EEG Synchronized TMS Trial for Depression

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.