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

描述（由申请人提供）：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。一种创新的理论认为，连接这两个区域的系统（额叶-皮层下回路；FSCs）的缺陷可能解释了精神疾病中广泛的症状和特征。最近的研究发现，在精神障碍正式发病的前驱期，额叶和内侧颞叶区域的灰质和白质发育异常，表明成熟变化与精神障碍的病因高度相关。尽管有证据表明成熟因素在精神病的病因学概念中起着突出作用，但尚不清楚FSC系统的神经成熟如何导致精神病的症状或特征行为；到目前为止，还没有发表的研究调查了这一关键系统中高风险参与者的纵向灰质和白质变化。然而，了解疾病前的神经重组是不可或缺的，因为它可以在广泛的药物使用和神经毒性可能混淆清晰的理解之前阐明潜在的致病机制，并且在检测和治疗高危青少年的背景下，可以导致识别易感性的生物学标记-指示哪些高危个体最有可能转化为精神病。强有力的证据表明，基于发育的FSC变化与新发精神病有关，表明自发运动异常（sma）（即运动障碍和帕金森病）被认为反映了FSC系统的受损，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，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FSC进行性功能障碍的标志。此外，到目前为止，高风险人群的SMA仅通过基于观察者的测量来评估，最近对精神病人群的研究表明，基于仪器的SMA测量显着更敏感，这暗示了可行的生物标志物的希望。该研究将验证前驱青少年灰质束和结缔组织白质束的不规则发育导致FSC的改变，从而导致sma、前驱症状和最终精神病发作的假设。我们建议利用sma的仪器测量（即力变异性和速度尺度）、磁共振成像（MRI）和弥散张量成像（DTI）来检查构成FSC系统的结构和结缔组织束，以下是75组患有前驱综合征的青少年（12-21岁）。在一年的时间里（基线和一年的随访），以确定sma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前驱人群并导致运动障碍和/或帕金森症），以及该系统和sma的发育异常（可能直接反映这种病理的潜在生物标志物）是否预示着较差的病程。

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.