Serum S100B protein and white matter changes in schizophrenia before and after medication.

Schizophrenia patients have abnormalities in white matter (WM) integrity in brain regions. S100B has been shown to be a marker protein for glial cells. The atypical antipsychotics have neuroprotective effects on the brain. It is not clear whether antipsychotics can induce S100B changes and improve symptoms by protecting oligodendrocytes. To investigate WM and S100B changes and associations and determine the effect of quetiapine on WM and S100B in schizophrenia patients, we determined serum S100B levels with solid phase immunochromatography and fractional anisotropy（FA）values of 36 patients and 40 healthy controls. Patients exhibited significantly higher serum concentrations of S100B and decreased FA values in left postcentral，right superior frontal，right thalamus, and left inferior occipital gyrus, while higher in right temporal cortex WM compared with healthy controls. Following treatment with quetiapine, patients had decreased S100B and higher FA values in right cerebellum，right superior frontal，right thalamus, and left parietal cortex，and decreased FA values in right temporal cortex WM compared with pre-treatment values. Furthermore, S100B were negatively correlated with PANSS positive scores and positively correlated with FA values in the left postcentral cortex. In addition，the percentage change in FA values in the right temporal cortex was positively correlated with the percentage change in the S100B, percentage reduction in PANSS scores, and percentage reduction in PANSS-positive scores. Our findings demonstrated abnormalities in S100B and WM microstructure in patients with schizophrenia. These abnormalities may be partly reversed by quetiapine treatment.

Reduced functional connectivity of the right dorsolateral prefrontal cortex at rest in obsessive-compulsive disorder.

BACKGROUND: Neuroimaging studies have revealed the role of the right dorsolateral prefrontal cortex (DLPFC) in the neurobiological mechanism of obsessive-compulsive disorder (OCD). However, only a few studies have examined the functional connectivity (FC) pattern of the right DLPFC at rest in OCD. OBJECTIVE: The aim of this research is to examine the FC patterns of the right DLPFC at rest in OCD. METHODS: Twenty-eight medication-free patients with OCD and 20 healthy controls underwent resting-state functional magnetic resonance imaging. Seed-based FC and support vector machine (SVM) were used to analyze the imaging data. RESULTS: The patients with OCD showed reduced FC values in the right middle temporal gyrus (MTG), right superior temporal gyrus, right ventral anterior cingulate cortex (vACC), and left Crus II. No brain regions showed a remarkable difference in FC values in patients with OCD after 8 weeks of medication treatment. The reduced right DLPFC-right MTG and right DLPFC-right vACC connectivities were correlated with the clinical symptoms of OCD. SVM results showed that reduced right DLPFC-right MTG connectivity at rest could predict the therapeutic response to OCD medication. CONCLUSIONS: The findings highlight the important role of the right DLPFC in the pathophysiological mechanism of OCD.

Decreased Resting-State Interhemispheric Functional Connectivity in Medication-Free Obsessive-Compulsive Disorder.

OBJECTIVE: Decreased homotopic connectivity of brain networks such as the cortico-striato-thalamo-cortical (CSTC) circuits may contribute to the pathophysiology of obsessive-compulsive disorder (OCD). However, little is known about interhemispheric functional connectivity (FC) at rest in OCD. In this study, the voxel-mirrored homotopic connectivity (VMHC) method was applied to explore interhemispheric coordination at rest in OCD. METHODS: Forty medication-free patients with OCD and 38 sex-, age-, and education level-matched healthy controls (HCs) underwent a resting-state functional magnetic resonance imaging. The VMHC and support vector machine (SVM) methods were used to analyze the data. RESULTS: Patients with OCD had remarkably decreased VMHC values in the orbitofrontal cortex, thalamus, middle occipital gyrus, and precentral and postcentral gyri compared with HCs. A combination of the VMHC values in the thalamus and postcentral gyrus could optimally distinguish patients with OCD from HCs. CONCLUSIONS: Our findings highlight the contribution of decreased interhemispheric FC within and outside the CSTC circuits in OCD and provide evidence to the pathophysiology of OCD.

Altered Global Brain Functional Connectivity in Drug-Naive Patients With Obsessive-Compulsive Disorder.

Abnormal functional connectivity (FC) within discrete brain networks is involved in the pathophysiology of obsessive-compulsive disorder (OCD) with inconsistent results. In the present study, we investigated the FC patterns of 40 drug-naive patients with OCD and 38 healthy controls (HCs) through an unbiased voxel-wise global brain FC (GFC) analysis at rest. Compared with HCs, patients with OCD showed decreased GFC within the default mode network (DMN) (i.e., left posterior cingulate cortex/lingual gyrus) and sensorimotor network (i.e., left precentral gyrus/postcentral gyrus) and increased GFC within the executive control network (ECN) (i.e., left dorsal lateral prefrontal cortex and left inferior parietal lobule). Receiver operating characteristic curve analyses further indicated that the altered GFC values within the DMN, ECN, and sensorimotor network may be used as neuroimaging markers to differentiate patients with OCD from HCs. These findings indicated the aberrant FC patterns of the DMN, ECN, and sensorimotor network associated with the pathophysiology of OCD and provided new insights into the changes in brain organization function in OCD.

Increased cerebellar-default-mode network connectivity at rest in obsessive-compulsive disorder.

Abnormalities of the cerebellum and default-mode network (DMN) in patients with obsessive-compulsive disorder (OCD) have been widely reported. However, alterations of reciprocal functional connections between the cerebellum and DMN at rest in OCD remain unclear. Forty patients with OCD and 38 gender-, age-, and education-matched healthy controls (HCs) underwent resting-state functional magnetic resonance imaging scan. Seed-based functional connectivity (FC) and support vector machine (SVM) were applied to analyze the imaging data. Compared with HCs, patients with OCD exhibited increased FCs between the left Crus I-left superior medial prefrontal cortex (MPFC) and between the right Crus I-left superior MPFC, left middle MPFC, and left middle temporal gyrus (MTG). A significantly negative correlation was observed between the right Crus I-left MTG connectivity and the Yale-Brown Obsessive-Compulsive Scale compulsion subscale scores in the OCD group (r = - 0.476, p = 0.002, Bonferroni corrected). SVM classification analysis indicated that a combination of the left Crus I-left superior MPFC connectivity and the right Crus I-left middle MPFC connectivity can be used to discriminate patients with OCD from HCs with a sensitivity of 85.00%, specificity of 68.42%, and accuracy of 76.92%. Our study highlights the contribution of the cerebellar-DMN connectivity in OCD pathophysiology and provides new findings to OCD research.

[The Protective Effect of Olanzapine on the Hippocampal Neuron of Depression Model Rats via Inhibiting NLRP3 Inflammasome Activation].

OBJECTIVE: To determine the impact olanzapine (OLA) on the hippocampal neuron of model rats with depression. METHODS: Rats were divided into five groups: control, chronic unpredicted stress (CUS), OAL (0.5, 1, 2 mg/kg), si-Atg5, and OAL (2 mg/kg)+si-Atg5. Open field and sucrose preference tests were performed to evaluate rat behaviors. Cell apoptosis was detected with Tunnel. The concentrations of interleukin (IL)-1ß and IL-18 were determined by ELISA. The expressions of cleaved Caspase-3, cleaved Caspase-9, LC3, Beclin1, P62, NLRP3 and cleaved Caspase-1 were measured by Western blot. RESULTS: OAL (0.5, 1, 2 mg/kg) increased the total moving distance, sucrose consumption and preference rate of CUS rats, and decreased serum IL-18, cell apoptosis and the expressions of cleaved Caspase-9, cleaved Caspase-1 and NLRP3 in the CA3 region of hippocampus. Although OAL (1, 2 mg/kg) decreased the expression of cleaved Caspase-3 and serum IL-1ß, OAL (0.5 mg/kg) showed no detectable effects. Si-Atg5 decreased the total moving distance, sucrose consumption and preference rate of CUS rats, enhanced the expressions of cleaved Caspase-3, cleaved Caspase-9, cleaved Caspase-1 and NLRP3, and weakened the effect of OAL (2 mg/kg). OAL (0.5, 1, 2 mg/kg) also increased the LC3Ⅱ/LC3Ⅰ ratio and the expression of Beclin1 in the CA3 region of hippocampus. OAL (1, 2 mg/kg) reduced the expression of p62, but not when it was reduced to 0.5 mg/kg. Si-Atg5 reduced the LC3Ⅱ/LC3Ⅰ ratio and the expression of Beclin1, and weakened the function of OAL (2 mg/kg). CONCLUSION: OAL can protect the hippocampal neuron of CUS rats via inhibiting NLRP3 inflammasome activation.

Abnormal Regional Homogeneity in Patients With Obsessive-Compulsive Disorder and Their Unaffected Siblings: A Resting-State fMRI Study.

Objective: Previous studies suggest that abnormal brain structure and function may be neuroimaging endophenotypes of obsessive-compulsive disorder (OCD). Comparing the intrinsic brain activity of OCD patients and their unaffected siblings will help to further understand the susceptibility to, and pathological mechanisms of, OCD. We used a case-control study design aiming to establish whether the abnormal regional homogeneity (ReHo) found in OCD patients also exists in their unaffected siblings. Method: Fifteen unmedicated OCD patients, 15 of their unaffected siblings, and 30 healthy controls (HCs) received resting-state functional magnetic resonance imaging (r-s fMRI) scanning and clinical evaluation. We used the ReHo method to analyze the inter-regional synchronized activity of all participants. One-way analysis of covariance with post hoc tests was used to compare the ReHo maps across groups. A Pearson correlation analysis was conducted to assess the correlations between clinical characteristics and abnormal ReHo in OCD patients. Results: Relative to HCs, OCD patients and their unaffected siblings showed overlapping higher ReHo values in the right dorsolateral prefrontal cortex (DLPFC). Patients with OCD showed increased ReHo in left middle frontal gyrus (MFG) relative to both their unaffected siblings and HCs. In addition to the right DLPFC and left MFG, OCD patients, compared with HCs, also showed abnormal ReHo in other regions, including higher ReHo in the right superior parietal cortex and lower ReHo in the left inferior parietal cortex, right parahippocampal region, left thalamus, and right inferior temporal cortex. Compared with HCs, the unaffected siblings of patients with OCD had significantly higher ReHo in the right inferior parietal cortex, right MFG, and right supplementary motor area. There was no association between clinical symptoms and abnormal ReHo values in OCD patients. Conclusions: This study found overlapping higher ReHo values in the right DLPFC of OCD patients and their unaffected siblings. Our results suggest that the higher ReHo in the right DLPFC may be a potential neuroimaging endophenotype, which may reflect an increased genetic risk of OCD.

Prenatal immune activation induces age-related alterations in rat offspring: Effects upon NMDA receptors and behaviors.

Prenatal exposure to polyriboinosinic-polyribocytidylic acid (poly I:C) results in psychotic-like behavior in mature rat offspring as well as enduring modifications of glutamatergic excitatory synaptic transmission. However, little is known about the dynamic behavioral and glutamate N-methyl-D-aspartate (NMDA) receptor changes in rat offspring following poly I:C treatment of pregnant dams. In this study, poly I:C was administered to rats intravenously at a dose of 10 mg/kg on gestational day 9 in order to assess changes in behavior and NMDA receptors in offspring over time. Results demonstrate progressive worsening behaviors in adolescents and adults that manifest as increased anxiety, cognitive impairment, and pre-pulse inhibition deficits. Age-related alteration of NMDA receptors in the prefrontal cortex and hippocampus, either total number or distribution, were observed from weaning to adulthood. These results suggest that abnormalities of NMDA receptors occur prior to obvious schizophrenia-like behavioral manifestations. Hence, NMDA receptors may be potential therapeutic targets to prevent disease development during asymptomatic periods of schizophrenia, and may serve as targets for preventive and/or therapeutic strategies for schizophrenia. Further, PSD95, a scaffolding protein that is a component of the NMDA receptor signaling complex, is increased in the hippocampus of adult offspring, when serious behavioral abnormalities emerge. This result suggests that PSD95 may be involved in behavioral abnormalities of schizophrenia.

Abnormalities of white matter microstructure in unmedicated patients with obsessive-compulsive disorder: Changes after cognitive behavioral therapy.

BACKGROUND: Cognitive behavioral therapy (CBT) is an effective treatment for Obsessive-compulsive disorder (OCD). Structural and functional white matter defects may suggest a vital neurobiological basis of OCD. However, the effects of CBT on white matter in OCD remain unknown. OBJECTIVE: The aim was to investigate white matter changes and the effect of CBT on white matter in OCD patients. METHODS: Fractional anisotropy (FA) maps were acquired using DTI. Participants included 85 patients with OCD and 90 healthy controls. VBM was then performed to detect regions with significant group differences. RESULTS: Obsessive-compulsive disorder patients exhibited significantly reduced FA values in bilateral OFC, right cerebellum, and left SPG, while higher FA values were observed in right PUT compared with healthy controls. Following CBT, OCD patients showed higher FA values in right MFG, left OFC, right cerebellum, and left MTG, and decreased FA values in right PUT in comparison with pretreatment. Furthermore, FA values in the left OFC of patients were significantly positively correlated with the Y-BOCS and its associated Compulsions subscale, and FA values in the right PUT were positively correlated with Compulsions subscale. In addition, the percentage change in FA values in left MTG was positively correlated with the percentage reduction in Compulsions subscale, while the percentage change in FA values in left OFC and right PUT was negatively correlated with the percentage reductions in Obsessive and Compulsions subscale, respectively. CONCLUSIONS: Our findings demonstrate the abnormalities of white matter microstructure in unmedicated patients with OCD. These abnormalities may be partly reversed by CBT.

The effects of cognitive behavioral therapy on resting-state functional brain network in drug-naive patients with obsessive-compulsive disorder.

Objectives: Although cognitive behavioral therapy (CBT) is an effective treatment for obsessive-compulsive disorder (OCD), the treatment mechanisms remain poorly understood. This study aimed to investigate the effects of CBT on changes in the intrinsic whole-brain functional network of OCD patients. Materials and Methods: Twenty drug-naive and noncomorbid OCD patients were recruited, and resting-state functional magnetic resonance imaging was performed before and after 12 weeks of CBT. Moreover, 20 healthy controls were scanned twice with a 12-week interval. A graph-theory degree centrality (DC) approach and functional connectivity method were used to analyze the whole-brain functional network hub and connectivity changes in OCD patients before and after CBT treatment. Results: A significant group × time interaction on DC was found in the left dorsolateral prefrontal cortex (DLPFC); the DC in the left DLPFC was significantly reduced after CBT treatment. Resting-state functional connectivity (RSFC) between the left DLPFC and right orbitofrontal cortex was increased in the OCD patients at baseline, and normalized after CBT treatment. RSFC changes between the left DLPFC and default mode network (DMN) positively correlated with changes in clinical symptoms in OCD patients. Conclusions: These findings suggest that CBT can modulate changes in intrinsic functional network hubs in the cortico-striato-thalamo-cortical circuit in OCD patients. Cognitive control network and DMN connectivity may be a potential imaging biomarker for evaluating CBT treatment for OCD.

Regional homogeneity of spontaneous brain activity in adult patients with obsessive-compulsive disorder before and after cognitive behavioural therapy.

BACKGROUND: Cognitive behavioural therapy (CBT) is an effective treatment for obsessive-compulsive disorder (OCD). Several neuroimaging studies have explored alterations of brain function in OCD patients as they performed tasks after CBT. However, the effects of CBT on the neural activityin OCD during rest remain unknown. Therefore, we investigated changes in regional homogeneity (ReHo) in OCD patients before and after CBT. METHODS: Twenty-two OCD patients and 22 well-matched healthy controls participated in the resting-state functional magnetic resonance imaging scans. We compared differences in ReHo between the OCD and control groups before treatment and investigated the changes of ReHo in 17 OCD patients who responded to CBT. RESULTS: Compared to healthy controls, OCD patients exhibited higher ReHo in the right orbitofrontal cortex (OFC), bilateral middle frontal cortex, right precuneus, left cerebellum, and vermis, as well as lower ReHo in the bilateral caudate, right calcarine, right posterior cingulate cortex, and right middle temporal cortex. Along with the clinical improvement in OCD patients after CBT, we found decreased ReHo in the right OFC, bilateral middle frontal cortex, left cerebellum and vermis, and increased ReHo in the left caudate. Improvement of OCD symptoms was significantly correlated with the changed ReHo in the right OFC and left cerebellum. CONCLUSIONS: Although these findings are preliminary and need to be replicated in larger samples, they indicate the presence of abnormal spontaneous brain activity of the prefrontal-striatal-cerebellar circuit in OCD patients, and provide evidence that CBT can selectively modulate the spontaneous brain activity of this circuit in OCD patients.

Abnormal topological organization in white matter structural networks revealed by diffusion tensor tractography in unmedicated patients with obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a chronic psychiatric disorder defined by recurrent thoughts, intrusive and distressing impulses, or images and ritualistic behaviors. Although focal diverse regional abnormalities white matter integrity in specific brain regions have been widely studied in populations with OCD, alterations in the structural connectivities among them remain poorly understood. OBJECTIVE: The aim was to investigate the abnormalities in the topological efficiency of the white matter networks and the correlation between the network metrics and Yale-Brown Obsessive-Compulsive Scale scores in unmedicated OCD patients, using diffusion tensor tractography and graph theoretical approaches. METHODS: This study used diffusion tensor imaging and deterministic tractography to map the white matter structural networks in 26 OCD patients and 39 age- and gender-matched healthy controls; and then applied graph theoretical methods to investigate abnormalities in the global and regional properties of the white matter network in these patients. RESULTS: The patients and control participants both showed small-world organization of the white matter networks. However, the OCD patients exhibited significant abnormal global topology, including decreases in global efficiency (t = -2.32, p = 0.02) and increases in shortest path length, Lp (t = 2.30, p = 0.02), the normalized weighted shortest path length, λ (t = 2.08, p=0.04), and the normalized clustering coefficient, γ (t = 2.26, p = 0.03), of their white matter structural networks compared with healthy controls. Further, the OCD patients showed a reduction in nodal efficiency predominately in the frontal regions, the parietal regions and caudate nucleus. The normalized weighted shortest path length of the network metrics was significantly negatively correlated with obsessive subscale of the Yale-Brown Obsessive-Compulsive Scale (r = -0.57, p = 0.0058). CONCLUSIONS: These findings demonstrate the abnormal topological efficiency in the white matter networks in OCD patients.

[Effect of pyrrolidinedithiocarbamate on neural developmental disorder of adult offspring with maternal systemic exposure to Poly(I:C) during pregnancy].

OBJECTIVE: To explore the correlation between the elevated expression of cytokines under the induction of Poly(I:C) (polycytidylic acid) in maternal hosts and the abnormal behaviors of adult offsprings and understand the intervening effects of nuclear factor NF-κB inhibitor pyrrolidinedithiocarbamate (PDTC). METHODS: Poly(I:C) or saline was administered to model the maternal infection during early pregnancy in rats. And the expression of cytokines was blocked with PDTC. The maternal levels of tumor necrosis factor alpha and interleukin-10 were determined by ELISA (enzyme-linked immunosorbent assay). The adult offsprings on different treatments were then compared with regards to prepulse inhibition (PPI), passive avoidance and active avoidance. RESULTS: After the administration of Poly(I:C), there was an elevated levels of serum cytokines as shown by the markedly increased serum levels of IL-10 and TNF-α. The serum levels of IL-10 and TNF-α in the model group were significantly higher than those in the control group [(18.26 ± 1.52) pg/ml, (119.64 ± 16.42) pg/ml vs. (0.16 ± 0.13) pg/ml and (11.21 ± 1.81) pg/ml]. The elevation was partly blocked by PDTC. The serum levels of IL-10 and TNF-α in the intervention group [(12.64 ± 2.04) pg/ml and (30.34 ± 2.19) pg/ml respectively] were lower than those in the model group, but still higher than those in the control group. The psychotic-like phenotypes including defects in PPI, passive avoidance and active avoidance were observed in Poly(I:C)-treated offsprings. Such an effect was blunted by the PDTC intervention. The PPI results demonstrated that the PP2 and PP8 difference between rats in 3 groups were statistically significant, with a lower PPI value in the model group than in the intervention group, in the intervention group than in the control group and much lower in the model group than in the control group. PP4 was lower in the model group than that in the intervention group, and also lower in the model group than in the control group. There was no significant difference between the control group and the intervention group. The passive avoidance results indicated that T1 was higher in the model group than in the control and intervention groups and there was no statistical difference between the control and intervention groups. T2 was lower in the model group than in the control and intervention groups and there was no statistical difference between the control and intervention groups. And the active avoidance test results showed that total conditioned reflex times of the control group was higher than those of the intervention and model groups. No statistical difference was found between the intervention and model groups. Total reflex rate of the control group was higher than that of the intervention and model groups. No statistical difference was found between the intervention and model groups. CONCLUSION: PDTC can interfere with neural developmental disorder of adult offsprings through blunting the cytokine-mediated maternal immune response.

An Inhibitor of the F1 subunit of ATP synthase (IF1) modulates the activity of angiostatin on the endothelial cell surface.

Angiostatin binds to endothelial cell (EC) surface F(1)-F(0) ATP synthase, leading to inhibition of EC migration and proliferation during tumor angiogenesis. This has led to a search for angiostatin mimetics specific for this enzyme. A naturally occurring protein that binds to the F1 subunit of ATP synthase and blocks ATP hydrolysis in mitochondria is inhibitor of F1 (IF1). The present study explores the effect of IF1 on cell surface ATP synthase. IF1 protein bound to purified F(1) ATP synthase and inhibited F(1)-dependent ATP hydrolysis consistent with its reported activity in studies of mitochondria. Although exogenous IF1 did not inhibit ATP production on the surface of EC, it did conserve ATP on the cell surface, particularly at low extracellular pH. IF1 inhibited ATP hydrolysis but not ATP synthesis, in contrast to angiostatin, which inhibited both. In cell-based assays used to model angiogenesis in vitro, IF1 did not inhibit EC differentiation to form tubes and only slightly inhibited cell proliferation compared with angiostatin. From these data, we conclude that inhibition of ATP synthesis is necessary for an anti-angiogenic outcome in cell-based assays. We propose that IF1 is not an angiostatin mimetic, but it can serve a protective role for EC in the tumor microenvironment. This protection may be overridden in a concentration-dependent manner by angiostatin. In support of this hypothesis, we demonstrate that angiostatin blocks IF1 binding to ATP synthase and abolishes its ability to conserve ATP. These data suggest that there is a relationship between the binding sites of IF1 and angiostatin on ATP synthase and that IF1 could be employed to modulate angiogenesis.