rTMS to Target Neural Connectivity and Rumination in Treatment-Resistant Depression

Repetitive Transcranial Magnetic Stimulation of the Ventromedial Prefrontal Cortex to Target Neural Connectivity and Rumination in Treatment-Resistant Major Depressive Disorder: A Pilot Study

The goal of this clinical trial is to learn if Transcranial Magnetic Stimulation (TMS) to part of the brain called the ventromedial prefrontal cortex (VMPFC) can treat a symptom called rumination in adults with major depression that has not responded to at least one medication trial. The main question it aims to answer are:

Does TMS to the VMPFC change brain activity on functional magnetic resonance imaging (fMRI) during a negative self-referential processing task in adults with depression? Does TMS to the VMPFC affect rumination in adults with depression? Researchers will compare brain scans and rumination scores before, during, and immediately after TMS.

Participants will:

Undergo three functional MRI scans Undergo a course of 20 TMS treatments Respond to clinical questionnaires and complete a computer behavioral task

Study Overview

• Status: Recruiting
• Conditions: Depression, Treatment Resistant
• Intervention / Treatment: Device: Transcranial magnetic stimulation

Detailed Description

This will be a single-site, pilot, open-label, within-subject design study. 20 participants with treatment-resistant depression, defined as a failure to respond to at least one antidepressant medication trial within a current major depressive episode, will be recruited. Prior to intervention, participants will undergo self-report and clinician-administered assessments (in-person or virtual with both audio and video on using secure health telecommunication method), as well as a fMRI during resting state and a self-referential processing task. The baseline scan will also include a high-resolution structural sequence for neuronavigational purposes. Then, participants will receive 20 daily (5 days/week) sessions of rTMS to the VMPFC along with weekly assessments. Participants will undergo a repeated fMRI scan early in the course of treatment (after session 5) when we would expect neural changes to be evident but prior to any robust overall antidepressant effect, as well as at the end of the rTMS course (after session 20). Scores on the depression and rumination scales will be recorded prior to intervention and weekly thereafter. Contact with subjects will be conducted once via telephone at two weeks after the end of study intervention as an adverse event assessment. In the event that new or persistent adverse events felt to be related to the study intervention occur following the termination of study procedures, subjects may be brought in for further safety assessments.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Susan K Conroy, MD PhD; Phone Number: 317-963-7300; Email: sconroy@iu.edu

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Recruiting
      • Goodman Hall Neuroscience Center
      • Contact: Susan K Conroy, MD PhD; Phone Number: 317-963-7300; Email: sconroy@iu.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of unipolar major depressive disorder without psychotic features by the Mini-International Neuropsychiatric Interview (MINI) and confirmed by study psychiatrist
• First depressive episode prior to age 50
• Current moderate to severe depression, Hamilton Depression Rating Scale (HDRS) ≥17)
• Failure to respond to ≥1 antidepressant medication at adequate dose and duration in the current depressive episode; (note: this criterion is designed to be consistent with the original 2008 FDA-labeled indication for TMS in Major Depressive Disorder, that specifies failure to respond to "one prior medication at or above the minimal effective dose and duration in the current episode" (https://www.accessdata.fda.gov/cdrh_docs/pdf8/K083538.pdf). ))
• Off psychotropic medications OR on a stable dose of medication(s) for 6 weeks, and willing to remain on stable medication dosage throughout the study
• Capacity to consent
• Ability to safely receive MRI

Exclusion Criteria:

• Actively/imminently suicidal, Quick Inventory of Depressive Symptomatology (QIDS) item 12 score >2)
• Current depressive episode duration > 5 years
• Presence of clinically significant psychiatric diagnoses other than unipolar, non-psychotic major depression, such as post-traumatic stress disorder (PTSD) or obsessive-compulsive disorder (OCD)
• Evidence of cognitive impairment, Montreal Cognitive Assessment (MOCA) < 23)
• Significant substance use disorder within past 6 months
• New-onset psychotherapy and/or somatic therapy (e.g., light therapy) within 6 weeks of screening
• Prior exposure to any form of TMS
• Have participated in any clinical trial with an investigational drug or device within the past 6 weeks prior to screening
• Failure to respond to Electroconvulsive therapy (ECT)
• Any history of neurosurgery to treat a neurologic or psychiatric disorder (e.g. Vagus nerve stimulation, cortical stimulation, deep brain stimulation, or ablative surgery)
• Unstable medical illness
• Evidence or history of significant neurological disorder, including moderate-severe head trauma, stroke, Parkinson's disease or other movement disorder (except benign essential tremor)
• Epilepsy
• History of seizures (except juvenile febrile seizures or provoked seizures at the PI's discretion) or any condition/concurrent medication that could notably lower seizure threshold
• Pregnancy or planned pregnancy during the study
• Presence of cardiac pacemaker, cochlear implant, or other implanted electronic device
• Any vision problem that will prevent them from seeing the adjectives presented inside the MRI scanner without glasses

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active TMS; All participants will receive active TMS to the VMPFC for 20 sessions	Device: Transcranial magnetic stimulation; rTMS delivered at 1 Hz for 1800 pulses over 30 minutes for 20 daily sessions, 5 days/week. Treatment will be directed to the ventromedial prefrontal cortex using each participant's structural MRI.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Functional Connectivity	Within-network functional connectivity of the default mode network during negative processing	Before Transcranial magnetic stimulation (TMS) - immediately following TMS
Rumination	Scores on the Ruminative Response Scale (Range 22-88, with higher worse)	Before TMS- immediately following TMS

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Depression Scores	Hamilton Depression Rating Scale (Range 0-52, with higher worse)	Before TMS- immediately following TMS

Collaborators and Investigators

• Sponsor: Indiana University
• Collaborators: National Center for Advancing Translational Sciences (NCATS)
• Investigators: Principal Investigator: Susan K Conroy, MD PhD, Indiana University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): January 2, 2024
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): June 30, 2026

Study Registration Dates

• First Submitted: July 8, 2024
• First Submitted That Met QC Criteria: July 15, 2024
• First Posted (Actual): July 22, 2024

Study Record Updates

• Last Update Posted (Estimated): September 29, 2025
• Last Update Submitted That Met QC Criteria: September 24, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: functional magnetic resonance imaging; transcranial magnetic stimulation
• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Depressive Disorder; Depressive Disorder, Treatment-Resistant; Therapeutics; Magnetic Field Therapy; Transcranial Magnetic Stimulation
• Other Study ID Numbers: 13322 (Stanford IRB); K12TR004415 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No