Individualized fMRI-guided TMS for Depression (R33 MDD)
Engaging the Subgenual Cingulate With Brain Stimulation for Depression
The goal of this clinical trial is to learn how transcranial magnetic stimulation (TMS) affects brain circuits involving the subgenual anterior cingulate cortex (sgACC) in adults with depression. The main questions it aims to answer are:
- Can brain responses in the sgACC before treatment predict improvement in depressive symptoms following TMS?
- Does a 6-week course of active TMS, compared with sham TMS, change brain responses in the sgACC?
- Are changes in sgACC responses during treatment associated with changes in depressive symptoms?
Researchers will compare active TMS with sham TMS to evaluate changes in the targeted brain circuit and depressive symptoms.
Participants will:
- Receive active or sham TMS every weekday for 6 weeks
- Undergo MRI scans with TMS before, during, and after the 6-week intervention to measure brain responses to stimulation
- Complete clinical assessments, questionnaires, and cognitive testing
- Complete follow-up assessments after the intervention
Study Overview
Status
Conditions
Detailed Description
This double-blind, randomized, sham-controlled clinical trial will investigate engagement and modulation of brain circuitry involving the subgenual anterior cingulate cortex (sgACC) using individualized resting-state functional magnetic resonance imaging (fMRI)-guided transcranial magnetic stimulation (TMS) in adults with depression.
Following screening, participants will undergo a baseline MRI session that includes structural, diffusion, and resting-state imaging. Resting-state functional connectivity will be used to identify individualized cortical stimulation targets that are positively and negatively connected with the sgACC. Participants will also complete baseline clinical assessments, questionnaires, and cognitive testing.
Before the 6-week intervention, participants will undergo a TMS/fMRI session to measure sgACC responses to stimulation. Single-pulse TMS will be delivered to three sites: an individualized target positively connected with the sgACC, an individualized target negatively connected with the sgACC, and a vertex control site. TMS/fMRI data will also be collected before and after brief intermittent theta burst stimulation (iTBS) to the positively and negatively connected targets. These procedures will be used to evaluate whether sgACC responses before treatment are associated with subsequent improvement in depressive symptoms.
Participants will then be randomized in a 1:1 ratio to receive active or sham iTBS delivered to the individualized positively connected sgACC target every weekday for 6 weeks (30 sessions). Sham procedures will be designed to resemble active stimulation without delivering the intended therapeutic magnetic stimulation to the targeted brain circuit.
The TMS/fMRI procedures will be repeated after approximately 3 weeks of treatment and again following the 6-week intervention. Changes in TMS-evoked sgACC responses over the course of treatment will be evaluated in relation to changes in depressive symptoms and compared between the active and sham groups to assess modulation of the targeted brain circuit.
Clinical assessments and questionnaires will be conducted throughout the study to evaluate depressive symptoms and related clinical outcomes. The Montgomery-Åsberg Depression Rating Scale (MADRS) will serve as the primary measure of depression severity, and the Patient Health Questionnaire-9 (PHQ-9) will serve as a secondary measure. Participants will also complete the NIH Toolbox Cognition Battery before and after the 6-week intervention to assess cognitive functioning and explore relationships between cognitive performance, clinical outcomes, and neuroimaging measures.
Participants will complete remote follow-up assessments at 1, 6, and 12 months after completion of the blinded intervention. After the 1-month follow-up, participants assigned to sham who continue to have clinically significant depressive symptoms and meet study eligibility criteria may be offered an optional open-label active TMS intervention. Data from the open-label phase will be analyzed separately from the randomized sham-controlled phase.
Study Type
Enrollment (Estimated)
Phase
- Early Phase 1
Contacts and Locations
Study Contact
- Name: Almaris Figueroa Gonzalez
- Phone Number: 2157466751
- Email: almaris.figueroa-gonzalez@pennmedicine.upenn.edu
Study Locations
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Pennsylvania
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Philadelphia, Pennsylvania, United States, 19104
- University of Pennsylvania
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Contact:
- Lab Manager
- Phone Number: 2157466751
- Email: almaris.figueroa-gonzalez@pennmedicine.upenn.edu
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Adult
- Older Adult
Accepts Healthy Volunteers
Description
Inclusion Criteria
In order to participate in this study, potential participants must meet all of the following eligibility criteria:
- 18-65 years old
- DSM-5 diagnosis of major depressive (at least 90%) or persistent depressive disorder (no more than 10%) as per SCID clinical interview.
- PHQ-9 score = or > than 10 (to maintain minimal severity of symptoms in the MDD sample)
- Comprehension of instructions in the English language.
- Capacity to provide informed consent and follow study procedures.
- Availability for the duration of the study.
Exclusion Criteria
Any individual who meets any of the following criteria at the time of enrollment will be excluded from participation:
- Implanted medical devices, metallic implants, or drug infusion pumps that are not MRI-safe (e.g., aneurysm clips, defibrillators, or cochlear implants)
- History of significant medical events (e.g., stroke, seizures, brain scarring) or neurological/neurodevelopmental conditions (e.g., epilepsy) that are contraindications for TMS and MRI or may adversely affect brain function and data interpretation.
- Current psychosis, mania, or substance use disorder
- Prior failed response to full rTMS or ECT/MST trial. Any successful prior treatments are acceptable and support a prognosis that a new rTMS treatment would be worth attempting.
- Inability to complete an MRI scan (e.g., claustrophobia, inability to remain still for extended periods).
- Inability to tolerate TMS administration
- Significant handicaps that would interfere with testing procedures
- Acute systemic infection, high fever
- Acute sleep deprivation or medication/substance intoxication or withdrawal (TMS seizure risk)
- Current use of cyclosporine, tacrolimus, or others that can cause leukoencephalopathy.
- Pregnancy
- Dialysis
- Suicide attempt in past 6 months (safety precaution); similarly, if ideation is particularly pronounced, Drs. Oathes and Sheline will decide with the patient whether the benefit of participating in a sham controlled (all patients given the option to receive active treatment eventually) study outweighs the risks. If the patient has a mental health provider and acquiesces, consultation with the provider will also be instrumental in this decision.
- Current use of Bupropion (Wellbutrin) above 300 mg, benzodiazepines, lithium, monoamine oxidase inhibitors (MAOIs), and/or high doses of stimulant medication is exclusionary. Note: Exclusionary dosages or medications may be reduced or discontinued under the supervision of a medical provider. For detailed information please refer to section 5.3.1.
- Transportation limits or physical limits to attending daily M-F treatment sessions.
- Per study physician discretion medications likely to interfere with blood flow or otherwise compromise functional imaging measures.
- Any other factor that in the investigators' judgment may affect patient safety or compliance (e.g. distance greater than 100 miles from procedure site; unlikely to be able to schedule daily treatment sessions, etc.)
Study Participation Expectations
During this study, participants will be asked to:
- Refrain from substance use (including marijuana and illicit drugs) for the duration of the study (self-attestation alone)
- Abstain from alcohol for 24 hours before study visits (self-attestation alone)
- Maintain a consistent level of caffeine consumption throughout the study period and avoid any significant increases (self-attestation).
- Not initiate, discontinue, or adjust any psychiatric medications or therapy treatments during the study period.
- Inform the study team of any new medical treatments or prescribed medications (e.g., antibiotics) to allow for safety review and determination of continued eligibility for the study.
Participants who do not follow these considerations will be evaluated on a case-by-case basis. Principal Investigator will determine if study withdrawal is appropriate.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Active iTBS
Participants will receive active intermittent theta burst stimulation (iTBS) delivered to an individualized cortical target selected based on positive resting-state functional connectivity with the subgenual anterior cingulate cortex (sgACC).
Active iTBS will be administered every weekday for 6 weeks (30 sessions) and is intended to stimulate the targeted cortical-sgACC circuit.
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The TMS intervention will involve two sets of intermittent theta-burst stimulation (iTBS) delivered every weekday for 6 weeks (30 sessions).
Each iTBS set consists of 40 trains and 1,200 pulses, for a total of 2,400 pulses per treatment session.
The two iTBS sets will be separated by approximately 5 minutes and delivered to the individualized cortical target selected based on positive resting-state functional connectivity with the subgenual anterior cingulate cortex (sgACC) using MRI-guided neuronavigation.
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Sham Comparator: Sham iTBS
Participants will receive sham iTBS at the same individualized cortical target selected based on positive resting-state functional connectivity with the subgenual anterior cingulate cortex (sgACC) every weekday for 6 weeks (30 sessions).
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The sham TMS intervention will follow the same treatment schedule and session structure as active TMS.
Sham stimulation will be delivered using the shielded side of the TMS coil together with synchronized scalp electrical stimulation to mimic the sensation of active TMS without delivering the intended magnetic stimulation to the targeted brain region.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
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Change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to post-intervention period.
Time Frame: ~6 weeks
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MADRS is a clinician-rated measure of depressive symptom severity with total scores ranging from 0 to 60, where higher scores indicate greater depression severity.
Change in MADRS total score will be calculated from baseline (pre-treatment) to post-treatment.
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~6 weeks
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Change in Patient Health Questionnaire-9 (PHQ-9) total score from baseline to post-intervention period follow up.
Time Frame: ~6 weeks
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PHQ-9 is a patient-reported score that ranges from 0 to 27, where higher scores indicate greater depression severity.
Change in PHQ-9 total score will be calculated from baseline (pre-treatment) to post-treatment.
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~6 weeks
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Collaborators and Investigators
Sponsor
Collaborators
Study record dates
Study Major Dates
Study Start (Estimated)
Primary Completion (Estimated)
Study Completion (Estimated)
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
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- 26-7480
- 4R33MH135428-03 (U.S. NIH Grant/Contract)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
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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