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

项目摘要 在先前的工作中，我们已经扩展了我们的多模态脑磁图（MEG）和磁共振 磁共振成像（MRI）的方法，并已表明，它是可能的模型，或预测，听觉的潜伏期， 诱发的神经磁场成分，M50，发生在儿童刺激后约50- 100 ms， 但ASD延迟，并通过脑磁图（MEG）测量，通过使用扩散磁 磁共振成像（dMRI）来量化听觉通路白色物质（特别是 丘脑皮质声辐射）。虽然这种方法解释了50%以上的差异， 典型的发展控制，它是混杂的异质性，在一个队列的约100名儿童自闭症 谱系障碍（ASD）。然而，这实际上允许识别ASD儿童的亚群 其M50响应表现为TD模型的“异常值”（即“不可预测的长M50”）;有趣的是， 这些儿童的γ-氨基丁酸（GABA）水平明显较低， 磁共振波谱（MRS）比他们的ASD同龄人，其LAST与TD一致 模型通过识别一个特定的群体，识别这个群体对治疗/干预具有重要意义。 分层的生物学基础（亚群定义），因此是干预的假定生物学靶点 (as以及定义用于选择该疗法的纳入标准的手段）。本提案扩大了 这项工作的科学和社会的关键组自闭症儿童与严重的语言和 认知障碍，他们在成像研究中被低估，但他们的重要参与是 通过我们最近开发的一种结合了行为和技术的协议，称为MEG-MERS， 它的MRI模拟物：MRI-MRI。为了确定延迟M50脑的临床和行为意义， 回应，我们也招募混合病因智力和发育障碍（IDD）的儿童，但不 自闭症，并寻求确定语言障碍，认知障碍和ASD的相对关联 M50潜伏期延迟的诊断，并研究这些相关性的生物物理学基础， 多模态MEG，MRI和MRS。我们还扩展到听觉反应时间的检查， 听觉和语言神经回路。振荡反应也检测到MEG和检查他们的 与GABA水平以及临床语言评估有关。总的来说，这项建议的重点是 几个层次的分层，以打击在ASD中观察到的强大异质性，关键是， 通过MEG-MRI和MRI-MRI方案使现有技术的多模式方法变得可行， 自闭症儿童（通常不包括在此类研究中），以评估 对广泛的自闭症谱系的观察。

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.