Impact of 40 Hz Transcranial Alternating Current Stimulation on Cerebral Tau Burden in Patients with Alzheimer's Disease: A Case Series

Abstract

Background: Alzheimer's disease (AD) is characterized by diffuse amyloid-β (Aβ) and phosphorylated Tau (p-Tau) aggregates as well as neuroinflammation. Exogenously-induced 40 Hz gamma oscillations have been showing to reduce Aβ and p-Tau deposition presumably via microglia activation in AD mouse models.

Objective: We aimed to translate preclinical data on gamma-induction in AD patients by means of transcranial alternating current stimulation (tACS).

Methods: Four participants with mild-to-moderate AD received 1 h of daily 40 Hz (gamma) tACS for 4 weeks (Monday to Friday) targeting the bitemporal lobes (20 h treatment duration). Participant underwent Aβ, p-Tau, and microglia PET imaging with [11C]-PiB, [18F]-FTP, and [11C]-PBR28 respectively, before and after the intervention along with electrophysiological assessment.

Results: No adverse events were reported, and an increase in gamma spectral power on EEG was observed after the treatment. [18F]-FTP PET revealed a significant decrease over 2% of p-Tau burden in 3/4 patients following the tACS treatment, primarily involving the temporal lobe regions targeted by tACS and especially mesial regions (e.g., entorhinal cortex). The amount of intracerebral Aβ as measured by [11C]-PiB was not significantly influenced by tACS, whereas 1/4 reported a significant decrease of microglia activation as measured by [11C]-PBR28.

Conclusion: tACS seems to represent a safe and feasible option for gamma induction in AD patients, with preliminary evidence of a possible effect on protein clearance partially mimicking what is observed in animal models. Longer interventions and placebo control conditions are needed to fully evaluate the potential for tACS to slow disease progression.

Keywords: Amyloid; dementia; electroencephalography; gamma; neurostimulation; positron-emission tomography; protein clearance; protein misfolding; tau; transcranial electrical stimulation.

Figures

Fig. 1.

Study Design. A) A simplified conceptual framework of the neuropathophysiology of AD is shown, describing the potential cascade involving interneuron dysfunction, altered excitation/inhibition balance, alterations of brain rhythms, neuroinflammatory response and protein accumulation. B) An attempt to map the different levels of the model directly in AD patients was made in the study design, with repeated EEG, amyloid-β, p-Tau and microglia PET imaging before and after the tACS treatment course. Neuroimaging and cognitive data were collected as well. Biophysical modeling displays the focus on bilateral temporal lobes and the resulting induced electrical field closely resembling p-Tau and amyloid-β accumulation.

Fig. 2.

tACS targets and SUVr parametric images for all participants. Axial and coronal views of the normal electric field induced by tACS in each participant are reported (yellow, En > 0.25 V/m on the structural MRI for anatomical reference), showing the tACS field affecting primarily the bilateral temporal lobes (left). Individual sagittal and coronal views of SUVr maps of [11C]-PiB, [18F]-FTP and [11C]-PBR28 data collected at baseline for each patient are shown, displaying high levels of amyloid-β in all the participants, as well as significant p-Tau accumulation and signs of neuroinflammation (white arrows) in the bilateral temporal lobes, thalamus and parietal regions. Note: images are shown in radiological convention.

Fig. 3.

Results. A) Participants reported a trend for an increase in spectral power of gamma oscillations, with a stronger effect for activity around the stimulation frequency (i.e., stim γ at 38–42 Hz). B) Daily EEG recordings before and after each tACS session showed an incremental effect of gamma spectral power over the stimulation electrodes placed on the temporal lobes (T8, P8, T7, P7), and no apparent changes in control electrodes indexing activity in frontal (Afz, F1, F2) and centro-parietal (C3, C4, Pz) regions. C) Delta SUVr between baseline and follow up are reported for the three PET tracers and specifically for SUVr values extracted from the individual tACS stimulation maps based on biophysical modeling (yellow, stimulation higher than 0.25 V/m). A significant (>1.98%) change in p-Tau deposition was observed for 3 patients (#2, #3, #4), as well as a decrease in microglia activation after tACS for patient #2. D) Individual data for participant #2, #3, and #4 showing example regions of putative change in p-Tau and microglia SUVr after tACS.