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EEG Synchronized TMS Trial for Depression

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ClinicalTrials.gov Identifier: NCT03421808
Recruitment Status : Not yet recruiting
First Posted : February 5, 2018
Last Update Posted : February 5, 2018
Sponsor:
Collaborator:
National Institute of Mental Health (NIMH)
Information provided by (Responsible Party):
Medical University of South Carolina

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Depression Device: Transcranial Magnetic Stimulation (TMS) Phase 2 Phase 3

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 : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: 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 TMS).
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: 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.
Primary Purpose: Treatment
Official Title: Randomized Controlled Trial of EEG/fMRI Controlled TMS For Treating Depression
Estimated Study Start Date : March 2018
Estimated Primary Completion Date : January 2021
Estimated Study Completion Date : March 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.
Device: Transcranial Magnetic Stimulation (TMS)
TMS

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.
Device: Transcranial Magnetic Stimulation (TMS)
TMS




Primary Outcome Measures :
  1. Remission Rate [ Time Frame: At the 4th week of treatment (or 6 weeks in those who continue to 6 weeks). ]
    Depression Remission, as defined by the Hamilton Rating Scale for Depression, 24 item, score less than 10


Secondary Outcome Measures :
  1. EEG phase synchronization [ Time Frame: At each treatment session and progressively over the 30 sessions ]
    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.

  2. 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). ]
    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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Ages Eligible for Study:   21 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03421808


Contacts
Contact: Morgan Dancy 8438765142 maddoxm@musc.edu
Contact: Minnie Dobbins 8438765142 dobbinsm@musc.edu

Locations
United States, South Carolina
Medical University of South Carolina Brain Stimulation Division
Charleston, South Carolina, United States, 29425
Sponsors and Collaborators
Medical University of South Carolina
National Institute of Mental Health (NIMH)
Investigators
Principal Investigator: Mark S George, MD Medical University of South Carolina

Responsible Party: Medical University of South Carolina
ClinicalTrials.gov Identifier: NCT03421808     History of Changes
Other Study ID Numbers: Pro00074695
R21MH106775-01 ( U.S. NIH Grant/Contract )
First Posted: February 5, 2018    Key Record Dates
Last Update Posted: February 5, 2018
Last Verified: January 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: No
Pediatric Postmarket Surveillance of a Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Medical University of South Carolina:
TMS
transcranial magnetic stimulation
brain stimulation

Additional relevant MeSH terms:
Depression
Depressive Disorder
Behavioral Symptoms
Mood Disorders
Mental Disorders