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

Central South University

Status: Not yet enrolling

Conditions: Cognitive Impairment; Depressive Disorder, Major

Treatments: Device: Sham Repetitive Transcranial Magnetic Stimulation; Drug: Selective Serotonin Reuptake Inhibitors or Serotonin-Norepinephrine Reuptake Inhibitors; Behavioral: Computerized Cognitive Remediation Therapy; Device: Repetitive Transcranial Magnetic Stimulation

Study type: Interventional

Funder types: Other

Identifiers

NCT07161492

KYZ20250118

Details and patient eligibility

About

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.

Full description

This is a mechanistic clinical trial investigating the neural basis of cognitive flexibility (CF) impairment in major depressive disorder (MDD) and the therapeutic effects of targeted neuromodulation. The study consists of three integrated components:

1. Component 1 (RCT: CCRT vs. TAU)

   MDD patients with CF impairment will be randomized to:

   • Arm A: Computerized Cognitive Remediation Therapy (CCRT) targeting CF + Treatment As Usual (TAU)
   • Arm B: TAU alone Objective : Examine whether CCRT improves CF and whether CF improvement translates to better clinical/functional outcomes.

2. Component 2 (Neuroimaging Biomarker Study)

   Cross-sectional comparison of:

   • CF-impaired MDD patients
   • CF-intact MDD patients Objective : Identify functional connectivity (FC) signatures of CF impairment using task-based fMRI during cognitive flexibility tasks.

3. Component 3 (RCT: Active vs. Sham rTMS)

CF-impaired MDD patients will be randomized to:

• Arm C: Individualized dual-target rTMS (left IPL-right dPFC) + TAU
• Arm D: Sham rTMS + TAU Objective : Test whether cc-PAS rTMS normalizes left IPL-right dPFC hypo-connectivity and improves CF.

Scientific Rationale :

Hypo-connectivity between left inferior parietal lobule (IPL) and right dorsal prefrontal cortex (dPFC) is hypothesized to be a key neural mechanism underlying persistent CF impairment in MDD. This study aims to:

• Validate this circuit as a therapeutic target
• Establish fMRI-guided cc-PAS rTMS as a precision intervention

Methodology :

Individualized targeting : fMRI-guided neuronavigation (Dolphin Robotics) to identify subject-specific IPL/dPFC coordinates Novel stimulation : Cortico-cortical paired associative stimulation (cc-PAS) to modulate directional connectivity Cognitive phenotyping : Wisconsin Card Sorting Test (WCST) and Trail Making Test (TMT-B/A) as primary CF measures

Enrollment: 182 estimated patients

Sex: All

Ages: 18 to 45 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

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

Exclusion criteria

1. Other DSM-5 psychiatric disorders (except MDD)

2. Received non-pharmacotherapy in past 6 months:

   • ECT
   • rTMS
   • Systematic psychotherapy (>10 sessions)

3. Prior CCRT treatment

4. Medications affecting cognition within specified washout periods:

   • Antipsychotics (1 month)
   • Cholinesterase inhibitors (donepezil:14d; galantamine:2d)
   • Memantine (20d)
   • Nootropics (e.g., piracetam:2d)

5. Significant medical comorbidities:

   • Thyroid disorders, SLE, diabetes
   • Hepatic/renal/pulmonary impairment
   • Active infections
   • Major trauma

6. History of traumatic brain injury with coma

7. Substance/alcohol abuse or dependence

8. Active suicidal ideation/attempt (MADRS item 10 ≥4)

9. Current corticosteroid therapy

10. Pregnancy, lactation, or planned pregnancy

11. Personal/family history of epilepsy

12. Metallic implants (e.g., pacemaker, dental prostheses)

13. Investigator-determined contraindications

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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182 participants in 4 patient groups

CCRT+TAU

Experimental group

Description:

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"

Treatment:

Behavioral: Computerized Cognitive Remediation Therapy

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

TAU Control

Active Comparator group

Description:

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

Treatment:

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

Active rTMS+TAU

Experimental group

Description:

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"

Treatment:

Device: Repetitive Transcranial Magnetic Stimulation

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

Sham rTMS+TAU

Sham Comparator group

Description:

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"

Treatment:

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

Device: Sham Repetitive Transcranial Magnetic Stimulation