TYPE Clinical Trial PUBLISHED 02 June 2023 DOI 10.3389/fnhum.2023.1168673 Tele-supervised home-based OPEN ACCESS transcranial alternating current EDITED BY Marco Filardi, University of Bari Aldo Moro, Italy stimulation (tACS) for Alzheimer’s REVIEWED BY Alberto Benussi, disease: a pilot study University of Brescia, Italy Jason R. Taylor, The University of Manchester, United Kingdom Davide Cappon1,2,3*, Rachel Fox1,2 , Tim den Boer1 , Wanting Yu1 , *CORRESPONDENCE Nicole LaGanke1 , Gabriele Cattaneo4,5,6 , Davide Cappon davidebaloscappon@hsl.harvard.edu Ruben Perellón-Alfonso7,8 , David Bartrés-Faz7,8 , Brad Manor1,9 and Alvaro Pascual-Leone1,2,3 RECEIVED 17February 2023 1 Hinda and Arthur Marcus Institute for Aging Research at Hebrew SeniorLife, Boston, MA, United States, ACCEPTED 27 April 2023 2 Deanna and Sidney Wolk Center for Memory Health at Hebrew SeniorLife, Boston, MA, United States, PUBLISHED 02 June 2023 3 Department of Neurology, Harvard Medical School, Boston, MA, United States, 4 Institut Guttmann, CITATION Institut Universitari de Neurorehabilitació Adscrit a la UAB, Barcelona, Spain, 5 Departament de Medicina, Cappon D, Fox R, den Boer T, Yu W, Universitat Autònoma de Barcelona, Bellaterra, Spain, 6 Fundació Institut d’Investigació en Ciències de la LaGanke N, Cattaneo G, Perellón-Alfonso R, Salut Germans Trias i Pujol, Badalona, Spain, 7 Department of Medicine, Faculty of Medicine and Health Bartrés-Faz D, Manor B and Pascual-Leone A Sciences, Institute of Neurosciences, University of Barcelona, Barcelona, Spain, 8 Institute of Biomedical (2023) Tele-supervised home-based Research August Pi i Sunyer (IDIBAPS), Barcelona, Spain, 9 Department of Medicine, Harvard Medical transcranial alternating current stimulation School, Boston, MA, United States (tACS) for Alzheimer’s disease: a pilot study. Front. Hum. Neurosci. 17:1168673. doi: 10.3389/fnhum.2023.1168673 COPYRIGHT © 2023 Cappon, Fox, den Boer, Yu, LaGanke, Background: Over 55 million people worldwide are currently diagnosed with Cattaneo, Perellón-Alfonso, Bartrés-Faz, Manor Alzheimer’s disease (AD) and live with debilitating episodic memory deficits. and Pascual-Leone. This is an open-access article distributed under the terms of the Current pharmacological treatments have limited efficacy. Recently, transcranial Creative Commons Attribution License alternating current stimulation (tACS) has shown memory improvement in AD by (CC BY). The use, distribution or reproduction normalizing high-frequency neuronal activity. Here we investigate the feasibility, in other forums is permitted, provided the original author(s) and the copyright owner(s) safety, and preliminary effects on episodic memory of an innovative protocol are credited and that the original publication in where tACS is administered within the homes of older adults with AD with the this journal is cited, in accordance with accepted academic practice. No use, help of a study companion (HB-tACS). distribution or reproduction is permitted which does not comply with these terms. Methods: Eight participants diagnosed with AD underwent multiple consecutive sessions of high-definition HB-tACS (40 Hz, 20-min) targeting the left angular gyrus (AG), a key node of the memory network. The Acute Phase comprised 14-weeks of HB-tACS with at least five sessions per week. Three participants underwent resting state electroencephalography (EEG) before and after the 14- week Acute Phase. Subsequently, participants completed a 2–3-month Hiatus Phase not receiving HB-tACS. Finally, in the Taper phase, participants received 2–3 sessions per week over 3-months. Primary outcomes were safety, as determined by the reporting of side effects and adverse events, and feasibility, as determined by adherence and compliance with the study protocol. Primary clinical outcomes were memory and global cognition, measured with the Memory Index Score (MIS) and Montreal Cognitive Assessment (MoCA), respectively. Secondary outcome was EEG theta/gamma ratio. Results reported as mean ± SD. Results: All participants completed the study, with an average of 97 HB-tACS sessions completed by each participant; reporting mild side effects during 25% of sessions, moderate during 5%, and severe during 1%. Acute Phase adherence was 98 ± 6.8% and Taper phase was 125 ± 22.3% (rates over 100% indicates participants completed more than the minimum of 2/week). After the Acute Phase, all participants showed memory improvement, MIS of Frontiers in Human Neuroscience 01 frontiersin.org Cappon et al. 10.3389/fnhum.2023.1168673 7.25 ± 3.77, sustained during Hiatus 7.00 ± 4.90 and Taper 4.63 ± 2.39 Phases compared to baseline. For the three participants that underwent EEG, a decreased theta/gamma ratio in AG was observed. Conversely, participants did not show improvement in the MoCA, 1.13 ± 3.80 after the Acute Phase, and there was a modest decrease during the Hiatus −0.64 ± 3.28 and Taper −2.56 ± 5.03 Phases. Conclusion: This pilot study shows that the home-based, remotely-supervised, study companion administered, multi-channel tACS protocol for older adults with AD was feasible and safe. Further, targeting the left AG, memory in this sample was improved. These are preliminary results that warrant larger more definite trials to further elucidate tolerability and efficacy of the HB-tACS intervention. NCT04783350. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT04783350? term=NCT04783350&draw=2&rank=1, identifier NCT04783350. KEYWORDS Alzheimer’s disease, neuromodulation, transcranial alternating current stimulation (tACS), memory, cognition, electroencephalography (EEG) Introduction excitability and improve cognitive functions by safely modulating brain activity at a precise frequency in targeted brain structures Over 55 million people worldwide are currently diagnosed with (Zaehle et al., 2010; Antal and Paulus, 2013; Herrmann et al., Alzheimer’s disease (AD) and this number is predicted to nearly 2013; Cappon et al., 2015, 2016). Recent initial studies in AD have double by the year 2050, due to the aging population (Alzheimer’s demonstrated that the application of tACS at gamma frequency Association, 2022; World Health Organization, 2022). Early on in targeting key nodes of the memory network improved episodic the course of their condition, AD patients typically have episodic memory and restored cholinergic neurotransmission (Benussi et al., memory loss, which is devastating to them as well as to their family 2021; Kim et al., 2021; Benussi et al., 2022; Zhou et al., 2022). and caregivers and is a useful indicator of how the disease will These recent findings are very encouraging for the application progress (El Haj et al., 2017; Abraham et al., 2020). of tACS as a safe and effective intervention in patients with AD. The targets of current pharmacological therapy for memory However, studies to date have been limited by the fact that only enhancement are beta-amyloid plaque (β-amyloid) deposition a single tACS session was administered in a clinic-lab setting, (Avgerinos et al., 2021; van Dyck et al., 2022), one of the which raises questions about how long memory effects will last pathophysiological hallmarks of AD, and the related dysregulation of the cholinergic system (Hampel et al., 2018). Alongside and whether it will be possible to scale up tACS interventions cholinergic dysregulation and β-amyloid accumulation, recent for patients who cannot afford to travel to a specialized clinic studies have shown that high frequency brain network activities center. Thus, there is an urgent need for a safe, effective, and more that support successful memory encoding and recall of new accessible home-based intervention for memory in AD. information are altered decades before AD clinical onset, and the We have previously developed an innovative methodology and disrupted networks predict future pathology and brain atrophy demonstrated the safety and feasibility of providing a home-based, (Koenig et al., 2005; Sperling et al., 2009; Babiloni et al., 2016; Palop remotely supervised, study companion (e.g., caregiver, family and Mucke, 2016; Palop, 2020). Specifically, recent research has member, friend) administered, multi-channel neuromodulation focused primarily on the role of gamma desynchronization (30– protocol for older adults (Cappon et al., 2022). This approach offers 80 Hz) in AD manifestation, raising the possibility of exploiting it the opportunity to integrate therapeutic benefit into the daily life as a novel therapeutic target. of participants and increasing access to tACS treatment. Caregivers In animal models of AD, entrainment-induced restoration of are also empowered as they play a vital role as study companions gamma oscillations reduces the pathogenic load of β-amyloid and directly assisting in treatment for their loved one. In the present significantly improves behavior (Iaccarino et al., 2016; Adaikkan pilot study, we report the results of a case series investigation et al., 2019; Etter et al., 2019; Martorell et al., 2019). Further, neuroimaging evidence indicate that the AG is a key node in the including eight AD-diagnosed participants who received multiple memory network, and gray matter volume reduction in the AG has sessions of home-based, remotely supervised, study companion been linked to AD memory symptoms (Oh et al., 2013; Humphreys administered, multi-channel tACS targeted at the left angular gyrus et al., 2021; van de Mortel et al., 2021). For the translation of these (L-AG). Assessing the intervention’s safety, feasibility, and early findings to humans, transcranial alternating current stimulation clinical impact on episodic memory were the study’s primary (tACS) has drawn interest for its ability to modulate cortical objectives. Frontiers in Human Neuroscience 02 frontiersin.org Cappon et al. 10.3389/fnhum.2023.1168673 Materials and methods of HB-tACS sessions completed during the study are displayed in Table 2. Participants Study design Ten participants were enrolled in the study, with two participants (P004 and P009) withdrawing due to personal reasons The study intervention consisted of multiple consecutive unrelated to their participation in the trial. Eight participants sessions of HB-tACS (40 Hz, 20-min) targeting the left angular diagnosed with AD received home-based transcranial alternating gyrus (L-AG), a key node of the memory network. The protocol current stimulation (HB-tACS) from March 3rd, 2021 to June 3rd, consisted of three phases: Acute Phase, Hiatus Phase, and 2022. Demographic and clinical characteristics of participants are the Taper Phase (see Figure 1). During the Acute Phase, the presented in Table 1. All participants had amnestic impairment, study companions conducted daily 20-min HB-tACS sessions for verified by the study neurologist. Inclusion criteria for participants 14 weeks, with a minimum of five sessions each week (maximum were: AD diagnosis (characterized by AD biomarker positivity and of one session per day, seven sessions per week). A subset of by in-person assessment by qualified health care personnel), over three participants completed an optional resting state high-density the age of 50, able to give consent, ability to read, write, and electroencephalography (HD-EEG) visit at baseline and at the end communicate in English, and able to identify an eligible study of the acute phase. HD-EEG was included to gain insight into companion to participate with them in the study to administer the underlying neurophysiological alterations induced by tACS, we the HB-tACS. Exclusion criteria included major psychiatric co- opted to make it optional to minimize the burden of additional morbidities, dermatological conditions on the scalp, an inability to assessments since it wasn’t a primary outcome of the present study. provide informed consent, or any contraindications to tACS (such After the Acute Phase, participants and their study companions as recent seizures, implanted medical devices, use of neuroactive completed 3 months without any stimulation during the Hiatus drugs, etc.). Inclusion criteria for study companions were: at least Phase. The goal of the Hiatus Phase was to capture the extent 21 years old, self-reported computer proficiency, able to read, to which any effects of HB-tACS on memory may have been write, and communicate in English, willingness to learn how to sustained after 3 months without stimulation. Subsequently, in administer HB-tACS, availability during weekdays of the study the Taper phase, we asked participants to complete 2–3 HB-tACS period to administer HB-tACS to the study participant, and a sessions per week over 3 months. The objective of this phase was MoCA score of 27–30 to demonstrate their cognitive capacity. to facilitate maintenance of any benefit derived from HB-tACS Study companions demographic characteristics and the number in the Acute Phase. Assessments were conducted at baseline and TABLE 1 Participant demographics and clinical characteristics. Participant Age Sex Education (years) Diagnosis MoCA score (Baseline) Memory Index Score (Baseline) P001 79 M 19 Late onset AD 21 0 P002 79 M 19 Late onset AD 23 0 P003 88 F 16 AD 28 0 P006 79 F 16 AD 17 1 P007 71 M 18 AD 18 0 P008 66 M 16 Moderate AD 10* 1 P010 53 M 16 Early onset moderate AD 10* 0 P011 76 M 16 AD 22 4 *Please note P008 and P010 were more impaired in their baseline MoCA score, but as this is a pilot study, we sought to be more inclusive of our participants and their level of decline. TABLE 2 Study companions demographic, level of education, and the number of sessions completed. Study companion Age Sex Education Number of HB-tACS sessions completed for (years) Acute Phase Taper Phase P001 78 F 16 70 48 P002 73 F 16 69 35 P003 88 M 18 64 20 P006 80 M 16 69 22 P007 64 F 16 79 24 P008 59 F 16 64 24 P010 53 F 16 68 26 P011 74 F 16 66 32 Frontiers in Human Neuroscience 03 frontiersin.org Cappon et al. 10.3389/fnhum.2023.1168673 FIGURE 1 Study design. The Acute Phase lasted 14 weeks, the study companions conducted daily 20-min HB-tACS sessions with a minimum of five sessions per week (maximum of one session per day, seven sessions per week). The Hiatus lasted 3 months no HB-tACS sessions were administered. In the Taper Phase, we asked participants to complete 2–3 HB-tACS sessions per week over 3 months. at the end of each of the three phases. Further, we monitored Optimized tACS current flow modeling adherence to the HB-tACS protocol through all phases and a to target the left angular gyrus member of the research staff called the study companions once a week during the Acute and the Taper Phase to check on the The specific tACS system used in this study is the Starstim - R participants’ condition and to record any subjective effects of tACS R Home Kit (Neuroelectrics Corp.). The Starstim device includes on their memory. a headcap that resembles a swimming cap with holes located where small electrodes can be attached and secured in place in the correct position on the scalp. These electrode holes are color- Study procedures and number-coded so that electrode leads with corresponding colors coming from the tACS device are appropriately attached The study was approved and monitored by an independent to the corresponding electrodes, eliminating the potential for Institutional Review Board (Advarra, Inc.) and registered as clinical accidental mismatching of the electrodes and the leads. Each trial at clinicaltrials.gov (NCT04783350). All subject interaction session involved a multichannel tACS montage with maximal was conducted either in-person at the Hebrew Rehabilitation anodal current targeting the left AG administered via 6 NG Center in Boston, MA, or remotely via videoconferencing Pistim electrodes (circular electrodes with a contact of area of R media. Prior to enrolling in the study, participants and 3.14 cm2 ) using the Starstim -Home system. Created using the R study companions attended a 45-min phone screening to Stimweaver algorithm (Ruffini et al., 2014), the montage was ensure they fulfilled eligibility criteria. If eligible, participants specifically designed to optimize stimulation over the left AG and then completed an in-person screening visit comprised of a at the same time minimize off target stimulation effects based on medication history, neurological exam, Clinical Dementia Rating a standard brain model (see Figure 2). During each sessions the (CDR), and a Montreal Cognitive Assessment (MoCA) (from currents delivered by any single electrode did not exceed 2.0 mA, which the Memory Index Score (MIS) is calculated) to assess well below recommended safety limits (Antal et al., 2017). The global cognitive status. Participants were given the choice to average E-field normal component on the target was En = 0.24 V/m, undergo resting state HD-EEG recording if they were eligible and En = 0.10 V/m on the surrounding regions. For all participants, for the study. current intensity was ramped up over 60 s, then sustained at the FIGURE 2 The multichannel tACS intervention for AD. (A) The red area on the default brain model represents the left angular gyrus, or Brodmann’s area 39 (BA39). This target area was used to develop the current flow modeling and electrode montage. (B) The optimized six-electrode montage developed in this study to target the left AG (anode shown in red, cathodes in blue) and normal component of the electric field to the cortex R induced by the montage (V/m). (C) Set-up of the Neuroelectrics Starstim Home Kit headcap and tablet. Frontiers in Human Neuroscience 04 frontiersin.org Cappon et al. 10.3389/fnhum.2023.1168673 stimulation intensity for 20 min, then ramped down over 60 s. This in the Taper Phase), was used to evaluate the feasibility of the home- standard approach is both well-tolerated and safe in older adults based tDCS protocol. This allowed us to capture how HB-tACS (Cappon et al., 2022). session administration can fit into the daily life of the participant and study companion and help determine if this method is feasible for future use in an older adult population. Home-based study companion-led tACS Clinical outcomes administration Clinical outcomes focused on memory and global cognitive functioning, as measured by the Memory Index Score (MIS) and After being enrolled, participants and their study companions the full Montreal Cognitive Assessment (MoCA), respectively. came to the laboratory on three consecutive days to receive hands- Research staff who have completed MoCA training and obtained on instruction in the administration of tACS. On the first day, certification administered these examinations to ensure consistency study companions were given an overview of the Starstim -HomeR in the administration. They were assessed at baseline, after the Kit (Neuroelectrics Corp.) tACS equipment by a trained research Acute Phase, after the Hiatus Phase, and after the Taper Phase. At staff member. On the same day, research staff administered the the end of each of the three phases, data were acquired and stored first tACS session to the study participant, instructing the study using a REDCap database, a secure platform for storing data and companion who observed the administration. On the second day, generating reports. the study companion was encouraged to carry out as much of the tACS session as possible without guidance from the research staff. Montreal cognitive assessment (MoCA) However, the study companion was allowed to ask for assistance The MoCA is a clinician-rated screening test consisting as necessary, and research staff corrected them if they made of 12 items across different cognitive domains, including any mistakes. On the third day, study companions independently visuospatial/executive functioning, animal naming, memory, administered the stimulation to the participant, while research attention, language, abstraction, delayed recall, and orientation. It staff assessed the performance of the study companion using can be administered within 10 min, resulting in a maximum total an evaluation check list adapted from Charvet et al. (2015). score of 30 points. Lower scores indicate greater cognitive decline, Participants then brought the HB-tACS device home to complete with MoCA scores below 26 indicating the presence of mild stimulation sessions independently with remote supervision from cognitive decline (Nasreddine et al., 2005). The 5-min telehealth research staff. For further explanation of this HB-tES training and MoCA was used over the telephone or videoconferencing media as supervision program, please see Cappon et al. (2022) and den Boer a way to assess cognition without requiring the participant to travel et al. (2022). to the research laboratory (Wong et al., 2015). The MoCA 5-min is comprised of five sub-tests that were taken from the MoCA and look at different cognitive domains: orientation, executive functions/language, verbal learning and memory, and attention. Study outcomes This shortened 5-min MoCA is highly correlated in score with the full 12-item MoCA (Wong et al., 2015). The version of the MoCA Safety (including MIS words) was randomized for each assessment to Side effects questionnaire and adverse events minimize practice effects, though we acknowledge that there is still Before and after each home-based tACS session, participants a potential impact of practice effects (Lei et al., 2022). were asked to report any side effects on questionnaires that were implemented using the Starstim -Home system smart tablet. Based R Memory Index Score (MIS) on previous published safety guidelines, participants were asked to The MIS is a measure of delayed recall memory that is report on any physical sensations, scalp abnormalities, cognitive calculated from the MoCA (either the full or 5-min). Five unrelated changes, or other symptoms that were present (Antal et al., 2017). words are spoken to the participant twice, and each time they are A list of the side effects that were asked about can be found in repeated by the participant to facilitate the encoding process. After Table 3. Participants were asked to report on the intensity of the a 5-min delay, participants are asked to recall the five words. If side effects, by stating whether their experience for each of the side freely recalled without a cue, 3 points per word is earned toward effects was: absent, mild, moderate, or severe. These responses were the MIS. If recalled with a categorical cue, 2 points per word is received via email by research staff through a study email inbox in earned. If recalled when presented with multiple choice options, 1 real-time. If participants indicated a moderate or severe experience point per word is earned, for a maximum possible score of 15 points of a side effect prior to the tACS, access to the stimulation was (Julayanont et al., 2014). Thus, the MIS score computation includes blocked until study staff could ensure that the participant was fit points for both the free recall and cued recall conditions, unlike the for stimulation. MoCA, which only accounts for points for the delayed free recall condition. Due to how the MIS is calculated, a large effect can be Feasibility seen in a participant’s MIS score, but only minimal changes seen in Adherence and compliance the MoCA overall score. The adherence to the treatment schedule, measured as the ratio of completed HB-tACS sessions to the required sessions as EEG recording and analysis prescribed in the study schedule (a minimum of five sessions per For those participants who opted in to this part of the week in the Acute Phase, and a minimum of two sessions per week study, 5 min of eyes closed resting state high density EEG were Frontiers in Human Neuroscience 05 frontiersin.org Cappon et al. 10.3389/fnhum.2023.1168673 recorded continuously using a 256 channels HydroCel Geodesic Results Sensor Net (Electrical Geodesic Inc., Eugene, OR, USA) at 1 KHz sampling rate and bandpass filtered 0.3 to 500 Hz. Electrode Safety impedance was kept under 50 Kohm. EEG data was pre-processed using EEGLAB (Delorme and Makeig, 2004) and custom-made Side effects questionnaire and adverse events Matlab (The MathWorks, Inc., Natick, MA, USA) scripts. First, All side effects reported from baseline to the end of the Taper face and neck electrodes were removed from the data. Then we Phase were transient. The most frequently reported side effects were retained only 62 of the remaining scalp electrodes that could mild and reported during less than 1% of sessions, as shown in be directly mapped to the 10–10 international electrode position Table 3. The two exceptions to this, however, were the side effects system (Luu and Ferree, 2005). Line noise (i.e., 60 Hz and “Sensations under the electrode” and “Sleepiness.” Participants harmonics) was then attenuated using the Zapline algorithm (de reported sensations under the electrode (such as a tingling or Cheveigné, 2020). Excessively noisy or disconnected electrode an itching feeling) during 25.6% of sessions. Feeling sleepy as a channels were spline interpolated and data was re-referenced to the consequence of the stimulation was reported during 4% of sessions, average of all channels. Next, the continuous data was segmented and found to be transient (Table 4). Overall, side effects were into non-overlapping two-second-long epochs. All epochs were reported in 33.4% of sessions, with participants reporting mild side visually inspected and those that contained any artifacts were effects during 26.6% of sessions, moderate side effects during 5.6% removed. The cleaned preprocessed data was then used for source of sessions, and severe side effects during 1.2% of sessions as seen in reconstruction in Brainstorm (Tadel et al., 2019). For each subject Table 3. Upon the participants reporting a moderate or severe side a forward model was estimated via the openMEEG algorithm effect, research staff was notified and would immediately contact (Kybic et al., 2005) using the default settings (i.e., 3 layers with participants and gather more information about the side effect 1,922 vertices each; skull and scalp conductivities of 1 and brain and how they were currently feeling. After this contact, research staff would report the situation to the medically responsible study conductivity of 0.0125; adaptative integration), and based on the physician, who would assess the event and advise participants on MNI ICBM152 average brain template (Mazziotta et al., 1995). how to proceed. The monitoring of adverse events showed that no The inverse solution was estimated using the minimum norm adverse events occurred during the course of the study. imaging method (Salmelin and Baillet, 2009). Sources were then computed as current density maps for constrained orientations Feasibility only (i.e., normal to cortex). We aimed to determine how much the Adherence HB-tACS intervention impacted the oscillatory power of gamma All eight participants and their study companions had very oscillations in the left angular gyrus. In source space, we then high adherence to our protocol, collectively completing 780 HB- defined a single region of interest (ROI) containing the left tACS sessions between baseline and the end of the Taper Phase. angular gyrus, based on the Desikan-Kiliani cortical parcellation The adherence of individual participants is shown in Table 5. (Desikan et al., 2006). Power spectral density estimates were then The average percent adherence to the tACS protocol for the extracted from all voxels of this ROI using the Welch method Acute Phase was 98% ± 6.8%, showing that participants and (Welch, 1967) and averaged. Finally, we computed relative power their study companions were able to strongly comply with daily frequency bands for theta (4–7.9 Hz), alpha (8–13.9 Hz), beta tACS. The average adherence in the Taper Phase is encouraging, (14–29.9 Hz), and gamma (30–50 Hz), and the ratio of theta to as when participants were empowered to choose the number of gamma. tACS sessions they completed, nearly all completed more than the TABLE 3 Total incidence of side effects and their severity inquired about in the side effect questionnaires pre and post tACS. Side effect Mild Moderate Severe Percentage of sessions Pre Post Pre Post Pre Post Headache 0 0 0 0 0 0 0% Neck pain 0 2 0 0 0 0 0.2% Scalp pain 0 2 1 2 0 1 0.81% Scalp burns 3 1 0 2 0 1 0.9% Sensations under the electrode 3 162* 1 27 0 6 25.6% Skin redness 1 3 0 0 0 0 0.5% Sleepiness 1 18 0 11 0 1 4% Trouble concentrating 0 9 0 0 0 0 1.2% Acute mood change 1 1 0 0 0 0 0.2% Other 0 0 0 0 0 0 0% Total % 1.2% 25.4% 0.2% 5.4% 0% 1.2% 33.4% *P007 and P010 reported the highest frequency of “sensations under the electrode”, accounting for over 79% of reports (see Table 4). Frontiers in Human Neuroscience 06 frontiersin.org Cappon et al. 10.3389/fnhum.2023.1168673 minimum of 2 sessions per week, with an average adherence of 125% ± 22.3%, or completing an average of 2.5 sessions each week. Adherence rates over 100% indicates participants completed more than the minimum required sessions per week. Cognitive outcomes Memory Index Score (MIS) All participants showed memory improvement at the end of the Acute Phase, with an average improvement of 7.25 ± 3.77 points. This was sustained during the Hiatus 7.00 ± 4.90 and Taper 4.63 ± 2.39 phases compared to baseline. Even at the end of the study period, all participants had maintained some of the original benefit from the Acute Phase. These average changes in scores FIGURE 3 Participant average score change from baseline on Memory Index are showed in Figure 3, with individual scores in Figure 4A. The Score (MIS) (green) and MoCA (purple). While global cognition individual MIS scores at each assessment point are also displayed measured by the MoCA stayed stable with a modest decrease over in Table 6. time, episodic memory measured by the MIS showed great improvement from baseline after the Acute Phase, which was sustained even after the Taper Phase. Montreal Cognitive Assessment (MoCA) Participants did not show any dramatic change in the MoCA at the end of the Acute Phase, with an average of 1.13 ± 3.80 points. There was a modest decrease during the Hiatus −0.64 ± 3.28 and Neurophysiological outcome Taper −2.56 ± 5.03 Phases from baseline. These average changes in EEG resting-state scores are showed in Figure 3, with individual scores in Figure 4B. As the EEG was optional in this study, only a subset of The individual MoCA scores at each assessment point are also three participants chose to take part: P007, P008, and P011. displayed in Table 7. Theta/gamma ratio, which was assessed in source space within the ROI including the left angular gyrus (L-AG), decreased in all 3 TABLE 4 Frequency with which participants reported sensations under participants after the Acute Phase (Figure 4C). the electrodes. Participant # Reported sensations under the electrodes Discussion P001 4 P002 1 In the present study, we adopted our recently developed P003 8 method of providing a home-based, remotely supervised, study companion (e.g., caregiver, family member, friend) administered, P006 46 multi-channel neuromodulation protocol for older adults (Cappon P007 63 et al., 2022). P008 1 We monitored side effects throughout the experiment using P010 65 a customized side-effect questionnaire administered on a tablet. P011 11 No serious adverse events occurred across the total of 780 HB- tACS sessions. The side effects recorded during the study were TABLE 5 Participant adherence to tACS protocol in the Acute Phase and mostly mild and transient. Specifically, of the 31% of sessions in Taper Phase. which side effects were reported, participants reported 80% mild, Participant Acute Phase Taper Phase 17% moderate and 3% severe side effects on an intensity rating adherence % adherence % with a range of mild, moderate, and severe options. This is in line (minimum 5 (minimum 2 with previous research that showed that tACS was well-tolerated sessions/week) sessions/week) and that no serious adverse events were reported when tACS was P001 100% 160%* administered in accordance with the safety guidelines (Antal et al., P002 99% 138%* 2017). P003 91% 91% We found that the study companions effectively conducted the P006 99% 100% tACS sessions at home after receiving instruction and training. This was demonstrated by the fact that, on average, 68.6 tACS P007 113%* 123%* sessions in the Acute Phase and 28.9 sessions in the Taper P008 91% 133%* Phase were delivered successfully by study companions. This is P010 97% 139%* promising for future research as it shows that the training in P011 94% 118%* tACS administration can empower study companions to conduct Average 98% (6.8) 125% (22.3) the stimulation sessions themselves in the home of the study *Adherence over 100% indicates participants completed more than the minimum required participants and that this approach can free up research staff sessions per week. members from having to conduct the tACS sessions, thereby Frontiers in Human Neuroscience 07 frontiersin.org Cappon et al. 10.3389/fnhum.2023.1168673 FIGURE 4 (A) Individual participant MIS scores over the course of the study duration. (B) Individual participant MoCA scores over the course of the study duration. Shortened 5-min MoCA were administered via videoconferencing media to assess potential short-term effects of the stimulation on global cognitive status and any incremental change at 1 and 2 months of the Acute Phase. (C) EEG results: theta/gamma ratio at baseline, and after the Acute Phase of tACS intervention course at the end of Acute Phase. Left panel shows a bar graph of each participant’s theta/gamma ratio at Baseline and at the end of the Acute Phase within the defined left angular gyrus ROI (see in Methods; EEG recording and analysis section). Right panel shows the distribution of theta/gamma ratio in source space and projected onto the MNI template; the red transparent contour highlights the ROI from which the bar graph data was extracted. substantially increasing the intervention’s scalability and access. later after the Hiatus Phase (7.00 points) and 6 months later after High adherence levels observed throughout the Acute Phase and the Taper Phase (4.63 points). The episodic memory enhancement Taper Phase provide evidence for the feasibility of the HB-tACS that was maintained at the end of the Taper Phase relative to approach. The 125% adherence during the Taper Phase indicates baseline is clinically encouraging given the progressive nature of that study companions were administering more sessions than the episodic memory deficits in AD. However, given the lack of control minimum amount requested by research staff. These findings are group in this study, it is impossible to determine whether these remarkable given that better treatment outcomes depend on higher effects were due to the stimulation or due to some other element levels of adherence and considering that individuals with chronic of trial participation. Importantly, potential practice effects on the conditions frequently lose interest in following their prescribed MIS test were minimized using different memory stimuli during treatment plan (Brown and Bussell, 2011). each iteration of the test. In fact, if memory from a previous run of All eight participants showed improvement in memory over the the test would have influenced performance, it likely will have been course of the trial. The improvement in memory at the end of the in a negative fashion through proactive interference. However, it Acute Phase (7.38 points in the MIS score) was sustained 3 months is possible that practice effects could have had a potential impact. Frontiers in Human Neuroscience 08 frontiersin.org Frontiers in Human Neuroscience Cappon et al. TABLE 6 Memory Index Scores (MIS) for all participants and comparisons to baseline. Participant Baseline Acute Phase month 1 Acute Phase month 2 Post-acute phase Post-hiatus phase Post-taper phase Score Score Score change Score Score change Score Score change Score Score change Score Score change from baseline from baseline from baseline from baseline from baseline P001 0 8.5 + 8.5 13 +13 14 + 14 14 + 14 4 +4 P002 0 5 +5 8.5 + 8.5 11 + 11 12 + 12 8 +8 P003 0 9 +9 5 +5 6 +6 6 +6 7 +7 P006 1 9 +8 6 +5 6 +5 10 +9 7 +6 P007 0 7 +7 7 +7 8 +8 1 +1 2 +2 P008 1 8 +7 9 +8 6 +5 3 +2 6 +5 P010 0 4.5 + 4.5 2.5 + 2.5 7 +7 5 +5 1 +1 P011 4 9 +5 9.5 + 5.5 6 +2 N/A N/A 8 +4 09 TABLE 7 MoCA scores for all participants during the course of the study and comparisons to baseline. Participant Baseline Acute Phase month 1 Acute Phase month 2 Post-acute phase Post-hiatus phase Post-taper phase Score Score Score change Score Score change Score Score change Score Score change Score Score change from baseline from baseline from baseline from baseline from baseline P001 21 24.5 + 3.5 26 +5 27 +6 22 +1 11.5 −9.5 P002 23 22 −1 23 +0 25 +2 21 −2 20 −3 P003 28 27 −1 23 −5 23 −5 24.5 −3.5 20.5 −7.5 P006 17 20.5 + 3.5 18 +1 16 −1 23 +6 20.5 + 3.5 10.3389/fnhum.2023.1168673 P007 18 15 −3 16 −2 15 −3 15 −3 12 −6 P008 10 13.5 + 3.5 16.5 + 6.5 14 +4 8 −2 14 +4 P010 10 11.5 + 1.5 12.5 + 2.5 14 +4 9 −1 7 −3 frontiersin.org P011 22 24 +2 27.5 + 5.5 24 +2 N/A N/A 23 +1 Cappon et al. 10.3389/fnhum.2023.1168673 It is worth noting that the MoCA scores remained the same even research with home-based neuromodulatory interventions for when MIS scores increased. This is in line with previous literature memory functioning in AD. Further, the preliminary evidence that suggests that targeting domains of cognitive functioning with about memory improvements and potential decreases in the non-invasive brain stimulation may be a net zero-sum game (Brem theta/gamma ratio merit larger and ultimately better controlled et al., 2014). This is something that merits further investigation in trials to more definitively determine the effect of tACS on memory larger, well controlled trials. functioning and on the underlying brain activity in AD. Finally, Finally, the observed EEG changes in the theta/gamma the differential effects on memory and global cognition should ratio may have a potential relation to the observed behavioral be further explored by, for example, administering complex improvement and might indicate neurophysiological changes neuromodulation interventions that target multiple cognitive induced by repeated tACS exposure. Specifically, it has been domains simultaneously. shown that increased theta/gamma ratio is associated with memory impairment in AD (Moretti et al., 2009) and it is predictive of progression from MCI to AD (Moretti et al., 2011). Our results could potentially indicate a relation between a decrease Data availability statement in theta/gamma ratio and improvement in memory function. However, these are very preliminary results, and our small sample The raw data supporting the conclusions of this article will be size for the EEG portion of this study makes it difficult to draw any made available by the authors, without undue reservation. robust conclusions. Further investigation is required to understand the relation between the behavioral and neurophysiological effects of HB-tACS targeted at the AG. As a feasibility trial testing a novel memory-focused Ethics statement intervention for AD, our study has relevant limitations. First, the sample size is small. A partial explanation for this is that the This study involving human participants was approved and novelty of this intervention approach required a preliminary pilot monitored by an independent Institutional Review Board (Advarra, study. However, this small sample does limit the generalizability Inc.). The patients/participants provided their written informed of the feasibility findings for this intervention. Secondly, as consent to participate in this study. the first study of its kind, it was impractical to enroll a control group of AD patients who did not receive tACS or that received sham tACS. Therefore, it is impossible to account for potential placebo effects. Thirdly, the methodology for measuring changes Author contributions in memory functioning was limited to a singular index. Future DC: conceptualization and design of the study, analysis and studies should aim to encompass a larger breadth of memory interpretation of data, writing of the original manuscript draft, measurements to build a more well-rounded idea of how memory reviewing and editing, and supervision. RF: acquisition of data, was impacted. Fourthly, the results of the EEG source localization writing of the original draft, reviewing and editing, figures are constrained by the elimination of a large number of electrodes preparation, and editing. TB: acquisition of data, writing of the due to noise, and the EEG was only assessed in a subset of original manuscript draft, and reviewing and editing. WY and NL: participants, a too small sample to allow any conclusions to be acquisition of data, and writing—review and editing. GC: writing— drawn. Despite these limitations, this study provides relevant review and editing. RP-A: analysis of data, interpretation of data, data for future tACS investigations in AD. Future studies should and writing—review and editing. DB-F: interpretation of data, and build off the present pilot study and aim to enroll higher writing—review and editing. BM: conceptualization and design of numbers of patients and include appropriate controls to test the study, interpretation of data, and writing—review and editing. clinical efficacy. AP-L: conceptualization and design of the study, interpretation of data, writing of the original manuscript draft, reviewing and editing of manuscript, and supervision. All authors contributed to Conclusion the article and approved the submitted version. This pilot study shows the feasibility and preliminary efficacy of a novel, home-based, remotely supervised, study companion- led, multi-channel neuromodulation intervention for older adults Funding with AD. We observed an improvement in memory scores throughout the duration of the intervention while global cognition DC was partially supported by the Brain and Behavior Research was relatively stable, indicating that future interventions might Foundation (30772) and a grant from the NIH (R01 AG076708). benefit from multifocal neuromodulation targeting multiple AP-L and BM were partially supported by grants from the cognitive domains. Future additional randomized controlled NIH (R01 AG059089 and R01 AG076708) and the Bright Focus studies will be required to determine the efficacy of HB- Foundation. DB-F was supported by an ICREA Académia 2019 tACS intervention. Our findings, which show safety and high award. GC was partially supported by Fundació La Marató de adherence to this intervention are encouraging for continuing TV3 (202129-30-31 and 202211-30-31). RP-A was supported Frontiers in Human Neuroscience 10 frontiersin.org Cappon et al. 10.3389/fnhum.2023.1168673 by a fellowship from “La Caixa” Foundation (ID 100010434; The remaining authors declare that the research was conducted Fellowship code: 390 LCF/BQ/DI19/11730050). in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Conflict of interest Publisher’s note AP-L is a co-founder of Linus Health and TI Solutions AG; serves on the scientific advisory boards for Starlab Neuroscience, All claims expressed in this article are solely those of the Magstim Inc., Radiant Hearts, Tetraneuron, and MedRhythms; authors and do not necessarily represent those of their affiliated and is listed as an inventor on several issued and pending organizations, or those of the publisher, the editors and the patents on the real-time integration of non-invasive brain reviewers. Any product that may be evaluated in this article, or stimulation with electroencephalography and magnetic resonance claim that may be made by its manufacturer, is not guaranteed or imaging. endorsed by the publisher. References Abraham, M., Seidenberg, M., Kelly, D. A., Nielson, K. A., Woodard, J. L., de Cheveigné, A. (2020). ZapLine: A simple and effective method to remove power Carson Smith, J., et al. (2020). Episodic memory and hippocampal volume line artifacts. NeuroImage 207:116356. doi: 10.1016/j.neuroimage.2019.116356 predict 5-year mild cognitive impairment conversion in healthy apolipoprotein Delorme, A., and Makeig, S. (2004). EEGLAB: An open source toolbox for analysis ε4 carriers. J. Int. Neuropsychol. Soc. 26, 733–738. doi: 10.1017/s13556177200 of single-trial EEG dynamics including independent component analysis. J. Neurosci. 00181 Methods 134, 9–21. doi: 10.1016/j.jneumeth.2003.10.009 Adaikkan, C., Middleton, S. J., Marco, A., Pao, P.-C., Mathys, H., Kim, den Boer, T., Fox, R., Yu, W., LaGanke, N., Manor, B., Pascual-Leone, A., et al. D. N.-W., et al. (2019). Gamma entrainment binds higher-order brain regions (2022). “A remote training and supervision program from transcranial electrical and offers neuroprotection. Neuron 102, 929–943.e8. doi: 10.1016/j.neuron.2019.0 stimulation in the home setting,” in Poster at the Cognitive Neuroscience Society Annual 4.011 Meeting, (San Francisco, CA). doi: 10.1177/1357633X19861830 Alzheimer’s Association (2022). 2022 Alzheimer’s disease facts and figures. Chicago, Desikan, R. S., Ségonne, F., Fischl, B., Quinn, B. T., Dickerson, B. C., Blacker, IL: Alzheimer’s Association. D., et al. (2006). An automated labeling system for subdividing the human cerebral Antal, A., Alekseichuk, I., Bikson, M., Brockmöller, J., Brunoni, A. R., Chen, R., et al. cortex on MRI scans into gyral based regions of interest. NeuroImage 31, 968–980. (2017). Low intensity transcranial electric stimulation: Safety, ethical, legal regulatory doi: 10.1016/j.neuroimage.2006.01.021 and application guidelines. Clin. Neurophysiol. 128, 1774–1809. doi: 10.1016/j.clinph. El Haj, M., Roche, J., Gallouj, K., and Gandolphe, M.-C. (2017). Autobiographical 2017.06.001 memory compromise in Alzheimer’s disease: A cognitive and clinical overview. Antal, A., and Paulus, W. (2013). Transcranial alternating current stimulation Gériatrie Psychol. Neuropsychiatr. Viellissement 15, 443–451. doi: 10.1684/pnv.2017. (tACS). Front. Hum. Neurosci. 7:317. doi: 10.3389/fnhum.2013.00317 0704 Avgerinos, K. I., Ferrucci, L., and Kapogiannis, D. (2021). Effects of monoclonal Etter, G., van der Veldt, S., Manseau, F., Zarrinkoub, I., Trillaud-Doppia, E., and antibodies against amyloid-β on clinical and biomarker outcomes and adverse event Williams, S. (2019). Optogenetic gamma stimulation rescues memory impairments in risks: A systematic review and meta-analysis of phase III RCTs in Alzheimer’s disease. an Alzheimer’s disease mouse model. Nat. Commun. 10:5322. doi: 10.1038/s41467- Ageing Res. Rev. 68:101339. doi: 10.1016/j.arr.2021.101339 019-13260-9 Babiloni, C., Lizio, R., Marzano, N., Capotosto, P., Soricelli, A., Triggiani, A. I., Hampel, H., Mesulam, M.-M., Cuello, A. C., Farlow, M. R., Giacobini, E., Grossberg, et al. (2016). Brain neural synchronization and functional coupling in Alzheimer’s G. T., et al. (2018). The cholinergic system in the pathophysiology and treatment of disease as revealed by resting state EEG rhythms. Int. J. Psychophysiol. 103, 88–102. Alzheimer’s disease. Brain 141, 1917–1933. doi: 10.1093/brain/awy132 doi: 10.1016/j.ijpsycho.2015.02.008 Herrmann, C. S., Rach, S., Neuling, T., and Strüber, D. (2013). Transcranial Benussi, A., Cantoni, V., Cotelli, M. S., Cotelli, M., Brattini, C., Datta, A., et al. alternating current stimulation: A review of the underlying mechanisms and (2021). Exposure to gamma tACS in Alzheimer’s disease: A randomized, double-blind, modulation of cognitive processes. Front. Hum. Neurosci. 7:279. doi: 10.3389/fnhum. sham-controlled, crossover, pilot study. Brain Stimul. 14, 531–540. doi: 10.1016/j.brs. 2013.00279 2021.03.007 Humphreys, G. F., Lambon Ralph, M. A., and Simons, J. S. (2021). A unifying Benussi, A., Cantoni, V., Grassi, M., Brechet, L., Michel, C. M., Datta, A., et al. account of angular gyrus contributions to episodic and semantic cognition. Trends (2022). Increasing brain gamma activity improves episodic memory and restores Neurosci. 44, 452–463. doi: 10.1016/j.tins.2021.01.006 cholinergic dysfunction in Alzheimer’s disease. Ann. Neurol. 92, 322–334. doi: 10.1002/ Iaccarino, H. F., Singer, A. C., Martorell, A. J., Rudenko, A., Gao, F., Gillingham, ana.26411 T. Z., et al. (2016). Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature 540, 230–235. doi: 10.1038/nature20587 Brem, A.-K., Fried, P. J., Horvath, J. C., Robertson, E. M., and Pascual-Leone, A. (2014). Is neuroenhancement by noninvasive brain stimulation a net zero-sum Julayanont, P., Brousseau, M., Chertkow, H., Phillips, N., and Nasreddine, Z. S. proposition? NeuroImage 85, 1058–1068. doi: 10.1016/j.neuroimage.2013.07.038 (2014). Montreal Cognitive Assessment Memory Index Score (MoCA-MIS) as a predictor of conversion from mild cognitive impairment to Alzheimer’s disease. J. Am. Brown, M. T., and Bussell, J. K. (2011). Medication adherence: WHO cares? Mayo Geriatr. Soc. 62, 679–684. doi: 10.1111/jgs.12742 Clin. Proc. 86, 304–314. doi: 10.4065/mcp.2010.0575 Kim, J., Kim, H., Jeong, H., Roh, D., and Kim, D. H. (2021). tACS as a promising Cappon, D., den Boer, T., Jordan, C., Yu, W., Lo, A., LaGanke, N., et al. (2022). Safety therapeutic option for improving cognitive function in mild cognitive impairment: and feasibility of tele-supervised home-based transcranial direct current stimulation A direct comparison between tACS and tDCS. J. Psychiatr. Res. 141, 248–256. doi: for major depressive disorder. Front. Aging Neurosci. 13:765370. doi: 10.3389/fnagi. 10.1016/j.jpsychires.2021.07.012 2021.765370 Koenig, T., Prichep, L., Dierks, T., Hubl, D., Wahlund, L. O., John, E. R., et al. Cappon, D., D’Ostilio, K., Garraux, G., Bisiacchi, P., and Rothwell, J. (2015). Cortical (2005). Decreased EEG synchronization in Alzheimer’s disease and mild cognitive modulation of automatic facilitation and inhibition by 10 Hz and 20 Hz transcranial impairment. Neurobiol. Aging 26, 165–171. doi: 10.1016/j.neurobiolaging.2004.03.008 alternating current stimulation (tACS). Brain Stimulation 8:356. doi: 10.1016/j.brs. 2015.01.149 Kybic, J., Clerc, M., Abboud, T., Faugeras, O., Keriven, R., and Papadopoulo, T. (2005). A common formalism for the Integral formulations of the forward EEG Cappon, D., D’Ostilio, K., Garraux, G., Rothwell, J., and Bisiacchi, P. (2016). Effects problem. IEEE Trans. Med. Imaging 24, 12–28. doi: 10.1109/tmi.2004.837363 of 10 Hz and 20 Hz transcranial alternating current stimulation on automatic motor control.ăBrain Stimulation 9, 518–524. doi: 10.1016/j.brs.2016.01.001 Lei, L., Lam, B., Lai, D., Bai, X., Li, J., Zou, Z., et al. (2022). Stability of montreal cognitive assessment in individuals with mild cognitive impairment: Potential Charvet, L., Shaw, M., Haider, L., Melville, P., and Krupp, L. (2015). Remotely- influence of practice effect. J. Alzheimers Dis. 87, 1401–1412. doi: 10.3233/JAD-220003 delivered cognitive remediation in multiple sclerosis (MS): Protocol and results from a pilot study. Multiple Scler. J. Exp. Transl. Clin. 1:205521731560962. doi: 10.1177/ Luu, P., and Ferree, T. (2005). Determination of the geodesic sensor nets’ 2055217315609629 average electrode positions and their 10 – 10 international equivalents. Technical Frontiers in Human Neuroscience 11 frontiersin.org Cappon et al. 10.3389/fnhum.2023.1168673 Note. Available online at: https://www.researchgate.net/publication/266609828_ pattern targeting from realistic modeling of electric fields. NeuroImage 89, 216–225. Determination_of_the_Geodesic_Sensor_Nets%27_Average_Electrode_Positions_ doi: 10.1016/j.neuroimage.2013.12.002 and_Their_10_-_10_International_Equivalents (accessed September 15, 2020). Salmelin, R., and Baillet, S. (2009). Electromagnetic brain imaging. Hum. Brain Martorell, A. J., Paulson, A. L., Suk, H.-J., Abdurrob, F., Drummond, G. T., Guan, Mapp. 30, 1753–1757. doi: 10.1002/hbm.20795 W., et al. (2019). Multi-sensory gamma stimulation ameliorates Alzheimer’s-associated Sperling, R. A., Laviolette, P. S., O’Keefe, K., O’Brien, J., Rentz, D. M., Pihlajamaki, pathology and improves cognition. Cell 177, 256–271.e22. doi: 10.1016/j.cell.2019.02. M., et al. (2009). Amyloid deposition is associated with impaired default network 014 function in older persons without dementia. Neuron 63, 178–188. doi: 10.1016/j. Mazziotta, J. C., Toga, A. W., Evans, A., Fox, P., and Lancaster, J. (1995). A neuron.2009.07.003 probabilistic atlas of the human brain: Theory and rationale for its development. Tadel, F., Bock, E., Niso, G., Mosher, J. C., Cousineau, M., Pantazis, D., et al. (2019). NeuroImage 2, 89–101. doi: 10.1006/nimg.1995.1012 MEG/EEG group analysis with brainstorm. Front. Neurosci. 13:76. doi: 10.3389/fnins. Moretti, D. V., Fracassi, C., Pievani, M., Geroldi, C., Binetti, G., Zanetti, 2019.00076 O., et al. (2009). Increase of theta/gamma ratio is associated with memory van de Mortel, L. A., Thomas, R. M., and van Wingen, G. A. (2021). Grey matter impairment. Clin. Neurophysiol. 120, 295–303. doi: 10.1016/j.clinph.2008. loss at different stages of cognitive decline: A role for the thalamus in developing 11.012 Alzheimer’s disease. J. Alzheimers Dis. 83, 705–720. doi: 10.3233/jad-210173 Moretti, D. V., Frisoni, G. B., Fracassi, C., Pievani, M., Geroldi, C., Binetti, G., van Dyck, C. H., Swanson, C. J., Aisen, P., Bateman, R. J., Chen, C., Gee, M., et al. (2011). MCI patients’ EEGs show group differences between those who progress et al. (2022). Lecanemab in early Alzheimer’s disease. N. Eng. J. Med. 388, 9–21. and those who do not progress to AD. Neurobiol. Aging 32, 563–571. doi: 10.1016/j. doi: 10.1056/nejmoa2212948 neurobiolaging.2009.04.003 Welch, P. (1967). The use of fast Fourier transform for the estimation of power Nasreddine, Z. S., Phillips, N. A., Bedirian, V., Charbonneau, S., Whitehead, V., spectra: a method based on time averaging over short, modified periodograms. IEEE Collin, I., et al. (2005). The montreal cognitive assessment, MoCA: A brief screening Trans. Audio Electroacoust. 15, 70–73. doi: 10.1109/TAU.1967.1161901 tool for mild cognitive impairment. J. Am. Geriatr. Soc. 53, 695–699. doi: 10.1111/j. 1532-5415.2005.53221.x Wong, A., Nyenhuis, D., Black, S. E., Law, L. S. N., Lo, E. S. K., Kwan, P. W. L., et al. (2015). Montreal cognitive assessment 5-minute protocol is a brief, valid, reliable, Oh, H., Madison, C., Villeneuve, S., Markley, C., and Jagust, W. J. (2013). Association and feasible cognitive screen for telephone administration. Stroke 46, 1059–1064. of gray matter atrophy with age, β-amyloid, and cognition in aging. Cereb. Cortex 24, doi: 10.1161/strokeaha.114.007253 1609–1618. doi: 10.1093/cercor/bht017 World Health Organization (2022). Dementia. Geneva: World Health Organization. Palop, J. J. (2020). Network abnormalities and interneuron dysfunction in Alzheimer’s disease. Alzheimers Dement. 16:e040396. doi: 10.1002/alz.040396 Zaehle, T., Rach, S., and Herrmann, C. S. (2010). Transcranial alternating current stimulation enhances individual alpha activity in human EEG. PLoS One 5:e13766. Palop, J. J., and Mucke, L. (2016). Network abnormalities and interneuron doi: 10.1371/journal.pone.0013766 dysfunction in Alzheimer disease. Nat. Rev. Neurosci. 17, 777–792. doi: 10.1038/nrn. Zhou, D., Li, A., Li, X., Zhuang, W., Liang, Y., Zheng, C.-Y., et al. (2022). Effects 2016.141 of 40 Hz transcranial alternating current stimulation (tACS) on cognitive functions Ruffini, G., Fox, M. D., Ripolles, O., Miranda, P. C., and Pascual-Leone, A. (2014). of patients with Alzheimer’s disease: A randomised, double-blind, sham-controlled Optimization of multifocal transcranial current stimulation for weighted cortical clinical trial. J. Neurol. Neurosurg. Psychiatry 93, 568–570. Frontiers in Human Neuroscience 12 frontiersin.org