Dept. of Radiology, Lurie Family Foundations MEG Imaging Center, Children's Hospital of Philadelphia, 3401 Civic Center Blvd., Philadelphia, PA, 19104, USA.
J Neurodev Disord. 2021 Sep 15;13(1):34. doi: 10.1186/s11689-021-09385-y.
This paper reviews a candidate biomarker for ASD, the M50 auditory evoked response component, detected by magnetoencephalography (MEG) and presents a position on the roles and opportunities for such a biomarker, as well as converging evidence from allied imaging techniques (magnetic resonance imaging, MRI and spectroscopy, MRS). Data is presented on prolonged M50 latencies in ASD as well as extension to include children with ASD with significant language and cognitive impairments in whom M50 latency delays are exacerbated. Modeling of the M50 latency by consideration of the properties of auditory pathway white matter is shown to be successful in typical development but challenged by heterogeneity in ASD; this, however, is capitalized upon to identify a distinct subpopulation of children with ASD whose M50 latencies lie well outside the range of values predictable from the typically developing model. Interestingly, this subpopulation is characterized by low levels of the inhibitory neurotransmitter GABA. Following from this, we discuss a potential use of the M50 latency in indicating "target engagement" acutely with administration of a GABA-B agonist, potentially distinguishing "responders" from "non-responders" with the implication of optimizing inclusion for clinical trials of such agents. Implications for future application, including potential evaluation of infants with genetic risk factors, are discussed. As such, the broad scope of potential of a representative candidate biological marker, the M50 latency, is introduced along with potential future applications.This paper outlines a strategy for understanding brain dysfunction in individuals with intellectual and developmental disabilities (IDD). It is proposed that a multimodal approach (collection of brain structure, chemistry, and neuronal functional data) will identify IDD subpopulations who share a common disease pathway, and thus identify individuals with IDD who might ultimately benefit from specific treatments. After briefly demonstrating the need and potential for scope, examples from studies examining brain function and structure in children with autism spectrum disorder (ASD) illustrate how measures of brain neuronal function (from magnetoencephalography, MEG), brain structure (from magnetic resonance imaging, MRI, especially diffusion MRI), and brain chemistry (MR spectroscopy) can help us better understand the heterogeneity in ASD and form the basis of multivariate biological markers (biomarkers) useable to define clinical subpopulations. Similar approaches can be applied to understand brain dysfunction in neurodevelopmental disorders (NDD) in general. In large part, this paper represents our endeavors as part of the CHOP/Penn NICHD-funded intellectual and developmental disabilities research center (IDDRC) over the past decade.
本文回顾了自闭症谱系障碍（ASD）的候选生物标志物——通过脑磁图（MEG）检测到的 M50 听觉诱发电位成分，并介绍了这种生物标志物的作用和机遇，以及来自联合成像技术（磁共振成像、MRI 和光谱学、MRS）的趋同证据。本文介绍了 ASD 中 M50 潜伏期延长的相关数据，并将其扩展到包括语言和认知障碍严重的 ASD 儿童，在这些儿童中，M50 潜伏期延迟加剧。通过考虑听觉通路白质的特性对 M50 潜伏期进行建模，在典型发育中是成功的，但在 ASD 中存在异质性的挑战；然而，这一点被利用来识别具有 ASD 的一个独特亚群，其 M50 潜伏期明显超出了从典型发育模型可预测的范围。有趣的是，这个亚群的特征是抑制性神经递质 GABA 水平较低。在此基础上，我们讨论了 M50 潜伏期在急性使用 GABA-B 激动剂时指示“靶点结合”的潜在用途，这可能会区分“有反应者”和“无反应者”，从而暗示优化此类药物临床试验的纳入。讨论了未来的应用，包括对具有遗传风险因素的婴儿的潜在评估。因此，引入了广泛的潜在候选生物标志物——M50 潜伏期，以及潜在的未来应用。本文概述了一种理解智力和发育障碍（IDD）个体大脑功能障碍的策略。提出了一种多模态方法（收集大脑结构、化学和神经元功能数据），将确定具有共同疾病途径的 IDD 亚群，并确定最终可能从特定治疗中受益的 IDD 个体。在简要论证了必要性和范围的潜力之后，来自检查自闭症谱系障碍（ASD）儿童大脑功能和结构的研究的例子说明了如何测量大脑神经元功能（来自脑磁图、MEG）、大脑结构（来自磁共振成像、MRI，特别是扩散 MRI）和大脑化学（磁共振波谱）可以帮助我们更好地理解 ASD 的异质性，并为使用多变量生物标志物（生物标志物）定义临床亚群奠定基础。类似的方法可以应用于理解神经发育障碍（NDD）的大脑功能障碍。在很大程度上，本文代表了我们作为 CHOP/Penn NICHD 资助的智力和发育障碍研究中心（IDDRC）过去十年努力的一部分。
