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

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 Overview

• Status: Not yet recruiting
• Conditions: Cognitive Impairment; Bipolar Disorder (BD)
• Intervention / Treatment: Device: Active Intermittent Theta Burst Stimulation; Behavioral: Online Cognitive Training; Device: Sham Intermittent Theta Burst Stimulation

• Study Type: Interventional
• Enrollment (Estimated): 88
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Hetong Zhou; Phone Number: +86 15157125762; Email: 1168600035@zju.edu.cn
• Study Contact Backup: Name: Renqin Hu; Phone Number: +86 18368536092; Email: 1754316886@qq.COM

Study Locations

• China
  • Hangzhou
    • Zhejiang, Hangzhou, China, 310000
      • The First Affiliated Hospital, Zhejiang University School of Medicine
      • Contact: Renqin Hu; Phone Number: +86 18368536092; Email: 1754316886@qq.COM
      • Contact: Hetong Zhou; Phone Number: +086 15157125762; Email: 1168600035@zju.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active iTBS + Online Cognitive Training; Participants 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.	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 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: Transcranial Magnetic Stimulation; iTBS; Theta Burst Stimulation; 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-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 Comparator: Sham iTBS + Online Cognitive Training; Participants 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.	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-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; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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.	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.	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.	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.	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 .	1 day before the intervention and within 2 days after completion of the intervention course.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	1 day before the intervention and within 2 days after completion of the intervention course.

Collaborators and Investigators

• Sponsor: First Affiliated Hospital of Zhejiang University

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2026
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): April 30, 2027

Study Registration Dates

• First Submitted: January 13, 2026
• First Submitted That Met QC Criteria: February 10, 2026
• First Posted (Actual): February 17, 2026

Study Record Updates

• Last Update Posted (Actual): February 17, 2026
• Last Update Submitted That Met QC Criteria: February 10, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: intermittent theta burst stimulation
• Additional Relevant MeSH Terms: Bipolar and Related Disorders; Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Mood Disorders; Cognitive Dysfunction; Bipolar Disorder; Therapeutics; Magnetic Field Therapy; Transcranial Magnetic Stimulation
• Other Study ID Numbers: IIT20250202C-R1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No