A randomized controlled trial of smell training and trigeminal nerve stimulation in the treatment of COVID-related persistent smell loss

摘要 COVID暴露了对新的和改进的化学感觉（即嗅觉和嗅觉）治疗干预的迫切需要。 味觉）功能障碍。有证据表明，与COVID相关的嗅觉丧失（SL）通常在恢复后持续很长时间。 初始感染，并与其他长期COVID神经精神症状高度相关，包括 情绪、睡眠和认知的损害。到目前为止，几乎没有干预措施可用于治疗COVID相关疾病。 持续性SL及其相关损伤。虽然嗅觉/嗅觉训练（ST）已经成为一种广泛的 处方，一线治疗与COVID相关的持续性SL，需要严格的研究来确定其 在长期COVID中的疗效。此外，鉴于ST是一个漫长的治疗，需要12周或更长的训练， 并且与缓慢改善、不依从、脱落和适度效应大小相关， 因此，有必要采取预防性措施来提高其疗效和恢复速度。在这里，我们提出了第一项研究， 研究三叉神经刺激（TNS）和ST组合治疗COVID后持续性 SL和相关的情绪、睡眠和认知障碍缺陷。我们以前的工作表明，TNS，一个 易于使用和非常安全的非侵入性脑刺激形式，增加嗅觉灵敏度，并具有 有可能改善长期COVID的其他症状，包括情绪，白天嗜睡和注意力。 因此，我们将进行一项更大规模的家庭随机对照试验，以确定TNS是否 增强ST在患有COVID相关持续性SL的成人中的作用。我们的主要目标是：（1）确定 与任何自然获得的功能相比，ST对嗅觉特异性缺陷的疗效（主动ST与假手术 ST），2）确定ST对嗅觉特异性缺陷的TNS增强效应（活性TNS+ST与活性TNS+ST）， ST），以及3）确定与ST相比，TNS+ST是否也在治疗其他肿瘤中更有效。 与SL和长期COVID相关的损害（即情绪、睡眠和认知）。虽然这项研究是 重点关注与COVID相关的持续SL，结果将为扩展研究提供必要的信息 以及使用ST和TNS来解决更广泛的化学感觉功能障碍。这种调查方式有可能 对如何治疗化学感觉功能障碍产生实质性影响，从而显著改善 目前的护理标准。

ABSTRACT COVID exposed the critical need for new and improved treatment interventions for chemosensory (i.e. smell and taste) dysfunction. Evidence indicates that COVID-related smell loss (SL) often endures well past recovery of the initial infection and is highly associated with other long COVID neuropsychiatric symptoms including impairments in mood, sleep, and cognition. To date, there are few interventions available to treat COVID-related persistent SL and its related impairments. While smell/olfactory training (ST) has emerged as a widely prescribed, front-line treatment for COVID-related persistent SL, rigorous study is required to determine its efficacy in long COVID. Moreover, given that ST is a lengthy treatment, requiring 12 weeks or longer of training, and is associated with slow improvement, non-compliance, drop-out, and modest effect size, additional study of adjunctive methods to improve its efficacy and speed of recovery are warranted. Here we propose the first study to investigate combinatorial trigeminal nerve stimulation (TNS) and ST in the treatment of post-COVID persistent SL and associated deficits in mood, sleep and cognitive impairment. Our previous work suggests that TNS, an easy-to-use and very safe form of non-invasive brain stimulation, increases olfactory sensitivity and has the potential to improve other symptoms of long COVID including mood, daytime sleepiness, and attention. Therefore, we will conduct a larger at-home, randomized, controlled trial of ST and determine whether TNS enhances the effects of ST in adults with COVID-related persistent SL. Our primary objectives are 1) to determine the efficacy of ST, compared to any natural gain in function, on olfactory-specific deficits (active ST versus sham ST), 2) to determine the TNS-enhanced effects of ST on olfactory-specific deficits (active TNS+ST versus active ST), and 3) to determine if TNS+ST, compared to ST, is also more efficacious in the treatment of other impairments (i.e. mood, sleep, and cognitive) associated with both SL and long COVID. While this research is focused on COVID-related persistent SL, the results will provide the necessary information to extend the study and use of ST and TNS to address wider chemosensory dysfunction. This line of investigation has the potential to make a substantial impact on how chemosensory dysfunction is treated and in turn significantly improve the current standard of care.