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Background and Hypothesis The integration of information that typifies working memory (WM) operation requires a flexible, dynamic functional relationship among brain regions. In schizophrenia, though WM capacity is prominently impaired at higher loads, the mechanistic underpinnings are unclear. As a result, we lack convincing cognitive remediation of load-dependent deficits. We hypothesize that reduced WM capacity arises from a disruption in dynamic functional connectivity when patients face cognitive demands. Study Design We calculate the dynamic voxel-wise degree centrality (dDC) across the functional connectome in 142 patients with schizophrenia and 88 healthy controls (HCs) facing different WM loads during an n-back task. We tested associations of the altered variability in dDC and clinical symptoms and identified intermediate connectivity configurations (clustered states) across time during WM operation. These analyses were repeated in another independent dataset of 169 subjects (102 with schizophrenia). Study Results Compared with HCs, patients showed an increased dDC variability of supplementary motor area (SMA) for the “2back vs. 0back” contrast. This instability at the SMA seen in patients correlated with increased positive symptoms and followed a limited “U-shape” pattern at rest-condition and 2 loads. In the clustering analysis, patients showed reduced centrality in the SMA, superior temporal gyrus, and putamen. These results were replicated in a constrained search in the second independent dataset. Conclusions Schizophrenia is characterized by a load-dependent reduction of stable centrality in SMA; this relates to the severity of positive symptoms, especially disorganized behaviour. Restoring SMA stability in the presence of cognitive demands may have a therapeutic effect in schizophrenia.

Cholangiocarcinoma (CCA) is a highly heterogeneous cancer with limited understanding and few effective therapeutic approaches. We aimed at providing a proteogenomic CCA characterization to inform biological processes and treatment vulnerabilities.Integrative genomic analysis with functional validation uncovered biological perturbations downstream of driver events including DPCR1, RBM47 mutations, SH3BGRL2 copy number alterations, and FGFR2 fusions in CCA. Proteomic clustering identified three subtypes with distinct clinical outcomes, molecular features, and potential therapeutics. Phosphoproteomics characterized targetable kinases in CCA, suggesting strategies for effective treatment with CDK and MAPK inhibitors. Patients with CCA with HBV infection showed increased antigen processing and presentation (APC) and T cell infiltration, conferring a favorable prognosis compared with those without HBV infection. The characterization of extrahepatic CCA recommended the feasible application of vascular endothelial-derived growth factor inhibitors. Multiomics profiling presented distinctive molecular characteristics of the large bile duct and the small bile duct of intrahepatic CCA. The immune landscape further revealed diverse tumor immune microenvironments, suggesting immune subtypes C1 and C5 might benefit from immune checkpoint therapy. TCN1 was identified as a potential CCA prognostic biomarker, promoting cell growth by enhancing vitamin B12 metabolism.We characterized the proteogenomic landscape of 217 CCAs with 197 paired normal adjacent tissues and identified their subtypes and potential therapeutic targets. The multiomics analyses with other databases and some functional validations have indicated strategies regarding the clinical, biological, and therapeutic approaches to the management of CCA.

China has implemented several control measures to mitigate PM

Working-memory deficit is associated with aberrant degree distribution of the brain connectome in schizophrenia. However, the brain neural mechanism underlying the degree redistribution pattern in schizophrenia is still uncertain.We examined the functional degree distribution of the connectome in 81 patients with schizophrenia and 77 healthy controls across different working-memory loads during an n-back task. We tested the associations between altered degree distribution and clinical symptoms, and we conducted functional connectivity analyses to investigate the neural mechanism underlying altered degree distribution. We repeated these analyses in a second independent data set of 96 participants. In the second data set, we employed machine-learning analysis to study whether the degree distribution pattern of one data set could be used to discriminate between patients with schizophrenia and controls in the other data set.Patients with schizophrenia showed decreased centrality in the dorsal posterior cingulate cortex (dPCC) for the "2-back versus 0-back" contrast compared to healthy controls. The dPCC centrality pattern across all working-memory loads was an inverted U shape, with a left shift of this pattern in patients with schizophrenia. This reduced centrality was correlated with the severity of delusions and related to reduced functional connectivity between the dPCC and the dorsal precuneus. We replicated these results with the second data set, and the machine-learning analyses achieved an accuracy level of 71%.We used a limited n-back paradigm that precluded the examination of higher working-memory loads.Schizophrenia is characterized by a load-dependent reduction of centrality in the dPCC, related to the severity of delusions. We suggest that restoring dPCC centrality in the presence of cognitive demands might have a therapeutic effect on persistent delusions in people with schizophrenia.

Background: Working memory deficits are a common feature in major depressive disorder and are associated with poor functional outcomes. Intact working memory performance requires the recruitment of large-scale brain networks. However, it is unknown how the disrupted recruitment of distributed regions belonging to these large-scale networks at the whole-brain level brings about working memory impairment seen in major depressive disorder. Methods: We used graph theory to examine the functional connectomic metrics (local and global efficiency) at the whole-brain and large-scale network levels in 38 patients with major depressive disorder and 41 healthy controls during a working memory task. Altered connectomic metrics were studied in a moderation model relating to clinical symptoms and working memory accuracy in patients, and a machine learning method was employed to assess whether these metrics carry enough illness-specific information to discriminate patients from controls. Results: Global efficiency of the frontoparietal network was reduced in major depressive disorder (false discovery rate corrected, p = 0.014); this reduction predicted worse working memory performance in patients with less severe illness burden indexed by Brief Psychiatric Rating Scale (β =–0.43, p = 0.035, t =–2.2, 95% confidence interval = [–0.043,–0.002]). We achieved a classification accuracy and area under the curve of 73.42% and 0.734, respectively, to discriminate patients from controls based on connectomic metrics, and the global efficiency of the frontoparietal network contributed most to the diagnostic classification. Conclusions: We report a putative mechanistic link between the global efficiency of the frontoparietal network and impaired n-back performance in major depressive disorder. This relationship is more pronounced at lower levels of symptom burden, indicating the possibility of multiple pathways to cognitive deficits in severe major depressive disorder.

The pattern of decreased prefronto-thalamic connectivity and increased sensorimotor-thalamic connectivity has been consistently documented in schizophrenia. However, whether this thalamo-cortical abnormality pattern is of genetic predisposition remains unknown. The present study for the first time aimed to investigate the common and distinct characteristics of this circuit in schizophrenia patients and their unaffected siblings who share half of the patient's genotype. Totally 293 participants were recruited into this study including 94 patients with schizophrenia, 96 their healthy siblings, and 103 healthy controls scanned using gradient-echo echo-planar imaging at rest. By using a fine-grained atlas of thalamus with 16 sub-regions, we mapped the thalamocortical network in three groups. Decreased thalamo-prefronto-cerebellar connectivity was shared between schizophrenia and their healthy siblings, but increased sensorimotor-thalamic connectivity was only found in schizophrenia. The shared thalamo-prefronto-cerebellar dysconnectivity showed an impressively gradient reduction pattern in patients and siblings comparing to controls: higher in the controls, lower in the patients and intermediate in the siblings. Anatomically, the decreased thalamic connectivity mostly centered on the pre-frontal thalamic subregions locating at the mediodorsal nucleus, while the increased functional connectivity with sensorimotor cortices was only observed in the caudal temporal thalamic subregion anchoring at the dorsal and ventral lateral nuclei. Moreover, both decreased thalamo-prefronto-cerebellar connectivity and increased sensorimotor-thalamic connectivity were related to clinical symptoms in patients. Our findings extend the evidence that the decreased thalamo-prefronto-cerebellar connectivity may be related to the high genetic risk in schizophrenia, while increased sensorimotor-thalamic connectivity potentially represents a neural biomarker for this severe mental disorder.

Supplemental material, sj-pdf-1-anp-10.1177_0004867420978284 for Decreased integration of the frontoparietal network during a working memory task in major depressive disorder by Wenjian Tan, Zhening Liu, Chang Xi, Mengjie Deng, Yicheng Long, Lena Palaniyappan and Jie Yang in Australian & New Zealand Journal of Psychiatry

Objective Thalamic circuit imbalance characterized by increased sensorimotor−thalamic connectivity and decreased prefrontal−thalamic connectivity has been consistently observed in adult-onset schizophrenia (AOS), although it is unclear whether this pattern is also a feature of early-onset schizophrenia (EOS). If this is the case, thalamic circuit imbalance can be considered as a core mechanistic defect in schizophrenia, unconfounded by the age of onset. Method A total of 116 adolescents with EOS (63 drug-naive EOS) and 55 matched healthy controls (HC) were recruited and underwent resting-state functional magnetic resonance imaging scans. To define the specific location of the thalamic subregions in thalamocortical circuit, 16 atlas-based thalamic subdivisions were used in functional connectivity analysis. Results The EOS group showed increased sensorimotor−thalamic connectivity and decreased prefrontal-cerebello−thalamic connectivity, consistent with AOS. Sensorimotor−thalamic hyperconnectivity was more prominent than prefrontal−thalamic hypoconnectivity, which was circumscribed to the medial prefrontal cortex (mPFC), in EOS. Of note, the EOS group specifically exhibited strengthened thalamic connectivity with the salience network (SN). In addition, the EOS showed a more prominent disruption of the lateral thalamic nuclear connectivity. Conclusion Thalamic dysconnectivity observed in the EOS extends the observations from adult patients. Sensorimotor−thalamic hyperconnectivity is critical for the expression of schizophrenia phenotype irrespective of the age of onset, raising the possibility of aberrant but accelerated functional network maturation in EOS. The specific thalamocortical dysconnectivity involving the SN and mPFC may underlie the distinctive features of multi-modal hallucinations and heightened emotional valence of psychosis seen in EOS.

Psychosocial rehabilitation has been established as a critical component of client-centered recovery-oriented services for people with serious mental illness. Despite its importance, the implementation of mental health rehabilitation services in low- or middle-income countries has not been well studied. In this study, the authors document the regional challenges of planning and implementing mental health rehabilitation services in clubhouses in Hunan Province in the People's Republic of China.Participants were purposively selected and consisted of diverse stakeholders, including rehabilitation directors and psychiatric hospital leaders in Hunan Province, China. Information was collected from 33 individuals by using three focus groups, 23 semistructured interviews of key informants, and participant observation. Interview transcripts were coded and analyzed by using standard qualitative methods.Implementation challenges were characterized by four themes: skepticism toward psychosocial rehabilitation services, resource shortage, insufficient system integration and incentives, and stigma of mental illness.Psychosocial rehabilitation is an emerging public health priority in China. This study on clubhouses in Hunan Province used qualitative methods to inform future directions for service development and research. Early identification of regional implementation challenges is a first step in assessing the applicability of psychosocial rehabilitation services locally in Hunan Province. Successful implementation of clubhouse psychosocial rehabilitation services will benefit not only from strong government commitment but also from developing standard evaluations of evidence-based practices, tackling stigma, and addressing low resource investment.

BACKGROUND: Psychological resilience is an important personality trait whose decrease is associated with many common psychiatric disorders, but the neural mechanisms underlying it remain largely unclear. In this study, we aimed to explore the neural correlates of psychological resilience in healthy adults by investigating its relationship with functional brain network flexibility, a fundamental dynamic feature of brain network defined by switching frequency of its modular community structures. METHODS: Resting-state functional magnetic resonance imaging (fMRI) scans were acquired from 41 healthy adults, whose psychological resilience was quantified by the Connor-Davidson Resilience Scale (CD-RISC). Dynamic functional brain network was constructed for each subject, whose flexibility was calculated at all the global, subnetwork and region-of-interest (ROI) levels. After that, the associations between CD-RISC score and brain network flexibility were assessed at all levels by partial correlations controlling for age, sex, education and head motion. Correlation was also tested between the CD-RISC score and modularity of conventional static brain network for comparative purposes. RESULTS: The CD-RISC score was significant negatively correlated with the brain network flexibility at global level (r=−0.533, P=0.001), and with flexibility of the visual subnetwork at subnetwork level (r=−0.576, corrected P=0.002). Moreover, significant (corrected P0.05). CONCLUSIONS: Our results suggest that excessive fluctuations of the functional brain community structures during rest may be indicative of a lower psychological resilience, and the visual and default-mode systems may play crucial roles in such relationship. These findings may provide important implications for improving our understanding of the psychological resilience.