TMS for Improving Cognitive Function in Bipolar Disorder

Official title

Targeting the Primary Visual Cortex-Hippocampus Circuit With Transcranial Magnetic Stimulation to Improve Cognition in Bipolar Disorder: A Randomized Controlled Trial

Overview

Bipolar disorder is a highly disabling psychiatric illness, and cognitive impairment is common in patients with bipolar depression as well as during remission, contributing substantially to functional disability and poorer prognosis. Currently, effective interventions specifically targeting cognitive deficits remain limited, highlighting the need for novel treatment strategies. Transcranial magnetic stimulation, a noninvasive neuromodulation technique, has shown potential benefits for depressive symptoms and cognitive functioning. Based on structural and functional neuroimaging evidence, this study proposes an individualized intermittent theta burst stimulation (iTBS) protocol targeting the primary visual cortex (V1) and its functional pathway to the hippocampus, combined with online cognitive training. This randomized, double-blind, parallel-group, sham-controlled trial will enroll 88 patients with bipolar disorder in remission phase and allocate them to active or sham stimulation. The intervention will be delivered over 5 days, with follow-up assessments through 6 weeks. The primary outcome is change in cognitive performance as measured by the Cambridge Neuropsychological Test Automated Battery (CANTAB). Secondary outcomes include changes in clinical symptom ratings, magnetic resonance imaging (MRI) biomarkers, and the incidence of adverse events. This study aims to evaluate the efficacy and safety of this targeted intervention and to provide evidence for precision treatment approaches to cognitive impairment in bipolar disorder.

Interventions

• Device Active Intermittent Theta Burst Stimulation
  Active iTBS will be delivered using MRI-guided neuronavigation system. Participants will receive two sessions per day for 5 consecutive days. The iTBS pattern consists of bursts of three pulses at 50 Hz, repeated at 5 Hz. Each train lasts 2 s and is followed by an 8-s inter-train interval. Stimulation will be administered at 90% of the resting motor threshold (RMT), with a total of 1,800 pulses per session. Each session will last approximately 10 minutes. For each participant, the individual st
• Behavioral Online Cognitive Training
  Participants in both arms will complete the same computerized pattern recall training paired with each stimulation session (twice daily) throughout the 5-day iTBS intervention period. In each block, one abstract, difficult-to-verbalize target figure is presented centrally for 5 seconds for encoding. Following target offset, participants complete 15 consecutive match/non-match judgments: a sequence of visually similar probe figures is presented one at a time (each for 1500 ms with a 500-ms inter-
• Device Sham Intermittent Theta Burst Stimulation
  Sham iTBS will be delivered over the individualized V1-HPC target using MRI-guided neuronavigation. The coil will be held perpendicular to the target scalp site and kept in contact throughout stimulation. Intensity will be set at 20% RMT, with all other iTBS parameters identical to the active group.

Primary outcome measures

• Cognitive performance will be assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB) Spatial Span (SSP) [Time frame: Time Frame: Assessments will be conducted at baseline prior to randomization (T0), immediately after completion of the intervention (T1), and at 6 weeks (T2) post-intervention follow-up.]
• CANTAB Pattern Recognition Memory (PRM) [Time frame: Time Frame: Assessments will be conducted at baseline prior to randomization (T0), immediately after completion of the intervention (T1), and at 6 weeks (T2) post-intervention follow-up.]
• CANTAB Rapid Visual Information Processing (RVP) [Time frame: Assessments will be conducted at baseline prior to randomization (T0), immediately after completion of the intervention (T1), and at 6 weeks (T2) post-intervention follow-up.]
• CANTAB Spatial Working Memory (SWM) [Time frame: Assessments will be conducted at baseline prior to randomization (T0), immediately after completion of the intervention (T1), and at 6 weeks (T2) post-intervention follow-up.]

Secondary outcome measures (8)

• Hamilton Depression Rating Scale 24-item (HAMD-24) [Time frame: Baseline prior to randomization (T0), immediately after completion of the intervention (T1), and at 6 weeks (T2) post-intervention follow-up.]
• Hamilton Anxiety Rating Scale (HAMA) [Time frame: Baseline prior to randomization (T0), immediately after completion of the intervention (T1), and at 6 weeks (T2) post-intervention follow-up.]
• Young Mania Rating Scale (YMRS) [Time frame: Baseline prior to randomization (T0), immediately after completion of the intervention (T1), and at 6 weeks (T2) post-intervention follow-up.]
• Self-Rating Depression Scale (SDS) [Time frame: Baseline prior to randomization (T0), immediately after completion of the intervention (T1), and at 6 weeks (T2) post-intervention follow-up.]
• Self-Rating Anxiety Scale (SAS) [Time frame: Baseline prior to randomization (T0), immediately after completion of the intervention (T1), and at 6 weeks (T2) post-intervention follow-up.]
• Perceived Deficits Questionnaire-Depression (PDQ-D) [Time frame: Baseline prior to randomization (T0), immediately after completion of the intervention (T1), and at 6 weeks (T2) post-intervention follow-up.]
• Adverse Event Report Form [Time frame: During the 5-day intervention period]
• Resting-state fMRI functional connectivity (FC) between V1 and hippocampus [Time frame: 1 day before the intervention and within 2 days after completion of the intervention course.]

Eligibility criteria

Inclusion criteria

1: Age between 18 and 45 years; 2: Right-handed; 3: Meet the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for bipolar disorder and are currently in a stable remission phase; 4: Hamilton Depression Rating Scale 24-item (HAMD-24) score < 8; 5: Young Mania Rating Scale (YMRS) score <= 7; 6: The participant and his/her legal guardian are willing to comply with the treatment procedures and provide written informed consent.

Exclusion criteria

1: Diagnosis of another primary psychiatric disorder judged by the investigators to be the predominant condition, with functional impairment exceeding that attributable to bipolar disorder; 2: Comorbid psychiatric disorders, including obsessive-compulsive disorder, personality disorders, anxiety spectrum disorders, intellectual disability, or substance use (dependence/abuse); 3: Inability to complete self-report symptom rating scales or the CANTAB cognitive assessment; 4: Prominent suicidal ideation (item 3 of the HAMD-24 >= 2); 5: History of severe physical illness or other medical conditions that may affect the central nervous system; 6: Neurological disorders or risk factors for seizures, such as a history of intracranial disease, head injury, abnormal electroencephalogram (EEG) findings, magnetic resonance imaging (MRI) evidence of structural brain abnormalities, or a family history of epilepsy; 8: Contraindications to MRI or transcranial magnetic stimulation, such as the presence of metallic or electronic implants (e.g., intracranial metallic foreign bodies, cochlear implants, cardiac pacemakers, vascular stents); 9: Receipt of electroconvulsive therapy (ECT) within 6 months prior to study enrollment; 10: Currently undergoing transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), or other neuromodulatory interventions; 11: Pregnant or breastfeeding women, and women of childbearing potential with a positive urine pregnancy test.

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

Double blind

Primary purpose

Treatment

Study locations

China · 1 center

• The First Affiliated Hospital, Zhejiang University School of Medicine — Zhejiang

Identifiers

NCT: NCT07414147 · IIT20250202C-R1

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗