Chronical electrical stimulation for treatment of aged voice

与年龄有关的声音减弱长期以来一直被忽视，但最近得到了考虑，因为声音耐力在许多职业中至关重要，直到更高的年龄。明显的声门间隙和声带（VF）弯曲是这些患者最突出的视频喉镜检查结果，主要与甲杓肌（TAM）萎缩有关。对于拟议的项目，我们假设，功能性电刺激（FES）的喉返神经（RLN）将抵消年龄相关的喉肌萎缩。基于以前的工作，我们假设特别是FES将导致肌纤维直径的增加，以及肌肉肥大的分子标志物的上调，而纤维类型分布没有随后的变化。肌纤维直径的增加将导致TAM体积的增加，从而减小声门间隙。我们进一步假设，FES引起的变化将导致显着改善发声特性被观察到改善喉动力学和声学评估的发声体外ex-vivo experiments.FES将首次在一个老年人在体内绵羊模型双侧。在手术过程中，刺激电极将在进入喉部之前放置在RLN的共同干附近，并将连接到位于颈部的喉部起搏植入物。一旦植入物被编程，预先设计的训练模式将自动提供并每隔一天重复一次，持续11周，因此在训练或随访内窥镜检查期间不需要进一步的麻醉或镇静。安乐死后，将在基于多模式的环境中评价结局参数，从细胞/分子水平（免疫组织学，基因表达，信号通路）到解剖学水平（微型CT扫描/3D重建），并将包括重要的功能测试（发声离体实验）。拟议的项目将结合副教授Markus Gugatschka博士的专业知识进行联合行动（奥地利格拉兹医科大学）和Michael Döllinger教授（德国埃尔朗根-纽伦堡弗里德里希-亚历山大大学）。Gugatschka副教授小组将执行与植入手术和随访相关的所有任务，以及在分子/细胞和解剖学水平上评估FES的结果参数，而Döllinger教授小组将执行离体发声实验。在这样一个模型中结合分子、组织学、解剖学和功能结果参数是一个至关重要的，但尚未实现的目标，并将创建一组前所未有的数据。通过直接刺激喉返神经，我们保留了喉的自然解剖结构和完整性。能直接对抗老视的潜在原因。在进入临床试验之前，在大型动物模型中进行此类实验是必不可少的。

Age related weakening of the voice has long been neglected, but gained consideration lately, as vocal endurance is essential in many professions up to higher ages. The noticeable glottal gap and vocal fold (VF) bowing are the most prominent video-laryngoscopic findings in these patients and are mainly related to the atrophy of the thyroarytenoid muscle (TAM). For the proposed project, we hypothesize that functional electrical stimulation (FES) of the recurrent laryngeal nerves (RLN) will counteract age related laryngeal muscular atrophy. Based on previous work we hypothesize in particular that FES will lead to an increase of muscle fiber diameters, and an upregulation of molecular markers of muscle hypertrophy with no subsequent changes of the fibre type distribution. An increase of muscle fibre diameters will lead to an increase of the volume of the TAM, thus diminishing the glottal gap. We furthermore hypothesize that the changes elicited by FES will lead to significantly improved phonatory characteristics being observable in improved laryngeal dynamics and acoustics as assessed by the phonatory ex-vivo experiments.FES will be done for the first time bilaterally in an aged in-vivo ovine model. During surgery, stimulation electrodes will be placed near the common trunk of the RLN before entering the larynx and will be connected to a laryngeal pacing implant located at the neck. Predesigned training patterns will be automatically delivered and repeated every second day for eleven weeks, once the implant was programmed, thus no further anaesthesia or sedation will be necessary during the training, or follow-up endoscopies. After euthanasia outcome parameters will be evaluated in a multi-modal based setting, reaching from the cellular/molecular (immuno-histology, gene expression, signalling pathways) to the anatomical level (micro CT scans/3D-reconstructions) and will comprise important functional testing (phonatory ex-vivo experiments).The proposed project will be pursued in a joint action combining the expertise of Assoc. Prof. Dr. Markus Gugatschka (Medical University Graz, Austria) and Prof. Dr. Michael Döllinger (Friedrich-Alexander University Erlangen-Nürnberg, Germany). While the group of Assoc. Prof. Gugatschka will perform all tasks related to implantation surgery and follow-up, as well as assessing the outcome parameters of FES on a molecular/cellular and anatomical level, the group of Prof. Döllinger will perform ex-vivo phonatory experiments. Combining molecular, histological, anatomical and functional outcome parameters in such a model is a crucial, yet an unmet goal and will create an unprecedented set of data. By direct stimulation of the RLN we preserve the natural anatomy and integrity of the larynx resp. the VF and can counteract directly the underlying reason of presbyphonia. Before going into clinical trials, experiments of this kind in large animal models are indispensable.