Transcranial Magnetic Stimulation in Progressive Supranuclear Palsy

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Transcranial Magnetic Stimulation in Progressive Supranuclear Palsy

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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.

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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

Parkinson's Disease Meta-Analyses[@bologna_2020]

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 treatment

Exclusion 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 therapies

Comparison 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)

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]

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📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

100%

Debates

0

Incoming

34

Outgoing

38

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

Transcranial Magnetic Stimulation in Progressive Supranuclear Palsy

Transcranial Magnetic Stimulation in PSP (NCT04468932)

Overview

Transcranial Magnetic Stimulation in PSP (NCT04468932)

Overview

Study Details

Background

PSP Pathophysiology

Frontal Cortical Dysfunction

rTMS as Therapeutic Modality

Neurophysiological Effects

Clinical Applications

rTMS in Parkinsonian Disorders

Parkinson's Disease Evidence

Evidence in PSP and CBS[@arranz_2019]

Trial Design

Treatment Protocol

Stimulation Parameters

Target Regions

Sham Control

Study Objectives

Primary Endpoints

Secondary Endpoints

Assessment Schedule

Mechanism of Action in PSP

Targeting Frontal Dysfunction

1. Cortical Excitability Modulation

2. Frontal Circuit Enhancement

3. Network Effects

4. Neuroplasticity

Evidence from Related Conditions

Parkinson's Disease Meta-Analyses[@bologna_2020]

Cognitive Effects in PD[@di_giacomo_2022]

Clinical Considerations

PSP Clinical Features and rTMS Potential

Patient Selection

Inclusion Considerations

Exclusion Considerations

Safety Profile

Common (mild, transient)

Rare (serious but uncommon)

Significance for PSP Treatment

Unmet Medical Needs in PSP

Pharmacological Approaches

Non-Pharmacological Approaches

rTMS Advantages for PSP

Comparison to Other PSP Trials

Future Directions

Combination Approaches

Biomarker Development

Related Mechanisms and Pathways

PSP Pathogenesis

rTMS Mechanisms

Related Clinical Trials

See Also

External Links

References

💬 Discussion