NCT07138677: MCI Network Guided TMS for Early Alzheimer's Disease

Safety and Efficacy of MCI Network Guided TMS for Early Alzheimer's Disease

Overview

This clinical trial investigates the safety and efficacy of neuronavigated theta-burst transcranial magnetic stimulation (TMS) for patients with mild cognitive impairment (MCI) due to Alzheimer's disease or mild Alzheimer's disease dementia. The trial uses a personalized, network-guided approach to target specific brain regions based on individual functional connectivity patterns.

Trial Details

Safety and Efficacy of MCI Network Guided TMS for Early Alzheimer's Disease

Overview

This clinical trial investigates the safety and efficacy of neuronavigated theta-burst transcranial magnetic stimulation (TMS) for patients with mild cognitive impairment (MCI) due to Alzheimer's disease or mild Alzheimer's disease dementia. The trial uses a personalized, network-guided approach to target specific brain regions based on individual functional connectivity patterns.

Trial Details

| Parameter | Value |
|-----------|-------|
| NCT Number | NCT07138677 |
| Title | Safety and Efficacy of MCI Network Guided TMS for Early Alzheimer's Disease: A Randomized, Double-blind Trial (SENS-eAD) |
| Status | Recruiting |
| Phase | Not Applicable (Phase 2/3) |
| Sponsor | Anhui Medical University |
| Principal Investigator | WANG KAI |
| Enrollment | 40 participants (planned) |
| Start Date | 2024 |
| Location | Anhui Medical University, Hefei, Anhui, China |

Study Design

| Design Element | Details |
|----------------|---------|
| Type | Interventional |
| Allocation | Randomized (1:1 ratio) |
| Intervention Model | Parallel |
| Masking | Double-blind (Participant, Outcomes Assessor) |
| Purpose | Treatment |

Intervention Arms

TMS Group (Experimental)

Neuronavigated theta-burst stimulation using:

• Navigation System: BrainSight neuronavigation
• Device: MagStim Rapid2
• Protocol: Personalized based on individual MCI network connectivity
• Treatment Duration: 2 weeks

Control Group (Sham)

Sham stimulation using identical parameters but with inactive coil placement.

Mechanism of Action

Theta-Burst Stimulation

Theta-burst stimulation (TBS) is a patterned rTMS protocol that delivers bursts of high-frequency stimulation designed to efficiently induce neuroplastic changes[@huang2005]. The protocol:

MCI Network-Guided Targeting

This trial introduces a novel approach of personalizing TMS targets based on individual functional connectivity:

Rationale for TMS in Alzheimer's Disease

In Alzheimer's disease, cognitive decline involves:

• Network dysfunction: Disrupted functional connectivity in default mode network (DMN)
• Synaptic failure: Loss of synaptic plasticity and function
• Cortical hyperexcitability: Altered excitation-inhibition balance
• Neuroinflammation: Inflammatory processes affecting neural circuits

Eligibility Criteria

Inclusion Criteria

Exclusion Criteria

• Active depression or anxiety disorders
• History of psychosis

• History of stroke or significant vascular lesions
• Epilepsy or seizure history
• Other neurodegenerative conditions

• Metal implants in head/neck
• Pacemaker or electronic devices
• History of seizures

• Uncontrolled medical conditions
• Active substance abuse

Outcome Measures

Primary Outcomes

| Outcome | Assessment Timing |
|---------|-------------------|
| Alzheimer's Disease Assessment Scale Cognitive section (ADAS-Cog) | Baseline, Week 2 |

The ADAS-Cog is the gold standard for cognitive assessment in AD clinical trials, measuring:

• Word recall
• Naming objects/ fingers
• Commands
• Constructional praxis
• Ideational praxis
• Orientation
• Word recognition memory
• Spoken language ability
• Difficulty with language
• Number cancellation

Secondary Outcomes

| Outcome | Assessment Timing |
|---------|-------------------|
| Mini Mental State Examination (MMSE) | Baseline, Week 2 |
| Montreal Cognitive Assessment (MoCA) | Baseline, Week 2 |
| Digital Span Test (DST) | Baseline, Week 2 |
| Hamilton Depression Scale (HAMD-17) | Baseline, Week 2 |
| Hamilton Anxiety Scale (HAMA-14) | Baseline, Week 2 |
| Neuropsychiatric Inventory (NPI) | Baseline, Week 2 |
| Judgment of Line Orientation Test (JLOT) | Baseline, Week 2 |
| Hooper Visual Organization Test (HVOT) | Baseline, Week 2 |
| Stroop Color Word Test | Baseline, Week 2 |
| EEG | Baseline, Week 2 |
| Logic Memory Test (LMT) | Baseline, Week 2 |
| Pittsburgh Sleep Quality Index (PSQI) | Baseline, Week 2 |

Significance for Alzheimer's Disease

Current Treatment Limitations

Current AD therapies include:

• Cholinesterase inhibitors (donepezil, rivastigmine, galantamine)
• NMDA receptor antagonist (memantine)
• Disease-modifying therapies (lecanemab, donanemab) — recently approved

• Provide only symptomatic benefits
• Do not halt disease progression
• Have limited efficacy in moderate-to-severe stages

Potential Benefits of Network-Guided TMS

This novel approach offers several advantages:

Comparison with Other TMS Protocols for AD

| Protocol | Target | Evidence | Status |
|----------|--------|----------|--------|
| Network-guided TBS (this trial) | Personalized | Emerging | Recruiting |
| Standard high-frequency rTMS | DLPFC | Growing | Various |
| iTBS | Multiple | Moderate | Various |
| Sham | N/A | Control | N/A |

Neuroimaging and Target Selection

Functional Connectivity Analysis

The MCI network-guided approach uses baseline imaging to identify:

Personalized Target Selection

Based on individual connectivity patterns:

• Posterior cingulate cortex targets for DMN dysfunction
• Dorsolateral prefrontal cortex for executive deficits
• Angular gyrus for memory retrieval issues
• Precuneus for spatial memory impairments

Clinical Evidence for TMS in AD

Systematic Review Findings

Meta-analyses of TMS in AD and MCI show[@tmsmci2022]:

| Outcome | Effect | Confidence |
|---------|--------|------------|
| Cognitive function | Moderate improvement | Moderate |
| ADAS-Cog scores | Statistically significant improvement | Low-Moderate |
| MMSE scores | Variable effects | Low |
| Memory function | Small-to-moderate improvement | Low-Moderate |

Mechanisms Supporting TMS in AD

Safety Considerations

TMS Safety Profile

rTMS is generally safe with well-characterized risks:

Common side effects:

• Headache (20-35%)
• Scalp discomfort
• Transient mood changes

• Seizures (<0.1% with appropriate parameters)
• Transient cognitive effects
• Hearing changes (with inadequate protection)

Neuronavigation Benefits

Using BrainSight neuronavigation provides:

Statistical Considerations

Sample Size Justification

With 40 participants (20 per group):

Design:

• 80% power to detect medium effect size
• α = 0.05 (two-tailed)
• Intention-to-treat analysis

• Mixed-effects model for repeated measures
• Per-protocol sensitivity analysis
• Subgroup analyses by baseline severity

Research Context

Anhui Medical University TMS Program

Anhui Medical University, under WANG KAI's leadership, has established a significant TMS research program:

Prior work:

• NCT06365190: rTMS for Parkinson's disease
• Multiple PD and AD TMS studies
• Published network-guided approaches[@netad2024]

• BrainSight neuronavigation
• MagStim Rapid2 system
• Comprehensive cognitive assessment battery

China's Growing Role in TMS Research

China has become a major center for non-invasive brain stimulation research:

Advantages:

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

Future Directions

Potential Extensions

If successful, this trial could lead to:

Personalized Medicine Approach

This trial represents a move toward personalized neuromodulation:

Related Resources

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Transcranial Magnetic Stimulation](/mechanisms/transcranial-magnetic-stimulation)
• [Theta-Burst Stimulation](/mechanisms/theta-burst-stimulation)
• [Mild Cognitive Impairment](/diseases/mild-cognitive-impairment)
• [Default Mode Network](/mechanisms/default-mode-network)
• [Non-Invasive Brain Stimulation](/mechanisms/non-invasive-brain-stimulation)
• [Anhui Medical University](/institutions/anhui-medical-university)

External Links

• [ClinicalTrials.gov Record](https://clinicaltrials.gov/study/NCT07138677)
• [PubMed Search](https://pubmed.ncbi.nlm.nih.gov/?term=NCT07138677)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving NCT07138677: MCI Network Guided TMS for Early Alzheimer's Disease discovered through SciDEX knowledge graph analysis: