Major depressive disorder (MDD) seriously endangers adolescent mental and physical health. Extracellular vesicles (EVs) are mediators of cellular communication and are involved in many physiological brain processes. Although EV miRNAshave been implicated in adults with major psychiatric disorders, investigation into their effects in adolescent MDDremains scarce. In discovery set, we conducted a genome-wide miRNA sequencing of serum EVs from 9 untreated adolescents with MDD and 8 matched healthy controls (HCs), identifying 32 differentially expressed miRNAs (18 upregulated and 14 downregulated). In the validation set, 8 differentially expressed and highly enriched miRNAs were verified in independent samples using RT-PCR, with 4 (miR-450a-2-3p, miR-3691-5p, miR-556-3p, and miR-2115-3p) of the 8 miRNAs found to be significantly elevated in 34 untreated adolescents with MDD compared with 38 HCs and consistent with the sequencing results. After the Bonferroni correction, we found that three miRNAs (miR-450a-2-3p, miR-556-3p, and miR-2115-3p) were still significantly different. Among them, miR-450a-2-3p showed the most markeddifferential expression and was able to diagnose disease with 67.6% sensitivity and 84.2% specificity. Furthermore, miR-450a-2-3p partially mediated the associations between total childhood trauma, emotional abuse, and physical neglect and adolescent MDD. We also found that the combination of miR-450a-2-3p and emotional abuse could effectively diagnose MDD in adolescents with 82.4% sensitivity and 81.6% specificity. Our data demonstrate the association of serum EV miRNA dysregulation with MDD pathophysiology and, furthermore, show that miRNAs may mediate the relationship between early stress and MDD susceptibility. We also provide a valid integrated model for the diagnosis of adolescent MDD.

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BackgroundNonsuicidal self-injury (NSSI) is a common mental health threat in adolescents, peaking in adolescence with a lifetime prevalence of ~17%–60%, making it a high-risk risk factor for suicide. In this study, we compared changes in microstate parameters in depressed adolescents with NSSI, depressed adolescents, and healthy adolescents during exposure to negative emotional stimuli, and further explored the improvement of clinical symptoms and the effect of microstate parameters of repetitive transcranial magnetic stimulation (rTMS) in depressed adolescents with NSSI, and more evidence was provided for potential mechanisms and treatment optimization for the occurrence of NSSI behaviors in adolescents.MethodsSixty-six patients with major depressive disorder (MDD) exhibiting NSSI behavior (MDD + NSSI group), 52 patients with MDD (MDD group), and 20 healthy subjects (HC group) were recruited to perform neutral and negative emotional stimulation task. The age range of all subjects was 12–17 years. All participants completed the Hamilton Depression Scale, the Patient Health Questionnaire-9, the Ottawa Self-Injury Scale and a self-administered questionnaire to collect demographic information. We provided two different treatments to 66 MDD adolescents with NSSI; 31 patients received medication and completed post-treatment scale assessments and EEG acquisitions, and 21 patients received medication combined with rTMS and completed post-treatment scale assessments and EEG acquisitions. Multichannel EEG was recorded continuously from 64 scalp electrodes using the Curry 8 system. EEG signal preprocessing and analysis was performed offline, using the EEGLAB toolbox in MATLAB. Use the Microstate Analysis Toolbox in EEGLAB for segmentation and computation of microstates, and calculate a topographic map of the microstate segmentation of the EEG signal for a single subject in each dataset, and four parameters were obtained for each microstate classification: global explained variance (GEV), mean duration (Duration), average number of occurrences per second (Occurrence), and average percentage of total analysis time occupied (Coverage), which were then statistically analyzed.ResultsOur results indicate that MDD adolescents with NSSI exhibit abnormalities in MS 3, MS 4, and MS 6 parameters when exposed to negative emotional stimuli compared to MDD adolescents and healthy adolescents. The results also showed that medication combined with rTMS treatment improved depressive symptoms and NSSI performance more significantly in MDD adolescents with NSSI compared to medication treatment, and affected MS 1, MS 2, and MS 4 parameters in MDD adolescents with NSSI, providing microstate evidence for the moderating effect of rTMS.ConclusionMDD adolescents with NSSI showed abnormal changes in several microstate parameters when receiving negative emotional stimuli, and compared to those not receiving rTMS treatment, MDD adolescents with NSSI treated with rTMS showed more significant improvements in depressive symptoms and NSSI performance, as well as improvements in EEG microstate abnormalities.