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.
| 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 |
| Design Element |
Details |
| Type |
Interventional |
| Allocation |
Randomized (1:1 ratio, stratified by age) |
| Intervention Model |
Parallel |
| Masking |
Triple-blind (Participant, Investigator, Outcomes Assessor) |
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
Standard antiparkinsonian medications with 8-week follow-up intervals including:
- Medication guidance
- Symptom assessment
Theta-burst stimulation is a patterned rTMS protocol that mimics natural brain oscillatory activity:
- Burst pattern: Three pulses at 50 Hz, repeated every 200 ms (5 Hz)
- cTBS: Continuous delivery for ~40 seconds (600 pulses)
- Neuroplastic effect: Long-term depression (LTD)-like effects on cortical excitability
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
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
cTBS may modulate SMA excitability and restore more normal motor planning function.
- Meet Chinese PD diagnostic criteria (2016 version)
- Age 40-80 years
- Stable medication use for ≥2 weeks
- MMSE score ≥24 (normal cognitive function)
- Able to cooperate with experiment
- No prior rTMS treatment
-
Psychiatric
- Serious mental illnesses (depression, psychosis, OCD)
-
Neurological
- Severe organic brain defects on imaging
- Epilepsy or unknown cause of unconsciousness
- Head injury, stroke, or neurological disease
-
Device-related
- Immovable metal objects on or near head
-
Substance-related
- Drug abuse within past 6 months
| 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
| 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 |
Current PD therapies include:
- Dopamine replacement (levodopa, dopamine agonists)
- Deep brain stimulation (for advanced cases)
- Physical therapy
However, many patients experience:
- Motor fluctuations ("on-off" phenomena)
- Dyskinesias with long-term levodopa use
- Non-motor symptoms not addressed by dopaminergic therapy
Non-invasive brain stimulation offers several advantages:
- Non-invasive — No surgical risk
- Targeted — Can modulate specific brain regions
- Adjunctive — Can be combined with standard therapy
- Modular — Can be repeated as needed
- Neuroplastic — May induce lasting changes
| 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 |
Parkinson's disease results from progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). This leads to:
- Reduced dopamine in striatum: Decreased inhibition of the indirect pathway
- Increased basal ganglia output: Excessive inhibitory output from GPi/SNr to thalamus
- Thalamocortical suppression: Reduced excitatory drive to motor cortex
- Movement poverty: Bradykinesia and rigidity result
The classic model suggests:
- Increased firing rate in GPi/SNr → inhibited thalamus → reduced cortical activation
- Loss of dopaminergic modulation of this circuitry
However, emerging evidence shows more complex changes:
- Altered firing patterns (bursting, oscillations)
- Synchronization abnormalities across circuits
- Cortical-subcortical coupling deficits[@basalganglia2024]
Beyond subcortical changes, PD involves cortical dysfunction:
- Reduced excitability
- Impaired plasticity (LTP/LTD)
- Altered sensorimotor integration
The SMA shows particular dysfunction in PD[@smapd2024]:
- Reduced activation during self-initiated movements
- Impaired motor sequence learning
- Abnormal movement sequencing
- Connection to bradykinesia
The SMA is critical for:
- Internal motor generation
- Sequence planning
- Self-initiated movements
- Motor set maintenance[@supplementary]
Theta-burst stimulation (TBS) is a patterned rTMS protocol that more closely mimics natural brain activity compared to conventional rTMS[@huang2005]:
- Bursts: 3 pulses at 50 Hz
- Repetition: Bursts repeat every 200 ms (5 Hz, theta frequency)
- Duration: Continuous for 40 seconds (cTBS) or intermittent (iTBS)
cTBS produces:
- Long-term depression (LTD)-like effects: Reduces cortical excitability
- Synaptic depression: Alters GABAergic and glutamatergic transmission
- Network effects: Modulates distributed neural circuits
The protocol's efficiency makes it attractive:
- 600 pulses in 40 seconds vs. 1800+ pulses in 30 minutes for conventional rTMS
- Equivalent or greater physiological effects[@ctbs2019]
The supplementary motor area is a rational target for PD:
- Motor planning deficits: SMA dysfunction correlates with bradykinesia
- Direct projections: SMA connects to basal ganglia via cortico-striatal pathways
- Movement initiation: SMA activity precedes self-initiated movements
- Therapeutic window: Modulating SMA may improve initiation without affecting direct motor pathways
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 |
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
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 |
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 |
The Unified Parkinson's Disease Rating Scale Part III is the gold standard:
- 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)
- 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 |
The trial is conducted in China, which has advantages:
- Large PD patient population
- Established rTMS expertise
- Cost-effective research infrastructure
- Growing neuroscience research investment
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
This longitudinal design captures:
- Treatment durability
- Potential delayed effects
- Natural progression rates
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
Imaging Exclusion Criteria:
The trial excludes patients with "severe organic brain defects on imaging," which would include:
- Space-occupying lesions
- Significant vascular pathology
- Malformations
- Prior traumatic brain injury sequelae
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
SPECT Imaging:
- Dopamine transporter (DAT) imaging to confirm dopaminergic deficit
- Postsynaptic dopamine receptor imaging
Advanced imaging could enhance understanding of cTBS effects:
- Task-based fMRI: Assess SMA connectivity changes post-treatment
- Resting-state fMRI: Network-level effects on motor and cognitive circuits
- PET neurotransmission: Neurotransmitter system changes
- Diffusion tensor imaging: White matter integrity effects
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
cTBS Anti-inflammatory Potential:
Theta-burst stimulation may modulate neuroinflammation:
- Microglial modulation: Reduced pro-inflammatory microglial phenotype
- Cytokine regulation: Decreased peripheral inflammatory markers
- Neurotrophic effects: Increased BDNF expression
¶ 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
cTBS and BDNF:
- TMS protocols can increase BDNF expression
- May enhance neuroplasticity in PD patients
- Potential for long-term benefits
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
Facial Expression (0-4):
- 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
Tremor at Rest (0-4):
- 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
Rigidity (0-4):
- 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
Finger Taps (0-4):
- 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 |
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
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)
Rare Complications:
- Seizures (risk <0.1% with appropriate parameters)
- Transient cognitive effects
- Syncope (vasovagal)
Contraindications:
- Metal implants in head/neck
- Seizure history
- Pacemaker or other electronic devices
- Pregnancy (relative)
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
Safety Monitoring:
- Regular neurological examinations
- Adverse event collection
- Vital signs monitoring
Headache Management:
- Over-the-counter analgesics (acetaminophen, ibuprofen)
- Pre-stimulation hydration
- Adjust stimulation intensity if needed
Scalp Discomfort:
- Reposition coil slightly
- Reduce stimulation intensity
- Topical anesthetic application (if severe)
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
Design Considerations:
- 1:1 randomization provides equal statistical power for each arm
- Stratification by age ensures balance across groups
- Triple-blinding reduces assessment bias
Primary Analysis:
- Mixed-effects model for repeated measures (MMRM)
- Intention-to-treat population
- Missing data handled via appropriate methods
Secondary Analyses:
- Per-protocol analysis
- Subgroup analyses by age, disease duration, baseline severity
- Correlation with neuroimaging findings
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
Next-Generation Protocols:
- Personalized stimulation parameters
- Navigated TMS targeting
- Paired associative stimulation
- Closed-loop stimulation systems
cTBS could complement standard PD treatments:
With Medication:
- May allow dose reduction in responders
- Could extend "on" time
- Potential synergistic effects
With Rehabilitation:
- Combined with physical therapy
- Speech therapy integration
- Occupational therapy approaches
With Neuromodulation:
- Potential for hybrid approaches
- Combined with DBS programming
- Non-invasive alternative to surgery
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
Challenges:
- Variable regulatory oversight historically
- Need for international standardization
- Publication and data sharing practices
This trial exemplifies the globalization of clinical research:
- Data sharing: Results available internationally
- Regulatory convergence: Chinese data acceptable to global agencies
- Collaborative opportunities: International research partnerships
- Patient access: Global enrollment strategies
¶ Research Gaps and Future Questions
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?
Clinical Questions:
- Optimal stimulation parameters?
- Long-term durability of benefits?
- Which patients respond best?
Based on this trial's design and results:
- Biomarker integration: Neuroimaging, CSF, blood markers
- Genetics: Pharmacogenomics of TMS response
- Long-term studies: Multi-year follow-up
- Combination approaches: TMS + medication + rehabilitation
¶ 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
Patients Requiring Caution:
- Advanced disease with significant disability
- Significant cognitive impairment
- Psychiatric symptoms (depression, psychosis)
- Medical comorbidities affecting safety
For patients considering TMS:
Benefits:
- Non-invasive (no surgery)
- No medication side effects
- Minimal discomfort
- Potential for improvement
Considerations:
- Daily visits for 2 weeks
- Unknown long-term effects
- May not work for all patients
- Requires transportation to clinic
- Unknown, NCT06365190 - Effects of a Periodic Repetitive Transcranial Magnetic Stimulation in Parkinson Disease (n.d.)
- Huang YZ, et al., Theta burst stimulation of the human motor cortex. Neuron. 2005
- Supplementary motor area dysfunction in PD - Brain
- rTMS for Parkinson's disease - Movement Disorders
- cTBS protocols in neurological disorders - Clinical Neurophysiology (2019)
- Neurophysiological mechanisms of Parkinson's disease - Nature Reviews Neurology (2024)
- Supplementary motor area connectivity and motor dysfunction in Parkinson's disease - Brain (2024)
- Transcranial magnetic stimulation for Parkinson's disease: A systematic review and meta-analysis - Clinical Neurophysiology (2023)
- Basal ganglia-thalamocortical circuit dysfunction in Parkinson's disease - Brain (2024)
- Principal Investigator: WANG KAI
- Institution: Anhui Medical University, China
- Department: Department of Neurology & Medical Psychology, Cognitive Neuropsychology Lab
- Unknown, NCT06365190 - Effects of a Periodic Repetitive Transcranial Magnetic Stimulation in Parkinson Disease (n.d.)
- Huang YZ, et al., Theta burst stimulation of the human motor cortex. Neuron. 2005 (2005)
- Unknown, Supplementary motor area dysfunction in PD - Brain (n.d.)
- Unknown, rTMS for Parkinson's disease - Movement Disorders (n.d.)
- Unknown, cTBS protocols in neurological disorders - Clinical Neurophysiology (2019)