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.

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.

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

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.