Discussion
TRD, transdiagnosis, depressive cognitions, depressive, depressed, depressive symptoms, MDD
PATHOPHYSIOLOGY
The present study examined brain functional connectivity changes in TRD patients participating in a clinical trial of SNT. By using an RCT design and performing analyses of the interaction between the treatment effect (before vs. after treatment) and the group effect (active vs. sham), we explored the functional response to treatment while controlling for placebo effects. Our pre-defined ROI approach identified three seed pairs with statistically significant changes with SNT. First, amygdala-DMN FC significantly increased from baseline to immediate-post after active SNT as compared to sham, and greater increases correlated with better clinical outcomes. Subsequent exploratory analysis was consistent with a possible normalization of pathological baseline FC. Second, amygdala-SN FC significantly decreased from baseline to immediate-post after active SNT as compared to sham. Again, greater decreases correlated with better outcomes. Third, striatum-SN FC significantly increased from baseline to immediate-post after active SNT as compared to sham. These results offer a unique insight into the putative mechanisms underlying the ATD effect of SNT—a high dose, fMRI-guided, accelerated intermittent TBS protocol—in TRD. Overall, our study confirmed that from a dimensional perspective the DLPFC targeted TMS is efficacious on depressive symptoms, as demonstrated recently in a transdiagnosis meta-analysis [Our findings highlight a central role of altered DMN FC as a mechanism of therapeutic effect and raise the possibility that this change could serve as a biomarker of therapeutic outcomes following SNT. DMN FC has been frequently reported to be abnormal in MDD but with inconsistencies in the differences observed [Antidepressant effects previously have been associated with a decrease within DMN FC [Moreover, we found a large effect of active stimulation on the AMY-DMN connectivity (ES = −0.872) suggesting a strong downstream effect of active SNT on this network. In addition, SNT altered other amygdala-centered connectivity patterns. Namely, following the SNT course, amygdala FC was increased with the DMN and decreased with the SN. Both FC patterns were associated with clinical changes with negative and positive correlations, respectively. Note that amygdala-DMN mean FC at the immediate-post visit was not statistically different from HC FC and was sustained at the one-month follow-up. Together with abnormal baseline FC (as compared to HC), our results suggest a modification of amygdala-DMN FC in the direction of HC. Across all results, amygdala-DMN FC change demonstrated the most robust evidence in terms of relevance to the mechanism of action of SNT. Several pieces of evidence in the literature support our findings. Indeed, a decreased amygdala-DMN FC has been related to an ongoing major depressive episode [The salience network is another important network identified as modulated by SNT in our study. We found increased connectivity between the SN and the striatum that reached HC group connectivity levels at the immediate-post visit as well as at one-month follow-up. In addition, decreased connectivity with the amygdala was noted and was associated with better clinical outcomes. The SN is thought to be a crucial contributor to MDD pathophysiology given its involvement in depressive cognitions [Our results must be interpreted considering several limitations. First, the small sample size might have affected our ability to detect additional relevant functional brain responses following SNT. Thus, we should mention that the amygdala-SN model was not well distributed residuals. A follow up study with a larger sample size is needed to replicate these findings and further explore the mechanistic basis of ATD response to FC-guided lDLPFC aiTBS. Second, our HC group was not matched by sex with our depressed patients, which may impact the results of those exploratory analyses in an unknown manner. Finally, we would like to highlight that in our depressed sample females represented 33.33% and 41.67% of both sham and active groups—respectively—which is an unusual sex ratio for this illness. Our results should be interpreted considering this characteristic of our sample.To conclude, our recently published clinical trial demonstrated the high efficacy of SNT, an accelerated, high-dose, iTBS protocol with functional MRI-guided targeting, for TRD [