One-Day cTBS Over the Precuneus

Treatment-resistant depression may involve dysfunction across distributed brain networks rather than a disturbance confined to a single brain region. The precuneus is a posterior hub of the default mode network and is involved in internally directed and self-referential processing. Altered interactions among the default mode, affective, and cognitive control networks have been implicated in depressive symptoms and rumination. In this study, precuneus continuous theta-burst stimulation (cTBS) is conceptualized as a hypothesis-driven network intervention that may modulate precuneus-centered network interactions implicated in depression.

A double-cone coil will be used to increase electric-field penetration toward the medial posteromedial cortex beneath the Pz scalp location of the international 10-20 electroencephalography system. Intermittent theta-burst stimulation (iTBS) of the left dorsolateral prefrontal cortex is included as an additional active treatment arm because this region is an established stimulation target for depression treatment. The three-arm design allows the novel precuneus target and the established left dorsolateral prefrontal cortex target to be evaluated within the same accelerated treatment framework and compared with sham stimulation.

Participants will be assigned to the three initial study groups using the minimal sufficient balance (MSB) randomization method, with sex and baseline depression severity, as measured by the Montgomery-Åsberg Depression Rating Scale, used as balancing factors. The target allocation ratio for the randomized, sham-controlled phase will be 1:1:1. Group allocation will be concealed from participants. Each active or sham intervention will consist of 20 stimulation sessions administered during a single day, with session onsets separated by approximately 30 minutes.

The primary efficacy analyses will use a longitudinal mixed-model framework to estimate treatment effects and evaluate the two prespecified active-versus-sham comparisons. The familywise type I error rate will be controlled across these two comparisons. The direct comparison between precuneus cTBS and left dorsolateral prefrontal cortex iTBS will be considered exploratory.

After completing the 4-week follow-up period, participants initially assigned to sham stimulation may elect to enter an open-label active TMS extension. Extension participants will be assigned to precuneus cTBS or left dorsolateral prefrontal cortex iTBS using the MSB method, with a target allocation ratio of 1:1. Sex and depression severity at the end of the sham-controlled phase, as measured by the Week 4 Montgomery-Åsberg Depression Rating Scale score, will be used as balancing factors. Because only a subset of participants assigned to sham stimulation is expected to enter the extension, extension analyses will be considered exploratory and hypothesis-generating.

Inclusion criteria

• Age 18 years or older.
• Able to speak, read, and understand English sufficiently to complete the study assessments and provide informed consent independently.
• Diagnosis of major depressive disorder according to DSM-5-TR criteria, confirmed by a qualified physician.
• Treatment-resistant depression, defined as an inadequate response to at least two adequate trials of antidepressant pharmacotherapy.
• Patient Health Questionnaire-9 (PHQ-9) total score of 10 or higher.

Exclusion criteria

• Any condition identified through TMS safety screening that, in the judgment of a study physician, presents an unacceptable safety risk for TMS. Such conditions may include:
• A history of a serious adverse reaction during TMS treatment.
• A history of seizure.
• A history of stroke.
• A history of serious head injury or neurosurgery.
• Metal in the head outside the mouth, such as shrapnel, surgical clips, or metal fragments.
• An implanted device, such as a cardiac pacemaker, cochlear implant, medical pump, or intracardiac line.
• Frequent or severe headaches.
• Another brain-related condition or an illness that caused brain injury.
• A family history of epilepsy.
• Permanent tattoos on the head or neck.
• Current recreational drug use.
• Current pregnancy or possible pregnancy.
• Use of a medication or combination of medications, a recent medication change, or medication withdrawal that, in the judgment of a study physician, presents an unacceptable safety risk, including a clinically significant increase in seizure risk.
• Current or lifetime diagnosis of bipolar I disorder, bipolar II disorder, a schizophrenia spectrum disorder, or another primary psychotic disorder.
• Active suicidal ideation with intent or plan requiring immediate clinical intervention, or another acute safety concern that cannot be safely managed within the study.