even without phase targeting. We hypothesize that systematically stimulating at the amplitude-suppressing phase will produce significantly greater tremor reduction, and that repeated phase-locked stimulation may result in cumulative effects. Supporting evidence comes from invasive stimulation studies in thalamus and subthalamic nucleus, where suppression of pathological oscillations can occur after only a few tremor cycles. These findings suggest that non-invasive phase-locked cortical stimulation could produce measurable tremor reduction with minimal safety risks.

Objectives and Outcome Measures This research comprises two interrelated studies.

Study 1 (Primary Objective):

• Evaluate the acute effectiveness of phase-locked TMS in reducing tremor.
• Primary Outcome Measure: Change in tremor power as measured by an inertial measurement unit (IMU) on the hand during stimulation compared to baseline (no stimulation).

Study 2 (Secondary Objective):

• Determine whether stimulation delivered at the individually determined maximal tremor-suppressing phase produces greater tremor reduction than minimal suppressing phases or sham stimulation.
• Secondary Outcome Measures: IMU-measured tremor power during maximal, minimal, and sham stimulation. In addition, participant-reported outcomes include QUEST (quality of life in ET), TETRAS (tremor severity in ET), and UPDRS (motor and non-motor daily living in PD). These scales will provide functional and subjective assessments of tremor impact.

Study Design Background and Rationale Tremor is one of the most common movement disorders in adults, and it can be physically disabling, socially limiting, and psychologically distressing. Tremor is characterized by involuntary, rhythmic oscillatory movements of a body part, often the hands or upper limbs, but it can also affect the head, voice, and lower extremities. Among the many causes of tremor, Essential Tremor (ET) and Parkinson's Disease (PD) are the most prevalent. ET is estimated to affect approximately 1% of the global population, with higher prevalence among older adults. ET manifests predominantly as postural and kinetic tremor, which can progressively worsen over time, leading to difficulties with fine motor tasks such as writing, eating, or using tools. Tremor may cause embarrassment and social avoidance, negatively affecting psychological well-being. PD tremor, typically seen as rest tremor, can co-occur with bradykinesia, rigidity, and postural instability, and is often less responsive to pharmacological therapy than the other cardinal PD symptoms.

Current pharmacological treatments for ET, including propranolol (a non-selective β-blocker) and primidone (an anticonvulsant), have been shown to reduce tremor amplitude in some patients. However, approximately 50% of patients discontinue these treatments over time due to insufficient benefit or adverse effects, which may include fatigue, dizziness, hypotension, or cognitive disturbances. In PD, tremor is often less responsive to dopaminergic therapy (e.g., Levodopa), with some patients experiencing persistent disabling tremor despite optimal medication regimens. Anticholinergic agents may be used in younger PD patients, but in older adults they can cause confusion, urinary retention, and cognitive impairment. Other pharmacological strategies, including β-blockers or benzodiazepines, provide inconsistent benefit in PD tremor. For severe tremor in either ET or PD, deep brain stimulation (DBS) targeting the thalamus or subthalamic nucleus can provide significant tremor reduction. Despite its efficacy, DBS is invasive, expensive, carries risks of surgical complications, and its effects may diminish over time. These limitations highlight the need for safer, non-invasive, and more effective therapeutic approaches.

Transcranial Magnetic Stimulation (TMS) represents a promising non-invasive intervention. TMS delivers brief magnetic pulses to cortical neurons, inducing electric currents that can modulate neural activity. Previous research demonstrates that TMS applied over the motor cortex at tremor frequencies (~5 Hz) can produce modest reductions in tremor amplitude in both ET and PD, even without precise timing relative to the tremor cycle. Recent findings suggest that phase-specific stimulation, delivered at a particular phase of the neural oscillation underlying tremor, may optimize tremor suppression. Neural oscillations can be thought of as repeating cycles, similar to a pendulum or child's swing, with specific phases corresponding to points along the oscillatory cycle. A push delivered at one phase may amplify the oscillation, whereas a push delivered at the opposite phase may reduce its amplitude. By timing TMS pulses to coincide with the amplitude-suppressing phase, we hypothesize that tremor reduction can be maximized. Furthermore, repeated phase-locked stimulation may produce cumulative effects, enhancing clinical benefit over multiple cycles. Supporting evidence comes from invasive stimulation studies of the thalamus and subthalamic nucleus, where oscillation suppression can be observed after as few as four tremor cycles, suggesting that even brief non-invasive phase-locked TMS could produce measurable effects.

In addition to the physiological rationale, phase-locked TMS is attractive because it is non-invasive, repeatable, and carries minimal risks compared to DBS. The approach targets central oscillatory networks directly, rather than relying solely on peripheral muscle co-activation, potentially producing more robust and sustained tremor suppression. By demonstrating the feasibility and effectiveness of phase-locked TMS, this study could lay the groundwork for future minimally invasive cortical stimulation interventions, including extradural or subdural stimulation, with broader therapeutic applications.

Study Objectives and Outcome Measures This research consists of two interrelated studies designed to evaluate the acute and phase-specific effects of TMS on tremor.

Primary Objective (Study 1):

• To determine whether phase-locked TMS can acutely reduce tremor amplitude in ET and PD.
• Primary Outcome Measure: Tremor power measured via an inertial measurement unit (IMU) placed on the dorsum of the hand during stimulation compared to baseline (no stimulation).

Secondary Objectives (Study 2):

• To determine whether stimulation delivered at the maximal tremor-suppressing phase produces greater tremor reduction than stimulation at the minimal suppressing phase or sham.
• Secondary Outcome Measures: IMU-measured tremor power and tremor-related EMG activity. Participant-reported measures include:
• Quality of Life in Essential Tremor Questionnaire (QUEST) - evaluating physical, psychosocial, and functional impact of tremor in ET.
• Tremor Research Group Essential Tremor Rating Scale (TETRAS) - quantifying tremor severity and impact on activities of daily living in ET.
• Unified Parkinson's Disease Rating Scale (UPDRS) - assessing motor and non-motor daily living experiences in PD.

These measures allow assessment of both objective tremor reduction and patient-centered functional outcomes.

Study Design A within-subject crossover design will be used. Study 1 involves two visits on separate days to determine the amplitude-suppressing phase for each participant. Study 2 involves three optional visits separated by at least one week, to compare maximal phase, minimal phase, and sham stimulation in randomized order. Each session is under two hours and includes setup, tremor recording, TMS application, and post-stimulation functional assessments.

Participants

• Sample Size: 20 participants with ET and 20 with PD.
• Inclusion Criteria: Age ≥18 years, symptomatic ET or PD tremor, ability to understand English, ability to provide informed consent, and eligibility for TMS per safety screening.
• Exclusion Criteria: Lack of consent capacity, concurrent research participation, history of epilepsy, significant psychiatric or neurological illness, fainting, cochlear implants, metallic implants, pacemakers, or intracardiac devices.

Participants may withdraw at any time, and replacements will be recruited if necessary.

Recruitment and Consent Participants will be recruited through online adverts, DeNDRoN, and participant literature. After expressing interest, participants receive the PIL and TMS screening form at least 24 hours before consent. Written informed consent is obtained by the CI or delegate, ensuring understanding and voluntary participation.

Study Procedures

Study 1 Procedures:

• Tremor medications may be omitted on study days to enhance interpretability.
• EMG electrodes record muscle activity from the first dorsal interosseous, abductor pollicis brevis, finger flexors, and extensors.
• An IMU records tremor from the dorsum of the affected hand.
• TMS is applied via a figure-of-eight coil over the contralateral motor cortex.
• Active motor threshold is determined during a weak pinch grip.
• Tremor is recorded without stimulation for 70 seconds.

Phase-Locked TMS:

• Tremor phase is estimated in real-time from IMU data.
• Stimulation is delivered in 3-second trains at one of eight phase values (0-320°, 40° increments) with ~7-second inter-train intervals.
• Each phase is randomized across 16 blocks, totaling 960 pulses.
• Post-stimulation tremor is recorded to evaluate immediate and potential cumulative effects.

Study 2 Procedures:

• Participants return for up to three sessions, separated by at least one week.
• Stimulation conditions: maximal suppressing phase, minimal suppressing phase, sham.
• The order is randomized, and participants are blinded.
• Outcome measures include IMU, EMG, QUEST, TETRAS, and UPDRS.
• The Bang's blinding index evaluates participants' ability to distinguish real from sham stimulation.

Safety Considerations TMS is low-risk but may induce scalp sensations, local muscle twitches, jaw or eye movements, loud clicking, or mild headaches. Ear protection is provided. EMG and IMU recordings are safe. Participants are monitored and may stop stimulation at any time. Serious adverse events (SAEs) are reported per UK regulations.

Data Management and Analysis IMU and EMG data undergo spectral analysis to estimate tremor power. Paired t-tests or Wilcoxon tests compare stimulation and control conditions. Data are pseudo-anonymized, stored securely on encrypted servers, and archived for 10 years. Anonymized data may be shared for research purposes with a valid proposal.

Ethical and Regulatory Compliance The study adheres to the Declaration of Helsinki, Good Clinical Practice, and institutional approvals (REC, HRA). Participants receive travel reimbursement but no financial compensation. Protocol deviations and serious breaches are documented and reported.

Quality Assurance Monitoring and auditing are conducted throughout the study. Weekly team meetings review progress and safety. Staff are trained in TMS and resuscitation, and procedures follow standard operating protocols.

Expected Outcomes and Implications This study will provide crucial evidence on the feasibility, safety, and efficacy of phase-locked TMS for tremor. Positive findings may establish non-invasive cortical stimulation as a novel therapeutic strategy, reducing reliance on medication or invasive procedures and improving functional outcomes and quality of life for individuals with ET and PD. This research may also inform the development of minimally invasive extradural or subdural stimulation strategies, ultimately broadening therapeutic options for tremor management.