Mechanisms Of Orbitofrontal Stimulation in Depression

Official title

Mechanisms Of Orbitofrontal Stimulation in Depression (MOOD)

Overview

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.

Detailed description

The main purpose of this study is to test a new treatment target for major depressive disorder (MDD) and to understand the brain mechanisms that may lead to antidepressant response. The treatment target of this study is the right orbitofrontal cortex (OFC), a brain region towards the front of the brain involved in emotion regulation, reward-processing, and decision-making. Other studies have shown that stimulating the OFC can improve depression symptoms. However, no study has yet directly compared the effects of real (active) versus placebo (sham) OFC stimulation on both mood and brain function. Comparison of active versus sham treatment is key in medical research. This study aims to fill that gap by comparing active versus sham stimulation of the right OFC in people with MDD who are currently experiencing moderate to severe symptoms. Participants will take part in a two phases: a triple-blind, randomized, sham-controlled phase, followed by an open-label phase where all participants receive active OFC stimulation.

Aim 1:

To determine whether active TMS targeting the right OFC, compared to sham stimulation at the same site, reduces depressive symptom severity in individuals with MDD.

Aim 2:

To test whether active TMS to the right OFC, compared to sham stimulation at the same site, reduces ruminative symptoms in individuals with MDD.

Interventions

• Device Sham TMS
  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.
• Device Active TMS
  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 s

Primary outcome measures

• Beck Depression Inventory II (BDI-II) [Time frame: 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 [Time frame: 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) [Time frame: 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.]

Eligibility criteria

Inclusion criteria

• 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

Exclusion criteria

• 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Crossover

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 1 center

• Beth Israel Deaconess Medical Center — Boston

Publications

• 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
• 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
• 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;54(14):3849-3862. doi: 10.1017/S0033291724002289. Epub 2024 Oct 23. PMID 39440449
• 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
• 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
• 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 2 PMID 37716637
• 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
• 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

Identifiers

NCT: NCT07230990 · 2025P000673

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗