Enhancing Speech Processing In A Rat Model Of Autism Using Vagus Nerve Stimulation

使用迷走神经刺激增强自闭症大鼠模型的语音处理

• 批准号: 10531205
• 负责人: Crystal T Engineer
• 金额: $ 38.25万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10531205
• 关键词: Acceleration; Acetylcholine; Animal Model; Animals; Auditory; Auditory area; Behavior Therapy; Behavioral; Brain-Derived Neurotrophic Factor; Clinical; Communication; Communication impairment; Consumption; Data; Development; Discrimination; Exhibits; Future; Goals; Human; Impairment; Implant; Individual; Intervention; Learning; Modeling; Neuromodulator; Neuronal Plasticity; Noise; Norepinephrine; Phase; Process; Rattus; Recovery of Function; Rehabilitation therapy; Role; Saline; Sensory; Series; Speech Discrimination; Speech Perception; Speech Sound; System; Techniques; Testing; Time; Training; Translating; Translations; Valproic Acid; auditory processing; auditory rehabilitation; autism spectrum disorder; awake; behavioral outcome; cholinergic; clinical translation; comparison control; efficacy testing; experience; experimental study; improved; in utero; individuals with autism spectrum disorder; insight; motor rehabilitation; neural; neurophysiology; neuroregulation; noradrenergic; novel; pre-clinical; prenatal; response; sound; speech processing; vagus nerve stimulation

One of the major obstacles facing individuals with autism is the inability to communicate effectively. While there are many reasons for this inability, an important component appears to be a serious deficit in the ability to process speech sounds effectively. Expensive, time-consuming behavioral interventions can improve behavioral outcomes, but many individuals undergo these interventions and still experience deficits. The development of adjunctive interventions that can increase the benefit of rehabilitation therapies is essential to improve the lives of individuals with autism spectrum disorders (ASD). We have developed a novel technique to drive robust neuroplasticity and enhance the benefits of rehabilitation. Vagus nerve stimulation (VNS) paired with the presentation of a sound triggers rapid, phasic release of plasticity promoting neuromodulators, which potentiate plasticity in the auditory network. Recent preclinical and clinical findings indicate that VNS paired with sensory or motor rehabilitative therapies can significantly enhance functional recovery compared to rehabilitative therapy alone. This proposal will evaluate whether VNS paired with auditory training can enhance the efficacy of rehabilitation in the context of autism. In utero valproic acid (VPA) exposure is a well-documented cause of autism in humans. Similar to individuals with autism, both speech discrimination ability and auditory cortical responses are impaired in VPA exposed rats. The objective of this proposal is to determine whether VNS paired with auditory training can reverse the neural and behavioral auditory processing deficits observed in VPA exposed rats. In Aim 1, we test the ability of both implanted and non-invasive VNS paired with auditory training to improve discrimination ability after prenatal VPA exposure. VPA exposed rats are significantly impaired at discriminating between speech sounds. We will evaluate discrimination accuracy in VPA or saline exposed rats undergoing VNS paired auditory training. In Aim 2, we evaluate awake behaving neurophysiological responses in auditory cortex to evaluate the VNS-dependent neural plasticity that may underlie improved auditory processing. VPA exposed rats exhibit altered auditory cortex responses compared to control rats. Previous results suggest that VNS pairing may strengthen auditory cortex responses more rapidly and to a greater degree than training alone. In Aim 3, we test the role of two neuromodulatory networks in the VNS-dependent enhancement of plasticity and sound discrimination ability in the context of VPA exposure. We will deplete cholinergic or noradrenergic afferents specifically to the auditory cortex to determine whether acetylcholine or norepinephrine depletion impairs VNS-related improvements in auditory processing. In addition to proof-of- concept evidence for clinical translation, this proposal will provide insight into the ability of plasticity-based therapies to be effective in treating ASD and lay the groundwork for more comprehensive future studies, with the goal of translating these critical first-in-animal preclinical experiments to a clinical therapy that could provide significant, tangible improvements in the lives of individuals with ASD.

自闭症患者面临的主要障碍之一是无法有效沟通。虽然 有许多原因，这种能力，一个重要的组成部分似乎是一个严重的缺陷，在处理能力 演讲听起来很有效。昂贵，耗时的行为干预可以改善行为 虽然这些干预措施取得了一些成果，但许多人接受了这些干预措施，仍然存在缺陷。的发展 可以增加康复治疗益处的预防性干预对于改善患者的生活至关重要 自闭症谱系障碍（ASD）的个体。我们开发了一种新技术， 神经可塑性和增强康复的好处。迷走神经刺激（VNS）与 声音的呈现触发了促进可塑性的神经调质的快速阶段性释放， 听觉网络的可塑性最近的临床前和临床研究结果表明，VNS与感觉神经 或运动康复疗法与康复疗法相比可以显著增强功能恢复 一个人这项建议将评估是否VNS配对听觉训练可以提高疗效， 自闭症的康复宫内丙戊酸（VPA）暴露是一种有充分记录的 人类的自闭症与自闭症患者相似，言语辨别能力和听觉皮层 VPA暴露大鼠的反应受损。本建议的目的是确定VNS是否配对 听觉训练可以逆转VPA中观察到的神经和行为听觉处理缺陷 暴露的老鼠在目标1中，我们测试了植入式和非侵入式VNS与听觉训练配对的能力 提高产前VPA暴露后的辨别能力。暴露于VPA的大鼠在 区分语音。我们将评估VPA或盐水暴露大鼠的辨别准确性 进行VNS配对听觉训练。在目标2中，我们评估清醒行为神经生理反应， 在听觉皮层，以评估VNS依赖的神经可塑性，可能是改善听觉 处理.与对照组大鼠相比，VPA暴露大鼠表现出听觉皮层反应的改变。先前 结果表明，VNS配对可以更快地加强听觉皮层反应，并在更大程度上 独自训练。在目标3中，我们测试了两种神经调节网络在VNS依赖性中的作用 VPA暴露背景下可塑性和声音辨别能力的增强。我们将耗尽 胆碱能或去甲肾上腺素能传入，特别是听觉皮层，以确定是否乙酰胆碱或 去甲肾上腺素耗竭损害听觉处理中的VNS相关改善。除了证明- 临床翻译的概念证据，这一建议将提供洞察能力的可塑性为基础的 治疗ASD的有效方法，并为未来更全面的研究奠定基础， 目标是将这些关键的首次动物临床前实验转化为临床治疗， 显著的，切实的改善ASD患者的生活。