Timing of Neural activity in Spasmodic Dysphonia

 描述（由申请人提供）：痉挛性发声障碍（SD）是一种使人衰弱的发声障碍，其中喉部肌肉间歇性痉挛。这会阻止声带有效地振动，并导致说话时不自觉的中断。SD的治疗选择有限，只有肉毒杆菌毒素（Botox）注射提供暂时的症状缓解。SD被认为是起源于中枢神经系统（CNS）的功能障碍，并且可能涉及发声期间感觉反馈的异常皮层处理。然而，SD的根本原因仍然模糊不清，在很大程度上是未知的。一些神经影像学研究已经检查了SD患者的发声，并发现了一些皮层和皮层下区域的异常激活。然而，由于这些研究是基于功能磁共振成像和PET，它们的时间分辨率很差，当这些异常激活与发声行为相关时，它们并没有解决。因此，关于导致SD的关键线索可能被遗漏了。我们的实验室已经做了大量的工作来模拟语音产生的动态。从我们的模型中，我们得出结论，从异常的中枢神经系统活动中推断SD的功能障碍需要知道更多，而不是在中枢神经系统中发生异常活动。它还需要知道何时处于发声行为中（例如，初始声门运动、声音起始和持续发声）。在这里，我们建议使用脑磁图成像（MEGI）来解决这个问题-这是我们实验室基于MEG开发的一种功能成像方法，它可以以毫秒级的精度和亚厘米级的分辨率重建皮层活动。在特定目标1中，我们将使用MEGI重建皮质活动，而受试者（SD患者和神经典型对照）反复产生稳态发声，我们用肌电图（EMG）监测他们的声门运动。声门运动前患者（与对照组相比）的运动前/运动皮质活动异常提示前馈运动准备受损。声门运动开始后立即异常活动，但在发声之前，将建议在躯体感觉反馈处理的选择性缺陷，而发声后的异常活动将建议在躯体感觉和/或听觉反馈处理的缺陷。为了分离SD是否特别涉及听觉反馈处理的缺陷，在特定目标2中，我们将使用MEGI来监测受试者发出声音时的皮层活动，当我们短暂干扰他们在正在进行的发声的音频反馈中听到的音高时。在代偿前患者中观察到的对扰动的异常皮层反应表明听觉反馈处理的缺陷，而在代偿开始后观察到的异常皮层反应表明对听觉反馈的异常运动反应。从拟议的研究结果将有助于我们隔离与SD相关的赤字何时何地出现在控制发声的皮层通路。这将有助于我们设计新颖的，也许更有效的治疗方法，也有助于我们更好地了解现有的治疗方法是如何工作的或可以改进的。

 DESCRIPTION (provided by applicant): Spasmodic dysphonia (SD) is a debilitating disorder of voicing where the laryngeal muscles are intermittently in spasm. This prevents the vocal folds from vibrating efficiently and results in involuntary interruptions during speech. Treatment options for SD are limited, with only temporary symptom relief provided by Botulinum toxin (Botox) injections. SD is thought to be a dysfunction originating in the central nervous system (CNS), and may involve abnormal cortical processing of sensory feedback during phonation. However, the underlying causes of SD remain ambiguous and largely unknown. Several neuroimaging studies have examined phonation in patients with SD and have found aberrant activations in a number of cortical and subcortical regions. However, because these studies were based on fMRI and PET, which have poor temporal resolution, they do not resolve when these aberrant activations occurred in relation to the phonation act. As a result, critical clues about what causes SD have likely been missed. Our lab has done extensive work modeling the dynamics of speech production. From our model, we conclude that inferring functional impairments in SD from aberrant CNS activity requires knowing more than where in the CNS the aberrant activity occurs. It also requires knowing when in the act of phonation (e.g., initial glottal movement, voice onset, and sustained phonation) it is occurring. Here we propose to address this issue using magnetoencephalographic imaging (MEGI) - a functional imaging method our lab has developed based on MEG, which can reconstruct cortical activity with millisecond accuracy and sub-centimeter resolution. In Specific Aim 1, we will reconstruct cortical activity using MEGI while subjects (patients with SD and neurotypical controls) repeatedly produce a steady-state phonation and we monitor their glottal movement with electromyography (EMG). Abnormal pre/motor cortical activity in patients (compared to controls) prior to glottal movement would suggest impairments in feed forward motor preparation. Abnormal activity immediately after glottal movement onset but prior to phonation would suggest selective deficits in somatosensory feedback processing, whereas abnormal activity following phonation would suggest deficits in somatosensory and/or auditory feedback processing. To isolate whether SD specifically involves deficits in auditory feedback processing, in Specific Aim 2 we will use MEGI to monitor cortical activity as subjects phonate when we briefly perturb the pitch they hear in the audio feedback of their ongoing phonation. Abnormal cortical responses to the perturbation seen in patients prior to compensation would suggest deficits in auditory feedback processing, while those seen after onset of compensation would suggest abnormal motor responses to auditory feedback. Results from proposed studies will help us to isolate where and when the deficits related to SD arise in the cortical pathways controlling phonation. This will help us to devise novel, and perhaps more effective, treatments for SD and also help us to better understand how existing treatments work or can be improved.