TMS for Improving Cognitive Function in Bipolar Disorder

ConditionsBipolar Disorder (BD)Cognitive Impairment

Trial statusNot yet recruiting

Trial phaseNot applicable

Trial typeInterventional

Biological sexAll

Age18-45

SponsorFirst Affiliated Hospital of Zhejiang University

About this trial

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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

None

Disqualifiers

None

Trial design

Design model

Parallel

Treatments tested in this trial

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.
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.
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.

Treatment groups

88 Participants

are divided into 2 treatment groups

Group A: Active iTBS + Online Cognitive TrainingExperimental treatment 2 interventions

Group B: Sham iTBS + Online Cognitive TrainingSham comparator 2 interventions

Trial outcomes

Primary outcomes

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.

Secondary outcomes

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.

Other outcomes

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

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.

Time frame

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

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.

Time frame

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

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.

Time frame

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

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

First Affiliated Hospital of Zhejiang University

Lead sponsor

Source ClinicalTrials.gov

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