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

描述（由申请人提供）：精神疾病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。一个创新的理论表明，连接这两个区域的系统（额叶皮层下回路; FSC）的缺陷可能解释了精神障碍中出现的广泛症状和特征。最近的研究检测异常的灰色和白色物质的发展，在额叶和内侧颞区的前驱症状，一个时期进行正式发病的精神病性障碍，表明成熟的变化是高度相关的精神病性障碍的病因。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，但目前还不清楚FSC系统中的神经成熟如何有助于精神病的症状或特征行为;迄今为止，还没有发表的研究检查了这一关键系统中高危参与者的纵向灰质和白色物质变化。然而，了解神经重组之前的疾病是不可或缺的，因为它代表阐明潜在的致病机制之前，广泛的药物使用和神经毒性可能混淆明确的理解，并进一步，在检测和治疗高危青少年的背景下，可以导致识别脆弱性的生物标志物-表明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，基于发育的FSC变化与新出现的精神病有关，这表明自发运动异常（SMA）（即，运动障碍和帕金森综合征），被认为反映了FSC系统受损，在青春期变得突出，随着年龄的增长，频率/严重程度继续增加，与症状相关，并预测最终转化为正式精神病。然而，到目前为止，还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可以作为进行性FSC功能障碍的标志。此外，迄今为止，仅使用基于工具的测量方法评估了高危人群中的SMA，最近在精神病人群中进行的研究表明，基于工具的SMA测量方法显着更敏感，暗示了可行生物标志物的前景。拟议的研究将测试的假设，灰色和结缔组织白色物质束的不规则发展的前驱青少年之间的FSC的改变，导致SMA，前驱症状，并最终精神病的发作。我们建议利用SMA的工具性措施（即，力变异性和速度标度）、磁共振成像（MRI）和扩散张量成像（DTI），以检查构成FSC系统的结构和连接束，随访75例前驱综合征青少年（12-21岁），和75名匹配的健康对照者在一年的时间里（基线和一年随访），以确定SMA的神经发育基础（如果FSC系统中灰质和白色物质的特定发育模式表征前驱人群并导致运动障碍和/或帕金森病）以及该系统和SMA（可能直接反映这种病理的潜在生物标志物）的发育异常是否预示着疾病进程更差。

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.