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

低语言 ASD 语言障碍的多模态 dMRI、MRS 和 MEG 研究

• 批准号: 10636420
• 负责人: Timothy P Roberts
• 金额: $ 70.32万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10636420
• 关键词: Acoustics; Address; Affect; Age; Auditory; Auditory area; Behavioral; Biological; Biological Assay; Biological Markers; Biological Response Modifier Therapy; Biophysics; Brain; Brain imaging; Chemicals; Child; Child Development; Clinical; Clinical assessments; Control Groups; Data; Dependence; Development; Diagnosis; Diagnostic; Diffusion Magnetic Resonance Imaging; Electrophysiology (science); Etiology; Exhibits; Frequencies; Heterogeneity; Image; Impaired cognition; Impairment; Intellectual functioning disability; Intervention; Language; Linear Models; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Magnetoencephalography; Measures; Meta-Analysis; Methodology; Modeling; Neurobiology; Neurotransmitters; Pathway interactions; Performance; Phenotype; Population; Protocols documentation; Radiation; Reaction Time; Research; Response Latencies; Role; School-Age Population; Selection for Treatments; Specificity; Stimulus; Stratification; Structure; Symptoms; Techniques; Work; analog; applied behavior analysis; auditory pathway; auditory processing; autism spectrum disorder; autistic children; biological heterogeneity; cognitive ability; cohort; combat; design; follow-up; gamma-Aminobutyric Acid; imaging approach; imaging study; improved; inclusion criteria; indexing; insight; interest; language impairment; lexical; lexical processing; minimally verbal; model development; multimodality; neural circuit; neurochemistry; neuroimaging; neuronal circuitry; non-verbal; peer; predicting response; prognostic; recruit; response; social; sound; specific language impairment; vector; verbal; white matter

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.

项目概要 在之前的工作中，我们扩展了多模态脑磁图 (MEG) 和磁共振 成像（MRI）方法并表明可以模拟或预测听觉的潜伏期 诱发神经磁场成分 M50，发生在儿童刺激后约 50-100 毫秒， 但自闭症谱系障碍 (ASD) 延迟，并通过脑磁图 (MEG) 测量，使用扩散磁 磁共振成像（dMRI）来量化听觉通路白质（特别是听觉通路白质）的微观结构 虽然这种方法解释了 50% 以上的差异。 通常是发育对照，但它因约 100 名自闭症儿童的队列中的异质性而混淆 然而，这实际上可以识别患有 ASD 的儿童亚群。 其 M50 响应似乎是 TD 模型的“异常值”（即“有趣的是，M50 的长度不可预测）； 根据预先估计，这些儿童的γ-氨基丁酸（GABA）水平明显较低 磁共振波谱 (MRS) 优于延迟与 TD 一致的 ASD 同行 通过识别一个模型，该群体的识别对治疗/干预具有重大影响。 分层的生物学基础（亚群体定义），因此是干预的假定生物学目标 （以及定义选择该疗法的纳入标准的方法）。 这项工作针对的是在科学和社会上持批评态度的患有自闭症谱系障碍 (ASD) 儿童群体，他们的语言和语言很严重 认知障碍，他们在影像学研究中的参与不足，但他们的参与至关重要 通过我们最近开发的行为和技术相结合的协议（称为 MEG-PLAN）可以实现，并且 其 MRI 模拟：MRI-PLAN 确定 M50 大脑延迟的临床和行为影响。 回应，我们还招募患有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 诊断 M50 潜伏期延迟并研究这些与 我们还超越了听觉反应时间的检查，扩展到了探头。 听觉和语言神经回路也通过 MEG 检测并检查它们。 综上所述，本提案的重点是与 GABA 水平以及临床语言评估的关系。 几个层次的分层来对抗自闭症谱系障碍中观察到的可怕的异质性，并且至关重要的是，采用 最先进的多模态方法，通过 MEG-PLAN 和 MRI-PLAN 协议成为可能， 患有 ASD 的严重受损儿童（通常不包括在此类研究中）来评估 对广泛的自闭症谱系的观察。