DepressionPhase 2/3NCT03421808
EEG Synchronized TMS Trial for Depression
A Phase 2/3 study testing Transcranial Magnetic Stimulation (TMS) in people with Depression, run by Medical University of South Carolina at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 21 to 70 years
- Conditions the study is for
- Depression
- What is being tested?
- Transcranial Magnetic Stimulation (TMS)
- Type of treatment
- Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 34 participants
- Where
- 1 siteUnited States
- Study dates
- 30 Nov 2018to 15 Jan 2024
- Phase
- Phase 2/3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
Medical University of South Carolina Brain Stimulation Division
Charleston, South Carolina, 29425
About this study
Official title: 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.
Read the 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.
- Conditions
- Depression
- Being tested
- Transcranial Magnetic Stimulation (TMS)
- Keywords
- TMS, transcranial magnetic stimulation, brain stimulation
- Medical subject headings
- Depression
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Transcranial Magnetic Stimulation (TMS)Device
TMS
| Study group | Role | What they receive |
|---|---|---|
| SYNC TMS | Experimental | 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. Receives: Device: Transcranial Magnetic Stimulation (TMS) |
| Non-Sync TMS | Active comparator | 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. Receives: Device: Transcranial Magnetic Stimulation (TMS) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Remission Rate
Depression Remission, as defined by the Hamilton Rating Scale for Depression, 24 item, score less than 10. Range is 0 to 52. Higher scores mean more severe depression.
Measured: At the 4th week of treatment (or 6 weeks in those who continue to 6 weeks).
Secondary outcomes (2)
Number of Participants With EEG Phase Synchronization Frequency Changes
EEG phase synchronization will be assessed by collecting real-time 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.
We investigated the relationship between the maximum percentage phase angle (i.e., the histogram peak in the circular space of phases) and the HAMD changes across sessions. this maximum percentage was our first measure of the robustness of (defined as the corresponding phase of the post-stimulation ITPC value in circular space) across the 6 weeks of treatment.
Measured: assessed at each treatment session up to 6 weeks, week 6 reported
EEG-TMS-fMRI Bold Changes in Cingulate Cortex
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.
Measured: At the 4th week of treatment (or 6 weeks in those who continue to 6 weeks).
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Feb 2018
- Study start30 Nov 2018
- Primary completion1 Jan 2022
- Study completion15 Jan 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for DepressionStudies of the same condition, open and under way.
- More trials run by Medical University of South CarolinaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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 blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 34 participants (actual)
Sponsor and investigators
- Lead sponsor
- Medical University of South Carolina
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute of Mental Health (NIMH)
- Responsible party
- Sponsor
- Investigators
- Mark S George, MD, Principal investigator, Medical University of South Carolina
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03421808
- Sponsor's protocol ID
- Pro00074695
- Other IDs
- R21MH106775-01
- Status last verified
- Oct 2025
- First submitted
- 23 Jan 2018
- Last updated
- 4 Nov 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 4 Nov 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Randomized Controlled Trial of EEG/fMRI Controlled TMS For Treating Depression
- ClinicalTrials.gov ID
- NCT03421808
- Acronym / sponsor ID
- Pro00074695
- Conditions
- Depression
- Keywords
- TMS, transcranial magnetic stimulation, brain stimulation
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 34 participants (actual)
- Lead sponsor
- Medical University of South CarolinaUniversity, hospital or other
- Collaborators
- National Institute of Mental Health (NIMH)
- Study start
- 30 Nov 2018 (actual)
- Primary completion
- 1 Jan 2022 (actual)
- Study completion
- 15 Jan 2024 (actual)
- First posted
- 5 Feb 2018 (actual)
- Results
- Posted 14 Aug 2025
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- 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).
| Arm | Type | Receives |
|---|---|---|
| SYNC TMS | Experimental | Device: Transcranial Magnetic Stimulation (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. |
| Non-Sync TMS | Active comparator | Device: Transcranial Magnetic Stimulation (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. |
Who may qualify
- Ages
- 21 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
- 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
Key exclusion criteria (2 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Transcranial Magnetic Stimulation (TMS)TMS | Device | Non-Sync TMS, SYNC TMS |
Primary outcome
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. Range is 0 to 52. Higher scores mean more severe depression.
2 secondary outcomes
Number of Participants With EEG Phase Synchronization Frequency Changes
Time frame: assessed at each treatment session up to 6 weeks, week 6 reported
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).
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Nov 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Mark S George, MD principal investigator
Medical University of South Carolina
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Transcranial Magnetic Stimulation (TMS) in people with Depression, run by Medical University of South Carolina at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 4 Nov 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 14 Aug 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Remission Rate (time frame: At the 4th week of treatment (or 6 weeks in those who continue to 6 weeks).). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Nov 2025.