节律性感觉提示对改善帕金森病运动功能的研究进展
2020年1月
中华神经科杂志，第53卷第1期 第72页-第78页
许梦圆,陈涛,刘月仙,杨彩飞,彭清韵,杨丹,雷小光
帕金森病（Parkinson′s disease）是最常见的神经退行性运动障碍，其运动症状主要以运动迟缓、静止性震颤、肌肉强直、姿势与步态异常为主要表现。药物治疗是帕金森病的一线治疗，但其长期疗效不稳定，且药物累积剂量与运动并发症的发生发展密切相关[1,2]。运动并发症表现为药物疗效减退、不自主运动和运动症状复杂化等，进一步降低帕金森病患者的运动功能，间接导致了大部分患者的残疾和死亡。深部脑刺激（deep brain stimulation，DBS）作为晚期帕金森病患者的二线选择[3,4]，仅对部分患者有效，且难以阻止疾病进展，亦可能诱发其他运动障碍。此外，以经颅磁刺激和经颅电刺激为代表的非侵入性脑刺激（noninvasive brain stimulation，NIBS）对缓解帕金森病运动症状的疗效相对较弱，目前仍亟待进一步临床研究和大宗临床随机对照试验提供更多证据[5]。鉴于此，研究者们仍在探索更多改善帕金森病运动功能的新方法。
实践发现，除了药物、DBS和NIBS，帕金森病患者的运动功能还可在一些条件下戏剧性地暂时改善。例如提示（cueing），一种来自外部的时间或空间刺激，可对帕金森病的运动障碍起到改善作用[6]。近来，越来越多的证据显示节律性感官（听觉、视觉）提示对改善帕金森病患者的运动迟缓、冻结步态、书写障碍等症状都有效果[7,8]。目前推测节律性感觉提示可能通过易化运动功能、修复患者受损的内部时钟、促进多巴胺释放并通过作用于认知功能维持步态等机制，改善帕金森病患者的运动功能。我们拟对上述研究进展及其临床应用前景进行综述。
声音和图像信息是节律性感觉提示中最常被人体主观感受到的成分。声音不只可以易化单突触反射如膝跳反射[9]，还能激发和改变脊髓运动神经元活动，产生复杂的反射活动，例如听觉惊吓反射（auditory startle reflex）[10]。听觉中枢至壳核间存在投射纤维，使听觉刺激能够诱导运动前皮质神经活动的耦合增加[11]。然而，有研究对帕金森病模型猴的左右颞叶分别进行经颅直流电刺激的阳极刺激干预[12]，结果并不能改善运动功能，这提示听觉刺激对帕金森病运动功能的影响可能不是简单地激活某个感觉脑区，其中可能涉及更复杂的脑网络机制。
视觉信息除了为运动提供所需的位置及方向等信息以外，还可通过特殊的视觉感知促进运动。运动过程中不断变化的动态视觉信息可以激活特殊的小脑视觉运动通路，调节步长，从而影响步行速度，实现对运动过程的实时反馈[13]。不仅如此，节律性的视觉刺激还能促进枕叶的视觉皮质神经元的自身活动频率与外部刺激频率同步[14]，参与调控分配注意力，从而提高行为的准确度及反应速度[15,16]。
听觉和视觉信息还可以通过情绪反应间接对运动产生"促进"的影响。听觉提示刺激经前庭蜗系统传至边缘系统，产生内在奖励（intrinsically rewarding）和自我增强（self-reinforcing），间接影响运动[17]。视觉信息经眼传入中脑上丘，再传至中脑的多巴胺神经元，唤起"视觉诱发的奖励预期"[18]，从而影响个体的行动策略[19]。
不仅如此，听觉与视觉还有交互影响。大脑在认知过程早期可将听觉和视觉两种信息进行整合，从而减少其中的感觉分歧[20]。由于人对听觉的早期反应（潜伏期15~20 ms）相对于视觉（潜伏期60~90 ms）更短[21,22]，因此听觉对视皮质内的视觉信息整合起到了前馈作用，增强视皮质的兴奋[23]，调节视觉感知[24,25]。
节律是附属在感觉信息上的，具有一定的"隐匿性"。研究发现，节律性感觉刺激较单纯感官刺激更能改善帕金森病患者运动症状[8]，这提示"节律"本身有着特殊作用。
人脑对"时间"的体验是以感觉为基础的[26]，但是与其他感觉信息不同，时间感知没有特定的感知器官。有研究推测，人脑中处理有关"时间"的主要区域是运动前皮质、顶叶下回、运动辅助区（supplementary motor area，SMA）、前运动辅助区（pre-SMA）、小脑和基底节[27,28,29,30,31]。人脑内存在一套内部时钟（internal clock），对感知到的时间信息进行校正处理[32,33]。与内部时钟相关的时间感知及处理是完成运动任务所必需的[34]。研究显示，帕金森病患者存在时间处理功能障碍[30]，与时间处理相关的脑区间神经通路的连接性和整合性降低[35]，结果以运动迟缓的症状形式表现[31]。
节律性感觉提示包含了"节律"这种时间结构信息的脉冲刺激。人体细胞的生理活动具备一定节律[36]，当自身节律与外部刺激的节律存在差异时，细胞的自身节律会通过"校正"的方式逐渐趋近外界节律，这种动态和持续的"校正"是自适应学习过程和可塑性的基础，是接纳外部节律信息并转变为自身经验和提高信息处理效率的过程[37]，能协调人体的运动功能[38]。对于帕金森病患者而言，外部的节律性感官刺激可使一些与处理时间信息有关的脑区受到激活，例如前额叶、SMA、运动前区[39,40,41]，也能"校正"自身运动频率（如步频）接近外部刺激节律，从而改善帕金森病患者受损的运动功能。
多巴胺是重要的神经调节因子，不仅是学习、决策、行为控制和注意力的基础[42,43,44]，还影响人的时间感知能力[31]。当帕金森病患者表现出运动症状时，其多巴胺神经元至少已损失80%，死亡的帕金森病患者其黑质致密部多巴胺能神经元的损失甚至高达98%[45,46]。多巴胺水平的显著降低，可直接影响额叶运动区神经元之间相互作用的方式，同时间接影响患者的注意力或内部时钟功能[33,47,48,49]。
目前尚无研究揭示节律性提示可直接促进多巴胺的释放，但由于节律性感觉提示可引导人产生对后续脉冲发放的预期[37,50,51]。当下一次脉冲的发放与所预期的节拍吻合时，人脑会获得近似奖励的体验[37]。我们已知安慰剂效应及奖赏效应都可以促进内源性多巴胺的释放[52]。推测节律性感官刺激诱导的"期待"通过与安慰剂及奖赏效应类似的机制促使内源性多巴胺的分泌，从而弥补帕金森病患者损失的多巴胺，改善运动功能。
认知功能在稳定步态中起重要作用，帕金森病患者在疾病早期通常可通过认知功能代偿步态障碍[53,54]，然而约90%的帕金森病患者随着疾病的进展会逐渐出现认知功能减退[55,56]。当认知负荷过重时，认知功能将不足以代偿步态障碍，患者步态异常即凸显出来，发生运动停滞或步态冻结[57]。例如，帕金森病患者在步行通过狭小的门框或进行双重任务（dual-task）时，不得不将有限的注意力分配于外部环境或同时用于进行两件任务，诱发冻结步态[55,57,58,59]。
目前认为节律性感觉提示可通过以下两个机制作用于认知功能从而改善帕金森病冻结步态：其一，节律性感觉提示可直接降低与运动任务无关的脑区兴奋性，使与运动任务有关的大脑区域在工作时少受其他脑区的干扰[60]，帮助帕金森病患者节省出用于维持步态的认知功能[61]，减少由于帕金森病患者认知功能不足导致在运动控制上的负担[57]。其二，被提示唤起的注意力可介导意识对运动过程的控制，允许运动皮质绕过功能异常的基底节，通过一条新的非自动运动通路重新引导运动，直接控制并改善步态[62,63,64]。但节律性感觉提示对进行较复杂任务的帕金森病患者（例如在行走过程中背诵复杂的文章时）步态改善不明显，这是因为当认知资源忙于应付过于复杂任务时，运动步态的控制又归于病变的基底节所致[65]。
早在1991年及1996年，节律性视觉[66]和听觉[67]提示就分别作为干预手段应用于帕金森病治疗，之后各种各样的节律性感觉提示相继被投入帕金森病临床研究。节律性感觉提示不仅可以改善帕金森病患者受损的步态参数[68,69,70]，还可以降低患者冻结步态的严重程度和发作次数[71,72]。
帕金森病患者步态参数的典型特征是步速减缓、步长变短及步频增快[73]。节律性听觉和视觉提示对帕金森病步态的影响各有侧重。节律性听觉提示可提高步速、增长步长、减慢步频[74]，其中对运动迟缓、步频增快的改善效果最佳[74,75]。节律性视觉提示可提高步速和增长步长[13]，同时协调步幅[76]。早期荟萃分析指出，无论从可行性还是灵敏性方面，听觉提示皆优于视觉提示[77]。
节拍器[78,79,80]、音乐[81,82]是目前常见的人工听觉提示形式。与节拍器相比，音乐更能使人感到愉快，近年研究中音乐常被用来替代节拍器作为节律性提示源，但由于音乐较节拍器提供的节奏更隐晦，帕金森病患者常在运动时易将注意力转移到与节律无关的地方，导致运动改善的效果弱于节拍器[8]。与传统人工听觉提示相比，新型"自然声音"听觉提示也逐渐受到关注。例如"脚步声"提示更易使人联想到"行走"，除了能提供节律信息外还能提供和步态相关的"生物"信息，因此对改善步态的效果优于传统人工提示[70]。另一方面，在患者记住外部声音节律的情况下，停止声音刺激，让患者通过自身哼唱来产生节律，可以有效减少外部听觉提示对认知的负荷，更好地改善运动功能[83]。
传统的视觉提示以标记于地面上的视觉条纹（stripes on the floor）为代表，但研究发现，并非所有的视觉条纹都可改善步态，例如锯齿条纹、与运动方向平行的条纹、间距狭窄的条纹、宽于1.8 m的条纹或没有背景颜色衬托的条纹都不能明显改善步态。与之相对的，间距超过0.45 m且有颜色对比的条纹更能有效改善步态[13,84]。传统模式下视觉条纹多被固定于某一场所，帕金森病患者接收视觉提示的场所常因此受到限制。移动设备如激光鞋[72,85]、激光拐杖或激光助步车[86,87]的开发，使得视觉提示源也跟随患者运动并实时投射在患者的视野范围内，解决了视觉提示设备的使用场所问题。虚拟现实（virtual reality）技术[88,89]及最新的智能眼镜技术[80,90]的发展使视觉提示有了更新的载体，但其改善冻结步态的疗效并未得到研究证实，这可能和智能眼镜及虚拟现实设备的佩戴使患者产生的不适感和新型设备分散了患者的注意力有关[90]。
半数进展期帕金森病患者可出现冻结步态（freezing of gait）。尽管患者试图继续迈步，但不能起步或继续前进，感到双脚"黏"在地上，这种情况在患者起步、转弯和通过窄小的门框时更易诱发[91]。与其他帕金森病运动症状（例如运动迟缓）不同，左旋多巴有时不仅无法有效改善冻结步态症状[92]，甚至可能加重该症状[93]。冻结步态的严重程度通常被新冻结步态量表（New Freezing Of Gait Questionnaire，NFOG-Q）量化评估[94]。一些研究也会以行走过程中患者的跌倒次数和冻结现象的发生次数作为评估冻结步态严重程度的补充手段[95]。
研究发现节律性听觉或视觉提示，能显著降低NFOG-Q分数和冻结现象的发生次数，改善行走过程中下肢间的协调能力，预防患者跌倒和帮助患者在行走过程中跨过障碍物[96,97]。节律性感觉提示还可协调行走过程中姿势与迈步的功能耦合，缓解冻结步态患者的起步困难[98]。其中节律性听觉提示改善冻结步态状态下帕金森病患者的起步困难效果良好[69]，节律性视觉提示降低冻结步态的严重程度效果更佳[72,99]。极少数患者使用视觉提示时跌倒次数增加，这可能与帕金森病患者长期接受节律性感觉提示训练后行走时过度自信或注意力被分散所致[95]。尽管节律性感觉提示最终不能帮助帕金森病患者由冻结转变为非冻结状态[71]，但其对冻结步态的有效改善填补了帕金森病药物治疗上的部分空白，具有不可替代的临床应用价值。
与单纯使用节律性听觉和视觉提示相比，节律性感觉提示联合跑步机等康复训练方式在改善帕金森病患者步态参数和冻结步态严重程度方面更具功效[100,101]。随着可穿戴设备的应用技术成熟，穿戴设备中携有的运动传感器可实现对帕金森病患者运动功能的实时监测并从中获取运动参数，这有助于分析帕金森病患者的运动模式并对患者当下是否发生冻结步态提供智能判断[102]。一些其他新兴的运动监测手段出现也为监测帕金森病患者的运动模式提供了便利。例如，飞行时间测距法（time-of-flight）相机接收向周围环境发射红外线的返回光线数据，通过计算不仅可获取帕金森病患者的运动模式，还可构建患者周围环境的三维示意图[103]。即时监测手段与闭环感觉反馈系统（close-loopsensory feedback）的联合应用，可通过算法自动评估帕金森病患者是否处于冻结步态状态；当冻结步态状态发生时，系统能自行启动程序、发放感觉提示帮助患者克服正在发生的冻结步态事件[8,102]。与传统的节律性感觉提示相比，这种新型的联合应用更具智能性与自适应性，有待投入未来的临床应用。
尽管节律性感觉提示治疗帕金森病患者的有效性得到了越来越多的肯定，感觉提示的提示源种类也多种多样，但并非所有节律性感觉提示都可对运动功能产生改善作用。研究显示，将与运动无关的节律提示（例如无明显节拍感的音乐）施与患者，可能妨碍患者的步态[104]。在节律参数设置方面，目前认为与节律相关的频率参数设置应取决于个体的基线频率。研究通常以患者基线步频为基础上调5%~10%，这样的节律参数很少使患者有不适感，同时又能提升患者的运动功能[67]。当节律参数设置与患者基线相差过大时，无论在设置过慢（当刺激频率比个体基线步频慢20%时）或过快（150次/min）的情况下，降低帕金森病患者步态时间变异性（一种保持步态稳定的能力）的负面效应便十分明显[76]，同时会加重患者的注意力负荷[105]，甚至会缩短患者的步长和步速[76]。除提示的频率参数设置外，目前尚无研究表明响度（听觉提示）、亮度（视觉提示）等常见设置参数是否会对疗效产生影响，有待更多的研究进行探讨。
节律性感觉提示作为一种干预帕金森病运动障碍的有效手段，由于其无创和可逆性，具有较高的临床安全性，正在获得越来越多的研究者和临床医师的重视。已有研究显示，节律性感觉提示可以通过易化运动、修复内部时钟、促进多巴胺释放、作用于认知功能等机制改善帕金森病患者的运动功能。节律性听觉及视觉提示可通过提高步速、增长步长、减慢步频、降低冻结步态严重程度等方面改善帕金森病患者的运动功能。当前移动设备的普及使节律性听觉与视觉投入临床应用的门槛不断降低，临床应用前景逐渐明晰。此外，如触觉、震动觉等其他感觉提示对帕金森病患者的应用也相继被投入临床试验，有助于未来节律性感觉提示的临床应用更加多元化。但节律性感觉提示相关刺激参数的调试尚缺乏大规模随机对照试验，仍待未来进一步研究。
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