Iodine/DMSO-mediated one-pot access towards 1-aryl-2-(pyrazol-5-yl)ethane-1,2-diones via a domino reaction from functionalized pent-2-ene-1,5-diones.

A facile one-pot cascade synthesis involving simultaneous in situ pyrazole formation followed by iodine/DMSO-mediated oxidation has been established to afford 1-aryl-2-(3-aryl)-1H-pyrazol-5-yl-ethane-1,2-diones. Primarily, a two-pot approach has been established which includes the reaction of 3-methylthio-1,5-diaryl-2-pentene-1,5-diones with hydrazine in the first step to afford pyrazole, which was eventually oxidized in the next steps in the presence of iodine in DMSO. Furthermore, we performed both steps in the same pot to afford 1,2-dicarbonyl compounds in good yield. The structure of one of the compounds was confirmed by single crystal X-ray analysis. DMSO served as a solvent as well as an oxidant. Moreover, N-substituted hydrazines provided 1-(1-substituted-3-aryl-1H-pyrazol-5-yl)-2-arylethane-1,2-diones regioselectively. Furthermore, for synthetic application, 1-aryl-2-(3-aryl)-1H-pyrazol-5-yl-ethane-1,2-diones were treated with o-phenylenediamine to afford pyrazole-functionalized quinoxaline in good yield. A control reaction was carried out to understand the mechanism of product formation.

Histoplasma capsulatum requires peroxisomes for multiple virulence functions including siderophore biosynthesis.

Peroxisomes are versatile eukaryotic organelles essential for many functions in fungi, including fatty acid metabolism, reactive oxygen species detoxification, and secondary metabolite biosynthesis. A suite of Pex proteins (peroxins) maintains peroxisomes, while peroxisomal matrix enzymes execute peroxisome functions. Insertional mutagenesis identified peroxin genes as essential components supporting the intraphagosomal growth of the fungal pathogen Histoplasma capsulatum. Disruption of the peroxins Pex5, Pex10, or Pex33 in H. capsulatum prevented peroxisome import of proteins targeted to the organelle via the PTS1 pathway. This loss of peroxisome protein import limited H. capsulatum intracellular growth in macrophages and attenuated virulence in an acute histoplasmosis infection model. Interruption of the alternate PTS2 import pathway also attenuated H. capsulatum virulence, although only at later time points of infection. The Sid1 and Sid3 siderophore biosynthesis proteins contain a PTS1 peroxisome import signal and localize to the H. capsulatum peroxisome. Loss of either the PTS1 or PTS2 peroxisome import pathway impaired siderophore production and iron acquisition in H. capsulatum, demonstrating compartmentalization of at least some biosynthetic steps for hydroxamate siderophore biosynthesis. However, the loss of PTS1-based peroxisome import caused earlier virulence attenuation than either the loss of PTS2-based protein import or the loss of siderophore biosynthesis, indicating additional PTS1-dependent peroxisomal functions are important for H. capsulatum virulence. Furthermore, disruption of the Pex11 peroxin also attenuated H. capsulatum virulence independently of peroxisomal protein import and siderophore biosynthesis. These findings demonstrate peroxisomes contribute to H. capsulatum pathogenesis by facilitating siderophore biosynthesis and another unidentified role(s) for the organelle during fungal virulence. IMPORTANCE The fungal pathogen Histoplasma capsulatum infects host phagocytes and establishes a replication-permissive niche within the cells. To do so, H. capsulatum overcomes and subverts antifungal defense mechanisms which include the limitation of essential micronutrients. H. capsulatum replication within host cells requires multiple distinct functions of the fungal peroxisome organelle. These peroxisomal functions contribute to H. capsulatum pathogenesis at different times during infection and include peroxisome-dependent biosynthesis of iron-scavenging siderophores to enable fungal proliferation, particularly after activation of cell-mediated immunity. The multiple essential roles of fungal peroxisomes reveal this organelle as a potential but untapped target for the development of therapeutics.

Effects of Antipsychotic Medications and Illness Duration on Brain Features That Distinguish Schizophrenia Patients.

BACKGROUND AND HYPOTHESIS: Previous studies have reported effects of antipsychotic treatment and illness duration on brain features. This study used a machine learning approach to examine whether these factors in aggregate impacted the utility of MRI features for differentiating individual schizophrenia patients from healthy controls. STUDY DESIGN: This case-control study used patients with never-treated first-episode schizophrenia (FES, n = 179) and long-term ill schizophrenia (LTSZ, n = 30), with follow-up of the FES group after treatment (n = 71), a group of patients who had received long-term antipsychotic treatment (n = 93) and age and sex-matched healthy controls (n = 373) for each patient group. A multiple kernel learning classifier combining both structural and functional brain features was used to discriminate individual patients from controls. STUDY RESULTS: MRI features differentiated untreated FES (0.73) and LTSZ (0.83) patients from healthy controls with moderate accuracy, but accuracy was significantly higher in antipsychotic-treated FES (0.94) and LTSZ (0.98) patients. Treatment was associated with significantly increased accuracy of case identification in both early course and long-term ill patients (both p < .001). Effects of illness duration, examined separately in treated and untreated patients, were less robust. CONCLUSIONS: Our results demonstrate that initiation of antipsychotic treatment alters brain features in ways that further distinguish individual schizophrenia patients from healthy individuals, and have a modest effect of illness duration. Intrinsic illness-related brain alterations in untreated patients, regardless of illness duration, are not sufficiently robust for accurate identification of schizophrenia patients.

Cortical Thickness Abnormalities at Different Stages of the Illness Course in Schizophrenia: A Systematic Review and Meta-analysis.

Importance: Questions of whether and how cortical thickness (CTh) alterations differ over the course of schizophrenia (SCZ) have yet to be resolved. Objective: To characterize CTh alterations across illness stages in SCZ. Data Sources: PubMed, Embase, Web of Science, and Science Direct were screened for CTh studies published before June 15, 2021. Study Selection: Original studies comparing whole-brain CTh alterations from healthy controls in individuals at clinical high-risk (CHR), first episode of psychosis (FEP), and long-term illness stages of SCZ were included. Data Extraction and Synthesis: This preregistered systematic review and meta-analysis followed PRISMA reporting guidelines. Separate and pooled meta-analyses were performed using seed-based d mapping. Meta-regression analyses were conducted. Main Outcomes and Measures: Cortical thickness differences from healthy control individuals across illness stages. Results: Ten studies comprising 859 individuals with CHR (mean [SD] age, 21.02 [2.66] years; male, 573 [66.7%]), 12 studies including 671 individuals with FEP (mean [SD] age, 22.87 [3.99] years; male, 439 [65.4%]), and 10 studies comprising 579 individuals with long-term SCZ (mean [SD] age, 41.58 [6.95] years; male, 396 [68.4%]) were included. Compared with healthy control individuals, individuals with CHR showed cortical thinning in bilateral medial prefrontal cortex (z = -1.01; P < .001). Individuals with FEP showed cortical thinning in right lateral superior temporal cortex (z = -1.34; P < .001), right anterior cingulate cortex (z = -1.44; P < .001), and right insula (z = -1.14; P = .002). Individuals with long-term SCZ demonstrated CTh reductions in right insula (z = -3.25; P < .001), right inferior frontal cortex (z = -2.19; P < .001), and left (z = -2.37; P < .001) and right (z = -1.94; P = .002) temporal pole. There were no significant CTh differences between CHR and FEP. Individuals with long-term SCZ showed greater cortical thinning in right insula (z = -2.58; P < .001), right inferior frontal cortex (z = -2.32; P < .001), left lateral temporal cortex (z = -1.91; P = .002), and right temporal pole (z = -1.82; P = .002) than individuals with FEP. Combining all studies on SCZ, accelerated age-related CTh reductions were found in bilateral lateral middle temporal cortex and right pars orbitalis in inferior frontal cortex. Conclusions and Relevance: The absence of significant differences between FEP and CHR noted in this systematic review and meta-analysis suggests that the onset of psychosis was not associated with robust CTh reduction. The greater cortical thinning in long-term SCZ compared with FEP with accelerated age-related reduction in CTh suggests progressive neuroanatomic alterations following illness onset. Caution in interpretation is needed because heterogeneity in samples and antipsychotic treatment may confound these results.

Iodine-Mediated Synthesis of 2-(Methylthio)-4H-chromen-4-ones and Study of Their Halogenation Reactions.

An efficient iodine-mediated method is developed for the synthesis of functionalized 2-(methylthio)-4H-chromen-4-ones by intramolecular cyclization of easily accessible 1-(2-benzyloxy-aryl)-3,3-bis-methylsulfanyl-propenones. The synthesized chromen-4-ones turn out to be a key precursor for various kinds of chemical reactions. Mechanistically, we observed that iodine-mediated intramolecular cyclization of ketene dithioacetal proceeded through a radical pathway. 3-Halo-2-(methylthio)-4H-chromen-4-ones were achieved via various two- or one-pot halogenation approaches.

Base mediated synthesis of functionalized 2-(alkynyl)arylnitriles and their molecular docking study with aromatase receptor.

A simple, efficient, and transition metal-free approach to synthesize functionalized 2-(alkynyl)benzonitriles has been developed using suitably functionalized 2H-pyran-2-ones and 4-phenyl/trimethylsilanyl-but-3-yn-2-ones as precursors. The reaction proceeds in the presence of a base at room temperature to yield internal as well as terminal alkynes. The structure of the synthesized compound was confirmed by single-crystal X-ray analysis. The molecular docking study was performed to evaluate the binding mode of action of newly synthesized alkyne derivatives with known human breast cancer target receptor aromatase (PDB ID: 3EQM).

Transition metal-free synthesis of sterically hindered allylarenes from 5-hexene-2-one.

A simple, efficient and transition metal-free strategy was established for the synthesis of highly functionalized, sterically hindered allylarenes (6, 7 & 8) by base-mediated ring transformation of 2-oxo-6-aryl-4-(methylthio/sec-amino)-2H-pyran-3-carbonitriles (3/4) with 5-hexene-2-one (5). This provides a method for the synthesis of allylarenes functionalized with different electron donating and withdrawing groups in one pot. The structures of isolated products 6c and 7a were ascertained by spectroscopic and single crystal X-ray diffraction analyses. In addition, we have performed a molecular docking study to predict the biological activity of the synthesized molecules for binding to estrogen receptor alpha (ERα) and estrogen receptor beta (ERß).

Aberrant Gray Matter Networks in Non-comorbid Medication-Naive Patients With Major Depressive Disorder and Those With Social Anxiety Disorder.

Major depressive disorder (MDD) and social anxiety disorder (SAD) are among the most prevalent and frequently co-occurring psychiatric disorders in adults and may have, at least in part, a common etiology. However, the unique and the shared neuroanatomical characteristics of the two disorders have not been fully identified. The aim of this study was to compare the topological organization of gray matter networks between non-comorbid medication-naive MDD patients and SAD patients. High-resolution T1-weighted images were acquired from 37 non-comorbid medication-naive MDD patients, 24 non-comorbid medication-naive SAD patients, and 41 healthy controls. Single-subject gray matter graphs were extracted from structural MRI scans, and whole-brain neuroanatomic organization was compared across the three groups. The relationships between brain network measures and clinical characteristics were analyzed. Relative to healthy controls, both the MDD and the SAD patients showed global decreases in clustering coefficient, normalized clustering coefficient, and small-worldness and locally decreased nodal centralities and morphological connections in the left insular, lingual, and calcarine cortices. Compared with healthy controls, the SAD patients exhibited increased nodal centralities and morphological connections mainly involving the prefrontal cortex and the sensorimotor network. Furthermore, compared to the SAD patients, the MDD patients showed increased characteristic path length, reduced global efficiency, and decreased nodal centralities and morphological connections in the right middle occipital gyrus and the right postcentral gyrus. Our findings provide new evidence for shared and specific similarity-based gray matter network alterations in MDD and SAD and emphasize that the psychopathological changes in the right middle occipital gyrus and the right postcentral gyrus might be different between the two disorders.

Functional Alterations of White Matter in Chronic Never-Treated and Treated Schizophrenia Patients.

BACKGROUND: Schizophrenia is one of the most severe psychiatric disorders and dysfunction of gray matter (GM) has been usually investigated by resting-state functional (f)MRI. However, functional organization of white matter (WM) in chronic schizophrenia remains unclear. PURPOSE: To investigate the WM functional alterations in chronic never-treated schizophrenia and the effects of long-term antipsychotic treatment. STUDY TYPE: Prospective. SUBJECTS: Twenty-five never-treated, 41 matched antipsychotic-treated schizophrenia, and 25 healthy comparison subjects. FIELD STRENGTH/SEQUENCE: Resting state (rs)-fMRI, T1 -weighted images (T1 WI), and diffusion tensor imaging (DTI) covering the whole brain were acquired with a 3.0T scanner. ASSESSMENT: Amplitude of low-frequency fluctuations (ALFF) in WM and the correlation coefficients between WM and GM were examined and compared among the three participant groups by two reviewers independently. Independent component analysis (ICA) was added to evaluate WM-fMRI signals. Statistical Tests: Analysis of covariance (ANCOVA); Pearson correlation analysis. RESULTS: Never-treated patients demonstrated lower ALFF in splenium of corpus callosum (SCC) relative to treated patients and controls (P < 0.001, false discovery rate [FDR]-corrected). While the extracted independent component also located in SCC and showed significantly decreased connectivity in never-treated patients when compared to controls (P < 0.05, FDR-corrected). The correlation coefficients of WM-GM displayed greater reductions in the genu of corpus callosum (GCC), pontine crossing tract (PC), bilateral cingulum (hippocampus) (CGH), and bilateral corticospinal tract (CST) in treated patients relative to controls (P < 0.05, FDR-corrected). DATA CONCLUSION: These findings provide new insight into WM functional alterations over the long-term course of schizophrenia with and without the potential effects of antipsychotic medication. Functional change and abnormal connectivity in SCC were both found greater in untreated patients than treated patients relative to healthy controls, suggesting that long-term antipsychotic treatment may show some protective effects on WM functional organization. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2020;52:752-763.

Association of peripheral cytokine levels with cerebral structural abnormalities in schizophrenia.

A large body of evidence indicates that both the altered cytokines that mediate the immune-inflammatory process and abnormal gray matter are associated with schizophrenia. Whether peripheral cytokines are related to cerebral structural abnormality remains unclear. Therefore, we aimed to investigate the association of peripheral cytokine levels with gray matter abnormalities at the whole brain level in schizophrenia. Forty-four outpatients with schizophrenia and 44 controls were recruited. The serum levels of interleukin-1 beta (IL-1ß), IL-2, IL-6, IL-8, interferon-gamma (IFN-γ), transforming growth factor-beta (TGF-ß), and IL-10 were measured using a quantitative chemiluminescence assay. High-resolution T1 weighted images were acquired from all subjects and processed using FreeSurfer software to obtain the cortical thickness, surface area, and cortical and subcortical gray matter volumes. The cytokines and cerebral structures were compared between patients and controls using analysis of covariance (ANCOVA). The association between the cytokines and whole cerebral structures was performed using stepwise linear regression. Patients had higher levels of IL-2, IL-6, IL-8, and IL-10 than controls. In patients, the IL-6 level was significantly associated with the cortical thickness in the left pars opercularis, right pars triangularis, left superior temporal gyrus, and right middle temporal gyrus, which showed structural differences between the two groups. Altered cytokine levels may be associated with particular but not all cortical abnormalities in schizophrenia, especially IL-6, which was significantly associated with the abnormal cortical thickness of the bilateral Broca's area and temporal gyrus, which provided neuroimaging evidence to support the relationship between peripheral cytokines and the cerebral cortex in schizophrenia.

Reduced cortical thickness related to single nucleotide polymorphisms in the major histocompatibility complex region in antipsychotic-naive schizophrenia.

INSTRUCTIONS: The aim of this study was to explore the relationships between changes in cortical thickness and single nucleotide polymorphisms (SNPs) in the major histocompatibility complex (MHC) region in a group of antipsychotic-naive schizophrenia (AN-SCZ) patients. Methods Twenty-five AN-SCZ patients and 51 healthy controls (HCs) participated in this study. General linear models were used to identify associations between the average cortical thicknesses of each brain region (N = 68) and each of the 11 SNPs in the MHC region in the AN-SCZ patients and HCs. Next, we performed independent-sample t tests to investigate whether cortical thickness was significantly lower in the AN-SCZ patients than in HCs in the brain regions that were significantly associated with the SNPs. Finally, we examined the correlations between clinical symptoms and cortical thickness in the above brain areas in the whole AN-SCZ group using Pearson correlation tests. Results Seven of the 11 SNPs within the MHC region were significantly associated with cortical thickness only in the AN-SCZ patients; these included rs1635, rs1736913, rs2021722, rs204999, rs2523722, rs3131296, and rs9272105. The AN-SCZ patients had significantly thinner cortical thicknesses in the above brain regions, especially the prefrontal cortex. Furthermore, the left entorhinal region was negatively correlated with Positive and Negative Symptom Scale (PANSS) activation scores in the AN-SCZ group (r = -0.601, p = 0.03). Conclusions This study provides evidence demonstrating the potential effects of MHC risk variants in cortical thickness deficits in AN-SCZ. These data also support the notion that the immune system plays critical roles in the pathology of schizophrenia, which is mediated via the modulation of the development of cerebral cortical structures.

Increased Peripheral Interleukin 10 Relate to White Matter Integrity in Schizophrenia.

Background: Schizophrenia is characterized by the disruption of microstructural white matter (WM) integrity, while the pathogenesis remains unclear. Inflammation has been associated with the WM pathology in schizophrenia. Interleukin 10 (IL-10) has been proven to be related to schizophrenia in both animal and human models. The aim of this study was to explore whether peripheral IL-10 was associated with microstructural WM integrity in schizophrenia. Methods: A total of 47 patients with schizophrenia (SZ) and 49 healthy controls (HC) underwent diffusion tensor imaging and venous blood sampling. Tract-based spatial statistics was conducted to explore the differences in fractional anisotropy (FA), radial diffusivity (RD), mean diffusivity (MD), and axial diffusivity (AD) between patients and controls. A quantitative chemiluminescence assay was performed to measure peripheral IL-10 levels. General linear regression analysis using a stepwise method was applied to examine the relationship between peripheral IL-10 and diffusion measures. Results: Compared with the HC, peripheral IL-10 levels were higher and a significant reduction of FA and AD, and increase of RD and MD were observed in SZ (corrected p < 0.05). A regression analysis revealed that peripheral IL-10 was negatively correlated with FA in the right posterior thalamic radiation and left inferior fronto-occipital fasciculus, in SZ (ß = -0.51, p = 0.01; ß = -0.47, p = 0.02, respectively) but not in HC (ß = -0.01, p = 0.95; ß = -0.003, p = 0.98, respectively), and the differences in regression curves were significant (z = 2.50, p = 0.01; z = 2.37, p = 0.02, respectively). IL-10 was negatively connected with MD in the right parietal arcuate fasciculus (ß = -0.40, p = 0.048) and body of the corpus callosum (ß = -0.43, p = 0.03) in SZ, while not in HC. The magnitude of correlation in the patient and control group was different (z = 2.48, p = 0.01 and z = 2.61, p < 0.01, respectively). In addition, IL-10 was positively correlated with RD in the right parietal arcuate fasciculus in patients (ß = 0.45, p = 0.04) but not in HC (ß = 0.26, p = 0.94), but the correlation coefficients were not significant (z = 0.98, p = 0.32). Conclusion: Our findings demonstrated that elevated peripheral IL-10 levels were associated with the disruption of microstructural WM integrity in schizophrenia, supporting the notion that inflammation plays a regulatory role in the pathology of microstructural WM and is associated with schizophrenia.

Age Related Changes in Topological Properties of Brain Functional Network and Structural Connectivity.

Introduction: There are still uncertainties about the true nature of age related changes in topological properties of the brain functional network and its structural connectivity during various developmental stages. In this cross- sectional study, we investigated the effects of age and its relationship with regional nodal properties of the functional brain network and white matter integrity. Method: DTI and fMRI data were acquired from 458 healthy Chinese participants ranging from age 8 to 81 years. Tractography was conducted on the DTI data using FSL. Graph Theory analyses were conducted on the functional data yielding topological properties of the functional network using SPM and GRETNA toolbox. Two multiple regressions were performed to investigate the effects of age on nodal topological properties of the functional brain network and white matter integrity. Result: For the functional studies, we observed that regional nodal characteristics such as node betweenness were decreased while node degree and node efficiency was increased in relation to increasing age. Perversely, we observed that the relationship between nodal topological properties and fasciculus structures were primarily positive for nodal betweenness but negative for nodal degree and nodal efficiency. Decrease in functional nodal betweenness was primarily located in superior frontal lobe, right occipital lobe and the global hubs. These brain regions also had both direct and indirect anatomical relationships with the 14 fiber bundles. A linear age related decreases in the Fractional anisotropy (FA) value was found in the callosum forceps minor. Conclusion: These results suggests that age related differences were more pronounced in the functional than in structural measure indicating these measures do not have direct one-to-one mapping. Our study also indicates that the fiber bundles with longer fibers exhibited a more pronounced effect on the properties of functional network.

Association between structural and functional brain alterations in drug-free patients with schizophrenia: a multimodal meta-analysis.

BACKGROUND: Neuroimaging studies have shown both structural and functional abnormalities in patients with schizophrenia. Recently, studies have begun to explore the association between structural and functional grey matter abnormalities. By conducting a meta-analysis on morphometric and functional imaging studies of grey matter alterations in drug-free patients, the present study aims to examine the degree of overlap between brain regions with anatomic and functional changes in patients with schizophrenia. METHODS: We performed a systematic search of PubMed, Embase, Web of Science and the Cochrane Library to identify relevant publications. A multimodal analysis was then conducted using Seed-based d Mapping software. Exploratory analyses included jackknife, subgroup and meta-regression analyses. RESULTS: We included 15 structural MRI studies comprising 486 drug-free patients and 485 healthy controls, and 16 functional MRI studies comprising 403 drug-free patients and 428 controls in our meta-analysis. Drug-free patients were examined to reduce pharmacological effects on the imaging data. Multimodal analysis showed considerable overlap between anatomic and functional changes, mainly in frontotemporal regions, bilateral medial posterior cingulate/paracingulate gyrus, bilateral insula, basal ganglia and left cerebellum. There were also brain regions showing only anatomic changes in the right superior frontal gyrus, left supramarginal gyrus, right lingual gyrus and functional alternations involving the right angular gyrus. LIMITATIONS: The methodological aspects, patient characteristics and clinical variables of the included studies were heterogeneous, and we cannot exclude medication effects. CONCLUSION: The present study showed overlapping anatomic and functional brain abnormalities mainly in the default mode (DMN) and auditory networks (AN) in drug-free patients with schizophrenia. However, the pattern of changes differed in these networks. Decreased grey matter was associated with decreased activation within the DMN, whereas it was associated with increased activation within the AN. These discrete patterns suggest different pathophysiological changes impacting structural and functional associations within different neural networks in patients with schizophrenia.

Association between structural and functional brain alterations in drug-free patients with schizophrenia: a multimodal meta-analysis

Background: Neuroimaging studies have shown both structural and functional abnormalities in patients with schizophrenia. Recently, studies have begun to explore the association between structural and functional grey matter abnormalities. By conducting a meta­-analysis on morphometric and functional imaging studies of grey matter alterations in drug-free patients, the present study aims to examine the degree of overlap between brain regions with anatomic and functional changes in patients with schizophrenia. Methods: We performed a systematic search of PubMed, Embase, Web of Science and the Cochrane Library to identify relevant publications. A multimodal analysis was then conducted using Seed-based d Mapping software. Exploratory analyses included jackknife, subgroup and meta-regression analyses. Results: We included 15 structural MRI studies comprising 486 drug-free patients and 485 healthy controls, and 16 functional MRI studies comprising 403 drug-free patients and 428 controls in our meta-analysis. Drug-free patients were examined to reduce pharmacological effects on the imaging data. Multimodal analysis showed considerable overlap between anatomic and functional changes, mainly in frontotemporal regions, bilateral medial posterior cingulate/paracingulate gyrus, bilateral insula, basal ganglia and left cerebellum. There were also brain regions showing only anatomic changes in the right superior frontal gyrus, left supramarginal gyrus, right lingual gyrus and functional alternations involving the right angular ­gyrus. Limitations: The methodological aspects, patient characteristics and clinical variables of the included studies were heterogeneous, and we cannot exclude medication effects. Conclusion: The present study showed overlapping anatomic and functional brain abnormalities mainly in the default mode (DMN) and auditory networks (AN) in drug-free patients with schizophrenia. However, the pattern of changes differed in these networks. Decreased grey matter was associated with decreased activation within the DMN, whereas it was associated with increased activation within the AN. These discrete patterns suggest different pathophysiological changes impacting structural and functional associations within different neural networks in patients with schizophrenia.

Association between structural and functional brain alterations in drug-free patients with schizophrenia: a multimodal meta-analysis.

BACKGROUND: Neuroimaging studies have shown both structural and functional abnormalities in patients with schizophrenia. Recently, studies have begun to explore the association between structural and functional grey matter abnormalities. By conducting a meta-analysis on morphometric and functional imaging studies of grey matter alterations in drug-free patients, the present study aims to examine the degree of overlap between brain regions with anatomic and functional changes in patients with schizophrenia. METHODS: We performed a systematic search of PubMed, Embase, Web of Science and the Cochrane Library to identify relevant publications. A multimodal analysis was then conducted using Seed-based d Mapping software. Exploratory analyses included jackknife, subgroup and meta-regression analyses. RESULTS: We included 15 structural MRI studies comprising 486 drug-free patients and 485 healthy controls, and 16 functional MRI studies comprising 403 drug-free patients and 428 controls in our meta-analysis. Drug-free patients were examined to reduce pharmacological effects on the imaging data. Multimodal analysis showed considerable overlap between anatomic and functional changes, mainly in frontotemporal regions, bilateral medial posterior cingulate/paracingulate gyrus, bilateral insula, basal ganglia and left cerebellum. There were also brain regions showing only anatomic changes in the right superior frontal gyrus, left supramarginal gyrus, right lingual gyrus and functional alternations involving the right angular gyrus. LIMITATIONS: The methodological aspects, patient characteristics and clinical variables of the included studies were heterogeneous, and we cannot exclude medication effects. CONCLUSION: The present study showed overlapping anatomic and functional brain abnormalities mainly in the default mode (DMN) and auditory networks (AN) in drug-free patients with schizophrenia. However, the pattern of changes differed in these networks. Decreased grey matter was associated with decreased activation within the DMN, whereas it was associated with increased activation within the AN. These discrete patterns suggest different pathophysiological changes impacting structural and functional associations within different neural networks in patients with schizophrenia.

Gray Matter Abnormalities in Non-comorbid Medication-naive Patients with Major Depressive Disorder or Social Anxiety Disorder.

BACKGROUND: An overlap of clinical symptoms between major depressive disorder (MDD) and social anxiety disorder (SAD) suggests that the two disorders exhibit similar brain mechanisms. However, few studies have directly compared the brain structures of the two disorders. The aim of this study was to assess the gray matter volume (GMV) and cortical thickness alterations between non-comorbid medication-naive MDD patients and SAD patients. METHODS: High-resolution T1-weighted images were acquired from 37 non-comorbid MDD patients, 24 non-comorbid SAD patients and 41 healthy controls (HCs). Voxel-based morphometry analysis of the GMV (corrected with a false discovery rate of p<0.001) and vertex-based analysis of cortical thickness (corrected with a clusterwise probability of p<0.001) were performed, and group differences were compared by ANOVA followed by post hoc tests. OUTCOMES: Relative to the HCs, both the MDD patients and SAD patients showed the following results: GMV reductions in the bilateral orbital frontal cortex (OFC), putamen, and thalamus; cortical thickening in the bilateral medial prefrontal cortex, posterior dorsolateral prefrontal cortex, insular cortex, left temporal pole, and right superior parietal cortex; and cortical thinning in the left lateral OFC and bilateral rostral middle frontal cortex. In addition, MDD patients specifically showed a greater thickness in the left fusiform gyrus and right lateral occipital cortex and a thinner thickness in the bilateral lingual and left cuneus. SAD patients specifically showed a thinner cortical thickness in the right precentral cortex. INTERPRETATION: Our results indicate that MDD and SAD share common patterns of gray matter abnormalities in the orbitofrontal-striatal-thalamic circuit, salience network and dorsal attention network. These consistent structural differences in the two patient groups may contribute to the broad spectrum of emotional, cognitive and behavioral disturbances observed in MDD patients and SAD patients. In addition, we found disorder-specific involvement of the visual processing regions in MDD and the precentral cortex in SAD. These findings provide new evidence regarding the shared and specific neuropathological mechanisms that underlie MDD and SAD.

Gray matter abnormalities in pediatric autism spectrum disorder: a meta-analysis with signed differential mapping.

The gray matter abnormalities revealed by magnetic resonance imaging are inconsistent, especially in pediatric individuals with autism spectrum disorder (ASD) (age < 18 years old), a phenomenon possibly related to the core pathophysiology of ASD. The purpose of our meta-analysis was to identify and map the specific gray matter abnormalities in pediatric ASD individuals thereby exploring the potential effects of clinical and demographic characteristics of these gray matter changes. A systematic search was conducted to identify voxel-based morphometry studies in pediatric individuals with ASD. The effect-size signed differential mapping method was used to quantitatively estimate the regional gray matter abnormalities in pediatric ASD individuals. Meta-regression was used to examine the associations among age, gender, intelligence quotient, symptom severity and gray matter changes. Fifteen studies including 364 pediatric individuals with ASD (male = 282, age = 10.3 ± 4.4 years) and 377 healthy controls (male = 289, age = 10.5 ± 4.2 years) were included. Pediatric ASD individuals showed significant gray matter increases in the right angular gyrus, left superior and middle frontal gyrus, left precuneus, left inferior occipital gyrus and right inferior temporal gyrus, most of which involving the default mode network, and decreases in the left cerebellum and left postcentral gyrus. The meta-regression analysis showed that the repetitive behavior scores of the Autism Diagnostic Interview-Revised were positively associated with increased gray matter volumes in the right angular gyrus. Increased rather than decreased gray matter volume, especially involving the angular gyrus and prefrontal cortex may be the core pathophysiology in the early course of ASD.

Altered brain network topology in left-behind children: A resting-state functional magnetic resonance imaging study.

Whether a lack of direct parental care affects brain function in children is an important question, particularly in developing countries where hundreds of millions of children are left behind when their parents migrate for economic or political reasons. In this study, we investigated changes in the topological architectures of brain functional networks in left-behind children (LBC). Resting-state functional magnetic resonance imaging data were obtained from 26 LBC and 21 children living within their nuclear family (non-LBC). LBC showed a significant increase in the normalized characteristic path length (λ), suggesting a decrease in efficiency in information access, and altered nodal centralities in the fronto-limbic regions and motor and sensory systems. Moreover, a decreased nodal degree and the nodal betweenness of the right rectus gyrus were positively correlated with annual family income. The present study provides the first empirical evidence that suggests that a lack of direct parental care could affect brain functional development in children, particularly involving emotional networks.