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. The trial is conducted at the Medical University of South Carolina 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 |
| 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:
- Initial safety and tolerability profiling in a small cohort
- Estimation of effect sizes for powering future randomized controlled trials
- Exploration of neural target engagement endpoints
- Assessment of patient adherence to the accelerated protocol
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:
- Reward and motivation circuitry: The dmPFC is a key node in the brain's reward and motivation network, connecting to anterior cingulate cortex (ACC), ventral striatum, and limbic structures[@dmPFC_motivation]
- Goal-directed behavior: The dmPFC plays a critical role in action selection, outcome evaluation, and behavioral activation[@apathy_neurocircuit]
- Network hub: Located at the intersection of cognitive control and emotional processing networks
- Previous TMS target: dmPFC stimulation has shown efficacy for treatment-resistant depression and other motivation-related conditions
Theta-burst stimulation (TBS) is a patterned rTMS protocol that mimics natural brain oscillatory activity[@huang2005]:
- Burst pattern: Three pulses at 50 Hz, repeated every 200 ms (5 Hz theta frequency)
- iTBS protocol: 2 seconds of stimulation followed by 8 seconds of silence, repeated for ~190 seconds
- Neuroplastic effect: Long-term potentiation (LTP)-like facilitation of cortical excitability
- Efficiency: 600 pulses in ~3 minutes vs. 1800+ pulses in 30 minutes for conventional high-frequency rTMS[@iTBS_protocol]
The accelerated protocol (multiple sessions per day) is based on:
- Dosing efficiency: Cumulative daily dosing may enhance target engagement
- Reduced burden: 6 treatment days vs. ~2 months of daily visits (conventional iTBS)
- Transcranial DCS precedent: Accelerated protocols in tDCS have shown enhanced effects
- Building evidence: Accelerated rTMS protocols are increasingly used in treatment-resistant depression and other conditions
Brainsight neuronavigation ensures precise targeting:
- MRI-based structural targeting
- Individualized coil positioning and angle
- Scalp-to-cortex distance tracking
- Maintains consistency across all 48 sessions
| 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]:
- Scores range from -36 to +36
- Higher scores indicate greater apathy
- Covers four dimensions: cognitive, emotional, behavioral, and auto-activation
- Separate patient and caregiver/informant versions
Resting-state fMRI:
- Functional connectivity of dmPFC to motivation/effort-related brain regions
- Pre- vs post-intervention comparison
- Connectivity changes would validate the mechanistic hypothesis
EEG:
- Waveform/response metrics during motivation/effort tasks
- Event-related potentials related to reward anticipation
- Neural signatures of motivational processing
| 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 |
- Age: 45-85 years
- Diagnosis: Parkinson's disease (clinical diagnosis)
- Apathy severity: Apathy Evaluation Scale (AES) score ≥37
- Medication: Stable PD medications
- Support: Caregiver informant available
- MRI/TMS contraindications: Metal implants, aneurysm clips, pacemaker, cochlear implant, etc.
- Cognitive impairment: Montreal Cognitive Assessment (MoCA) <21
- Psychiatric disorders: Bipolar disorder, schizophrenia, active substance use disorder
- Seizure history: Personal or family history of seizures
- Suicidality: Acute suicidality (C-SSRS) or suicide attempt within previous year
- Pregnancy
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.
¶ Prevalence and Impact
Apathy affects approximately 30-50% of Parkinson's disease patients[@pd_apathy_prevalence], making it one of the most common non-motor symptoms:
- Prevalence: 40% at diagnosis, increasing with disease duration
- Independent of motor symptoms: Apathy can occur without depression or anxiety
- Quality of life: Strongly associated with reduced QoL, caregiver burden, and functional impairment
- Treatment resistance: Dopaminergic medications often fail to address apathy, and SSRIs can worsen symptoms
Apathy in PD involves dysfunction in multiple neural circuits:
flowchart TD
subgraph Motivation_Circuit["Motivation Circuit Dysfunction in PD"]
A["Dopaminergic neuron loss<br/>in substantia nigra"] --> B["Reduced mesolimbic<br/>dopamine transmission"]
B --> C["Ventral striatum<br/>hypoactivation"]
C --> D["Dorsomedial prefrontal cortex<br/>and ACC dysfunction"]
D --> E["Impaired goal-directed behavior<br/>and behavioral activation"]
E --> F["Apathy phenotype"]
G["Mesocortical pathway dysfunction"] --> D
H["Basal ganglia-thalamocortical<br/>circuit disruption"] --> D
style F fill:#ffcdd2,stroke:#333
style A fill:#ffcdd2,stroke:#333
end
The apathy phenotype in PD involves three separable domains:
- Cognitive apathy: Reduced interest in novelty, planning, and decision-making — associated with dmPFC dysfunction
- Emotional apathy: Blunted emotional responses to positive/negative events — associated with ventral striatal and limbic dysfunction
- Behavioral apathy: Reduced spontaneous movement and self-initiated actions — associated with premotor and supplementary motor area dysfunction
¶ Current Treatment Landscape
| 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:
- Directly modulate dmPFC and connected motivation circuits
- Be combined with standard dopaminergic therapy
- Be delivered without systemic side effects
- Potentially induce lasting neuroplastic changes
Intermittent theta-burst stimulation induces long-term potentiation (LTP)-like changes in cortical excitability[@huang2005]:
- Pattern: Mimics theta-frequency oscillations (5 Hz) that are associated with memory encoding and novelty detection
- Frequency: 50 Hz triplet bursts mimic gamma-band activity nested within theta rhythm
- Duration: 2-second trains with 8-second intervals allow for cumulative facilitation
flowchart LR
AiTBS["AiTBS to dmPFC"] --> B["Local cortical<br/>excitation"]
B --> C["Subcortical<br/>projections activated"]
C --> D["Ventral striatum<br/>modulation"]
D --> E["Anterior cingulate<br/>cortex activation"]
E --> F["Motivation circuit<br/>facilitation"]
F --> G["Increased goal-directed<br/>behavior"]
G --> H["Reduced apathy<br/>severity"]
style A fill:#e1f5fe,stroke:#333
style H fill:#c8e6c9,stroke:#333
The resting-state fMRI component tests whether iTBS produces functional changes:
- dmPFC connectivity to ventral striatum: Reward valuation and anticipation
- dmPFC connectivity to ACC: Conflict monitoring and behavioral adjustment
- dmPFC connectivity to amygdala: Emotional response to motivationally relevant stimuli
- Default mode network interactions: Self-referential processing and future-oriented thinking
EEG measures during motivation/effort tasks assess:
- Event-related potentials: P3b (attention/resource allocation), reward positivity
- Alpha power: Changes in arousal and attentional allocation
- Theta activity: Source connectivity related to memory and motivation integration
¶ Safety and Tolerability
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 |
- Seizures: Risk <0.1% with appropriate parameters and screening
- Syncope: Vasovagal responses (rare, managed by lying down)
- Hearing threshold changes: Prevented with earplugs
The accelerated protocol (8 sessions/day) raises specific safety considerations:
- Cumulative dose monitoring across all sessions
- Rest intervals (10-15 min) between sessions for cortical recovery
- Real-time tolerability assessment before/after each session
- Blood pressure and heart rate monitoring
| 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:
- MRI-based individual head model
- Target localization (left dmPFC, slightly off midline)
- Coil positioning with real-time tracking
- Scalp-to-cortex distance measurement
- Angle and orientation optimization
The rMT is determined once on Day 1 using standard protocols[@rMT_protocol]:
- Single-pulse TMS to motor cortex
- Minimum intensity producing motor evoked potentials
- Used for all subsequent sessions at 120% intensity
With 15 participants, this pilot study is powered to:
- Establish feasibility (adherence >80%)
- Characterize tolerability (no >5% severe adverse events)
- Estimate effect sizes for LARS change (expected d = 0.6-0.8)
- Provide preliminary target engagement signals
Primary Analysis:
- Descriptive statistics for adherence and tolerability
- Paired t-tests or Wilcoxon signed-rank for LARS change (baseline vs. post-treatment)
- Effect size estimation (Cohen's d)
Secondary Analysis:
- Correlation of neural target engagement with behavioral outcomes
- Exploratory subgroup analyses by age, disease duration, baseline severity
The accelerated paradigm is theoretically grounded in:
- Cumulative dosing: Multiple daily sessions may produce additive neuroplastic effects
- Metaplasticity: Rest periods between sessions may prime cortex for subsequent stimulation
- Practicality: Reduces patient burden and clinic visits
- Precedent: Accelerated protocols have shown promise in depression and other disorders
¶ Comparison with Standard Protocols
| 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:
- It is prevalent and disabling
- Current treatments have limited efficacy
- It is distinct from depression and requires separate treatment approaches
- It profoundly impacts quality of life and caregiver burden
- Target: dmPFC for motivation — novel compared to motor cortex targeting in most PD TMS trials
- Paradigm: Accelerated iTBS — first application to PD apathy
- Measure: Neural target engagement (fMRI + EEG) — mechanistic validation
- Design: Open-label pilot to establish feasibility before RCT
The dmPFC is connected to Parkinson's disease pathology through:
- Dopaminergic loss: Mesocortical pathway projects from VTA to dmPFC; dopamine depletion in this pathway contributes to motivational deficits
- Basal ganglia circuits: dmPFC integrates with ACC and basal ganglia for action selection and monitoring
- Alpha-synuclein pathology: Lewy body pathology in prefrontal cortex is common in PD with dementia
- Lench DH, et al., Accelerated TMS for Apathy in PD - NCT07399496 (2025)
- Huang YZ, et al., Theta burst stimulation of the human motor cortex. Neuron. 2005
- Chung SW, et al., What's left? What's right? Navigating the landscape of iTBS protocols. Clinical Neurophysiology. 2022
- Pagonabarraga J, et al., Apathy in Parkinson's disease: clinical features and treatment. Movement Disorders. 2015
- Holland CC, et al., Prefrontal contributions to motivated behavior. Neuropsychopharmacology. 2023
- Le Heron C, et al., The neuropsychology of apathy: a review. Neuropsychology Review. 2023
- Dujardin K, et al., Lille apathy rating scale. Movement Disorders. 2009
- Barone P, et al., The PRIAMO study. Movement Disorders. 2009