TRanscranial AlterNating current stimulation FOR patients with mild Alzheimer's Disease (TRANSFORM-AD): a randomized controlled clinical trial

Abstract

Background: The mechanistic effects of gamma transcranial alternating current stimulation (tACS) on hippocampal gamma oscillation activity in Alzheimer's Disease (AD) remains unclear. This study aimed to clarify beneficial effects of gamma tACS on cognitive functioning in AD and to elucidate effects on hippocampal gamma oscillation activity.

Methods: This is a double-blind, randomized controlled single-center trial. Participants with mild AD were randomized to tACS group or sham group, and underwent 30 one-hour sessions of either 40 Hz tACS or sham stimulation over consecutive 15 days. Cognitive functioning, structural magnetic resonance imaging (MRI), and simultaneous electroencephalography-functional MRI (EEG-fMRI) were evaluated at baseline, the end of the intervention and at 3-month follow-up from the randomization.

Results: A total of 46 patients were enrolled (23 in the tACS group, 23 in the sham group). There were no group differences in the change of the primary outcome, 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog) score after intervention (group*time, p = 0.449). For secondary outcomes, compared to the control group, the intervention group showed significant improvement in MMSE (group*time, p = 0.041) and MoCA scores (non-parametric test, p = 0.025), which were not sustained at 3-month follow-up. We found an enhancement of theta-gamma coupling in the hippocampus, which was positively correlated with improvements of MMSE score and delayed recall. Additionally, fMRI revealed increase of the local neural activity in the hippocampus.

Conclusion: Effects on the enhancement of theta-gamma coupling and neural activity within the hippocampus suggest mechanistic models for potential therapeutic mechanisms of tACS.

Trial registration: ClinicalTrials.gov, NCT03920826; Registration Date: 2019-04-19.

Keywords: Alzheimer’s disease; Gamma oscillation; Hippocampus; Theta-gamma coupling; Transcranial alternating current stimulation.

Fig. 1

Increase of gamma power in EEG channels from baseline to the end of the intervention. (a) The distribution of the gamma power change in the sham group and the tACS group is shown. Channels are grouped into four regions: left frontal, right frontal, left posterior, and right posterior regions, shown by the dotted lines. (b) The change of gamma power in both tACS group and sham group are presented. Error bars represent the 95% confidence interval * uncorrected p < 0.05. Those results were not significant after false discovery rate correction

Fig. 2

The flowchart of our study

Fig. 3

EEG source signals in the hippocampus. Due to data quality issue, only a part of the participants was included in the EEG analysis (n = 34). (a) The changes of theta-gamma coupling from baseline to the end of the intervention were contrasted between the tACS group (n = 16) and the sham group (n = 18). The results are displayed for the left and right hippocampus within the range of theta phase (4–8 Hz) and gamma power (30–50 Hz). (b) A statistically significant correlation was observed between the change of theta-gamma coupling at 5.5–41.5 Hz and the change of MMSE (left, n = 34). There was also a statistically significant correlation between the theta-gamma coupling at 6.5–30 Hz and the delayed recall score in the tACS group (n = 16) at the end of intervention (right) TGC, theta-gamma coupling

Fig. 4

The changes of fMRI outcomes. (a) The changes of fALFF in the left and right hippocampus in the tACS group. (b) The changes of coefficients derived from regression of hippocampus BOLD signals by gamma power fluctuation in PO8 channel in the tACS group. fALFF, fractional amplitude of low-frequency fluctuation * p < 0.05