Neurodevelopment of Mesolimbic Afferents in Healthy Adolescents and First-Episode Psychosis

健康青少年和首发精神病中脑边缘传入神经发育

• 批准号: 10227963
• 负责人: Vishnu Pradeep Murty
• 金额: $ 16.57万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-09 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227963
• 关键词: Adolescence; Adolescent; Adolescent Development; Adult; Age; Age-Years; Animal Model; Antipsychotic Agents; Award; Behavior; Biological Assay; Caregivers; Chronic; Clinical; Communities; Data Analyses; Deterioration; Development; Diffusion; Disease; Dopamine; Economics; Emotional; Etiology; Foundations; Functional Magnetic Resonance Imaging; Functional disorder; Grant; Hippocampus (Brain); Human; Individual; Intervention; Investigation; K-Series Research Career Programs; Knowledge; Learning; Measures; Medial; Mediating; Mentors; Modeling; Nature; Participant; Pathology; Pathway Analysis; Patients; Pharmaceutical Preparations; Phase; Play; Population; Positron-Emission Tomography; Prefrontal Cortex; Psychopathology; Psychoses; Regulation; Research; Research Domain Criteria; Research Training; Rest; Rewards; Risk; Role; Sampling; Schizophrenia; Signal Transduction; Structure; Substantia nigra structure; System; Systems Development; Techniques; Testing; Time; Training; Translating; Translations; Universities; Ventral Tegmental Area; Visit; Work; archive data; archived data; base; clinical predictors; cognitive neuroscience; dopamine system; dopaminergic neuron; emerging adult; first episode psychosis; follow-up; insight; lens; mesolimbic system; multimodality; neurodevelopment; neuroimaging; neuroimaging marker; neuroregulation; novel; phenomenological models; programs; recruit; relating to nervous system; remediation; social; spectrograph; translational neuroscience; white matter; young adult

Project Summary/Abstract The objective of this Career Development Award is to support new mentored training in cognitive neuroscience studies of dopamine-related function in healthy adolescents and first-episode psychosis, as the candidate begins an independent research program. Psychosis is a devastating illness that afflicts ~3% of the world’s population, and has sever economic and social/emotional consequences for both patients and their caregivers. Prior research has implicated deficits in dopamine systems in both the etiology and pathology of the disorder, and thus remediation of this system has been a prominent target for intervention. Although these deficits have been well documented, open questions remains as to how and why these deficits emerge. Prominent models of psychosis have implicated aberrant development of neural systems regulating the activation of dopamine systems. However, very little research has investigated how these regulatory systems develop in normative populations; let alone how deviations from normative development may be implicated in psychosis. Thus, a full understanding of psychosis necessitates a characterization of dopamine-related networks in healthy adolescence and deviations from these trajectories in psychosis. These findings will provide insight into determinants of risk for conversion from a developmental perspective and in turn the timing of interventions. The proposed award will build upon the candidate’s prior training in cognitive neuroscience, to extend this knowledge into the domain of normative development in adolescents and aberrant development in psychosis within dopamine-related networks. Aim 1 will investigate the normative development of neural systems regulating engagement of the ventral tegmental area and substantia nigra, the core of the mesolimbic dopamine system, using multimodal neuroimaging. These developmental neuroimaging markers will then be associated with direct and indirect measures of dopamine to assess how they relate to dopaminergic function. Aim 2 will evaluate how individuals with first-episode psychosis deviate from the normative trajectories characterized in Aim 1, and further probe how these deviations relate to anti-psychotic medication status. Finally, Aim 3 will have first-episode patients return for a 2-year follow-up to characterize how the clinical course of psychosis relates to early markers of dopamine-related dysfunction. Mentored training will compliment the candidate’s expertise in neuroimaging of dopamine-related circuits in healthy adults. Paralleling the proposed research, training will focus on the candidate gaining expertise in conducting neuroimaging studies in adolescent (Aim 1) and psychosis populations (Aim 2,3). Further, the candidate will gain expertise in the translation of animal models of behavior in adolescent and psychosis population, with a focus on understanding the nature of homology across multiple species (Aims 1-3). Finally, the candidate will gain expertise in experimental techniques associated with studying neurodevelopment (e.g., longitudinal data analysis; Aims 1-3), psychosis (e.g., adjustment for antipsychotic medication, characterizing clinical phenomenology; Aims 2-3), and translational neuroscience (e.g., integration of direct/indirect measures of dopamine; Aim 3). The candidate has recruited a mentoring team with expertise in all of the above domains led by mentor Dr. Bea Luna, an expert in adolescent development, and co-mentor Deanna Barch, an expert in neuroimaging in psychosis populations. Further, the candidate will take advantage of the known strengths of the schizophrenia and adolescent research communities, as well as the emphasis on cross-species translation at the University of Pittsburgh. The proposed research will offer novel insight into dopamine dysfunction in psychosis through the lens of adolescent neurodevelopment. Further, the training will lay the foundation for an independent research program assaying the neurodevelopmental of neuromodulatory systems in psychosis. !

项目总结/摘要 该职业发展奖的目的是支持认知神经科学的新导师培训 健康青少年和首发精神病患者的多巴胺相关功能研究，作为候选人 开始独立的研究计划。精神病是一种毁灭性的疾病，折磨着世界上约3%的人。 人口，并对患者及其护理人员造成严重的经济和社会/情感后果。 先前的研究表明，多巴胺系统的缺陷与该疾病的病因和病理学有关， 因此，该系统的补救已成为干预的突出目标。尽管这些赤字 尽管有充分的文献记载，但这些赤字是如何以及为何出现的，仍存在一些悬而未决的问题。突出的模式 精神病的发病与调节多巴胺激活的神经系统的异常发育有关 系统.然而，很少有研究调查这些监管制度如何发展， 更不用说偏离正常发展可能与精神病有关。一个完整的 精神病的理解需要对健康人中多巴胺相关网络的特征进行描述。 青春期和精神病偏离这些轨迹。这些发现将提供深入了解 从发展的角度来看，风险转换的决定因素，反过来又是干预措施的时机。 拟议的奖项将建立在候选人在认知神经科学方面的先前培训的基础上， 这些知识进入青少年的规范发展和青少年的异常发展领域， 多巴胺相关网络中的精神病目的1：探讨神经系统发育的规范性 调节腹侧被盖区和黑质（中脑边缘系统的核心）参与的系统 多巴胺系统，使用多模态神经成像。这些发育神经影像学标记物将被 与多巴胺的直接和间接测量相关，以评估它们与多巴胺能功能的关系。 目标2将评估首发精神病患者如何偏离正常轨迹 特征在于目的1，并进一步探讨这些偏差如何与抗精神病药物治疗状态相关。 最后，Aim 3将让首次发作患者返回进行2年随访，以描述临床 精神病的病程与多巴胺相关功能障碍的早期标志物有关。指导培训将 称赞候选人在健康成年人多巴胺相关回路神经成像方面的专业知识。 除了拟议的研究，培训将侧重于候选人获得专业知识，在进行 青少年（目标1）和精神病人群（目标2，3）的神经影像学研究。此外，候选人将 获得在青少年和精神病人群的行为动物模型的翻译专业知识， 专注于理解跨多个物种的同源性的本质（目标1-3）。最后，候选人将 获得与研究神经发育相关的实验技术的专业知识（例如，纵向数据 分析;目的1-3），精神病（例如，调整抗精神病药物，表征临床 现象学;目标2-3），和转化神经科学（例如，直接/间接措施的综合 多巴胺; Aim 3）。候选人已经招募了一个在上述所有领域都有专业知识的指导团队， 由导师Bea Luna博士，青少年发展专家，和共同导师Deanna Barch， 精神病人群的神经影像学研究。此外，候选人将利用 精神分裂症和青少年研究社区，以及对跨物种翻译的重视 在匹兹堡大学。这项拟议中的研究将为多巴胺功能障碍提供新的见解， 通过青少年神经发育的透镜来观察精神病。此外，培训将奠定基础， 独立的研究项目，分析精神病中神经调节系统的神经发育。 !

项目成果

Differential patterns of contextual organization of memory in first-episode psychosis.

• DOI: 10.1038/s41537-018-0046-8
• 发表时间: 2018-02-15
• 期刊: NPJ schizophrenia
• 影响因子: 5.4
• 作者: Murty VP;McKinney RA;DuBrow S;Jalbrzikowski M;Haas GL;Luna B
• 通讯作者: Luna B

Memory for social interactions throughout early childhood.

整个幼儿期的社交互动记忆。

• DOI: 10.1016/j.cognition.2020.104324
• 发表时间: 2020
• 期刊: Cognition
• 影响因子: 3.4
• 作者: Murty,VishnuP;Fain,MatthewR;Hlutkowsky,Christina;Perlman,SusanB
• 通讯作者: Perlman,SusanB

Decision uncertainty during hypothesis testing enhances memory accuracy for incidental information.

• DOI: 10.1101/lm.053458.121
• 发表时间: 2022-04
• 期刊: Learning & memory (Cold Spring Harbor, N.Y.)
• 作者: Shen X;Ballard IC;Smith DV;Murty VP
• 通讯作者: Murty VP

Children show adult-like hippocampal pattern similarity for familiar but not novel events.

对于熟悉但不新颖的事件，儿童表现出类似成人的海马模式相似性。

• DOI: 10.1016/j.brainres.2022.147991
• 发表时间: 2022-09-15
• 期刊: Brain research
• 影响因子: 2.9

Context-specific abnormalities of the central executive network in first-episode psychosis: relationship with cognition.

• DOI: 10.1017/s0033291720004201
• 发表时间: 2022-09
• 期刊: PSYCHOLOGICAL MEDICINE
• 影响因子: 6.9
• 作者: Sarpal, Deepak K.;Tarcijonas, Goda;Calabro, Finnegan J.;Foran, William;Haas, Gretchen L.;Luna, Beatriz;Murty, Vishnu P.
• 通讯作者: Murty, Vishnu P.