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      Using gamma-band transcranial alternating current stimulation (tACS) to improve sleep quality and cognition in patients with mild neurocognitive disorders due to Alzheimer’s disease: A study protocol for a randomized controlled trial

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          Abstract

          Background

          Sleep disturbances are highly prevalent in patients with age-related neurodegenerative diseases, which severely affect cognition and even lead to accumulated β-amyloid. Encouraging results from recent studies on transcranial direct current stimulation (tDCS) showed moderate positive effects on sleep quality in preclinical Alzheimer’s disease (AD). Compared to tDCS, transcranial alternating current stimulation (tACS) enables the entrainment of neuronal activity with optimized focality through injecting electric current with a specific frequency and has significant enhancement effects on slow wave activities.

          Methods and design

          This is a randomized, double-blind, sham-controlled clinical trial comparing 40 Hz tACS with tDCS in mild neurocognitive disorders due to AD with sleep disturbances. Magnetic resonance imaging (MRI) data is used to construct personalized realistic head model. Treatment outcomes, including sleep quality, cognitive performance and saliva A β levels will be conducted at baseline, 4 th week, 8 th week, 12 th week and 24 th week.

          Conclusions

          It is expected that the repeated gamma-band tACS will show significant improvements in sleep quality and cognitive functions compared to tDCS and sham tDCS. The findings will provide high-level evidence and guide further advanced studies in the field of neurodegenerative diseases and sleep medicine.

          Trial registration

          ClinicalTrials.gov Identifier: NCT05544201.

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          Most cited references38

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          SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials

          High quality protocols facilitate proper conduct, reporting, and external review of clinical trials. However, the completeness of trial protocols is often inadequate. To help improve the content and quality of protocols, an international group of stakeholders developed the SPIRIT 2013 Statement (Standard Protocol Items: Recommendations for Interventional Trials). The SPIRIT Statement provides guidance in the form of a checklist of recommended items to include in a clinical trial protocol. This SPIRIT 2013 Explanation and Elaboration paper provides important information to promote full understanding of the checklist recommendations. For each checklist item, we provide a rationale and detailed description; a model example from an actual protocol; and relevant references supporting its importance. We strongly recommend that this explanatory paper be used in conjunction with the SPIRIT Statement. A website of resources is also available (www.spirit-statement.org). The SPIRIT 2013 Explanation and Elaboration paper, together with the Statement, should help with the drafting of trial protocols. Complete documentation of key trial elements can facilitate transparency and protocol review for the benefit of all stakeholders.
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            Physiological basis of transcranial direct current stimulation.

            Since the rediscovery of transcranial direct current stimulation (tDCS) about 10 years ago, interest in tDCS has grown exponentially. A noninvasive stimulation technique that induces robust excitability changes within the stimulated cortex, tDCS is increasingly being used in proof-of-principle and stage IIa clinical trials in a wide range of neurological and psychiatric disorders. Alongside these clinical studies, detailed work has been performed to elucidate the mechanisms underlying the observed effects. In this review, the authors bring together the results from these pharmacological, neurophysiological, and imaging studies to describe their current knowledge of the physiological effects of tDCS. In addition, the theoretical framework for how tDCS affects motor learning is proposed.
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              Gamma frequency entrainment attenuates amyloid load and modifies microglia.

              Changes in gamma oscillations (20-50 Hz) have been observed in several neurological disorders. However, the relationship between gamma oscillations and cellular pathologies is unclear. Here we show reduced, behaviourally driven gamma oscillations before the onset of plaque formation or cognitive decline in a mouse model of Alzheimer's disease. Optogenetically driving fast-spiking parvalbumin-positive (FS-PV)-interneurons at gamma (40 Hz), but not other frequencies, reduces levels of amyloid-β (Aβ)1-40 and Aβ 1-42 isoforms. Gene expression profiling revealed induction of genes associated with morphological transformation of microglia, and histological analysis confirmed increased microglia co-localization with Aβ. Subsequently, we designed a non-invasive 40 Hz light-flickering regime that reduced Aβ1-40 and Aβ1-42 levels in the visual cortex of pre-depositing mice and mitigated plaque load in aged, depositing mice. Our findings uncover a previously unappreciated function of gamma rhythms in recruiting both neuronal and glial responses to attenuate Alzheimer's-disease-associated pathology.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Project administrationRole: Resources
                Role: Validation
                Role: Project administration
                Role: Resources
                Role: Methodology
                Role: Resources
                Role: SoftwareRole: Visualization
                Role: Editor
                Journal
                PLoS One
                PLoS One
                plos
                PLOS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                4 August 2023
                2023
                : 18
                : 8
                : e0289591
                Affiliations
                [1 ] Department of Psychiatry, The Chinese University of Hong Kong, Hong Kong SAR, China
                [2 ] The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China
                [3 ] Department of Mechanical and Automation Engineering, The Chinese University of Hong Kong, Hong Kong SAR, China
                University Medical Center Goettingen, GERMANY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                https://orcid.org/0000-0002-9090-258X
                Article
                PONE-D-22-35237
                10.1371/journal.pone.0289591
                10403094
                37540692
                de3e47b8-e62d-466c-9912-142b1b2abc5d
                © 2023 Lu et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 20 January 2023
                : 21 July 2023
                Page count
                Figures: 2, Tables: 0, Pages: 12
                Funding
                Funded by: Hong Kong Research Grant Council (RGC) - General Research Fund (GRF)
                Award ID: 14111021
                Award Recipient :
                This clinical trial is supported by the Hong Kong Research Grant Council (RGC)-General Research Fund (GRF) (Grant No. 14111021). HL received the award. URL: https://www.ugc.edu.hk/eng/rgc/ The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Study Protocol
                Biology and Life Sciences
                Physiology
                Physiological Processes
                Sleep
                Research and Analysis Methods
                Bioassays and Physiological Analysis
                Electrophysiological Techniques
                Brain Electrophysiology
                Transcranial Stimulation
                Transcranial Direct-Current Stimulation
                Biology and Life Sciences
                Physiology
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                Neurophysiology
                Brain Electrophysiology
                Transcranial Stimulation
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                Biology and Life Sciences
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                Research and Analysis Methods
                Bioassays and Physiological Analysis
                Electrophysiological Techniques
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                Transcranial Stimulation
                Transcranial Alternating Current Stimulation
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                Data cannot be shared publicly because of personal medical information. Data are available from the CUHK Data Access / Ethics Committee (contact via hannalu@ 123456cuhk.edu.hk ) for researchers who meet the criteria for access to confidential data.

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