Discussion
TMS-related cognitive improvements, bipolar disorder, bipolar depression, cognitive improvements, Baeken et
SECONDARY, CORTEX
The present study was a secondary analysis of an initial pilot trial investigating the efficacy of iTBS in bipolar depression, and the first to evaluate potential cognitive improvement with iTBS in bipolar disorder, as well as to explore whether cognitive changes were associated with increased hippocampal volumes. Overall, there was no evidence of cognitive improvement with iTBS delivered to the left DLPFC on global or specific cognitive domains. However, there was a non-significant trend for a modest increase in left hippocampal volume in the iTBS compared to the sham group, and this volume increase was associated with improved nonverbal memory functioning.This study contributes to the mixed findings reported in studies investigating possible TMS-related cognitive improvements in bipolar disorder. Our results are in line with two prior TMS studies that also failed to observe cognitive improvements (Hu et al. Although we failed to observe cognitive improvements associated with iTBS, patients in the active group did exhibit a trend towards the expected finding of increased ipsilateral hippocampal volumes relative to the sham group. Hippocampal volume increases have also been observed in a previous iTBS trial in bipolar disorder (Baeken et al. The current findings provide some support for the hypothesis that iTBS induces neuroplasticity within prefrontal-temporal networks. However, DLPFC stimulation alone may not be the most efficient and direct means of modulating hippocampal function. Previous studies in healthy participants reveal that by virtue of the strong connections between parietal cortex and medial temporal lobe regions, TMS of the former may serve as a form of ‘hippocampal-targeted’ TMS that induces strong effects on hippocampal based memory functions (Wang et al. Several strengths of this study included the utilisation of an iTBS TMS protocol, investigation of underlying hippocampal volumetric biomarkers of cognitive change, and assessment of multiple cognitive domains. However, several study limitations may have contributed to the negative cognitive findings reported herein. Although the sample size was modest, it was in line with the prior positive studies (Yang et al. 