Timing of Neural activity in Spasmodic Dysphonia

 描述(申请人提供)：痉挛性发音困难(SD)是一种发声功能障碍，喉部肌肉间歇性痉挛。这会阻止声带有效地振动，并导致在说话过程中不自觉地中断。SD的治疗选择有限，只能通过注射肉毒杆菌毒素(Botox)来暂时缓解症状。SD被认为是起源于中枢神经系统(CNS)的一种功能障碍，可能涉及发声过程中感觉反馈的皮质异常处理。然而，SD的根本原因仍然是模棱两可的，很大程度上是未知的。几项神经成像研究已经检查了SD患者的发声，并发现在许多皮质和皮质下区域有异常激活。然而，由于这些研究是基于时间分辨率较差的功能磁共振成像和正电子发射计算机断层扫描，它们没有解决这些异常激活何时发生与发声行为有关的问题。因此，关于SD原因的关键线索可能被遗漏了。我们的实验室已经对语音产生的动态进行了大量的建模工作。从我们的模型中，我们得出结论，从异常的CNS活动推断SD的功能损害需要比知道CNS中发生异常活动的位置更多的知识。它还需要知道在发声动作中(例如，声门初始运动、发声和持续发声)它何时发生。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脑磁图开发的一种功能成像方法，可以以毫秒的精度和亚厘米的分辨率重建大脑皮质活动。在具体目标1中，我们将使用MEGI重建皮质活动，同时受试者(SD患者和神经典型对照)重复产生稳定的发音，并通过肌电(EMG)监测他们的声门运动。声门运动前患者(与对照组相比)的前/运动皮质异常活动可能提示前馈运动准备受损。声门运动开始后、发声前的异常活动提示躯体感觉反馈加工的选择性缺陷，而发声后的异常活动提示躯体感觉和/或听觉反馈加工的缺陷。为了分离SD是否具体涉及听觉反馈处理的缺陷，在特定目标2中，当我们短暂扰乱受试者在其正在进行的发声的音频反馈中听到的音调时，我们将使用MEGI来监测受试者发声时的皮质活动。代偿前患者对扰动的异常皮质反应表明听觉反馈处理存在缺陷，而代偿开始后出现的异常皮质反应表明对听觉反馈的异常运动反应。拟议的研究结果将帮助我们分离控制发声的皮质通路中与SD相关的缺陷出现的地点和时间。这将帮助我们设计新的，也许更有效的治疗SD的方法，也有助于我们更好地了解现有的治疗方法是如何起作用的或可以改进的。

 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.