Cortical Electrical Suppression of Noise-Induced Tinnitus

描述(申请人提供)：耳鸣是在没有外部刺激的情况下出现的幻觉声音。它可能会对数百万患者产生虚弱的影响，给我们的社会带来重大的经济影响。在众多的治疗策略中，听觉皮质电刺激(ACE)最近已被用于临床抑制耳鸣。这种治疗方法已经取得了有希望的结果，并有可能成为治疗耳鸣的重要方法。然而，ACES诱导的耳鸣抑制的疗效在不同个体之间存在很大的差异，阻碍了它成为一种可靠的治疗方法。本项目的目标是建立一种抑制耳鸣的ACES大鼠模型。在目标1中，我们将检验ACES抑制噪声诱导的大鼠耳鸣的假设。为了验证这一假设，我们将在大鼠的听觉皮质(AC)植入慢性电极阵列。手术后恢复后，噪声暴露前的基线行为数据将使用间隙检测惊吓反射范例来评估耳鸣。为了诱发耳鸣，每只动物都将暴露在124-130dBSPL的16 kHz倍频程噪声中15分钟或2小时。一旦确认耳鸣的存在，将对交流进行电刺激。在ACES后，将再次进行耳鸣的行为测试，以确定其对耳鸣行为证据的抑制作用。在噪声暴露诱导耳鸣前后，通过脉冲前抑制惊厥反射和听觉诱发的听性脑干反应来测量听力阈值。这些数据将被用来区分耳鸣阳性而没有听力损失的动物和听力损失的动物。在目标2中，我们将优化ACE的刺激策略，以抑制噪声性耳鸣。我们将进行比较研究，以确定在哪里和如何刺激，以获得最大限度地抑制耳鸣。将比较刺激同侧和对侧AC对操作的耳朵、听觉核心和带区，以及硬膜外和实质内(皮质内)组织的影响。此外，我们将考察不同刺激参数的抑制效果，如单脉冲和串脉冲、强度、脉率和持续时间。发展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。建立这个模型还将允许深入研究ACE诱导的耳鸣抑制的机制。对这些机制的清楚了解将反过来促进ACE作为一种可靠的治疗方法的发展。最后，这方面的研究将有助于对耳鸣的机制有更多的了解。耳鸣是一种流行的公共卫生问题，影响着数以百万计的人，并给社会带来巨大的经济负担。在众多的治疗策略中，听觉皮质电刺激(ACES)已成为治疗耳鸣的一种重要且有前景的方法。本项目的目标是建立一种抑制耳鸣的ACES动物模型。发展这一动物模型将使深入研究ACE诱导的耳鸣抑制的机制，刺激先进的临床试验，并促进ACE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.