This Phase 2 clinical trial at Kuopio University Hospital in Finland investigates whether 40 Hz gamma-frequency transcranial alternating current stimulation (tACS) delivered over the superior parietal cortex can improve cognitive function in patients with Alzheimer's Disease. The study aims to enroll 200 participants, making it one of the larger non-invasive neuromodulation trials for AD to date.
Gamma tACS is based on the hypothesis that impaired gamma oscillations (30-100 Hz) in the brains of AD patients contribute to cognitive deficits, and that externally applied gamma-frequency stimulation can restore normal neural activity patterns.
| Parameter |
Value |
| NCT Number |
NCT05326750 |
| Status |
Recruiting |
| Sponsor |
Kuopio University Hospital |
| Phase |
Phase 2 |
| Study Type |
Interventional |
| Design |
Randomized, Double-Blind, Sham-Controlled |
| Enrollment |
200 participants (estimated) |
| Start Date |
2023 |
| Estimated Completion |
2026 |
| Location |
Kuopio University Hospital, Kuopio, Finland |
The trial employs a randomized, double-blind, sham-controlled design:
- Active Stimulation Group — 40 Hz tACS over superior parietal cortex
- Sham Control Group — Identical electrode placement with no active stimulation
Participants are randomized 1:1 to active or sham groups. The primary endpoint is change in cognitive performance after the treatment period. Both participants and assessors are blinded to group assignment.
- Stimulation Frequency: 40 Hz (gamma band)
- Target Region: Superior parietal cortex
- Session Duration: 30 minutes per session
- Treatment Period: Daily sessions for 4 weeks (20 sessions total)
- Follow-up: Assessments at 4 weeks (post-treatment) and 12 weeks (follow-up)
Gamma oscillations (30-100 Hz) are critical for:
- Attention and perception: Gamma activity synchronizes neural populations for sensory integration
- Memory formation: Hippocampal gamma coordinates information transfer during encoding
- Cognitive processing: Working memory tasks elicit robust gamma responses
In Alzheimer's Disease, gamma oscillations are disrupted:
- Reduced gamma power observed in AD patients during cognitive tasks
- Impaired gamma synchronization correlates with memory deficits
- Animal models show gamma activity reduction precedes cognitive decline
The gamma entrainment hypothesis suggests that external 40 Hz stimulation can:
- Restore deficient gamma oscillations
- Improve neural circuit function
- Enhance cognitive performance
Animal studies support gamma tACS mechanisms:
- Amyloid reduction: 40 Hz sensory or electrical stimulation reduced amyloid-beta plaques in AD mouse models
- Tau modulation: Gamma tACS reduced tau phosphorylation and aggregation in tauopathy models
- Microglial activation: 40 Hz stimulation enhanced microglial clearance of pathological proteins
- Neuroprotection: Gamma entrainment protected neurons from amyloid-induced toxicity
The superior parietal cortex was selected as the stimulation target because:
- Attention networks: The superior parietal lobule is central to attentional networks that are impaired in AD
- Memory integration: This region integrates information from multiple sensory modalities during memory tasks
- Default mode network: The superior parietal region is part of the default mode network, disrupted in AD
- Accessibility: The location is accessible for non-invasive stimulation with good spatial resolution
Research has demonstrated that the superior parietal cortex shows early hypometabolism and atrophy in AD, making it a rational target for neuromodulation.
tACS delivers alternating current through electrodes on the scalp. At gamma frequency (40 Hz):
- Entrainment: Neural populations synchronously oscillate at the stimulation frequency
- Network reset: Periodic stimulation phases may reset dysfunctional network activity
- Plasticity enhancement: Prolonged gamma stimulation may promote long-term potentiation
- Anti-inflammatory effects: Gamma stimulation may modulate microglial activity
Previous studies have established tACS safety:
- No serious adverse events in published trials
- Common side effects: mild tingling, itching at electrode sites
- Unlike tDCS, tACS does not cause直流极化 effects
- Suitable for repeated administrations
A systematic review confirmed the favorable safety profile of high-frequency tACS in neurodegenerative populations.
- Cognitive Function: Change from baseline in comprehensive neuropsychological battery
- Montreal Cognitive Assessment (MoCA)
- Rey Auditory Verbal Learning Test (RAVLT)
- Trail Making Test A and B
- Digit Symbol Substitution Test
- Gamma oscillation activity: EEG measures of spontaneous gamma power
- Functional connectivity: Resting-state fMRI connectivity patterns
- Quality of life: Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL)
- Biomarkers: CSF and blood-based AD biomarkers (optional substudy)
- Adverse event monitoring
- Electroencephalogram (EEG) before and after treatment
- Cognitive side effect monitoring
- Diagnosis of Alzheimer's Disease (NIA-AA criteria)
- Mild to moderate disease severity (MMSE 18-26)
- Age 55-85 years
- Stable AD medication for at least 4 weeks
- Ability to attend daily treatment sessions
- Informed consent from participant or legally authorized representative
- Other neurological disorders (stroke, Parkinson's, epilepsy)
- Severe psychiatric conditions (major depression, psychosis)
- Metal implants in the head (non-MRI compatible implants)
- History of seizures
- Uncontrolled medical conditions
- Current participation in other clinical trials
If successful, this trial could establish:
- Novel therapeutic approach: Non-invasive gamma tACS as a disease-modifying intervention
- Mechanistic validation: Evidence that gamma entrainment improves AD pathology
- Combination potential: Integration with existing AD medications
- Home-based feasibility: Potential for at-home maintenance stimulation
| Trial |
Method |
Target |
Status |
| NCT05326750 |
tACS (40 Hz) |
Superior parietal cortex |
Recruiting |
| NCT06295458 |
Sensory flicker |
Visual cortex |
Recruiting |
| Various |
Sensory stimulation |
Auditory/visual |
Completed |
Gamma tACS research extends to: