Individualized fMRI-guided TMS for Depression

NCT07804459 | Not Yet Recruiting Early Phase 1 DMC FDA Device

• 2 other identifiers: 26-74804R33MH135428-03
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

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

Conditions

Depression; Major Depressive Disorder (MDD); Depression - Major Depressive Disorder; Persistent Depressive Disorder; PDD; MDD

Keywords

TMS; Transcranial Magnetic Stimulation; Brain Stimulation; Brain Imaging; Depression; fMRI; MDD; PDD; non-invasive brain stimulation; TMS treatment; TMS for depression; individualized treatment

Outcome Measures

Primary Outcomes (2)

• Change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to post-intervention period.

  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.

  ~6 weeks

• Change in Patient Health Questionnaire-9 (PHQ-9) total score from baseline to post-intervention period follow up.

  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.

  ~6 weeks

Study Arms (2)

Active iTBS

EXPERIMENTAL

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.

Device: Active Repetitive Transcranial Magnetic Stimulation (rTMS)

Sham iTBS

SHAM COMPARATOR

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).

Device: Sham Transcranial Magnetic Stimulation (TMS)

Interventions

Active Repetitive Transcranial Magnetic Stimulation (rTMS) DEVICE

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.

Active iTBS

Sham Transcranial Magnetic Stimulation (TMS) DEVICE

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.

Sham iTBS

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• In order to participate in this study, potential participants must meet all of the following eligibility criteria:
• 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.

You may not qualify if:

• 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.
• Transportation limits or physical limits to attending daily M-F treatment sessions.

Sponsors & Collaborators

• National Institute of Mental Health (NIMH): collaborator
• University of Pennsylvania: lead

Study Sites (1)

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

MeSH Terms

Conditions

Depression; Depressive Disorder, Major

Condition Hierarchy (Ancestors)

Behavioral Symptoms; Behavior; Depressive Disorder; Mood Disorders; Mental Disorders

Central Study Contacts

Almaris Figueroa Gonzalez

CONTACT

2157466751; almaris.figueroa-gonzalez@pennmedicine.upenn.edu

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: 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.

Study Record Dates

• First Submitted: August 31, 2026
• First Posted: September 4, 2026
• Study Start: September 15, 2026
• Primary Completion (Estimated): June 30, 2028
• Study Completion (Estimated): August 31, 2028
• Last Updated: September 9, 2026

Record last verified: 2026-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)