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Accelerated TMS for Apathy in Parkinson's Disease (NCT07399496)

Overview

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.

Trial Details

...

Accelerated TMS for Apathy in Parkinson's Disease (NCT07399496)

Overview

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.

Trial Details

| 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 |

Study Design

| Design Element | Details |
|----------------|---------|
| Type | Interventional |
| Allocation | Not applicable (single group) |
| Intervention Model | Single-group |
| Masking | None (open-label) |
| Primary Purpose | Treatment |

Single-Group Design Rationale

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

Intervention

Accelerated iTBS 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 |

Why the Dorsomedial Prefrontal Cortex?

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 Mechanism

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]

Acceleration Rationale

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

Neuronavigation

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

Outcomes

Primary Outcomes

| 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) |

Lille Apathy Rating Scale (LARS)

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

Target Engagement: Neural Measures

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

Secondary Outcomes

| 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 |

Eligibility Criteria

Inclusion Criteria

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

Exclusion Criteria

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

Key Criteria Explained

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 in Parkinson's Disease

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

Pathophysiology

Apathy in PD involves dysfunction in multiple neural circuits:

Mermaid diagram (expand to render)

Neural Substrates

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 |

Why TMS for Apathy?

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

Mechanism of iTBS in Motivation Networks

Neurophysiological Basis

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

Target Engagement Pathway

Mermaid diagram (expand to render)

Functional Connectivity Effects

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 Correlates

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

TMS Safety Profile

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 |

Rare Complications

Seizures: Risk <0.1% with appropriate parameters and screening
Syncope: Vasovagal responses (rare, managed by lying down)
Hearing threshold changes: Prevented with earplugs

Accelerate Protocol Considerations

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

Contraindications Checked

| 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 |

Study Procedures

Timeline

| 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 |

Neuronavigation Procedure

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

Resting Motor Threshold (rMT) Determination

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

Statistical Considerations

Sample Size Justification

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

Analysis Plan

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

Rationale for Accelerated Protocol

Rationale for Compression

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 |

Significance for Parkinson's Disease Research

Addressing an Unmet Need

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

Innovation Points

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

Connection to Parkinson's Disease Neurobiology

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

[Parkinson's Disease](/diseases/parkinsons-disease)
[Non-Invasive Brain Stimulation](/treatments/non-invasive-brain-stimulation)
[Repetitive Transcranial Magnetic Stimulation](/treatments/repetitive-transcranial-magnetic-stimulation)
[Apathy in Neurodegeneration](/treatments/apathy-management-neurodegeneration) (if exists)

Contact Information

Principal Investigator: Daniel Lench, PhD (Assistant Professor)
Study Coordinator: Emily Laramie
Email: laramie@musc.edu
Phone: +1 (843) 792-3873
Institution: Medical University of South Carolina, Charleston, SC
URL: https://clinicaltrials.gov/study/NCT07399496

References

[Lench DH, et al., Accelerated TMS for Apathy in PD - NCT07399496 (2025)](https://clinicaltrials.gov/study/NCT07399496)

[Huang YZ, et al., Theta burst stimulation of the human motor cortex. Neuron. 2005](https://doi.org/10.1016/j.neuron.2005.08.035)

[Chung SW, et al., What's left? What's right? Navigating the landscape of iTBS protocols. Clinical Neurophysiology. 2022](https://doi.org/10.1016/j.clinph.2022.03.012)

[Pagonabarraga J, et al., Apathy in Parkinson's disease: clinical features and treatment. Movement Disorders. 2015](https://pubmed.ncbi.nlm.nih.gov/26293030/)

[Holland CC, et al., Prefrontal contributions to motivated behavior. Neuropsychopharmacology. 2023](https://doi.org/10.1038/s41386-023-01615-2)

[Le Heron C, et al., The neuropsychology of apathy: a review. Neuropsychology Review. 2023](https://doi.org/10.1007/s11065-023-09548-x)

[Dujardin K, et al., Lille apathy rating scale. Movement Disorders. 2009](https://pubmed.ncbi.nlm.nih.gov/19266683/)

[Barone P, et al., The PRIAMO study. Movement Disorders. 2009](https://doi.org/10.1002/mds.22643)

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📊 Evidence Profile

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accelerated-tms-apathy-pd-nct07399496

Accelerated TMS for Apathy in Parkinson's Disease (NCT07399496)

Overview

Trial Details

Accelerated TMS for Apathy in Parkinson's Disease (NCT07399496)

Overview

Trial Details

Study Design

Single-Group Design Rationale

Intervention

Accelerated iTBS Protocol

Why the Dorsomedial Prefrontal Cortex?

Theta-Burst Stimulation Mechanism

Acceleration Rationale

Neuronavigation

Outcomes

Primary Outcomes

Lille Apathy Rating Scale (LARS)

Target Engagement: Neural Measures

Secondary Outcomes

Eligibility Criteria

Inclusion Criteria

Exclusion Criteria

Key Criteria Explained

Apathy in Parkinson's Disease

Prevalence and Impact

Pathophysiology

Neural Substrates

Current Treatment Landscape

Why TMS for Apathy?

Mechanism of iTBS in Motivation Networks

Neurophysiological Basis

Target Engagement Pathway

Functional Connectivity Effects

EEG Correlates

Safety and Tolerability

TMS Safety Profile

Rare Complications

Accelerate Protocol Considerations

Contraindications Checked

Study Procedures

Timeline

Neuronavigation Procedure

Resting Motor Threshold (rMT) Determination

Statistical Considerations

Sample Size Justification

Analysis Plan

Rationale for Accelerated Protocol

Rationale for Compression

Comparison with Standard Protocols

Significance for Parkinson's Disease Research

Addressing an Unmet Need

Innovation Points

Connection to Parkinson's Disease Neurobiology

Related Pages

Contact Information

References

💬 Discussion