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. Methods: 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). Results: 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. Conclusions: DTI-guided multimodal neuro-stimulation mode significantly improves cognitive impairments and is safe for BD patients.