- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03421808
EEG Synchronized TMS Trial for Depression
Randomized Controlled Trial of EEG/fMRI Controlled TMS For Treating Depression
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.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 3
Contacts and Locations
Study Locations
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South Carolina
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Charleston, South Carolina, United States, 29425
- Medical University of South Carolina Brain Stimulation Division
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Diagnosis of unipolar major depressive disorder, in a current major depressive episode, without psychotic features
- Pretreatment Hamilton score ≥ 20
- Age between 21 and 70 years
- 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
- 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
- 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
- No current Vagus Nerve Stimulation
- 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
- No contraindication to MRI
- 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)
- No history of autoimmune, endocrine, viral, or vascular disorder. No unstable cardiac disease, uncontrolled hypertension, or sleep apnea
- No active suicidal intent or plan, or history of attempt within the past 12 months
- Willing to provide informed consent
Exclusion Criteria:
- 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.
- Patients must have a recordable alpha frequency.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: SYNC TMS
Patients will receive daily left prefrontal transcranial magnetic stimulation (TMS), 120% MT, 3000 pulses/session, for 30 sessions.
They will have EEG and the TMS will be delivered at their individual alpha frequency (IAF) (8-12 Hz) and the first TMS pulse in each train of 40 pulses will be synchronized with the EEG so that the TMS pulse fires during the rising phase of the alpha rhythm.
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TMS
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Active Comparator: Non-Sync TMS
Patients will receive daily left prefrontal transcranial Magnetic stimulation (TMS), 120% MT, 3000 pulses/session, for 30 sessions.
They will have EEG and the TMS will be delivered at their individual alpha frequency (IAF) (8-12 Hz) and the first TMS pulse in each train of 40 pulses will NOT be synchronized with the EEG so that the TMS pulse fires during the rising phase of the alpha rhythm.
This is the way conventional TMS is delivered now and is FDA approved.
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TMS
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Remission Rate
Time Frame: At the 4th week of treatment (or 6 weeks in those who continue to 6 weeks).
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Depression Remission, as defined by the Hamilton Rating Scale for Depression, 24 item, score less than 10
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At the 4th week of treatment (or 6 weeks in those who continue to 6 weeks).
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
EEG phase synchronization
Time Frame: At each treatment session and progressively over the 30 sessions
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EEG phase synchronization will be assessed by collecting realtime EEG, and then calculating whether the person's EEG frequency changed after the first few pulses in the train to where the EEG then matches the TMS pulses exactly and all TMS pulses are delivered at precisely the same time in the EEG cycle.
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At each treatment session and progressively over the 30 sessions
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EEG-TMS-fMRI Bold changes in cingulate cortex
Time Frame: At the 4th week of treatment (or 6 weeks in those who continue to 6 weeks).
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EEG-TMS-fMRI Bold changes in cingulate cortex.
We will measure the BOLD fMRI changes that are caused by a TMS pulse over the prefrontal cortex, and determine whether they increase more after 4 weeks of therapy.
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At the 4th week of treatment (or 6 weeks in those who continue to 6 weeks).
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Collaborators and Investigators
Collaborators
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- Pro00074695
- R21MH106775-01 (U.S. NIH Grant/Contract)
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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