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

摘要 新冠肺炎暴露了对新的和改进的化学感觉治疗干预措施(即气味和 味觉)功能障碍。有证据表明，与COVID相关的气味丧失(SL)在恢复后通常会持续很长时间 最初的感染与其他长期冠状病毒神经精神症状高度相关，包括 情绪、睡眠和认知方面的障碍。到目前为止，几乎没有可用的干预措施来治疗与COVID相关的 持续性SL及其相关损害。虽然嗅觉/嗅觉训练(ST)已经成为一种广泛的 COVID相关持续性SL的一线处方药治疗，需要严格的研究来确定其 长冠状病毒感染的疗效。此外，鉴于ST是一项漫长的治疗，需要12周或更长时间的训练， 并与缓慢的改善、不合规、退出和适度的效果大小有关，额外的研究 有必要辅以提高其疗效和恢复速度的方法。在这里，我们提出了第一项研究 三叉神经电刺激与ST联合治疗COVID后持续性呼吸窘迫综合征 SL及其相关的情绪、睡眠和认知障碍方面的缺陷。我们之前的工作表明，TNS，一种 易于使用且非常安全的非侵入性脑刺激，增加嗅觉敏感度，并具有 有可能改善慢性COVID的其他症状，包括情绪、白天嗜睡和注意力集中。 因此，我们将对ST进行一项更大规模的家庭随机对照试验，并确定TNS是否 在患有COVID相关持续性SL的成人中增强ST的效果。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(活动ST与假ST)的疗效 ST)，2)确定TNS对嗅觉特异性缺陷的增强效应(活动TNS+ST与活动 ST)，以及3)确定TNS+ST是否也比ST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 重点是与COVID相关的持续性SL，结果将为扩大研究提供必要的信息 并使用ST和TNS来解决更广泛的化学感觉障碍。这条调查路线有可能 对化学感觉障碍的治疗方式产生实质性影响，进而显著改善 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.