Electrophysiological Signatures of Language Impairment in Autism Spectrum Disord

描述(由申请者提供)：脑磁图(MEG)对自闭症谱系障碍(ASD)儿童脑活动的研究，包括今年R01‘S之前资助期发表的研究，已经确定了区分自闭症儿童和典型发育中(TD)对照儿童的功能标志物。值得注意的是，在ASD儿童中，对简单音调的颞上回(STG)听觉诱发反应的~100ms(M100)成分表现出短暂但深刻的延迟(~10ms)，尤其是在右脑，尤其是对人类语言中占主导地位的频率(300-500 Hz)的音调。解释M100延迟的两个主要假说：(1)ASD患者丘脑皮质声辐射投射的传导速度，伴有未成熟白质(WM)；(2)ASD患者STG突触传递异常，伽马频段相位同步性减弱。来自前一个资助期的数据为这两个假设提供了支持，并激励了分层模型，其中这两个因素都对M100延迟起到了作用(尽管不一定是相等的)。可以独立研究这些机制对M100潜伏期的贡献，使用扩散磁共振来评估声辐射(听觉通路WM的丘脑-皮质投射)(特定目标1)，并使用脑磁图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“振荡病”)，从而隐含突触传递(特定目标2)。使用脑磁图和弥散磁共振测量，ASD队列将根据白质缺乏症(WM+/-)和振荡病(OSC+/-)的中位数分裂分为4个亚型，从而为每个受试者确定一个“显性缺陷症”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/振荡病亚型通过评估组间表型差异和组内表型差异的减少以及确定特定亚型内临床症状(例如，语言功能、语音处理和一般认知能力)之间的联系来降低ASD的异质性的能力来检验(具体目标3)。因此，我们将确定电生理指标，如听觉M100潜伏期，以及WM微观结构和振荡活动的从属指标，可以在多大程度上被视为ASD儿童的特征和分层使用的生物标志物。这种分层的未来影响可以在不同的患者管理策略以及对靶向药物的选择和监测中预期。最后，R01的更新将确定ASD的听觉诱发反应异常是特定于听域还是反映更广泛的现象，潜伏期延迟也在初级视觉和躯体感觉皮质中发现(特定目标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).