Normal And Disordered Laryngeal And Speech Systems

正常和紊乱的喉部和言语系统

• 批准号: 6843228
• 负责人: Christy Leslie Ludlow
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6843228
• 关键词: adolescence (12-20); brain stem; child (0-11); clinical research; communication disorders; disease /disorder prevention /control; disease /disorder proneness /risk; dystonia; family genetics; gene mutation; genetic disorder; genetic screening; human subject; in situ hybridization; laryngoscopy; larynx disorder; larynx muscle; motor neurons; nervous system disorder; nervous system prosthesis; neuromuscular function; sensory feedback; speech; speech disorders; swallowing; voice

Our goal is to improve the treatment and prevention of voice, speech and swallowing disorders. For this purpose, the pathogenesis and pathophysiology of neurogenic idiopathic disorders are being studied. Currently we are: 1) determining the role of sensory feedback in the production of symptoms in spasmodic dysphonia; 2) identifying gene mutations involved in familial laryngeal disorders; 3) determining the role of perceptual and learning abnormalities in idiopathic speech disorders; and, 4) developing effective new treatments for voice, speech and swallowing disorders. Significant advances have been made during the last year in all these areas. 1) Many patients report laryngitis, airway irritation, or laryngeal injury prior to the onset of spasmodic dysphonia (SD) and muscular tension dysphonia (MTD). To map out the laryngeal sensory pathways in the medulla we used the Becker strain of pseudorabies virus (PRV) in an animal model. Prior to a unilateral mucosal PRV injection, the opposing superior laryngeal nerve (SLN) and ipsilateral recurrent laryngeal nerve (RLN) were sectioned to isolate the ipsilateral SLN afferents for PRV transport to the brain stem for different survival times. In a control, the ipsilateral SLN and RLN were sectioned leaving the contralateral SLN intact. Blinded counts of PRV labeled neurons demonstrated count increases with increased survival times at several levels. Early labeling was mainly ipsilateral in particular subnuclei of the nucleus tractus solitarius (NTS), the area postrema, and the spinal trigeminal n. (5SP) and did not increase with survival. Later increases occurred bilaterally in the same regions at more rostral levels. The pathway of laryngeal afferent connections started from ipsilateral NTS subnuclei ascending to the contralateral NTS subnuclei and bilaterally to the lateral tegmental field and 5SP while descending later to neurons bilaterally in the caudal lateral reticular tract. Another animal model was developed this year to study changes in these brain stem pathways as a result of peripheral laryngeal inflammation. New techniques were successful for inducing acute localized laryngeal inflammation and quantifying the subsequent changes in neuronal activation and cytokine expression in the laryngeal sensori-motor pathways in the medulla. We are collaborating with another group to use in situ hybridization to confirm our initial findings. To examine the role of sensory feedback in symptom generation in spasmodic dysphonia (SD), laryngeal tremor and muscular tension dysphonia (MTD), a temporary bilateral chemical block of the superior laryngeal nerve was confirmed with air puff threshold testing. Blinded spectrographic measures of voice symptoms before and after block, demonstrated a significant group by treatment interaction. Voice breaks were reduced in SD and increased in vocal tremor while aperiodicity was reduced only in MTD. Afferent feedback played an important but different role in symptom generation in these disorders. Because MTD also improved following afferent block, this disorder may have a similar pathophysiology to SD. A double-blind study using a mucosal lidocaine drip is investigating the role of laryngeal sensation in symptom generation in these disorders. 2) A gene mutation responsible for a motor neuronopathy first affecting the larynx was found in collaboration with the Neurogenetics Branch, NINDS. A family with an automsomal dominant motor neuronopathy showed linkage to chromsome 2p13 with a maximum of score of 4.05. A single base-pair change in the p150 subunit of the transporter protein dynactin was present in all the affected members The phenotype was distinctive, with an abductor laryngeal paralysis causing an airway obstruction first followed by hand muscle atrophy. The particular role that this mutation has in the laryngeal motor neuron pathology is unclear and is under consideration for future research. 3) Studies of idiopathic familial speech disorders determined that distinctive perceptual and learning deficits occur in affected members in families with these disorders. By studying adults with persistent developmental speech disorder (PDSD), perception and learning impairments were examined independent of development. The PDSD adults were impaired in nonsense word learning task during recall, repetition, and perception. Significant differences also occurred in short-term memory. PDSD subjects were particularly impaired on non-English-like consonant combinations. Speech learning deficits in persons following developmental speech disorders may impact their language learning skills throughout life. In the same adults, a second study examined their perception of brief acoustic cues for speech perception involving discrimination of minimal pairs (?stay versus ?say). The PDSD adults had difficulties perceiving brief acoustic cues (formant transitions) in words and fast temporal cues in nonspeech stimuli. Therefore both perception, learning and memory deficits may play a role in this persistent speech production disorder. We have found autosomal dominant inheritance in a large kindred; a genome ?wide screen is being conducted in collaboration with the Section on System Biology of Communication Disorders, in the National Institute on Other Communication Disorders and Deafness. Adults who stutter, however, did not differ from controls on tests of speech motor learning skills, auditory perception for fine acoustic cues in speech, or the detection of brief temporal cues in nonspeech stimuli. This suggests that developmental stuttering does not involve the learning or perceptual skills affecting other developmental speech disorders. 4) We previously found that agents producing selective N-methyl-D-aspartate receptor blockade actively suppressed the occurrence of late R2 laryngeal adductor responses in the cat. One of these agents was dextromethorphan, a widely used antitussive agent. This year, we have initiated a double-blind acute study of the effects of dextromethorphan in contrast with lorazepam and a placebo to determine if there is a significant reduction in symptoms in SD. The pilot portion was completed with four subjects, and six subjects have completed all three phases of the study. This new line of translational research show promises in delivering the first oral therapy to control the symptoms of SD. Dysphagia, a significant health problem, usually stems from central nervous system injury, leaving peripheral muscles intact and functional but without appropriate control. Our aim is to initiate and augment movement for swallowing through functional electrical neuromuscular stimulation (FES) in an effort to prevent aspiration while eating. This year, we tested the hypothesis that muscle stimulation can be self-synchronized with volitional swallowing by normal adults. Following baseline recordings, volunteers repeatedly swallowed while triggering neuromuscular stimulation of an ipsilateral pair of muscles for laryngeal elevation over ten trials. By the fourth trial, the onset of contralateral muscle activation and self-stimulation were coincident; demonstrating that normal subjects could easily combine stimulation with swallowing. To determine if subjects would spontaneously modify their patterns to adapt to stimulation, we examined the effects of repeated stimulation trials on patterns of muscle activation for swallowing. No changes in muscle patterning occurred suggesting that muscle stimulation might be prescribed to augment a patient?s residual movement pattern to improve control and prevent aspiration. Both studies are now ongoing in persons with dysphagia. A patent application entitled, Methods and Devices for Intramuscular Stimulation of Upper Airway and Swallowing Muscle Groups,was filed this year based on this research.

我们的目标是改善语音，言语和吞咽障碍的治疗和预防。为此，正在研究神经源性特发性疾病的发病机理和病理生理学。目前，我们是：1）确定感觉反馈在痉挛性吞咽困难中产生症状的作用； 2）鉴定涉及家族性喉部疾病的基因突变； 3）确定感知和学习异常在特发性语音障碍中的作用；以及4）为语音，言语和吞咽障碍开发有效的新疗法。去年在所有这些领域都取得了重大进展。 1）许多患者报告痉挛性吞咽困难（SD）和肌肉张力刺激性刺激性（MTD）之前，报告喉炎，气道刺激或喉损伤。为了绘制髓质中的喉感觉途径，我们在动物模型中使用了伪造病毒（PRV）的贝克菌株。在进行单侧粘膜PRV注射之前，对相对的上喉神经（SLN）和同侧复发性喉神经（RLN）进行了切除，以分离出iPsilfornal SLN的传入，以使PRV转运到脑干，以使脑干的生存时间不同。在对照中，将同侧SLN和RLN切开，使对侧SLN完整。 PRV标记的神经元的盲名计数显示出数量增加的数量，在多个级别的生存时间增加。早期的标记主要是尤其是核的同侧核，索他叶核（NTS），postrema区和脊柱三叉神经n。 （5SP），并且没有随着生存而增加。后来增加的增加在同一区域以更高的水平发生。喉部传入连接的途径始于同侧NTS子核升，升到对侧NTS亚核中，双侧至侧向段场和5SP，而后来又下降到尾尾侧片的腹侧腹膜侧面的神经元。 今年开发了另一种动物模型，以研究由于周围喉部炎症而导致这些脑干途径的变化。新技术成功地诱导急性局部喉部炎症，并量化喉喉喉部感觉运动途径中神经元激活和细胞因子表达的随后变化。我们正在与另一个小组合作，用于使用原位杂交来确认我们的初始发现。 为了检查感觉反馈在症状产生中的作用，在痉挛性吞咽困难（SD），喉震和肌肉张力刺激性（MTD）中，通过空气泡芙阈值测试确认了上喉神经的临时双侧化学块。通过治疗相互作用，盲目的语音症状的光谱学测量表明了一组重要的组。 SD中的语音断裂减少了，声音震颤的增加，而仅在MTD中降低了大幅度。传入反馈在这些疾病中的症状产生中起着重要但不同的作用。由于MTD在传入阻滞后也有所改善，因此该疾病可能具有与SD相似的病理生理学。一项使用粘膜利多卡因滴水的双盲研究正在研究喉感觉在这些疾病中症状产生中的作用。 2）与Ninds神经遗传学分支合作发现了负责运动神经疾病的原因。一个具有自体占主导性运动神经疾病的家庭与Chromsome 2p13的联系最高分4.05。在所有受影响的成员中，表型都存在于转运蛋白的P150亚基中的单个碱基对变化，表型是独特的，绑架者的喉部瘫痪，引起气道阻塞，首先是手动肌肉萎缩。该突变在喉运动神经元病理中的特殊作用尚不清楚，并且正在考虑以后的研究。 3）对特发性家庭语音障碍的研究确定，这些疾病家庭中受影响的成员发生了独特的感知和学习缺陷。通过研究患有持续发展性言语障碍（PDSD）的成年人，对发展和学习障碍的研究独立于发展。在召回，重复和感知期间，PDSD成年人在胡说八道的学习任务中受到了损害。短期记忆也发生了显着差异。 PDSD受试者在非英语般的辅音组合中尤其受损。遵循发展性言语障碍的人的语音学习缺陷可能会影响他们一生的语言学习能力。在同一成年人中，第二项研究检查了他们对短暂的声学提示的看法，以涉及最小对歧视的语音感知（？留下来与？说）。 PDSD成年人在单词和非语音刺激中以词语和快速的时间提示中的简短声明提示（强型跃迁）遇到困难。因此，感知，学习和记忆缺陷均可能在这种持续的语音生产障碍中发挥作用。我们发现常染色体占主导地位的继承。国立沟通障碍和耳聋研究所的有关沟通障碍系统生物学的部分进行了基因组？ 然而，口吃的成年人与对语音运动技能测试的控制，言语提示的听觉感知或在非语音刺激中的短暂时间提示中发现。这表明发展口吃不涉及影响其他发展语音障碍的学习或感知技能。 4）我们以前发现，产生选择性N-甲基-D-天冬氨酸受体阻滞的药物积极抑制了CAT中R2喉后加合物反应的发生。这些药物之一是右美甲泛，是一种广泛使用的抗呼吸剂。今年，我们已经开始了双盲急性研究，对右美甲苯克的影响与劳拉西ep和安慰剂相比，以确定SD症状是否显着降低。飞行员部分由四个受试者完成，六个受试者完成了这项研究的所有三个阶段。这项新的转化研究系列有望提供第一种口服治疗以控制SD症状。 吞咽困难，这是一个重大的健康问题，通常源自中枢神经系统损伤，使周围肌肉完好无损，但没有适当的控制。我们的目的是通过功能性神经肌肉刺激（FES）启动和增强运动，以防止进食时抽吸。今年，我们检验了以下假设：正常成年人的自愿吞咽可以自同步。基线记录后，志愿者在触发了十项试验中的同侧肌肉中，在触发同侧肌肉的神经肌肉刺激时反复吞咽。通过第四次试验，对侧肌肉激活和自刺激的发作是一致的。证明正常受试者很容易将刺激与吞咽结合在一起。为了确定受试者是否会自发地修改其模式以适应刺激，我们检查了反复刺激试验对吞咽肌肉激活模式的影响。没有发生肌肉模式的变化，这表明可以开处方肌肉刺激以增加患者的残留运动模式以改善控制和防止抽吸。现在，这两项研究都在患有吞咽困难的人正在进行中。今年根据这项研究提出了一项专利申请，标题为肌肉内刺激和吞咽肌肉群的方法和设备。