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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
88
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.
The First Affiliated Hospital, Zhejiang University School of Medicine
Zhejiang, Hangzhou, China
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: 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: 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).
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)
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.
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.
Hamilton Depression Rating Scale 24-item (HAMD-24)
Clinician-rated measure of depressive symptom severity. Total score range 0-76; higher scores indicate more severe depressive symptoms.
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)
Clinician-rated measure of anxiety symptom severity. Total score range 0-56; higher scores indicate more severe anxiety symptoms.
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)
Clinician-rated measure of manic symptom severity. Total score range 0-60; higher scores indicate more severe manic symptoms.
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)
Self-reported measure of depressive symptom severity. Total (raw) score range 20-80; higher scores indicate more severe depressive symptoms.
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)
Self-reported measure of anxiety symptom severity. Total (raw) score range 20-80; higher scores indicate more severe anxiety symptoms.
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)
Self-reported measure of subjective cognitive difficulties (e.g., attention, memory, planning). Total score range 0-80; higher scores indicate greater perceived cognitive impairment.
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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
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.
Time frame: During the 5-day intervention period
Resting-state fMRI functional connectivity (FC) between V1 and hippocampus
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 .
Time frame: 1 day before the intervention and within 2 days after completion of the intervention course.