TMS for Improving Cognitive Function in Bipolar Disorder
Targeting the Primary Visual Cortex-Hippocampus Circuit With Transcranial Magnetic Stimulation to Improve Cognition in Bipolar Disorder: A Randomized Controlled Trial
1 other identifier
interventional
88
1 country
1
Brief Summary
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for not_applicable
Started Mar 2026
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
January 13, 2026
CompletedFirst Posted
Study publicly available on registry
February 17, 2026
CompletedStudy Start
First participant enrolled
March 1, 2026
CompletedPrimary Completion
Last participant's last visit for primary outcome
March 1, 2027
ExpectedStudy Completion
Last participant's last visit for all outcomes
April 30, 2027
February 17, 2026
February 1, 2026
1 year
January 13, 2026
February 10, 2026
Conditions
Keywords
Outcome Measures
Primary Outcomes (4)
Cognitive performance will be assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB) Spatial Span (SSP)
SSP is a computerised version of the Corsi Blocks task, assessing working memory capacity. The span length ranges from 0 to 9 items, with higher scores indicating greater short-term memory capacity.
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)
CANTAB PRM evaluates visual pattern recognition memory. The task comprises two sets of 12 stimuli: one assesses immediate recognition, and the other assesses delayed recognition. Higher corrects indicate better recognition memory performance.
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)
RVP assesses sustained visual attention and processing speed. Outcome indices include RVP A' (ranges from 0.00 to 1.00, with higher values indicating better target detection performance, and is derived from the hit rate P(hit) and false-alarm rate P(fa)), Total Hits (number of correct target detections), and Mean Latency (mean reaction time for correct responses).
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)
SWM assesses the ability to retain spatial information and manipulate remembered locations within working memory. The error index reflects the number of times a participant returns to boxes in which a token has already been found; higher error counts indicate poorer working memory performance. The strategy score indexes the efficiency of search behavior, with higher scores reflecting a more disorganized search strategy.
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 Outcomes (8)
Hamilton Depression Rating Scale 24-item (HAMD-24)
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)
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)
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)
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)
Baseline prior to randomization (T0), immediately after completion of the intervention (T1), and at 6 weeks (T2) post-intervention follow-up.
- +3 more secondary outcomes
Other Outcomes (3)
Resting-state fMRI amplitude of low-frequency fluctuations (ALFF) in V1 and hippocampus
1 day before the intervention and within 2 days after completion of the intervention course.
Resting-state fMRI fractional amplitude of low-frequency fluctuations (fALFF) in V1 and hippocampus
1 day before the intervention and within 2 days after completion of the intervention course.
Resting-state fMRI regional homogeneity (ReHo) in V1 and hippocampus
1 day before the intervention and within 2 days after completion of the intervention course.
Study Arms (2)
Active iTBS + Online Cognitive Training
EXPERIMENTALParticipants will receive active iTBS over the individualized left V1-HPC target using MRI-guided neuronavigation, delivered twice daily for 5 consecutive days (90% RMT; 1,800 pulses per session; \~10 minutes). Each stimulation session will be paired with the same online computerized pattern recall training.
Sham iTBS + Online Cognitive Training
SHAM COMPARATORParticipants will receive sham iTBS over the individualized left V1-HPC target using MRI-guided neuronavigation, delivered twice daily for 5 consecutive days (20% RMT; all other iTBS parameters identical to the active group). Each stimulation session will be paired with the same online computerized pattern recall training.
Interventions
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 stimulation target will be defined within the left V1 as the subregion showing the strongest functional connectivity with the hippocampus. Target coordinates will be mapped onto each participant's native anatomical space and implemented using robot-assisted, MRI-guided neuronavigation based on the participant's T1-weighted structural MRI to ensure accurate and reproducible coil positioning across sessions.
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-stimulus interval), and participants indicate whether each probe is identical to the target figure. Upon completion of the 15 judgments, a new target figure is introduced and the next block begins. Task progression is self-paced; therefore, the number of blocks completed within a session may vary across participants depending on response speed. Ten parallel task versions will be used and kept consistent across sessions to align training content with each iTBS visit.
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.
Eligibility Criteria
You may qualify if:
- : 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.
You may not qualify if:
- : 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.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (1)
The First Affiliated Hospital, Zhejiang University School of Medicine
Zhejiang, Hangzhou, 310000, China
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- not applicable
- Allocation
- RANDOMIZED
- Masking
- DOUBLE
- Who Masked
- PARTICIPANT, OUTCOMES ASSESSOR
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
January 13, 2026
First Posted
February 17, 2026
Study Start
March 1, 2026
Primary Completion (Estimated)
March 1, 2027
Study Completion (Estimated)
April 30, 2027
Last Updated
February 17, 2026
Record last verified: 2026-02
Data Sharing
- IPD Sharing
- Will not share
This study collects sensitive clinical, neurocognitive, and MRI data. Because the current informed consent, ethics approval, and institutional data governance do not permit external sharing of IPD. Study-level summary results will be disseminated via peer-reviewed publications.