Exposure to gamma tACS in Alzheimer's disease: A randomized, double-blind, sham-controlled, crossover, pilot study.

Objective: To assess whether exposure to non-invasive brain stimulation with transcranial alternating current stimulation at γ frequency (γ-tACS) applied over Pz (an area overlying the medial parietal cortex and the precuneus) can improve memory and modulate cholinergic transmission in mild cognitive impairment due to Alzheimer's disease (MCI-AD).
Methods: In this randomized, double-blind, sham controlled, crossover pilot study, participants were assigned to a single 60 min treatment with exposure to γ-tACS over Pz or sham tACS. Each subject underwent a clinical evaluation including assessment of episodic memory pre- and post-γ-tACS or sham stimulation. Indirect measures of cholinergic transmission evaluated using transcranial magnetic stimulation (TMS) pre- and post-γ-tACS or sham tACS were evaluated.
Results: Twenty MCI-AD participants completed the study. No tACS-related side effects were observed, and the intervention was well tolerated in all participants. We observed a significant improvement at the Rey auditory verbal learning (RAVL) test total recall (5.7 [95% CI, 4.0 to 7.4], p < 0.001) and long delayed recall scores (1.3 [95% CI, 0.4 to 2.1], p = 0.007) after γ-tACS but not after sham tACS. Face-name associations scores improved during γ-tACS (4.3 [95% CI, 2.8 to 5.8], p < 0.001) but not after sham tACS. Short latency afferent inhibition, an indirect measure of cholinergic transmission evaluated with TMS, increased only after γ-tACS (0.31 [95% CI, 0.24 to 0.38], p < 0.001) but not after sham tACS.
Conclusions: exposure to γ-tACS over Pz showed a significant improvement of memory performances, along with restoration of intracortical connectivity measures of cholinergic neurotransmission, compared to sham tACS.
Competing Interests: Declaration of competing interest Alberto Benussi, MD was partially supported by the Airalzh-AGYR2020; and is listed as an inventor on issued and pending patents on the use of non-invasive brain stimulation for the differential diagnosis of dementia and to increase cognitive functions in patients with neurodegenerative disorders. Maria Sofia Cotelli, MD received financial support by the Italian Ministry of Health (Ricerca Corrente). Emiliano Santarnecchi, PsyD, PhD: is consultant for Neuroelectrics and Neurocare Group Italy. Alvaro Pascual-Leone, MD, PhD is a co-founder of Linus Health and TI Solutions AG; serves on the scientific advisory boards for Starlab Neuroscience, Neuroelectrics, Magstim Inc., Nexstim, Cognito, and MedRhythms; and is listed as an inventor on several issued and pending patents on the real-time integration of noninvasive brain stimulation with electroencephalography and magnetic resonance imaging. Dr. Pascual-Leone was partly supported by the National Institutes of Health (R01MH100186, R21AG051846, R01MH111875, R01MH115949, R01 MH117063, R24AG06142, and P01 AG031720), the National Science Foundation, DARPA, and the Barcelona Brain Health Initiative (La Caixa and Institute Guttmann). Barbara Borroni, MD, is listed as an inventor on issued and pending patents on the use of non-invasive brain stimulation for the differential diagnosis of dementia and to increase cognitive functions in patients with neurodegenerative disorders. Valentina Cantoni, MS, Maria Cotelli, PhD, Chiara Brattini, MS, Abhishek Datta, PhD, Chris Thomas, BS, report no disclosures.
(Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)