A new chamigrane sesquiterpene from the basidiomycete Antrodiella albocinnamomea.

One new chamigrane sesquiterpene, antroalbol A (1), was isolated from the cultures of the higher fungus Antrodiella albocinnamomea. Its structure was established by means of spectroscopic methods, and the absolute configuration of 1 was confirmed by single crystal x-ray diffraction analysis. The compound was evaluated for its cytotoxicity against five human cancer cell lines, but no significant cytotoxicity was found.

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.

A new chamigrane sesquiterpene from the rice fermentation of Antrodiella albocinnamomea.

A new chamigrane sesquiterpene, albocimea A (1), and one known compound, 6-hydroxy-8-methoxy-3S,5-dimethylisochroman (2), were isolated from the rice fermentation of the fungus Antrodiella albocinnamomea. The structure of new compound was elucidated by extensive spectroscopic analyses and electronic circular dichroism (ECD) calculations. Both compounds were evaluated for their cytotoxicity against five human cancer cell lines, but no significant cytotoxicity was found (IC50 values > 40 µM).

Production of Minor Ginsenosides from Panax notoginseng Flowers by Cladosporium xylophilum.

Panax notoginseng flowers have the highest content of saponins compared to the other parts of Panax notoginseng, but minor ginsenosides have higher pharmacological activity than the main natural ginsenosides. Therefore, this study focused on the transformation of the main ginsenosides in Panax notoginseng flowers to minor ginsenosides using the fungus of Cladosporium xylophilum isolated from soil. The main ginsenosides Rb1, Rb2, Rb3, and Rc and the notoginsenoside Fa in Panax notoginseng flowers were transformed into the ginsenosides F2 and Rd2, the notoginsenosides Fd and Fe, and the ginsenoside R7; the conversion rates were 100, 100, 100, 88.5, and 100%, respectively. The transformation products were studied by TLC, HPLC, and MS analyses, and the biotransformation pathways of the major ginsenosides were proposed. In addition, the purified enzyme of the fungus was prepared with the molecular weight of 66.4 kDa. The transformation of the monomer ginsenosides by the crude enzyme is consistent with that by the fungus. Additionally, three saponins were isolated from the transformation products and identified as the ginsenoside Rd2 and the notoginsenosides Fe and Fd by NMR and MS analyses. This study provided a unique and powerful microbial strain for efficiently transformating major ginsenosides in P. notoginseng flowers to minor ginsenosides, which will help raise the functional and economic value of the P. notoginseng flower.

Highly Regioselective Biotransformation of Protopanaxadiol-type and Protopanaxatriol-type Ginsenosides in the Underground Parts of Panax notoginseng to 18 Minor Ginsenosides by Talaromyces flavus.

The transformation of major ginsenosides to minor ginsenosides by microorganisms was considered to be an environmentally friendly method. Compared with GRAS (generally recognized as safe) strains, non-food-grade microorganisms could transform polar ginsenosides to various minor ginsenosides. In this study, Talaromyces flavus screened from the P. notoginseng rhizosphere was capable of transforming PPD-type and PPT-type ginsenosides in the underground parts of P. notoginseng to 18 minor ginsenosides. The transformation reactions invovled deglycosylation, epimerization, and dehydration. To the best of our knowledge, this transformation characteristic of T. flavus was first reported in fungi. Its crude enzyme can efficiently hydrolyze the outer glucose linked to C-20 and C-3 in major ginsenosides Rb1, Rb2, Rb3, Rc, Rd, and 20(S)-Rg3 within 48 h. The transformation of major ginsenosides to minor ginsenosides by T. flavus will help raise the functional and economic value of P. notoginseng.

Four New Sesquiterpenoids from the Rice Fermentation of Antrodiella albocinnamomea.

Albocimea B-E (1-4), four new sesquiterpenoids, and four known compounds, steperoxide A (5), dankasterone (6), 1H-indole-3-carboxylic acid (7), and (+)-formylanserinone B (8), were isolated from the rice fermentation of the fungus Antrodiella albocinnamomea. The structures of new compounds were elucidated by comprehensive spectroscopic techniques, the planar structures of new compounds were determined by comprehensive spectroscopic techniques, and their absolute configurations were confirmed via gauge-independent atomic orbital calculations (GIAO), calculation of the electronic circular dichroism (ECD), and optical rotation (OR). These were determined by spectroscopic data analysis.

Changes in metabolomics and lipidomics in brain tissue and their correlations with the gut microbiome after chronic food-derived arsenic exposure in mice.

Arsenic can cause neurodegenerative diseases of the brain, but the definite mechanism is still unknown. In this study, to discuss the disturbances on brain metabolome and lipidome under subchronic arsenic exposure, we treated mice with the arsenic-containing feed (concentration of total arsenic = 30 mg/kg) prepared in accordance with the proportion of rice arsenicals for 16 weeks and performed metabolomics and lipidomics studies respectively using UHPLC-Triple-TOF-MS/MS and UHPLC-Q Exactive Focus MS/MS on mice brain. In addition, the distributions of arsenical metabolites along the feed-gut-blood-brain chain were analyzed by ICP-MS and HPLC-ICP-MS, and fecal microbial variations were investigated by 16 s sequencing. The data showed that although only a tiny amount of arsenic (DMA=0.101 mg/kg, uAs=0.071 mg/kg) enters the brain through the blood-brain barrier, there were significant changes in brain metabolism, including 118 metabolites and 17 lipids. These different metabolites were involved in 30 distinct pathways, including glycometabolism, and metabolisms of lipid, nucleic acid, and amino acid were previously reported to be correlated with neurodegenerative diseases. Additionally, these different metabolites were significantly correlated with 12 gut bacterial OTUs, among which Lachnospiraceae, Muribaculaceae, Ruminococcaceae, and Erysipelotrichaceae were also previously reported to be related to the distortion of metabolism, indicating that the disturbance of metabolism in the brain may be associated with the disturbance of gut microbes induced by arsenic. Thus, the current study demonstrated that the brain metabolome and lipidome were significantly disturbed under subchronic arsenic exposure, and the disturbances also significantly correlated with some gut microbiome and may be associated with neurodegenerative diseases. Although preliminary, the results shed some light on the pathophysiology of arsenic-caused neurodegenerative diseases.

Inferior frontal gyrus seed-based resting-state functional connectivity and sustained attention across manic/hypomanic, euthymic and depressive phases of bipolar disorder.

OBJECTIVE: Seed-based resting-state functional connectivity (rs-FC) of inferior frontal gyrus (IFG), as well as sustained attention cognitive deficit are consistently reported to be impaired in bipolar disorders. However, whether these deficits exist across mood states and euthymic state are lacking. We compared rs-FC of IFG and sustained attention of bipolar patients in (hypo) mania, depression and euthymia, with controls. We also explored the interrelationships between clinical, cognitive, and imaging measurements. METHODS: Participants included 110 bipolar subjects: 46 manic/hypomanic, 35 euthymic, and 29 depressed, matched with 41 healthy controls (HCs) underwent structural magnetic resonance imaging (MRI) and resting-state functional MRI scans. Seed-based functional connectivity analyses were performed focused on bilateral IFG seeds. Clinical symptoms and sustained attention function were measured. Stepwise linear regression analysis was conducted to explore predictors of sustained attention measurements. RESULTS: Increased rs-FC between right IFG and bilateral frontal pole/superior frontal gyrus, precuneus, and posterior cingulate gyrus, as well as decreased rs-FC between right IFG and sensorimotor areas, anterior middle cingulate gyrus were found in all three bipolar subgroups compared with HCs. Impaired sustained attention measurement was found in bipolar manic/hypomanic and depressive subgroups compared with HCs. Linear regression analyses revealed a significant impact of the manic symptoms and psychotic symptoms on the performance of sustained attention task. CONCLUSIONS: Our results revealed that IFG seed-based resting-state functional networks involved in emotion regulation and cognitive function were trait-like deficit in bipolar patients. Higher manic levels and psychotic symptoms were predictors of a worse sustained attention performance.

Association between the 2D:4D ratio and schizophrenia.

OBJECTIVE: To investigate the potential association between the ratio of the second digit length to the fourth digit length (2D:4D) and schizophrenia, to provide evidence regarding the pathogenesis of schizophrenia. METHODS: In this study, we enrolled 843 patients with schizophrenia (387 men and 456 women), all of whom met the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), and 1050 normal healthy controls (477 men and 573 women). The digit lengths of both hands were measured in all subjects and the 2D:4D ratio was analyzed. RESULTS: In the healthy controls, the 2D:4D ratio was sexually dimorphic, with a larger value in women than in men. In addition, the 2D:4D ratio in the schizophrenia patients was significantly larger than in the healthy controls. The 2D:4D ratio of the right hand was more sexually dimorphic than the left hand. Furthermore, the difference in 2D:4D ratios between the male patients and male controls was significantly larger than in their female counterparts. CONCLUSIONS: By analyzing the 2D:4D ratio and considering alternative factors related to schizophrenia, our findings support the hypothesis that there are abnormal cerebral conditions in schizophrenia patients.

Anterior cingulate cortex, insula and amygdala seed-based whole brain resting-state functional connectivity differentiates bipolar from unipolar depression.

OBJECTIVE: The frontal-limbic circuit is hypothesized as sub-serving emotional regulation. We performed whole brain resting-state functional connectivity (rs-FC) analysis by studying the key hubs of frontal-limbic circuit: anterior cingulate cortex (ACC), bilateral insula subregions, bilateral amygdala (Amy) as seeds, separately, to discriminate bipolar depression (BipD) from unipolar depression (UniD). METHODS: We compared seed-based rs-FC of the frontal-limbic seeds with whole brain among 23 BipD participants; 23 age, gender, and depression severity matched patients with UniD, and 23 healthy controls (HCs). We also used support vector machine learning to study classification based on the rs-FC of ACC, bilateral insula subregions, and bilateral Amy seeds with whole brain. RESULTS: BipD showed increased rs-FC between the left ventral anterior insula (vAI) seed and the left anterior supramarginal gyrus (aSMG) and left postcentral gyrus, as well as increased rs-FC between left amygdala seed and the left aSMG when compared to HCs and UniD. Compared to UniD, BipD was associated with increased rs-FC between right dorsal anterior insula seed and right superior frontal gyrus, as well as increased rs-FC between left posterior insula seed and right precentral gyrus and right thalamus. Combined rs-FC of ACC, bilateral insula subregions and bilateral Amy seeds with the whole brain discriminated BipD from UniD with an accuracy of 91.30%. CONCLUSIONS: Rs-FC of the emotional regulation circuit is more widely disturbed in BipD than UniD. Using rs-FC with this circuit may lead to further developments in diagnostic decision-making.

Metabolic Effects of 7 Antipsychotics on Patients With Schizophrenia: A Short-Term, Randomized, Open-Label, Multicenter, Pharmacologic Trial.

OBJECTIVE: To compare longitudinal metabolic effects of 7 antipsychotics, including body mass index (BMI), waist circumference (WC), blood pressure (BP), glucose, triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C); to investigate risk factors for metabolic syndrome (MetS); and to make recommendations on frequency and timing of monitoring metabolic measurements. METHODS: This randomized, open-label, pharmacologic trial was conducted among patients with schizophrenia (DSM-IV) in 32 hospitals across China. Patients were randomly assigned to 7 groups and assessed at baseline, 2, 4, and 6 weeks. Linear mixed-effect models were used to assess changes of metabolic measures over time. Multivariable logistic regression analysis was performed to investigate the risk factors for MetS. RESULTS: In total, 2,550 (718 drug-naïve) of 2,774 patients finished the study between July 6, 2010, and November 30, 2011. We found significant (P < .05) changes for BMI, WC, TG, and LDL-C, with TG and LDL-C reaching a plateau. Interactions between baseline metabolic condition and changes over time were observed for BMI (χ² = 43.11, P < .001), WC (χ² = 36.34, P < .001), systolic BP (χ² = 11.92, P = .002), glucose (χ² = 6.09, P = .01), and TG (χ² = 6.01, P = .01). Antipsychotics generally had greater adverse effects on patients who were initially screened as metabolically normal. After controlling for other associated factors, we found that antipsychotics resulted in differing risk for incident MetS, with a similar pattern to findings in other populations: olanzapine (odds ratio [OR] = 3.36, P < .001) > quetiapine (OR = 3.29, P < .001) > perphenazine (OR = 2.73, P = .007) > risperidone (OR = 2.21, P = .02) > aripiprazole (OR = 1.74, P = .15) ≈ haloperidol (OR = 1.75, P = .22) ≈ ziprasidone (OR = 1, reference). CONCLUSIONS: Metabolic traits should be monitored frequently in early stages of antipsychotic treatment due to rapid and substantial changes. Clinicians should not assume low risk for patients with normal metabolic parameters at baseline. TRIAL REGISTRATION: Chinese Clinical Trial Registry identifier: ChiCTR-TRC-10000934.

Depth-dependent abnormal cortical myelination in first-episode treatment-naïve schizophrenia.

Myelination is key to effective message passing in the central nervous system and is likely linked to the pathogenesis of schizophrenia (SZ). Emerging evidence indicates that a large portion of intracortical myelin insulates inhibitory interneurons that are highly relevant to pathogenesis of schizophrenia. Here for the first time, we characterized intracortical myelination across the entire cortical surface in first-episode treatment-naïve patients with schizophrenia (FES) using T1w/T2w ratio of structural MRI, FES patients exhibited significantly higher myelin content in the left inferior parietal lobe, supramarginal gyrus, and superior temporal gyrus in the superficial layer, as well as left IPL in the middle layer, but significantly lower myelin content in the left middle insula and posterior cingulate gyrus. Years of education, a proxy for onset of functional decline, significantly altered the relationship between abnormal parietal and posterior cingulate myelination and clinical symptoms, indicating that the pathoplastic role of myelination hinges on the age of onset of functional decline. In addition, higher myelination generally related to better cognitive function in younger subjects but worse cognitive function in older subjects. We conclude that FES is characterized by increased myelination of the superficial layers of the parietal-temporal association cortex, but reduced myelination of the cingulo-insular midcortical layer cortex. Intracortical myelin content affects both cognitive functioning and symptom burden in FES, with the effect conditional upon age and timing of onset of functional decline. These results suggest myelination might be a critical biological target for procognitive interventions in SZ.

[An MRI Study of the Relationship Between Duration of Untreated Psychosis and Morphology of Cerebral Cortex in First-episode Schizophrenia].

OBJECTIVE: We analyzed the brain structure of schizophrenia patients from multiple perspectives to explore the relationship between the duration of untreated psychosis (DUP) and clinical outcomes. METHODS: For 85 patients and 86 controls, clinical symptoms and cognitive function were evaluated, magnetic resonance imaging (MRI) and free surfer analysis were used to extract the cortical indicator, such as brain cortex thickness, surface area, volume, and so on. The patients were divided into four subgroups according to the boundary of March, June and two year due to the distribution and median of DUP. Finally multi-group comparison and correlation analysis for above indicators were analysed. RESULTS: DUP was associated with the surface area of the left insula, parsorbitalis, right hippocampus, superior frontal gyrus, frontal pole, and temporal pole; DUP mainly influenced the cortical thickness of left posterior cingulate gyrus, postcentral gyrus, right lateral occipital cortex, parsopercularis, medial orbitofrontal cortex, and the bilateral precentral gyrus. For cortical volume, DUP significantly affected left postcentral gyrus, right precuneus, lateral occipital cortex, parsopercularis, lingual gyrus, superior temporal gyrus, bilateral cuneus, pericalcarine cortex, precentral gyrus,superior parietal lobule, and insula.The first three months after onset is a critical period for the deterioration of cortical morphology and clinical function. CONCLUSION: DUP in first-episode schizophrenia is associated with cortical morphological changes of temporal lobe, precentral, orbitofrontal cortex and the majority of medial regions of occipital lobe, it is very important to conduct early intervention for patients.

Prognostic Utility of Multivariate Morphometry in Schizophrenia.

Background: Voxel-based morphometry studies have repeatedly highlighted the presence of distributed gray matter changes in schizophrenia, but to date, it is not clear if clinically useful prognostic information can be gleaned from structural imaging. The suspected association between gray matter volume (GMV) and duration of psychotic illness, antipsychotic exposure, and symptom severity also limits the prognostic utility of morphometry. We address the question of whether morphometric information from patients with drug-naive first-episode psychosis can predict the linear trajectory of symptoms following early antipsychotic intervention using a longitudinal design. Method: Sixty-two first-episode, drug-naive patients with schizophrenia underwent brain magnetic resonance imaging scans at baseline, treated with antipsychotics, and rescanned after 1-year follow-up. Positive and Negative Syndrome Scale (PANSS) was used to assess their clinical manifestations. A multivariate approach to detect covariance-based network-like spatial components [Source Based Morphometry (SBM)] was performed to analyze the GMV. Paired t tests were used to study changes in the loading coefficients of GMV in the spatial components between two time points. The reduction in PANSS scores between the baseline (T0) and 1-year follow-up (T1) expressed as a ratio of the baseline scores (reduction ratio) was computed for positive, negative, and disorganization symptoms. Separate multiple regression analyses were conducted to predict the longitudinal change in symptoms (treatment response) using the loading coefficients of spatial components that differed between T0 and T1 with age, gender, duration of illness, and antipsychotic dose as covariates. We also tested the putative "toxicity" effects of baseline symptom severity on the GMV at 1 year using multiple regression analysis. Results: Of the 30 spatial components of gray matter extracted using SBM, loading coefficients of anterior cingulate cortex (ACC), insula and inferior frontal gyrus (IFG), superior temporal gyrus (STG), middle temporal gyrus (MTG), precuenus, and dorsolateral prefrontal cortex (DLPFC) reduced with time in patients. Specifically, the lower volume of insula and IFG at baseline predicted a lack of improvement in positive and disorganization symptoms. None of the symptom severity scores (positive, negative, or disorganization) at baseline independently predicted the reduced GMV at 1 year. Conclusions: The baseline deficit in a covariance-based network-like spatial component comprising of insula and IFG is predictive of the clinical course of schizophrenia. We do not find any evidence to support the notion of symptoms per se being neurotoxic to gray matter tissue. If judiciously combined with other available predictors of clinical outcome, multivariate morphometric information can improve our ability to predict prognosis in schizophrenia.

Progressive brain structural changes after the first year of treatment in first-episode treatment-naive patients with deficit or nondeficit schizophrenia.

Progressive brain volume atrophy has been reported in patients with schizophrenia. However, whether this progress differs between patients with primary negative symptoms (deficit schizophrenia; DS) and those without such symptoms (nondeficit schizophrenia; NDS) is unknown. Here, we examined grey matter volume (GMV) and white matter volume (WMV) changes over 12 months in 34 first-episode treatment-naive patients with schizophrenia (14 DS and 20 NDS) and 32 healthy controls (HCs) using structural magnetic resonance imaging and voxel-based morphometry. At baseline, compared to HCs, patients with DS but not NDS had less WMV in bilateral posterior limb of the internal capsule (PLIC) and cerebellar tonsil (P < 0.05, FDR corrected) and smaller GMV in the cerebellar culmen (P < 0.05, FWE corrected). At follow-up, NDS group showed WMV reduction in bilateral PLIC (P < 0.05, FDR corrected), while DS group showed no progressive WMV changes. While both patient groups exhibited GMV reduction in the hippocampus and insular cortex, patients with NDS showed additional GMV loss in the frontal and cingulate cortex and a selective increase in GMV in the left thalamus (P < 0.05 FWE corrected). Our study revealed double dissociations in developmental brain volume changes in the first year after clinical contact for psychosis in DS versus NDS patients.

Age-Related Reduction in Cortical Thickness in First-Episode Treatment-Naïve Patients with Schizophrenia.

Substantial evidence supports the neurodevelopmental hypothesis of schizophrenia. Meanwhile, progressive neurodegenerative processes have also been reported, leading to the hypothesis that neurodegeneration is a characteristic component in the neuropathology of schizophrenia. However, a major challenge for the neurodegenerative hypothesis is that antipsychotic drugs used by patients have profound impact on brain structures. To clarify this potential confounding factor, we measured the cortical thickness across the whole brain using high-resolution T1-weighted magnetic resonance imaging in 145 first-episode and treatment-naïve patients with schizophrenia and 147 healthy controls. The results showed that, in the patient group, the frontal, temporal, parietal, and cingulate gyri displayed a significant age-related reduction of cortical thickness. In the control group, age-related cortical thickness reduction was mostly located in the frontal, temporal, and cingulate gyri, albeit to a lesser extent. Importantly, relative to healthy controls, patients exhibited a significantly smaller age-related cortical thickness in the anterior cingulate, inferior temporal, and insular gyri in the right hemisphere. These results provide evidence supporting the existence of neurodegenerative processes in schizophrenia and suggest that these processes already occur in the early stage of the illness.

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.

Classification of First-Episode Schizophrenia Using Multimodal Brain Features: A Combined Structural and Diffusion Imaging Study.

Recent neuroanatomical pattern recognition studies have shown some promises for developing an objective neuroimaging-based classification related to schizophrenia. This study explored the feasibility of reliably identifying schizophrenia using single and multimodal multivariate neuroimaging features. Multiple brain measures including regional gray matter (GM) volume, cortical thickness, gyrification, fractional anisotropy (FA), and mean diffusivity (MD) were extracted using fully automated procedures. We used Gradient Boosting Decision Tree to identify the most frequently selected features of each set of neuroanatomical metric and fused multimodal measures. The current classification model was trained and validated based on 98 patients with first-episode schizophrenia (FES) and 106 matched healthy controls (HCs). The classification model was trained and tested in an independent dataset of 54 patients with FES and 48 HCs using imaging data acquired on a different magnetic resonance imaging scanner. Using the most frequently selected features from fused structural and diffusion tensor imaging metrics, a classification accuracy of 75.05% was achieved, which was higher than accuracy derived from a single imaging metric. Most prominent discriminative features included cortical thickness of left transverse temporal gyrus and right parahippocampal gyrus, the FA of left corticospinal tract and right external capsule. In the independent cohort, average accuracy was 76.54%, derived from combined features selected from cortical thickness, gyrification, FA, and MD. These features characterized by GM abnormalities and white matter disruptions have discriminative power with respect to the underlying pathological changes in the brain of individuals having schizophrenia. Our results further highlight the potential advantage of multimodal data fusion for identifying schizophrenia.

Abnormal Resting-State Connectivity in a Substantia Nigra-Related Striato-Thalamo-Cortical Network in a Large Sample of First-Episode Drug-Naïve Patients With Schizophrenia.

Objective: The dopamine hypothesis is one of the most influential theories of the neurobiological background of schizophrenia (SCZ). However, direct evidence for abnormal dopamine-related subcortical-cortical circuitry disconnectivity is still lacking. The aim of this study was therefore to test dopamine-related substantia nigra (SN)-based striato-thalamo-cortical resting-state functional connectivity (FC) in SCZ. Method: Based on our a priori hypothesis, we analyzed a large sample resting-state functional magnetic resonance imaging (fMRI) dataset from first-episode drug-naïve SCZ patients (n = 112) and healthy controls (n = 82) using the SN as the seed region for an investigation of striato-thalamo-cortical FC. This was done in the standard band of slow frequency oscillations and then in its subfrequency bands (Slow4 and Slow5). Results: The analysis showed in SCZ: (1) reciprocal functional hypo-connectivity between SN and striatum, with differential patterns for Slow5 and Slow4; (2) functional hypo-connectivity between striatum and thalamus, as well as functional hyper-connectivity between thalamus and sensorimotor cortical areas, specifically in Slow4; (3) correlation of thalamo-sensorimotor functional hyper-connectivity with psychopathological symptoms. Conclusions: We demonstrate abnormal dopamine-related SN-based striato-thalamo-cortical FC in slow frequency oscillations in first-episode drug-naive SCZ. This suggests that altered dopaminergic function in the SN leads to abnormal neuronal synchronization (as indexed by FC) within subcortical-cortical circuitry, complementing the dopamine hypothesis in SCZ on the regional level of resting-state activity.