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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Active tACS | Experimental | Gamma (40 Hz) tACS at the precuneus region |
|
| Sham tACS | Sham Comparator | Sham tACS at the precuneus region |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Gamma (40 Hz) tACS at the precuneus region | Device | 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) |
| 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 |
| 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) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Willem de Haan, dr. | Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Amsterdam UMC, The Netherlands | Amsterdam | North Holland | 1081HV | Netherlands |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33762220 | Background | 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. | |
| 35607946 |
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The individual participant data will be made available upon reasonable request to the corresponding author in consultation with the data protection officer
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Data will be shared after the study completion indefinitely
Upon reasonable request
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| ID | Term |
|---|---|
| D000544 | Alzheimer Disease |
| D060825 | Cognitive Dysfunction |
| ID | Term |
|---|---|
| D003704 | Dementia |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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Randomized, sham-controlled, crossover trial
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|
| Sham tACS at the precuneus region | Device | 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) |
|
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 |
| 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. |
| 37224229 | Background | 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. |
| 27929004 | Background | 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. |
| 34029743 | Background | 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. |
| 27829687 | Background | 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. |
| D024801 |
| Tauopathies |
| D019636 | Neurodegenerative Diseases |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D003072 | Cognition Disorders |