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

NCT07161492 | Not Yet Recruiting

• 1 other identifier: KYZ20250118
• Study Type: interventional
• Target: 105
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Depressive Disorder, Major; Cognitive Impairment

Outcome Measures

Primary Outcomes (1)

• Change in Cognitive Flexibility

  Baseline, immediately post-treatment (Day 10), and at 2-week and 4-week follow-ups

Secondary Outcomes (1)

• Change in Depressive Symptom Severity

  Baseline, immediately post-treatment (Day 10), and at 2-week and 4-week follow-ups

Study Arms (3)

Active Dual-Target rTMS Group

EXPERIMENTAL

Participants receive active repetitive transcranial magnetic stimulation (rTMS) over both the left inferior parietal lobule (IPL) and the right dorsolateral prefrontal cortex (DLPFC) using MRI-guided neuronavigation. Stimulation is delivered in 5 paired sessions per day (with a 50-minute inter-session interval) for 10 consecutive days. All participants continue stable SSRI or SNRI antidepressant treatment as usual (TAU).

Device: Repetitive Transcranial Magnetic Stimulation

Active Single-Target rTMS Group

ACTIVE COMPARATOR

Participants receive active rTMS over the left inferior parietal lobule (IPL) and sham stimulation over the right dorsolateral prefrontal cortex (DLPFC) using MRI-guided neuronavigation. Stimulation is delivered in 5 paired sessions per day (with a 50-minute inter-session interval) for 10 consecutive days. All participants continue stable SSRI or SNRI antidepressant treatment as usual (TAU).

Device: Repetitive Transcranial Magnetic Stimulation

Sham rTMS Control Group

SHAM COMPARATOR

Participants receive sham rTMS over both the left inferior parietal lobule (IPL) and the right dorsolateral prefrontal cortex (DLPFC) using MRI-guided neuronavigation. Sham stimulation mimics the sensation of active rTMS without delivering magnetic stimulation. Stimulation is delivered in 5 paired sessions per day (with a 50-minute inter-session interval) for 10 consecutive days. All participants continue stable SSRI or SNRI antidepressant treatment as usual (TAU).

Device: Repetitive Transcranial Magnetic Stimulation

Interventions

Repetitive Transcranial Magnetic Stimulation DEVICE

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's structural magnetic resonance imaging. Each stimulation session consists of paired target stimulation (IPL and DLPFC) with a 50-minute inter-session interval. Treatment is administered as 5 paired sessions per day for 10 consecutive days. Sham stimulation uses the same device and coil placement but delivers no active magnetic stimulation, mimicking the sensory experience of active r

Also known as: rTMS

Active Dual-Target rTMS Group; Active Single-Target rTMS Group; Sham rTMS Control Group

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Second Xiangya Hospital of Central South University: lead
• Fujian Mental Health Center: collaborator
• Xianyue Hospital, Xiamen: collaborator

Study Sites (1)

Xiangya Second Hospital of Central South University

Changsha, Hunan, 410011, China

Location

Related Publications (11)

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• Liu J, Chen Y, Xie X, Liu B, Ju Y, Wang M, Dong Q, Lu X, Sun J, Zhang L, Guo H, Zhao F, Li W, Zhang L, Li Z, Liao M, Li L, Zhang Y. The percentage of cognitive impairment in patients with major depressive disorder over the course of the depression: A longitudinal study. J Affect Disord. 2023 May 15;329:511-518. doi: 10.1016/j.jad.2023.02.133. Epub 2023 Feb 28.

  PMID: 36863474 RESULT

• Liu J, Zhao X, Wei X, Yan D, Ou W, Liao M, Ji S, Peng Y, Wu S, Wang M, Ju Y, Zhang L, Li Z, Liu B, Li L, Zhang Y. Empirical evidence for the neurocognitive effect of nitrous oxide as an adjunctive therapy in patients with treatment resistant depression: A randomized controlled study. Psychiatry Res. 2023 Aug;326:115326. doi: 10.1016/j.psychres.2023.115326. Epub 2023 Jun 26.

  PMID: 37390601 RESULT

• Guo W, Liu B, Wei X, Ju Y, Wang M, Dong Q, Lu X, Sun J, Zhang L, Guo H, Zhao F, Li W, Li Z, Liao M, Zhang L, Liu J, Zhang Y, Li L. The longitudinal change pattern of cognitive subtypes in medication-free patients with major depressive disorder: a cluster analysis. Psychiatry Res. 2023 Sep;327:115413. doi: 10.1016/j.psychres.2023.115413. Epub 2023 Aug 12.

  PMID: 37579539 RESULT

MeSH Terms

Conditions

Depressive Disorder, Major; Cognitive Dysfunction

Interventions

Transcranial Magnetic Stimulation

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Cognition Disorders; Neurocognitive Disorders

Intervention Hierarchy (Ancestors)

Magnetic Field Therapy; Therapeutics

Central Study Contacts

Jin Liu

CONTACT

13123392823; liujin975@csu.edu.cn

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 30, 2025
• First Posted: September 8, 2025
• Study Start: July 1, 2026
• Primary Completion (Estimated): August 1, 2028
• Study Completion (Estimated): October 1, 2028
• Last Updated: June 25, 2026

Record last verified: 2026-06

Locations

CN (1)