Impact of multisession 40Hz tACS on hippocampal perfusion in patients with Alzheimer's disease

Giulia Sprugnoli, Fanny Munsch, Davide Cappon, Rachel Paciorek, Joanna Macone, Ann Connor, Georges El Fakhri, Ricardo Salvador, Giulio Ruffini, Kevin Donohoe, Mouhsin M Shafi, Daniel Press, David C Alsop, Alvaro Pascual Leone, Emiliano Santarnecchi, Giulia Sprugnoli, Fanny Munsch, Davide Cappon, Rachel Paciorek, Joanna Macone, Ann Connor, Georges El Fakhri, Ricardo Salvador, Giulio Ruffini, Kevin Donohoe, Mouhsin M Shafi, Daniel Press, David C Alsop, Alvaro Pascual Leone, Emiliano Santarnecchi

Abstract

Background: Alzheimer's disease (AD) is associated with alterations in cortical perfusion that correlate with cognitive impairment. Recently, neural activity in the gamma band has been identified as a driver of arteriolar vasomotion while, on the other hand, gamma activity induction on preclinical models of AD has been shown to promote protein clearance and cognitive protection.

Methods: In two open-label studies, we assessed the possibility to modulate cerebral perfusion in 15 mild to moderate AD participants via 40Hz (gamma) transcranial alternating current stimulation (tACS) administered 1 h daily for 2 or 4 weeks, primarily targeting the temporal lobe. Perfusion-sensitive MRI scans were acquired at baseline and right after the intervention, along with electrophysiological recording and cognitive assessments.

Results: No serious adverse effects were reported by any of the participants. Arterial spin labeling MRI revealed a significant increase in blood perfusion in the bilateral temporal lobes after the tACS treatment. Moreover, perfusion changes displayed a positive correlation with changes in episodic memory and spectral power changes in the gamma band.

Conclusions: Results suggest 40Hz tACS should be further investigated in larger placebo-controlled trials as a safe, non-invasive countermeasure to increase fast brain oscillatory activity and increase perfusion in critical brain areas in AD patients.

Trial registration: Studies were registered separately on ClinicalTrials.gov ( NCT03290326 , registered on September 21, 2017; NCT03412604 , registered on January 26, 2018).

Keywords: CBF; Cerebral blood flow; Dementia; EEG; Gamma activity; Gamma band; Hippocampus; Neuromodulation; Neurostimulation; tES.

Conflict of interest statement

DCA is the inventor of the pseudo-continuous ASL technique employed for perfusion MRI in this work. He receives post-market royalties through his institution from licenses to GE Healthcare, Philips Healthcare, Hitachi Medical, Siemens Healthineers, and UIH America. GR is co-founder of Neuroelectrics and RS is an employer. ES and APL are listed co-inventors on an issued patent on the use of tACS in AD. All other authors declare they have no competing interests.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Experimental protocol. A Study design and relevant pre-post tACS measures. Fifteen participants with mild to moderate dementia due to AD were enrolled in total (mean age 72 years, male = 9; MMSE = 23.53, SD = 3.35). Participants received 1 h of daily tACS for 2 or 4 weeks in hospital settings (Monday to Friday), with baseline (pre-tACS) and follow-up (post-tACS) assessments composed of cognitive and memory testing, EEG, and perfusion MRI (ASL) data. Participants underwent additional assessments pre/post tACS not reported in the present manuscript and beyond the scope of the present study, e.g. PET imaging for Aβ and p-tau, transcranial magnetic stimulation (TMS) measures, combined TMS-EEG recording, voice biomarkers recording, blood biomarkers. tACS was conducted targeting the normal component of the electric field either to the bilateral temporal lobes (bitemporal tACS hereafter) or unilateral (right) temporal and frontal lobes (temporo-frontal tACS hereafter), thus always impacting the right temporal lobe across all participants (corresponding to T8 on the 10/20 EEG system). Therefore, participants can be subdivided into three subgroups: (i) subjects receiving 2 weeks (10 sessions = 10h) of unilateral temporo-frontal tACS (Group 1; n=5); (ii) subjects receiving 2 weeks (10 sessions = 10h) of bitemporal tACS (Group 2; n=5); (iii) subjects receiving 4 weeks (20 sessions = 20h) of bitemporal tACS (Group 3; n=5). Common site of stimulation across montages was represented by the right temporal lobe. B On the left, normal electrical field (En-field) for representative subject receiving unilateral temporo-frontal tACS (Group 1), on the right En-field for participants receiving bilateral temporal lobe stimulation (Groups 2 and 3)
Fig. 2
Fig. 2
Perfusion results. A CBF increase after tACS. Paired t test (post>pre, p<0.05, FDR-corrected) revealed an increase of CBF selectively involving the right temporal lobe, representing the common site of stimulation across participants (n = 15). B Whole cortical brain CBF analyses of participants who received the highest dose of tACS (20h of bilateral temporal lobe stimulation over 4 weeks, n = 5, Group 3) revealed a selective increase in CBF in the bilateral temporal lobes, accordingly to the stimulation template (p<0.05, FDR-corrected). C Examples of CBF variations in two representative participants belonging to Group 2 (pt #8) and 3 (pt #14)
Fig. 3
Fig. 3
Comparison of CBF increases between tACS montages. A When looking at significant CBF increase after tACS in Group #1 of participants who received right temporo-frontal stimulation, a pattern of predominant right temporo-frontal CBF increases was found, matching with tACS targeting. B CBF increase in participants from Group #2 + #3 (n = 10) who received bilateral temporal lobe stimulation showed a significant increase of CBF predominantly localized in bilateral temporal regions
Fig. 4
Fig. 4
CBF changes, EEG results and correlations with cognition. A Changes in spectral power in the gamma band for a cluster of EEG electrodes indexing regions displaying post-tACS increase in perfusion (T8, P8, P7, T7; left panel) are reported, as well as for the electrode T8 (right panel) representing the common tACS electrode across all participants and the scalp electrode more proximal to the right anterior temporal lobe displaying the highest change in CBF post-tACS. B Spectral power changes in the narrow gamma band (38-42 Hz) detected on T8 significantly correlate with CBF changes in the right temporal lobe (left panel). Significant CBF variations also showed a significant correlation with variations in memory performance scores pre-post tACS. Specifically, CBF variation in the right temporal regions across all participants (n=15) positively correlated with performance changes at both paraphrase (mid panel) and verbatim (right panel) recollection components of an episodic memory task

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