A Study on Functional Connectome and rTMS Intervention of Cognitive Flexibility Impairment in Patients With Major Depressive Disorder

NCT07161492 | Not Yet Recruiting

• 1 other identifier: KYZ20250118
• Study Type: interventional
• Target: 182
• Locations: 1 country
• Sites: 1

Brief Summary

Persistent cognitive impairment in major depressive disorder (MDD) affects both treatment outcomes and psychosocial functioning, emphasizing the critical need for effective treatment. However, there is still a lack of effective treatment at present. Our previous studies found that the impairment in cognitive flexibility (CF) persisted even in remitted patients with MDD. This impairment was correlated with hypo-connectivity between the left inferior parietal lobule (IPL) and the right dorsal prefrontal cortex (dPFC). Based on these findings, we hypothesize that the hypo-connectivity between the left IPL and the right dPFC is the neural basis of CF impairment, and targeted interventions of this connection may alleviate CF impairment and thus improve treatment outcomes as well as psychosocial functioning of patients with MDD. The present study proposes to employ cognitive training for MDD patients with CF impairment. By comparing changes in CF and brain functional connectivity via task-based fMRI before and after the intervention, we aim to clarify the effect of cognitive training on cognitive performance, treatment outcomes and psychosocial functioning, and identify the critical role of the hypo-connectivity between the left IPL and the right dPFC underlying CF impairment. Furthermore, we will conduct a randomized controlled trial to investigate the effect of individualized dual-target repetitive transcranial magnetic stimulation (rTMS) on CF by targeting the hypo connectivity between the left IPL and the right dPFC. The results will further validate the critical role of this connection in modulating CF performance and provide a reliable intervention target for reducing CF impairment.

Conditions

Depressive Disorder, Major; Cognitive Impairment

Outcome Measures

Primary Outcomes (1)

• Change in cognitive flexibility assessed by Trail Making Test Part B minus Part A (TMT B-A)

  Time difference in seconds between completion of TMT-B and TMT-A. Higher values indicate greater impairment in cognitive flexibility. Measured at baseline and 4 weeks post-intervention

  Baseline to 4 weeks

Study Arms (4)

CCRT+TAU

EXPERIMENTAL

Participants receive: 1. Computerized Cognitive Remediation Therapy (CCRT): * Cognitive flexibility module (4-6 exercises per session) * 45-60 min/session, 5 sessions/week for 4 weeks * Difficulty progression based on performance 2. Treatment As Usual (TAU): * Stable-dose SSRIs/SNRIs (e.g., paroxetine 20-40mg/day) * Continued throughout study"

Behavioral: Computerized Cognitive Remediation Therapy; Drug: Selective Serotonin Reuptake Inhibitors or Serotonin-Norepinephrine Reuptake Inhibitors

TAU Control

ACTIVE COMPARATOR

Participants receive: * Treatment As Usual (TAU) only: * Stable-dose SSRIs/SNRIs (e.g., paroxetine 20-40mg/day) * No CCRT intervention"

Drug: Selective Serotonin Reuptake Inhibitors or Serotonin-Norepinephrine Reuptake Inhibitors

Active rTMS+TAU

EXPERIMENTAL

Participants receive: 1. Individualized dual-target rTMS: * Target: Left IPL-right dPFC connectivity (fMRI-guided) * Protocol: cc-PAS (100 pulse-pairs/session, 0.2Hz) * Intensity: 90-120% resting motor threshold * Duration: 8.3 min/session, 5 sessions/week for 4 weeks * Device: MagPro X100 with Cool-B65 coil 2. Treatment As Usual (TAU): * Stable-dose SSRIs/SNRIs"

Device: Repetitive Transcranial Magnetic Stimulation; Drug: Selective Serotonin Reuptake Inhibitors or Serotonin-Norepinephrine Reuptake Inhibitors

Sham rTMS+TAU

SHAM COMPARATOR

Participants receive: 1. Sham rTMS: * Identical setup as active arm * Coil tilted 90° with magnetic shield * Sound/sensation matched 2. Treatment As Usual (TAU): * Stable-dose SSRIs/SNRIs"

Device: Sham Repetitive Transcranial Magnetic Stimulation; Drug: Selective Serotonin Reuptake Inhibitors or Serotonin-Norepinephrine Reuptake Inhibitors

Interventions

Repetitive Transcranial Magnetic Stimulation DEVICE

Individualized dual-target rTMS delivered using MRI-guided neuronavigation (Dolphin Robotics). Stimulation parameters: * Targets: Left IPL and right dPFC connectivity hotspots * Protocol: 100 pulse-pairs/session at 0.2Hz * Intensities: Conditioning stimulus 90% RMT, test stimulus 120% RMT * Duration: 8.3 min/session, 5 sessions/week × 4 weeks

Active rTMS+TAU

Computerized Cognitive Remediation Therapy BEHAVIORAL

Structured computer-based training targeting cognitive flexibility, consisting of 4-6 exercises per session. Each exercise includes 8-24 progressively challenging tasks. Administered for 45-60 minutes per session, 5 sessions/week over 4 weeks. Delivered via specialized software on desktop computers.

CCRT+TAU

Sham Repetitive Transcranial Magnetic Stimulation DEVICE

Inactive stimulation using identical equipment with: * Coil tilted at 90° to scalp * Magnetic shielding insert * Matched acoustic artifact All other parameters identical to active rTMS arm.

Sham rTMS+TAU

Selective Serotonin Reuptake Inhibitors or Serotonin-Norepinephrine Reuptake Inhibitors DRUG

Background antidepressant therapy maintained at stable doses throughout the study. Minimum dose requirements: * SSRIs: Paroxetine ≥20mg/day, Sertraline ≥50mg/day * SNRIs: Venlafaxine ≥75mg/day, Duloxetine ≥60mg/day Dosage adjustments prohibited during trial participation.

Active rTMS+TAU; CCRT+TAU; Sham rTMS+TAU; TAU Control

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Meets DSM-5 criteria for Major Depressive Episode confirmed by two attending psychiatrists using SCID-5
• Currently in depressive episode (MADRS ≥22)
• Stable dose of SSRIs/SNRIs for ≥4 weeks prior to randomization
• Age 18-45 years
• Han Chinese ethnicity, right-handed
• Minimum junior high school education; no color blindness; capable of providing informed consent
• Willing to sign informed consent and complete all assessments

You may not qualify if:

• Other DSM-5 psychiatric disorders (except MDD)
• Received non-pharmacotherapy in past 6 months:
• ECT
• rTMS
• Systematic psychotherapy (\>10 sessions)
• Prior CCRT treatment
• Medications affecting cognition within specified washout periods:
• Antipsychotics (1 month)
• Cholinesterase inhibitors (donepezil:14d; galantamine:2d)
• Memantine (20d)
• Nootropics (e.g., piracetam:2d)
• Significant medical comorbidities:
• Thyroid disorders, SLE, diabetes
• Hepatic/renal/pulmonary impairment
• Active infections

Sponsors & Collaborators

• Second Xiangya Hospital of Central South University: lead

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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

MeSH Terms

Conditions

Depressive Disorder, Major; Cognitive Dysfunction

Interventions

Transcranial Magnetic Stimulation; Selective Serotonin Reuptake Inhibitors; Serotonin and Noradrenaline Reuptake Inhibitors

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Magnetic Field Therapy; Therapeutics; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Neurotransmitter Agents; Serotonin Agents; Physiological Effects of Drugs

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: September 1, 2025
• Primary Completion (Estimated): August 1, 2028
• Study Completion (Estimated): October 1, 2028
• Last Updated: September 8, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)