Maintenace rTMS for chronic tinnitus relief

描述（由申请人提供）：主观性耳鸣是指在没有外界刺激的情况下，对铃声、嗡嗡声或嘶嘶声的感觉。耳鸣是一种严重的神经系统疾病，影响着5100万美国公民。没有治疗方法。1200万患者因睡眠障碍、情感障碍和注意力不集中而寻求治疗，300万患者无法正常工作。目前的治疗方法在减少耳鸣感觉方面收效甚微。相比之下，重复性经颅磁刺激（rTMS）是一种无创的区域脑刺激方法，可显著减少50%患者的主观耳鸣；然而，治疗效果是暂时的，在一周的标准治疗后持续1至2周。我们的初步工作表明，可以通过改变rTMS的应用方式来克服这一限制。我们观察到，rTMS对耳鸣的效果在对标准疗程有积极反应的人（即治疗反应者）中是非常可靠的，当耳鸣复发时（即维持治疗）重新应用rTMS会产生持续时间的额外益处。我们假设，维持rTMS的工作原理是通过逆转由正常感觉输入丧失（即丘脑皮质节律异常）引起的病理过程来实现的，我们将在治疗前后使用高密度脑电图记录来验证这一假设。我们期望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控制，它将阻止复发。我们将研究重点放在30名治疗应答者身上，他们将接受假性和主动维持性rTMS，采用双盲研究设计，治疗交叉。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为期3天的rTMS疗程，以固定的3周间隔分开。主要结果测量将包括耳鸣严重程度问卷，耳鸣响度和烦恼的视觉模拟评分，改善/恶化的强制选择测量，耳鸣频率和响度的物理固定测量以及脑电图频带的频谱功率和一致性。维持治疗效果的时间和持续时间将通过计算疗程结束和耳鸣恢复之间的天数来评估。随访评估将在3个月时进行，以评估主要结局指标的变化，以及与生活质量相关的耳鸣的临床、行为、情绪和感知方面的基线评估。分析将比较标准维持治疗和主动维持治疗以及主动维持治疗和假维持治疗之间从基线开始的主要结果测量的变化评分。磨损和缺失的数据将被替换受试者。这个项目意义重大，因为它有可能产生一种治疗慢性耳鸣的方法。我们使用维持性rTMS的创新方法可以改变rTMS如何应用于其他临床疾病的范例和模型。我们期望维持rTMS能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地点试验，以确定rTMS作为耳鸣的一线治疗方法，并获得FDA的批准。

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.