Maintenace rTMS for chronic tinnitus relief

描述(申请人提供)：主观耳鸣是在没有外部刺激的情况下感觉到的声音，如铃声、嗡嗡声或嘶嘶声。耳鸣是一种严重的神经系统疾病，影响着5100万美国公民。没有治愈的方法。1200万患者因睡眠、情绪和注意力障碍而寻求治疗，300万患者无法在工作中发挥作用。目前的治疗方法实际上对减少耳鸣知觉几乎没有什么作用。相比之下，重复经颅磁刺激(RTMS)是一种非侵入性的局部脑刺激方法，可显著减少50%患者的主观耳鸣；然而，治疗效果是暂时的，在标准疗程长达一周后持续1至2周。我们的初步工作表明，这一限制可以通过改变rTMS的应用方式来克服。我们观察到，在对标准疗程有积极反应的人(即治疗应答者)中，rTMS对耳鸣的影响是非常可靠的，当耳鸣复发时重新应用rTMS(即维持治疗)会产生额外的益处，并随着时间的推移保持下去。我们假设维持性rTMS的工作原理是逆转由正常感觉输入丧失(即丘脑皮质节律失常)启动的病理过程，我们将使用治疗前后的高密度脑电记录来验证这一假设。我们预计维持治疗将以一种附加的方式改善耳鸣，并且相对于标准治疗和假治疗对照，它将防止复发。我们将重点研究30名治疗应答者，他们将接受假的和积极的维持rTMS，采用交叉治疗的盲法研究设计。将对30名无反应者进行研究，以了解哪些患者特征可以预测治疗反应。维持治疗将包括四个疗程，为期3天的rTMS，间隔固定的3周。主要结果指标将包括耳鸣严重程度问卷、耳鸣响度和烦扰的视觉模拟评级、改善/恶化的强制选择措施、耳鸣频率和响度的物理锚定指标以及脑电频段的频谱功率和相干性。维持治疗效果的时间和持续时间将通过计算一个疗程结束和耳鸣复发之间的天数来评估。随访评估将在3个月后进行，以评估主要结局指标的变化，以及与生活质量有关的耳鸣的临床、行为、情绪和知觉方面的基线评估。分析将比较标准维持治疗和积极维持治疗之间以及积极维持治疗和假维持治疗之间的主要结果衡量基准的变化分数。磨损和丢失的数据将通过主题替换进行处理。这个项目意义重大，因为它有可能产生一种治疗方法，可以长期减少耳鸣的感觉。我们使用维持性rTMS的创新方法可以改变目前rTMS如何应用于其他使用rTMS治疗的临床疾病的范例和模式。我们预计维持性rTMS将使一半的耳鸣患者受益。我们预计，这些发现将支持更大规模的多点试验，这些试验可以将rTMS确立为耳鸣的一线治疗方法，并获得FDA的批准。 公共卫生相关性：这项研究的目标是为主观耳鸣(“耳鸣”)提供持久的治疗；这是一种严重的、致残的神经疾病，缺乏有效的治疗。耳鸣将通过在13周的疗程中以预定的间隔发射强磁脉冲来刺激大脑的听觉区域来非侵入性地治疗(即维持rTMS)。我们应用rTMS的独特方法可以将其确立为治疗耳鸣和可能使用rTMS治疗的其他临床疾病的一线方法。

DESCRIPTION (provided by applicant): Subjective tinnitus is perception of sound like ringing, buzzing, or hissing in the absence of external stimulation. Tinnitus is a significant neurological disorder that affects 51 million US citizens. There is no cure. Twelve million patients seek treatment for disturbances of sleep, affect and concentration and 3 million are unable to function occupationally. Current treatments do little to actually reduce tinnitus perception. In contrast, repetitive transcranial magnetic stimulation (rTMS) is a non-invasive method of regional brain stimulation that can significantly reduce subjective tinnitus in 50% of patients; however, the treatment effect is temporary, lasting 1 to 2 weeks after a week-long course of standard treatment. Our preliminary work indicates that this limitation can be overcome by changing the way rTMS is applied. We have observed that the rTMS effect on tinnitus is very reliable among persons who respond positively to a standard course of treatment (i.e., treatment responders) and that reapplying rTMS when tinnitus returns (i.e., maintenance treatment) produces added benefits that are sustained over time. We hypothesize that maintenance rTMS works by reversing pathological processes which are set in motion by a loss of normal sensory input (i.e., a thalamocortical dysrhythmia) and we will test this hypothesis using high density EEG recordings before and after treatment. We expect that maintenance treatment will improve tinnitus in an additive fashion and that it will impede relapse relative to standard treatment and to a sham-treatment control. We will focus the study on 30 treatment responders who will receive sham and active maintenance rTMS using a blinded study design with treatment crossover. Thirty non responders will be studied to learn what patient characteristics predict a treatment response. Maintenance treatment will consist of four, 3-day courses of rTMS separated by fixed 3-week intervals. Primary outcome measures will include a questionnaire of tinnitus severity, visual analogue ratings of tinnitus loudness and annoyance, forced- choice measures of improvement/worsening, a physically anchored measures of tinnitus frequency and loudness and the spectral power and coherence of EEG frequency bands. The timing and duration of maintenance treatment effects will be assessed by counting the number of days between the end of a course of treatment and the return of tinnitus. Follow-up assessment will be conducted at 3 months to evaluate change in the primary outcome measures and in the baseline assessments of clinical, behavioral, emotional, and perceptual aspects of tinnitus related to quality of life. Analyses will compare change scores from baseline on the primary outcome measures between standard and active maintenance treatment and between active and sham maintenance treatment. Attrition and missing data will be treated with subject replacement. This project is significant because it has potential to produce a treatment that decreases tinnitus perception chronically. Our innovative approach of using maintenance rTMS can shift current paradigms and models of how rTMS is applied in other clinical disorders treated with rTMS. We expect maintenance rTMS to benefit half of patients with tinnitus. We anticipate that these findings will support larger, multisite trials that can establish rTMS as a frst line treatment approach for tinnitus and gain FDA approval for this use. PUBLIC HEALTH RELEVANCE: The goal of this research is to produce a lasting treatment for subjective tinnitus ("ringing in the ears"); a significant and disabling neurological condition tha lacks effective treatment. Tinnitus will be treated noninvasively by stimulating auditory regions o the brain with strong magnetic pulses delivered at scheduled intervals over a course of 13 weeks (i.e., Maintenance rTMS). Our unique method of applying rTMS could establish it as a first-line approach for tinnitus and possibly other clinical disorders treated with rTMS.