Pub Date : 2024-10-04DOI: 10.1038/s41398-024-03113-5
Caroline Gora, Ana Dudas, Océane Vaugrente, Lucile Drobecq, Emmanuel Pecnard, Gaëlle Lefort, Lucie P Pellissier
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by impairments in social interaction and communication, as well as restrained or stereotyped behaviors. The inherent heterogeneity within the autism spectrum poses challenges for developing effective pharmacological treatments targeting core features. Successful clinical trials require the identification of robust markers to enable patient stratification. In this study, we identified molecular markers within the oxytocin and immediate early gene families across five interconnected brain structures of the social circuit. We used wild-type and four heterogeneous mouse models, each exhibiting unique autism-like behaviors modeling the autism spectrum. While dysregulations in the oxytocin family were model-specific, immediate early genes displayed widespread alterations, reflecting global changes across the four models. Through integrative analysis, we identified Egr1, Foxp1, Homer1a, Oxt, and Oxtr as five robust and discriminant molecular markers that allowed the successful stratification of the four models. Importantly, our stratification demonstrated predictive values when challenged with a fifth mouse model or identifying subgroups of mice potentially responsive to oxytocin treatment. Beyond providing insights into oxytocin and immediate early gene mRNA dynamics, this proof-of-concept study represents a significant step toward the potential stratification of individuals with ASD. This work has implications for the success of clinical trials and the development of personalized medicine in autism.
{"title":"Deciphering autism heterogeneity: a molecular stratification approach in four mouse models.","authors":"Caroline Gora, Ana Dudas, Océane Vaugrente, Lucile Drobecq, Emmanuel Pecnard, Gaëlle Lefort, Lucie P Pellissier","doi":"10.1038/s41398-024-03113-5","DOIUrl":"10.1038/s41398-024-03113-5","url":null,"abstract":"<p><p>Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by impairments in social interaction and communication, as well as restrained or stereotyped behaviors. The inherent heterogeneity within the autism spectrum poses challenges for developing effective pharmacological treatments targeting core features. Successful clinical trials require the identification of robust markers to enable patient stratification. In this study, we identified molecular markers within the oxytocin and immediate early gene families across five interconnected brain structures of the social circuit. We used wild-type and four heterogeneous mouse models, each exhibiting unique autism-like behaviors modeling the autism spectrum. While dysregulations in the oxytocin family were model-specific, immediate early genes displayed widespread alterations, reflecting global changes across the four models. Through integrative analysis, we identified Egr1, Foxp1, Homer1a, Oxt, and Oxtr as five robust and discriminant molecular markers that allowed the successful stratification of the four models. Importantly, our stratification demonstrated predictive values when challenged with a fifth mouse model or identifying subgroups of mice potentially responsive to oxytocin treatment. Beyond providing insights into oxytocin and immediate early gene mRNA dynamics, this proof-of-concept study represents a significant step toward the potential stratification of individuals with ASD. This work has implications for the success of clinical trials and the development of personalized medicine in autism.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"416"},"PeriodicalIF":5.8,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11452541/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142376092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-04DOI: 10.1038/s41398-024-03123-3
Robson C Lillo Vizin, Hisakatsu Ito, Caroline M Kopruszinski, Megumi Ikegami, Daigo Ikegami, Xu Yue, Edita Navratilova, Aubin Moutal, Stephen L Cowen, Frank Porreca
Sleep disruption and negative affect are attendant features of many psychiatric and neurological conditions that are often co-morbid including major depressive disorder, generalized anxiety disorder and chronic pain. Whether there is a causal relationship between negative affect and sleep disruption remains unclear. We therefore asked if mechanisms promoting negative affect can disrupt sleep and whether inhibition of pathological negative affect can normalize disrupted sleep. Signaling at the kappa opioid receptor (KOR) elicits dysphoria in humans and aversive conditioning in animals. We tested the possibility that (a) increased KOR signaling in the anterior cingulate cortex (ACC), a brain region associated with negative emotions, would be sufficient to promote both aversiveness and sleep disruption and (b) inhibition of KOR signaling would normalize pathological negative affect and sleep disruption induced by chronic pain. Chemogenetic Gi-mediated inhibition of KOR-expressing ACC neurons produced conditioned place aversion (CPA) as well as sleep fragmentation in naïve mice. CRISPR/Cas9 editing of ACC KOR normalized both the negative affect and sleep disruption elicited by pathological chronic pain while maintaining the physiologically critical sensory features of pain. These findings suggest therapeutic utility of KOR antagonists for treatment of disease conditions that are associated with both negative affect and sleep disturbances.
睡眠障碍和消极情绪是许多精神和神经疾病的伴随特征,这些疾病往往同时存在,包括重度抑郁症、广泛性焦虑症和慢性疼痛。负面情绪与睡眠紊乱之间是否存在因果关系,目前仍不清楚。因此,我们想知道促进负面情绪的机制是否会扰乱睡眠,以及抑制病理性负面情绪是否能使扰乱的睡眠恢复正常。卡巴阿片受体(KOR)的信号在人类和动物中都会引起幻觉。我们测试了以下可能性:(a) 前扣带回皮层(ACC)是一个与负面情绪相关的脑区,KOR信号的增加足以促进厌恶情绪和睡眠紊乱;(b) KOR信号的抑制将使慢性疼痛引起的病理性负面情绪和睡眠紊乱恢复正常。化学遗传 Gi- 介导的对表达 KOR 的 ACC 神经元的抑制会产生条件性场所厌恶(CPA),并使天真小鼠的睡眠破碎化。CRISPR/Cas9 编辑 ACC KOR 使病理性慢性疼痛引起的负面情绪和睡眠中断正常化,同时保持了生理上关键的疼痛感觉特征。这些发现表明,KOR拮抗剂可用于治疗与负面情绪和睡眠障碍相关的疾病。
{"title":"Cortical kappa opioid receptors integrate negative affect and sleep disturbance.","authors":"Robson C Lillo Vizin, Hisakatsu Ito, Caroline M Kopruszinski, Megumi Ikegami, Daigo Ikegami, Xu Yue, Edita Navratilova, Aubin Moutal, Stephen L Cowen, Frank Porreca","doi":"10.1038/s41398-024-03123-3","DOIUrl":"10.1038/s41398-024-03123-3","url":null,"abstract":"<p><p>Sleep disruption and negative affect are attendant features of many psychiatric and neurological conditions that are often co-morbid including major depressive disorder, generalized anxiety disorder and chronic pain. Whether there is a causal relationship between negative affect and sleep disruption remains unclear. We therefore asked if mechanisms promoting negative affect can disrupt sleep and whether inhibition of pathological negative affect can normalize disrupted sleep. Signaling at the kappa opioid receptor (KOR) elicits dysphoria in humans and aversive conditioning in animals. We tested the possibility that (a) increased KOR signaling in the anterior cingulate cortex (ACC), a brain region associated with negative emotions, would be sufficient to promote both aversiveness and sleep disruption and (b) inhibition of KOR signaling would normalize pathological negative affect and sleep disruption induced by chronic pain. Chemogenetic Gi-mediated inhibition of KOR-expressing ACC neurons produced conditioned place aversion (CPA) as well as sleep fragmentation in naïve mice. CRISPR/Cas9 editing of ACC KOR normalized both the negative affect and sleep disruption elicited by pathological chronic pain while maintaining the physiologically critical sensory features of pain. These findings suggest therapeutic utility of KOR antagonists for treatment of disease conditions that are associated with both negative affect and sleep disturbances.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"417"},"PeriodicalIF":5.8,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11452529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142376091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-03DOI: 10.1038/s41398-024-03130-4
Tsuyoshi Nishiguchi, Kyosuke Yamanishi, Shivani Patel, Johnny R Malicoat, Nathan James Phuong, Tomoteru Seki, Takaya Ishii, Bun Aoyama, Akiyoshi Shimura, Nipun Gorantla, Takehiko Yamanashi, Masaaki Iwata, Andrew A Pieper, Gen Shinozaki
Delirium is a multifactorial medical condition of waxing and waning impairment across various domains of mental functioning over time. Importantly, delirium is also one of the greatest risk factors for prolonged hospitalization, morbidity, and mortality. Studying this important condition is challenging due to the difficulty in both objective diagnosis in patients and validation of laboratory models. As a result, there is a lack of protective treatments for delirium. Our recent studies report the efficacy of bispectral electroencephalography (BSEEG) in diagnosing delirium in patients and predicting patient outcomes, advancing the concept that this simple measure could represent an additional vital sign for patients. Here, we applied BSEEG to characterize and validate a novel lipopolysaccharide (LPS) mouse model of infection-related delirium. We then applied this model to evaluate the protective efficacy of three putative therapeutic agents: the conventional antipsychotic medication haloperidol, the neuroprotective compound P7C3-A20, and the antibiotic minocycline. Aged mice were more susceptible than young mice to LPS-induced aberration in BSEEG, reminiscent of the greater vulnerability of older adults to delirium. In both young and old mice, P7C3-A20 and minocycline administration prevented LPS-induced BSEEG abnormality. By contrast, haloperidol did not. P7C3-A20 and minocycline have been shown to limit different aspects of LPS toxicity, and our data offers proof of principle that these agents might help protect patients from developing infection-related delirium. Thus, utilization of BSEEG in a mouse model for infection-related delirium can identify putative therapeutic agents for applications in patient clinical trials.
{"title":"Discovery of novel protective agents for infection-related delirium through bispectral electroencephalography.","authors":"Tsuyoshi Nishiguchi, Kyosuke Yamanishi, Shivani Patel, Johnny R Malicoat, Nathan James Phuong, Tomoteru Seki, Takaya Ishii, Bun Aoyama, Akiyoshi Shimura, Nipun Gorantla, Takehiko Yamanashi, Masaaki Iwata, Andrew A Pieper, Gen Shinozaki","doi":"10.1038/s41398-024-03130-4","DOIUrl":"10.1038/s41398-024-03130-4","url":null,"abstract":"<p><p>Delirium is a multifactorial medical condition of waxing and waning impairment across various domains of mental functioning over time. Importantly, delirium is also one of the greatest risk factors for prolonged hospitalization, morbidity, and mortality. Studying this important condition is challenging due to the difficulty in both objective diagnosis in patients and validation of laboratory models. As a result, there is a lack of protective treatments for delirium. Our recent studies report the efficacy of bispectral electroencephalography (BSEEG) in diagnosing delirium in patients and predicting patient outcomes, advancing the concept that this simple measure could represent an additional vital sign for patients. Here, we applied BSEEG to characterize and validate a novel lipopolysaccharide (LPS) mouse model of infection-related delirium. We then applied this model to evaluate the protective efficacy of three putative therapeutic agents: the conventional antipsychotic medication haloperidol, the neuroprotective compound P7C3-A20, and the antibiotic minocycline. Aged mice were more susceptible than young mice to LPS-induced aberration in BSEEG, reminiscent of the greater vulnerability of older adults to delirium. In both young and old mice, P7C3-A20 and minocycline administration prevented LPS-induced BSEEG abnormality. By contrast, haloperidol did not. P7C3-A20 and minocycline have been shown to limit different aspects of LPS toxicity, and our data offers proof of principle that these agents might help protect patients from developing infection-related delirium. Thus, utilization of BSEEG in a mouse model for infection-related delirium can identify putative therapeutic agents for applications in patient clinical trials.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"413"},"PeriodicalIF":5.8,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-03DOI: 10.1038/s41398-024-03133-1
Yuan-Yuan Ma, Xin Li, Zhong-Yuan Yu, Tong Luo, Cheng-Rong Tan, Yu-Di Bai, Gang Xu, Bin-Da Sun, Xian-Le Bu, Yu-Hui Liu, Wang-Sheng Jin, Yu-Qi Gao, Xin-Fu Zhou, Juan Liu, Yan-Jiang Wang
Chronic hypobaric hypoxia at high altitudes can impair cognitive functions, especially causing deficits in learning and memory, which require therapeutic intervention. Here, we showed that mice subjected to hypobaric hypoxia (simulating an altitude of 5000 m) for one month experienced significant cognitive impairment, accompanied by increased biomarker levels of oxidative stress in the brain and blood. Oral administration of a novel formulation of edaravone, a free radical scavenger approved for the treatment of ischaemic stroke and amyotrophic lateral sclerosis, significantly alleviated oxidative stress and cognitive impairments caused by chronic hypobaric hypoxia. Furthermore, oral edaravone treatment also mitigated neuroinflammation and restored hippocampal neural stem cell exhaustion. Additionally, periostin (Postn) is vital in the cognitive deficits caused by chronic hypobaric hypoxia and may be a molecular target of edaravone. In conclusion, our results suggest that oxidative stress plays a crucial role in the cognitive deficits caused by chronic hypobaric hypoxia and that oral edaravone is a potential medicine for protecting against cognitive deficits caused by chronic hypobaric hypoxia in high-altitude areas.
{"title":"Oral antioxidant edaravone protects against cognitive deficits induced by chronic hypobaric hypoxia at high altitudes.","authors":"Yuan-Yuan Ma, Xin Li, Zhong-Yuan Yu, Tong Luo, Cheng-Rong Tan, Yu-Di Bai, Gang Xu, Bin-Da Sun, Xian-Le Bu, Yu-Hui Liu, Wang-Sheng Jin, Yu-Qi Gao, Xin-Fu Zhou, Juan Liu, Yan-Jiang Wang","doi":"10.1038/s41398-024-03133-1","DOIUrl":"10.1038/s41398-024-03133-1","url":null,"abstract":"<p><p>Chronic hypobaric hypoxia at high altitudes can impair cognitive functions, especially causing deficits in learning and memory, which require therapeutic intervention. Here, we showed that mice subjected to hypobaric hypoxia (simulating an altitude of 5000 m) for one month experienced significant cognitive impairment, accompanied by increased biomarker levels of oxidative stress in the brain and blood. Oral administration of a novel formulation of edaravone, a free radical scavenger approved for the treatment of ischaemic stroke and amyotrophic lateral sclerosis, significantly alleviated oxidative stress and cognitive impairments caused by chronic hypobaric hypoxia. Furthermore, oral edaravone treatment also mitigated neuroinflammation and restored hippocampal neural stem cell exhaustion. Additionally, periostin (Postn) is vital in the cognitive deficits caused by chronic hypobaric hypoxia and may be a molecular target of edaravone. In conclusion, our results suggest that oxidative stress plays a crucial role in the cognitive deficits caused by chronic hypobaric hypoxia and that oral edaravone is a potential medicine for protecting against cognitive deficits caused by chronic hypobaric hypoxia in high-altitude areas.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"415"},"PeriodicalIF":5.8,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11450176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-03DOI: 10.1038/s41398-024-03119-z
Eduardo R Butelman, Yuefeng Huang, Flurin Cathomas, Pierre-Olivier Gaudreault, Panos Roussos, Scott J Russo, Rita Z Goldstein, Nelly Alia-Klein
Opioid use disorders cause major morbidity and mortality, and there is a pressing need for novel mechanistic targets and biomarkers for diagnosis and prognosis. Exposure to mu-opioid receptor (MOR) agonists causes changes in cytokine and inflammatory protein networks in peripheral blood, and also in brain glia and neurons. Individuals with heroin use disorder (iHUD) show dysregulated levels of several cytokines in the blood. However, there is limited data on a comprehensive panel of such markers in iHUD versus healthy controls (HC), especially considered as a multi-target biomarker. We used a validated proximity extension assay for the relative quantification of 92 cytokines and inflammatory proteins in the serum of iHUD on medication-assisted therapy (MAT; n = 21), compared to HC (n = 24). Twenty-nine targets showed significant group differences (primarily iHUD>HC), surviving multiple comparison corrections (p = 0.05). These targets included 19 members of canonical cytokine families, including specific chemokines, interleukins, growth factors, and tumor necrosis factor (TNF)-related proteins. For dimensionality reduction, data from these 19 cytokines were entered into a principal component (PC) analysis, with PC1 scores showing significant group differences (iHUD > HC; p < 0.0001). A receiver-operating characteristic (ROC) curve analysis yielded an AUROC = 91.7% (p < 0.0001). This PC1 score remained a positive predictor of being in the HUD group in a multivariable logistic regression, that included select demographic/clinical variables. Overall, this study shows a panel of cytokines that differ significantly between iHUD and HC, providing a multi-target "cytokine biomarker score" for potential diagnostic purposes, and future examination of disease severity.
{"title":"Serum cytokines and inflammatory proteins in individuals with heroin use disorder: potential mechanistically based biomarkers for diagnosis.","authors":"Eduardo R Butelman, Yuefeng Huang, Flurin Cathomas, Pierre-Olivier Gaudreault, Panos Roussos, Scott J Russo, Rita Z Goldstein, Nelly Alia-Klein","doi":"10.1038/s41398-024-03119-z","DOIUrl":"10.1038/s41398-024-03119-z","url":null,"abstract":"<p><p>Opioid use disorders cause major morbidity and mortality, and there is a pressing need for novel mechanistic targets and biomarkers for diagnosis and prognosis. Exposure to mu-opioid receptor (MOR) agonists causes changes in cytokine and inflammatory protein networks in peripheral blood, and also in brain glia and neurons. Individuals with heroin use disorder (iHUD) show dysregulated levels of several cytokines in the blood. However, there is limited data on a comprehensive panel of such markers in iHUD versus healthy controls (HC), especially considered as a multi-target biomarker. We used a validated proximity extension assay for the relative quantification of 92 cytokines and inflammatory proteins in the serum of iHUD on medication-assisted therapy (MAT; n = 21), compared to HC (n = 24). Twenty-nine targets showed significant group differences (primarily iHUD>HC), surviving multiple comparison corrections (p = 0.05). These targets included 19 members of canonical cytokine families, including specific chemokines, interleukins, growth factors, and tumor necrosis factor (TNF)-related proteins. For dimensionality reduction, data from these 19 cytokines were entered into a principal component (PC) analysis, with PC1 scores showing significant group differences (iHUD > HC; p < 0.0001). A receiver-operating characteristic (ROC) curve analysis yielded an AUROC = 91.7% (p < 0.0001). This PC1 score remained a positive predictor of being in the HUD group in a multivariable logistic regression, that included select demographic/clinical variables. Overall, this study shows a panel of cytokines that differ significantly between iHUD and HC, providing a multi-target \"cytokine biomarker score\" for potential diagnostic purposes, and future examination of disease severity.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"414"},"PeriodicalIF":5.8,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11450096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-02DOI: 10.1038/s41398-024-03098-1
Lydia M Federmann, Friederike S David, Christiane Jockwitz, Thomas W Mühleisen, Dominique I Pelzer, Markus M Nöthen, Svenja Caspers, Katrin Amunts, Janik Goltermann, Till F M Andlauer, Frederike Stein, Katharina Brosch, Tilo Kircher, Sven Cichon, Udo Dannlowski, Lisa Sindermann, Andreas J Forstner
A previously published genome-wide association study (GWAS) meta-analysis across eight neuropsychiatric disorders identified antagonistic single-nucleotide polymorphisms (SNPs) at eleven genomic loci where the same allele was protective against one neuropsychiatric disorder and increased the risk for another. Until now, these antagonistic SNPs have not been further investigated regarding their link to brain structural phenotypes. Here, we explored their associations with cortical surface area and cortical thickness (in 34 brain regions and one global measure each) as well as the volumes of eight subcortical structures using summary statistics of large-scale GWAS of brain structural phenotypes. We assessed if significantly associated brain structural phenotypes were previously reported to be associated with major neuropsychiatric disorders in large-scale case-control imaging studies by the ENIGMA consortium. We further characterized the effects of the antagonistic SNPs on gene expression in brain tissue and their association with additional cognitive and behavioral phenotypes, and performed an exploratory voxel-based whole-brain analysis in the FOR2107 study (n = 754 patients with major depressive disorder and n = 847 controls). We found that eight antagonistic SNPs were significantly associated with brain structural phenotypes in regions such as anterior parts of the cingulate cortex, the insula, and the superior temporal gyrus. Case-control differences in implicated brain structural phenotypes have previously been reported for bipolar disorder, major depressive disorder, and schizophrenia. In addition, antagonistic SNPs were associated with gene expression changes in brain tissue and linked to several cognitive-behavioral traits. In our exploratory whole-brain analysis, we observed significant associations of gray matter volume in the left superior temporal pole and left superior parietal region with the variants rs301805 and rs1933802, respectively. Our results suggest that multiple antagonistic SNPs for neuropsychiatric disorders are linked to brain structural phenotypes. However, to further elucidate these findings, future case-control genomic imaging studies are required.
此前发表的一项全基因组关联研究(GWAS)荟萃分析发现,在八个神经精神疾病的十一个基因组位点上存在拮抗性单核苷酸多态性(SNPs),其中相同的等位基因对一种神经精神疾病具有保护作用,而对另一种神经精神疾病则会增加患病风险。迄今为止,这些拮抗 SNPs 与大脑结构表型的联系尚未得到进一步研究。在此,我们利用大规模脑结构表型 GWAS 的汇总统计,探讨了它们与皮质表面积和皮质厚度(分别在 34 个脑区和一个总体测量中)以及 8 个皮质下结构体积的关联。我们评估了在 ENIGMA 联盟进行的大规模病例对照成像研究中,与大脑结构表型明显相关的疾病是否与主要神经精神疾病有关。我们进一步确定了拮抗 SNP 对脑组织基因表达的影响及其与其他认知和行为表型的关联,并在 FOR2107 研究(n = 754 例重度抑郁障碍患者和 n = 847 例对照)中进行了基于体素的全脑探索性分析。我们发现,8 个拮抗 SNP 与扣带皮层前部、岛叶和颞上回等区域的大脑结构表型有显著关联。以前曾有报道称,在双相情感障碍、重度抑郁障碍和精神分裂症中,病例对照与大脑结构表型存在相关性差异。此外,拮抗 SNP 与脑组织中的基因表达变化有关,并与几种认知行为特征相关。在我们的探索性全脑分析中,我们观察到左上颞极和左上顶叶区的灰质体积分别与变异 rs301805 和 rs1933802 显著相关。我们的研究结果表明,神经精神疾病的多个拮抗 SNP 与大脑结构表型有关。然而,要进一步阐明这些发现,还需要未来的病例对照基因组成像研究。
{"title":"Associations between antagonistic SNPs for neuropsychiatric disorders and human brain structure.","authors":"Lydia M Federmann, Friederike S David, Christiane Jockwitz, Thomas W Mühleisen, Dominique I Pelzer, Markus M Nöthen, Svenja Caspers, Katrin Amunts, Janik Goltermann, Till F M Andlauer, Frederike Stein, Katharina Brosch, Tilo Kircher, Sven Cichon, Udo Dannlowski, Lisa Sindermann, Andreas J Forstner","doi":"10.1038/s41398-024-03098-1","DOIUrl":"10.1038/s41398-024-03098-1","url":null,"abstract":"<p><p>A previously published genome-wide association study (GWAS) meta-analysis across eight neuropsychiatric disorders identified antagonistic single-nucleotide polymorphisms (SNPs) at eleven genomic loci where the same allele was protective against one neuropsychiatric disorder and increased the risk for another. Until now, these antagonistic SNPs have not been further investigated regarding their link to brain structural phenotypes. Here, we explored their associations with cortical surface area and cortical thickness (in 34 brain regions and one global measure each) as well as the volumes of eight subcortical structures using summary statistics of large-scale GWAS of brain structural phenotypes. We assessed if significantly associated brain structural phenotypes were previously reported to be associated with major neuropsychiatric disorders in large-scale case-control imaging studies by the ENIGMA consortium. We further characterized the effects of the antagonistic SNPs on gene expression in brain tissue and their association with additional cognitive and behavioral phenotypes, and performed an exploratory voxel-based whole-brain analysis in the FOR2107 study (n = 754 patients with major depressive disorder and n = 847 controls). We found that eight antagonistic SNPs were significantly associated with brain structural phenotypes in regions such as anterior parts of the cingulate cortex, the insula, and the superior temporal gyrus. Case-control differences in implicated brain structural phenotypes have previously been reported for bipolar disorder, major depressive disorder, and schizophrenia. In addition, antagonistic SNPs were associated with gene expression changes in brain tissue and linked to several cognitive-behavioral traits. In our exploratory whole-brain analysis, we observed significant associations of gray matter volume in the left superior temporal pole and left superior parietal region with the variants rs301805 and rs1933802, respectively. Our results suggest that multiple antagonistic SNPs for neuropsychiatric disorders are linked to brain structural phenotypes. However, to further elucidate these findings, future case-control genomic imaging studies are required.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"406"},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446931/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dietary habits may impact the prevention and management of schizophrenia (SCZ) and bipolar disorder (BD), and genetic and environmental factors can influence both these habits and these disorders. This study investigated the effects of genetic predispositions to SCZ and BD on current dietary habits among older adults with lifestyle-related diseases, potentially offering insights for preventive mental health strategies. A cohort of 730 older patients who were diagnosed with or suspected of having lifestyle-related diseases was assessed for eight current dietary categories: miso soup, Japanese tea, green and yellow vegetables, light-colored vegetables, fruits, pickles, meats, and soybeans. Polygenic risk scores (PRSs) for the risk of SCZ and BD, including BD types I and II, the shared risk of SCZ and BD, and the differentiation of SCZ from BD, were calculated utilizing data from large-scale genome-wide association studies (GWASs). Our findings revealed that PRSs for SCZ and BD risk significantly influenced specific dietary habits, particularly decreased consumption of nutrient-rich foods such as light-colored vegetables (SCZ, R2 = 0.0096, p = 3.54 × 10-3; BD, R2 = 0.0074, p = 9.09 × 10-3) and soybeans (SCZ, R2 = 0.0061, p = 0.019; BD, R2 = 0.014, p = 8.38 × 10-4). Notable differences in dietary effects were observed between PRSs for BD I and BD II, with a more pronounced impact associated with BD I (e.g., light-colored vegetables, BD I, R2 = 0.015, p = 3.11 × 10-4; BD II, p > 0.05). Moreover, shared genetic factors for SCZ and BD were correlated with lower intakes of miso soup (R2 = 0.013, p = 1.21 × 10-3), Japanese tea (R2 = 0.0092, p = 5.59 × 10-3), light-colored vegetables (R2 = 0.010, p = 2.92 × 10-3), and soybeans (R2 = 0.014, p = 3.13 × 10-4). No significant correlations were found between PRSs for differentiating SCZ from BD and any dietary patterns (p > 6.25 × 10-3). Genetic risks shared by individuals with SCZ and BD may influence dietary choices in older adults, emphasizing the potential for dietary modifications as part of comprehensive strategies for the prevention of the SCZ and BD onset, as well as for the treatment of individuals at risk of or diagnosed with SCZ and BD.
{"title":"Dietary habits and genetic susceptibility: correlations between nutritional intake and genetic risks for schizophrenia and bipolar disorder.","authors":"Kazutaka Ohi, Daisuke Nishizawa, Taiga Saito, Taichi Goto, Itsuki Kubota, Tomoya Shinoda, Daisuke Fujikane, Junko Hasegawa, Naomi Sato, Fumihiko Tanioka, Haruhiko Sugimura, Kazutaka Ikeda, Toshiki Shioiri","doi":"10.1038/s41398-024-03105-5","DOIUrl":"10.1038/s41398-024-03105-5","url":null,"abstract":"<p><p>Dietary habits may impact the prevention and management of schizophrenia (SCZ) and bipolar disorder (BD), and genetic and environmental factors can influence both these habits and these disorders. This study investigated the effects of genetic predispositions to SCZ and BD on current dietary habits among older adults with lifestyle-related diseases, potentially offering insights for preventive mental health strategies. A cohort of 730 older patients who were diagnosed with or suspected of having lifestyle-related diseases was assessed for eight current dietary categories: miso soup, Japanese tea, green and yellow vegetables, light-colored vegetables, fruits, pickles, meats, and soybeans. Polygenic risk scores (PRSs) for the risk of SCZ and BD, including BD types I and II, the shared risk of SCZ and BD, and the differentiation of SCZ from BD, were calculated utilizing data from large-scale genome-wide association studies (GWASs). Our findings revealed that PRSs for SCZ and BD risk significantly influenced specific dietary habits, particularly decreased consumption of nutrient-rich foods such as light-colored vegetables (SCZ, R<sup>2</sup> = 0.0096, p = 3.54 × 10<sup>-3</sup>; BD, R<sup>2</sup> = 0.0074, p = 9.09 × 10<sup>-3</sup>) and soybeans (SCZ, R<sup>2</sup> = 0.0061, p = 0.019; BD, R<sup>2</sup> = 0.014, p = 8.38 × 10<sup>-4</sup>). Notable differences in dietary effects were observed between PRSs for BD I and BD II, with a more pronounced impact associated with BD I (e.g., light-colored vegetables, BD I, R<sup>2</sup> = 0.015, p = 3.11 × 10<sup>-4</sup>; BD II, p > 0.05). Moreover, shared genetic factors for SCZ and BD were correlated with lower intakes of miso soup (R<sup>2</sup> = 0.013, p = 1.21 × 10<sup>-3</sup>), Japanese tea (R<sup>2</sup> = 0.0092, p = 5.59 × 10<sup>-3</sup>), light-colored vegetables (R<sup>2</sup> = 0.010, p = 2.92 × 10<sup>-3</sup>), and soybeans (R<sup>2</sup> = 0.014, p = 3.13 × 10<sup>-4</sup>). No significant correlations were found between PRSs for differentiating SCZ from BD and any dietary patterns (p > 6.25 × 10<sup>-3</sup>). Genetic risks shared by individuals with SCZ and BD may influence dietary choices in older adults, emphasizing the potential for dietary modifications as part of comprehensive strategies for the prevention of the SCZ and BD onset, as well as for the treatment of individuals at risk of or diagnosed with SCZ and BD.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"404"},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447016/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-02DOI: 10.1038/s41398-024-03093-6
Wentao Wang, Dan Wang, Di Zhao, Lihong Xu, Shujun Jiang, Yu Zhang, Minghu Cui, Jing Liu, Fantao Meng, Cuilan Liu, Dunjiang Liu, Wei Li, Chen Li
Dopamine (DA) neurons play a crucial role in the development and manifestation of depression, as well as in response to antidepressant treatments. While the function of the predominantly distributed DA neurons in the ventral tegmental area (VTA) is well established, the contribution of a small fraction of DA neurons in the dorsal raphe nucleus (DRN) during depression remains unclear. In this study, we found that chronic unpredictable stress (CUS) induces depression-related behaviors and decreases spontaneous firing rates, excitatory and inhibitory postsynaptic currents of DA neurons in the DRN associated with reduced excitatory synaptic transmission in male and female mice. The chemogenetic inhibition of DA neurons in the DRN produces depressive phenotypes. Conversely, their activation completely reversed the anhedonic and despair behaviors induced by CUS. Furthermore, we showed that a DRN dopaminergic projecting to the dorsal bed nucleus of the stria terminalis (dBNST) selectively controls depressive behaviors by influencing the neural activity and N-methyl-D-aspartate receptor (NMDAR) mediating EPSC of calcium/calmodulin-dependent protein kinase II+ (CaMKII+) target neurons by regulating dopamine neurotransmitter and dopamine receptor 2 (DR2) in the dBNST. Overall, these findings highlight the essential role of the DRNDA → dBNSTCaMKII+ neural circuit in bi-directionally mediating stress-induced depression-related behaviors. Our findings indicate that DRN DA neurons are a key component of the neural circuitry involved in regulating depression-related behaviors, making them a potential therapeutic target for depression.
{"title":"Dorsal raphe dopaminergic neurons target CaMKII<sup>+</sup> neurons in dorsal bed nucleus of the stria terminalis for mediating depression-related behaviors.","authors":"Wentao Wang, Dan Wang, Di Zhao, Lihong Xu, Shujun Jiang, Yu Zhang, Minghu Cui, Jing Liu, Fantao Meng, Cuilan Liu, Dunjiang Liu, Wei Li, Chen Li","doi":"10.1038/s41398-024-03093-6","DOIUrl":"10.1038/s41398-024-03093-6","url":null,"abstract":"<p><p>Dopamine (DA) neurons play a crucial role in the development and manifestation of depression, as well as in response to antidepressant treatments. While the function of the predominantly distributed DA neurons in the ventral tegmental area (VTA) is well established, the contribution of a small fraction of DA neurons in the dorsal raphe nucleus (DRN) during depression remains unclear. In this study, we found that chronic unpredictable stress (CUS) induces depression-related behaviors and decreases spontaneous firing rates, excitatory and inhibitory postsynaptic currents of DA neurons in the DRN associated with reduced excitatory synaptic transmission in male and female mice. The chemogenetic inhibition of DA neurons in the DRN produces depressive phenotypes. Conversely, their activation completely reversed the anhedonic and despair behaviors induced by CUS. Furthermore, we showed that a DRN dopaminergic projecting to the dorsal bed nucleus of the stria terminalis (dBNST) selectively controls depressive behaviors by influencing the neural activity and N-methyl-D-aspartate receptor (NMDAR) mediating EPSC of calcium/calmodulin-dependent protein kinase II<sup>+</sup> (CaMKII<sup>+)</sup> target neurons by regulating dopamine neurotransmitter and dopamine receptor 2 (DR2) in the dBNST. Overall, these findings highlight the essential role of the DRN<sup>DA</sup> → dBNST<sup>CaMKII+</sup> neural circuit in bi-directionally mediating stress-induced depression-related behaviors. Our findings indicate that DRN DA neurons are a key component of the neural circuitry involved in regulating depression-related behaviors, making them a potential therapeutic target for depression.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"408"},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447211/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Phosphodiesterase 10 A (PDE10A), a pivotal element of the second messenger signaling downstream of the dopamine receptor stimulation, is conceived to be crucially involved in the mood instability of bipolar I disorder (BD-I) as a primary causal factor or in response to dysregulated dopaminergic tone. We aimed to determine whether striatal PDE10A availability is altered in patients with BD-I and assessed its relationship with the clinical characteristics of BD-I. This case-control study used positron emission tomography (PET) with 2-(2-(3-(4-(2-[18F]fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([18F]MNI-659), a radioligand that binds to PDE10A, to examine the alterations of the striatal PDE10A availability in the living brains of individuals with BD-I and their association with the clinical characteristics of BD-I. [18F]MNI-659 PET data were acquired from 25 patients with BD-I and 27 age- and sex-matched healthy controls. Patients with BD-I had significantly lower PDE10A availability than controls in the executive (F = 8.86; P = 0.005) and sensorimotor (F = 6.13; P = 0.017) subregions of the striatum. Lower PDE10A availability in the executive subregion was significantly associated with a higher frequency of mood episodes in patients with BD-I (r = -0.546; P = 0.007). This study provides the first evidence of altered PDE10A availability in patients with BD-I. Lower PDE10A availability in the executive subregion of the striatum is associated with an increased recurrence risk, suggesting that PDE10A may prevent BD-I relapse. Further studies are required to elucidate the role of PDE10A in BD-I pathophysiology and explore its potential as a treatment target.
{"title":"Alterations of striatal phosphodiesterase 10 A and their association with recurrence rate in bipolar I disorder.","authors":"Yasunori Sano, Yasuharu Yamamoto, Manabu Kubota, Sho Moriguchi, Kiwamu Matsuoka, Shin Kurose, Kenji Tagai, Hironobu Endo, Bun Yamagata, Hisaomi Suzuki, Ryosuke Tarumi, Kie Nomoto, Yuhei Takado, Kazunori Kawamura, Ming-Rong Zhang, Hajime Tabuchi, Masaru Mimura, Hiroyuki Uchida, Makoto Higuchi, Keisuke Takahata","doi":"10.1038/s41398-024-03107-3","DOIUrl":"10.1038/s41398-024-03107-3","url":null,"abstract":"<p><p>Phosphodiesterase 10 A (PDE10A), a pivotal element of the second messenger signaling downstream of the dopamine receptor stimulation, is conceived to be crucially involved in the mood instability of bipolar I disorder (BD-I) as a primary causal factor or in response to dysregulated dopaminergic tone. We aimed to determine whether striatal PDE10A availability is altered in patients with BD-I and assessed its relationship with the clinical characteristics of BD-I. This case-control study used positron emission tomography (PET) with 2-(2-(3-(4-(2-[<sup>18</sup>F]fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([<sup>18</sup>F]MNI-659), a radioligand that binds to PDE10A, to examine the alterations of the striatal PDE10A availability in the living brains of individuals with BD-I and their association with the clinical characteristics of BD-I. [<sup>18</sup>F]MNI-659 PET data were acquired from 25 patients with BD-I and 27 age- and sex-matched healthy controls. Patients with BD-I had significantly lower PDE10A availability than controls in the executive (F = 8.86; P = 0.005) and sensorimotor (F = 6.13; P = 0.017) subregions of the striatum. Lower PDE10A availability in the executive subregion was significantly associated with a higher frequency of mood episodes in patients with BD-I (r = -0.546; P = 0.007). This study provides the first evidence of altered PDE10A availability in patients with BD-I. Lower PDE10A availability in the executive subregion of the striatum is associated with an increased recurrence risk, suggesting that PDE10A may prevent BD-I relapse. Further studies are required to elucidate the role of PDE10A in BD-I pathophysiology and explore its potential as a treatment target.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"403"},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-02DOI: 10.1038/s41398-024-03108-2
Azzurra Invernizzi, Stefano Renzetti, Christoph van Thriel, Elza Rechtman, Alessandra Patrono, Claudia Ambrosi, Lorella Mascaro, Daniele Corbo, Giuseppa Cagna, Roberto Gasparotti, Abraham Reichenberg, Cheuk Y Tang, Roberto G Lucchini, Robert O Wright, Donatella Placidi, Megan K Horton
Coronavirus disease 2019 (COVID-19) has been associated with brain functional, structural, and cognitive changes that persist months after infection. Most studies of the neurologic outcomes related to COVID-19 focus on severe infection and aging populations. Here, we investigated the neural activities underlying COVID-19 related outcomes in a case-control study of mildly infected youth enrolled in a longitudinal study in Lombardy, Italy, a global hotspot of COVID-19. All participants (13 cases, 27 controls, mean age 24 years) completed resting-state functional (fMRI), structural MRI, cognitive assessments (CANTAB spatial working memory) at baseline (pre-COVID) and follow-up (post-COVID). Using graph theory eigenvector centrality (EC) and data-driven statistical methods, we examined differences in ECdelta (i.e., the difference in EC values pre- and post-COVID-19) and Volumetricdelta (i.e., the difference in cortical volume of cortical and subcortical areas pre- and post-COVID) between COVID-19 cases and controls. We found that ECdelta significantly between COVID-19 and healthy participants in five brain regions; right intracalcarine cortex, right lingual gyrus, left hippocampus, left amygdala, left frontal orbital cortex. The left hippocampus showed a significant decrease in Volumetricdelta between groups (p = 0.041). The reduced ECdelta in the left amygdala associated with COVID-19 status mediated the association between COVID-19 and disrupted spatial working memory. Our results show persistent structural, functional and cognitive brain changes in key brain areas associated with olfaction and cognition. These results may guide treatment efforts to assess the longevity, reversibility and impact of the observed brain and cognitive changes following COVID-19.
{"title":"COVID-19 related cognitive, structural and functional brain changes among Italian adolescents and young adults: a multimodal longitudinal case-control study.","authors":"Azzurra Invernizzi, Stefano Renzetti, Christoph van Thriel, Elza Rechtman, Alessandra Patrono, Claudia Ambrosi, Lorella Mascaro, Daniele Corbo, Giuseppa Cagna, Roberto Gasparotti, Abraham Reichenberg, Cheuk Y Tang, Roberto G Lucchini, Robert O Wright, Donatella Placidi, Megan K Horton","doi":"10.1038/s41398-024-03108-2","DOIUrl":"10.1038/s41398-024-03108-2","url":null,"abstract":"<p><p>Coronavirus disease 2019 (COVID-19) has been associated with brain functional, structural, and cognitive changes that persist months after infection. Most studies of the neurologic outcomes related to COVID-19 focus on severe infection and aging populations. Here, we investigated the neural activities underlying COVID-19 related outcomes in a case-control study of mildly infected youth enrolled in a longitudinal study in Lombardy, Italy, a global hotspot of COVID-19. All participants (13 cases, 27 controls, mean age 24 years) completed resting-state functional (fMRI), structural MRI, cognitive assessments (CANTAB spatial working memory) at baseline (pre-COVID) and follow-up (post-COVID). Using graph theory eigenvector centrality (EC) and data-driven statistical methods, we examined differences in EC<sub>delta</sub> (i.e., the difference in EC values pre- and post-COVID-19) and Volumetric<sub>delta</sub> (i.e., the difference in cortical volume of cortical and subcortical areas pre- and post-COVID) between COVID-19 cases and controls. We found that EC<sub>delta</sub> significantly between COVID-19 and healthy participants in five brain regions; right intracalcarine cortex, right lingual gyrus, left hippocampus, left amygdala, left frontal orbital cortex. The left hippocampus showed a significant decrease in Volumetric<sub>delta</sub> between groups (p = 0.041). The reduced EC<sub>delta</sub> in the left amygdala associated with COVID-19 status mediated the association between COVID-19 and disrupted spatial working memory. Our results show persistent structural, functional and cognitive brain changes in key brain areas associated with olfaction and cognition. These results may guide treatment efforts to assess the longevity, reversibility and impact of the observed brain and cognitive changes following COVID-19.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"402"},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}