Abstract Aim: To investigate neural oscillatory networks in major depressive disorder (MDD), effects of home-based transcranial direct current stimulation (tDCS) treatment, and potential predictors of treatment remission. Methods: In a randomised controlled trial (RCT) of home-based tDCS treatment, EEG data were acquired a subset: 21 MDD participants (16 women) (mean age 36.63 ± 9.71 years) in current depressive episode of moderate to severe severity (mean Hamilton Depression Rating Scale (HAMD) score 18.42 ± 1.80). Participants were randomised to either active (n=11) or sham tDCS (n=8). Treatment was home-based tDCS treatment for 10 weeks in a bifrontal montage (anode over left dorsolateral prefrontal cortex) consisting of 5 sessions per week for 3 weeks and 3 sessions per week for 7 weeks. Active tDCS was 2mA and sham tDCS 0mA with brief ramp up and ramp down period to mimic active stimulation. Each session was 30 minutes. Clinical remission was defined as HAMD score ≤ 7. Resting-state EEG data were acquired at baseline, prior to the start of treatment, and at 10-week end of treatment. EEG data were acquired using portable 4-channel EEG device (electrode positions: AF7, AF8, TP9, TP10). EEG band power was extracted for each electrode and functional connectivity phase synchronization by phase locking value (PLV). Deep learning was applied to baseline PLV features to identify predictors of treatment remission. Results: Main effect of group was observed in gamma PLV in frontal and temporal regions, in which active tDCS treatment group showed higher connectivity as compared to sham group. In active treatment group, significant positive correlations between changes in delta, theta, alpha, and beta PLV and improvement in depression severity were observed. The highest treatment remission prediction was achieved by combining PLV features from theta, alpha, and beta: accuracy 71.94% (sensitivity 52.88%, specificity 83.06%). Conclusions: Synchronized brain activity across large-scale networks as reflected in gamma PLV is a potential mechanism of active tDCS as compared to placebo-sham tDCS. Baseline resting-state EEG is a potential predictor of treatment remission. Home-based EEG measures are feasible and potentially useful predictors of clinical outcome.

Conflict of interest AHY reports the following declaration of interests: Paid lectures and advisory boards for the following companies with drugs used in affective and related disorders: Flow Neuroscience, Novartis, Roche, Janssen, Takeda, Noema pharma, Compass, Astrazenaca, Boehringer Ingelheim, Eli Lilly, LivaNova, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, Sage, Novartis, Neurocentrx. Principal Investigator for the following studies: 1. the Restore-Life VNS registry study funded by LivaNova; 2. ESKETINTRD3004: "An Open-label, Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression"; 3. The Effects of Psilocybin on Cognitive Function in Healthy Participants; 4. The Safety and Efficacy of Psilocybin in Participants with Treatment-Resistant Depression (P-TRD); 5. A Double-Blind, Randomized, Parallel-Group Study with Quetiapine Extended Release as Comparator to Evaluate the Efficacy and Safety of Seltorexant 20 mg as Adjunctive Therapy to Antidepressants in Adult and Elderly Patients with Major Depressive Disorder with Insomnia Symptoms Who Have Responded Inadequately to Antidepressant Therapy. (Janssen); 6. An Open-label, Long-term, Safety and Efficacy Study of Aticaprant as Adjunctive Therapy in Adult and Elderly Participants with Major Depressive Disorder (MDD). (Janssen); 7. A Randomized, Double-blind, Multicentre, Parallel-group, Placebo-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Aticaprant 10 mg as Adjunctive Therapy in Adult Participants with Major Depressive Disorder (MDD) with Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy; 8. A Study of Disease Characteristics and Real-life Standard of Care Effectiveness in Patients with Major Depressive Disorder (MDD) With Anhedonia and Inadequate Response to Current Antidepressant Therapy Including an SSRI or SNR. (Janssen). UK Chief Investigator for the following studies: 1. Novartis MDD study MIJ821A12201; 2. Compass; COMP006 & COMP007 studies. Grant funding (past and present): NIMH (USA); CIHR (Canada); NARSAD (USA); Stanley Medical Research Institute (USA); MRC (UK); Wellcome Trust (UK); Royal College of Physicians (Edin); BMA (UK); UBC-VGH Foundation (Canada); WEDC (Canada); CCS Depression Research Fund (Canada); MSFHR (Canada); NIHR (UK). Janssen (UK) EU Horizon 2020. Editor of Journal of Psychopharmacology and Deputy Editor, BJPsych Open. No shareholdings in pharmaceutical companies. CHYF has received grant funding from: Milken Institute Baszucki Brain Research (BD00000029), National Institute of Mental Health (R01MH134236), Rosetrees Trust (CF20212104), Flow Neuroscience. SS reports the following declaration of interests: Research grant funding on behalf of the University of Texas Health Science Center at Houston from Flow Neuroscience. Paid advisory boards for the following companies: Worldwide Clinical Trials and Inversago; Vicore pharma. SS is a fulltime employee of Intra-Cellular Therapies, Inc. He has received grants/research support from NIMH, United States (1R21MH119441-01A1), NIMH (1R21MH129888-01A1), NICHD 1R21HD106779-01A1, and SAMHSA (6H79FG000470-01M003). He has received research funding as a Principal investigator or study/sub-investigator from and/or participated as consultant/speaker for Flow Neuroscience, COMPASS Pathways, LivaNova, Janssen, Relmada, and Psychiatry education forum. JCS has received grant funding from Flow Neuroscience. Intra-Cellular Therapies (ITI) or NIH or SAMHSA or any other organizations had no role in the study's design and conduct; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. This study's content is solely the responsibility of the authors and does not necessarily represent the official views of the ITI or NIH or SAMHSA. Authors WX, JCM, RDW, NL, HH, GS, ARGN, PJL and RMV declare that they have no competing interests to declare. tDCS devices were provided by Flow Neuroscience.

NCT05202119

The study was funded by Flow Neuroscience.

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