Recent evidence suggests that early life stress (ELS) changes stress reactivity via reduced resting state functional connectivity (rs-FC) between amygdala and the prefrontal cortex. Oxytocin (OXT) modulates amygdala connectivity and attenuates responses to psychosocial stress, but its effect appears to be moderated by ELS. Here we first investigate the effect of ELS on amygdala-prefrontal rs-FC, and examine whether ELS-associated changes of rs-FC in this neural circuit predict its response to psychosocial stress. Secondly, we explore the joint effect of OXT and ELS on the amygdala-prefrontal circuit. Eighteen healthy young males participated in a resting-state fMRI study of OXT effects using a double-blind, randomized, placebo-controlled, within-subject crossover design. We measured the rs-FC to bilateral amygdalae and subsequently assessed changes of state anxiety and prefrontal responses to psychosocial stress. Multiple linear regressions showed that ELS, specifically emotional abuse, predicted reduced rs-FC between the right amygdala and pregenual anterior cingulate cortex (pgACC), which in turn predicted elevated state anxiety after psychosocial stress. In subjects with lower ELS scores, stronger pgACC-amygdala rs-FC predicted stronger pgACC deactivation during the psychosocial stress task, and this rest-task interaction was attenuated by OXT. In subjects with higher ELS scores however, the rest-task interaction was altered and OXT showed no significant effect. These findings highlight that ELS reduces pgACC-amygdala rs-FC and alters how rs-FC of this circuit predicts its stress responsiveness. Such changes in pgACC-amygdala functional dynamics may underlie the altered sensitivity to the effects of OXT after ELS.

Major depressive disorder (MDD) is often accompanied by severe impairments in working memory (WM). Neuroimaging studies investigating the mechanisms underlying these impairments have produced conflicting results. It remains unclear whether MDD patients show hyper- or hypoactivity in WM-related brain regions and how potential aberrations in WM processing may contribute to the characteristic dysregulation of cognition-emotion interactions implicated in the maintenance of the disorder. In order to shed light on these questions and to overcome limitations of previous studies, we applied a multivoxel pattern classification approach to investigate brain activity in large samples of MDD patients (N = 57) and matched healthy controls (N = 61) during a WM task that incorporated positive, negative, and neutral stimuli. Results showed that patients can be distinguished from healthy controls with good classification accuracy based on functional activation patterns. ROI analyses based on the classification weight maps showed that during WM, patients had higher activity in the left DLPFC and the dorsal ACC. Furthermore, regions of the default-mode network (DMN) were less deactivated in patients. As no performance differences were observed, we conclude that patients required more effort, indexed by more activity in WM-related regions, to successfully perform the task. This increased effort might be related to difficulties in suppressing task-irrelevant information reflected by reduced deactivation of regions within the DMN. Effects were most pronounced for negative and neutral stimuli, thus pointing toward important implications of aberrations in WM processes in cognition-emotion interactions in MDD.

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IMPORTANCEMajor depressive disorder (MDD) affects approximately 10% of the population globally. Approximately 20% to 30% of patients with MDD do not sufficiently respond to standard treatment. Therefore, there is a need to develop more effective treatment strategies.OBJECTIVE To investigate whether the efficacy of cognitive behavioral therapy (CBT) for the treatment of MDD can be enhanced by concurrent transcranial direct current stimulation (tDCS). DESIGN, SETTING, AND PARTICIPANTSThe double-blind, placebo-controlled randomized clinical trial PsychotherapyPlus was conducted at 6 university hospitals across Germany. Enrollment took place between June 2, 2016, and March 10, 2020; follow-up was completed August 27, 2020. Adults aged 20 to 65 years with a single or recurrent depressive episode were eligible. They were either not receiving medication or were receiving a stable regimen of antidepressant medication (selective serotonin reuptake inhibitor and/or mirtazapine). A total of 148 women and men underwent randomization: 53 individuals were assigned to CBT alone (group 0), 48 to CBT plus tDCS (group 1), and 47 to CBT plus sham-tDCS (group 2).INTERVENTIONS Participants attended a 6-week group intervention comprising 12 sessions of CBT. If assigned, tDCS was applied simultaneously. Active tDCS included stimulation with an intensity of 2 mA for 30 minutes (anode over F3, cathode over F4). MAIN OUTCOMES AND MEASURESThe primary outcome was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to posttreatment in the intention-to-treat sample. Scores of 0 to 6 indicate no depression; 7 to 19, mild depression; 20 to 34, moderate depression; and 34 and higher, severe depression.RESULTS A total of 148 patients (89 women, 59 men; mean [SD] age, 41.1 [13.7] years; MADRS score at baseline, 23.0 [6.4]) were randomized. Of these, 126 patients (mean [SD] age, 41.5 [14.0] years; MADRS score at baseline, 23.0 [6.3]) completed the study. In each of the intervention groups, intervention was able to reduce MADRS scores by a mean of 6.5 points (95% CI, 3.82-9.14 points). The Cohen d value was -0.90 (95% CI, -1.43 to -0.50), indicating a significant effect over time. However, there was no significant effect of group and no significant interaction of group × time, indicating the estimated additive effects were not statistically significant. There were no severe adverse events throughout the whole trial, and there were no significant differences of self-reported adverse effects during and after stimulation between groups 1 and 2. CONCLUSIONS AND RELEVANCEBased on MADRS score changes, this trial did not indicate superior efficacy of tDCS-enhanced CBT compared with 2 CBT control conditions. The study confirmed that concurrent group CBT and tDCS is safe and feasible. However, additional research on mechanisms of neuromodulation to complement CBT and other behavioral interventions is needed.