Memory Enhancement Using Transcranial Alternating Current Stimulation (Memento)

The 32 million Alzheimer's disease (AD) and 69 million prodromal AD patients worldwide contribute to a large economic burden. Effective and safe therapies that slow or prevent the progression from mild cognitive impairment (MCI) to AD are therefore of high priority. Transcranial alternating current stimulation (tACS) is a safe and patient-friendly non-invasive brain stimulation technique that serves as a potential candidate for reducing and/or slowing cognitive impairment. Application of tACS in the gamma frequency range, specifically around 40 Hz, has been studied in patients with AD and MCI due to AD. In these patients, a single session of 40 Hz tACS at the precuneus showed to improve episodic memory and to increase gamma power, as measured with electroencephalography. These findings will be replicated in the current study in patients with MCI due to AD, using magnetoencephalography (MEG) recorded before, during and after tACS. In this way, brain activity and network changes that underlie this improvement in episodic memory can be studied with greater temporal and spatial detail.

Study Overview

• Status: Completed
• Conditions: Alzheimer Disease; Mild Cognitive Impairment
• Intervention / Treatment: Device: Sham tACS at the precuneus region; Device: Gamma (40 Hz) tACS at the precuneus region

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • North Holland
    • Amsterdam, North Holland, Netherlands, 1081HV
      • Amsterdam UMC, The Netherlands

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Recent (not more than 6 months ago) amnestic MCI diagnosis, which consensus is obtained in a multidisciplinary meeting after an extended multidisciplinary test battery at the memory clinic, including confirmation of AD pathology with cerebrospinal fluid biomarkers: abnormal p-tau/Aβ42 ratio of > 0.023

Exclusion Criteria:

• Suffering from serious neurological, psychiatric or somatic comorbidity
• Suffering from epileptic seizures or severe claustrophobia
• Intensive use of psychoactive medication
• Having a cardiac pacemaker, internal cardiac defibrillator or other intracorporeal device that interferes with MEG recordings

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active tACS; Gamma (40 Hz) tACS at the precuneus region	Device: Gamma (40 Hz) tACS at the precuneus region; 40 Hz tACS applied at a current of 3.2 milliampere peak-to-peak using a NuroStym transcranial electrical stimulation (tES) system of NeuroDevice for four times 12 minutes (48 minutes in total) at the Pz (according to the 10-20 international EEG coordinates)
Sham Comparator: Sham tACS; Sham tACS at the precuneus region	Device: Sham tACS at the precuneus region; Sham tACS applied with no effective stimulation between the ramp-up and ramp-down of the current using a NuroStym tES system of NeuroDevice for four times 12 minutes (48 minutes in total) at the Pz (according to the 10-20 international EEG coordinates)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Rey Auditory Verbal Learning test scores	The Rey Auditory Verbal Learning (RAVL) test evaluates verbal episodic memory and is designed as a list-learning paradigm in which the subject hears a list of 15 nouns. The participant is asked to recall as many words from the list as possible after each of 5 repetitions of free-recall (total recall), and 15 minutes after an interference trial (long delayed recall). Scores range from 0 to 75 (total recall) and 0 to 15 (long delayed recall), with higher scores meaning a better outcome. An increase in RAVL test (total and long delayed recall) after active but not sham tACS is expected.	Immediately before and after intervention
Change in Face-Name Association Task scores	The Face-Name Association Task assesses associative episodic memory and is a computer paradigm consisting of an encoding and a retrieval phase of face-name pairs. During the encoding phase, participants are instructed to remember a set of 12 faces and names they are paired. In two additional learning trials, participants are shown the previously learned faces and are asked to recall the correct name associated with each face (inital recognition). This recall of the correct name associated with a learned face is repeated 5 minutes after the learning trials during the retrieval phase (associative recognition). Scores range from 0 to 24 (inital recognition) and 0 to 12 (associative recognition), with higher scores meaning a better outcome. An increase in FNAT score (initial and associative recognition) after active but not sham tACS is expected.	Immediately before and after intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in spectral source space resting-state MEG (relative power)	Change in relative power will be used, expecting an increase in relative power in higher alpha, beta and gamma bands and decrease in relative power in theta band after active but not sham tACS.	Immediately before and after intervention
Change in spectral source space resting-state MEG (posterior peak frequency)	Change in posterior peak frequency will be used, expecting an increase in posterior peak frequency after active but not sham tACS.	Immediately before and after intervention
Change in functional connectivity source space resting-state MEG (AEC-c)	Change in corrected amplitude envelope correlation (AEC-c) will be used, expecting an increase in AEC-c in higher alpha, beta and gamma bands after active but not sham tACS.	Immediately before and after intervention
Change in functional connectivity source space resting-state MEG (PLI)	Change in phase lag index (PLI) will be used, expecting a decrease in PLI in theta band after active but not sham tACS.	Immediately before and after intervention
Change in source space resting-state MEG network structure (MST variables)	Change in graph theory parameters will be used as a measure of global network structure. Restoration of overall network configuration (expressed by shift of multiple Minimum spanning tree (MST) parameters towards healthy state, e.g. stronger hierarchy) after active but not sham tACS is expected.	Immediately before and after intervention
Change in source space resting-state MEG network structure (clustering coefficient and path length)	Change in graph theory parameters will be used as a measure of global network structure. Preserved small-world configuration (shift of small world index (clustering coefficient/path length) towards less random topology) after active but not sham tACS is expected.	Immediately before and after intervention
Change in source space resting-state MEG network structure (modulatory index, degree and eigenvector centrality)	Change in graph theory parameters will be used as a measure of mesoscale network structure (modularory measures) and nodal characteristics (degree and eigenvector centrality). Restoration of hub disruption (stronger modularity index, increase in degree and eigenvector centrality) of precuneus-posterior cingulate and medial temporal lobe after active but not sham tACS is expected.	Immediately before and after intervention

Collaborators and Investigators

• Sponsor: Amsterdam UMC, location VUmc
• Investigators: Principal Investigator: Willem de Haan, dr., Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Publications and helpful links

General Publications

• Benussi A, Cantoni V, Cotelli MS, Cotelli M, Brattini C, Datta A, Thomas C, Santarnecchi E, Pascual-Leone A, Borroni B. Exposure to gamma tACS in Alzheimer's disease: A randomized, double-blind, sham-controlled, crossover, pilot study. Brain Stimul. 2021 May-Jun;14(3):531-540. doi: 10.1016/j.brs.2021.03.007. Epub 2021 Mar 21.
• Benussi A, Cantoni V, Grassi M, Brechet L, Michel CM, Datta A, Thomas C, Gazzina S, Cotelli MS, Bianchi M, Premi E, Gadola Y, Cotelli M, Pengo M, Perrone F, Scolaro M, Archetti S, Solje E, Padovani A, Pascual-Leone A, Borroni B. Increasing Brain Gamma Activity Improves Episodic Memory and Restores Cholinergic Dysfunction in Alzheimer's Disease. Ann Neurol. 2022 Aug;92(2):322-334. doi: 10.1002/ana.26411. Epub 2022 Jun 6.
• Grover S, Fayzullina R, Bullard BM, Levina V, Reinhart RMG. A meta-analysis suggests that tACS improves cognition in healthy, aging, and psychiatric populations. Sci Transl Med. 2023 May 24;15(697):eabo2044. doi: 10.1126/scitranslmed.abo2044. Epub 2023 May 24.
• Maestu F, de Haan W, Busche MA, DeFelipe J. Neuronal excitation/inhibition imbalance: core element of a translational perspective on Alzheimer pathophysiology. Ageing Res Rev. 2021 Aug;69:101372. doi: 10.1016/j.arr.2021.101372. Epub 2021 May 21.
• Palop JJ, Mucke L. Network abnormalities and interneuron dysfunction in Alzheimer disease. Nat Rev Neurosci. 2016 Dec;17(12):777-792. doi: 10.1038/nrn.2016.141. Epub 2016 Nov 10.
• Iaccarino HF, Singer AC, Martorell AJ, Rudenko A, Gao F, Gillingham TZ, Mathys H, Seo J, Kritskiy O, Abdurrob F, Adaikkan C, Canter RG, Rueda R, Brown EN, Boyden ES, Tsai LH. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature. 2016 Dec 7;540(7632):230-235. doi: 10.1038/nature20587.

Study record dates

Study Major Dates

• Study Start (Actual): November 15, 2024
• Primary Completion (Actual): April 28, 2026
• Study Completion (Actual): May 7, 2026

Study Registration Dates

• First Submitted: December 22, 2023
• First Submitted That Met QC Criteria: January 9, 2024
• First Posted (Actual): January 12, 2024

Study Record Updates

• Last Update Posted (Actual): June 2, 2026
• Last Update Submitted That Met QC Criteria: May 29, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Alzheimer's disease; Magnetoencephalography; Transcranial alternating current stimulation; Episodic memory
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Cognitive Dysfunction; Alzheimer Disease
• Other Study ID Numbers: 20212222

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The individual participant data will be made available upon reasonable request to the corresponding author in consultation with the data protection officer
• IPD Sharing Time Frame: Data will be shared after the study completion indefinitely
• IPD Sharing Access Criteria: Upon reasonable request

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No