Increasing Brain Gamma Activity Improves Episodic Memory and Restores Cholinergic Dysfunction in Alzheimer's Disease

Abstract

Objective This study aimed to assess whether non‐invasive brain stimulation with transcranial alternating current stimulation at gamma‐frequency (γ‐tACS) applied over the precuneus can improve episodic memory and modulate cholinergic transmission by modulating cerebral rhythms in early Alzheimer's disease (AD). Methods In this randomized, double‐blind, sham controlled, crossover study, 60 AD patients underwent a clinical and neurophysiological evaluation including assessment of episodic memory and cholinergic transmission pre and post 60 minutes treatment with γ‐tACS targeting the precuneus or sham tACS. In a subset of 10 patients, EEG analysis and individualized modelling of electric field distribution were carried out. Predictors to γ‐tACS efficacy were evaluated. Results We observed a significant improvement in the Rey Auditory Verbal Learning (RAVL) test immediate recall (p < 0.001) and delayed recall scores (p < 0.001) after γ‐tACS but not after sham tACS. Face‐name associations scores improved with γ‐tACS (p < 0.001) but not after sham tACS. Short latency afferent inhibition, an indirect measure of cholinergic transmission, increased only after γ‐tACS (p < 0.001). ApoE genotype and baseline cognitive impairment were the best predictors of response to γ‐tACS. Clinical improvement correlated with the increase in gamma frequencies in posterior regions and with the amount of predicted electric field distribution in the precuneus. Interpretation Precuneus γ‐tACS, able to increase γ‐power activity on the posterior brain regions, showed a significant improvement of episodic memory performances, along with restoration of intracortical excitability measures of cholinergic transmission. Response to γ‐tACS was dependent on genetic factors and disease stage. ANN NEUROL 2022;92:322–334

Cognitive and Neuropathophysiological Outcomes of Gamma-tACS in Dementia: A Systematic Review

“…Authors replicated these findings in a subsequent study with a sample of mild AD patients (Benussi et al, 2022). Sixty patients assigned to the main study received 60 min of 40 Hz tACS and sham tACS one week apart targeting the precuneus.…”

“…These tests have been specifically developed to detect AD-related cognitive impairment. Two studies (Kehler et al, 2020;Moussavi et al, 2021) adopted the WMS to evaluate memory impairment, while other studies adopted the RAVLT and the FNAT (Benussi et al, 2021(Benussi et al, , 2022, the Reversal Motor Learning (Naro et al, 2016), and the Craft Story 21 Recall Immediate and Delayed (Sprugnoli et al, 2021;Bréchet et al, 2021) tested the efficacy and feasibility of a patient-tailored home-based tACS protocol. A personalized montage was defined by using tACS-induced electric field modeling.…”

“…AD patients reported a qualitative increase in the Memory Index Score (defined by the National Alzheimer's Coordinating Center) assessed every 2 weeks during the treatment. The studies from Benussi et al (2021Benussi et al ( , 2022 were the only that adopted two parallel versions of the RAVLT. To the best of our knowledge, no parallel versions are available for the ADAS-Cog, MMSE, and WMS.…”

“…One study comprised both MCI and AD patients. The outcomes were assessed offline (before and after tACS administration), except for two studies (Benussi et al, 2021(Benussi et al, , 2022, in which a cognitive task was administered during tACS and another immediately after. Five studies also assessed the feasibility of gamma-tACS treatment in terms of compliance (i.e., the number of participants that completed the study, or the dropout rate of the session), safety, and tolerability (self-reported serious and minor side effects, respectively).…”

Editorial: Recording and modulating neural activity in neurodegenerative diseases: Pathophysiological and therapeutic implications

“…This set the foundation for the translation of advanced therapeutic neuromodulation strategies that hold promise to optimize symptom control and potentially modify disease course in the future. In this Research Topic, we aimed to investigate the role of specific neurophysiological abnormalities in neurodegenerative diseases that serve as electrophysiological target for invasive and non-invasive neuromodulation techniques, such as deep brain stimulation (DBS; Tinkhauser et al, 2017 ; Bocci et al, 2021 ) and transcranial alternating current stimulation (tACS; Benussi et al, 2022 ; Guerra et al, 2022 ). Parkinson's disease (PD) is an exemplary condition for targeting brain oscillatory activities for therapeutic purposes.…”