Cortical Electrical Suppression of Noise-Induced Tinnitus

描述（由申请人提供）：耳鸣是一种在没有外部刺激的情况下发生的幻音。它可能对数百万患者产生削弱作用，对我们的社会产生重大的经济影响。在众多的管理策略正在寻求，听觉皮层电刺激（ACES）最近已被临床用于抑制耳鸣。这种治疗已经取得了可喜的成果，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。本课题的目的是建立一种耳鸣抑制的ACES大鼠模型。在目标1中，我们将测试ACES抑制大鼠噪声诱导的耳鸣的假设。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，将使用间隙检测惊吓反射范例评价噪声暴露前的基线行为数据是否有耳鸣。为诱导耳鸣，将每只动物暴露于以124-130 dB SPL传递的16 kHz倍频程噪声15分钟或2小时。在确认耳鸣的存在后，将进行AC的电刺激。耳鸣的行为测试将在ACES后再次进行，以确定其对耳鸣行为证据的抑制作用。在噪声暴露的耳鸣诱导前后，将通过前脉冲抑制惊吓反射和声学诱发的听性脑干反应来测量听阈。这些数据将用于区分无听力损失的耳鸣阳性动物和听力损失动物。在目标2中，我们将优化ACES的刺激策略以抑制噪声引起的耳鸣。我们将进行比较研究，以确定在哪里以及如何刺激，以获得对耳鸣的最大抑制。将对同侧和对侧AC刺激到操纵耳、听觉核心和带状区域以及硬膜外和实质内（皮质内）组织之间进行比较。此外，我们将使用不同的刺激参数，如单脉冲和脉冲串，强度，脉冲频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。建立这种模型也将允许深入调查的机制，ACES诱导的耳鸣抑制。对这些机制的清楚理解将反过来促进ACES作为一种可靠的治疗方法的发展。最后，在这个方向的研究将有助于获得更多的见解耳鸣的机制。耳鸣是一个普遍存在的公共卫生问题，影响到数百万人，并给社会带来沉重的经济负担。在众多的管理策略正在寻求，听觉皮层电刺激（ACES）已成为一个重要的和有前途的方法在管理耳鸣。本课题的目的是建立ACES的动物模型，以抑制耳鸣。开发这种动物模型将允许深入研究ACES诱导的耳鸣抑制的机制，刺激先进的临床试验，并促进ACES作为一种可靠的治疗方法的发展。

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.