Chuanjun Zhuo

Performances of diffusion kurtosis imaging and diffusion tensor imaging in detecting white matter abnormality in schizophrenia.

Diffusion kurtosis imaging (DKI) is an extension of diffusion tensor imaging (DTI), exhibiting improved sensitivity and specificity in detecting developmental and pathological changes in neural tissues. However, little attention was paid to the performances of DKI and DTI in detecting white matter abnormality in schizophrenia. In this study, DKI and DTI were performed in 94 schizophrenia patients and 91 sex- and age-matched healthy controls. White matter integrity was assessed by fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), mean kurtosis (MK), axial kurtosis (AK) and radial kurtosis (RK) of DKI and FA, MD, AD and RD of DTI. Group differences in these parameters were compared using tract-based spatial statistics (TBSS) (P < 0.01, corrected). The sensitivities in detecting white matter abnormality in schizophrenia were MK (34%) > AK (20%) > RK (3%) and RD (37%) > FA (24%) > MD (21%) for DKI, and RD (43%) > FA (30%) > MD (21%) for DTI. DKI-derived diffusion parameters (RD, FA and MD) were sensitive to detect abnormality in white matter regions (the corpus callosum and anterior limb of internal capsule) with coherent fiber arrangement; however, the kurtosis parameters (MK and AK) were sensitive to reveal abnormality in white matter regions (the juxtacortical white matter and corona radiata) with complex fiber arrangement. In schizophrenia, the decreased AK suggests axonal damage; however, the increased RD indicates myelin impairment. These findings suggest that diffusion and kurtosis parameters could provide complementary information and they should be jointly used to reveal pathological changes in schizophrenia.

Altered Spontaneous Brain Activity in Schizophrenia: A Meta-Analysis and a Large-Sample Study

Altered spontaneous brain activity as measured by ALFF, fALFF, and ReHo has been reported in schizophrenia, but no consensus has been reached on alternations of these indexes in the disorder. We aimed to clarify the regional alterations in ALFF, fALFF, and ReHo in schizophrenia using a meta-analysis and a large-sample validation. A meta-analysis of activation likelihood estimation was conducted based on the abnormal foci of ten studies. A large sample of 86 schizophrenia patients and 89 healthy controls was compared to verify the results of the meta-analysis. Meta-analysis demonstrated that the alternations in ALFF and ReHo had similar distribution in schizophrenia patients. The foci with decreased ALFF/fALFF and ReHo in schizophrenia were mainly located in the somatosensory cortex, posterior parietal cortex, and occipital cortex; however, foci with increased ALFF/fALFF and ReHo were mainly located in the bilateral striatum, medial temporal cortex, and medial prefrontal cortex. The large-sample study showed consistent findings with the meta-analysis. These findings may expound the pathophysiological hypothesis and guide future research.

Altered resting-state cerebral blood flow and its connectivity in schizophrenia

Small sample sizes and large inter-subject variations result in inconsistent findings in resting-state cerebral blood flow (CBF) in schizophrenia. The CBF connectivity alterations in schizophrenia remain unclear. Recently, three-dimensional pseudo-continuous arterial spin labeling (pcASL) imaging was performed to measure the resting-state CBF in 100 schizophrenia patients and 94 healthy comparison subjects. The normalized CBF was used to reduce the inter-subject variations. Both group comparisons in the CBF and correlations between the CBF alterations and clinical parameters were assessed. The CBF connectivity of the brain regions with regional CBF differences was also compared between the groups. Compared with the healthy controls, the schizophrenia patients exhibited increased CBF in the bilateral inferior temporal gyri, thalami and putamen and decreased CBF in the left insula and middle frontal gyrus and the bilateral anterior cingulate cortices and middle occipital gyri. In the schizophrenia patients, significant correlations were identified between the CBF and clinical parameters. Importantly, the schizophrenia patients exhibited CBF disconnections between the left thalamus and right medial superior frontal gyrus and between the left insula and left postcentral gyrus. Our results suggest that schizophrenia patients may exhibit both regional CBF abnormalities and deficits in CBF connectivity, which may underlie the clinical symptoms of schizophrenia.

Functional connectivity density alterations in schizophrenia

Background: Schizophrenia is characterized by altered resting-state functional connectivity. Most previous studies have focused on changes in connectivity strengths; however, the alterations in connectivity density in schizophrenia remain largely unknown. Here, we aimed to investigate changes in resting-state functional connectivity density (rsFCD) in schizophrenia. Methods: A total of 95 schizophrenia patients and 93 sex- and age-matched healthy controls (HCs) underwent resting-state functional MRI examinations. The rsFCD, which reflects the total number of functional connections between a given brain voxel and all other voxels in the entire brain, was calculated for each voxel of each subject. Voxel-based comparisons were performed to identify brain regions with significant rsFCD differences between patients and controls (P < 0.05, corrected). Results: Compared with HCs, patients with schizophrenia showed significantly increased rsFCD in the bilateral striatum and hippocampus and significantly decreased rsFCD in the bilateral sensorimotor cortices and right occipital cortex. However, the rsFCD values of these brain regions were not correlated with antipsychotic dosage, illness duration, or clinical symptom severity. Conclusions: The striatal and hippocampal regions and parietal-occipital regions exhibited completely different changes in rsFCD in schizophrenia, which roughly correspond to dopamine activity in these regions in schizophrenia. These findings support the connectivity disorder hypothesis of schizophrenia and increase our understanding of the neural mechanisms of schizophrenia.

Altered Cerebral Blood Flow Covariance Network in Schizophrenia

Many studies have shown abnormal cerebral blood flow (CBF) in schizophrenia; however, it remains unclear how topological properties of CBF network are altered in this disorder. Here, arterial spin labeling (ASL) MRI was employed to measure resting-state CBF in 96 schizophrenia patients and 91 healthy controls. CBF covariance network of each group was constructed by calculating across-subject CBF covariance between 90 brain regions. Graph theory was used to compare intergroup differences in global and nodal topological measures of the network. Both schizophrenia patients and healthy controls had small-world topology in CBF covariance networks, implying an optimal balance between functional segregation and integration. Compared with healthy controls, schizophrenia patients showed reduced small-worldness, normalized clustering coefficient and local efficiency of the network, suggesting a shift toward randomized network topology in schizophrenia. Furthermore, schizophrenia patients exhibited altered nodal centrality in the perceptual-, affective-, language-, and spatial-related regions, indicating functional disturbance of these systems in schizophrenia. This study demonstrated for the first time that schizophrenia patients have disrupted topological properties in CBF covariance network, which provides a new perspective (efficiency of blood flow distribution between brain regions) for understanding neural mechanisms of schizophrenia.

Altered functional connectivity of the cingulate subregions in schizophrenia.

Schizophrenia patients have shown altered resting-state functional connectivity (rsFC) of the cingulate cortex; however, it is unknown whether rsFCs of the cingulate subregions are differentially affected in this disorder. We aimed to clarify the issue by comparing rsFCs of each cingulate subregion between healthy controls and schizophrenia patients. A total of 102 healthy controls and 94 schizophrenia patients underwent resting-state functional magnetic resonance imaging with a sensitivity-encoded spiral-in imaging sequence to reduce susceptibility-induced signal loss and distortion. The cingulate cortex was divided into nine subregions, including the subgenual anterior cingulate cortex (ACC), areas 24 and 32 of the pregenual ACC, areas 24 and 32 of the anterior mid-cingulate cortex (aMCC), posterior MCC (pMCC), dorsal (dPCC) and ventral (vPCC) posterior cingulate cortex (PCC) and retrosplenial cortex (RSC). The rsFCs of each cingulate subregion were compared between the two groups and the atrophy effect was considered. Results with and without global signal regression were reported. Most cingulate subregions exhibited decreased rsFCs in schizophrenia after global signal regression (GSR). Without GSR, only increased rsFC was found in schizophrenia, which primarily restricted to the aMCC, PCC and RSC. Some of these increased rsFCs were also significant after GSR. These findings suggest that GSR can greatly affect between-group differences in rsFCs and the consistently increased rsFCs may challenge the functional disconnection hypothesis of schizophrenia.

LncRNA H19 inhibits autophagy by epigenetically silencing of DIRAS3 in diabetic cardiomyopathy

We previously generated a rat model of diabetic cardiomyopathy and found that the expression of long non-coding RNA H19 was downregulated. The present study was aimed to explore the pathogenic role of H19 in the development of diabetic cardiomyopathy. Overexpression of H19 in diabetic rats attenuated cardiomyocyte autophagy and improved left ventricular function. High glucose was found to reduce H19 expression and increase autophagy in cultured neonatal cardiomyocytes. The results of RNA-binding protein immunoprecipitation showed that H19 could directly bind with EZH2 in cardiomyocytes. The chromatin immunoprecipitation assays indicated that H19 knockdown could reduce EZH2 occupancy and H3K27me3 binding in the promoter of DIRAS3. In addition, overexpression of H19 was found to downregulate DIRAS3 expression, promote mTOR phosphorylation and inhibit autophagy activation in cardiomyocytes exposed to high glucose. Furthermore, we also found that high glucose increased DIRAS3 expression in cardiomyocytes and DIRAS3 induced autophagy by inhibiting mTOR signaling. In conclusion, our study suggested that H19 could inhibit autophagy in cardiomyocytes by epigenetically silencing of DIRAS3, which might provide novel insights into understanding the molecular mechanisms of diabetic cardiomyopathy.

Alterations of Functional and Structural Networks in Schizophrenia Patients with Auditory Verbal Hallucinations

Background: There have been many attempts at explaining the underlying neuropathological mechanisms of auditory verbal hallucinations (AVH) in schizophrenia on the basis of regional brain changes, with the most consistent findings being that AVH are associated with functional and structural impairments in auditory and speech-related regions. However, the human brain is a complex network and the global topological alterations specific to AVH in schizophrenia remain unclear. Methods: Thirty-five schizophrenia patients with AVH, 41 patients without AVH, and 50 healthy controls underwent resting-state functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI). The whole-brain functional and structural networks were constructed and analyzed using graph theoretical approaches. Inter-group differences in global network metrics (including small-world properties and network efficiency) were investigated. Results: We found that three groups had a typical small-world topology in both functional and structural networks. More importantly, schizophrenia patients with and without AVH exhibited common disruptions of functional networks, characterized by decreased clustering coefficient, global efficiency and local efficiency, and increased characteristic path length; structural networks of only schizophrenia patients with AVH showed increased characteristic path length compared with those of healthy controls. Conclusion: Our findings suggest that less “small-worldization” and lower network efficiency of functional networks may be an independent trait characteristic of schizophrenia, and regularization of structural networks may be the underlying pathological process engaged in schizophrenic AVH symptom expression.

LncRNA TINCR attenuates cardiac hypertrophy by epigenetically silencing CaMKII

In the previous study, we established a mouse model of cardiac hypertrophy using transverse aortic constriction (TAC) and found that the expression of long non-coding RNAs TINCR was downregulated in myocardial tissue. The present study was designed to determine the potential role of TINCR in the pathogenesis of cardiac hypertrophy. Our results showed that enforced expression of TINCR could attenuate cardiac hypertrophy in TAC mice. Angiotensin II (Ang-II) was found to be associated with reduced TINCR expression and increased hypertrophy in cultured neonatal cardiomyocytes. RNA-binding protein immunoprecipitation assay confirmed that TINCR could directly bind with EZH2 in cardiomyocytes. The results of chromatin immunoprecipitation assay revealed that EZH2 could directly bind to CaMKII promoter region and mediate H3K27me3 modification. Knockdown of TINCR was found to reduce EZH2 occupancy and H3K27me3 binding in the promoter of CaMKII in cardiomyocytes. In addition, enforced expression of TINCR was found to decrease CaMKII expression and attenuate Ang-II-induced cardiomyocyte hypertrophy. Furthermore, our results also showed that Ang-II could increase CaMKII expression in cardiomyocytes, which consequently contributed to cellular hypertrophy. In conclusion, our findings demonstrated that TINCR could attenuate myocardial hypertrophy by epigenetically silencing of CaMKII, which may provide a novel therapeutic strategy for cardiac hypertrophy.

The selective impairment of resting-state functional connectivity of the lateral subregion of the frontal pole in schizophrenia

Objective Although extensive resting-state functional connectivity (rsFC) changes have been reported in schizophrenia, rsFC changes of the frontal pole (FP) remain unclear. The FP contains several subregions with different connection patterns; however, it is unknown whether the FP subregions are differentially affected in schizophrenia. To explore this possibility, we compared rsFC differences of the FP subregions between schizophrenia patients and healthy controls. Method One hundred healthy controls and 91 patients with schizophrenia underwent resting-state functional MRI with a sensitivity-encoded spiral-in (SENSE-SPIRAL) imaging sequence to reduced susceptibility-induced signal loss and distortion. The FP was subdivided into the orbital (FPo), medial (FPm), and lateral (FPl) subregions. Mean fMRI time series were extracted for each FP subregion and entered into a seed-based rsFC analysis. Results The FP subregions exhibited differential rsFC patterns in both healthy controls and schizophrenia patients. Direct comparison between groups revealed reduced rsFCs between the bilateral FPl and several cognitive-related regions, including the dorsolateral prefrontal cortex, medial prefrontal cortex, anterior cingulate cortex, posterior cingulate cortex/precuneus, temporal cortex and inferior parietal lobule in schizophrenia. Although the FPl exhibited obvious atrophy, rsFC changes were unrelated to volumetric atrophy in the FPl, to duration of illness, and to antipsychotic medication dosage. No significant differences were observed in the rsFCs of other FP subregions. Conclusion These findings suggest a selective (the lateral subregion) functional disconnection of the FP subregions in schizophrenia.