Network effects of Stanford Neuromodulation Therapy (SNT) in treatment-resistant major depressive disorder: a randomized, controlled trial

Abstract

Here, we investigated the brain functional connectivity (FC) changes following a novel accelerated theta burst stimulation protocol known as Stanford Neuromodulation Therapy (SNT) which demonstrated significant antidepressant efficacy in treatment-resistant depression (TRD). In a sample of 24 patients (12 active and 12 sham), active stimulation was associated with significant pre- and post-treatment modulation of three FC pairs, involving the default mode network (DMN), amygdala, salience network (SN) and striatum. The most robust finding was the SNT effect on amygdala-DMN FC (group*time interaction F(1,22) = 14.89, p < 0.001). This FC change correlated with improvement in depressive symptoms (rho (Spearman) = -0.45, df = 22, p = 0.026). The post-treatment FC pattern showed a change in the direction of the healthy control group and was sustained at the one-month follow-up. These results are consistent with amygdala-DMN connectivity dysfunction as an underlying mechanism of TRD and bring us closer to the goal of developing imaging biomarkers for TMS treatment optimization.Trial registration: ClinicalTrials.gov NCT03068715.

Fig. 1. Glass brain visualization of the three FC pairs that survived Bonferroni correction (Table 1).

Networks name: AMY: amygdala, DMN: default mode network, SN: salience network, STR: striatum. The thickness of each connecting edge is representative of the F-statistic, strength of connection, between corresponding seeds.

Fig. 2. Grids summarizing the three FC pairs that demonstrated the strongest group*time interaction, relationship between FC and clinical changes or trend to normalization to HC FC level (Bonferroni corrected).

A LH AMY S—LH DMN PFC3, B RH AMY S—LH SN Med3, C RH STR sensorimotor—RH SN FrOperIns1. Panels 1: group*time interaction plot from baseline to immediate-post; Panels 2: Correlation between MADRS changes and FC changes from baseline to immediate-post; Panels 3: barplot illustrating mean FC z-score post-hoc comparisons between group FC across three timepoints and healthy control group; Panels 4: glass brain visualization of the corresponding FC pair. LH: left hemisphere, RH: right hemisphere. Networks name: AMY (red nodes): amygdala, DMN (yellow nodes): default mode network, SN (light blue nodes): salience network, STR (green nodes): striatum. The thickness of each connecting edge is representative of the F-statistic, strength of connection, between corresponding seeds. FC: functional connectivity; HC: healthy control group. ****p ≤ 0.001, *p ≤ 0.05.