¶ Safety and Efficacy of MCI Network Guided TMS for Early Alzheimer's Disease
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.
| 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 |
| Design Element |
Details |
| Type |
Interventional |
| Allocation |
Randomized (1:1 ratio) |
| Intervention Model |
Parallel |
| Masking |
Double-blind (Participant, Outcomes Assessor) |
| Purpose |
Treatment |
Neuronavigated theta-burst stimulation using:
- Navigation System: BrainSight neuronavigation
- Device: MagStim Rapid2
- Protocol: Personalized based on individual MCI network connectivity
- Treatment Duration: 2 weeks
Sham stimulation using identical parameters but with inactive coil placement.
Theta-burst stimulation (TBS) is a patterned rTMS protocol that delivers bursts of high-frequency stimulation designed to efficiently induce neuroplastic changes. The protocol:
- Burst pattern: Three pulses at 50 Hz, repeated every 200 ms (5 Hz)
- Continuous TBS (cTBS): Continuous delivery for ~40 seconds
- Neuroplastic effect: Modulates cortical excitability and synaptic plasticity
This trial introduces a novel approach of personalizing TMS targets based on individual functional connectivity:
- Baseline imaging: fMRI or functional connectivity analysis to identify individual's MCI-related network dysfunction
- Personalized targets: Stimulation sites selected based on the most significant network impairments
- Network modulation: Goals are to restore normal connectivity patterns in memory and cognitive networks
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
TBS may improve cognitive function by:
- Modulating cortical excitability: Restoring normal excitation-inhibition balance
- Enhancing neuroplasticity: Facilitating LTP-like synaptic changes
- Reducing network dysfunction: Improving functional connectivity in targeted networks
- Anti-inflammatory effects: Potentially modulating neuroinflammatory responses
- Diagnosis: Mild cognitive impairment due to AD or mild AD dementia
- Cognitive score: MMSE score 18-28
- Clinical rating: CDR score 0.5-1
- Age: 45-85 years
- Medication: Stable on cholinesterase inhibitors or memantine for ≥6 months
- Capacity: Able to provide informed consent
-
Psychiatric
- Active depression or anxiety disorders
- History of psychosis
-
Neurological
- History of stroke or significant vascular lesions
- Epilepsy or seizure history
- Other neurodegenerative conditions
-
TMS Contraindications
- Metal implants in head/neck
- Pacemaker or electronic devices
- History of seizures
-
Medical
- Uncontrolled medical conditions
- Active substance abuse
| 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
| 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 |
Current AD therapies include:
However, these treatments:
- Provide only symptomatic benefits
- Do not halt disease progression
- Have limited efficacy in moderate-to-severe stages
This novel approach offers several advantages:
- Personalized treatment — targets individual network dysfunction
- Network-level effects — modulates distributed brain circuits
- Non-invasive — no surgical risk
- Disease-modifying potential — may alter disease trajectory
- Combination potential — can be combined with existing therapies
| 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
The MCI network-guided approach uses baseline imaging to identify:
- Default Mode Network (DMN) abnormalities
- Frontoparietal network dysfunction
- Memory network impairment
- Salience network alterations
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
Meta-analyses of TMS in AD and MCI show:
| 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 |
- Synaptic plasticity: Enhanced LTP-like effects
- Neural connectivity: Improved functional connectivity
- Neurotrophic factors: Increased BDNF expression
- Network normalization: Restored network dynamics
- Anti-inflammatory: Modulated microglial activation
rTMS is generally safe with well-characterized risks:
Common side effects:
- Headache (20-35%)
- Scalp discomfort
- Transient mood changes
Rare complications:
- Seizures (<0.1% with appropriate parameters)
- Transient cognitive effects
- Hearing changes (with inadequate protection)
Using BrainSight neuronavigation provides:
- Precise targeting: Sub-millimeter accuracy
- Consistent dose delivery: Real-time coil positioning
- Personalization: Individual anatomy integration
- Safety: Avoidance of critical structures
With 40 participants (20 per group):
Design:
- 80% power to detect medium effect size
- α = 0.05 (two-tailed)
- Intention-to-treat analysis
Analysis plan:
- Mixed-effects model for repeated measures
- Per-protocol sensitivity analysis
- Subgroup analyses by baseline severity
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
Infrastructure:
- BrainSight neuronavigation
- MagStim Rapid2 system
- Comprehensive cognitive assessment battery
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
If successful, this trial could lead to:
- Larger confirmatory trials (Phase 3)
- Combination protocols with existing AD medications
- Biomarker integration for patient selection
- Maintenance protocols for long-term benefit
- Earlier intervention studies in preclinical AD
This trial represents a move toward personalized neuromodulation:
- Network-based targeting: Functional connectivity guides target selection
- Individualized parameters: Dose based on individual response
- Predictive biomarkers: Identifying who responds best
- Adaptive protocols: Real-time adjustment based on monitoring