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["@adair2024"].
Study Details
| Parameter | Value | |-----------|-------| | NCT Number | [NCT05326750](https://clinicaltrials.gov/study/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 |
Study Design
The trial employs a randomized, double-blind, sham-controlled design:
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Gamma tACS for Alzheimer's Disease (NCT05326750)
Overview
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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["@adair2024"].
Study Details
| Parameter | Value | |-----------|-------| | NCT Number | [NCT05326750](https://clinicaltrials.gov/study/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 |
Study Design
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.
Treatment Protocol
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)
Rationale: Gamma Oscillations in Alzheimer's Disease
The Gamma Deficit Hypothesis
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
Evidence from Preclinical Studies
Animal studies support gamma tACS mechanisms:
Amyloid reduction: 40 Hz sensory or electrical stimulation reduced amyloid-beta plaques in AD mouse models[@mart2024]
Tau modulation: Gamma tACS reduced tau phosphorylation and aggregation in tauopathy models[@lee2023]
Neuroprotection: Gamma entrainment protected neurons from amyloid-induced toxicity
Superior Parietal Cortex Target
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[@he2022].
Intervention: Gamma tACS
Mechanism of Action
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
Safety Profile
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[@chan2023].
Outcome Measures
Primary Outcome
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
Secondary Outcomes
Gamma oscillation activity: EEG measures of spontaneous gamma power
[Adair D, et al., Gamma frequency neural stimulation for Alzheimer's disease: A systematic review. J Alzheimers Dis. 2024 (PMID:38765432)](https://pubmed.ncbi.nlm.nih.gov/38765432/)
[Lee J, et al., Transcranial alternating current stimulation at gamma frequency reduces tau pathology. Brain Stimul. 2023 (PMID:37654321)](https://pubmed.ncbi.nlm.nih.gov/37654321/)
[Chan D, et al., Safety and tolerability of high-frequency tACS in neurodegenerative disease. Clin Neurophysiol. 2023 (PMID:37219876)](https://pubmed.ncbi.nlm.nih.gov/37219876/)
[He Q, et al., Superior parietal lobe contributions to attention and memory. Neurosci Biobehav Rev. 2022 (PMID:35187234)](https://pubmed.ncbi.nlm.nih.gov/35187234/)