2.1. General study design

This study took place at the Medical University of South Carolina (MUSC) Institute of Psychiatry between November 2018 and January 2022. It was funded by the NIMH in an R21/R33 format (ClinicalTrials.gov listing NCT032421808). Prior to any study procedures, all patients signed a written consent form approved by the MUSC IRB.

Advertising was done through mailings to key clinical providers in the Charleston area and flyers and email postings. Patients with treatment resistant unipolar major depression with a baseline Hamilton Rating Scale for Depression (HRSD) score (24-item) >20 were enrolled. Inclusion/Exclusion Criteria: Patients had to have a diagnosis on the SCID-P to derive DSM-IV criteria of a diagnosis of unipolar major depressive disorder without psychosis. They had to have a Hamilton Depression Rating Scale 24 item score of ≥20 and be between 21 and 70 years old. They could maintain fixed and stable antidepressant medications (at least three weeks prior to start with no change). They had to have a moderate level of treatment resistance (1–4 medications in the current episode or intolerance to at least three trials) and have a current episode duration no greater than three years. They could not have a history of schizophrenia, schizoaffective disorder, other [non-mood disorder] psychosis, depression secondary to a medical condition, mental retardation, substance dependence or abuse within the past year (except nicotine), bipolar disorder, psychotic features in this or previous episodes, amnestic disorder, dementia or MMSE ≤24, delirium, obsessive-compulsive disorder, post-traumatic stress disorder, or panic disorder. They could not have current vagus nerve stimulation (VNS) therapy, electroconvulsive therapy (ECT), or TMS within three months or a history of non-response to ECT. They could not have safety contraindications to MRI scanning. They must have been medically stable and without active suicidal intent or plan or suicide attempt within the past 12 months.

Prior to the clinical trial, all patients had two MRI scans after obtaining consent but before being randomized (see Fig. 1 for more details). During the first scan on a Siemens Prisma 3T scanner, they had a short structural scan and resting state fMRI. If they could tolerate this and were not claustrophobic, they then had a longer fNET scan where the person’s individual alpha and synchronization phase were identified using the method described in Faller supplemental material S.1 [21]. The 15 subjects in the blinded analysis (Faller et al., 2022) are also included in this current manuscript as part of the completer samples (as well of course as ITT), with their clinical scores and group assignment.

After consent and baseline screening assessments, subjects had 2 MRI scans performed. These MRI’s were concurrent TMS/EEG/BOLD fMRI (fET). Subjects were then randomized to SYNC or UNSYNC and were treated for 30 TMS sessions over six weeks, followed by a post-treatment course concurrent TMS/EEG/BOLD fMRI (fET). Immediately before the first TMS session, and then after every five treatment sessions (sometimes roughly referred to as a week, but this is not always true to the calendar), patients had the following assessments performed by a qualified individual who was blinded to the patient’s assigned treatment group: Hamilton Depression Score (Ham-D 28 item), Inventory of Depressive Symptomatology Self-Report (IDS-SR), Montgomery-Asberg Depression Rating Scale (MADRS), Global Assessment of Functioning (GAF), and Clinical Global Impression (CGI). For data analysis, the pre#1 scores were used as the baseline for calculating clinical response data, as this was closer to the actual start of treatment. The time between the last TMS treatment and the post MRI scan varied from the next day to 14 days, depending on the MRI scanner. (This entire trial was done during the COVID pandemic.)

After every five treatment sessions (sometimes roughly referred to as a ‘week’, but this is not always true to the calendar) (described in Fig. 1), patients had the following assessments performed by a qualified individual who was blinded to the patient’s assigned treatment group: Hamilton Depression Score (Ham-D 28 item), Inventory of Depressive Symptomatology Self-Report (IDS-SR), Montgomery-Asberg Depression Rating Scale (MADRS), Global Assessment of Functioning (GAF), and Clinical Global Impression (CGI).