Discussion
MDD, depression, anxiety, ADHD
REGRESSION, REMISSION
The main clinical finding of the present multicenter study is that treatment of MPFC-ACC with the H7 coil in patients with MDD, who did not respond to antidepressant medications in the current episode, produced a strong and noninferior effect relative to that induced by LPFC stimulation with the H1 coil. Both H-coils induced similar decrease of depression and anxiety levels, similar increase in quality of life, and similarly high response and remission rates in these patients with MDD. As expected from a study including 2 active arms, response and remission rates were higher than those achieved in the original sham-controlled study that led to the clearance of the H1 coil by the FDA (We also identified an easy-to-use C-DEPTH for the clinical outcome, composed of mood and anxiety items derived from HDRS-21 (The construction of an E-DEPTH model is nuanced, as data for each group include response to only 1 H-coil (converse to the uniform C-DEPTH for both groups). Nevertheless, individual outcome scores were correlated with activity in a coil-specific manner. As expected, alpha activity over the stimulated area of each coil, which was suggested to reflect cortical inhibition level (Together, the electrophysiological correlates for response to Deep TMS in this study support and extend findings from a previous study in patients with ADHD treated by a different H-coil (This may be in line with results of the cross-lagged regression model, which revealed that depression and anxiety were treated independently and simultaneously by the H1 coil, while the H7 coil demonstrated a different and distinct pattern of a lagged reduction of anxiety that followed a decrease in depression. Together, the deeper and broader effective electric fields of Deep TMS relative to traditional figure eight coils, and the different interactions of the H1 and H7 coils with brain activity and symptoms’ alleviation, may provide an explanation for the advantage of the H1 coil in patients with more severe C-DEPTH, compared with the H7 coil, figure eight coil, and pharmacotherapy.It is interesting to compare the efficacy of the H7 coil targeting the MPFC-ACC with previous TMS studies in MDD patients that targeted these brain areas. In previous open studies or RCTs that did not include a sham arm (A limitation of the C-DEPTH and E-DEPTH is a lack of crossover data in which patients were selected for treatment based on their baseline clinical score or brain response during a single session (Taken together, our main findings are that MPFC-ACC stimulation using the H7 coil is an effective tool for the treatment of patients with MDD who did not respond to pharmacological treatment in the current episode and that the effectiveness of this intervention is noninferior to that induced by the FDA-cleared LPFC stimulation using the H1 coil. However, patients expressing higher severity in a cluster combining depression and anxiety symptoms (C-DEPTH > 0.5) responded better to LPFC stimulation with the H1 coil, while those expressing lower severity of this cluster (C-DEPTH ≤ 0.5) responded better to MPFC-ACC stimulation with the H7 coil. The present study also indicates potentially different underlying mechanisms of action for lateral and medial stimulation. By identifying specific clinical and electrophysiological predictors for response to each intervention, this study serves as an important step toward personalized TMS treatments of MDD.