Cortical Electrical Suppression of Noise-Induced Tinnitus

描述（由申请人提供）：耳鸣是在没有外界刺激的情况下发生的幻音。它会对数百万患者造成虚弱的影响，对我们的社会产生重大的经济影响。在众多正在寻求的管理策略中，听觉皮层电刺激（ACES）最近被用于临床抑制耳鸣。这种治疗已经产生了有希望的结果，并有可能成为管理耳鸣的重要方法。然而，aces诱导的耳鸣抑制在个体间的疗效差异很大，阻碍了其发展成为一种可靠的治疗方法。本项目的目的是建立ace大鼠耳鸣抑制模型。在Aim 1中，我们将验证ace抑制大鼠噪声性耳鸣的假设。为了验证这一假设，我们将在大鼠听觉皮层（AC）植入慢性电极阵列。手术恢复后，使用间隙检测惊吓反射范式评估噪声暴露前的基线行为数据。为了诱发耳鸣，每只动物将暴露在16 kHz频带的噪声中，噪声强度为124-130 dB SPL，持续15分钟或2小时。在确认耳鸣的存在后，将对交流进行电刺激。耳鸣行为测试将在ace后再次进行，以确定其对耳鸣行为证据的抑制作用。在噪声诱发耳鸣前后，通过脉冲前抑制惊吓反射和声诱发的听觉脑干反应来测量听力阈值。这些数据将用于区分没有听力损失的耳鸣阳性动物和听力损失的动物。在Aim 2中，我们将优化ace的刺激策略来抑制噪声性耳鸣。我们将进行比较研究，以确定刺激的位置和方式，以最大限度地抑制耳鸣。将比较同侧和对侧AC对操纵耳、听核和听带区域、硬膜外和实质内（皮质内）组织的刺激。此外，我们将使用不同的刺激参数，如单脉冲和训练脉冲、强度、脉冲速率和持续时间来检查抑制效果。开发这种动物模型是确定最佳刺激策略的关键一步-直接影响临床相关问题。建立这个模型也将允许深入研究ace诱导耳鸣抑制的机制。对这些机制的清晰理解将反过来促进ace作为一种可靠的治疗方法的发展。最后，在这个方向上的研究将有助于对耳鸣的机制有更多的了解。耳鸣是一种普遍存在的公共卫生问题，影响着数百万人，给社会带来了重大的经济负担。在众多的治疗策略中，听觉皮层电刺激（ace）已成为治疗耳鸣的重要和有前途的方法。本课题的目的是建立ace抑制耳鸣的动物模型。建立这种动物模型将有助于深入研究ace诱导耳鸣抑制的机制，刺激高级临床试验，并促进ace作为一种可靠治疗方法的发展。

DESCRIPTION (provided by applicant): Tinnitus is a phantom sound that occurs in the absence of external stimulation. It can have debilitating effects on millions of patients, creating a significant economic impact on our society. Among numerous management strategies being sought, auditory cortex electrical stimulation (ACES) has recently been used clinically to suppress tinnitus. This treatment has yielded promising results and has the potential of becoming an important approach in managing tinnitus. However, large variability in the efficacy of ACES-induced tinnitus suppression across individuals has hindered its development into a reliable therapy. The goal of this project is to develop an ACES rat model of tinnitus suppression. In Aim 1, we will test the hypothesis that ACES suppresses noised-induced tinnitus in rats. To test this hypothesis, we will implant chronic electrode arrays in the rat auditory cortex (AC). Following recovery from surgery, baseline behavioral data before noise exposure will be evaluated for tinnitus using a gap detection startle reflex paradigm. To induce tinnitus, each animal will be exposed to a 16 kHz octave band noise delivered at 124-130 dB SPL for 15 minutes or 2 hours. Upon confirming the presence of tinnitus, electrical stimulation of the AC will be performed. Behavioral testing for tinnitus will again be performed after ACES to determine its suppressive effects on the behavioral evidence of tinnitus. Before and after tinnitus induction with noise exposure, hearing thresholds will be measured by the pre-pulse inhibition startle reflex and the acoustically evoked auditory brainstem responses. The data will be used to separate tinnitus positive animals without hearing loss from those with hearing loss. In Aim 2, we will optimize stimulation strategies of ACES to suppress noise-induced tinnitus. We will conduct comparative studies to determine where and how to stimulate in order to obtain maximum suppression of tinnitus. The comparisons will be made between stimulation of the ipsilateral and contralateral AC to a manipulated ear, auditory core and belt regions, and epidural and intra-parenchymal (intracortical) tissues. In addition, we will examine the suppressive effects using different stimulation parameters such as single and train pulses, intensity, pulse rate, and duration. Developing this animal model is a crucial step for identifying optimal stimulation strategies - directly impacting clinically relevant issues. Establishing this model will also allow an in-depth investigation of the mechanisms that underlie ACES-induced tinnitus suppression. A clear understanding of these mechanisms will in turn facilitate the development of ACES as a reliable therapy. Finally, research in this direction will help gain more insights into the mechanisms of tinnitus. Tinnitus is a prevalent public health problem that affects millions of people and imposes a significant economic burden to society. Among numerous management strategies being sought, auditory cortex electrical stimulation (ACES) has become an important and promising approach in managing tinnitus. The goal of this project is to establish an animal model of ACES to suppress tinnitus. Developing this animal model will allow in-depth investigation of the mechanisms underlying ACES-induced tinnitus suppression, stimulate advanced clinical trials and facilitate development of ACES as a reliable therapy.