Frontal-Subcortical Development, Movement Abnormalities, and Risk for Psychosis

描述(申请人提供)：精神障碍，如精神分裂症，与额叶功能障碍以及皮质下区域的异常调节有关。一项创新的理论表明，连接这两个区域(额叶-皮质下回路；FSCS)的系统缺陷可能是精神病患者出现的一系列症状和特征的原因。最近的研究发现，在精神障碍正式发病之前的前驱症状期间，额叶和内侧颞叶区域的灰质和白质发育异常，这表明成熟变化与精神障碍的病因学高度相关。尽管有证据表明成熟因素在精神病的病因学概念化中起着突出的作用，但FSC系统中的神经成熟如何可能有助于精神病的症状或特征行为尚不清楚；到目前为止，还没有发表的研究检查这一关键系统中高危参与者的灰质和白质的纵向变化。然而，了解疾病之前的神经重组是不可或缺的，因为它可以在广泛使用药物和神经毒性可能扰乱明确理解之前阐明潜在的致病机制，并进一步在检测和治疗高危青少年的背景下导致识别脆弱性的生物标记物-指示哪些高危个体最有可能转化为精神病。一系列强有力的证据表明，基于发育期的FSC变化与新出现的精神病有关，表明自发运动异常(SMA)(即运动障碍和帕金森症)被认为反映了FSC系统受损，在青春期变得突出，频率/严重程度随着年龄的增长而继续发展，与症状相关，并预测最终转变为正式的精神病。然而，到目前为止，尚不清楚哪些特定的成熟变化可能是SMA的基础，或者这些运动是否确实是进行性FSC功能障碍的标志。此外，到目前为止，高危人群中的SMA仅通过基于观察者的测量和最近在精神病人群中的研究进行评估，这表明基于工具的SMA测量明显更敏感，这暗示了一种可行的生物标记物的前景。这项拟议的研究将检验这一假设，即前驱症状青少年中灰质和连接白质束的不规则发育导致FSC的变化，导致SMA、前驱症状，最终导致精神病的发生。我们建议利用SMAS的仪器测量(即力变异性和速度标度)、磁共振成像(MRI)和扩散张量成像(DTI)来检查构成FSC系统的结构和连接束，跟踪75名患有前驱综合征的青少年(年龄12-21岁)，和75名配对的健康对照，在一年的时间里(基线和按年随访)，以确定SMAS的神经发育基础(如果FSC系统中灰质和白质的特定发育模式表征了前驱体人群并导致运动障碍和/或帕金森综合症)，以及该系统和SMA(可能直接反映这种病理的潜在生物标记物)的发育异常是否预测了较差的病程。 与公共卫生相关：了解大脑在青春期是如何变化的，这一时期的特点是显著的神经重组，而且紧接在精神分裂症等精神障碍的典型发病年龄之前，这对于改善我们对导致这些障碍的原因的概念是必要的，这可能有助于努力识别、提供早期治疗，并随后改善这些障碍高危青少年的病程。这项拟议的研究对患有精神障碍的高危青少年进行为期一年的调查，以确定额叶皮质下回路系统中的大脑发育，连接额叶和皮质下脑区的大脑区域(在患有正式精神障碍的成年人中都是高度相关的区域)是否有助于患上精神病，以及运动异常(也是患有精神病的成年人的特征)是否反映额叶皮质下回路系统的异常发育，从而可以用作易于检测的标记物来提高鉴别力，从而暗示这些高危青少年更容易患上精神病。

DESCRIPTION (provided by applicant): Psychotic disorders such as schizophrenia have been associated with both frontal lobe dysfunction as well as abnormal regulation of subcortical regions. An innovative theory suggests that deficits in the system linking these two areas (the frontal-subcortical circuits; FSCs) may account for the wide range of symptoms and characteristics seen in psychotic disorders. Recent research detecting abnormal grey and white matter development in the frontal and medial temporal regions during the prodrome, a period proceeding formal onset of psychotic disorders, suggests that maturational changes are highly relevant in the etiology of psychotic disorders. Despite the evidence suggesting a prominent role of maturational factors in etiological conceptualizations of psychosis, it is unclear how neuromaturation in the FSC system may contribute to symptoms or characteristic behaviors of psychosis; to date no published studies have examined longitudinal grey and white matter changes in high-risk participants in this critical system. However, understanding the neural-reorganization preceding illness is integral as it stands to elucidate underlying pathogenic mechanisms prior to when widespread medication usage and neurotoxicity may confound clear understanding and further, within the context of detecting and treating high-risk adolescents, can lead to identifying biological markers of vulnerability- indicating which high-risk individuals are most likely to convert to psychosis. A strong line of evidence implicating that developmentally based FSC changes are tied to emerging psychosis, indicates that spontaneous movement abnormalities (SMAs) (i.e., dyskinesia and Parkinsonisms), presumed to reflect a compromised FSC system, become salient during adolescence, continue to progress in frequency/severity with age, are associated with symptoms, and predict eventual conversion to formal psychosis. However, to date it is unclear which particular maturational changes may underlie SMAs, or if these movements do indeed serve as a marker of progressive FSC dysfunction. Further, to date SMAs in high-risk populations have only been assessed with observer-based measures, and recent studies in psychotic populations, suggesting that instrumentally based measures of SMA are significantly more sensitive, hint at promise for a viable biomarker. The proposed study will test the hypothesis that irregular development in grey and connective white matter tracts among prodromal adolescents contributes to alterations in FSC, resulting in SMAs, prodromal symptoms, and eventually the onset of psychosis. We propose to utilize instrumental measures of SMAs (i.e., Force Variability and Velocity Scaling), magnetic resonance imaging (MRI), and diffusion tensor imaging (DTI), to examine structures and connective tracts comprising the FSC system, following groups of 75 adolescents with a prodromal syndrome (age 12-21), and 75 matched healthy controls over the period of one-year (baseline and on year follow-up) to determine the neurodevelopmental underpinnings of SMAs (if specific developmental patterns of grey and white matter in the FSC system characterize prodromal populations and result in dyskinesias and/or Parkinsonisms) and if developmental abnormalities in this system and SMAs (a potential biomarker that may directly reflect this pathology) predict a poorer course of illness. PUBLIC HEALTH RELEVANCE: Understanding how the brain changes during adolescence, a period that is characterized by significant neural- restructuring and also immediately precedes the typical age of onset for psychotic disorders such as schizophrenia, is necessary for improving our conceptions of what causes the disorders, and may help efforts to identify, provide early treatment, and subsequently improve the course of illness for adolescents at heightened risk for developing these disorders. The proposed research investigates adolescents at high-risk for developing psychotic disorders, for a period of one-year, to determine if brain development in the frontal subcortical circuit system, linking frontal and subcortical brain regions (both highly implicated regions in adults with formal psychotic disorders) contributes to developing psychosis, and if movement abnormalities (also characteristic of adults with psychosis) reflects abnormal development in the frontal subcortical circuit system, and can thereby be utilized as a readily detectable marker to improve identification, implicating those high-risk adolescents at heightened vulnerability for developing psychosis.