Hippocampal Dynamic Functional Connectivity, HPA Axis Activity, and Personality Trait in Bipolar Disorder with Suicidal Attempt.

INTRODUCTION: Suicide in bipolar disorder (BD) is a multifaceted behavior, involving specific neuroendocrine and psychological mechanisms. According to previous studies, we hypothesized that suicidal BD patients may exhibit impaired dynamic functional connectivity (dFC) variability of hippocampal subregions and hypothalamic-pituitary-adrenal (HPA) axis activity, which may be associated with suicide-related personality traits. The objective of our study was to clarify this. METHODS: Resting-state functional magnetic resonance imaging data were obtained from 79 patients with BD, 39 with suicidal attempt (SA), and 40 without SA, and 35 healthy controls (HCs). The activity of the HPA axis was assessed by measuring morning plasma adrenocorticotropic hormone (ACTH) and cortisol (CORT) levels. All participants underwent personality assessment using Minnesota Multiphasic Personality Inventory-2 (MMPI-2). RESULTS: BD patients with SA exhibited increased dFC variability between the right caudal hippocampus and the left superior temporal gyrus (STG) when compared with non-SA BD patients and HCs. BD with SA also showed significantly lower ACTH levels in comparison with HCs, which was positively correlated with increased dFC variability between the right caudal hippocampus and the left STG. BD with SA had significantly higher scores of Hypochondriasis, Depression, and Schizophrenia than non-SA BD. Additionally, multivariable regression analysis revealed the interaction of ACTH × dFC variability between the right caudal hippocampus and the left STG independently predicted MMPI-2 score (depression evaluation) in suicidal BD patients. CONCLUSION: These results suggested that suicidal BD exhibited increased dFC variability of hippocampal-temporal cortex and less HPA axis hyperactivity, which may affect their personality traits.

Association Study between SNPs in MST1 and MST2 and H. pylori Infection as well as Noncardia Gastric Carcinogenesis.

INTRODUCTION: Gastric cancer (GC) remains a global health challenge, and H. pylori infection is a main risk factor for noncardia GC. The present study aimed to investigate the association between single nucleotide polymorphisms (SNPs) in mammalian sterile 20-like kinase 1 (MST1) and MST2, H. pylori (H. pylori) infection, and the risk of noncardia gastric cancer (GC). METHODS: A case-control study was conducted using enzyme-linked immunosorbent assay (ELISA) and TaqMan method to detect the titer of anti-H. pylori antibody in normal human serum and genotype 9 SNPs of MST1 and MST2 genes among 808 samples. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between SNPs and H. pylori infection, as well as the risk of noncardia gastric cancer in codominant, dominant, overdominant, recessive, and log-additive genetic models. Haplotypes were constructed using the Haploview 4.2 software. RESULTS: The CC genotype of MST2 SNP rs10955176 was associated with a reduced risk of H. pylori infection compared to the TT + CT genotype. None of other SNPs were associated with H. pylori infection. The TT genotype of MST2 SNP rs7827435 was associated with a reduced risk of noncardia gastric cancer compared to the AA + AT genotype. None of the SNPs were associated with noncardia gastric cancer. There were no associations between haplotypes and H. pylori infection or the risk of noncardia gastric cancer. CONCLUSIONS: The CC genotype of rs10955176 and the TT genotype of rs7827435 may serve as protective factors against H. pylori infection and noncardia gastric cancer risk, respectively.

Sex-differential cognitive performance on MCCB of youth with BD-II depression.

BACKGROUND: Recent evidences have shown sex-differential cognitive deficits in bipolar disorder (BD) and differences in cognitions across BD subtypes. However, the sex-specific effect on cognitive impairment in BD subtype II (BD-II) remains obscure. The aim of the current study was to examine whether cognitive deficits differ by gender in youth with BD-II depression. METHOD: This cross-sectional study recruited 125 unmedicated youths with BD-II depression and 140 age-, sex-, and education-matched healthy controls (HCs). The Chinese version of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) was used to assess cognitive functions. Mood state was assessed using the 24-item Hamilton Depression Rating Scale (24-HDRS) and the Young Mania Rating Scale (YMRS). Multivariate analysis of covariance (MANCOVA) was conducted. RESULT: ​Compared with HCs, patients with BD-II depression had lower scores on MCCB composite and its seven cognitive domains (all p < 0.001). After controlling for age and education, MANCOVA revealed significant gender-by-group interaction on attention/vigilance (F = 6.224, df = 1, p = 0.013), verbal learning (F = 9.847, df = 1, p = 0.002), visual learning (F = 4.242, df = 1, p = 0.040), and composite (F = 8.819, df = 1, p = 0.003). Post hoc analyses suggested that males performed worse in the above-mentioned MCCB tests than females in BD-II depression. CONCLUSION: Our study demonstrated generalized cognitive deficits in unmedicated youths with BD-II depression. Male patients performed more serious cognitive impairment on attention/vigilance, verbal learning, and visual learning compared to female patients.

Alterations of insular dynamic functional connectivity and psychological characteristics in unmedicated bipolar depression patients with a recent suicide attempt.

BACKGROUND: Mounting evidence showed that insula contributed to the neurobiological mechanism of suicidal behaviors in bipolar disorder (BD). However, no studies have analyzed the dynamic functional connectivity (dFC) of insular Mubregions and its association with personality traits in BD with suicidal behaviors. Therefore, we investigated the alterations of dFC variability in insular subregions and personality characteristics in BD patients with a recent suicide attempt (SA). METHODS: Thirty unmedicated BD patients with SA, 38 patients without SA (NSA) and 35 demographically matched healthy controls (HCs) were included. The sliding-window analysis was used to evaluate whole-brain dFC for each insular subregion seed. We assessed between-group differences of psychological characteristics on the Minnesota Multiphasic Personality Inventory-2. Finally, a multivariate regression model was adopted to predict the severity of suicidality. RESULTS: Compared to NSA and HCs, the SA group exhibited decreased dFC variability values between the left dorsal anterior insula and the left anterior cerebellum. These dFC variability values could also be utilized to predict the severity of suicidality (r = 0.456, p = 0.031), while static functional connectivity values were not appropriate for this prediction. Besides, the SA group scored significantly higher on the schizophrenia clinical scales (p < 0.001) compared with the NSA group. CONCLUSIONS: Our findings indicated that the dysfunction of insula-cerebellum connectivity may underlie the neural basis of SA in BD patients, and highlighted the dFC variability values could be considered a neuromarker for predictive models of the severity of suicidality. Moreover, the psychiatric features may increase the vulnerability of suicidal behavior.

Abnormal dynamic functional connectivity of hippocampal subregions associated with working memory impairment in melancholic depression.

BACKGROUND: Previous studies have demonstrated structural and functional changes of the hippocampus in patients with major depressive disorder (MDD). However, no studies have analyzed the dynamic functional connectivity (dFC) of hippocampal subregions in melancholic MDD. We aimed to reveal the patterns for dFC variability in hippocampus subregions - including the bilateral rostral and caudal areas and its associations with cognitive impairment in melancholic MDD. METHODS: Forty-two treatment-naive MDD patients with melancholic features and 55 demographically matched healthy controls were included. The sliding-window analysis was used to evaluate whole-brain dFC for each hippocampal subregions seed. We assessed between-group differences in the dFC variability values of each hippocampal subregion in the whole brain and cognitive performance on the MATRICS Consensus Cognitive Battery (MCCB). Finally, association analysis was conducted to investigate their relationships. RESULTS: Patients with melancholic MDD showed decreased dFC variability between the left rostral hippocampus and left anterior lobe of cerebellum compared with healthy controls (voxel p < 0.005, cluster p < 0.0125, GRF corrected), and poorer cognitive scores in working memory, verbal learning, visual learning, and social cognition (all p < 0.05). Association analysis showed that working memory was positively correlated with the dFC variability values of the left rostral hippocampus-left anterior lobe of the cerebellum (r = 0.338, p = 0.029) in melancholic MDD. CONCLUSIONS: These findings confirmed the distinct dynamic functional pathway of hippocampal subregions in patients with melancholic MDD, and suggested that the dysfunction of hippocampus-cerebellum connectivity may be underlying the neural substrate of working memory impairment in melancholic MDD.

Neural mechanism underlying the beneficial effect of Theory of Mind psychotherapy on early-onset schizophrenia: a randomized controlled trial.

BACKGROUND: Psychosocial interventions have emerged as an important component of a comprehensive therapeutic approach in early-onset schizophrenia, typically representing a more severe form of the disorder. Despite the feasibility and efficacy of Theory of Mind (ToM) psychotherapy for schizophrenia, relatively little is known regarding the neural mechanism underlying its effect on early-onset schizophrenia. METHODS: We performed a randomized, active controlled trial in patients with early-onset schizophrenia, who were randomly allocated into either an intervention (ToM psychotherapy) or an active control (health education) group. Diffusion tensor imaging data were collected to construct brain structural networks, with both global and regional topological properties measured using graph theory. RESULTS: We enrolled 28 patients with early-onset schizophrenia in our study. After 5 weeks of treatment, both the intervention and active control groups showed significant improvement in psychotic symptoms, yet the improvement was greater in the intervention group. Importantly, in contrast with no brain structural network change after treatment in the active control group, the intervention group showed increased nodal centrality of the left insula that was associated with psychotic symptom improvement. LIMITATIONS: We did not collect important information concerning the participants' cognitive abilities, particularly ToM performance. CONCLUSION: These findings suggest a potential neural mechanism by which ToM psychotherapy exerts a beneficial effect on early-onset schizophrenia via strengthening the coordination capacity of the insula in brain structural networks, which may provide a clinically translatable biomarker for monitoring or predicting responses to ToM psychotherapy.Clinical trial registration: NCT05577338; ClinicalTrials.gov.

Association between serum copper, zinc, and selenium concentrations and depressive symptoms in the US adult population, NHANES (2011-2016).

BACKGROUND: Evidence suggests that alterations in serum trace element concentrations are closely associated with mental illness. However, ​studies on the relationship between serum copper, zinc, and selenium concentrations and depressive symptoms are limited and with controversial results. We aimed to investigate the association between serum concentrations of these trace elements and depressive symptoms in US adults. METHODS: Data from the National Health and Nutrition Examination Survey (NHANES) (2011-2016) were used in this cross-sectional study. The Patient Health Questionnaire-9 Items (PHQ-9) was employed to assess depressive symptoms. Multiple logistic regression was performed to determine the relationship between the serum concentrations of copper, zinc, and selenium and depressive symptoms. RESULTS: A total of 4552 adults were included. Subjects with depressive symptoms had higher serum copper concentrations (123.88 ± 1.87) than those without depressive symptoms (116.99 ± 0.86) (p < 0.001). In Model 2, weighted logistic regression analysis showed that the second (Q2) quartile of zinc concentrations (odds ratio [OR] = 1.534, 95% confident interval [CI]: 1.018 to 2.313) were significantly associated with an increased risk of depressive symptoms. Subgroup analysis revealed that the third (Q3) and fourth (Q4) quartiles of copper concentrations (Q3: OR = 2.699, 95% CI: 1.285 to 5.667; Q4: OR = 2.490, 95% CI: 1.026 to 6.046) were also positively associated with depressive symptoms in obese individuals after controlling for all confounders. However, no significant relationship between serum selenium concentrations and depressive symptoms was observed. CONCLUSIONS: Obese US adults with high serum copper concentrations, as well as US adults in general with low serum zinc concentrations, were susceptible to depressive symptoms. Nevertheless, the causal mechanisms underlying these relationships need to be further explored.

Shared and specific patterns of dynamic functional connectivity variability of striato-cortical circuitry in unmedicated bipolar and major depressive disorders.

BACKGROUND: Accumulating studies have found structural and functional abnormalities of the striatum in bipolar disorder (BD) and major depressive disorder (MDD). However, changes in intrinsic brain functional connectivity dynamics of striato-cortical circuitry have not been investigated in BD and MDD. This study aimed to investigate the shared and specific patterns of dynamic functional connectivity (dFC) variability of striato-cortical circuitry in BD and MDD. METHODS: Brain resting-state functional magnetic resonance imaging data were acquired from 128 patients with unmedicated BD II (current episode depressed), 140 patients with unmedicated MDD, and 132 healthy controls (HCs). Six pairs of striatum seed regions were selected: the ventral striatum inferior (VSi) and the ventral striatum superior (VSs), the dorsal-caudal putamen (DCP), the dorsal-rostral putamen (DRP), and the dorsal caudate and the ventral-rostral putamen (VRP). The sliding-window analysis was used to evaluate dFC for each seed. RESULTS: Both BD II and MDD exhibited increased dFC variability between the left DRP and the left supplementary motor area, and between the right VRP and the right inferior parietal lobule. The BD II had specific increased dFC variability between the right DCP and the left precentral gyrus compared with MDD and HCs. The MDD had increased dFC variability between the left VSi and the left medial prefrontal cortex compared with BD II and HCs. CONCLUSIONS: The patients with BD and MDD shared common dFC alteration in the dorsal striatal-sensorimotor and ventral striatal-cognitive circuitries. The patients with MDD had specific dFC alteration in the ventral striatal-affective circuitry.

Variation in Thyroid-Stimulating Hormone and Cognitive Disorders in Unmedicated Middle-Aged Patients with Major Depressive Disorder: A Proton Magnetic Resonance Spectroscopy Study.

Background: Middle-aged (45-59 years old) patients with major depressive disorder (MDD) have a predilection for dementia and cognitive disorders (CDs); however, the characteristics and mechanisms of CDs in these patients remain unclear. There are also known connections between thyroid-stimulating hormone (TSH), brain biochemical metabolism, and cognitive function (CF); however, there is scanty of information about these connections in middle-aged MDD patients. Methods: Cognitive assessment was performed on 30 first-episode, untreated middle-aged patients with MDD and 30 well-matched healthy controls (HCs) using the MATRICS Consensus Cognitive Battery (MCCB). N-acetyl aspartate (NAA)/creatine (Cr) and choline (Cho)/Cr ratios in the prefrontal cortex (PFC) and cerebellum were also obtained via proton magnetic resonance spectroscopy (1H-MRS), and the TSH level was measured by chemiluminescence analysis. Results: MDD patients presented significantly lower processing speed, working memory, verbal learning, reasoning problem-solving, visual learning, and composite cognition scores than controls, with a statistically lower NAA/Cr ratio in the right cerebellum. Age was positively related to reasoning problem-solving in the MDD group (r = 0.6249, p = 0.0220). Education also showed a positive association with visual learning, social cognition, and composite cognition. The 24-item Hamilton Depression Rating Scale (HDRS-24) score was negatively related to all domains of CF. TSH levels were markedly decreased in the MDD group, and a positive connection was determined between the NAA/Cr ratio in the right PFC and the TSH level. Conclusions: Middle-aged MDD patients have multidimensional CDs. There are changes in PFC and cerebellar biochemical metabolism in middle-aged patients with MDD, which may be related to CDs or altered TSH levels.

Inflammation is correlated with abnormal functional connectivity in unmedicated bipolar depression: an independent component analysis study of resting-state fMRI.

BACKGROUND: Inflammation might play a role in bipolar disorder (BD), but it remains unclear the relationship between inflammation and brain structural and functional abnormalities in patients with BD. In this study, we focused on the alterations of functional connectivity (FC), peripheral pro-inflammatory cytokines and their correlations to investigate the role of inflammation in FC in BD depression. METHODS: In this study, 42 unmedicated patients with BD II depression and 62 healthy controls (HCs) were enrolled. Resting-state-functional magnetic resonance imaging was performed in all participants and independent component analysis was used. Serum levels of Interleukin-6 (IL-6) and Interleukin-8 (IL-8) were measured in all participants. Correlation between FC values and IL-6 and IL-8 levels in BD was calculated. RESULTS: Compared with the HCs, BD II patients showed decreased FC in the left orbitofrontal cortex (OFC) implicating the limbic network and the right precentral gyrus implicating the somatomotor network. BD II showed increased IL-6 (p = 0.039), IL-8 (p = 0.002) levels. Moreover, abnormal FC in the right precentral gyrus were inversely correlated with the IL-8 (r = -0.458, p = 0.004) levels in BD II. No significant correlation was found between FC in the left OFC and cytokines levels. CONCLUSIONS: Our findings that serum IL-8 levels are associated with impaired FC in the right precentral gyrus in BD II patients suggest that inflammation might play a crucial role in brain functional abnormalities in BD.

Long non-coding RNA HNF1A-AS1 upregulates OTX1 to enhance angiogenesis in colon cancer via the binding of transcription factor PBX3.

Colon cancer shows characteristics of metastasis, which is associated with angiogenesis. Increasing evidence highlights long non-coding RNAs (lncRNAs) as important participants in angiogenesis of cancers, including colon cancer. Hence, this study investigated the role of HNF1A-AS1 in angiogenesis of colon cancer. RT-qPCR and Western blot analysis were applied to detect HNF1A-AS1 and OTX1 expression in colon cancer tissues and cell lines. Then the interactions among HNF1A-AS1, PBX3, OTX1 and ERK/MAPK pathway were evaluated with RNA pull-down, RIP, ChIP and dual-luciferase reporter gene assays. Next, HCT116 and SW620 cells were treated with si-HNF1A-AS1 and/or oe-OTX1 plasmids to assess the effects of HNF1A-AS1 and OTX1 on angiogenesis, which was further evaluated in nude mice injected with SW620 cells transfected with sh-HNF1A-AS1 or sh-OTX1 lentivirus. HNF1A-AS1 and OTX1 were highly expressed in colon cancer. Silencing of HNF1A-AS1 inhibited angiogenesis of colon cancer in vivo and in vitro. HNF1A-AS1 increased the OTX1 expression by binding to transcription factor PBX3 to promote angiogenesis in colon cancer. Further, HNF1A-AS1 upregulated OTX1 to activate the ERK/MAPK pathway. Altogether, our findings identified HNF1A-AS1 as a tumor-promoting RNA in colon cancer, which could serve as a potential therapeutic target for colon cancer treatment.

Long non-coding RNA LINC00858 inhibits colon cancer cell apoptosis, autophagy, and senescence by activating WNK2 promoter methylation.

Accumulating evidence shows the involvement of long non-coding RNAs (lncRNAs) in tumorigenesis of many types of human cancers. However, the role of LINC00858 in colon cancer has not been fully elucidated. Therefore, we investigated the involvement of LINC00858 in the progression of colon cancer and identified its downstream targets. After examining the expression of LINC00858 in colon cancer tissues and cell lines, we then identified the possible interaction between LINC00858 and WNK lysine deficient protein kinase 2 (WNK2) by fluorescence in situ hybridization, RNA immunoprecipitation, chromatin immunoprecipitation, and RNA pull-down assays. Next, the role of the LINC00858/WNK2 axis was explored by evaluating the apoptosis, autophagy, and senescence of colon cancer cells in vitro after ectopic expression and depletion experiments in HCT116 cells. Moreover, a mouse xenograft model of HCT116 cells was established to verify the function of the LINC00858/WNK2 axis in vivo. There was high expression of LINC00858 and low expression of WNK2 in colon cancer tissues and cell lines. Silencing of LINC00858 promoted apoptosis, senescence, and autophagy in colon cancer cells. Additionally, the enrichment of WNK2 was promoted when LINC00858 bound to DNA methyltransferases. Furthermore, in vivo assays demonstrated that silencing of LINC00858 resulted in inhibited tumor growth by upregulating WNK2. In summary, LINC00858 acts as a tumor-promoting lncRNA in colon cancer by downregulating WNK2. Our results may provide novel targets for the treatment for colon cancer.

Classification of Unmedicated Bipolar Disorder Using Whole-Brain Functional Activity and Connectivity: A Radiomics Analysis.

The aim of this study was to develop and validate a method of disease classification for bipolar disorder (BD) by functional activity and connectivity using radiomics analysis. Ninety patients with unmedicated BD II as well as 117 healthy controls underwent resting-state functional magnetic resonance imaging (rs-fMRI). A total of 4 types of 7018 features were extracted after preprocessing, including mean regional homogeneity (mReHo), mean amplitude of low-frequency fluctuation (mALFF), resting-state functional connectivity (RSFC), and voxel-mirrored homotopic connectivity (VMHC). Then, predictive features were selected by Mann-Whitney U test and removing variables with a high correlation. Least absolute shrinkage and selection operator (LASSO) method was further used to select features. At last, support vector machine (SVM) model was used to estimate the state of each subject based on the selected features after LASSO. Sixty-five features including 54 RSFCs, 7 mALFFs, 1 mReHo, and 3 VMHCs were selected. The accuracy and area under curve (AUC) of the SVM model built based on the 65 features is 87.3% and 0.919 in the training dataset, respectively, and the accuracy and AUC of this model validated in the validation dataset is 80.5% and 0.838, respectively. These findings demonstrate a valid radiomics approach by rs-fMRI can identify BD individuals from healthy controls with a high classification accuracy, providing the potential adjunctive approach to clinical diagnostic systems.

Differences in verbal and spatial working memory in patients with bipolar II and unipolar depression: an MSI study.

BACKGROUND: Depressive symptoms could be similarly expressed in bipolar and unipolar disorder. However, changes in cognition and brain networks might be quite distinct. We aimed to find out the difference in the neural mechanism of impaired working memory in patients with bipolar and unipolar disorder. METHOD: According to diagnostic criteria of bipolar II disorder of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and assessments, 13 bipolar II depression (BP II), 8 unipolar depression (UD) patients and 15 healthy controls (HC) were recruited in the study. We used 2-back tasks and magnetic source imaging (MSI) to test working memory functions and get the brain reactions of the participants. RESULTS: Compared with HC, only spatial working memory tasks accuracy was significantly worse in both UD and BP II (p = 0.001). Pearson correlation showed that the stronger the FCs' strength of MFG-IPL and IPL-preSMA, the higher accuracy of SWM task within left FPN in patients with UD (r = 0.860, p = 0.006; r = 0.752, p = 0.031). However, the FC strength of IFG-IPL was negatively correlated with the accuracy of SWM task within left FPN in patients with BP II (r = - 0.591, p = 0.033). CONCLUSIONS: Our study showed that the spatial working memory of patients with whether UD or BP II was impaired. The patterns of FCs within these two groups of patients were different when performing working memory tasks.

[Advances in Imaging Genetics of Suicidal Behavior].

Suicide,a major public health problem,is the death caused by injuring oneself with the intent to die.In this paper,we reviewed the genes encoding serotonin system,calcium voltage-gated channel subunit alpha1 C,γ-aminobutyric acid,and spindle and kinetochore associated complex subunit 2,as well as their related brain regions,from the perspective of imaging genetics,aiming to provide new ideas for the research and intervention on suicidal behavior.

Correlations Among mRNA Expression Levels of ATP7A, Serum Ceruloplasmin Levels, and Neuronal Metabolism in Unmedicated Major Depressive Disorder.

BACKGROUND: Previous studies have found that elevated copper levels induce oxidation, which correlates with the occurrence of major depressive disorder (MDD). However, the mechanism of abnormal cerebral metabolism of MDD patients remains ambiguous. The main function of the enzyme ATPase copper-transporting alpha (ATP7A) is to transport copper across the membrane to retain copper homeostasis, which is closely associated with the onset of mental disorders and cognitive impairment. However, less is known regarding the association of ATP7A expression in MDD patients. METHODS: A total of 31 MDD patients and 21 healthy controls were recruited in the present study. Proton magnetic resonance spectroscopy was used to assess the concentration levels of N-acetylaspartate, choline (Cho), and creatine (Cr) in brain regions of interest, including prefrontal white matter (PWM), anterior cingulate cortex (ACC), thalamus, lentiform nucleus, and cerebellum. The mRNA expression levels of ATP7A were measured using polymerase chain reaction (SYBR Green method). The correlations between mRNA expression levels of ATP7A and/or ceruloplasmin levels and neuronal biochemical metabolite ratio in the brain regions of interest were evaluated. RESULTS: The decline in the mRNA expression levels of ATP7A and the increase in ceruloplasmin levels exhibited a significant correlation in MDD patients. In addition, negative correlations were noted between the decline in mRNA expression levels of ATP7A and the increased Cho/Cr ratios of the left PWM, right PWM, and right ACC in MDD patients. A positive correlation between elevated ceruloplasmin levels and increased Cho/Cr ratio of the left PWM was noted in MDD patients. CONCLUSIONS: The findings suggested that the decline in the mRNA expression levels of ATP7A and the elevated ceruloplasmin levels induced oxidation that led to the disturbance of neuronal metabolism in the brain, which played important roles in the pathophysiology of MDD. The decline in the mRNA expression levels of ATP7A and the elevated ceruloplasmin levels affected neuronal membrane metabolic impairment in the left PWM, right PWM, and right ACC of MDD patients.

Abnormal dynamic functional network connectivity in unmedicated bipolar and major depressive disorders based on the triple-network model.

BACKGROUND: Previous studies have analyzed brain functional connectivity to reveal the neural physiopathology of bipolar disorder (BD) and major depressive disorder (MDD) based on the triple-network model [involving the salience network, default mode network (DMN), and central executive network (CEN)]. However, most studies assumed that the brain intrinsic fluctuations throughout the entire scan are static. Thus, we aimed to reveal the dynamic functional network connectivity (dFNC) in the triple networks of BD and MDD. METHODS: We collected resting state fMRI data from 51 unmedicated depressed BD II patients, 51 unmedicated depressed MDD patients, and 52 healthy controls. We analyzed the dFNC by using an independent component analysis, sliding window correlation and k-means clustering, and used the parameters of dFNC state properties and dFNC variability for group comparisons. RESULTS: The dFNC within the triple networks could be clustered into four configuration states, three of them showing dense connections (States 1, 2, and 4) and the other one showing sparse connections (State 3). Both BD and MDD patients spent more time in State 3 and showed decreased dFNC variability between posterior DMN and right CEN (rCEN) compared with controls. The MDD patients showed specific decreased dFNC variability between anterior DMN and rCEN compared with controls. CONCLUSIONS: This study revealed more common but less specific dFNC alterations within the triple networks in unmedicated depressed BD II and MDD patients, which indicated their decreased information processing and communication ability and may help us to understand their abnormal affective and cognitive functions clinically.

Inflammation is associated with decreased functional connectivity of insula in unmedicated bipolar disorder.

BACKGROUND: Systemic inflammation and immune dysregulation have been considered as risk factors in the pathophysiology of mood disorders including bipolar disorder (BD). Previous neuroimaging studies have demonstrated metabolic, structural and functional abnormalities in the insula in BD, proposed that the insula played an important role in BD. We herein aimed to explore neural mechanisms underlying inflammation-induced in the insular subregions functional connectivity (FC) in patients with BD. METHODS: Brain resting-state functional magnetic resonance imaging (rs-fMRI) data were acquired from 41 patients with unmedicated BD II (current episode depressed), 68 healthy controls (HCs). Three pairs of insular seed regions were selected: the bilateral anterior insula (AI), the bilateral middle insula (MI) and the bilateral posterior insula (PI), and calculated the whole-brain FC for each subregion. Additionally, the serum levels of pro-inflammatory cytokines in patients and HCs, including IL-6 and TNF-α, were detected. Then the partial correlation coefficients between the abnormal insular subregions FC values and pro-inflammatory cytokines levels in patients with BD II depression were calculated. RESULTS: The BD II depression group exhibited decreased FC between the right PI and the left postcentral gyrus, and increased FC between the left AI and the bilateral insula (extended to the right putamen) when compared with the HC group. Moreover, the patients with BD II depression showed higher IL-6 and TNF-α levels than HCs, and IL-6 level was negatively correlated with FC of the right PI to the left postcentral gyrus. CONCLUSIONS: Our results demonstrated that abnormal FC between the bilateral insula, and between the insula and sensorimotor areas in BD. Moreover, disrupted FC between the insula and sensorimotor areas was associated with elevated pro-inflammatory cytokine levels of IL-6 in BD.

Association analysis between SNPs in LATS1 and LATS2 and non-cardia gastric cancer.

BACKGROUND: Many studies have found that large tumor suppressor kinase 1 (LATS1) and LATS2 play important roles in many diseases, but studies have been rare on the relationship between these genes and non-cardia gastric cancer (GC). We performed a case-control association study to investigate the associations between single nucleotide polymorphisms (SNPs) in LATS1 and LATS2 genes and Helicobacter pylori (H. pylori) infection as well as the risk of non-cardia GC. METHODS: First, H. pylori infection was determined by the serological test using enzyme-linked immunoassay. Then genotyping of SNPs was performed for 808 samples by the Taqman method. Finally, unconditional logistic regression was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for age and gender, for the association of each SNP with the infection of H. pylori, the risk of non-cardia gastric cancer, as well as the expression of LATS1 and LATS2 proteins in non-cardia GC tissues, using the codominant, dominant, recessive, overdominant, and log-additive inheritance models, respectively. RESULTS: The statistical results showed that LATS2 rs9552315 was associated with H. pylori infection, and the CC + CT genotype could reduce the risk of H. pylori infection (odds ratio [OR]: 0.549, 95% confidence interval [CI]: 0.339-0.881, P < 0.05) compared with the TT genotype in a dominant model. LATS1 rs9393175 was associated with the risk of non-cardia GC, and the AG genotype reduced the risk of non-cardia GC (OR: 0.702, 95% CI: 0.516-0.952, P < 0.05) compared with the GG + AA genotype in an overdominant model. LATS2 rs9509492 was associated with the risk of GC in an log-additive model. No associations were found between five SNPs and expression of LATS1 and LATS2 proteins in non-cardia GC tissue. CONCLUSIONS: LATS2 rs9552315 CT genotype may be a protective factor against infection of H. pylori. LATS1 rs9393175 AG genotype and LATS2 rs9509492 GG genotype may be protective factors for non-cardia GC.

Alleviation of cognitive deficits and high copper levels by an NMDA receptor antagonist in a rat depression model.

BACKGROUND: Major depressive disorder (MDD) is frequently associated with cognitive deficits and high copper levels. Dysfunction of N-methyl-d-aspartate (NMDA) receptors has been postulated to underlie MDD pathogenesis. This study sought to investigate the curative effect of the NMDA receptor antagonist memantine on cognitive deficits in depression and the underlying mechanisms. METHODS: Adult male Sprague-Dawley rats received corticosterone (CORT) (20 mg/kg) bi-weekly via subcutaneous injection and/or copper gluconate (7 mg/kg) via daily intragastric administration. After 3 weeks, sucrose preference tests and open field tests showed anhedonia and high anxiety in both the CORT and CORT+Cu groups. Memantine intervention (20 mg/kg daily via intragastric administration for 14 days) led to recovery of anhedonia and anxiety behaviors. Memantine also remarkably suppressed serum copper ion levels. Moreover, memantine treatment effectively rescued depression-related spatial memory deficits as shown by the Morris water maze task. RESULTS: Compared to the pre-memantine treatment results, the results of behavioral tests and cognitive function after memantine treatment were significantly normalized, and the copper concentration was decreased in all groups. CONCLUSIONS: Collectively, our findings suggest that the NMDA receptor antagonist memantine may improve symptoms of anhedonia and anxiety and the cognitive deficits associated with depression, likely be related to suppress serum copper ion levels.