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NCT Number: NCT07414147

TMS for Improving Cognitive Function in Bipolar Disorder

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.

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Key information

Conditions

Bipolar Disorder (BD) Bipolar Disorder Bipolar and Related Disorders Cognition Disorders Cognitive Dysfunction Cognitive Impairment Mental Disorders Mood Disorders Neurocognitive Disorders

Age range

18 year–45 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Active Intermittent Theta Burst Stimulation

Device

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.

Other names: iTBS, Theta Burst Stimulation, Transcranial Magnetic Stimulation

Online Cognitive Training

Behavioral

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.

Other names: Computerized cognitive training, Pattern recall training

Sham Intermittent Theta Burst Stimulation

Device

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 outcomes

  1. 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.

    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.

  2. 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 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.

  3. 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.

    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).

  4. 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.

    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.

Secondary outcomes

  1. 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.

    Clinician-rated measure of depressive symptom severity. Total score range 0-76; higher scores indicate more severe depressive symptoms.

  2. 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.

    Clinician-rated measure of anxiety symptom severity. Total score range 0-56; higher scores indicate more severe anxiety symptoms.

  3. 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.

    Clinician-rated measure of manic symptom severity. Total score range 0-60; higher scores indicate more severe manic symptoms.

  4. 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-reported measure of depressive symptom severity. Total (raw) score range 20-80; higher scores indicate more severe depressive symptoms.

  5. 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.

    Self-reported measure of anxiety symptom severity. Total (raw) score range 20-80; higher scores indicate more severe anxiety symptoms.

  6. 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.

    Self-reported measure of subjective cognitive difficulties (e.g., attention, memory, planning). Total score range 0-80; higher scores indicate greater perceived cognitive impairment.

  7. Adverse Event Report Form

    Time frame: During the 5-day intervention period

    Safety outcomes were assessed using an adverse event report form that captures overall AE severity (total score 0-54) and participant-rated treatment-relatedness (total score 0-72). Higher scores indicate greater AE severity and stronger perceived relatedness to the intervention, respectively.

  8. 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.

    Resting-state FC will be quantified as the Pearson correlation between the mean BOLD time series extracted from the individualized V1 stimulation target and the hippocampus. Higher Fisher z values indicate stronger V1-HPC coupling .

Other outcomes

  1. Resting-state fMRI amplitude of low-frequency fluctuations (ALFF) in V1 and hippocampus

    Time frame: 1 day before the intervention and within 2 days after completion of the intervention course.

    ALFF will be calculated within the V1 stimulation target and hippocampus as the amplitude of spontaneous low-frequency BOLD fluctuations. The outcome is the change in ALFF from baseline to post-intervention. Higher ALFF reflects greater amplitude of low-frequency spontaneous activity.

  2. Resting-state fMRI fractional amplitude of low-frequency fluctuations (fALFF) in V1 and hippocampus

    Time frame: 1 day before the intervention and within 2 days after completion of the intervention course.

    fALFF will be calculated within the V1 stimulation target and hippocampus ROI as the ratio of low-frequency power (typically 0.01-0.10 Hz) to the total detectable frequency range of the BOLD signal. The outcome is the change in fALFF from baseline to post-intervention. fALFF ranges from 0 to 1; higher values indicate a larger fraction of low-frequency fluctuations.

  3. Resting-state fMRI regional homogeneity (ReHo) in V1 and hippocampus

    Time frame: 1 day before the intervention and within 2 days after completion of the intervention course.

    ReHo will be computed within the V1 stimulation target and hippocampus as the local synchrony of BOLD time series among neighboring voxels. The outcome is the change in ReHo from baseline to post-intervention. Higher ReHo indicates stronger local synchronization.

Study contacts

Contact information is provided by the study sponsor or research team.

Hetong Zhou

CONTACT

[email protected]

+86 15157125762

Renqin Hu

CONTACT

[email protected]

+86 18368536092

Sponsors and collaborators

Lead sponsor

First Affiliated Hospital of Zhejiang University

Other

Registry information

Official study title

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

Important dates

Study start
2026
Primary completion
2027
Study completion
2027
First posted
Feb 17, 2026
Registry last updated
Feb 17, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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