Translational landscape in human early neural fate determination.

Gene expression regulation in eukaryotes is a multi-level process, including transcription, mRNA translation and protein turnover. Many studies have reported sophisticated transcriptional regulation during neural development, but the global translational dynamics are still ambiguous. Here, we differentiate human embryonic stem cells (ESCs) into neural progenitor cells (NPCs) with high efficiency and perform ribosome sequencing and RNA sequencing on both ESCs and NPCs. Data analysis reveals that translational controls engage in many crucial pathways and contribute significantly to regulation of neural fate determination. Furthermore, we show that the sequence characteristics of the untranslated region (UTR) might regulate translation efficiency. Specifically, genes with short 5'UTR and intense Kozak sequence are associated with high translation efficiency in human ESCs, whereas genes with long 3'UTR are related to high translation efficiency in NPCs. In addition, we have identified four biasedly used codons (GAC, GAT, AGA and AGG) and dozens of short open reading frames during neural progenitor differentiation. Thus, our study reveals the translational landscape during early human neural differentiation and provides insights into the regulation of cell fate determination at the translational level.

Interactions between overweight/obesity and alcohol dependence impact human brain white matter microstructure: evidence from DTI.

There is inconsistent evidence for an association of obesity with white matter microstructural alterations. Such inconsistent findings may be related to the cumulative effects of obesity and alcohol dependence. This study aimed to investigate the possible interactions between alcohol dependence and overweight/obesity on white matter microstructure in the human brain. A total of 60 inpatients with alcohol dependence during early abstinence (44 normal weight and 16 overweight/obese) and 65 controls (42 normal weight and 23 overweight/obese) were included. The diffusion tensor imaging (DTI) measures [fractional anisotropy (FA) and radial diffusivity (RD)] of the white matter microstructure were compared between groups. We observed significant interactive effects between alcohol dependence and overweight/obesity on DTI measures in several tracts. The DTI measures were not significantly different between the overweight/obese and normal-weight groups (although widespread trends of increased FA and decreased RD were observed) among controls. However, among the alcohol-dependent patients, the overweight/obese group had widespread reductions in FA and widespread increases in RD, most of which significantly differed from the normal-weight group; among those with overweight/obesity, the alcohol-dependent group had widespread reductions in FA and widespread increases in RD, most of which were significantly different from the control group. This study found significant interactive effects between overweight/obesity and alcohol dependence on white matter microstructure, indicating that these two controllable factors may synergistically impact white matter microstructure and disrupt structural connectivity in the human brain.

Auditory event-related potentials, neurocognition, and global functioning in drug naïve first-episode schizophrenia and bipolar disorder.

BACKGROUND: Deficits in event-related potential (ERP) including duration mismatch negativity (MMN) and P3a have been demonstrated widely in chronic schizophrenia (SZ) but inconsistent findings were reported in first-episode patients. Psychotropic medications and diagnosis might contribute to different findings on MMN/P3a ERP in first-episode patients. The present study examined MMN and P3a in first episode drug naïve SZ and bipolar disorder (BPD) patients and explored the relationships among ERPs, neurocognition and global functioning. METHODS: Twenty SZ, 24 BPD and 49 age and sex-matched healthy controls were enrolled in this study. Data of clinical symptoms [Positive and Negative Symptoms Scale (PANSS), Young Manic Rating Scale (YMRS), Hamilton Depression Rating Scale (HAMD)], neurocognition [Wechsler Adult Intelligence Scale (WAIS), Cattell's Culture Fair Intelligence Test (CCFT), Delay Matching to Sample (DMS), Rapid Visual Information Processing (RVP)], and functioning [Functioning Assessment Short Test (FAST)] were collected. P3a and MMN were elicited using a passive auditory oddball paradigm. RESULTS: Significant MMN and P3a deficits and impaired neurocognition were found in both SZ and BPD patients. In SZ, MMN was significantly correlated with FAST (r = 0.48) and CCFT (r = -0.31). In BPD, MMN was significantly correlated with DMS (r = -0.54). For P3a, RVP and FAST scores were significant predictors in SZ, whereas RVP, WAIS and FAST were significant predictors in BPD. CONCLUSIONS: The present study found deficits in MMN, P3a, neurocognition in drug naïve SZ and BPD patients. These deficits appeared to link with levels of higher-order cognition and functioning.

Ameliorative patterns of grey matter in patients with first-episode and treatment-naïve schizophrenia.

BACKGROUND: Grey matter (GM) reduction is a consistent observation in established late stages of schizophrenia, but patients in the untreated early stages of illness display an increase as well as a decrease in GM distribution relative to healthy controls (HC). The relative excess of GM may indicate putative compensatory responses, though to date its relevance is unclear. METHODS: 343 first-episode treatment-naïve patients with schizophrenia (FES) and 342 HC were recruited. Multivariate source-based morphometry was performed to identify covarying 'networks' of grey matter concentration (GMC). Neurocognitive scores using the Cambridge Neuropsychological Test Automated Battery (CANTAB) and symptom burden using the Positive and Negative Symptoms Scale (PANSS) were obtained. Bivariate linear relationships between GMC and cognition/symptoms were studied. RESULTS: Compared to healthy subjects, FES had prominently lower GMC in two components; the first consists of the anterior insula, inferior frontal gyrus, anterior cingulate and the second component with the superior temporal gyrus, precuneus, inferior/superior parietal lobule, cuneus, and lingual gyrus. Higher GMC was seen in adjacent areas of the middle and superior temporal gyrus, middle frontal gyrus, inferior parietal cortex and putamen. Greater GMC of this component was associated with lower duration of untreated psychosis, less severe positive symptoms and better performance on cognitive tests. CONCLUSIONS: In untreated stages of schizophrenia, both a distributed lower and higher GMC is observable. While the higher GMC is relatively modest, it occurs across frontoparietal, temporal and subcortical regions in association with reduced illness burden suggesting a compensatory role for higher GMC in the early stages of schizophrenia.

Altered MRI Diffusion Properties of the White Matter Tracts Connecting Frontal and Thalamic Brain Regions in First-Episode, Drug-Naïve Patients With Postpartum Depression.

BACKGROUND: Although progress has been made in exploring postpartum depression (PPD), the involvement of cerebral structure connectivity in PPD patients keeps unclear. PURPOSE: To explore structural connectivity alternations in mothers with PPD, diffusion tensor imaging (DTI) and automated fiber quantification (AFQ) were used to calculate brain white matter microstructure properties. STUDY TYPE: Cross-sectional. POPULATION: A total of 51 women with first-episode, treatment-näive PPD, and 49 matched healthy postpartum women (HPW) controls. FIELD STRENGTH: A 3.0 T; single-shot echo-planar imaging sequence. ASSESSMENT: DTI measurements of fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD) and mean diffusivity (MD) were obtained for 18 specific white matter tracts. The relationship between PDD symptoms, hormone levels, and postpartum days was also investigated. STATISTICAL TESTS: Two sample t test and Pearson's correlation analysis. The analysis was performed by using a permutation-based multiple-comparison correction approach, with the threshold of P < 0.05 (family wise error corrected [FWE-corrected]) separately across the four different outcome measures. RESULTS: Women with PPD showed significantly increased FA and AD in right anterior thalamic radiation (ATR) tract and significantly increased FA and significantly reduced RD in the cingulum tract, compared to women without PPD. The RD values of right cingulum were significantly positively correlated with postpartum days in HPW (r = 0.39). There were no significant relationships between brain measures and hormone levels in either patients or controls. DATA CONCLUSIONS: DTI measures have revealed altered integrity in the white matter of the cortical-thalamic circuits in women with PPD compared to HPW. Damage to these circuits may be a structural basis for the impaired emotional regulation and blunted mother-infant bonding in mothers with PPD and a potential target for the development of new treatments. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 3.

Altered Functional Connectivity Strength in Distinct Brain Networks of Children With Early-Onset Schizophrenia.

BACKGROUND: Schizophrenia is regarded as a brain network or connectome disorder that is associated with neurodevelopment. Children with early-onset schizophrenia (EOS) provide an opportunity to evaluate the neuropathology of schizophrenia at a very early stage without potential confounding factors. But dysfunction in brain networks of schizophrenia is inconsistent. PURPOSE: To identify abnormal functional connectivity (FC) in EOS patients and relationships with clinical symptoms, we aimed to reveal neuroimaging phenotypes of EOS. STUDY TYPE: Prospective, cross-sectional. POPULATION: Twenty-six female/22 male patients (age:14.3 ± 3.45 years) with first-episode EOS, 27 female/22 male age- and gender-matched healthy controls (HC) (age:14.1 ± 4.32). FIELD STRENGTH/SEQUENCE: 3-T, resting-state (rs) gradient-echo echo-planar imaging and three-dimensional magnetization-prepared rapid gradient-echo imaging. ASSESSMENT: Intelligence quotient (IQ) was measured by the Wechsler Intelligence Scale-Fourth edition for Children (WISC-IV). The clinical symptoms were evaluated by the Positive and Negative Syndrome Scale (PANSS). FC strength (FCS) from rs functional MRI (rsfMRI) was used to investigate functional integrity of global brain regions. In addition, associations between regionally altered FCS and clinical symptoms in EOS patients were examined. STATISTICAL TESTS: Two-sample t-test controlling for sample size, diagnostic method, brain volume algorithm, and age of the subjects, Bonferroni correction, Pearson's correlation analysis. A P-value <0.05 with a minimum cluster size of 50 voxels was considered statistically significant. RESULTS: Compared with HC, EOS patients had significantly lower total IQ scores (IQ:91.5 ± 16.1), increased FCS in the bilateral precuneus, left dorsolateral prefrontal cortex, left thalamus, and left parahippocampus (paraHIP), and decreased FCS in the right cerebellum posterior lobe and right superior temporal gyrus. The PANSS total score of EOS patients (PANSS total score:74.30 ± 7.23) was found to be positively correlated to FCS in the left paraHIP (r = 0.45). DATA CONCLUSION: Our study revealed that disrupted FC of brain hubs illustrate multiple abnormalities in brain networks in EOS patients. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY STAGE: 2.

Abnormal dynamics of resting-state functional activity and couplings in postpartum depression with and without anxiety.

Postpartum depression (PPD) and PPD comorbid with anxiety (PPD-A) are highly prevalent and severe mental health problems in postnatal women. PPD and PPD-A share similar pathopsychological features, leading to ongoing debates regarding the diagnostic and neurobiological uniqueness. This paper aims to delineate common and disorder-specific neural underpinnings and potential treatment targets for PPD and PPD-A by characterizing functional dynamics with resting-state functional magnetic resonance imaging in 138 participants (45 first-episode, treatment-naïve PPD; 31 PDD-A patients; and 62 healthy postnatal women [HPW]). PPD-A group showed specifically increased dynamic amplitude of low-frequency fluctuation in the subgenual anterior cingulate cortex (sgACC) and increased dynamic functional connectivity (dFC) between the sgACC and superior temporal sulcus. PPD group exhibited specifically increased static FC (sFC) between the sgACC and ventral anterior insula. Common disrupted sFC between the sgACC and middle temporal gyrus was found in both PPD and PPD-A patients. Interestingly, dynamic changes in dFC between the sgACC and superior temporal gyrus could differentiate PPD, PPD-A, and HPW. Our study presents initial evidence on specifically abnormal functional dynamics of limbic, emotion regulation, and social cognition systems in patients with PDD and PPD-A, which may facilitate understanding neurophysiological mechanisms, diagnosis, and treatment for PPD and PPD-A.

Data-driven study on resting-state functional magnetic resonance imaging during early abstinence of alcohol dependence in male patients and its predictive value for relapse.

BACKGROUND: Alcohol dependence is a mental disorder with a high relapse rate. However, specific neuroimaging biomarkers have not been determined for alcohol dependence and its relapse. We conducted data-driven research to investigate resting-state functional magnetic resonance imaging (rs-fMRI) during early abstinence from alcohol dependence and its potential ability to predict relapse. METHODS: Participants included 68 alcohol-dependent patients and 68 healthy controls (HCs). The regional homogeneity (ReHo) and fractional amplitude of low-frequency fluctuations (fALFF) were compared between the alcohol dependence group and the HCs and between the relapse group and the nonrelapse group. The brain regions that presented significantly different ReHo and/or fALFF between the alcohol-dependent patients and HCs and/or between the relapsed and nonrelapsed patients were selected as the seeds to calculate the functional connectivities (FCs). RESULTS: During a 6-month follow-up period, 52.24% of alcohol-dependent patients relapsed. A regression model for differentiating alcohol-dependent patients and HCs showed that reductions in ReHo in the left postcentral region, fALFF in the right fusiform region, and FC in the right fusiform region to the right middle cingulum were independently associated with alcohol dependence, with an area under the receiver operating characteristic curve (AUC) of 0.841. The baseline FC of the left precentral to the left cerebellum of the relapse group was significantly lower than that of the nonrelapse group. The AUC of this FC to predict relapse was 0.774. CONCLUSIONS: Our findings contribute to advancing research on the neurobiological etiology and predictive biomarkers for relapse associated with alcohol dependence.

Automated Digital Interventions and Smoking Cessation: Systematic Review and Meta-analysis Relating Efficiency to a Psychological Theory of Intervention Perspective.

BACKGROUND: Smoking remains a highly significant preventable global public health problem. In this context, digital interventions offer great advantages in terms of a lack of biological side effects, possibility of automatic delivery, and consequent human resource savings relative to traditional interventions. Such interventions have been studied in randomized controlled trials (RCTs) but have not been systematically reviewed with the inclusion of text-based and multiplatform-based interventions. In addition, this area has not been evaluated from the perspective of the psychological theoretical basis of intervention. OBJECTIVE: The aim of this paper is to assess the efficiency of digital interventions in RCT studies of smoking cessation and to evaluate the effectiveness of the strategies used for digital interventions. METHODS: An electronic search of RCTs was conducted using PubMed, Embase, and the Cochrane Library by June 30, 2021. Eligible studies had to compare automated digital intervention (ADI) to the use of a self-help guideline or no intervention. Participants were current smokers (aged 16 years or older). As the main outcome, abstinence after endpoint was extracted from the studies. Systematic review and meta-analysis were conducted to assess the efficiency of ADIs. Metaregressions were conducted to assess the relationship between intervention theory and effectiveness. RESULTS: A total of 19 trials (15,472 participants) were included in the analysis. The overall abstinence rate (95% CI) at the endpoint was 17.8% (17.0-18.7). The overall risk ratio of the intervention group compared to the controls at the endpoint was 17.8% (17.0-18.7). Cochrane risk-of-bias tool for randomized trials (ROB 2) suggested that most of the studies had a low risk of bias (56.3%). Psychological theory-related constructs or predictors, which refer to other theory-based concepts (rather than only behavioral theory) such as craving or anxiety, are associated with effectiveness. CONCLUSIONS: This study found that ADI had a clear positive effect compared to self-help guidelines or to no intervention, and effectiveness was associated with theory-related constructs or predictors. ADIs should be promoted by policy makers and clinical practitioners to address the huge gap between the need for smoking cessation and availability of traditional treatment resources. Possible increases in ADI efficiency may be achieved by optimally integrating psychotherapeutic theories and techniques. TRIAL REGISTRATION: PROSPERO CRD42021256593; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=256593.

The interactions between childhood adversities and recent stress were associated with early-adulthood depression among Chinese undergraduate students.

BACKGROUND: It is widely acknowledged that childhood adversities (CAs) and recent stress are potential risk factors for adult depression. However, the mechanism(s) by which interactions of CAs with recent stress affect adult depression remain unclear. AIMS: To investigate the predictive association of the interaction among CAs and recent stress with early-adult depression. METHOD: We conducted an annual survey of all freshmen for the period of 2016-2018 in a Chinese comprehensive university, with a sample size of 23,206. An online questionnaire including standardized self-report instruments was used to assess sociodemographic factors, childhood experiences of left-behind (CELB), and maltreatments (CEMTs) including beating (CEB), neglect (CEN), sexual abuse (CESA), recent stress, and current depression (measured by the 9-item Patient Health Questionnaire). RESULTS: The correlation of Individual CAs and recent stress was significant. In addition to their significant independent/direct incremental effects, all surveyed CAs were associated with increased severity of early-adult depression, and increased frequency of clinically significant depression (CSD), through significant associations with recent stress (mediation effect). History of CEMTs including CEB, CEN, and CESA significantly increased the effects of recent stress on depression (moderation effect). CONCLUSIONS: Chinese undergraduate students reported frequent history of exposure to CAs, which increased the likelihood of depression in early adulthood, not only directly but also through the increasing the likelihood (mediation effect) and impact (moderation effect) of recent stress on depression. These novel findings may help to extend our understanding of environmental determinants of depression, and to guide further research, clinical practice, and policy in this context.

Lower regional grey matter in alcohol use disorders: evidence from a voxel-based meta-analysis.

BACKGROUND: Previous research using whole-brain neuroimaging techniques has revealed structural differences of grey matter (GM) in alcohol use disorder (AUD) patients. However, some of the findings diverge from other neuroimaging studies and require further replication. The quantity of relevant research has, thus far, been limited and the association between GM and abstinence duration of AUD patients has not yet been systematically reviewed. METHODS: The present research conducted a meta-analysis of voxel-based GM studies in AUD patients published before Jan 2021. The study utilised a whole brain-based d-mapping approach to explore GM changes in AUD patients, and further analysed the relationship between GM deficits, abstinence duration and individual differences. RESULTS: The current research included 23 studies with a sample size of 846 AUD patients and 878 controls. The d-mapping approach identified lower GM in brain regions including the right cingulate gyrus, right insula and left middle frontal gyrus in AUD patients compared to controls. Meta-regression analyses found increasing GM atrophy in the right insula associated with the longer mean abstinence duration of the samples in the studies in our analysis. GM atrophy was also found positively correlated with the mean age of the samples in the right insula, and positively correlated with male ratio in the left middle frontal gyrus. CONCLUSIONS: GM atrophy was found in the cingulate gyrus and insula in AUD patients. These findings align with published meta-analyses, suggesting they are potential deficits for AUD patients. Abstinence duration, age and gender also affect GM atrophy in AUD patients. This research provides some evidence of the underlying neuroanatomical nature of AUD.

Lasting effects of residential mobility during childhood on psychopathology among Chinese University students.

BACKGROUND: Residential mobility during childhood increases risk of psychopathology in adulthood and is a common experience among Chinese children. This study investigated associations between number and age of first move, etiological risk factors for psychopathology, and common mental disorders in adolescence and early adulthood. METHODS: The sample included 39,531 undergraduates (84.5% completion rate) age 15-34 years in their first year at a Chinese comprehensive university in annual cross-sectional surveys during 2014-2018. Common mental disorders measured using standardised self-report instruments. Data analysed using logistic regression models and interaction analysis. RESULTS: Half of all students experienced one or more moves of residence before age 15 years. Outcomes of Depression, Somatisation, Obsessive-compulsive disorder, Hallucinations and Delusions, and Suicide attempts showed dose-response relationships with increasing number of moves. Other etiological risk factors, including childhood disadvantage and maltreatment, showed similar dose response relationships but did not confound associations with mobility. We found interactions between reporting any move and being a left-behind child on depression and somatisation; number of moves and younger age at first move on depression, somatisation, suicide attempts and hallucinations and delusions. CONCLUSIONS: Residential mobility in childhood is associated with psychopathology in adulthood and this association increases with increasing number of moves. Mobility is also associated with childhood disadvantage and maltreatment but associations with psychopathology are independent of these factors. Multiplicative effects were shown for multiple moves starting at a younger age and if the participant had been a left-behind child.

Testing extra-linearity across a psychosis continuum.

BACKGROUND: It is unclear whether psychotic experiences (PEs) gradually merge into states of clinical psychosis along a continuum which correspond to a dimensional classification or whether latent classes appear above a certain severity threshold which correspond better to diagnostic categories of psychosis. METHODS: Annual cross-sectional surveys, 2014-19, among Chinese undergraduates (N = 47,004) measured PEs, depression and etiological risk factors using standardized self-report instruments. We created a psychosis continuum with five levels and tested linear and extra-linear contrasts in associated etiological risk factors, before and after adjustment for depression. We carried out latent class analysis. RESULTS: Categorical expression of psychosis, including hallucinations and delusions, nuclear symptoms, and nuclear symptoms and depression were found at severe level 5. Etiological risk factors which impacted linearly across the continuum were more common for depression. Child maltreatment impacted extra-linearly on both psychosis and depression. Family history of psychosis impacted linearly on psychosis; male sex and urban birth impacted extra-linearly and were specific for psychosis. Four latent classes were found, but only at level 5. These corresponded to nuclear schizophrenia symptoms, nuclear schizophrenia and depressive symptoms, severe depression, and an unclassified category with moderate prevalence of PEs. CONCLUSION: Quantitative and qualitative changes in the underlying structure of psychosis were observed at the most severe level along a psychosis continuum, where four latent classes emerged. These corresponded to existing categorical classifications but require confirmation with clinical interview. PEs are non-specific and our findings suggest some are on a continuum with depression, whilst others are on a continuum with non-affective psychosis. Differing patterns of impact from etiological risk factors across the spectrum of psychopathology determine outcome at the most severe level of these continua.

Impact of urban birth and upbringing on expression of psychosis in a Chinese undergraduate population.

BACKGROUND: Urban birth and upbringing show consistent associations with psychotic illness but the key urban exposures remain unknown. Associations with psychotic-like experiences (PEs) are inconsistent. These could be confounded by common mental disorders associated with PEs. Furthermore, associations between PEs and urban exposures may not extrapolate to psychotic disorders such as schizophrenia. METHODS: Annual cross-sectional surveys among first year Chinese undergraduates 2014-2019 (n = 47,004). Self-reported, hierarchical categorisation of psychosis: from psychoticism, paranoid ideation, schizotypal symptoms, nuclear syndrome using SCL-90-R, to clinical diagnosis of schizophrenia. Depressive symptoms using PHQ 9. Dissociative symptoms and posttraumatic stress disorder (PTSD) measured using PCL-C. Etiological factors of family history and childhood disadvantage. We studied effects of urban birth, urban living and critical times of exposure in childhood on psychosis phenotypes. RESULTS: Associations with urbanicity were found only after adjustments for depression. Urban birth was associated with paranoia (AOR 1.34, 1.18-1.53), schizotypal symptoms (AOR 1.59, 1.29-1.96), and schizophrenia (AOR 2.07, 1.10-3.87). The same phenotypes showed associations with urban residence > 10 years. Only schizophrenia showed an association with urban exposure birth-3 years (AOR 7.01, 1.90-25.86). Child maltreatment was associated with both psychosis and depression. Urbanicity measured across the total sample did not show any associations with demography, family history of psychosis, or child maltreatment. Sensitivity analysis additionally adjusting for dissociative symptoms and PTSD showed the same pattern of findings. CONCLUSIONS: Urban birth and urban living showed a hierarchical pattern of increasing associations from paranoid ideation to schizotypal disorder to schizophrenia, confirming that associations for psychotic experiences could be extrapolated to schizophrenia, but only after adjusting for confounding from depression, dissociative symptoms and PTSD. Several etiological factors were the same for psychosis and depression. Future studies of PEs should adjust for confounding from common mental disorders and dissociative symptoms. Effects of urbanicity on psychosis were not explained by demography, family history of mental disorder, or child maltreatment.

Sustained effects of left-behind experience during childhood on mental health in Chinese university undergraduates.

Rapid industrialization and urbanization in China have resulted in labor migrants leaving children behind. For left-behind children (LBC), disrupted parental attachment may increase the risk of psychiatric morbidity in adulthood. To investigate psychopathological consequences for university students who were LBC and to estimate the effects of one or both parents being migrants, the duration of left-behind experience, and parental absence during critical periods of growth on psychiatric morbidity. We conducted an annual survey of all freshmen at a Chinese university from 2014 to 2018. The questionnaire collected information on left-behind experiences and psychiatric morbidity using standardized self-report instruments. Regression coefficients derived from logistic regression were used to measure the associations among total time left behind, absence of one parent or both parents, age when left behind and psychopathological consequences. A total of 42,505 students were included. Students who were LBC had more psychopathology, including depression, anxiety, somatoform disorder, obsessive-compulsive disorder, self-reported suicide attempts and deliberate self-harm, than those who were not. Students for whom one or both parents were migrants showed a greater risk of psychiatric morbidity. The risk of psychiatric morbidity increased with the length of parental absence. Left-behind experience during childhood represents sustained impacts for university students into early adulthood. The higher prevalence of psychiatric morbidity in young adults who experienced the absence of one or both of their parents, especially in their early childhood, suggests that other factors besides attachment, such as protection from other risks, are important and that further research is necessary.

Associations of Internet Addiction Severity With Psychopathology, Serious Mental Illness, and Suicidality: Large-Sample Cross-Sectional Study.

BACKGROUND: Internet addiction has become a major global concern and a burden on mental health. However, there is a lack of consensus on its link to mental health outcomes. OBJECTIVE: The aim of this study was to investigate the associations between internet addiction severity and adverse mental health outcomes. METHODS: First-year undergraduates enrolled at Sichuan University during September 2015, 2016, 2017, and 2018 were invited to participate in the current study survey, 85.13% (31,659/37,187) of whom fully responded. Young's 20-item Internet Addiction Test, Patient Health Questionnaire-15, Patient Health Questionnaire-9, Symptom Checklist 90, Six-Item Kessler Psychological Distress Scale, and Suicidal Behaviors Questionnaire-Revised were used to evaluate internet addiction, four psychopathologies (high somatic symptom severity, clinically significant depression, psychoticism, and paranoia), serious mental illness, and lifetime suicidality. RESULTS: The prevalence of students with mild, moderate, and severe internet addiction was 37.93% (12,009/31,659), 6.33% (2003/31,659), and 0.20% (63/31,659), respectively. The prevalence rates of high somatic symptom severity, clinically significant depression, psychoticism, paranoid ideation, and serious mental illness were 6.54% (2072/31,659), 4.09% (1294/31,659), 0.51% (160/31,659), 0.52% (165/31,659), and 1.88% (594/31,659), respectively, and the lifetime prevalence rates of suicidal ideation, suicidal plan, and suicidal attempt were 36.31% (11,495/31,659), 5.13% (1624/31,659), and 1.00% (315/31,659), respectively. The prevalence rates and odds ratios (ORs) of the four psychopathologies and their comorbidities, screened serious mental illness, and suicidalities in the group without internet addiction were much lower than the average levels of the surveyed population. Most of these metrics in the group with mild internet addiction were similar to or slightly higher than the average rates; however, these rates sharply increased in the moderate and severe internet addiction groups. Among the four psychopathologies, clinically significant depression was most strongly associated with internet addiction after adjusting for the confounding effects of demographics and other psychopathologies, and its prevalence increased from 1.01% (178/17,584) in the students with no addiction to 4.85% (582/12,009), 24.81% (497/2,003), and 58.73% (37/63) in the students with mild, moderate, and severe internet addiction, respectively. The proportions of those with any of the four psychopathologies increased from 4.05% (713/17,584) to 11.72% (1408/12,009), 36.89% (739/2003), and 68.25% (43/63); those with lifetime suicidal ideation increased from 24.92% (4382/17,584) to 47.56% (5711/12,009), 67.70% (1356/2003), and 73.02% (46/63); those with a suicidal plan increased from 2.59% (456/17,584) to 6.77% (813/12,009), 16.72% (335/2003), and 31.75% (20/63); and those with a suicidal attempt increased from 0.50% (88/17,584) to 1.23% (148/12,009), 3.54% (71/2003), and 12.70% (8/63), respectively. CONCLUSIONS: Moderate and severe internet addiction were strongly associated with a broad group of adverse mental health outcomes, including somatic symptoms that are the core features of many medical illnesses, although clinically significant depression showed the strongest association. This finding supports the illness validity of moderate and severe internet addiction in contrast to mild internet addiction. These results are important for informing health policymakers and service suppliers from the perspective of resolving the overall human health burden in the current era of "Internet Plus" and artificial intelligence.

Network analysis reveals disrupted functional brain circuitry in drug-naive social anxiety disorder.

Social anxiety disorder (SAD) is a common and disabling condition characterized by excessive fear and avoidance of public scrutiny. Psychoradiology studies have suggested that the emotional and behavior deficits in SAD are associated with abnormalities in regional brain function and functional connectivity. However, little is known about whether intrinsic functional brain networks in patients with SAD are topologically disrupted. Here, we collected resting-state fMRI data from 33 drug-naive patients with SAD and 32 healthy controls (HC), constructed functional networks with 34 predefined regions based on previous meta-analytic research with task-based fMRI in SAD, and performed network-based statistic and graph-theory analyses. The network-based statistic analysis revealed a single connected abnormal circuitry including the frontolimbic circuit (termed the "fear circuit", including the dorsolateral prefrontal cortex, ventral medial prefrontal cortex and insula) and posterior cingulate/occipital areas supporting perceptual processing. In this single altered network, patients with SAD had higher functional connectivity than HC. At the global level, graph-theory analysis revealed that the patients exhibited a lower normalized characteristic path length than HC, which suggests a disorder-related shift of network topology toward randomized configurations. SAD-related deficits in nodal degree, efficiency and participation coefficient were detected in the parahippocampal gyrus, posterior cingulate cortex, dorsolateral prefrontal cortex, insula and the calcarine sulcus. Aspects of abnormal connectivity were associated with anxiety symptoms. These findings highlight the aberrant topological organization of functional brain network organization in SAD, which provides insights into the neural mechanisms underlying excessive fear and avoidance of social interactions in patients with debilitating social anxiety.

Genes in immune pathways associated with abnormal white matter integrity in first-episode and treatment-naïve patients with schizophrenia.

BACKGROUND: Previous studies have inferred a strong genetic component in schizophrenia. However, the genetic variants involved in the susceptibility to schizophrenia remain unclear.AimsTo detect potential gene pathways and networks associated with schizophrenia, and to explore the relationship between common and rare variants in these pathways and abnormal white matter integrity in schizophrenia. METHOD: The analysis included 100 first-episode treatment-naïve patients with schizophrenia and 140 healthy controls. A network-based analysis was carried out on the data collected from the Psychiatric Genomics Consortium Phase I (PGC-I). Based on our genome-wide association study and whole-exome sequencing data-sets, we performed a gene-set analysis to detect associations between the combining effects of common and rare genetic variants and abnormal white matter integrity in schizophrenia. RESULTS: Patients had significantly reduced functional anisotropy in the left and right anterior cingulate cortex, left and right precuneus and extra-nuclear (t = 4.61-5.10, PFDR < 0.01), compared with controls. Generated from co-expression network analysis of the PGC-1 summary statistics of schizophrenia, a subnetwork of 207 genes associated with schizophrenia was identified (P < 0.01), and 176 genes were co-expressed in four gene modules. Functional enrichment analysis for genes in each module revealed that the yellow module was enriched with highly co-expressed, innate immune response genes. Furthermore, rare variants of enriched genes in the yellow module were associated with reduced functional anisotropy in the left anterior cingulate cortex (P = 0.006; Padjusted = 0.024) in patients only. CONCLUSIONS: The pathogenesis of schizophrenia may be substantially influenced by genes involved in the immune system, via both pathway and network.Declaration of interestsNone.

Common and distinct patterns of grey matter alterations in borderline personality disorder and bipolar disorder: voxel-based meta-analysis.

BACKGROUND: Whether borderline personality disorder (BPD) and bipolar disorder are the same or different disorders lacks consistency.AimsTo detect whether grey matter volume (GMV) and grey matter density (GMD) alterations show any similarities or differences between BPD and bipolar disorder. METHOD: Web-based publication databases were searched to conduct a meta-analysis of all voxel-based studies that compared BPD or bipolar disorder with healthy controls. We included 13 BPD studies (395 patients with BPD and 415 healthy controls) and 47 bipolar disorder studies (2111 patients with bipolar disorder and 3261 healthy controls). Peak coordinates from clusters with significant group differences were extracted. Effect-size signed differential mapping meta-analysis was performed to analyse peak coordinates of clusters and thresholds (P < 0.005, uncorrected). Conjunction analyses identified regions in which disorders showed common patterns of volumetric alteration. Correlation analyses were also performed. RESULTS: Patients with BPD showed decreased GMV and GMD in the bilateral medial prefrontal cortex network (mPFC), bilateral amygdala and right parahippocampal gyrus; patients with bipolar disorder showed decreased GMV and GMD in the bilateral medial orbital frontal cortex (mOFC), right insula and right thalamus, and increased GMV and GMD in the right putamen. Multi-modal analysis indicated smaller volumes in both disorders in clusters in the right medial orbital frontal cortex. Decreased bilateral mPFC in BPD was partly mediated by patient age. Increased GMV and GMD of the right putamen was positively correlated with Young Mania Rating Scale scores in bipolar disorder. CONCLUSIONS: Our results show different patterns of GMV and GMD alteration and do not support the hypothesis that bipolar disorder and BPD are on the same affective spectrum.Declaration of interestNone.

Neural substrate of unrelenting negative symptoms in schizophrenia: a longitudinal resting-state fMRI study.

Developing a mechanistic insight into the specific brain processes that underpin improvement in negative symptoms can help us design novel chemical and physical treatments against these unrelenting symptoms. The aim of the present study is to explore the longitudinal changes in the brain's regional functional efficiency that accompany improvement in negative symptoms seen in first-episode patients with schizophrenia when treated with antipsychotic for 1 year. Forty-seven first-episode patients with schizophrenia were scanned at a drug-naive baseline state and followed up for 1 year to identify negative symptom responders (Rn) and non-responders (NRn). Fractional amplitude of low-frequency fluctuations (fALFF) and Granger analysis of effective connectivity (EC) were used to examine the different patterns of regional function and connectivity between Rn and NRn during the 1 year follow-up. Increase of fALFF in the left superior temporal gyrus (STG) and increase of EC from the left STG to the dorsolateral prefrontal cortex (DLPFC) was found in Rn compared to NRn. We further validated that the identified changes in fALFF/EC of STG occur specifically in relation to negative symptoms only (i.e., not pseudo-specific in relation to positive, extrapyramidal or depressive symptoms), and occur irrespective of arbitrary clinical categorization of treatment response. An increase in fALFF in the precuneus and the inferior parietal lobule, and a decrease in EC from the left STG to the occipital cortex, were also found at the 1 year follow-up irrespective of improvement in negative symptoms. Interventions that improve the functional efficiency of left STG and its prefrontal connectivity may show efficacy in alleviating negative symptoms in first-episode schizophrenia.