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":null,"pages":null},"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}
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":null,"pages":null},"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":null,"pages":null},"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}
Pub Date : 2024-10-02DOI: 10.1038/s41398-024-03077-6
Timothy A Fenton, Olivia Y Haouchine, Elizabeth B Hallam, Emily M Smith, Kiya C Jackson, Darlene Rahbarian, Cesar P Canales, Anna Adhikari, Alex S Nord, Roy Ben-Shalom, Jill L Silverman
Disruption of SYNGAP1 directly causes a genetically identifiable neurodevelopmental disorder (NDD) called SYNGAP1-related intellectual disability (SRID). Without functional SynGAP1 protein, individuals are developmentally delayed and have prominent features of intellectual disability (ID), motor impairments, and epilepsy. Over the past two decades, there have been numerous discoveries indicating the critical role of Syngap1. Several rodent models with a loss of Syngap1 have been engineered, identifying precise roles in neuronal structure and function, as well as key biochemical pathways key for synapse integrity. Homozygous loss of SYNGAP1/Syngap1 is lethal. Heterozygous mutations of Syngap1 result in a broad range of behavioral phenotypes. Our in vivo functional data, using the original mouse model from the Huganir laboratory, corroborated behaviors including robust hyperactivity and deficits in learning and memory in young adults. Furthermore, we described impairments in the domain of sleep, characterized using neurophysiological data that was collected with wireless, telemetric electroencephalography (EEG). Syngap1+/- mice exhibited elevated spiking events and spike trains, in addition to elevated power, most notably in the delta power frequency. For the first time, we illustrated that primary neurons from Syngap1+/- mice displayed: 1) increased network firing activity, 2) greater bursts, 3) and shorter inter-burst intervals between peaks, by utilizing high density microelectrode arrays (HD-MEA). Our work bridges in vitro electrophysiological neuronal activity and function with in vivo neurophysiological brain activity and function. These data elucidate quantitative, translational biomarkers in vivo and in vitro that can be utilized for the development and efficacy assessment of targeted treatments for SRID.
{"title":"Hyperexcitability and translational phenotypes in a preclinical mouse model of SYNGAP1-related intellectual disability.","authors":"Timothy A Fenton, Olivia Y Haouchine, Elizabeth B Hallam, Emily M Smith, Kiya C Jackson, Darlene Rahbarian, Cesar P Canales, Anna Adhikari, Alex S Nord, Roy Ben-Shalom, Jill L Silverman","doi":"10.1038/s41398-024-03077-6","DOIUrl":"10.1038/s41398-024-03077-6","url":null,"abstract":"<p><p>Disruption of SYNGAP1 directly causes a genetically identifiable neurodevelopmental disorder (NDD) called SYNGAP1-related intellectual disability (SRID). Without functional SynGAP1 protein, individuals are developmentally delayed and have prominent features of intellectual disability (ID), motor impairments, and epilepsy. Over the past two decades, there have been numerous discoveries indicating the critical role of Syngap1. Several rodent models with a loss of Syngap1 have been engineered, identifying precise roles in neuronal structure and function, as well as key biochemical pathways key for synapse integrity. Homozygous loss of SYNGAP1/Syngap1 is lethal. Heterozygous mutations of Syngap1 result in a broad range of behavioral phenotypes. Our in vivo functional data, using the original mouse model from the Huganir laboratory, corroborated behaviors including robust hyperactivity and deficits in learning and memory in young adults. Furthermore, we described impairments in the domain of sleep, characterized using neurophysiological data that was collected with wireless, telemetric electroencephalography (EEG). Syngap1<sup>+/-</sup> mice exhibited elevated spiking events and spike trains, in addition to elevated power, most notably in the delta power frequency. For the first time, we illustrated that primary neurons from Syngap1<sup>+/-</sup> mice displayed: 1) increased network firing activity, 2) greater bursts, 3) and shorter inter-burst intervals between peaks, by utilizing high density microelectrode arrays (HD-MEA). Our work bridges in vitro electrophysiological neuronal activity and function with in vivo neurophysiological brain activity and function. These data elucidate quantitative, translational biomarkers in vivo and in vitro that can be utilized for the development and efficacy assessment of targeted treatments for SRID.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447000/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366634","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/s41398-024-03127-z
Lei Li, Weijing Kan, Yi Zhang, Tianyi Wang, Feng Yang, Tengfei Ji, Gang Wang, Jing Du
Major depressive disorder (MDD) is a common disease affecting 300 million people worldwide. The existing drugs are ineffective for approximately 30% of patients, so it is urgent to develop new antidepressant drugs with novel mechanisms. Here, we found that norisoboldine (NOR) showed an antidepressant efficacy in the chronic social defeat stress (CSDS) depression model in the tail suspension, forced swimming, and sucrose consumption tests. We then utilized the drug-treated CSDS mice paradigm to segregate and gain differential protein groups of CSDS versus CON (CSDSCON), imipramine (IMI)-treated versus CSDS (IMICSDS), and NOR-treated versus CSDS (NORCSDS) from the prefrontal cortex. These protein expression alterations were first analyzed by ANOVA with p < 0.05. The protein cluster 1 and cluster 3, in which the pattern of protein levels similar to the mood pattern, showed enrichment in functions and localizations related to mitochondrion, ribosome and synapses. Further GO analysis of the common proteins for NORCSDS groups and NORIMI groups supported the findings from ANOVA analysis. We employed Protein-Protein interaction (PPI) analysis to examine the proteins of NORCSDS and NORIMI, revealing an enrichment of the proteins associated with the mitochondrial ribosomal and synaptic functions. Further independent analysis using parallel reaction monitoring (PRM) revealed that Cox7c, Mrp142, Naa30, Ighm, Apoa4, Ssu72, Mrps30, Apoh, Acbd5, and Cdv3, exhibited regulation in the NOR-treated group to support the homeostasis of mitochondrial functions. Additionally, Dcx, Arid1b, Rnf112, and Fam3c, were also observed to undergo modulation in the NOR-treated groups to support the synaptic formation and functions. These findings suggest that the proteins involved in depression treatment exert effects in strengthen the mitochondrial and synaptic functions in the mice PFC. Western blot analysis supported the data that the levels of Mrpl42, Cox7c, Naa30, Rnf112, Dcx Apoa4, Apoh and Fam3c were altered in the CSDS mice, and rescued by NOR treatment, supporting the PRM data. NOR treatment also rescued the NLRP3 inflammasome activation in CSDS mice. In summary, the current proteomic research conducted on the prefrontal cortex has provided valuable insights into the specific and shared molecular mechanisms underlying pathophysiology and treatment to CSDS-induced depression, shedding light on the therapeutic effects of Norisoboldine.
重度抑郁症(MDD)是一种常见疾病,影响着全球 3 亿人。现有药物对大约 30% 的患者无效,因此开发具有新机制的新型抗抑郁药物迫在眉睫。在这里,我们发现诺异波定(NOR)在慢性社会挫败应激(CSDS)抑郁模型的尾悬、强迫游泳和蔗糖消耗试验中显示出抗抑郁疗效。然后,我们利用药物治疗 CSDS 小鼠范例,从前额叶皮层分离并获得了 CSDS 与 CON(CSDSCON)、丙咪嗪(IMI)治疗与 CSDS(IMICSDS)以及 NOR 治疗与 CSDS(NORCSDS)的不同蛋白质组。这些蛋白质表达的变化首先通过方差分析进行了分析,CSDS 组和 NORIMI 组的 p 支持方差分析的结果。我们采用蛋白质-蛋白质相互作用(PPI)分析来研究 NORCSDS 和 NORIMI 的蛋白质,结果显示与线粒体核糖体和突触功能相关的蛋白质得到了富集。利用平行反应监测(PRM)进行的进一步独立分析表明,Cox7c、Mrp142、Naa30、Ighm、Apoa4、Ssu72、Mrps30、Apoh、Acbd5 和 Cdv3 在 NOR 处理组中表现出调节作用,以支持线粒体功能的平衡。此外,还观察到 Dcx、Arid1b、Rnf112 和 Fam3c 也在 NOR 处理组中受到调节,以支持突触的形成和功能。这些发现表明,参与抑郁治疗的蛋白质具有增强小鼠前脑功能区线粒体和突触功能的作用。Western印迹分析表明,CSDS小鼠体内Mrpl42、Cox7c、Naa30、Rnf112、Dcx Apoa4、Apoh和Fam3c的水平发生了改变,而NOR治疗可以挽救这些改变,这支持了PRM数据。NOR 治疗还能缓解 CSDS 小鼠 NLRP3 炎性体的激活。总之,目前对前额叶皮层进行的蛋白质组学研究为CSDS诱导的抑郁症的病理生理学和治疗提供了有价值的见解,揭示了诺力索波定的治疗效果。
{"title":"Quantitative proteomics combined independent PRM analysis reveals the mitochondrial and synaptic mechanism underlying norisoboldine's antidepressant effects.","authors":"Lei Li, Weijing Kan, Yi Zhang, Tianyi Wang, Feng Yang, Tengfei Ji, Gang Wang, Jing Du","doi":"10.1038/s41398-024-03127-z","DOIUrl":"10.1038/s41398-024-03127-z","url":null,"abstract":"<p><p>Major depressive disorder (MDD) is a common disease affecting 300 million people worldwide. The existing drugs are ineffective for approximately 30% of patients, so it is urgent to develop new antidepressant drugs with novel mechanisms. Here, we found that norisoboldine (NOR) showed an antidepressant efficacy in the chronic social defeat stress (CSDS) depression model in the tail suspension, forced swimming, and sucrose consumption tests. We then utilized the drug-treated CSDS mice paradigm to segregate and gain differential protein groups of CSDS versus CON (CSDS<sub>CON</sub>), imipramine (IMI)-treated versus CSDS (IMI<sub>CSDS</sub>), and NOR-treated versus CSDS (NOR<sub>CSDS</sub>) from the prefrontal cortex. These protein expression alterations were first analyzed by ANOVA with p < 0.05. The protein cluster 1 and cluster 3, in which the pattern of protein levels similar to the mood pattern, showed enrichment in functions and localizations related to mitochondrion, ribosome and synapses. Further GO analysis of the common proteins for NOR<sub>CSDS</sub> groups and NOR<sub>IMI</sub> groups supported the findings from ANOVA analysis. We employed Protein-Protein interaction (PPI) analysis to examine the proteins of NOR<sub>CSDS</sub> and NOR<sub>IMI,</sub> revealing an enrichment of the proteins associated with the mitochondrial ribosomal and synaptic functions. Further independent analysis using parallel reaction monitoring (PRM) revealed that Cox7c, Mrp142, Naa30, Ighm, Apoa4, Ssu72, Mrps30, Apoh, Acbd5, and Cdv3, exhibited regulation in the NOR-treated group to support the homeostasis of mitochondrial functions. Additionally, Dcx, Arid1b, Rnf112, and Fam3c, were also observed to undergo modulation in the NOR-treated groups to support the synaptic formation and functions. These findings suggest that the proteins involved in depression treatment exert effects in strengthen the mitochondrial and synaptic functions in the mice PFC. Western blot analysis supported the data that the levels of Mrpl42, Cox7c, Naa30, Rnf112, Dcx Apoa4, Apoh and Fam3c were altered in the CSDS mice, and rescued by NOR treatment, supporting the PRM data. NOR treatment also rescued the NLRP3 inflammasome activation in CSDS mice. In summary, the current proteomic research conducted on the prefrontal cortex has provided valuable insights into the specific and shared molecular mechanisms underlying pathophysiology and treatment to CSDS-induced depression, shedding light on the therapeutic effects of Norisoboldine.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366637","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/s41398-024-03136-y
Maximilian Tufvesson-Alm, Cajsa Aranäs, Sebastian Blid Sköldheden, Jesper Vestlund, Christian E Edvardsson, Elisabet Jerlhag
The underlying neurobiology of alcohol use disorder (AUD) is complex and needs further unraveling, with one of the key mechanisms being the gut-brain peptide ghrelin and its receptor (GHSR). However, additional substrates of the ghrelin pathway, such as liver-expressed antimicrobial peptide 2 (LEAP2), an endogenous GHSR inverse agonist, may contribute to this neurobiological framework. While LEAP2 modulates feeding and reward through central mechanisms, its effects on alcohol responses are unknown. The aim of the present study was therefore to identify the impact of central LEAP2 on the ability of alcohol to activate the mesolimbic dopamine system and to define its ability to control alcohol intake. These experiments revealed that central LEAP2 (i.e. into the third ventricle) prevented the ability of alcohol to cause locomotor stimulation in male mice, suppressed the memory of alcohol reward and attenuated the dopamine release in the nucleus accumbens caused by alcohol. Moreover, central LEAP2 reduced alcohol consumption in both male and female rats exposed to alcohol for 6 weeks before treatment. However, the serum levels of LEAP2 were similar between high- and low- alcohol-consuming (male) rats. Furthermore, central LEAP2 lowered the food intake in the alcohol-consuming male rats and reduced the body weight in the females. Collectively, the present study revealed that central LEAP2 mitigates alcohol-related responses in rodents, contributing to our understanding of the ghrelin pathway's role in alcohol effects.
{"title":"LEAP2, a ghrelin receptor inverse agonist, and its effect on alcohol-related responses in rodents.","authors":"Maximilian Tufvesson-Alm, Cajsa Aranäs, Sebastian Blid Sköldheden, Jesper Vestlund, Christian E Edvardsson, Elisabet Jerlhag","doi":"10.1038/s41398-024-03136-y","DOIUrl":"10.1038/s41398-024-03136-y","url":null,"abstract":"<p><p>The underlying neurobiology of alcohol use disorder (AUD) is complex and needs further unraveling, with one of the key mechanisms being the gut-brain peptide ghrelin and its receptor (GHSR). However, additional substrates of the ghrelin pathway, such as liver-expressed antimicrobial peptide 2 (LEAP2), an endogenous GHSR inverse agonist, may contribute to this neurobiological framework. While LEAP2 modulates feeding and reward through central mechanisms, its effects on alcohol responses are unknown. The aim of the present study was therefore to identify the impact of central LEAP2 on the ability of alcohol to activate the mesolimbic dopamine system and to define its ability to control alcohol intake. These experiments revealed that central LEAP2 (i.e. into the third ventricle) prevented the ability of alcohol to cause locomotor stimulation in male mice, suppressed the memory of alcohol reward and attenuated the dopamine release in the nucleus accumbens caused by alcohol. Moreover, central LEAP2 reduced alcohol consumption in both male and female rats exposed to alcohol for 6 weeks before treatment. However, the serum levels of LEAP2 were similar between high- and low- alcohol-consuming (male) rats. Furthermore, central LEAP2 lowered the food intake in the alcohol-consuming male rats and reduced the body weight in the females. Collectively, the present study revealed that central LEAP2 mitigates alcohol-related responses in rodents, contributing to our understanding of the ghrelin pathway's role in alcohol effects.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446955/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366635","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/s41398-024-03118-0
Illana Gozes, Jason Blatt, Alexandra Lobyntseva
Background: The tauopathy inhibitor, davunetide shows sex-dependent efficacy in women suffering from progressive supranuclear palsy. Extending these findings to prodromal Alzheimer's disease, we submitted a double-blind, placebo-controlled, 12 weeks/16 weeks follow-up, davunetide clinical trial results in amnestic mild cognitive impairment (ClinicalTrials.gov ID NCT00422981), to a sex-dependent analysis.
Methods: One hundred forty-four individuals, separated into eight groups (1:2 placebo-and 2 doses, 5 mg davunetide/daily or 15 mg davunetide/twice-daily, with matching placebo intranasal volumes), were evaluated.
Results: Significant dose-dependent cognitive increases were observed in men compared to women with a test of delayed (12 ss) visual matching to the sample. In a test of semantic working memory and attention (digit span), women showed a significant low-dose placebo effect, ensuing in a high dose significant davunetide improvement, over the matched placebo. Correlating anxiety with cognition showed sex-opposing results, with women depicting significant anxiety correlations with delayed matching to sample.
Discussion: In conclusion, sex-specific prodromal Alzheimer's drug development is encouraged, with davunetide playing a lead initiative role.
背景:tauopathy抑制剂达呋奈肽对患有进行性核上性麻痹的女性具有性别依赖性疗效。为了将这些发现推广到阿尔茨海默病的前驱期,我们提交了一项双盲、安慰剂对照、12周/16周随访、达武内肽治疗失忆性轻度认知障碍的临床试验结果(ClinicalTrials.gov ID NCT00422981),并进行了性别依赖性分析:方法:将144人分为8组(1:2安慰剂和2个剂量,5毫克达武尼肽/天或15毫克达武尼肽/天两次,同时配合安慰剂鼻内用量)进行评估:在对样本进行延迟(12 秒)视觉匹配测试时,男性的认知能力明显高于女性。在语义工作记忆和注意力(数字跨度)测试中,女性表现出显著的低剂量安慰剂效应,而高剂量达芙尼肽则比匹配的安慰剂有显著改善。将焦虑与认知相关联的结果与性别相反,女性在延迟与样本匹配的情况下表现出显著的焦虑相关性:总之,我们鼓励开发针对不同性别的阿尔茨海默氏症前驱期药物,其中达呋奈肽将发挥主导作用。
{"title":"Davunetide sex-dependently boosts memory in prodromal Alzheimer's disease.","authors":"Illana Gozes, Jason Blatt, Alexandra Lobyntseva","doi":"10.1038/s41398-024-03118-0","DOIUrl":"10.1038/s41398-024-03118-0","url":null,"abstract":"<p><strong>Background: </strong>The tauopathy inhibitor, davunetide shows sex-dependent efficacy in women suffering from progressive supranuclear palsy. Extending these findings to prodromal Alzheimer's disease, we submitted a double-blind, placebo-controlled, 12 weeks/16 weeks follow-up, davunetide clinical trial results in amnestic mild cognitive impairment (ClinicalTrials.gov ID NCT00422981), to a sex-dependent analysis.</p><p><strong>Methods: </strong>One hundred forty-four individuals, separated into eight groups (1:2 placebo-and 2 doses, 5 mg davunetide/daily or 15 mg davunetide/twice-daily, with matching placebo intranasal volumes), were evaluated.</p><p><strong>Results: </strong>Significant dose-dependent cognitive increases were observed in men compared to women with a test of delayed (12 ss) visual matching to the sample. In a test of semantic working memory and attention (digit span), women showed a significant low-dose placebo effect, ensuing in a high dose significant davunetide improvement, over the matched placebo. Correlating anxiety with cognition showed sex-opposing results, with women depicting significant anxiety correlations with delayed matching to sample.</p><p><strong>Discussion: </strong>In conclusion, sex-specific prodromal Alzheimer's drug development is encouraged, with davunetide playing a lead initiative role.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446927/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366606","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/s41398-024-03069-6
Xian-Tao Li
Depression is a common and complex psychiatric illness with multiple clinical symptoms, even leading to the disability and suicide. Owing to the partial understanding of the pathogenesis of depressive-like disorders, available pharmacotherapeutic strategies are developed mainly based on the "monoamine hypothesis", resulting in a limited effectiveness and a number of adverse effects in the clinical practice. The concept of multiple pathogenic factors be helpful for clarifying the etiology of depression and developing the antidepressants. It is well documented that K+ channels serve crucial roles in modulating the neuronal excitability and neurotransmitter release in the brain, and abnormality of these channels participated in the pathogenic process of diverse central nervous system (CNS) pathologies, such as seizure and Alzheimer's disease (AD). The clinical and preclinical evidence also delineates that the involvement of several types of K+ channels in depressive-like behaviors appear to be evident, suggesting these channels being one of the multiple factors in the etiology of this debilitating disorder. Emerging data manifest that diverse antidepressants impact distinct K+ channels, such as Kv, Kir and K2P, meaning the functioning of these drug via a "multi-target" manner. On the other hand, the scenario of antidepressants impinging K+ channels could render an alternative interpretation for the pharmacological effectiveness and numerous side effects in clinical trials. Furthermore, these channels serve to be considered as a "druggable target" to develop novel therapeutic compound to antagonize this psychiatry.
{"title":"The involvement of K<sup>+</sup> channels in depression and pharmacological effects of antidepressants on these channels.","authors":"Xian-Tao Li","doi":"10.1038/s41398-024-03069-6","DOIUrl":"10.1038/s41398-024-03069-6","url":null,"abstract":"<p><p>Depression is a common and complex psychiatric illness with multiple clinical symptoms, even leading to the disability and suicide. Owing to the partial understanding of the pathogenesis of depressive-like disorders, available pharmacotherapeutic strategies are developed mainly based on the \"monoamine hypothesis\", resulting in a limited effectiveness and a number of adverse effects in the clinical practice. The concept of multiple pathogenic factors be helpful for clarifying the etiology of depression and developing the antidepressants. It is well documented that K<sup>+</sup> channels serve crucial roles in modulating the neuronal excitability and neurotransmitter release in the brain, and abnormality of these channels participated in the pathogenic process of diverse central nervous system (CNS) pathologies, such as seizure and Alzheimer's disease (AD). The clinical and preclinical evidence also delineates that the involvement of several types of K<sup>+</sup> channels in depressive-like behaviors appear to be evident, suggesting these channels being one of the multiple factors in the etiology of this debilitating disorder. Emerging data manifest that diverse antidepressants impact distinct K<sup>+</sup> channels, such as Kv, Kir and K<sub>2P</sub>, meaning the functioning of these drug via a \"multi-target\" manner. On the other hand, the scenario of antidepressants impinging K<sup>+</sup> channels could render an alternative interpretation for the pharmacological effectiveness and numerous side effects in clinical trials. Furthermore, these channels serve to be considered as a \"druggable target\" to develop novel therapeutic compound to antagonize this psychiatry.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366638","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/s41398-024-03099-0
James D Clelland, Hannah Hesson, Krista Ramiah, Julia Anderson, Abraham Thengampallil, Ragy R Girgis, Catherine L Clelland
Individuals at clinical high-risk (CHR) of developing psychosis, as well as patients with recent psychosis onset (RO), experience significant negative symptoms that detrimentally impact daily-life functioning and are associated with poor outcomes, even in those who do not convert to psychosis. Targeting negative symptoms may thus hold promise for the treatment of CHR and RO patients. Building from previous findings we examined whether the catechol-O-methyltransferase (COMT) Val158Met functional polymorphism and fasting peripheral proline concentration predicts the severity of negative symptoms experienced by adolescents and young adults at CHR or those with RO. As hypothesized, the interaction between fasting plasma proline and COMT predicted negative symptoms, as measured via the Scale for the Assessment of Negative Symptoms (SANS) total (n = 50, β = 0.066, adjusted p = 0.007) and global severity scores (n = 50, coefficient = 0.026, adjusted p = 0.003): Higher proline was beneficial for Val/Val subjects, but detrimental to those with the Met allele. In a secondary analysis, the COMT x proline interaction also predicted symptoms measured via the Clinical Assessment Interview for Negative Symptoms (CAINS) total scores (n = 50, β-coefficient = 0.035, adjusted p = 0.044), although this result did not reach the Benjamini-Hochberg's threshold for significance. Further, there was a trend towards significance for an association with social and interpersonal function (Global Functioning-Social, coefficient = -0.005, adjusted p = 0.055). Negative symptoms are intractable and largely unaddressed by current medications. This study further supports a relationship between peripheral proline and COMT influencing negative symptoms such as anhedonia, in young CHR individuals and those with RO. That higher proline has converse effects on symptoms by COMT may have implications for the development of therapeutics to intervene early and specifically target the interaction pathway.
罹患精神病的临床高危人群(CHR)以及近期发病的精神病患者(RO)都会出现严重的负面症状,这些症状会对日常生活功能产生不利影响,并与不良预后有关,即使是那些没有转为精神病的患者也是如此。因此,针对消极症状的治疗可能会为治疗新近精神病发作(CHR)和新近精神病发作(RO)患者带来希望。在之前研究结果的基础上,我们研究了儿茶酚-O-甲基转移酶(COMT)Val158Met功能多态性和空腹外周脯氨酸浓度是否能预测CHR青少年和年轻成人或RO患者所经历的消极症状的严重程度。正如假设的那样,空腹血浆脯氨酸和 COMT 之间的相互作用可预测消极症状,通过消极症状评估量表(SANS)总分(n = 50,β = 0.066,调整后 p = 0.007)和总体严重性得分(n = 50,系数 = 0.026,调整后 p = 0.003)来衡量:较高的脯氨酸对 Val/Val 受试者有利,但对 Met 等位基因受试者不利。在一项辅助分析中,COMT x 脯氨酸交互作用也能预测通过消极症状临床评估访谈(CAINS)总分测量的症状(n = 50,β系数 = 0.035,调整后 p = 0.044),尽管这一结果未达到本杰明-霍奇伯格的显著性阈值。此外,与社交和人际交往功能(社交整体功能,系数 = -0.005,调整后 p = 0.055)的相关性也有显著性趋势。阴性症状很顽固,目前的药物基本上无法解决。这项研究进一步证实了外周脯氨酸与 COMT 之间的关系,这种关系会影响年轻 CHR 患者和 RO 患者的消极症状,如失乐症。较高的脯氨酸通过 COMT 对症状产生反向影响,这可能对开发早期干预和专门针对相互作用途径的治疗药物具有重要意义。
{"title":"The relationship between COMT, proline, and negative symptoms in clinical high risk and recent psychosis onset.","authors":"James D Clelland, Hannah Hesson, Krista Ramiah, Julia Anderson, Abraham Thengampallil, Ragy R Girgis, Catherine L Clelland","doi":"10.1038/s41398-024-03099-0","DOIUrl":"10.1038/s41398-024-03099-0","url":null,"abstract":"<p><p>Individuals at clinical high-risk (CHR) of developing psychosis, as well as patients with recent psychosis onset (RO), experience significant negative symptoms that detrimentally impact daily-life functioning and are associated with poor outcomes, even in those who do not convert to psychosis. Targeting negative symptoms may thus hold promise for the treatment of CHR and RO patients. Building from previous findings we examined whether the catechol-O-methyltransferase (COMT) Val<sup>158</sup>Met functional polymorphism and fasting peripheral proline concentration predicts the severity of negative symptoms experienced by adolescents and young adults at CHR or those with RO. As hypothesized, the interaction between fasting plasma proline and COMT predicted negative symptoms, as measured via the Scale for the Assessment of Negative Symptoms (SANS) total (n = 50, β = 0.066, adjusted p = 0.007) and global severity scores (n = 50, coefficient = 0.026, adjusted p = 0.003): Higher proline was beneficial for Val/Val subjects, but detrimental to those with the Met allele. In a secondary analysis, the COMT x proline interaction also predicted symptoms measured via the Clinical Assessment Interview for Negative Symptoms (CAINS) total scores (n = 50, β-coefficient = 0.035, adjusted p = 0.044), although this result did not reach the Benjamini-Hochberg's threshold for significance. Further, there was a trend towards significance for an association with social and interpersonal function (Global Functioning-Social, coefficient = -0.005, adjusted p = 0.055). Negative symptoms are intractable and largely unaddressed by current medications. This study further supports a relationship between peripheral proline and COMT influencing negative symptoms such as anhedonia, in young CHR individuals and those with RO. That higher proline has converse effects on symptoms by COMT may have implications for the development of therapeutics to intervene early and specifically target the interaction pathway.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366639","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/s41398-024-03101-9
João Paulo Lima Santos, Amelia Versace, Manan Arora, Michele A Bertocci, Henry W Chase, Alex Skeba, Simona Graur, Lisa Bonar, Chiara Maffei, Anastasia Yendiki, Steven A Rasmussen, Suzanne N Haber, Mary L Phillips
Obsessive-compulsive disorder is a psychiatric disorder characterized by intrusive thoughts and repetitive behaviors. There are two prominent features: Harm Avoidance (HA) and Incompleteness (INC). Previous resting-state studies reported abnormally elevated connectivity between prefrontal cortical (PFC) and subcortical regions (thalamus, striatum) in OCD participants. Yet, little is known about the white matter (WM) structural abnormalities in these connections. Using brain parcellation and segmentation, whole brain tractography, and Neurite Orientation Dispersion and Density Imaging (NODDI), we aimed to characterize WM structural abnormalities in OCD vs. healthy controls and determine the extent to which NODDI indices of these connections were associated with subthreshold-threshold HA, INC and overall OCD symptom severity across all participants. Four PFC regions were segmented: ventral medial (vmPFC), ventrolateral (vlPFC), dorsomedial (dmPFC), and dorsolateral (dlPFC). NODDI Neurite Density (NDI) and Orientation Dispersion (ODI) indices of WM structure were extracted from connections between these PFC regions and the thalamus (42 OCD, 44 healthy controls, mean age[SD] = 23.65[4.25]y, 63.9% female) and striatum (38 OCD, 41 healthy controls, mean age[SD] = 23.59[4.27]y, 64.5% female). Multivariate analyses of covariance revealed no between-group differences in these indices. Multivariate regression models revealed that greater NDI in vmPFC-thalamus, greater NDI and ODI in vmPFC-striatum, and greater NDI in dmPFC-thalamus connections were associated with greater INC severity (Q ≤ 0.032). These findings highlight the utility of NODDI in the examination of WM structure in OCD, provide valuable insights into specific WM alterations underlying dimensional INC, and can facilitate the development of customized treatments for OCD individuals with treatment-resistant symptoms.
{"title":"Examining relationships among NODDI indices of white matter structure in prefrontal cortical-thalamic-striatal circuitry and OCD symptomatology.","authors":"João Paulo Lima Santos, Amelia Versace, Manan Arora, Michele A Bertocci, Henry W Chase, Alex Skeba, Simona Graur, Lisa Bonar, Chiara Maffei, Anastasia Yendiki, Steven A Rasmussen, Suzanne N Haber, Mary L Phillips","doi":"10.1038/s41398-024-03101-9","DOIUrl":"10.1038/s41398-024-03101-9","url":null,"abstract":"<p><p>Obsessive-compulsive disorder is a psychiatric disorder characterized by intrusive thoughts and repetitive behaviors. There are two prominent features: Harm Avoidance (HA) and Incompleteness (INC). Previous resting-state studies reported abnormally elevated connectivity between prefrontal cortical (PFC) and subcortical regions (thalamus, striatum) in OCD participants. Yet, little is known about the white matter (WM) structural abnormalities in these connections. Using brain parcellation and segmentation, whole brain tractography, and Neurite Orientation Dispersion and Density Imaging (NODDI), we aimed to characterize WM structural abnormalities in OCD vs. healthy controls and determine the extent to which NODDI indices of these connections were associated with subthreshold-threshold HA, INC and overall OCD symptom severity across all participants. Four PFC regions were segmented: ventral medial (vmPFC), ventrolateral (vlPFC), dorsomedial (dmPFC), and dorsolateral (dlPFC). NODDI Neurite Density (NDI) and Orientation Dispersion (ODI) indices of WM structure were extracted from connections between these PFC regions and the thalamus (42 OCD, 44 healthy controls, mean age[SD] = 23.65[4.25]y, 63.9% female) and striatum (38 OCD, 41 healthy controls, mean age[SD] = 23.59[4.27]y, 64.5% female). Multivariate analyses of covariance revealed no between-group differences in these indices. Multivariate regression models revealed that greater NDI in vmPFC-thalamus, greater NDI and ODI in vmPFC-striatum, and greater NDI in dmPFC-thalamus connections were associated with greater INC severity (Q ≤ 0.032). These findings highlight the utility of NODDI in the examination of WM structure in OCD, provide valuable insights into specific WM alterations underlying dimensional INC, and can facilitate the development of customized treatments for OCD individuals with treatment-resistant symptoms.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366610","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}