Brain Functional Connectivity Mechanism of Cognitive Flexibility Impairment and rTMS Intervention in Major Depressive Disorder

Major depressive disorder (MDD) often involves cognitive deficits, particularly in cognitive flexibility, which is inadequately addressed by standard antidepressants. This study tests an innovative brain stimulation regimen: individualized dual-target repetitive transcranial magnetic stimulation (rTMS) to improve cognitive flexibility in MDD patients. This is a randomized, double-blind, sham-controlled trial that plans to enroll 105 MDD patients with cognitive flexibility impairment. Participants will be randomly assigned to one of three groups: (1) Active dual-target group - receiving active rTMS over both the left inferior parietal lobule (IPL) and the right dorsolateral prefrontal cortex (DLPFC); (2) Active single-target group - receiving active rTMS over the left IPL and sham stimulation over the right DLPFC; (3) Sham control group - receiving sham stimulation over both targets. All participants will continue their stable antidepressant medication (SSRI or SNRI). The rTMS intervention lasts 10 days, with 5 stimulation sessions per day. Cognitive flexibility, depressive symptoms, and brain functional connectivity will be assessed at baseline, immediately after the 10-day treatment, and at 2-week and 4-week follow-ups using neurocognitive tests, clinical rating scales (e.g., HAMD), and functional MRI. The results will help confirm the role of the IPL-DLPFC connectivity in cognitive flexibility and may establish a new treatment target for cognitive dysfunction in MDD.

Inclusion Criteria: Meet DSM-5 criteria for major depressive episode confirmed by the Structured Clinical Interview for DSM-5 Disorders (SCID-5), with no prior manic or hypomanic episodes; diagnosed as major depressive disorder without psychotic features by two attending psychiatrists. First episode or recurrent, currently in a depressive episode (HAMD\_17≥17). Age 18 to 45 years, all sexes and genders. Han Chinese, right-handed. Junior high school education or above, no color blindness, able to understand and provide informed consent, and complete assessments and tests. Willing to participate voluntarily and sign written informed consent. Exclusion Criteria: Meet DSM-5 diagnostic criteria for any psychiatric disorder other than major depressive disorder. Received non-pharmacological treatments within the past 6 months, such as electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), or systematic psychotherapy (≥ 10 sessions). Prior treatment with CCRT. Received antipsychotics or other medications affecting cognitive function within the past month, or cholinergic agents (e.g., donepezil, galantamine) within 14 days, memantine within 20 days, or other racetam drugs (e.g., piracetam) within 2 days prior to randomization. Organic brain disorders or severe physical illnesses (e.g., thyroid disease, lupus erythematosus, diabetes, liver/kidney/lung impairment, infection, major trauma). History of traumatic brain injury with loss of consciousness or other conditions that may interfere with this study. History of alcohol or substance abuse or dependence. Severe suicidal ideation or suicide attempt . Currently receiving hormonal therapy. Pregnancy, lactation, possibility of pregnancy, or planned pregnancy. History of epilepsy or family history of epilepsy. Implanted metal materials in the body (e.g., pacemaker, dental implants, metal intrauterine device). Any other factors that, in the investigator's opinion, place the participant at potential risk or interfere with the study participation.