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

Individualized Dual-Target Repetitive Transcranial Magnetic Stimulation (rTMS) Targeting Left Inferior Parietal Lobule and Right Dorsolateral Prefrontal Cortex Functional Connectivity for Cognitive Flexibility Impairment in Major Depressive Disorder: A Randomized, Double-Blind-Controlled Trial

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.

Major depressive disorder (MDD) is a highly prevalent and recurrent chronic psychiatric illness. Over 50% of patients in the acute phase show widespread and significant cognitive impairments affecting executive function, attention, processing speed, and memory. Among executive subdomains, cognitive flexibility - the capacity to adapt thoughts and behaviors to changing environmental demands - is particularly difficult to treat. Even after 6 months of antidepressant treatment, cognitive flexibility often fails to return to healthy levels, and its impairment worsens with recurrent episodes and longer illness duration.

Functional MRI (fMRI) evidence points to the inferior parietal lobule (IPL) as a key node activated during cognitive flexibility tasks, while the dorsolateral prefrontal cortex (DLPFC) mediates top-down cognitive control. We therefore hypothesize that decreased functional connectivity between the left IPL and right DLPFC is the critical neural basis for cognitive flexibility impairment in MDD, and that targeted modulation of this connection can improve flexibility.

Study Design

This is a randomized, double-blind, sham-controlled, multi-center trial. A total of 105 MDD patients with cognitive flexibility impairment will be enrolled and allocated 1:1:1 to:

Active dual-target group (n=35): active rTMS over left IPL + active rTMS over right DLPFC; Active single-target group (n=35): active rTMS over left IPL + sham over right DLPFC; Sham control group (n=35): sham rTMS over both targets. All participants will continue their stable SSRI or SNRI treatment as usual (TAU). rTMS will be delivered using MRI-guided neuronavigation for individualized target localization. The stimulation regimen consists of 5 paired sessions per day (with a 50-minute inter-session interval) for 10 consecutive days.

Outcomes and Follow-up

Assessments will occur at baseline, immediately post-treatment (Day 10), and at 2-week and 4-week post-treatment:

Primary outcome: cognitive flexibility, measured by the Trail Making Test difference score (TMT-B minus TMT-A) and by task-switching behavioral performance.

Secondary outcomes: depressive symptom severity (HAMD), anxiety (HAMA, ), functional disability (Sheehan Disability Scale, SDS), suicidal ideation (Beck Suicidal Ideation scale, BSI), and other clinical measures.

Imaging: structural, resting-state acquired on a Siemens 3.0T MRI scanner to assess IPL-DLPFC functional connectivity changes.

Safety: adverse events, vital signs, and pain rating (Visual Analogue Scale, VAS).

Significance This study may identify the key functional connectivity basis of cognitive flexibility impairment in MDD and provide a novel, individually-targeted rTMS strategy. If effective, it will offer new evidence for treating cognitive dysfunction in depression and establish a clinically actionable brain network target.

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.