Recent studies have found that transcutaneous cervical vagus nerve stimulation (VNS) can improve gait symptoms in Parkinson's disease (PD).^1-3 Noninvasive VNS can be performed also on the auricular branch of the vagus nerve, with significant opportunities in terms of feasibility and costs. Data on the effects of transcutaneous auricular VNS (taVNS) in PD, however, are still missing. Hence we aimed at investigating the effects of taVNS on the gait of 12 patients with idiopathic PD, which were consecutively enrolled in a pilot-controlled study with a double-blind randomized crossover design, at the tertiary movement disorders clinic of our institution. Patients were selected according to the following criteria: (1) chronic levodopa therapy without a history of levodopa-induced dyskinesias, (2) walking difficulties but still able to walk unassisted (Unified Parkinson's Disease Rating Scale [UPDRS] Part II item 15 = 1 or 2), and (3) modified Hoehn & Yahr score <3 while on medication. Patients with early signs of cognitive impairment or atypical parkinsonism and individuals on anticholinergics and/or affected by any other known condition able to influence the gait were not included. Therapy changes between visits were not allowed. taVNS was delivered either on the left internal tragus (real) or the earlobe (control) in trains lasting 30 seconds each, composed of 600 pulses (frequency 20 Hz; duration 0.3 millisecond) repeated every 4.5 minutes for 30 minutes (six cycles) (Supporting Information Materials). Patients were randomized to one stimulation and after 1 week, all subjects were crossed over to the other. Patients were evaluated before and after the stimulation with UPDRS Part III, a flanker test (reaction time), a digital 10-m timed up and go (10mTUG) test performed in duplicate (Mon4t clinic, https://mon4t.com), and a Visual Analogue Scale (VAS 0–10, “How do you perceive your walking performance?”). The flanker is an acknowledged VNS-responsive parameter,⁴ while the 10mTUG provides data on total time (stand, rotation, sit, and gait time), gait speed, stride length, number of steps, mediolateral sway, and swing amplitude.⁵ The experiments took place in the morning while all of the patients were on levodopa. The patients' awareness about the condition (i.e., whether real or control) was verified with a questionnaire (Supporting Information Materials). Variables are presented as mean ± standard deviation. Data were tested for normality (Shapiro–Wilks test), compared through t test or Wilcoxon signed rank test for paired data (JMP software v16.0; SAS Institute Inc.), and corrected for multiple comparisons with the Benjamini–Hochberg method (false discovery rate set at 0.05).³ Demographic and disease features are reported in Table S1. All 12 subjects completed both the real and the control stimulation; no dropouts were reported. Baseline data were similar between the two visits (Table S2). The UPDRS Part III and the Visual Analogue Scale scores showed an improvement both after the real and the control stimulation, likely because of a placebo effect; however, both scales showed a better trend following the real stimulation. Stride length, swing amplitude, gait speed, and gait time showed significant changes only after the taVNS. Rotation time, stand time, and sit time did not show any significant variation. Finally, the flanker reaction time improved after taVNS, corroborating our findings. Differences across variables and conditions are reported in Table 1. This is the first experiment reporting a systematic evaluation of taVNS in PD. In this sample of patients with mild-to-moderate PD, the taVNS in add-on to levodopa improved several objective gait parameters. Despite direct data on duration not being collected, the putative taVNS effect persisted for the time duration of the UPDRS motor assessment, the flanker test (mean completion time 52 ± 13.7 seconds), and two consecutive gait assessments (single 10mTUG test mean completion time 28 ± 7.3 seconds). The latter might give useful information for future biomarker (eg, neurophysiological) studies.⁶ Preclinical studies showed that VNS can improve structural and functional aspects of PD.⁷ Even though its mechanism of action is still debated, VNS can entrain the ascending cholinergic and noradrenergic pathways,^{6, 8} which are involved in cognitive processing and in locomotor abilities.^{4, 7} In this study, taVNS improved some dopamine-dependent gait parameters (eg, stride length).⁹ If proven true, this would add information to the growing literature on the association between the vagus nerve and the dopaminergic system.¹⁰ However, despite our results being in line with recent noninvasive cervical VNS experiments,^1-3 it is still not possible to draw a firm conclusion. Indeed, we collected data on the gait of patients with PD through a single sensor. This is a trusted methodology, but the use of a more comprehensive gait analysis system would allow a more precise analysis of gait and of gait-related PD issues (ie, freezing).^{1, 3} Moreover, the study should be replicated on a larger sample, allowing a more robust statistical methodology, eventually exploring VNS dosage and duration.¹¹ Nonetheless, given the manageability of the portable commercialized taVNS devices, they may be considered a valuable tool in the neuromodulation landscape of PD.

最近的研究发现，经皮颈迷走神经刺激 (VNS) 可以改善帕金森病 (PD) 患者的步态症状。^1-3无创 VNS 也可以在迷走神经的耳支上进行，在可行性和成本方面都有很大的机会。然而，关于经皮耳 VNS (taVNS) 在 PD 中的影响的数据仍然缺失。因此，我们的目的是调查 taVNS 对 12 名特发性 PD 患者步态的影响，这些患者在我们机构的三级运动障碍诊所连续参加了一项采用双盲随机交叉设计的试验对照研究。根据以下标准选择患者：(1) 长期接受左旋多巴治疗，无左旋多巴诱发的运动障碍病史，(2) 行走困难但仍能独立行走（统一帕金森病评定量表 [UPDRS] 第二部分第 15 项 = 1或 2), 和 (3) 改良的 Hoehn & Yahr 分数 <3 而在药物。不包括具有认知障碍或非典型帕金森病早期迹象的患者以及服用抗胆碱能药物和/或受任何其他已知能够影响步态的疾病影响的个体。不允许在访问之间更改治疗。taVNS 在左侧内耳屏（真实）或耳垂（对照）上输送，每次持续 30 秒，由 600 个脉冲（频率 20 Hz；持续时间 0.3 毫秒）组成，每 4.5 分钟重复一次，持续 30 分钟（六个周期）（支持信息材料）。患者被随机分配到一种刺激，1 周后，所有受试者都交叉接受另一种刺激。在刺激前后对患者进行了 UPDRS 第 III 部分评估、侧翼测试（反应时间）、数字 10 米计时起步 (10mTUG) 测试，一式两份进行（Mon4t 诊所，https://mon4t. com）和视觉模拟量表（VAS 0-10，“你如何看待你的步行表现？”）。侧卫是公认的 VNS 响应参数，⁴而 10mTUG 提供总时间（站立、旋转、坐下和步态时间）、步态速度、步幅长度、步数、内侧摇摆和摆动幅度的数据。⁵实验在早上进行，当时所有患者都服用左旋多巴。患者对病情的认识（即，是真实的还是对照的）通过问卷（支持信息材料）进行验证。变量表示为平均值±标准偏差。数据经过正态性测试（Shapiro-Wilks 检验），通过配对数据的t检验或 Wilcoxon 符号秩检验（JMP 软件 v16.0；SAS Institute Inc.）进行比较，并使用 Benjamini-Hochberg 方法（错误）进行多重比较校正发现率设置为 0.05）。^3个表 S1 中报告了人口统计学和疾病特征。所有 12 名受试者都完成了真实刺激和对照刺激；没有辍学的报告。两次就诊的基线数据相似（表 S2）。UPDRS 第 III 部分和视觉模拟量表评分在真实刺激和对照刺激后均显示出改善，这可能是因为安慰剂效应；然而，在真正的刺激之后，两个量表都显示出更好的趋势。步幅、摆动幅度、步态速度和步态时间仅在 taVNS 后显示出显着变化。旋转时间、站立时间和静置时间没有显示出任何显着变化。最后，taVNS 后侧翼反应时间有所改善，证实了我们的发现。表 1 报告了变量和条件之间的差异。这是第一个报告 PD 中 taVNS 系统评估的实验。在这个轻度至中度 PD 患者样本中，添加左旋多巴的 taVNS 改善了几个客观步态参数。尽管未收集有关持续时间的直接数据，但假定的 taVNS 效应在 UPDRS 运动评估、侧翼测试（平均完成时间 52 ± 13.7 秒）和两次连续步态评估（单个 10mTUG 测试平均完成时间 28 ± 7.3 秒）。后者可能为未来的生物标志物（例如，神经生理学）研究提供有用的信息。假定的 taVNS 效应在 UPDRS 运动评估、侧翼测试（平均完成时间 52 ± 13.7 秒）和两次连续步态评估（单次 10mTUG 测试平均完成时间 28 ± 7.3 秒）的持续时间内持续存在。后者可能为未来的生物标志物（例如，神经生理学）研究提供有用的信息。假定的 taVNS 效应在 UPDRS 运动评估、侧翼测试（平均完成时间 52 ± 13.7 秒）和两次连续步态评估（单次 10mTUG 测试平均完成时间 28 ± 7.3 秒）的持续时间内持续存在。后者可能为未来的生物标志物（例如，神经生理学）研究提供有用的信息。⁶临床前研究表明，VNS 可以改善 PD 的结构和功能方面。⁷尽管其作用机制仍有争议，但 VNS 可以引起上行胆碱能和去甲肾上腺素能通路， ^6、8这些通路与认知处理和运动能力有关。^{4, 7}在这项研究中，taVNS 改善了一些多巴胺依赖性步态参数（例如，步幅）。⁹如果证明属实，这将为越来越多关于迷走神经和多巴胺能系统之间关联的文献增加信息。¹⁰然而，尽管我们的结果与最近的非侵入性颈椎 VNS 实验一致， ^1-3现在还不能得出肯定的结论。事实上，我们通过单个传感器收集了 PD 患者步态的数据。这是一种值得信赖的方法，但使用更全面的步态分析系统可以更精确地分析步态和与步态相关的 PD 问题（即冻结）。^1、3此外，该研究应该在更大的样本上进行复制，从而允许使用更强大的统计方法，最终探索 VNS 剂量和持续时间。¹¹尽管如此，鉴于便携式商业化 taVNS 设备的可管理性，它们可能被认为是 PD 神经调节领域中的一个有价值的工具。