Major depressive disorder (MDD) is a serious mental illness characterized by dysfunctional connectivity among distributed brain regions. Previous connectome studies based on functional magnetic resonance imaging (fMRI) have focused primarily on undirected functional connectivity and existing directed effective connectivity (EC) studies concerned mostly task-based fMRI and incorporated only a few brain regions. To overcome these limitations and understand whether MDD is mediated by within-network or between-network connectivities, we applied spectral dynamic causal modeling to estimate EC of a large-scale network with 27 regions of interests from four distributed functional brain networks (default mode, executive control, salience, and limbic networks), based on large sample-size resting-state fMRI consisting of 100 healthy subjects and 100 individuals with first-episode drug-naive MDD. We applied a newly developed parametric empirical Bayes (PEB) framework to test specific hypotheses. We showed that MDD altered EC both within and between high-order functional networks. Specifically, MDD is associated with reduced excitatory connectivity mainly within the default mode network (DMN), and between the default mode and salience networks. In addition, the network-averaged inhibitory EC within the DMN was found to be significantly elevated in the MDD. The coexistence of the reduced excitatory but increased inhibitory causal connections within the DMNs may underlie disrupted self-recognition and emotional control in MDD.Guoshi Li and Yujie Liu contributed equally to this study. Hum Brain Mapp. 2020;41:865-881. wileyonlinelibrary.com/journal/hbm 865 SUPPORTING INFORMATION Additional supporting information may be found online in the Supporting Information section at the end of this article. How to cite this article: Li G, Liu Y, Zheng Y, et al. Largescale dynamic causal modeling of major depressive disorder based on resting-state functional magnetic resonance imaging.

Background: Major depressive disorder (MDD) is one of the most common and costly psychiatric disorders. In addition to significant changes in mood, MDD patients face an increased risk of developing cognitive dysfunction. It is important to gain an improved understanding of cognitive impairments and find a biomarker for cognitive impairment diagnosis in MDD.Methods: One hundred MDD patients and 100 normal controls (NCs) completed resting-state fMRI (rs-fMRI) scan, in which 34 MDD patients and 34 NCs had scores in multiple cognitive domains (executive function, verbal fluency, and processing speed). Twenty-seven regions of interest from the default mode network (DMN), central executive network (CEN), salience network (SN), and limbic system (LS) were selected as seeds for functional connectivity (FC) analyses with the voxels in the whole brain. Finally, partial correlations were conducted for cognitive domain scores and FCs with significant differences between the MDD and NC groups.Results: Significant FC differences between groups were identified among the seeds and clusters in the DMN, CEN, LS, visual network, somatomotor network, ventral attention network, and dorsal attention network. In the MDD patients, the magnitude of the Stroop interference effect was positively correlated with the illness duration, and the illness duration was negatively correlated with the FC between the right ventral hippocampal gyrus and the left inferior frontal gyrus. However, the correlation between the Stroop interference effect and the FC of the right anterior prefrontal cortex with the left cerebellum_4_5 was disrupted in these patients. Liu et al.Executive Function Impairment in MDD Conclusions: The MDD patients have altered FCs among multiple brain networks and a disrupted correlation between the FC of prefrontal cortex and executive function. The disrupted correlation could present before the symptoms develop and may be the core process in the development of executive function impairment.

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Sperm DNA integrity is an essential factor for accurate transmission of genetic information. Human sperm DNA damage is a common cause of male infertility but the exact mechanism remains poorly understood. Considering the vital role of microRNA (miRNA) in multiple pathophysiological processes, we hypothesised that testicular miRNA is involved in sperm DNA damage during spermatogenesis. Infertile patients with high sperm DNA fragment index (DFI; n=94) were selected from 1090 infertile men and a total of 18 testis-specific seminal miRNAs previously identified from human seminal plasma were chosen and tested. miR-29c and miR-424 were downregulated in men with high DFI. The inhibition of these two miRNAs in mice confirmed the role of miR-424 (murine homologue miR-322) in sperm DNA damage during spermatogenesis; by contrast, miR-29c exhibited a negative result. Thus, miR-424/322 is involved in sperm DNA damage. Furthermore, the dysregulation of this miRNA can induce DNA double-strand breaks during spermatogenesis.