Cognitive Enhancement in Bipolar Disorder: A Double-Blind, Randomized Controlled Trial Utilizing a Novel DTI-Guided Multimodal Neuro-stimulation Protocol

Background Traditional neuromodulation strategies for enhancing cognitive abilities in bipolar disorder (BD) patients have shown promise, yet there remains a need for novel intervention modalities to improve therapeutic outcomes.

This study introduces a novel multi-modal neuro-stimulaton (MNS) protocol using individualized DTI data to identify fiber tracts between the DLPFC and dACC. The highest structural connectivity point is selected as the individualized stimulation target, which is targeted using a combination of optimized tACS and robot-assisted navigated rTMS. A double-blind randomized controlled trial (Trial registration number: NCT05964777) was conducted to investigate the clinical efficacy of this innovative neuromodulation approach on cognitive abilities in BD patients. One hundred BD patients were randomly assigned to four groups: Group A (Active tACS-Active rTMS (MNS Protocol)), Group B (Sham tACS-Active rTMS), Group C (Active tACS-Sham rTMS), and Group D (Sham tACS-Sham rTMS). Participants underwent 15 sessions over three weeks. Cognitive assessments (THINC integrated tool) were conducted at baseline (Week 0), post-treatment (Week 3), and follow-up (Week 8).

Sixty-six participants completed all 15 sessions. Group A (MNS Protocol) showed superior improvements in Spotter CRT, TMT, and DSST scores compared to other groups at Week 3, with sustained cognitive enhancement in Spotter CRT at Week 8 (P < 0.01). Only Group A exhibited significant activation in the left frontal region post-MNS intervention. The novel MNS protocol was well tolerated, with no significant side effects observed.

DTI-guided multimodal neuro-stimulation mode significantly improves cognitive impairments and is safe for BD patients. Highlights Using DTI-derived neural fiber density to determine the target sites for tACS and rTMS in patients with bipolar disorder. Combining sequential tACS and rTMS to significantly improve cognitive function in the bipolar disorder patients. Utilizing individually optimized tACS and robot-assisted navigated rTMS to achieve high-precision transcranial stimulation. Competing Interest Statement The authors have declared no competing interest. Clinical Trial NCT05964777 Funding Statement Research supported by the National Key Research and Development Program of China (2023YFC2506200), the Research Project of Jinan Microecological Biomedicine Shandong Laboratory (No. JNL 2023001B), the Zhejiang Provincial Key Research and Development Program (2021C03107), the Leading Talent of Scientific and Technological Innovation Ten Thousand Talents Program of Zhejiang Province (No. 2021R52016), the Innovation team for precision diagnosis and treatment of major brain diseases (No. 2020R01001), Chinese Medical Education Association (2022KTZ004), the National Natural Science Foundation of China (82201675) and the Fundamental Research Funds for the Central Universities (226 2022 00193, 226 2022 00002, 2023ZFJH01 01, 2024ZFJH01 01). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Clinical Research Ethics Committee of the First Affiliated Hospital, Zhejiang University School of Medicine gave ethical approval for this work (Approval number: IIT20230058C-R1). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes