Multimodal dMRI, MRS and MEG studies of language impairment in low-verbal ASD

项目总结 在之前的工作中，我们扩展了我们的多模式脑磁图(MEG)和磁共振 成像(MRI)方法，并已表明有可能建模，或预测，听觉的潜伏期 诱发的神经磁场成分，M50，发生在儿童刺激后大约50-100ms， 但在ASD中延迟，并通过脑磁图(MEG)通过扩散磁测量 磁共振成像(DMRI)，以量化听觉通路白质的微观结构(特别是 丘脑皮质声辐射)。虽然这种方法可以解释50%以上的 在典型的对照组中，它被大约100名自闭症儿童的异质性搞混了 谱系障碍(ASD)。然而，这实际上允许确定患有自闭症的儿童的亚群。 其M50响应出现为TD模型的“异常值”(即“不可预测的长M50‘S”)；有趣的是， 据Advance估计，这些儿童的伽马氨基丁酸(GABA)水平明显较低 磁共振波谱(MRS)与潜伏期与TD一致的ASD同龄人 模特。这一群体的识别对治疗/干预具有重大意义，因为它识别了一个 分层的生物学基础(亚种群定义)，因此是一个假定的干预生物学目标 (以及定义选择该疗法的纳入标准的一种手段)。本提案延长了 这项工作针对的是对科学和社会具有批判性的自闭症儿童群体，这些儿童有严重的语言和 认知障碍，在成像研究中未被包括在内，但其重要的参与是 通过我们最近开发的名为MEG-PLAN的综合行为和技术协议，以及 它的MRI模拟：MRI-PLAN。确定延迟性M50脑损伤的临床和行为学意义 我们也招募患有混合病因性智力和发育障碍(IDD)的儿童，但不是 自闭症，并试图确定语言障碍、认知障碍和自闭症的相关联系 M50潜伏期延迟的诊断，并调查这些关联的生物物理基础 多模式脑磁图、核磁共振和磁共振波谱检查我们还超越了对听觉反应时间的检查，扩展到 听觉和语言的神经元回路。脑磁图也检测到振荡反应，并检查其 与GABA水平以及临床语言评估的关系。综上所述，这项建议侧重于 几个层次的分层来对抗ASD中观察到的可怕的异质性，关键的是，采用了 最先进的多模式方法，由MEG-PLAN和MRI-PLAN协议使之可行， 严重受损的自闭症儿童(通常不包括在这类研究中)，以评估泛化 在广泛的自闭症谱系中的观察。

PROJECT SUMMARY In the prior work we have extended our multimodal magnetoencephalography (MEG) and magnetic resonance imaging (MRI) approaches and have shown that it is possible to model, or predict, the latency of the auditory evoked neuromagnetic field component, the M50, occurring approximately 50-100ms post stimulus in children, but delayed in ASD, and measured by magnetoencephalography (MEG), by using diffusion magnetic resonance imaging (dMRI) to quantify the microstructure of the auditory pathway white matter (in particular the thalamocortical acoustic radiations). While this approach accounted for more than 50% of the variance in typically developing controls, it was confounded by heterogeneity in a cohort of ~100children with autism spectrum disorder (ASD). However, this actually allowed identification of a sub-population of children with ASD whose M50 responses appeared as “outliers” to the TD model (i.e. “unpredictably long M50’s); interestingly, these children showed significantly lower levels of gamma-aminobutyric acid (GABA) estimated by advance magnetic resonance spectroscopy (MRS) than their ASD peers whose latencies were consistent with the TD model. Identification of this group has significant implications for treatment/intervention by identifying a biological basis for stratification (sub-population definition) and thus a putative biological target for intervention (as well as a means of defining an inclusion criterion for selecting that therapy). The present proposal extends this work to the scientifically and societally critical group of children with ASD with severe language and cognitive impairments, who are under-included in imaging research, but whose vital participation is made possible by a combined behavioral and technical protocol we have recently developed, called MEG-PLAN, and its MRI analog: MRI-PLAN. To ascertain the clinical and behavioral implications of delayed M50 brain responses, we also recruit children with mixed etiology intellectual and developmental disability (IDD), but not autism, and seek to identify the relative associations of language impairment, cognitive impairment and ASD diagnosis to the M50 latency delay and to investigate the biophysical underpinnings of these association with multimodal MEG, MRI and MRS. We also extend beyond examination of auditory response timing to probes of auditory and language neuronal circuitry via. oscillatory responses also detected by MEG and examine their relation to GABA levels as well as to clinical language assessment. Taken together, this proposal focuses on several levels of stratification to combat the formidable heterogeneity observed in ASD and, critically, employs state of the art multimodal methodologies, made feasible by the MEG-PLAN and MRI-PLAN protocols, in severely-impaired children with ASD (conventionally not included in such research) to assess generalization of observations across the broad autism spectrum.