PROSPECTIVE STUDIES OF THE PATHOGENESIS OF SCHIZOPHRENIA

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 精神分裂症与MRI上脑结构的细微异常有关，包括侧脑室扩大、皮质灰质体积减少、海马体积减少以及白色物质中的异常扩散特性。虽然有人假设这些大脑异常出现在早期大脑发育过程中，但几乎没有直接证据支持这一观点。在Conte中心项目的第一个资助期内，我们开发了磁共振图像（MRI）采集和图像分析工具，以研究精神分裂症高危儿童的早期大脑发育。其中包括一个遗传性高风险组-精神分裂症妇女的后代，和一个“结构性”高风险组-产前孤立性轻度脑室扩大的儿童。我们的研究结果表明，与正常对照组相比，患有精神分裂症的母亲的后代在新生儿MRI上的皮质灰质体积减少。这是第一个具体的证据表明，早期皮质发育受到遗传脆弱性的影响。围产期和出生后早期是皮层连接发展的关键时期之一-突触快速生长的时期-这是康特中心的重点。此外，我们还建立了一个大型的正常对照队列。在第二个资助期，我们建议继续研究正常和高危儿童的每一个早期大脑发育，应用我们新颖的图像分析方法来研究扩大队列中的灰质和白色物质发育，并研究纵向大脑发育变化，因为我们跟随我们的队列进入童年中期。具体来说，我们将研究纵向脑发育的儿童在精神分裂症的高风险与3 T MRI（包括扩散张量成像）和神经发育评估在0岁，1岁，2岁，4岁和6岁。我们还将研究双相情感障碍母亲的后代的早期大脑发育，作为药物和慢性疾病非特异性影响的对照组。最后，我们获得了大量正常新生儿的DNA和MRI，并将确定风险基因的多态性是否影响生命最早阶段的皮质发育。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Schizophrenia is associated with subtle abnormalities of brain structure on MRI, including enlarged lateral ventricles, reduced cortical gray matter volumes, reduced hippocampal volumes, as well as abnormal diffusion properties in white matter. While it has been hypothesized that these brain abnormalities arise during early brain development, there has been little direct evidence to support this idea. In the first funding period of this Conte Center project, we developed the magnetic resonance image (MRI) acquisition and image analysis tools to study very early brain development in children at high risk for schizophrenia. These included a genetic high risk group - the offspring of women with schizophrenia, and a "structural" high risk group - children with prenatal isolated mild ventriculomegaly. Our results to data indicate that compared to normal controls, the offspring of mothers with schizophrenia have reduced cortical gray matter volumes on neonatal MRI. This is the first concrete evidence that early cortical development is compromised by genetic vulnerability. The perinatal and early postnatal period is one of the critical periods in the development of cortical connectivity - a time of rapid synapse growth - one that is a focus of this Conte Center. In addition, we have developed a large cohort of normal controls. In the second funding period, we propose to continue our study of every early brain development in normal and high risk children, applying our novel image analysis methodologies to study gray and white matter development in an expanding cohort, and to study longitudinal brain developmental changes as we follow our cohort into mid childhood. Specifically we will study longitudinal brain development in children at high risk for schizophrenia with 3T MRI (including diffusion tensor imaging) and neurodevelopmental assessments at ages 0, 1, 2, 4, and 6 years of age. We will also study early brain development in the offspring of mothers with bipolar illness as a comparison group for non-specific effects of medication and chronic illness. Finally, we have obtained DNA and MRIs on a large group of normal neonates and will determine if polymorphisms of risk genes influence cortical development at this earliest stage of life.