Mechanisms Of Orbitofrontal Stimulation in Depression

NCT07230990 | Not Yet Recruiting DMC FDA Device

• 1 other identifier: 2025P000673
• Study Type: interventional
• Target: 80
• Locations: 0 countries
• Sites: N/A

Brief Summary

The orbitofrontal cortex (OFC), a region involved in emotional regulation, decision making, and reward processing, is a key area linked to antidepressant response. This study tests whether noninvasive stimulation of the OFC using transcranial magnetic stimulation (TMS) can improve depressive symptoms. TMS uses magnetic fields generated by a coil placed next to the scalp to alter brain activity.

Conditions

Major Depressive Disorder (MDD)

Keywords

Depression; Transcranial magnetic stimulation (TMS); orbitofrontal cortex; Frontal pole

Outcome Measures

Primary Outcomes (3)

• Beck Depression Inventory II (BDI-II)

  The BDI-II is a 21-item self-report questionnaire assessing the severity of depressive symptoms over the past two weeks. Each item is rated from 0 to 3, reflecting increasing symptom severity. The total score range is 0 to 63 points, where higher scores indicate worse depressive symptoms. The investigators will examine the change in BDI-II scores in each experimental phase (randomized and open-label).

  The survey will be administered at 4 timepoints: Day 1 (baseline) and Day 10 (last day) of randomized phase; Day 1 (baseline) and Day 10 (last day) of open-label phase.

• Hamilton Depression Rating Scale (HDRS) - 24 item version

  The HDRS is a clinician-rated scale assessing the severity of depressive symptoms across mood, somatic, and cognitive domains. Items are scored on either 3- or 5-point scales depending on the symptom. The score ranges from 0 to 76, with higher scores reflecting greater severity.

  The survey will be administered at 4 timepoints: Day 1 (baseline) and Day 10 (last day) of randomized phase; Day 1 (baseline) and Day 10 (last day) of open-label phase.

• Rumination Response Scale (RRS)

  The RRS is a 22-item self-report questionnaire measuring the tendency to engage in repetitive, negative thinking about one's distress or mood. Each item is rated from 1 ("almost never") to 4 ("almost always"). Scores range from 22 to 88 points, with higher scores indicating greater rumination.

  The survey will be administered at 4 timepoints: Day 1 (baseline) and Day 10 (last day) of randomized phase; Day 1 (baseline) and Day 10 (last day) of open-label phase.

Study Arms (2)

Active OFC stimulation

ACTIVE COMPARATOR

Continuous intermittent theta burst stimulation (cTBS, a type of inhibitory TMS) to the right OFC.

Device: Active TMS

Sham OFC stimulation

SHAM COMPARATOR

Sham TMS treatment to the right OFC

Device: Sham TMS

Interventions

Sham TMS DEVICE

The MagVenture MagPro system's active/sham coil (e.g., Cool-B65 A/P) will be used to deliver either active or sham TMS. The sham mode reproduces the same clicking sound and scalp sensation as active stimulation but does not induce cortical activation. The built-in MagPro double-blind feature ensures operator, participant, and investigator blinding. All participants will be randomized to receive active or sham TMS to the OFC in the first phase.

Sham OFC stimulation

Active TMS DEVICE

TMS uses magnetic fields generated by a coil placed next to the scalp to alter brain activity at a specific region (i.e., OFC) protocol. Here, active TMS protocol is continuous intermittent theta burst stimulation (cTBS, a type of inhibitory TMS) to the right OFC. Investigators will use the MagVenture MagPro system's active/sham coil (e.g., Cool-B65 A/P) to deliver either active or sham TMS. All participants will be randomized to receive active or sham TMS to the OFC in the first phase. In the second phase, all participants will receive active TMS to the OFC. The active protocol to the right OFC is: continuous intermittent theta burst stimulation (cTBS, a type of inhibitory TMS).

Active OFC stimulation

Eligibility Criteria

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

You may qualify if:

• Age 18-65 years
• Must be able to read, speak and understand English
• DSM-5 diagnosis of major depressive disorder, experiencing a moderate to severe depressive episode (Hamilton Depression Rating Scale score greater than or equal to 17 points)
• Must be judged by study staff to be capable of completing the study procedures
• Participants will be in stable outpatient treatment with no recent (within the past 30 days) hospitalizations or changes in their medication regimens

You may not qualify if:

• DSM-5 moderate to severe substance use disorder within the past three months, based on Structured Clinical Interview for DSM-5
• Conditions that might result in increased risks of side effects or complications from rTMS or MRI, including:
• History of fainting spells of unknown or undetermined etiology that might constitute seizures
• Diagnosis of epilepsy with the exception of a single seizure of benign etiology (e.g., febrile seizures) in the judgment of a board-certified neurologist
• Current or past history of a neurological disorder, such as stroke, a progressive neurologic disease, or intracranial brain lesion(s); and history of previous neurosurgery or head trauma that resulted in residual neurologic impairment
• Any unstable medical condition
• Any metal in the brain or skull (excluding dental fillings) unless cleared by the responsible covering MD
• Any devices which could be affected by TMS or MRI such as a pacemaker, medication pump, nerve stimulator, cochlear implant, TENS unit, ventriculo-peritoneal shunt unless cleared by the responsible covering MD
• Pregnancy; All female participants will be required to have a pregnancy test; any participant who is pregnant will not be enrolled in the study. The pregnancy test will be administered by study staff trained to administer point of care pregnancy testing that complies with institutional laboratory policies

Sponsors & Collaborators

• Subha Subramanian: lead

Related Publications (9)

• Stolinsky DC. Asklepios. Ann Intern Med. 1996 Aug 1;125(3):253-4. doi: 10.7326/0003-4819-125-3-199608010-00021. No abstract available.

  PMID: 8686990 BACKGROUND

• Hanlon CA, Dowdle LT, Correia B, Mithoefer O, Kearney-Ramos T, Lench D, Griffin M, Anton RF, George MS. Left frontal pole theta burst stimulation decreases orbitofrontal and insula activity in cocaine users and alcohol users. Drug Alcohol Depend. 2017 Sep 1;178:310-317. doi: 10.1016/j.drugalcdep.2017.03.039. Epub 2017 May 30.

  PMID: 28686990 RESULT

• Cui H, Ding H, Hu L, Zhao Y, Shu Y, Voon V. A novel dual-site OFC-dlPFC accelerated repetitive transcranial magnetic stimulation for depression: a pilot randomized controlled study. Psychol Med. 2024 Oct 23;54(14):1-14. doi: 10.1017/S0033291724002289. Online ahead of print.

  PMID: 39440449 RESULT

• Kringelbach ML. The human orbitofrontal cortex: linking reward to hedonic experience. Nat Rev Neurosci. 2005 Sep;6(9):691-702. doi: 10.1038/nrn1747.

  PMID: 16136173 RESULT

• Fettes P, Schulze L, Downar J. Cortico-Striatal-Thalamic Loop Circuits of the Orbitofrontal Cortex: Promising Therapeutic Targets in Psychiatric Illness. Front Syst Neurosci. 2017 Apr 27;11:25. doi: 10.3389/fnsys.2017.00025. eCollection 2017.

  PMID: 28496402 RESULT

• Tadayonnejad R, Citrenbaum C, Ngo TDP, Corlier J, Wilke SA, Slan A, Distler MG, Hoftman G, Adelekun AE, Leuchter MK, Koek RJ, Ginder ND, Krantz D, Artin H, Strouse T, Bari AA, Leuchter AF. Right lateral orbitofrontal cortex inhibitory transcranial magnetic stimulation for treatment of refractory mood and depression. Brain Stimul. 2023 Sep-Oct;16(5):1374-1376. doi: 10.1016/j.brs.2023.09.011. Epub 2023 Sep 15. No abstract available.

  PMID: 37716637 RESULT

• Prentice A, Kolken Y, Tuttle C, van Neijenhof J, Pitch R, van Oostrom I, Kruiver V, Downar J, Sack AT, Arns M, van der Vinne N. 1Hz right orbitofrontal TMS benefits depressed patients unresponsive to dorsolateral prefrontal cortex TMS. Brain Stimul. 2023 Nov-Dec;16(6):1572-1575. doi: 10.1016/j.brs.2023.10.005. Epub 2023 Oct 13. No abstract available.

  PMID: 37839775 RESULT

• Feffer K, Fettes P, Giacobbe P, Daskalakis ZJ, Blumberger DM, Downar J. 1Hz rTMS of the right orbitofrontal cortex for major depression: Safety, tolerability and clinical outcomes. Eur Neuropsychopharmacol. 2018 Jan;28(1):109-117. doi: 10.1016/j.euroneuro.2017.11.011. Epub 2017 Nov 17.

  PMID: 29153927 RESULT

• Rao VR, Sellers KK, Wallace DL, Lee MB, Bijanzadeh M, Sani OG, Yang Y, Shanechi MM, Dawes HE, Chang EF. Direct Electrical Stimulation of Lateral Orbitofrontal Cortex Acutely Improves Mood in Individuals with Symptoms of Depression. Curr Biol. 2018 Dec 17;28(24):3893-3902.e4. doi: 10.1016/j.cub.2018.10.026. Epub 2018 Nov 29.

  PMID: 30503621 RESULT

MeSH Terms

Conditions

Depressive Disorder, Major; Depression

Condition Hierarchy (Ancestors)

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

Central Study Contacts

Subha Subramanian, MD

CONTACT

6176675247; ssubram5@bidmc.harvard.edu

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Participants, care providers, investigators, and outcome assessors will be blinded to treatment allocation (active vs. sham TMS). Blinding will be maintained using coded assignments that indicate which side of the MagPro Cool B65 A/P coil (MagVenture A/S, Denmark) is positioned for stimulation. This procedure ensures that all study personnel remain unaware of stimulation condition throughout the trial.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Instructor of Psychiatry, TMS Director

Model Details: Participants will be randomized into active or sham TMS groups and active or sham TMS to the right OFC. They will then undergo a washout period. After this, all participants will receive active TMS to the OFC. This region corresponds to the FP2 electrode location in the international 10-20 EEG system and is also referred to as the frontal pole.

Study Record Dates

• First Submitted: November 6, 2025
• First Posted: November 17, 2025
• Study Start: January 1, 2026
• Primary Completion (Estimated): December 1, 2030
• Study Completion (Estimated): December 1, 2030
• Last Updated: November 17, 2025

Record last verified: 2025-11