nct06365190-rtms-pd

Effects of Periodic Repetitive Transcranial Magnetic Stimulation in Parkinson Disease

Pathway Diagram

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PD -->|"causes"| DOPAMINERGIC_NEURONS
synucleinopathies["synucleinopathies"]
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neurodegeneration["neurodegeneration"]
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PARKIN -->|"associated with"| PD
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Effects of Periodic Repetitive Transcranial Magnetic Stimulation in Parkinson Disease

Pathway Diagram

Overview

This clinical trial investigates the effects of continuous theta-burst stimulation (cTBS), a form of repetitive transcranial magnetic stimulation (rTMS), on motor symptoms in patients with Parkinson's disease. The study targets the left supplementary motor area (SMA) and compares cTBS against standard antiparkinsonian medication management.

rTMS is a non-invasive brain stimulation technique that uses magnetic fields to induce electrical currents in specific brain regions. Theta-burst stimulation (TBS) is a patterned rTMS protocol that delivers bursts of high-frequency stimulation, designed to more efficiently induce neuroplastic changes compared to conventional rTMS protocols.

Trial Details

| Parameter | Value |
|-----------|-------|
| NCT Number | NCT06365190 |
| Title | Effects of a Periodic Repetitive Transcranial Magnetic Stimulation in Parkinson Disease |
| Status | Active, not recruiting |
| Phase | Not Applicable |
| Sponsor | Anhui Medical University |
| Principal Investigator | WANG KAI (Head, Dept of Neurology & Medical Psychology, Director, Cognitive Neuropsychology Lab) |
| Enrollment | 47 participants (actual) |
| Start Date | April 6, 2020 |
| Primary Completion | July 31, 2024 |
| Location | China |

Study Design

| Design Element | Details |
|----------------|---------|
| Type | Interventional |
| Allocation | Randomized (1:1 ratio, stratified by age) |
| Intervention Model | Parallel |
| Masking | Triple-blind (Participant, Investigator, Outcomes Assessor) |

Intervention Arms

cTBS Group (Experimental)

Continuous theta-burst stimulation targeting the left supplementary motor area:

• Protocol: 14 consecutive days of treatment
• Sessions: Three rounds daily with 15-minute intervals
• Pulses per session: 600 pulses at 80% resting motor threshold
• Total pulses: 25,200 pulses over the treatment period

Drug Group (Control)

Standard antiparkinsonian medications with 8-week follow-up intervals including:

• Medication guidance
• Symptom assessment

Mechanism of Action

Theta-Burst Stimulation

Theta-burst stimulation is a patterned rTMS protocol that mimics natural brain oscillatory activity:

Supplementary Motor Area Target

The supplementary motor area is chosen because:

• Motor planning: The SMA is critical for self-initiated movements
• PD dysfunction: SMA activity is reduced in Parkinson's disease
• Motor cortex influence: SMA projects to primary motor cortex via cortico-cortical pathways
• Clinical rationale: SMA stimulation may improve motor initiation and reduce bradykinesia

Rationale for cTBS in PD

In Parkinson's disease, motor symptoms arise from:

• Dopaminergic neuron loss in the substantia nigra pars compacta
• Basal ganglia-thalamocortical circuit dysfunction
• Reduced cortical activation during self-initiated movements

Eligibility Criteria

Inclusion Criteria

Exclusion Criteria

• Serious mental illnesses (depression, psychosis, OCD)

• Severe organic brain defects on imaging
• Epilepsy or unknown cause of unconsciousness
• Head injury, stroke, or neurological disease

• Immovable metal objects on or near head

• Drug abuse within past 6 months

Outcomes

Primary Outcomes

| Outcome | Assessment Timing |
|---------|-------------------|
| Unified Parkinson's Disease Rating Scale III (UPDRS III) | Baseline, Week 3, Week 13, Week 23, Week 33 |

The UPDRS Part III is the standard clinical rating scale for motor symptoms in PD, measuring:

• Speech
• Facial expression
• Tremor at rest
• Action tremor
• Rigidity
• Finger taps
• Hand movements
• Pronation-supination
• Leg agility
• Arising from chair
• Posture
• Gait
• Postural stability
• Bradykinesia

Secondary Outcomes

| Outcome | Assessment Timing |
|---------|-------------------|
| Hoehn-Yahr stage (1-5) | Baseline, Week 3, Week 13, Week 23, Week 33 |
| Levodopa equivalent dose | Baseline, Week 3, Week 13, Week 23, Week 33 |

Significance for Parkinson's Disease

Current Treatment Limitations

Current PD therapies include:

• Dopamine replacement (levodopa, dopamine agonists)
• Deep brain stimulation (for advanced cases)
• Physical therapy

• Motor fluctuations ("on-off" phenomena)
• Dyskinesias with long-term levodopa use
• Non-motor symptoms not addressed by dopaminergic therapy

Potential Benefits of rTMS

Non-invasive brain stimulation offers several advantages:

Comparison with Other rTMS Protocols for PD

| Protocol | Frequency | Duration | Typical Target | Evidence Level |
|----------|-----------|----------|----------------|----------------|
| cTBS (this trial) | 50 Hz bursts | 40 sec | SMA | Emerging |
| High-frequency rTMS | 5-25 Hz | 15-30 min | M1 | Moderate |
| Low-frequency rTMS | 1 Hz | 15-30 min | M1/SMA | Moderate |
| iTBS | Intermittent | 3 min | M1 | Growing |

Neurophysiology of Parkinson's Disease

Basal Ganglia Dysfunction

Parkinson's disease results from progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). This leads to:

The classic model suggests:

• Increased firing rate in GPi/SNr → inhibited thalamus → reduced cortical activation
• Loss of dopaminergic modulation of this circuitry

• Altered firing patterns (bursting, oscillations)
• Synchronization abnormalities across circuits
• Cortical-subcortical coupling deficits[@basalganglia2024]

Cortical Pathology in PD

Beyond subcortical changes, PD involves cortical dysfunction:

Motor Cortex

• Reduced excitability
• Impaired plasticity (LTP/LTD)
• Altered sensorimotor integration

Supplementary Motor Area

• Reduced activation during self-initiated movements
• Impaired motor sequence learning
• Abnormal movement sequencing
• Connection to bradykinesia

• Internal motor generation
• Sequence planning
• Self-initiated movements
• Motor set maintenance[@supplementary]

Theta-Burst Stimulation: Mechanism

Neurophysiological Basis

Theta-burst stimulation (TBS) is a patterned rTMS protocol that more closely mimics natural brain activity compared to conventional rTMS[@huang2005]:

Pattern Structure

Effects on Neural Tissue

cTBS produces:

• Long-term depression (LTD)-like effects: Reduces cortical excitability
• Synaptic depression: Alters GABAergic and glutamatergic transmission
• Network effects: Modulates distributed neural circuits

• 600 pulses in 40 seconds vs. 1800+ pulses in 30 minutes for conventional rTMS
• Equivalent or greater physiological effects[@ctbs2019]

Why Target the SMA?

The supplementary motor area is a rational target for PD:

cTBS Protocol Details

Treatment Parameters

The trial uses an intensive protocol:

| Parameter | Value | Rationale |
|-----------|-------|-----------|
| Total sessions | 14 consecutive days | Cumulative effect |
| Sessions per day | 3 | Repeated dosing |
| Interval between sessions | 15 minutes | Safety margin |
| Pulses per session | 600 | Standard cTBS dose |
| Resting motor threshold | 80% | Sub-threshold for safety |
| Total pulses | 25,200 | High dose approach |

Safety Considerations

cTBS is generally well-tolerated:

• No serious adverse events in PD studies
• Mild headache is most common complaint
• No seizures reported at parameters used
• Contraindications include metal implants, epilepsy

Clinical Evidence for rTMS in PD

Meta-Analysis Findings

Systematic reviews support rTMS benefits in PD[@tmsmeta2023]:

| Outcome | Effect Size | Confidence |
|---------|-------------|------------|
| UPDRS Part III | SMD -0.42 | Moderate |
| Bradykinesia | SMD -0.38 | Moderate |
| Rigidity | SMD -0.35 | Low-Moderate |
| Gait | SMD -0.28 | Low |

Protocol Comparison

| Protocol | Typical Effect | Best For |
|----------|----------------|----------|
| High-frequency M1 | Motor improvement | Bradykinesia, rigidity |
| Low-frequency M1 | Tremor reduction | Tremor-dominant PD |
| SMA stimulation | Movement initiation | General motor function |
| cTBS (this trial) | Under investigation | To be determined |

Extended Outcome Assessment

UPDRS Part III Details

The Unified Parkinson's Disease Rating Scale Part III is the gold standard:

Examination Components

• Finger taps: 10 rapid finger taps (0-4)
• Hand movements: Opening/closing hands (0-4)
• Pronation-supination: 10 cycles (0-4)
• Leg agility: 10 foot taps (0-4)
• Arising from chair: Stand without assistance (0-4)
• Gait: 10+ steps, turns (0-4)
• Postural stability: Pull test (0-4)

Scoring Interpretation

• 0: Normal
• 1: Slight impairment
• 2: Mild impairment
• 3: Moderate impairment
• 4: Severe impairment

Hoehn and Yahr Staging

| Stage | Description |
|-------|-------------|
| 1 | Unilateral involvement |
| 2 | Bilateral involvement, no balance impairment |
| 3 | Mild-moderate bilateral disease, some postural instability |
| 4 | Severe disability, still able to walk/stand |
| 5 | Wheelchair bound or bedridden |

Trial Implementation

Chinese Clinical Context

The trial is conducted in China, which has advantages:

• Large PD patient population
• Established rTMS expertise
• Cost-effective research infrastructure
• Growing neuroscience research investment

Assessment Schedule

Multiple timepoints allow:

• Baseline: Pre-treatment status
• Week 3: Early treatment effects
• Week 13: Mid-treatment assessment
• Week 23: Sustained effects
• Week 33: Extended follow-up

• Treatment durability
• Potential delayed effects
• Natural progression rates

Neuroimaging Correlates

Structural MRI Findings in PD

Baseline neuroimaging is critical for patient characterization:

Key MRI Findings in PD:

• Substantia nigra pars compacta: Loss of the "swallow-tail" appearance
• Red nucleus: Altered signal characteristics
• Hippocampal volume: May show early atrophy in PD with dementia
• White matter hyperintensities: Variable, associated with disease duration

• Space-occupying lesions
• Significant vascular pathology
• Malformations
• Prior traumatic brain injury sequelae

Functional Imaging Correlates

While not explicitly stated in the trial design, functional imaging could provide insights into cTBS mechanisms:

FDG-PET Patterns in PD:

• Reduced glucose metabolism in posterior cortical regions
• Hypermetabolism in the cerebellar hemisphere (compensatory)
• Correlations with motor and cognitive dysfunction

• Dopamine transporter (DAT) imaging to confirm dopaminergic deficit
• Postsynaptic dopamine receptor imaging

Future Imaging Integration

Advanced imaging could enhance understanding of cTBS effects:

Neuroimmunology Considerations

Neuroinflammation in PD

Emerging evidence links neuroinflammation to PD progression:

Key Inflammatory Mediators:

• Microglial activation: TSPO PET shows increased binding in substantia nigra
• Cytokine elevation: IL-1β, TNF-α, IL-6 in CSF and blood
• Complement activation: Related to dopaminergic neuron loss

Theta-burst stimulation may modulate neuroinflammation:

BDNF and Neuroplasticity

Brain-derived neurotrophic factor plays a key role in TMS mechanisms:

BDNF in PD:

• Reduced levels in PD patients
• Associated with disease severity
• Linked to motor learning deficits

• TMS protocols can increase BDNF expression
• May enhance neuroplasticity in PD patients
• Potential for long-term benefits

Clinical Outcome Measures Deep Dive

UPDRS Part III Scoring Details

The Unified Parkinson's Disease Rating Scale Part III provides comprehensive motor assessment:

Speech (0-4):

• 0: Normal
• 1: Slight loss of expression, diction, volume
• 2: Monotone, slurred but understandable
• 3: Considerable impairment, difficult to understand
• 4: Unintelligible

• 0: Normal
• 1: Minimal hypomimia, blink rate decreased
• 2: Obviously decreased expression, blink rate decreased
• 3: Masked facies, infrequent blink
• 4: Fixed expression, no blink

• Assessed in each limb (face, right upper, left upper, right lower, left lower)
• 0: No tremor
• 1: Tremor <1 cm, infrequent
• 2: Tremor 1-5 cm, present >50% of time
• 3: Tremor 1-5 cm, present >75% of time
• 4: Tremor >5 cm

• Assessed with passive movement
• 0: No rigidity
• 1: Slight catch, minimal resistance
• 2: Moderate resistance, full range easily achieved
• 3: Significant resistance, full range difficult
• 4: Extreme resistance, cannot complete range

• 10 taps as fast as possible
• 0: Normal (≥15 taps/5 sec)
• 1: Slight slowing, 11-14 taps
• 2: Moderate slowing, 7-10 taps
• 3: Severely impaired, 3-6 taps
• 4: Can barely attempt, 0-2 taps

Hoehn and Yahr Stages Explained

| Stage | Clinical Features | Prognostic Implications |
|-------|-------------------|------------------------|
| 1 | Unilateral disease, minimal functional impact | Excellent response to treatment |
| 1.5 | Unilateral and axial involvement | Early axial signs |
| 2 | Bilateral disease, no postural instability | Maintains independence |
| 2.5 | Mild bilateral, recovery on pull test | Early postural instability |
| 3 | Mild-moderate bilateral, some postural instability | Requires assistance in some activities |
| 4 | Severe disability, still walks unassisted | Marked functional limitations |
| 5 | Wheelchair bound or bedridden | Total dependence |

Levodopa Equivalent Dose

Standardizing antiparkinsonian medication is essential for comparison:

LED Calculation Factors:

| Medication | Conversion Factor |
|------------|-------------------|
| Levodopa standard | 1 mg |
| Levodopa CR | 0.7 mg |
| Pramipexole | 100 mg |
| Ropinirole | 20 mg |
| Rotigotine | 30 mg |
| Selegiline | 10 mg |
| Amantadine | 1 mg |
| Entacapone | 0.33 mg |

The trial tracks LED to ensure comparability between arms and account for medication effects.

Safety and Adverse Events

TMS Safety Profile

rTMS is generally safe with well-characterized risks:

Common Side Effects:

• Headache (up to 30% of patients)
• Scalp discomfort at stimulation site
• Transient hearing threshold changes (with proper ear protection)

• Seizures (risk <0.1% with appropriate parameters)
• Transient cognitive effects
• Syncope (vasovagal)

• Metal implants in head/neck
• Seizure history
• Pacemaker or other electronic devices
• Pregnancy (relative)

cTBS-Specific Considerations

The intensive cTBS protocol requires attention to:

Cumulative Dose Effects:

• 25,200 total pulses over 14 days
• Higher than typical rTMS protocols
• Close monitoring for adverse effects

• Regular neurological examinations
• Adverse event collection
• Vital signs monitoring

Management of Adverse Events

Headache Management:

• Over-the-counter analgesics (acetaminophen, ibuprofen)
• Pre-stimulation hydration
• Adjust stimulation intensity if needed

• Reposition coil slightly
• Reduce stimulation intensity
• Topical anesthetic application (if severe)

Statistical Considerations

Sample Size Justification

With 47 participants (actual enrollment):

Statistical Power:

• Assuming α = 0.05 (two-tailed)
• Expected effect size based on prior rTMS meta-analyses
• Adequate power to detect clinically meaningful UPDRS differences

• 1:1 randomization provides equal statistical power for each arm
• Stratification by age ensures balance across groups
• Triple-blinding reduces assessment bias

Analysis Plan

Primary Analysis:

• Mixed-effects model for repeated measures (MMRM)
• Intention-to-treat population
• Missing data handled via appropriate methods

• Per-protocol analysis
• Subgroup analyses by age, disease duration, baseline severity
• Correlation with neuroimaging findings

Future Directions

TMS in Movement Disorders

This trial contributes to the growing evidence for TMS in PD:

Potential Applications:

• Motor symptoms (bradykinesia, rigidity, tremor)
• Non-motor symptoms (depression, cognitive dysfunction)
• Gait and balance difficulties
• Freezing of gait

• Personalized stimulation parameters
• Navigated TMS targeting
• Paired associative stimulation
• Closed-loop stimulation systems

Integration with Other Therapies

cTBS could complement standard PD treatments:

With Medication:

• May allow dose reduction in responders
• Could extend "on" time
• Potential synergistic effects

• Combined with physical therapy
• Speech therapy integration
• Occupational therapy approaches

• Potential for hybrid approaches
• Combined with DBS programming
• Non-invasive alternative to surgery

China Clinical Research Context

Growth of TMS Research in China

China has become a major center for TMS clinical research:

Advantages:

• Large patient population
• Cost-effective research operations
• Strong neuroscience research infrastructure
• Government support for medical research

• Variable regulatory oversight historically
• Need for international standardization
• Publication and data sharing practices

Implications for Global Research

This trial exemplifies the globalization of clinical research:

Research Gaps and Future Questions

Unanswered Questions in PD TMS

This trial addresses some gaps while highlighting others:

Mechanism Questions:

• Precisely how does cTBS improve motor function?
• Which neuroplasticity mechanisms are engaged?
• Are effects disease-modifying or purely symptomatic?

• Optimal stimulation parameters?
• Long-term durability of benefits?
• Which patients respond best?

Future Research Directions

Based on this trial's design and results:

Patient Selection Considerations

Optimal Candidates for cTBS

Based on inclusion/exclusion criteria:

Ideal Patient Profile:

• Early-to-mid stage PD (Hoehn-Yahr 1-3)
• Stable medication regimen
• Intact cognition (MMSE ≥24)
• No psychiatric comorbidities
• No contraindications to TMS

• Advanced disease with significant disability
• Significant cognitive impairment
• Psychiatric symptoms (depression, psychosis)
• Medical comorbidities affecting safety

Patient Perspective

For patients considering TMS:

Benefits:

• Non-invasive (no surgery)
• No medication side effects
• Minimal discomfort
• Potential for improvement

• Daily visits for 2 weeks
• Unknown long-term effects
• May not work for all patients
• Requires transportation to clinic

Related Resources

• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Repetitive Transcranial Magnetic Stimulation](/mechanisms/repetitive-tms)
• [Supplementary Motor Area](/cell-types/supplementary-motor-area)
• [Substantia Nigra](/brain-regions/substantia-nigra)
• [Motor Cortex](/brain-regions/motor-cortex)
• [Dopamine](/proteins/dopamine)
• [Non-Invasive Brain Stimulation](/mechanisms/non-invasive-brain-stimulation)
• [Basal Ganglia Circuitry](/mechanisms/basal-ganglia-circuitry)

External Links

• [ClinicalTrials.gov Record](https://clinicaltrials.gov/study/NCT06365190)
• [PubMed Search](https://pubmed.ncbi.nlm.nih.gov/?term=NCT06365190)

References

• Principal Investigator: WANG KAI
• Institution: Anhui Medical University, China
• Department: Department of Neurology & Medical Psychology, Cognitive Neuropsychology Lab

References

See Also

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• [Circuit-level neural dynamics in neurodegeneration](/analysis/SDA-2026-04-02-26abc5e5f9f2)
• [Digital biomarkers and AI-driven early detection of neurodegeneration](/analysis/SDA-2026-04-01-gap-012)
• [What are the mechanisms by which gut microbiome dysbiosis influences Parkinson's](/analysis/SDA-2026-04-01-gap-20260401-225155)

• [Cytochrome Therapeutics](/experiment/exp-wiki-experiments-lipid-droplet-lysosome-axis-parkinsons)
• [Alpha-Synuclein Aggregation Triggers — Sporadic PD Initiation Mechanisms](/experiment/exp-wiki-experiments-alpha-synuclein-aggregation-triggers-sporadic-pd)
• [tACS Connectivity Trial in Early Alzheimer's](/experiment/exp-wiki-experiments-brain-connectivity-tacs-alzheimers)

Pathway Diagram

The following diagram shows the key molecular relationships involving nct06365190-rtms-pd discovered through SciDEX knowledge graph analysis: