Schizophrenia (SZ) and mood disorders (including bipolar disorder (BD) and major depressive disorder (MDD)) are major psychiatric disorders in adults. For these psychiatric disorders, it is believed that both environmental and genetic factors play an important role in their pathogenesis. In recent years, the relationship between psychiatric disorders and immune-related factors, especially infectious and inflammatory factors has become a hot research issue. With the enrichment of data accumulated from epidemiological research, clinical study, as well as omics research in psychiatric disorders, it has become a big challenge for researchers to identify risk factors of disease by multi-level data-mining. In this study, to explore the relationship between infectious and inflammatory factors and psychiatric disorders, considering both environmental and genetic factors of psychiatric disorders, we collected three-level data including clinical data, genetic data and expression data, then carried out researches in three parts by methods of bioinformatics analysis. In the first part, we investigated the association between infectious agents and risk of mood disorders by meta-analysis. Thirty-five studies with a total of 15242 participants covering seven infectious agents including T.gondii, HSV-1, HSV-2, CMV, HHV-6, EBV, BDV were analyzed. Among them, T.gondii, CMV, HHV-6 and BDV were found to be significantly associated with risk of mood disorders. In subgroup analyses, significant higher prevalence of T.gondii, CMV and BDV was observed in BD patients than controls, while no significant association was observed among any investigated infectious agents (T.gondii, EBV and BDV) with MDD, which showed different effect of T.gondii and BDV infection on disease risk between BD and MDD. Meanwhile, previous meta-analyses also demonstrated that T.gondii and BDV was significantly associated with SZ, suggesting that BD and SZ might share some infectious factors. In the second part, we first performed a meta-analysis to investigate the association of cytokine polymorphisms with SZ and mood disorders, then conducted expression quantitative trait loci (eQTL) to detect functional effects of the risk cytokine polymorphisms. Data from 64 studies with a total of 41993 participants were available for meta-analysis. After correction, rs1800872 and two haplotypes of rs1800896 - rs1800871 - rs1800872 in IL10 showed significant associations with SZ; while rs1800629 in TNF , rs19664 in IL1B and rs2430561 in IFNG showed significant associations with mood disorders. Results of eQTL analyses showed that rs19664 and rs1800872 was significantly associated expression level of IL1B and IL10 respectively. This study supported the involvement of infection and inflammation related cytokines in the pathogenesis of major psychiatric disorders on both genetic and expression level. In the third part, we performed pathway based analyses (PBA) using data from both GWAS and expression microarray on SZ, BD and MDD. Infection and inflammation related pathways were identified to be significantly associated in all three disorders. In GWAS PBA, the number of such significant pathways was 9 (SZ), 20 (BD) and 9 (MDD), while in PBA of expression data, that number was which 5 (SZ), 8 (BD) and 8 (MDD) respectively. Among these significant pathways, virus infection related pathways were identified in all three disorders, while interleukin related pathways were mainly identified in mood disorders. Besides, interferon related pathways were mainly identified in MDD; while in BD, a viral infection related pathway, which was involved with interaction between cytokines and calcium channel gene ( a previously identified BD susceptibility gene) was identified. In summary, in this study, to explore the relationship between infectious and inflammatory factors and psychiatric disorders, we collected three-level data and carried out researches in three parts by methods of bioinformatics analysis
MicroRNAs are small (about 21-23nt in length), single-stranded, non-coding RNA molecules, they bind to target mRNAs and repress gene expression, acting as key regulators in cellular processes. A variety of MicroRNAs have been found in the central nervous system (CNS), and are belived to play critical roles in brain. Interestingly, several recent studies suggest that brain-expressed microRNAs may be involved in the pathophysiology of psychiatric disorders, moreover, SNP on miRNA may affect the generation and function of miRNA. Therefore, we recruited 576 schizophrenia patients, 528 bipolar disorders and 528 controls in Chinese Han population and tested 15 SNPs in MicroRNA coding region and flanking region in genome for association study. 13 SNPs were successed in genotyping. Two SNPs rs384262（P=0.021;OR=1.349, 95% CI 1.046-1.739）and rs895819（P=0.0197，OR=1.253，CI 1.037-1.515）showed significant difference in schizophrenia and controls, which provided important evidence that MicroRNA may in the pathophysiology of psychiatric disorders.While this field is still in its infancy, we consider their potentical for developing new antipsychotics.The brainderived neurotrophic factor (BDNF), which is belong to the superfamily of the neurotrophin, plays a critical role in promoting and modifying growth, differentiation, and survival of neurons in the central nervous system (CNS). Several North American and European studies have reported a significant association between Val66Met and BPD. We therefore genotyped the Val66Met polymorphism in a Han Chinese population sample (498 cases and 501 control subjects). We found that the BDNF genotype is associated with BPD in this population (χ2=9.4666,d.f.=2, P=0.00884), even divided into bipolar I disorders(χ2=7.882, d.f.=2, P=0.0391) and bipolar II disorders(χ2=8.022, d.f.=2, P=0.0364). Furthermore, our data suggested that the Met allele rather than the Val allele increased the risk for BPD in our Han population (OR=1.44 95% CI= 1.070-1.950; P=0.016). Further studies are necessary to elucidate the involvement of the BDNF gene in the pathophysiology of BPD.
The interaction of neural inhibition and excitation is the basis of cortical information processing. Since the inhibitory system is complex and plays a vital role in information processing, alterations of inhibition cause many kinds of brain dysfunctions. Previous studies have suggested that aging and mental disease generally reduces neuronal inhibition in the visual system. Here, we investigated how aging, schizophrenia, and bipolar disease affect intra-cortical inhibition using a motion direction discrimination task based on the motion repulsion phenomenon. Motion repulsion refers to the phenomenon by which observers overestimate the perceived angle when two superimposed dot patterns are moving at an acute angle. The misperception has been interpreted as mutual inhibition between nearby direction-tuned neurons within the same cortical area.We found that elderly exhibited much stronger motion repulsion than young adults. Our results indicate that intra-cortical inhibition increases with age. We then compared this effect to how aging affects feedback inhibition by adopting the surround suppression paradigm previously used by Betts and colleagues. We found that elderly showed less change in the discrimination threshold when the size of a high-contrast drifting Gabor was increased, indicating reduced surround suppression compared to young adults. Our results suggest that aging does not always lead to a decrease of neuronal inhibition in the visual system.We then used motion repulsion to explore the alteration of intra-area mutual inhibition in schizophrenia and bipolar patients. We found enhanced motion repulsion in patient subjects compared to normal controls in both of the diseases. We also looked for correlations between motion repulsion and PANSS scores in schizophrenia patients, and found no significant correlations. There were no significant correlations between motion repulsion and depression and anxiety scores in bipolar patients. In sum, our results suggest t
The study of negative symptoms and cognitive dysfunction are still hot spots in schizophrenia research considering the less effectiveness of available antipsychotic drugs. Among the numerous hypotheses, it is widely accepted that hypofrontality is a core mechanism of negative symptoms and cognitive dysfunction of schizophrenia patients. Improvement of the prefrontal cortex function is critical not only for understanding the schizophrenia pathophysiology but also for the treatment of negative symptoms and cognitive dysfunction which are resistant to traditional medication. Because of the important role of magnesium in synapse plasticity and brain function, the present study was designed to examine the potential antipsychotic effect of Mg2+ in phencyclidine (PCP)-induced rat model of schizophrenia and to explore the role of Mg2+ in PFC function improvement, using MgT as a Magnesium supplement compound. Rats were treated with MgT for 3 weeks via drinking water at a dose of 604mg/kg/Day (50mg/kg/Day elemental Mg2+). The behavioral tests showed that MgT treatment blocked PCP acute administration induced hyperlocomotion and reversed prepulse inhibition (PPI) deficits. Additionally, MgT treatment improved social withdraw and novel object recognition impairment in rats that were pretreated with PCP chronically (7.5mg/kg for 14 days, i.p.). Chronic supplyment of NaT failed to block the effects of PCP, suggesting that the antipsychotic effect of MgT was based on the action of Mg2+. Fluorescent Immunostaining of Prefrontal cortex (PFC, PrL and IL region) and Ventral tegmental area (VTA) showed that the reduced synaptophysin-positive puncta level in the PFC of chronic PCP treated (7.5mg/kg for 14 days, i.p.) rats was restored by MgT, while failed in VTA. Using a 35S]GTP-S binding assay we demonstrated that MgT improved the function of PFC dopamine D1 receptor. Additionally, MgT could ameliorate chronic PCP induced down-regulation of NR2B and p-CREB, as well as BDNF in PFC, but not in VTA. Further electrophysiological studies employing single-unit recording in intact or MgT treated animals demonstrated that the increased firing activity induced by PCP (0.9mg/kg, i.v.) administration could be inhibited by MgT.Furthermore, we found that subthreshold dose of clozpine, co-administrated with MgT, showed moderate effect in PCP induced sensory-motor gating dysfunction and cognition impairment which were resistant to medication. This could be meaningful because the co-administration can improve the refractory symptoms as well as reduce the side effects of traditional antipsychotic drugs due to the low dose we used. Taken together, these results indicate that MgT exhibited a positive effect in PCP induced schizophrenia model. The antipsychotic effect of MgT may be based on the improvement of PCP caused hypofrontality by Mg2+. This may provide a hint for the pathology and pharmacology investigation.
Emotion deficits may play an important role in the development of negative symptoms of schizophrenia. However, inconsistent findings on emotion deficits in schizophrenia suggest that there might be subtypes of emotion deficits. Previous studies on the emotion deficits in schizophrenia have focused on experiential pleasure and emotion expression rather than emotion regulation. In this study, we aimed to propose a theoretical framework of experiential pleasure, expression and regulation to identify subtypes in schizophrenia and across different diagnostic groups. In Study 1, we conducted two experiments to identify and validate the different subtypes of emotion deficits in patients with schizophrenia. In Experiment 1, we recruited 146 patients with schizophrenia and 132 demographically matched healthy controls. A set of checklists capturing experiential pleasure, emotion expression and regulation were administered to all participants. We also assessed the severity of negative symptoms in patients with schizophrenia. We used a two-stage cluster analysis to analyze the profile of experiential pleasure, emotion expression and regulation. We found that the best solution consisted of three-cluster, namely “experiential pleasure and emotion regulation deficits”, “emotion expression deficits”, and “experiential pleasure, emotion expression and regulation deficits”. Group-level comparisons showed that patients with “experiential pleasure and emotion expression deficits” reported more severe depressive and anhedonia symptoms than the other two groups. Moreover, patients with “experiential pleasure and emotion expression deficits” had more affective flattening than patients with “emotion expression deficits”. In Experiment 2, we randomly selected 59 schizophrenia patients and 36 healthy controls from Experiment 1 to complete an Affective Incentives Delay task. We found that on anticipating positive stimuli, patients with “experiential pleasure and emotion regulati
Neurological soft signs (NSS) are traditionally defined as minor non-localizable neurological abnormalities. Another unclear issue of NSS is whether it is the “trait marker” of schizophrenia. Nowadays, studies have found that patients with bipolar disorder have also showed significantly higher prevalence of NSS than healthy controls. In this dissertation, we conducted four experiments to examine these issues systematically. In study one, we examined the prevalence of NSS in a total of 120 participants, with 30 participants in each group of schizophrenia, bipolar disorder, major depression, healthy controls. We used Analysis of Variance (ANOVA) and discriminant analysis to test the specificity prevalence of NSS among the four groups. ANOVA analysis showed that both patients with schizophrenia and bipolar disorder but not major depression showed significantly higher NSS than healthy controls. The discriminant analysis showed that the NSS discriminant power was about 70% to 90%. In study two, we conducted an Activation Likelihood Estimation (ALE) meta-analysis of the brain imaging studies of NSS. Seven structural Magnetic Resonance Imaging (sMRI) studies and 14 functional Magnetic Resonance Imaging (fMRI) studies of NSS were included in the final ALE analysis according to a set of rigorous inclusion and exclusion criteria. The results of the ALE showed that the left cerebellum,left pre-central gyrus (BA6) and some other brain regions may the brain location of NSS.In study three, we examined the structural neural basis of NSS in patients with psychotic disorders. Eight patients with schizophrenia, 16 patients with bipolar disorder, 17 patients with major depression and 26 healthy controls were recruited for the structural brain scan. We used the Voxel-Based Morphometry (VBM) analysis from SPM8. Negative correlation of NSS and brain structures were demonstrated across the four groups. These brain regions included the temporal lobe, the prefrontal lobe, the pre- and post-central gyrus, the parahippocampal gyrus and the culmen of cerebellum.In study four, we investigated the neural basis and activation of a motor coordination signs, namely the “fist-edge-palm” signs in the same participants from study 3. We administered an imaging paradigm analogue to the “fist-edge-palm” task. Findings showed that patients with major depression only demonstrated hypo-activity in the parahippocampal gyrus, cerebellum and the insular as compared to healthy controls. On the other hand, patients with bipolar disorder demonstrated a wider neural abnormalities of brain activation in the cingulate gyrus, the temporal gyrus, the prefrontal gyrus as compared to healthy controls. Patients with schizophrenia showed significantly hyper-activity in the caudate, insular, and cingulate gyrus as compared to healthy controls. Taken together, the current findings suggested that NSS might not be only limited to patients with schizophrenia but also patients with bipolar disorders. Neuroimaging findings showed that NSS were associated with both structural and functional brain abnormalities in patients with psychotic disorders, with patients with schizophrenia showing significantly more severe impairments in brain structures and functional activation. Brain regions associated with NSS included the temporal lobe, the prefrontal lobe, the cerebellum, the pre- and post- central lobe, parahippocampal gyrus, thalamus and cingulate gyrus.
Major psychiatric disorders, including attention deficit hyperactivity disorder, autism, bipolar disorder, major depression disorder and schizophrenia, are highly heritable and polygenic disorders. Evidence suggests that these five disorders have both shared and distinct genetic risks and neural mechanisms. The present work aims to help understand the neural and genetic mechanisms of these five major psychiatric disorders based on brain imaging and genomics. At first, the relationships between cross-disorder polygenic risk scores and polygenic risk scores for specific psychiatric disorders and functional connectivity were examined. Two independent general populations (N = 360 and N = 323) were separately examined to investigate whether the cross-disorder PGRS and PGRS for a specific disorder were associated with individual variability in functional connectivity. Consistent altered functional connectivity was found with the bilateral insula: for the left supplementary motor area and the left superior temporal gyrus with the cross-disorder PGRS, for the left insula and right middle and superior temporal lobe associated with the PGRS for autism, for the bilateral midbrain, posterior cingulate, cuneus, and precuneus associated with the PGRS for BD, and for the left angular gyrus and the left dorsolateral prefrontal cortex associated with the PGRS for schizophrenia. No significant functional connectivity was found associated with the PGRS for ADHD and MDD. Our findings indicated that genetic effects on the cross-disorder and disorder-specific neural connectivity of common genetic risk loci are detectable in the general population. Our findings also indicated that polygenic risk contributes to the main neurobiological phenotypes of psychiatric disorders and that identifying cross-disorder and specific functional connectivity related to polygenic risks may elucidate the neural pathways for these disorders. In addition, the heritability of cortical surface area and gray mat
Psychiatric disorder is one of the most severe complex diseases worldwide. Epidemiologic studies demonstrated that genetic components played pivotal roles in the etiology of many psychiatric disorders, such as schizophrenia and bipolar disorder, but the precise pathogenic mechanisms are still unclear. So far, through genetic analyses and functional studies, many susceptible genes have been reported, such as DISC1. However, to dissect the primary cause of psychiatric disorders, there are still many unsolved questions, (1) numerous susceptibility genes cannot be successfully replicated among populations with different genetic backgrounds; (2) the reasons for the heterogeneity between different ethnic populations in genetic association analyses are unknown; (3) the roles of many susceptibility genes in brain development are still unclear.