Daily prefrontal TMS for depression, as developed by the PI, involves delivering TMS pulses to the prefrontal cortex and not assessing what the actual EEG phase is of the person's brain. In cardiology, in order to stimulate the heart effectively, one has to know the rhythm and phase of the heartbeat in order to perform cardioversion. The investigators wonder if it is important to time the brain stimulation with the phase of the person's brain. The brain has definite rhythms, and cycles through being excited or resting. A common EEG rhythm is alpha frequency. Theoretically, the effect of the TMS pulse might be diminished if it was delivered when the brain was temporarily cycling into an off state.

In the r21 part of this grant, the investigators designed and constructed a combined TMS/EEG/fMRI system. With that equipment the investigators found that TMS pulses have different effects deeper in the brain as a function of the EEG alpha phase. Pulses delivered during a rising phase produce larger blood flow changes deeper in the brain than do pulses delivered during a falling phase.

In the R33 phase of the grant the investigators now take that idea into a small clinical trial in depression to test if synchronized pulses have a larger clinical effect than do non-synchronized pulses.

The investigators have completed the first R21 phase of this combined two phase grant. Essentially, the investigators succeeded in creating for the first time on planet Earth a fully working combined and integrated TMS-fMRI-EEG system, and then used that in healthy controls to show that the secondary effect of the TMS pulse is greater when it is delivered to the cortex during the rising phase of the EEG alpha wave for that person. The group then also showed that they can monitor a subject with EEG and then predict and time a TMS pulse to be able to hit this time window.

The goal of the R33 phase of this R21/R33 grant is to test the hypothesis that synchronized stimulation has clinical implications; specifically that the increased rACC inhibition due to increased cortical activation of the DLPFC by synchronizing the TMS pulse application to an individual patient's alpha rhythm will have a significant effect on the anti-depressive treatment response rate for TMS, sufficient to justify a future, more extensive clinical trial.

In this study, the investigators will look first at the BOLD activity from the rACC as a measure of target engagement because there is a substantial literature suggesting that reductions in activity in the rACC are an integral part of the depression network and may predict eventual antidepressant effect. 1-5 Moreover, the investigators and others have shown that stimulation of the left DLPFC causes a reciprocal change in rACC. 6-9. The studies proposed for the R33 will randomize a cohort of 60 medication free depressed patients to standard TMS treatment (NON-SYNC) or timing optimized TMS treatment (SYNC). For the later cohort the investigators will use the results of the R21 phase to measure the optimum timing of the TMS pulses with respect to each individual's EEG rhythms to maximize inhibition of the rACC following TMS. This will be done at entry into the trial and after the therapy is complete. Both experimental and control group will undergo these measurements but they will only be used in the former group. To enable the 4 week (5 days/wk) TMS treatment plan to be able to use this individually determined timing, the investigators will integrate a second EEG system with our treatment TMS unit. The R33 specific aims are:

Specific Aim 1: Integrate a similar EEG system with our treatment TMS scanner with similar feedback circuitry as that in SA 3 in the R21.

Specific Aim 2: Carry out a 4 week trial (2 extra weeks for responders but not remitters) of anti-depressive therapy randomized between optimum timed TMS (SYNC) and standardized non-synchronous TMS (NON-SYNC) in a cohort of depressed patients to estimate the success rate of such an optimized treatment.

This study will provide the data needed for a go/no-go decision on a full clinical trial for this potential novel therapy.

Hypothesis: In a double blind, randomized (1:1) trial enrolling only at MUSC over three years in 60 treatment resistant depressed patients, we hypothesize that daily prefrontal rTMS over 4-6 weeks with the initial TMS pulse of each train synchronized to the subject's alpha phase (SYNC TMS), will result in improvement in depression, and that these improvements will be greater than the improvements seen using the same form of treatment but not with the initial pulse synchronized (NON-SYNC). As this work is a first ever use of this technology, the investigators wish to compare the antidepressant effects to standard therapy to see if synchronization boosts the clinical effect. A power analysis for this number of subjects exists but the investigators are really most interested in comparing the overall outcome between the two groups, and looking at response predictors. Thus it is not a formal efficacy or even inferiority trial, rather a comparative early phase trial.

Inclusion Criteria:

1. Diagnosis of unipolar major depressive disorder, in a current major depressive episode, without psychotic features
2. Pretreatment Hamilton score ≥ 20
3. Age between 21 and 70 years
4. Fixed and stable antidepressant medications for 3 weeks prior and during the rTMS trial. Limit on benzodiazapenes to lorazepam (or equivalent) up to 3 mg every day
5. Moderate level of resistance to antidepressant treatment in the current episode, defined as failure of 1-4 adequate medication trials or intolerance to at least 3 trials, and duration of current episode ≤ 3 years
6. No 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, panic disorder
7. No current Vagus Nerve Stimulation
8. No history of failing to respond to an adequate course of ECT in this or any episode, and no ECT within the past 3 months
9. No contraindication to MRI
10. No contraindication to rTMS (history of neurological disorder or seizure (except induced by ECT), increased intracranial pressure, brain surgery, or head trauma with loss of consciousness for >15 minutes, implanted electronic device, metal in the head, or pregnancy)
11. No history of autoimmune, endocrine, viral, or vascular disorder. No unstable cardiac disease, uncontrolled hypertension, or sleep apnea
12. No active suicidal intent or plan, or history of attempt within the past 12 months
13. Willing to provide informed consent

Exclusion Criteria:

1. To ensure that baseline levels of depression severity are stable at the time of study enrollment, patients will be dropped if they show > 30% improvement in the HRSD score from the time of initial intake (e.g., screening) to the baseline assessment.
2. Patients must have a recordable alpha frequency.

The full extent of the trial, June 2019 until February 2022. For each subject this covered the time of clinical participation and 6 month follow-up. More specifically, this was the time of clinical participation (up to 6 weeks) and 6 month follow-up, approximately 7.5 months,

Limitations are a small sample, using the intrinsic alpha frequency in each group, and the preferred synchronization was done before the trial and may have changed over time.

All subjects will get EEGS and TMS, but in one group the TMS pulses are synchronized to the EEG, and in the other not. There is no way for the subject or treater or anyone to detect who is in which arm.