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

Official title

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

Overview

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.

Detailed description

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.

Interventions

• Device Repetitive Transcranial Magnetic Stimulation
  Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that uses magnetic pulses to modulate neuronal activity in targeted cortical regions. In this study, rTMS is delivered using a commercially available magnetic stimulator with a figure-of-eight coil. Stimulation targets - the left inferior parietal lobule (IPL) and the right dorsolateral prefrontal cortex (DLPFC) - are individually localized using MRI-guided neuronavigation based on each participant'

Primary outcome measures

• Change in Cognitive Flexibility [Time frame: Baseline, immediately post-treatment (Day 10), and at 2-week and 4-week follow-ups]

Secondary outcome measures (1)

• Change in Depressive Symptom Severity [Time frame: Baseline, immediately post-treatment (Day 10), and at 2-week and 4-week follow-ups]

Eligibility criteria

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.

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

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

China · 1 center

• Xiangya Second Hospital of Central South University — Changsha

Publications

• Chen Y, Liu J, Li Z, Liu B, Ji Y, Ju Y, Fang H, Zheng Q, Wang M, Guo W, Li H, Lu X, Li L. The Tendency of Modified Electroconvulsive Therapy-Related Working Memory and Subjective Memory Deficits in Depression: A Prospective Follow-up Study. J ECT. 2020 Sep;36(3):198-204. doi: 10.1097/YCT.0000000000000668. PMID 32118689
• Liu J, Dong Q, Lu X, Sun J, Zhang L, Wang M, Liu B, Ju Y, Wan P, Guo H, Zhao F, Zhang X, Zhang Y, Li L. Influence of comorbid anxiety symptoms on cognitive deficits in patients with major depressive disorder. J Affect Disord. 2020 Jan 1;260:91-96. doi: 10.1016/j.jad.2019.08.091. Epub 2019 Aug 29. PMID 31493645
• Ju Y, Horien C, Chen W, Guo W, Lu X, Sun J, Dong Q, Liu B, Liu J, Yan D, Wang M, Zhang L, Guo H, Zhao F, Zhang Y, Shen X, Constable RT, Li L. Connectome-based models can predict early symptom improvement in major depressive disorder. J Affect Disord. 2020 Aug 1;273:442-452. doi: 10.1016/j.jad.2020.04.028. Epub 2020 May 11. PMID 32560939
• Wang M, Ju Y, Lu X, Sun J, Dong Q, Liu J, Zhang L, Zhang Y, Zhang S, Wang Z, Liu B, Li L. Longitudinal changes of amplitude of low-frequency fluctuations in MDD patients: A 6-month follow-up resting-state functional magnetic resonance imaging study. J Affect Disord. 2020 Nov 1;276:411-417. doi: 10.1016/j.jad.2020.07.067. Epub 2020 Jul 20. PMID 32871671
• Liu J, Fan Y, Ling-Li Zeng, Liu B, Ju Y, Wang M, Dong Q, Lu X, Sun J, Zhang L, Guo H, Futao Zhao, Weihui Li, Zhang L, Li Z, Liao M, Zhang Y, Hu D, Li L. The neuroprogressive nature of major depressive disorder: evidence from an intrinsic connectome analysis. Transl Psychiatry. 2021 Feb 4;11(1):102. doi: 10.1038/s41398-021-01227-8. PMID 33542206
• Liu J, Ju Y, Fan Y, Liu B, Zeng LL, Wang M, Dong Q, Lu X, Sun J, Zhang L, Guo H, Zhao F, Li W, Zhang L, Li Z, Liao M, Zhang X, Zhang Y, Hu D, Li L. Functional connectivity evidence for state-independent executive function deficits in patients with major depressive disorder. J Affect Disord. 2021 Aug 1;291:76-82. doi: 10.1016/j.jad.2021.04.080. Epub 2021 May 21. PMID 34023750
• Guo W, Liu J, Liu B, Wang M, Dong Q, Lu X, Sun J, Zhang L, Guo H, Zhao F, Li W, Li Z, Liao M, Zhang L, Zhang Y, Ju Y, Li L. Relationship between childhood maltreatment and cognitive function in medication-free patients with major depressive disorder. Eur Arch Psychiatry Clin Neurosci. 2023 Aug;273(5):1073-1083. doi: 10.1007/s00406-022-01458-w. Epub 2022 Jul 29. PMID 35902412
• Ju Y, Wang M, Liu J, Liu B, Yan D, Lu X, Sun J, Dong Q, Zhang L, Guo H, Zhao F, Liao M, Zhang L, Zhang Y, Li L. Modulation of resting-state functional connectivity in default mode network is associated with the long-term treatment outcome in major depressive disorder. Psychol Med. 2023 Oct;53(13):5963-5975. doi: 10.1017/S0033291722002628. Epub 2022 Sep 27. PMID 36164996

Identifiers

NCT: NCT07161492 · KYZ20250118

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗