NPJ Schizophrenia最新文献

Subtle features in people's everyday language may harbor the signs of future mental illness. Machine learning offers an approach for the rapid and accurate extraction of these signs. Here we investigate two potential linguistic indicators of psychosis in 40 participants of the North American Prodrome Longitudinal Study. We demonstrate how the linguistic marker of semantic density can be obtained using the mathematical method of vector unpacking, a technique that decomposes the meaning of a sentence into its core ideas. We also demonstrate how the latent semantic content of an individual's speech can be extracted by contrasting it with the contents of conversations generated on social media, here 30,000 contributors to Reddit. The results revealed that conversion to psychosis is signaled by low semantic density and talk about voices and sounds. When combined, these two variables were able to predict the conversion with 93% accuracy in the training and 90% accuracy in the holdout datasets. The results point to a larger project in which automated analyses of language are used to forecast a broad range of mental disorders well in advance of their emergence.

Impaired illness awareness (Imp-IA) in schizophrenia is associated with interhemispheric imbalance, resulting in left hemisphere dominance, primarily within the posterior parietal area (PPA). This may represent an interhemispheric "disconnection syndrome" between PPAs. To test this hypothesis, we aimed to determine if diffusion-based measures of white matter integrity were disrupted in the corpus callosal tracts linking PPAs (i.e., splenium) in patients with Imp-IA in schizophrenia. T1-weighted and diffusion-weighted scans were acquired on a 1.5T GE scanner for 100 participants with a DSM-IV-TR diagnosis of schizophrenia and 134 healthy controls aged 18 to 79 years. The corpus callosal white matter tracts were compared among patients with Imp-IA (n = 40), intact illness awareness (n = 60), and healthy controls. White matter disruption was measured with fractional anisotropy (FA) and mean diffusivity (MD). Group differences in FA were found in the splenium, with patients with Imp-IA having the lowest FA, which remained significant after controlling for sex, age, global cognition, and premorbid intelligence. No group differences in MD were observed. Splenial white matter tracts of the corpus callosum appear compromised in patients with Imp-IA. Transcallosal interhemispheric PPA white matter disruption may represent a "disconnection syndrome", manifesting as Imp-IA in schizophrenia. Future studies are required to investigate the effects of noninvasive brain stimulation interventions, such as transcranial direct current or magnetic stimulation, on Imp-IA in association with white matter changes in patients with schizophrenia.

Antipsychotic drugs are one of the largest types of prescribed drugs. However, antipsychotic-induced weight gain (AIWG) is a major problem for the patients. AIWG increases cardiovascular and cerebrovascular morbidity and mortality, and reduces quality of life and drug compliance. To characterize changes in gene expression related to AIWG, we sequenced total messenger RNA from the blood samples of two groups of schizophrenia patients before and after 3 months of treatment with antipsychotics. The "weight gain" group was defined by an increase of body mass index (BMI) >1.5 points (18 patients; median BMI increase = 2.69) and the "no weight gain" group was defined by a change of BMI between <1.0 and >-1.0 points (18 patients; median BMI increase = 0.26). We found 115 genes with significant differential expression in the weight gain group before and after medication and 156 in the no weight gain group before and after medication. The weight gain group was significantly enriched with genes related to "obesity" and "BMI" (Fisher; p = 0.0002 and 0.01, respectively) according to the Gene Reference into Function (GeneRIF) database. In the no weight gain group, the enrichment was much smaller (Fisher; p = 0.02 and 0.79). This study is a first step toward detecting genetic factors that cause AIWG and to generating prediction tests in future studies with larger data sets.

One of the most robust neurochemical abnormalities reported in patients living with schizophrenia is an increase in dopamine (DA) synthesis and release in the dorsal striatum (DS). Importantly, it appears that this increase progresses as a patient transitions from a prodromal stage to the clinical diagnosis of schizophrenia. Here we have recreated this pathophysiology in an animal model by increasing the capacity for DA synthesis preferentially within the DS. To achieve this we administer a genetic construct containing the rate-limiting enzymes in DA synthesis-tyrosine hydroxylase (TH), and GTP cyclohydrolase 1 (GCH1) (packaged within an adeno-associated virus)-into the substantia nigra pars compacta (SNpc) of adolescent animals. We refer to this model as "Enhanced Dopamine in Prodromal Schizophrenia" (EDiPS). We first confirmed that the TH enzyme is preferentially increased in the DS. As adults, EDiPS animals release significantly more DA in the DS following a low dose of amphetamine (AMPH), have increased AMPH-induced hyperlocomotion and show deficits in pre-pulse inhibition (PPI). The glutamatergic response to AMPH is also altered, again in the DS. EDiPS represents an ideal experimental platform to (a) understand how a preferential increase in DA synthesis capacity in the DS relates to "positive" symptoms in schizophrenia; (b) understand how manipulation of DS DA may influence other neurotransmitter systems shown to be altered in patients with schizophrenia; (c) allow researchers to follow an "at risk"-like disease course from adolescence to adulthood; and (d) ultimately allow trials of putative prophylactic agents to prevent disease onset in vulnerable populations.

The study of patients with schizophrenia (SZ) at different clinical stages may help clarify what effects could be due to the disease itself, to the pharmacological treatment, or to the disease progression. We compared expression levels of targeted genes in blood from individuals in different stages of SZ: clinical high risk for psychosis (CHR), first episode of psychosis (FEP), and chronic SZ (CSZ). Then, we further verified whether single-nucleotide polymorphisms (SNPs) could be related to gene expression differences. We investigated 12 genes in 394 individuals (27 individuals with CHR, 70 antipsychotic-naive individuals with FEP, 157 CSZ patients, and 140 healthy controls (HCs)). For a subsample, genotype data were also available, and we extracted SNPs that were previously associated with the expression of selected genes in whole blood or brain tissue. We generated a mediation model in which a putative cause (SNP) is related to a presumed effect (disorder) via an intermediate variable (gene expression). MBP and NDEL1 were upregulated in FEP compared to all other groups; DGCR8 was downregulated in FEP compared to HC and CHR; DGCR2 was downregulated in CSZ compared to FEP and HCs; DISC1 was upregulated in schizophrenia compared to controls or FEP, possibly induced by the rs3738398 and rs10864693 genotypes, which were associated with DISC1 expression; and UFD1 was upregulated in CSZ and CHR compared to FEP and HC. Our results indicated changes in gene expression profiles throughout the different clinical stages of SZ, reinforcing the need for staging approaches to better capture SZ heterogeneity.

The accelerated aging hypothesis of schizophrenia (SCZ) has been proposed. DNA methylation profiles were developed for determining "epigenetic age." Here, we assessed intrinsic and extrinsic epigenetic age acceleration (IEAA and EEAA, respectively) in SCZ. We examined two independent cohorts of Japanese ancestry. The first cohort consisted of 80 patients with SCZ under long-term or repeated hospitalization and 40 controls, with the economical DNA pooling technique. The second cohort consisted of 24 medication-free patients with SCZ and 23 controls. Blood of SCZ subjects exhibited decreased EEAA in the first cohort (p = 0.0162), but not in the second cohort. IEAA did not differ in either cohort. We performed replication analyses using publicly available datasets from European ancestry (three blood and one brain datasets). One blood dataset showed increased EEAA in SCZ (p = 0.0228). Overall, our results provide evidence for decreased EEAA in SCZ associated with hospitalization in the Japanese population.

Oligodendrocyte (OLG)-related abnormalities have been broadly observed in schizophrenia (SZ); however, the etiology of these abnormalities remains unknown. As SZ is broadly believed to be a developmental disorder, the etiology of the myelin abnormalities in SZ may be related to OLG fate specification during development. Noncoding RNAs (ncRNAs) are an important part of multifaceted transcriptional complexes participating in neurogenic commitment and regulation of postmitotic cell function. The long ncRNA, NEAT1, is a structural component of paraspeckles (subnuclear bodies in interchromatin regions) that may control activity of developmental enhancers of OLG fate specification. Gene expression studies of multiple cortical regions from individuals with SZ showed strong downregulation of NEAT1 levels relative to controls. NEAT1-deficient mice show significant decreases in the numbers of OLG-lineage cells in the frontal cortex. To gain further insight into biological processes affected by NEAT1 deficiency, we analyzed RNA-seq data from frontal cortex of NEAT1^-/- mice. Analyses of differentially expressed gene signature from NEAT1^-/- mice revealed a significant impact on processes related to OLG differentiation and RNA posttranscriptional modification with the underlying mechanisms involving Wnt signaling, cell contact interactions, and regulation of cholesterol/lipid metabolism. Additional studies revealed evidence of co-expression of SOX10, an OLG transcription factor, and NEAT1, and showed enrichment of OLG-specific transcripts in NEAT1 purified chromatin isolates from human frontal cortex. Reduced nuclear retention of quaking isoform 5 in NEAT1^-/- mice shed light on possible mechanism(s) responsible for reduced expression of OLG/myelin proteins and supported the involvement of NEAT1 in oligodendrocyte function.

In the literature, there are substantial machine learning attempts to classify schizophrenia based on alterations in resting-state (RS) brain patterns using functional magnetic resonance imaging (fMRI). Most earlier studies modelled patients undergoing treatment, entailing confounding with drug effects on brain activity, and making them less applicable to real-world diagnosis at the point of first medical contact. Further, most studies with classification accuracies >80% are based on small sample datasets, which may be insufficient to capture the heterogeneity of schizophrenia, limiting generalization to unseen cases. In this study, we used RS fMRI data collected from a cohort of antipsychotic drug treatment-naive patients meeting DSM IV criteria for schizophrenia (N = 81) as well as age- and sex-matched healthy controls (N = 93). We present an ensemble model -- EMPaSchiz (read as 'Emphasis'; standing for 'Ensemble algorithm with Multiple Parcellations for Schizophrenia prediction') that stacks predictions from several 'single-source' models, each based on features of regional activity and functional connectivity, over a range of different a priori parcellation schemes. EMPaSchiz yielded a classification accuracy of 87% (vs. chance accuracy of 53%), which out-performs earlier machine learning models built for diagnosing schizophrenia using RS fMRI measures modelled on large samples (N > 100). To our knowledge, EMPaSchiz is first to be reported that has been trained and validated exclusively on data from drug-naive patients diagnosed with schizophrenia. The method relies on a single modality of MRI acquisition and can be readily scaled-up without needing to rebuild parcellation maps from incoming training images.

The 14-3-3 family of proteins is genetically linked to several psychiatric disorders, including schizophrenia. Our 14-3-3 functional knockout (FKO) mice, as well as other 14-3-3 knockout models, have been shown to exhibit behavioral endophenotypes related to schizophrenia. While specific forebrain regions, such as the prefrontal cortex (PFC) and hippocampus (HP), have been implicated in schizophrenic pathophysiology, the role of these brain regions in the top-down control of specific schizophrenia-associated behaviors has not been examined. Here, we used an adeno-associated virus (AAV) delivered shRNA to knock down the expression of the 14-3-3-inhibitor transgene, thus selectively restoring the function of 14-3-3 in the forebrain of the 14-3-3 FKO mice, we found that injection of the AAV-shRNA into both the PFC and the HP is necessary to attenuate psychomotor activity of the 14-3-3 FKO mice. Furthermore, we found that acute inhibition of 14-3-3, through the delivery of an AAV expressing the 14-3-3 inhibitor to both the PFC and HP, can trigger psychomotor agitation. Interestingly, when assessing the two brain regions separately, we determined that AAV-mediated expression of the 14-3-3 inhibitor specifically within the HP alone is sufficient to induce several behavioral deficits including hyperactivity, impaired associative learning and memory, and reduced sensorimotor gating. In addition, we show that post-synaptic NMDA receptor levels are regulated by acute 14-3-3 manipulations. Taken together, findings from this study directly link 14-3-3 inhibition in specific forebrain regions to certain schizophrenia-associated endophenotypes.

Microglial activation has been proposed to be involved in the pathophysiology of schizophrenia (SCZ). We hypothesized that dystrophic alterations of oligodendrocytes previously reported in the prefrontal white matter in SCZ might be associated with microglial activation in the acute state of SCZ. White matter of the prefrontal cortex (BA10) was studied in post-mortem brain tissue from 21 SCZ cases and 20 normal controls. The SCZ group included 12 subjects with predominantly positive symptoms and 9 subjects with predominantly negative symptoms. Electron microscopy was applied to estimate cell density, size, volume fraction (Vv) and the number (N) of organelles in oligodendrocytes adjacent to microglia and in oligodendrocytes adjacent to myelin, neurons and capillaries and not adjacent to microglia. Cell density of oligodendrocytes was not changed in the SCZ group as compared to controls. Vv and N of mitochondria were significantly decreased, while Vv of vacuoles of endoplasmic reticulum and lipofuscin granules were significantly increased in oligodendrocytes adjacent to either microglia or myelin in the SCZ group and in patients displaying predominantly positive symptoms as compared to the control group. There were no significant differences between oligodendrocytes adjacent to microglia and to myelin. Vv and N of lipofuscin were also increased in peri-capillary oligodendrocytes. There was no effect of clinical subgroups on the parameters of peri-capillary and peri-neuronal oligodendrocytes. Though many ameboid and dystrophic microglia adjacent to oligodendrocytes were found in the SCZ samples, we provide no quantitative evidence that oligodendrocyte dystrophy is associated with microglial activation in white matter in SCZ.