This single-site, open-label pilot study evaluates accelerated intermittent theta-burst stimulation (iTBS) targeting the dorsomedial prefrontal cortex (dmPFC) for apathy in individuals with [Parkinson's disease](/diseases/parkinsons-disease). The trial is conducted at the [Medical University of South Carolina](https://www.musc.edu) and represents a novel approach to addressing apathy — a debilitating non-motor symptom of Parkinson's disease that affects up to 50% of patients[@pd_apathy_prevalence].
Apathy in Parkinson's disease manifests as loss of motivation, diminished goal-directed behavior, and reduced emotional engagement. Unlike depression, apathy is characterized by blunted affective responses and reduced initiative, even when patients retain the capacity for pleasure. Current pharmacological treatments have limited efficacy, making non-invasive neuromodulation an attractive alternative therapeutic avenue.
The trial uses an accelerated protocol — delivering 8 iTBS sessions per day over 6 treatment days, totaling 28,800 pulses. This "accelerated" paradigm compresses treatment into a two-week window, reducing the number of clinic visits required while maintaining or potentially enhancing efficacy through cumulative dose effects.
This single-site, open-label pilot study evaluates accelerated intermittent theta-burst stimulation (iTBS) targeting the dorsomedial prefrontal cortex (dmPFC) for apathy in individuals with [Parkinson's disease](/diseases/parkinsons-disease). The trial is conducted at the [Medical University of South Carolina](https://www.musc.edu) and represents a novel approach to addressing apathy — a debilitating non-motor symptom of Parkinson's disease that affects up to 50% of patients[@pd_apathy_prevalence].
Apathy in Parkinson's disease manifests as loss of motivation, diminished goal-directed behavior, and reduced emotional engagement. Unlike depression, apathy is characterized by blunted affective responses and reduced initiative, even when patients retain the capacity for pleasure. Current pharmacological treatments have limited efficacy, making non-invasive neuromodulation an attractive alternative therapeutic avenue.
The trial uses an accelerated protocol — delivering 8 iTBS sessions per day over 6 treatment days, totaling 28,800 pulses. This "accelerated" paradigm compresses treatment into a two-week window, reducing the number of clinic visits required while maintaining or potentially enhancing efficacy through cumulative dose effects.
| Parameter | Value |
|-----------|-------|
| NCT Number | [NCT07399496](https://clinicaltrials.gov/study/NCT07399496) |
| Title | Accelerated Transcranial Magnetic Stimulation (TMS) for Apathy in Parkinson's Disease |
| Status | Recruiting |
| Phase | Not Applicable (Device) |
| Sponsor | Medical University of South Carolina |
| Principal Investigator | Daniel Lench, PhD (Assistant Professor) |
| Enrollment | 15 participants (estimated) |
| Start Date | June 2026 (estimated) |
| Primary Completion | March 2027 (estimated) |
| Location | Charleston, South Carolina, United States |
| Study Type | Interventional |
| Design | Single-group, open-label pilot |
| Design Element | Details |
|----------------|---------|
| Type | Interventional |
| Allocation | Not applicable (single group) |
| Intervention Model | Single-group |
| Masking | None (open-label) |
| Primary Purpose | Treatment |
This is a pilot study (Phase I/II equivalent) designed to establish feasibility and tolerability before moving to a larger, controlled trial. The single-group design allows:
The intervention uses accelerated intermittent theta-burst stimulation, a patterned rTMS protocol[@huang2005]:
| Parameter | Value |
|-----------|-------|
| Target | Left dorsomedial prefrontal cortex (dmPFC) |
| System | MagVenture MagPro with cooled figure-of-eight coil |
| Navigation | Brainsight neuronavigation (slightly off midline) |
| Intensity | 120% resting motor threshold (rMT) |
| Pattern | 50 Hz triplets; 2 s on / 8 s off |
| Pulses/session | 600 pulses (~190 seconds) |
| Sessions/day | 8 |
| Inter-session interval | 10-15 minutes |
| Pulses/day | 4,800 |
| Treatment days | 6 (over ~2 weeks, non-contiguous days possible) |
| Total pulses | 28,800 |
The dorsomedial prefrontal cortex is a rational target for apathy treatment because:
Theta-burst stimulation (TBS) is a patterned rTMS protocol that mimics natural brain oscillatory activity[@huang2005]:
The accelerated protocol (multiple sessions per day) is based on:
Brainsight neuronavigation ensures precise targeting:
| Outcome | Measure | Timepoints |
|---------|---------|------------|
| TMS Adherence | Proportion of planned sessions completed (48 scheduled) | Day 1-14 |
| Tolerability | Frequency/severity of side effects via standardized questionnaire | During each treatment day (pre/post sessions) |
| Apathy Severity | Lille Apathy Rating Scale (LARS) patient and caregiver versions | Baseline, Day 14, 2-week follow-up, 4-week follow-up |
| Target Engagement | (1) Resting-state fMRI dmPFC functional connectivity; (2) EEG during motivation/effort tasks | Baseline (Days 0-1), Post-treatment (Days 14-15) |
The LARS is a validated instrument specifically designed for apathy assessment[@lars_scale]:
Resting-state fMRI:
| Outcome | Measure | Timepoints |
|---------|---------|------------|
| Goal Attainment | Bangor Goal-Setting Interview (BGSI) | Baseline, Day 14, 2-week follow-up, 4-week follow-up |
| Apathy (DAS) | Dimensional Apathy Scale — executive, emotional, behavior/cognitive initiation subscales (0-24 each) | Baseline, Day 14, 2-week follow-up, 4-week follow-up |
| Apathy (FrSBe) | Frontal Systems Behavior Scale — apathy component (14 questions, 0-4 each, range 0-56) | Baseline, Day 14, 2-week follow-up, 4-week follow-up |
AES ≥37: This threshold ensures participants have clinically significant apathy, not merely mild or subclinical motivation deficits. The AES is a well-validated 18-item scale assessing behavioral, cognitive, and emotional aspects of apathy.
MoCA <21: Excludes patients with moderate-to-severe cognitive impairment, as they may not reliably report outcomes or benefit from cognitive-behavioral interventions. Cognitive impairment can also confound apathy assessment.
Stable PD medications: Ensures that apathy changes are attributable to TMS rather than medication adjustments. Apathy can worsen with dopamine agonist reduction or with disease progression.
Caregiver informant: The trial uses both patient and caregiver versions of apathy scales, as patients with apathy may under-report their symptoms due to reduced insight.
Apathy affects approximately 30-50% of Parkinson's disease patients[@pd_apathy_prevalence], making it one of the most common non-motor symptoms:
Apathy in PD involves dysfunction in multiple neural circuits:
The apathy phenotype in PD involves three separable domains:
| Approach | Efficacy | Limitations |
|----------|----------|-------------|
| Dopamine agonists | Moderate for motor symptoms | Limited effect on apathy; side effects |
| Antidepressants (SSRIs) | Modest for depression | May worsen apathy; sexual side effects |
| Cholinesterase inhibitors | Mixed evidence | GI side effects, cardiac conduction issues |
| Cognitive behavioral therapy | Limited evidence | Requires intact cognition, motivation to engage |
| Non-invasive brain stimulation | Emerging | This trial addresses this gap |
TMS offers a non-pharmacological approach that can:
Intermittent theta-burst stimulation induces long-term potentiation (LTP)-like changes in cortical excitability[@huang2005]:
The resting-state fMRI component tests whether iTBS produces functional changes:
EEG measures during motivation/effort tasks assess:
rTMS is generally safe with well-characterized risks:
| Side Effect | Frequency | Management |
|-------------|-----------|------------|
| Headache | 20-30% | Acetaminophen, ibuprofen |
| Scalp discomfort | 15-25% | Reposition coil, reduce intensity if needed |
| Facial twitching | 5-15% | Reassurance; adjust coil position |
| Fatigue | 10-20% | Usually transient |
| Fear/anxiety | 5-10% | Pre-session education, gradual acclimation |
The accelerated protocol (8 sessions/day) raises specific safety considerations:
| Contraindication | Screening Method |
|------------------|-----------------|
| Metal in head/neck | Patient history, metal detector |
| Seizure history | Medical history |
| Cardiac devices | Device interrogation |
| Pregnancy | Urine test |
| Cochlear implants | Medical history |
| Phase | Timing | Activities |
|-------|--------|------------|
| Screening | Day -14 to -7 | Informed consent, eligibility confirmation, baseline assessments |
| Baseline | Days 0-1 | Baseline MRI/EEG, LARS, DAS, FrSBe, Bangor Goal-Setting Interview, rMT determination |
| Treatment | Days 1-14 (6 treatment days) | 8 iTBS sessions/day with pre/post tolerability assessments |
| Post-treatment | Days 14-15 | Post-treatment MRI/EEG, outcome measures |
| 2-week follow-up | Day 28 | Outcome measures |
| 4-week follow-up | Day 42 | Outcome measures |
For each session:
The rMT is determined once on Day 1 using standard protocols[@rMT_protocol]:
With 15 participants, this pilot study is powered to:
Primary Analysis:
The accelerated paradigm is theoretically grounded in:
| Protocol | Sessions | Days | Total Pulses | Target |
|----------|----------|------|-------------|--------|
| Standard iTBS | 1/day | 20-30 | 12,000-18,000 | Varies |
| Accelerated iTBS (this trial) | 8/day | 6 | 28,800 | dmPFC |
| Accelerated HF-rTMS (depression) | 10/day | 5 | 45,000-60,000 | DLPFC |
Apathy is a major unmet therapeutic need in Parkinson's disease:
The dmPFC is connected to Parkinson's disease pathology through: