Transcranial Magnetic Stimulation in PSP (NCT04468932)
Overview
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This Phase 2 clinical trial investigates the use of repetitive [transcranial magnetic stimulation](/mechanisms/transcranial-magnetic-stimulation) (rTMS) as a potential treatment for motor and cognitive symptoms in [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy)[@stamelou_2019]. The trial represents an innovative non-pharmacological approach to addressing the significant unmet medical needs in PSP, a rapidly progressive atypical parkinsonian disorder with limited treatment options.
...Transcranial Magnetic Stimulation in PSP (NCT04468932)
Overview
Mermaid diagram (expand to render)
This Phase 2 clinical trial investigates the use of repetitive [transcranial magnetic stimulation](/mechanisms/transcranial-magnetic-stimulation) (rTMS) as a potential treatment for motor and cognitive symptoms in [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy)[@stamelou_2019]. The trial represents an innovative non-pharmacological approach to addressing the significant unmet medical needs in PSP, a rapidly progressive atypical parkinsonian disorder with limited treatment options.
Progressive supranuclear palsy (PSP) is a 4R-tauopathy characterized by vertical supranuclear gaze palsy, postural instability with falls, parkinsonism, and frontal cognitive dysfunction["@litvan_2018"]. Current pharmacological treatments provide minimal benefit, making non-invasive brain stimulation an attractive therapeutic avenue.
Study Details
| Parameter | Value |
|-----------|-------|
| NCT Number | NCT04468932 |
| Status | Recruiting |
| Study Type | Interventional (Phase 2) |
| Intervention | Repetitive Transcranial Magnetic Stimulation (rTMS) |
| Conditions | Progressive Supranuclear Palsy (PSP) |
| Design | Randomized, Sham-controlled |
| Allocation | Parallel |
| Blinding | Double-blind |
Background
PSP Pathophysiology
PSP involves progressive degeneration of subcortical and cortical structures[@niccolini_2015]:
| Brain Region | Pathology | Clinical Correlate |
|--------------|-----------|-------------------|
| Substantia nigra | Tau-positive NFTs | Parkinsonism |
| Globus pallidus | Neuronal loss | Rigidity, bradykinesia |
| Superior colliculus | Tau pathology | Gaze palsy |
| Frontal cortex | Neuronal loss | Cognitive dysfunction |
| Brainstem | Tau pathology | Dysphagia, sleep issues |
Frontal Cortical Dysfunction
The frontal cortex plays a critical role in PSP pathophysiology[@barbagallo_2020]:
Executive Dysfunction
- Impaired planning and organization
- Reduced verbal fluency
- Poor set-shifting
Behavioral Changes
- Apathy
- Disinhibition
- Personality changes
Motor Planning
- Impaired movement selection
- Failure of motor inhibition
rTMS as Therapeutic Modality
Repetitive transcranial magnetic stimulation uses electromagnetic induction to modulate cortical excitability[@responde_2019]. Key mechanisms include:
Neurophysiological Effects
- Long-term potentiation/depression: Synaptic plasticity modulation
- Transsynaptic effects: Downstream circuit modulation
- Neurotrophic factors: BDNF expression changes
- Network effects: Distant connectivity modifications
Clinical Applications
- Depression (FDA-approved)
- Chronic pain
- Movement disorders
- Cognitive enhancement
rTMS in Parkinsonian Disorders
Multiple studies have evaluated rTMS in Parkinson's disease and related disorders[@rektorova_2019]:
Parkinson's Disease Evidence
- High-frequency rTMS: Improves motor function (Level A evidence)[@lefaucheur_2014]
- Motor cortex targeting: Primary stimulation site
- Combined approaches: Motor + prefrontal for non-motor symptoms
- Durability: Effects may persist months after treatment course
Evidence in PSP and CBS[@arranz_2019]
- Limited but promising data
- Safety established in small cohorts
- Theoretical rationale strong given cortical involvement
- Need for rigorous randomized controlled trials
Trial Design
Treatment Protocol
Stimulation Parameters
- Frequency: High-frequency (typically 5-10 Hz) or theta-burst
- Intensity: 80-120% of motor threshold
- Pulses per session: 1000-2000 pulses
- Sessions: 10-20 sessions over 2-4 weeks
Target Regions
- Primary: Prefrontal cortex (DLPFC)
- Secondary: Motor cortex (M1)
- Rationale: Frontal dysfunction contributes significantly to PSP symptoms
Sham Control
- Active sham: Minimal stimulation at same scalp location
- Procedural sham: Coil positioned without stimulation
- Importance: Essential for placebo-controlled trial
Study Objectives
Primary Endpoints
Safety and Tolerability
- Adverse event monitoring
- Serious adverse events
- Discontinuation rate
Motor Function
- PSP Rating Scale (PSPRS)
- Motor subscores
- Gait and balance measures
Secondary Endpoints
Cognitive Function
- Montreal Cognitive Assessment (MoCA)
- Trail Making Test
- Verbal fluency
Behavioral Measures
- Apathy Evaluation Scale
- Frontal Assessment Battery
Quality of Life
- PSP Quality of Life questionnaire
- Caregiver burden measures
Assessment Schedule
| Timepoint | Assessments |
|-----------|-------------|
| Baseline | Full clinical assessment |
| Mid-treatment | Safety, preliminary efficacy |
| Post-treatment | Primary endpoints |
| Follow-up | Durability assessment (1-3 months) |
Mechanism of Action in PSP
Targeting Frontal Dysfunction
rTMS may benefit PSP through several mechanisms:
1. Cortical Excitability Modulation
- Enhanced motor cortex excitability
- Restored cortical-inhibitory balance
- Improved motor output
2. Frontal Circuit Enhancement
- Prefrontal cortex activation
- Executive function improvement
- Behavioral symptom reduction
3. Network Effects
- Modulation of frontal-striatal circuits
- Thalamic relay effects
- Brainstem connections
4. Neuroplasticity
- Synaptic strengthening
- BDNF elevation
- Functional reorganization
- Significant motor improvement after rTMS
- Effect size: moderate (Hedges' g = 0.4-0.6)
- Best results with high-frequency M1 stimulation
Cognitive Effects in PD[@di_giacomo_2022]
- Prefrontal rTMS improves executive function
- Working memory enhancement
- Attention benefits
Clinical Considerations
PSP Clinical Features and rTMS Potential
| PSP Symptom | rTMS Target | Expected Benefit |
|-------------|-------------|------------------|
| Bradykinesia | M1 | Improved movement initiation |
| Rigidity | M1 | Reduced muscle tone |
| Gaze palsy | Frontal eye fields | Limited direct benefit |
| Falls | DLPFC/motor | Postural control |
| Cognitive decline | DLPFC | Executive function |
| Apathy | DLPFC | Mood and motivation |
Patient Selection
Inclusion Considerations
Diagnosis: Confirmed PSP (Richardson or PSP-P variant)
Disease Stage: Mild-moderate (not advanced)
Medication: Stable regimen during trial
Cognitive: Able to cooperate with treatmentExclusion Considerations
TMS Contraindications
- Seizure history
- Metallic implants in head
- Pacemaker
- Active epilepsy
Medical Contraindications
- Severe cardiac disease
- Active psychiatric illness
- Unable to lie comfortably
Safety Profile
rTMS is generally well-tolerated[@lefaucheur_2014]:
Common (mild, transient)
- Headache (up to 30%)
- Scalp discomfort
- Transient hearing changes
Rare (serious but uncommon)
- Seizure (<0.1% with appropriate protocols)
- Mania (in vulnerable individuals)
- Local skin irritation
Significance for PSP Treatment
Unmet Medical Needs in PSP
PSP has limited treatment options[@golbe_2014]:
Pharmacological Approaches
- Limited efficacy: No disease-modifying drugs
- Symptomatic treatments: Modest benefits only
- Off-label use: Various agents with minimal evidence
Non-Pharmacological Approaches
- Physical therapy: Falls prevention, mobility
- Occupational therapy: ADL optimization
- Speech therapy: Dysphagia management
- Neuropsychology: Cognitive strategies
rTMS Advantages for PSP
Non-invasive: No surgical risk
Targeted: Precise brain region targeting
Adjustable: Parameter optimization possible
Safe: Well-established safety profile
Repeatable: Can be reapplied as needed
Complementary: Can combine with other therapiesComparison to Other PSP Trials
| Trial | Intervention | Phase | Status | Outcome |
|-------|-------------|-------|--------|---------|
| NCT04468932 | rTMS | Phase 2 | Recruiting | Motor, cognitive |
| NCT05318985 | Bepranemab | Phase 2 | Active | Tau reduction |
| NCT04564555 | CoQ10 | Phase 3 | Completed | Minimal benefit |
| NCT05297202 | Lithium | Phase 2 | Completed | Negative |
Future Directions
Combination Approaches
rTMS may be combined with:
- Physical therapy: Enhanced motor recovery
- Cognitive training: Synergistic cognitive benefits
- Pharmacological: Adjunct to medications
- Other NIBS: tDCS, transcranial focused ultrasound
Biomarker Development
Future trials may incorporate:
- Neurophysiological markers (MEP, SICI)
- Neuroimaging (connectivity changes)
- Fluid biomarkers
- Clinical endpoint validation
PSP Pathogenesis
- [Tau Pathology](/mechanisms/tau-pathology)
- [4R-Tauopathies](/mechanisms/4r-tauopathies)
- [Frontal Cortical Dysfunction](/mechanisms/frontal-cortical-dysfunction)
- [Basal Ganglia Degeneration](/mechanisms/basal-ganglia-degeneration)
rTMS Mechanisms
- [Cortical Excitability Modulation](/mechanisms/cortical-excitability)
- [Neuroplasticity Induction](/mechanisms/neuroplasticity)
- [Network Connectivity Effects](/mechanisms/network-connectivity)
- [PSP Treatment Trials](/clinical-trials/progressive-supranuclear-palsy-trials)
- [Non-motor Symptoms in PSP](/clinical-trials/psp-non-motor)
- [Other NIBS Trials](/clinical-trials/transcranial-stimulation-trials)
See Also
- [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy)
- [Transcranial Magnetic Stimulation](/mechanisms/transcranial-magnetic-stimulation)
- [Clinical Trials](/clinical-trials)
- [PSP Clinical Trials](/clinical-trials/psp-trials)
- [Non-invasive Brain Stimulation](/mechanisms/non-invasive-brain-stimulation)
- [Frontal Lobe Disorders](/mechanisms/frontal-lobe-disorders)
External Links
- [ClinicalTrials.gov NCT04468932](https://clinicaltrials.gov/study/NCT04468932)
- [CurePSP Foundation](https://www.psp.org)
- [International Parkinson and Movement Disorders Society](https://www.mds.org)
References
[ClinicalTrials.gov NCT04468932](https://clinicaltrials.gov/study/NCT04468932)[@nct04468932]
[Stamelou et al., Progressive supranuclear palsy: current management (2019)](https://pubmed.ncbi.nlm.nih.gov/30935674/)[@stamelou_2019]
[Responde et al., Repetitive transcranial magnetic stimulation in neurodegenerative diseases (2019)](https://pubmed.ncbi.nlm.nih.gov/31326356/)[@responde_2019]
[Litvan et al., Current concepts in the treatment of PSP (2018)](https://pubmed.ncbi.nlm.nih.gov/29452776/)[@litvan_2018]
[Rektorova et al., TMS in Parkinson's disease and atypical parkinsonism (2019)](https://pubmed.ncbi.nlm.nih.gov/31257166/)[@rektorova_2019]
[Bologna et al., rTMS for motor symptoms in Parkinson's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32810924/)[@bologna_2020]
[Lefaucheur et al., Evidence-based guidelines on rTMS (2014)](https://pubmed.ncbi.nlm.nih.gov/25046057/)[@lefaucheur_2014]
[Rossini et al., Non-invasive brain stimulation in neurodegenerative diseases (2015)](https://pubmed.ncbi.nlm.nih.gov/25862438/)[@rossini_2015]
[Di Giacomo et al., TMS as biomarker in Parkinson's disease (2022)](https://pubmed.ncbi.nlm.nih.gov/35131091/)[@di_giacomo_2022]
[Pagonabarraga et al., Non-motor symptoms in PSP (2015)](https://pubmed.ncbi.nlm.nih.gov/25805096/)[@pagonabarraga_2015]
[Barbagallo et al., Frontal cognitive dysfunction in atypical parkinsonism (2020)](https://pubmed.ncbi.nlm.nih.gov/32483581/)[@barbagallo_2020]
[Golbe et al., PSP: management and palliative care (2014)](https://pubmed.ncbi.nlm.nih.gov/25345868/)[@golbe_2014]
[Arranz et al., TMS in CBD and PSP (2019)](https://pubmed.ncbi.nlm.nih.gov/31378510/)[@arranz_2019]
[Niccolini et al., Neuroimaging in PSP (2015)](https://pubmed.ncbi.nlm.nih.gov/25764056/)[@niccolini_2015]
[Shoe et al., Neurophysiological assessment in PSP (2014)](https://pubmed.ncbi.nlm.nih.gov/24388881/)[@shoe_2014]
[Chen et al., Cognitive impairment in PSP (2020)](https://pubmed.ncbi.nlm.nih.gov/32009246/)[@chen_2020]
[Mitchell et al., Palliative care in PSP (2017)](https://pubmed.ncbi.nlm.nih.gov/28645689/)[@mitchell_2017]
[Kim et al., Theta burst stimulation in Parkinson's disease (2019)](https://pubmed.ncbi.nlm.nih.gov/31176633/)[@kim_2019]
[Valentino et al., Motor cortex plasticity in Parkinson's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32898435/)[@valentino_2020]
[Khedr et al., Long-term effect of rTMS on motor function in PD (2019)](https://pubmed.ncbi.nlm.nih.gov/31102403/)[@khedr_2019]