Electrophysiological Signatures of Language Impairment in Autism Spectrum Disord

描述（由申请人提供）：脑磁图（MEG）研究检查了自闭症谱系障碍（ASD）儿童的大脑活动，包括本R01之前资助期发表的研究，已经确定了区分ASD儿童与典型发育（TD）对照的功能标记。值得注意的是，ASD儿童的颞上回（STG）听觉诱发反应的~100毫秒（M100）部分显示出对简单音调的短暂但深刻的延迟（~10ms），特别是在右半球，特别是对人类语言中占主导地位的音调（300-500Hz）。目前出现了两种主要的假设来解释M100延迟：(1)ASD中丘脑-皮质声辐射投射的传导速度，伴有未成熟的白质（WM）； (2) ASD中STG突触传递异常，伴有伽马带相位同步减少。来自先前资助期的数据为这两种假设提供了支持，并激发了分层模型，其中这两种因素都对M100延迟做出了贡献（尽管不一定相等）。这些机制对M100潜伏期的贡献可以独立检查，使用扩散MRI评估声辐射（听觉通路WM的丘脑-皮质投影）（特定目标1），使用MEG测量神经振荡活动来探测局部电路的完整性（或缺乏，标记为“示波器病”），并暗示突触传递（特定目标2）。根据白质缺陷（WM+/-）和示波器病变（Osc+/-）的中位分裂，使用MEG和弥散MRI测量将ASD群体分为4个亚型，从而确定每个受试者的“显性缺陷”或其组合：WM-/Osc-、WM-/Osc+、WM+/Osc-、WM+/Osc+。这些STG听觉系统缺陷的临床意义将通过评估WM/示波器病亚型通过评估组间表型差异和组内表型方差的减少来减少ASD异质性的能力，以及确定特定亚型中临床症状（例如语言功能、语音加工和一般认知能力）之间的关联来检验（specific Aim 3）。因此，我们将确定在多大程度上电生理测量，如听觉M100潜伏期，以及WM微观结构和振荡活动的附属测量，可以被视为用于ASD儿童表征和分层的生物标志物。这种分层的未来意义可以在不同的患者管理策略中预测，以及选择和监测靶向药物的活性。最后，这个R01的更新将确定ASD的听觉诱发反应异常是特定于听觉域还是反映了一个更广泛的现象，在初级视觉和体感皮层也发现了潜伏期延迟（specific Aim 4）。

DESCRIPTION (provided by applicant): Magnetoencephalographic (MEG) studies examining brain activity in children with autism spectrum disorder (ASD), including published studies from this R01's previous funding period, have identified functional markers that discriminate children with ASD from typically developing (TD) controls. Of note, the ~100 ms (M100) component of the superior temporal gyrus (STG) auditory evoked response to simple tones demonstrates a short but profound delay (~10ms) in children with ASD, especially in the right hemisphere, and especially for tones with frequencies dominant in human speech (300-500Hz). Two dominant hypotheses have emerged to account for M100 delays: (1) conduction velocity of the thalamo-cortical acoustic radiations projections, with immature white matter (WM) in ASD, and (2) abnormal STG synaptic transmission, with diminished gamma- band phase synchrony in ASD. Data from the prior funding period provides support for both hypotheses and motivates a stratification model, where both factors contribute (although not necessarily equally) to M100 delays. The contribution of these mechanisms to M100 latency can be independently examined, using diffusion MRI to assess the acoustic radiations (the thalamo-cortical projections of the auditory pathway WM) (Specific Aim 1) and using MEG measures of neural oscillatory activity to probe integrity (or lack thereof, labeled as "oscillopathy") of local circuitry and by implication synaptic transmission (Specific Aim 2). Using the MEG and diffusion MRI measures the ASD cohort will be divided into 4 subtypes, based on a median-split in white-matter deficit (WM+/-) and oscillopathy (Osc+/-), thus identifying a "dominant deficit", or combination thereof, for each subject: WM-/Osc-, WM-/Osc+, WM+/Osc-, WM+/Osc+. The clinical significance of these STG auditory system deficits will be examined by evaluating the ability of the WM/oscillopathy subtypes to reduce heterogeneity in ASD via assessment of between-group phenotypic differences and within-group reduction in phenotype variance as well as identification of associations between clinical symptoms (e.g., language function, phonological processing, and general cognitive ability) within specific subtypes (Specific Aim 3). Thus, we will determine the extent to which electrophysiological measures such as the auditory M100 latency, as well as subordinate measures of WM microstructure and oscillatory activity, can be considered as biomarkers for use in the characterization and stratification of children with ASD. Future implications of such stratification can be anticipated in differential patient management strategies as well as selection for, and monitoring the activity of, targeted pharmaceuticals. Finally, this R01 renewal will determine whether the auditory evoked response abnormalities in ASD are specific to the auditory domain or reflect a more widespread phenomenon, with latency delays identified also in primary visual and somatosensory cortex (Specific Aim 4).