Depression, Major Depressive Disorder (MDD), Depression - Major Depressive Disorder, Persistent Depressive Disorder, PDD, MDD
Conditions
Keywords
TMS, Transcranial Magnetic Stimulation, Brain Stimulation, Brain Imaging, Depression, fMRI, MDD, PDD, non-invasive brain stimulation, TMS treatment, TMS for depression, individualized treatment
Brief summary
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
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.
Interventions
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.
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.
Sponsors
University of Pennsylvania
National Institute of Mental Health (NIMH)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Outcomes Assessor)
Intervention model description
Participants will be randomized 1:1 to receive active or sham iTBS every weekday for 6 weeks (30 sessions). In both groups, stimulation will be delivered to an individualized cortical target selected based on positive resting-state functional connectivity with the subgenual anterior cingulate cortex (sgACC). The active group will receive iTBS intended to stimulate the targeted cortical-sgACC circuit, while the sham group will undergo procedures of the same duration and appearance without the intended magnetic stimulation of the targeted circuit.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
In order to participate in this study, potential participants must meet all of the following eligibility criteria: 1. 18-65 years old 2. DSM-5 diagnosis of major depressive (at least 90%) or persistent depressive disorder (no more than 10%) as per SCID clinical interview. 3. PHQ-9 score = or \> than 10 (to maintain minimal severity of symptoms in the MDD sample) 4. Comprehension of instructions in the English language. 5. Capacity to provide informed consent and follow study procedures. 6. 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: 1. Implanted medical devices, metallic implants, or drug infusion pumps that are not MRI-safe (e.g., aneurysm clips, defibrillators, or cochlear implants) 2. 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. 3. Current psychosis, mania, or substance use disorder 4. 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. 5. Inability to complete an MRI scan (e.g., claustrophobia, inability to remain still for extended periods). 6. Inability to tolerate TMS administration 7. Significant handicaps that would interfere with testing procedures 8. Acute systemic infection, high fever 9. Acute sleep deprivation or medication/substance intoxication or withdrawal (TMS seizure risk) 10. Current use of cyclosporine, tacrolimus, or others that can cause leukoencephalopathy. 11. Pregnancy 12. Dialysis 13. 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. 14. 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. 15. Transportation limits or physical limits to attending daily M-F treatment sessions. 16. Per study physician discretion medications likely to interfere with blood flow or otherwise compromise functional imaging measures. 17. 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: 1. Refrain from substance use (including marijuana and illicit drugs) for the duration of the study (self-attestation alone) 2. Abstain from alcohol for 24 hours before study visits (self-attestation alone) 3. Maintain a consistent level of caffeine consumption throughout the study period and avoid any significant increases (self-attestation). 4. Not initiate, discontinue, or adjust any psychiatric medications or therapy treatments during the study period. 5. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to post-intervention period. | ~6 weeks | 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. |
| Change in Patient Health Questionnaire-9 (PHQ-9) total score from baseline to post-intervention period follow up. | ~6 weeks | 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. |
Countries
United States
Contacts
CONTACTAlmaris Figueroa Gonzalez
Outcome results
None listed