Early-onset mental disorders are associated with disrupted neurodevelopmental processes during adolescence.The methylazoxymethanol acetate(MAM)animal model,in which disruption in neurodevelopmental processes is induce...Early-onset mental disorders are associated with disrupted neurodevelopmental processes during adolescence.The methylazoxymethanol acetate(MAM)animal model,in which disruption in neurodevelopmental processes is induced,mimics the abnormal neurodevelopment associated with early-onset mental disorders from an etiological perspective.We conducted longitudinal structural magnetic resonance imaging(MRI)scans during childhood,adolescence,and adulthood in MAM rats to identify specific brain regions and critical windows for intervention.Then,the effect of repetitive transcranial magnetic stimulation(rTMS)intervention on the target brain region during the critical window was investigated.In addition,the efficacy of this intervention paradigm was tested in a group of adolescent patients with early-onset mental disorders(diagnosed with major depressive disorder or bipolar disorder)to evaluate its clinical translational potential.The results demonstrated that,compared to the control group,the MAM rats exhibited significantly lower striatal volume from childhood to adulthood(all P<0.001).In contrast,the volume of the hippocampus did not show significant differences during childhood(P>0.05)but was significantly lower than the control group from adolescence to adulthood(both P<0.001).Subsequently,rTMS was applied to the occipital cortex,which is anatomically connected to the hippocampus,in the MAM models during adolescence.The MAM-rTMS group showed a significant increase in hippocampal volume compared to the MAM-sham group(P<0.01),while the volume of the striatum remained unchanged(P>0.05).In the clinical trial,adolescents with early-onset mental disorders showed a significant increase in hippocampal volume after rTMS treatment compared to baseline(P<0.01),and these volumetric changes were associated with improvement in depressive symptoms(r=−0.524,P=0.018).These findings highlight the potential of targeting aberrant hippocampal development during adolescence as a viable intervention for earlyonset mental disorders with neurodevelopmental etiology as well as the promise of rTMS as a therapeutic approach for mitigating aberrant neurodevelopmental processes and alleviating clinical symptoms.展开更多
We read Winter et al.’s recent article published in JAMA Psychiatry with strong interest[1].Despite that their systematical evaluations on machine learning-based approach were incapable of identifying multivariate ne...We read Winter et al.’s recent article published in JAMA Psychiatry with strong interest[1].Despite that their systematical evaluations on machine learning-based approach were incapable of identifying multivariate neuroimaging biomarker for major depressive disorder(MDD),we argue that achieving no biomarker does not necessarily equate to their non-existence.Rather than dwelling on howWinter et al.’s study should be optimized,however,the focal point in the current psychiatric context might primarily revolve around the utilization of neuroimaging in the absence of diagnostic biomarkers,the justification for such warrants,and how current findings could be effectively translated into clinical applications for MDD.展开更多
Introduction:Non-suicidal self-injury(NSSI)has become increasingly prevalent among adolescents,representing a significant public health concern with profound impacts on both physical and mental wellbeing.This study ai...Introduction:Non-suicidal self-injury(NSSI)has become increasingly prevalent among adolescents,representing a significant public health concern with profound impacts on both physical and mental wellbeing.This study aims to determine the prevalence of NSSI among adolescents in Jiangsu Province and develop a prediction model to facilitate early identification and intervention.Methods:This study is based on the“School-based Evaluation and Response to Child Health(SEARCH)”project.A cross-sectional survey was conducted among students from 11 schools in Jiangsu Province,China in 2023.Following data cleaning,11,427 students were included in the analysis.Machine learning methods were employed to establish a risk prediction model for NSSI among adolescents.Results:The prevalence of NSSI among adolescents aged 10–18 was 12.72%.Eight key predictors of NSSI were identified:insomnia,emotional symptoms,cohesion of family environment,history of drinking alcohol,gender,conflict of family environment,conduct problems,and academic level.The XGBoost model demonstrated an area under the curve(AUC)of 0.800[95%confidence interval(CI):0.776,0.823]and an accuracy(ACC)of 0.886 in the testing set.Conclusions:This study underscores the importance of personalized prevention strategies for NSSI and highlights the necessity of implementing comprehensive behavioral interventions,including mental health support,sleep quality enhancement,and cultivation of supportive family environments.展开更多
Background： Valproic acid （VPA） exposure during pregnancy has been proven to contribute to congenital heart disease （CHD）. Our previous findings implied that disruption of planar cell polarity （PCP） signaling p...Background： Valproic acid （VPA） exposure during pregnancy has been proven to contribute to congenital heart disease （CHD）. Our previous findings implied that disruption of planar cell polarity （PCP） signaling pathway in cardiomyocytes might be a factor for the cardiac teratogenesis of VPA. In addition, the teratogenic ability of VPA is positively correlated to its histone deacetylase （HDAC） inhibition activity. This study aimed to investigate the effect of the VPA on cardiac morphogenesis, HDAC1/2/3, and PCP key genes （Vangl2/Scrib/Rac 1）, subsequently screening out the specific HDACs regulating PCP pathway. Methods： VPA was administered to pregnant C57BL mice at 700 mg/kg intraperitoneally on embryonic day ! 0.5. Dams were sacrificed on E15.5, and death/absorption rates of embryos were evaluated. Embryonic hearts were observed by hematoxylin-eosin staining to identify cardiac abnormalities. H9C2 cells （undifferentiated rat cardiomyoblasts） were transfected with Hdac1/2/3 specific small interfering RNA （siRNA）. Based on the results of siRNA transfection, cells were transfected with Hdac3 expression plasmid and subsequently mock-treated or treated with 8.0 mmol/L VPA. Hdac1/2/3 as well as Vangl2/Scrib/Racl mRNA and protein levels were determined by real-time quantitative polymerase chain reaction and Western blotting, respectively. Total HDAC activity was detected by colorimetric assay.Results： VPA could induce CHD （P 〈 0.001） and inhibit mRNA or protein expression of Hdac1/2/3 as well as Vangl2/Scrib in fetal hearts, in association with total Hdac activity repression （all P 〈 0.05）. In vitro, Hdac3 inhibition could significantly decrease Vangl2/Scrib expression （P 〈 0.01 ）, while knockdown of Hdac 1/2 had no influence （P 〉 0.05）, VPA exposure dramatically decreased the expression of Vanlg2/Scrib together with Hdac activity （P 〈 0.01 ）, while overexpression of Hdac3 could rescue the VPA-induced inhibition （P 〉 0.05）. Conclusion： VPA could inhibit Hdac1/2/3, Vang12/Scrib, or total Hdac activity both in vitro and in vivo and Hdac3 might participate in the process of VPA-induced cardiac developmental anomalies.展开更多
Background： Placental multidrug resistance-associated protein 2 （MRP2）, encoded by ABCC2 gene in human, plays a significant role in regulating drugs＇ transplacental transfer rates. Studies o11 placental MRP2 regul...Background： Placental multidrug resistance-associated protein 2 （MRP2）, encoded by ABCC2 gene in human, plays a significant role in regulating drugs＇ transplacental transfer rates. Studies o11 placental MRP2 regulation could provide more therapeutic targets for individualized and safe pharmacotherapy during pregnancy. Currently, the roles of epigenetic mechanisms in regulating placental drug transporters are still unclear. This study aimed to investigate the effect of histone deacetylases （HDACs） inhibition on MRP2 expression in the placental trophoblast cell line and to explore whether HDAC 1/2/3 are preliminarily involved in this process. Methods： The human choriocarcinoma-derived trophoblast cell line （Bewo cells） was treated with the HDAC inhibitors-trichostatin A （TSA） at different concentration gradients of 0.5, 1.0, 3.0, and 5.0 μmol/L. Cells were harvested after 24 and 48 h treatment. Small interfering RNA （siRNA） specific for HDACI/HDAC2/HDAC3 or control siRNA was transfected into cells. Total HDAC activity was detected by colorimetric assay kits. HDAC 1/2/3/ABCC2 messenger RNA （mRNA） and protein expressions were determined by real-time quantitative polymerase chain reaction and Western-blot analysis, respectively. Immunofluorescence for MRP2 protein expression was visualized and assessed using an immunofluorescence microscopy and ImageJ software, respectively. Results： TSA could inhibit total HDAC activity and HDAC 1/2/3 expression in company with increase ofM RP2 expression in Bewo cells. Reduction of HDAC 1 protein level was noted after 24 h of TSA incubation at 1.0, 3.0, and 5.0 μmol/L （vs. vehicle group, all P 〈 0.001 ）, accompanied with dose-dependent induction of MRP2 expression （P = 0.045 for 1.0 μmol/L, P = 0.001 for 3.0 μmol/L, and P 〈 0.001 for 5.0 μmol/L）, whereas no significant diferences in MRP2 expression were noted after HDAC2/3 silencing. Fluorescent micrograph images of MRP2 protein were expressed on the cell membrane. The fluorescent intensities of MRP2 in the control, HDAC2, and HDAC3 siRNA-transfected cells weir week, and no significant differences were noticed among these three groups （all P 〉 0.05）. However, MRP2 expression was remarkably elevated in H DAC1 siRNA-transfected cells, which displayed an almost 3.19-fold changes in comparison with the control siRNA-transfected cells （P 〈 0.001 ）. Conclusions： HDACs inhibition could up-regulate placental MRP2 expression in ritzy, and HDAC 1 was probably to be involved in this process.展开更多
Summary What is already known about this topic?Mental health issues in Chinese children and adolescents have emerged as a substantial public health concern,causing distress and strain among families and society.What i...Summary What is already known about this topic?Mental health issues in Chinese children and adolescents have emerged as a substantial public health concern,causing distress and strain among families and society.What is added by this report?This study examines the effects of gender and school grade on mental health symptoms and risky behaviors among Chinese children and adolescents,with a particular focus on the role of family and school environments.展开更多
The prefrontal cortex(PFC)is a critical non-invasive brain stimulation(NIBS)target for treating depression.However,the alterations of brain activations post-intervention remain inconsistent and the clinical moderators...The prefrontal cortex(PFC)is a critical non-invasive brain stimulation(NIBS)target for treating depression.However,the alterations of brain activations post-intervention remain inconsistent and the clinical moderators that could improve symptomatic effectiveness are unclear.The study aim was to systematically review the effectiveness of NIBS on depressive symptoms targeting PFC in functional magnetic resonance imaging(fMRI)studies.In our study,we delivered a combined activation likelihood estimation(ALE)meta-analysis and meta-regression.Until November 2020,three databases(PubMed,Web of Science,EMBASE)were searched and 14 studies with a total sample size of 584 were included in the ALE meta-analysis;after NIBS,four clusters in left cerebrum revealed significant activation while two clusters in right cerebrum revealed significant deactivation(P<0.001,cluster size>150 mm3).Eleven studies were statistically reanalyzed for depressive symptoms pre–post active-NIBS and the pooled effect size was very large[(d=1.82,95%CI(1.23,2.40)];significant moderators causing substantial heterogeneity(Chi squared=75.25,P<0.01;I2=87%)were detected through subgroup analysis and univariate meta-regression.Multivariate meta-regression was then conducted accordingly and the model suggested good fitness(Q=42.32,P<0.01).In all,NIBS targeting PFC balanced three core depressive-related neurocognitive networks(the salience network,the default mode network,and the central executive network);the striatum played a central role and might serve as a candidate treatment biomarker;gender difference,treatment-resistant condition,comorbidity,treatment duration,and localization all contributed to moderating depressive symptoms during NIBS.More high-quality,multi-center randomized controlled trails delivering personalized NIBS are needed for clinical practice in the future.展开更多
基金supported by the National Science Fund for Distinguished Young Scholars(81725005)the National Natural Science Foundation Regional Innovation and Development Joint Fund(U20A6005)+5 种基金the National Natural Science Foundation of China(82151315 and 62176129)the National Key Research and Development Program(2022YFC2405605)the Jiangsu Provincial Key Research and Development Program(BE2021617 and BE2022160)the Key Project supported by Medical Science and Technology Development Foundation,Jiangsu Commission of Health(ZD2021026)the Jiangsu Funding Program for Excellent Postdoctoral Talent(2023ZB818)the Postdoctoral Research Project of Changzhou Medical Center,Nanjing Medical University(CMCP202305).
文摘Early-onset mental disorders are associated with disrupted neurodevelopmental processes during adolescence.The methylazoxymethanol acetate(MAM)animal model,in which disruption in neurodevelopmental processes is induced,mimics the abnormal neurodevelopment associated with early-onset mental disorders from an etiological perspective.We conducted longitudinal structural magnetic resonance imaging(MRI)scans during childhood,adolescence,and adulthood in MAM rats to identify specific brain regions and critical windows for intervention.Then,the effect of repetitive transcranial magnetic stimulation(rTMS)intervention on the target brain region during the critical window was investigated.In addition,the efficacy of this intervention paradigm was tested in a group of adolescent patients with early-onset mental disorders(diagnosed with major depressive disorder or bipolar disorder)to evaluate its clinical translational potential.The results demonstrated that,compared to the control group,the MAM rats exhibited significantly lower striatal volume from childhood to adulthood(all P<0.001).In contrast,the volume of the hippocampus did not show significant differences during childhood(P>0.05)but was significantly lower than the control group from adolescence to adulthood(both P<0.001).Subsequently,rTMS was applied to the occipital cortex,which is anatomically connected to the hippocampus,in the MAM models during adolescence.The MAM-rTMS group showed a significant increase in hippocampal volume compared to the MAM-sham group(P<0.01),while the volume of the striatum remained unchanged(P>0.05).In the clinical trial,adolescents with early-onset mental disorders showed a significant increase in hippocampal volume after rTMS treatment compared to baseline(P<0.01),and these volumetric changes were associated with improvement in depressive symptoms(r=−0.524,P=0.018).These findings highlight the potential of targeting aberrant hippocampal development during adolescence as a viable intervention for earlyonset mental disorders with neurodevelopmental etiology as well as the promise of rTMS as a therapeutic approach for mitigating aberrant neurodevelopmental processes and alleviating clinical symptoms.
文摘We read Winter et al.’s recent article published in JAMA Psychiatry with strong interest[1].Despite that their systematical evaluations on machine learning-based approach were incapable of identifying multivariate neuroimaging biomarker for major depressive disorder(MDD),we argue that achieving no biomarker does not necessarily equate to their non-existence.Rather than dwelling on howWinter et al.’s study should be optimized,however,the focal point in the current psychiatric context might primarily revolve around the utilization of neuroimaging in the absence of diagnostic biomarkers,the justification for such warrants,and how current findings could be effectively translated into clinical applications for MDD.
基金Supported by the Jiangsu Provincial Key Research and Development Program(BE2021617).
文摘Introduction:Non-suicidal self-injury(NSSI)has become increasingly prevalent among adolescents,representing a significant public health concern with profound impacts on both physical and mental wellbeing.This study aims to determine the prevalence of NSSI among adolescents in Jiangsu Province and develop a prediction model to facilitate early identification and intervention.Methods:This study is based on the“School-based Evaluation and Response to Child Health(SEARCH)”project.A cross-sectional survey was conducted among students from 11 schools in Jiangsu Province,China in 2023.Following data cleaning,11,427 students were included in the analysis.Machine learning methods were employed to establish a risk prediction model for NSSI among adolescents.Results:The prevalence of NSSI among adolescents aged 10–18 was 12.72%.Eight key predictors of NSSI were identified:insomnia,emotional symptoms,cohesion of family environment,history of drinking alcohol,gender,conflict of family environment,conduct problems,and academic level.The XGBoost model demonstrated an area under the curve(AUC)of 0.800[95%confidence interval(CI):0.776,0.823]and an accuracy(ACC)of 0.886 in the testing set.Conclusions:This study underscores the importance of personalized prevention strategies for NSSI and highlights the necessity of implementing comprehensive behavioral interventions,including mental health support,sleep quality enhancement,and cultivation of supportive family environments.
基金This work was supported by grants from Science-technology Support Plan Projects in Sichuan province （No. 2016FZ0088, and No. 2017SZ0117）, National Natural Science Foundation of China （No. 81602817,No. 81741026, and No. 81571515）, and Research Projects of Health and Family Planing Commission of Sichuan Province （No. 17PJ258）.
文摘Background： Valproic acid （VPA） exposure during pregnancy has been proven to contribute to congenital heart disease （CHD）. Our previous findings implied that disruption of planar cell polarity （PCP） signaling pathway in cardiomyocytes might be a factor for the cardiac teratogenesis of VPA. In addition, the teratogenic ability of VPA is positively correlated to its histone deacetylase （HDAC） inhibition activity. This study aimed to investigate the effect of the VPA on cardiac morphogenesis, HDAC1/2/3, and PCP key genes （Vangl2/Scrib/Rac 1）, subsequently screening out the specific HDACs regulating PCP pathway. Methods： VPA was administered to pregnant C57BL mice at 700 mg/kg intraperitoneally on embryonic day ! 0.5. Dams were sacrificed on E15.5, and death/absorption rates of embryos were evaluated. Embryonic hearts were observed by hematoxylin-eosin staining to identify cardiac abnormalities. H9C2 cells （undifferentiated rat cardiomyoblasts） were transfected with Hdac1/2/3 specific small interfering RNA （siRNA）. Based on the results of siRNA transfection, cells were transfected with Hdac3 expression plasmid and subsequently mock-treated or treated with 8.0 mmol/L VPA. Hdac1/2/3 as well as Vangl2/Scrib/Racl mRNA and protein levels were determined by real-time quantitative polymerase chain reaction and Western blotting, respectively. Total HDAC activity was detected by colorimetric assay.Results： VPA could induce CHD （P 〈 0.001） and inhibit mRNA or protein expression of Hdac1/2/3 as well as Vangl2/Scrib in fetal hearts, in association with total Hdac activity repression （all P 〈 0.05）. In vitro, Hdac3 inhibition could significantly decrease Vangl2/Scrib expression （P 〈 0.01 ）, while knockdown of Hdac 1/2 had no influence （P 〉 0.05）, VPA exposure dramatically decreased the expression of Vanlg2/Scrib together with Hdac activity （P 〈 0.01 ）, while overexpression of Hdac3 could rescue the VPA-induced inhibition （P 〉 0.05）. Conclusion： VPA could inhibit Hdac1/2/3, Vang12/Scrib, or total Hdac activity both in vitro and in vivo and Hdac3 might participate in the process of VPA-induced cardiac developmental anomalies.
文摘Background： Placental multidrug resistance-associated protein 2 （MRP2）, encoded by ABCC2 gene in human, plays a significant role in regulating drugs＇ transplacental transfer rates. Studies o11 placental MRP2 regulation could provide more therapeutic targets for individualized and safe pharmacotherapy during pregnancy. Currently, the roles of epigenetic mechanisms in regulating placental drug transporters are still unclear. This study aimed to investigate the effect of histone deacetylases （HDACs） inhibition on MRP2 expression in the placental trophoblast cell line and to explore whether HDAC 1/2/3 are preliminarily involved in this process. Methods： The human choriocarcinoma-derived trophoblast cell line （Bewo cells） was treated with the HDAC inhibitors-trichostatin A （TSA） at different concentration gradients of 0.5, 1.0, 3.0, and 5.0 μmol/L. Cells were harvested after 24 and 48 h treatment. Small interfering RNA （siRNA） specific for HDACI/HDAC2/HDAC3 or control siRNA was transfected into cells. Total HDAC activity was detected by colorimetric assay kits. HDAC 1/2/3/ABCC2 messenger RNA （mRNA） and protein expressions were determined by real-time quantitative polymerase chain reaction and Western-blot analysis, respectively. Immunofluorescence for MRP2 protein expression was visualized and assessed using an immunofluorescence microscopy and ImageJ software, respectively. Results： TSA could inhibit total HDAC activity and HDAC 1/2/3 expression in company with increase ofM RP2 expression in Bewo cells. Reduction of HDAC 1 protein level was noted after 24 h of TSA incubation at 1.0, 3.0, and 5.0 μmol/L （vs. vehicle group, all P 〈 0.001 ）, accompanied with dose-dependent induction of MRP2 expression （P = 0.045 for 1.0 μmol/L, P = 0.001 for 3.0 μmol/L, and P 〈 0.001 for 5.0 μmol/L）, whereas no significant diferences in MRP2 expression were noted after HDAC2/3 silencing. Fluorescent micrograph images of MRP2 protein were expressed on the cell membrane. The fluorescent intensities of MRP2 in the control, HDAC2, and HDAC3 siRNA-transfected cells weir week, and no significant differences were noticed among these three groups （all P 〉 0.05）. However, MRP2 expression was remarkably elevated in H DAC1 siRNA-transfected cells, which displayed an almost 3.19-fold changes in comparison with the control siRNA-transfected cells （P 〈 0.001 ）. Conclusions： HDACs inhibition could up-regulate placental MRP2 expression in ritzy, and HDAC 1 was probably to be involved in this process.
基金Supported by the National Natural Science Foundation of China-Guangdong Joint Fund(U20A6005)Jiangsu Provincial Key Research and Development Program(BE2021617)+1 种基金Jiangsu Provincial Talent of Entrepreneurship and Innovation(JSSCRC2021565)the National Key Research and Development Program(2022YFC2405605).
文摘Summary What is already known about this topic?Mental health issues in Chinese children and adolescents have emerged as a substantial public health concern,causing distress and strain among families and society.What is added by this report?This study examines the effects of gender and school grade on mental health symptoms and risky behaviors among Chinese children and adolescents,with a particular focus on the role of family and school environments.
基金supported by National Science Fund for Distinguished Young Scholars(81725005 to Fei Wang)National Natural Science Foundation Regional Innovation and Development Joint Fund(U20A6005 to Fei Wang)+1 种基金Jiangsu Provincial Key Research and Development Program(BE2021617 to Fei Wang)National Natural Science Foundation of China(62176129 to Xizhe Zhang).
文摘The prefrontal cortex(PFC)is a critical non-invasive brain stimulation(NIBS)target for treating depression.However,the alterations of brain activations post-intervention remain inconsistent and the clinical moderators that could improve symptomatic effectiveness are unclear.The study aim was to systematically review the effectiveness of NIBS on depressive symptoms targeting PFC in functional magnetic resonance imaging(fMRI)studies.In our study,we delivered a combined activation likelihood estimation(ALE)meta-analysis and meta-regression.Until November 2020,three databases(PubMed,Web of Science,EMBASE)were searched and 14 studies with a total sample size of 584 were included in the ALE meta-analysis;after NIBS,four clusters in left cerebrum revealed significant activation while two clusters in right cerebrum revealed significant deactivation(P<0.001,cluster size>150 mm3).Eleven studies were statistically reanalyzed for depressive symptoms pre–post active-NIBS and the pooled effect size was very large[(d=1.82,95%CI(1.23,2.40)];significant moderators causing substantial heterogeneity(Chi squared=75.25,P<0.01;I2=87%)were detected through subgroup analysis and univariate meta-regression.Multivariate meta-regression was then conducted accordingly and the model suggested good fitness(Q=42.32,P<0.01).In all,NIBS targeting PFC balanced three core depressive-related neurocognitive networks(the salience network,the default mode network,and the central executive network);the striatum played a central role and might serve as a candidate treatment biomarker;gender difference,treatment-resistant condition,comorbidity,treatment duration,and localization all contributed to moderating depressive symptoms during NIBS.More high-quality,multi-center randomized controlled trails delivering personalized NIBS are needed for clinical practice in the future.
