CN113425976A - 20～40Hz频闪光对应激相关障碍的改善或治疗作用 - Google Patents
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Abstract
本发明公开了一种用于治疗有需要的受试者中的应激相关障碍的方法。所述方法包括以下步骤：非侵入性地向所述受试者递送具有20～40Hz的频闪光。本发明采用的频闪光能刺激γ振荡脑电波，改善应激相关障碍的γ振荡脑电波弱化的特点；同时按照昼夜生物节律的变化特点，早晚分别给予视觉频闪光，强化视觉的节律性振荡，从而达到应激相关障碍的治疗效果。
Description
技术领域
本发明属于应激相关障碍技术领域，具体涉及20～40Hz频闪光对应激相 关障碍的改善或治疗作用。
背景技术
应激相关障碍(Stressor-Related Disorder,SRD)是指暴露于创伤或应激事件而引起的精神障碍，患病率为2.0％～8.0％，对个体的心理和生理均产生不同程 度的损害。
研究表明：SRD可引起中枢及外周内分泌-炎症-免疫反应失调,伴随情绪 低落、学习记忆能力降低、胃肠功能紊乱等全身性的异常症状。许多应激相关 障碍的发生，例如创伤后应激障碍PTSD患者出现睡眠-觉醒周期、褪黑素相位、 食欲、体温等生理节律异常。目前治疗方法SRD的方法药物治疗、心理治疗和 物理治疗等方式，但都存在着不同程度的局限性。药物治疗结合心理辅导是目 前临床实践中最常用的治疗方法。临床上治疗抑郁症的药物主要分为三类，即 单胺氧化酶抑制剂(MAOI)、三环类抗抑郁药(TCA)和选择性5-HT再摄取抑制药 (SSRI)。遗憾的是，即使是SSRIs类药物也存在有效率不高，起效延迟(4-6周起效)，存在性功能障碍、胃肠道不适等毒副反应，尤其是导致自杀倾向，从而限 制了其临床应用。因此，探讨安全、有效、副作用低的干预措施对抑郁防治尤 为关键，也能够为精确治疗提供理论依据。
大脑神经环路解析以及功能调控是当前神经科学与神经工程研究的热点和 难点。随着神经网络解析认知和技术的提高，特别光对神经网络调控的研究拓 展到治疗抑郁、失眠、老年痴呆等神经系统疾病等领域。光对生物节律、心理 和生理有重要的影响，也可用做治疗手段。作为一种无创性的物理治疗手段,光 疗具备有效、安全、副作用低等优点,通过发光装置产生不同波长和强度的光 线,刺激自主神经和脑干网状结构,调节血液循环和内分泌功能,改善症状。 2015年JAMA Psychiatry杂志发表临床研究论文：光疗技术比抗抑郁药治疗非季 节性重度抑郁症更有效,明亮的光联合抗抑郁药能够极大地提高了非季节性重 度抑郁症的治疗效果。这篇文章的发表在精神病学及心理健康研究领域引起了 不小的轰动。随后，暨南大学任超然课题组和苏国辉院士团队合作发现视网膜 M4型自身感光视网膜神经节细胞(retinal ganglion cells，RGCs)直接投射至外侧 缰核(lateral habenula，LHb)腹侧外膝体及膝状体间小叶(vLGN/IGL)可抑制外侧僵 核LHb神经元活动，进而减少抑郁样行为这一光信息传导通路，深入阐释了光 疗抗抑郁作用产生的神经环路机制。这项研究开创了新的抑郁相关光信息传导 通路的研究,加深了人类对光在调控情绪中的功能及机制的理解，也为光疗在 精神疾病的应用提供了理论依据。光疗技术的发展目前只是处于起步阶段,但 其在脑疾病的早期干预及神经系统损伤修复中的巨大潜力不容忽视。
神经网络振荡是一种反应神经元潜在同步性的节律波动,在哺乳动物脑电 活动中广泛存在。局部场电位(local field potential,LFP)可集中地反映大脑皮层 局部空间内神经元突触活动所导致的电场变化,利用LFP可对神经振荡活动进 行定量测量,按频率大体可将其分为δ(1～4Hz)、θ(4～8Hz)、α(8～12Hz)、β(12 ～32Hz)和γ神经振荡。γ神经振荡缺少精确的频段定位,一般规定为30～100Hz, 也有人将其细分为24～40Hz的低频和60Hz以上的高频。大脑中很多局部神经 环路都能产生γ节律振荡，包括大脑皮质、丘脑、海马、杏仁核、纹状体和小 脑等γ节律振荡被认为是多种认知活动的神经基础，包括感觉信息处理、感知 与运动整合、记忆和注意等。脑电波图研究表明:精神疾病通常伴随有特征性神经振荡活动的异常。如抑郁行为的产生与背侧海马齿状回的γ振荡活动密切 相关，急性应激诱导会引起背侧海马齿状回γ神经振荡活动的减弱，在伏隔核 深部脑刺激治疗后γ神经振荡活动增加。
近年来，基于神经网络调控的视觉光刺激技术在重大脑疾病中的研究取得 了重大研究进展。麻省理工学院研究人员利用一种非侵入式刺激脑神经元的方 法，即以40Hz的γ振荡频率闪灯照射阿尔茨海默症AD模型鼠,小鼠初级视皮 层产生视觉振荡能降低早期AD小鼠视觉皮层内β-淀粉样蛋白水平达50％，也 减少了皮层淀粉样蛋白斑块数量；大脑视觉皮层区域处理的视觉信息可以增强 海马区域动态的突触可塑性，40Hz的光刺激同步效应可增强海马区CA3区域 突触前神经递质的囊泡释放,进而增强CA1突触后动作电位，提高突触连接强 度。此外，研究发现：脑卒中后海马CA3-CA1神经环路低频γ振荡受损、神 经递质释放紊乱、突触可塑性降低，进而导致神经元死亡。40Hz光刺激提高 CA3-CA1神经环路低频γ振荡，调控神经递质释放，增强突触可塑性，进而保 护神经细胞免受脑缺血缺氧损伤，提高康复速度。提示基于低频γ振荡的光刺 激能够有效的改善神经系统疾病的病理损伤，促进神经功能的恢复。蛋白质组 学分析表明视觉光刺激后差异表达蛋白与突触功能、细胞死亡以及转录和翻译 等相关。功能验证实验表明：光可诱导突触神经传递调节蛋白RGS12的高表达 以增强突触可塑性。光照除了影响蛋白本身水平的表达以外，还会影响蛋白翻译后修饰而参与认知功能相关的脑网络结构和功能的调控。但目前基于低频γ 振荡的神经网络调控技术在抑郁症模型的研究尚无报道。
发明内容
本发明的目的在于提供20～40Hz频闪光对应激相关障碍的改善或治疗作 用。
一种用于治疗有需要的受试者中的应激相关障碍的方法，所述方法包括以 下步骤：非侵入性地向所述受试者递送具有20～40Hz的频闪光。
所述频闪光与γ振荡脑电波同步,采用节律性视觉振荡的方式治疗或改善 应激相关情绪障碍和认知功能。
所述节律性视觉振荡的方式为：每日早、晚各1小时,持续7-28天。
所述频闪光采用方波电流信号驱动发光二极管的阵列产生。
本发明的有益效果：传统的光疗主要采用单色光，通过照度、色温的调节 达到治疗的效果，而本发明采用的频闪光能刺激γ振荡脑电波，改善应激相关 障碍的γ振荡脑电波弱化的特点；同时按照昼夜生物节律的变化特点，早晚分 别给予视觉频闪光，强化视觉的节律性振荡，从而达到应激相关障碍的治疗效 果。
附图说明
图1为40Hz频闪光刺激改善慢性皮质酮注射抑郁模型鼠抑郁行为及认知 功能障碍；
图中，A为40Hz频闪光照射7天对慢性应激模型小鼠抑郁行为的改善作 用；B为40Hz频闪光照射14天对慢性应激模型小鼠抑郁行为的改善作用；C 为40Hz频闪光照射21天对慢性应激模型小鼠抑郁行为的改善作用；D为40Hz 频闪光照射21天对慢性应激模型小鼠认知功能的改善作用，*p<0.05，** p<0.01,n＝10.Flx:氟西汀组、Light：频闪光组、Light+Flx：频闪光加氟西汀组。
图2为40Hz频闪光刺激改善慢性束缚抑郁模型小鼠抑郁行为及认知功能 障碍；
图中，A为40Hz频闪光照射对慢性束缚应激模型小鼠抑郁行为的改善作用； B为40Hz频闪光照射对慢性束缚应激模型小鼠中枢抑制摄食的改善作用；C为 40Hz频闪光照射对慢性束缚应激模型小鼠认知功能的改善作用；D为40Hz频 闪光照射对慢性束缚应激模型自发活动的改善作用；*p<0.05,**p<0.01,n＝10。
具体实施方式
为了便于理解本发明，下面将对本发明进行更全面的描述。但是，本发明 可以以许多不同的形式来实现，并不限于本文所描述的实施例。相反地，提供 这些实施例的目的是使对本发明的公开内容的理解更加透彻全面。
下述实施例中，材料SPF级雄性C57BL/6J小鼠(北京维通利华有限公司)， 10～12周龄，27～32g，饲养于军事医学研究院实验动物中心。蔗糖(国药集团 化学试剂有限公司),电子天平(美国METTLER TOLEDO公司),小动物运动 轨迹跟踪系统ANY-Maze(上海新软公司)。
实施例1动物模型建立
1.慢性束缚应激模型(Chronic Restraint Stress Model，CRS)
在正式实验前，将C57BL/6J小鼠置于行为学实验室适应1周，12h昼夜 循环，自由饮水和摄食。小鼠经体重、糖水偏好、旷场实验等初筛后选择行为 得分相近的小鼠40只，随机分为正常对照(normal control,NC)组和CRS组2组， 每组20只。将CRS组小鼠置于50ml离心管所做的束缚管中(离心管提前烫制 出气孔，分散于整个管身，在盖子的中心有一小孔，小鼠尾巴穿于其中而暴露 在空气中，连续束缚21d，每天4h，CRS组小鼠束缚期间禁食禁水，NC组 小鼠自由饮水和摄食。
2.皮质酮CORT注射诱导小鼠慢性应激模型
动物准备工作如前所述，根据文献报道给予小鼠皮下注射CORT，按 20mg/kg/day剂量给予皮下注射CORT混悬液(混悬液浓度为2g/L)，对照组每天 皮下注射相同剂量生理盐水，连续注射4周后称量体重，进行行为学测试。
3.慢性应激动物模型行为学检测
糖水偏爱测试(saccharin preference test,SPT)：利用糖水偏爱测试来检测 小鼠的快感缺乏的状态，从而判断其抑郁症的严重程度，糖水偏爱测试包括两 个阶段：适应训练阶段和测试阶段。首先进行糖水偏爱测试的适应阶段：分别 在每笼中放置两瓶10％蔗糖溶液并持续24h,第二天将其中一瓶10％蔗糖溶液 换成水溶液并持续24h。适应阶段结束后小鼠禁食禁水14h后对所有小鼠进行 24h SPT基线测试,糖水偏爱测试的测试阶段：所有小鼠单笼饲养，分别在每 笼中放置一瓶150ml盛有10％蔗糖溶液的水瓶和一瓶盛有150ml水溶液的水瓶 (每间隔12h交换两瓶的位置,避免小鼠的位置偏好性)，小鼠自由饮水24h，记录测试前后水瓶的重量。计算测试前后的糖精溶液消耗量和水的消耗量。计 算方法为：糖水消耗百分数(％)＝糖精溶液消耗量/(糖精溶液消耗量+水消耗量) ×100％。
新物体识别实验：准备阶段：在进行测试前，要和小鼠消除陌生感，每天 抚摸小鼠，以免操作时对小鼠产生刺激。适应期：小鼠在实验装置内(无物体) 自由运动10分钟；熟悉期，在装置中放入2个相同的物体(AB，确保物体没有 气味，不被推动)，物体距离两侧壁10cm，将小鼠背朝物体从距物体等距离处 放入装置中，用摄像头及软件来纪录小鼠在每个物体上的探索时间(以嘴或者鼻 子接触到物体和凑近物体约2-3cm范围都算对物体的探索)，在5min内(许多实 验已经证实熟悉期2min，动物已经对新奇事物有很好的偏好，当然熟悉3min 则偏好更加明显)测定动物探索每个物体的次数、时间和距离。测试期：一般选择第2阶段完成后的1h作为检测记忆的时间间隔(更长的时间间隔可用来评价 改善记忆的效果)。将两个相同物体中的一个物体替换成一个不同的物体放入装 置中(AC或BC)，同样将小鼠背朝物体从距物体等距离处放入装置中5min，测 定动物探索每个物体的次数、时间和距离。
实施例2视觉频闪的实施及对应激相关障碍的改善作用
视觉光刺激的实施：频闪光闪烁频率在40Hz，与γ振荡脑电波同步,采用 节律性视觉振荡的方式(每日早8:00、晚20:00各1小时，持续16天)。
利用40Hz频闪光对慢性应激模型小鼠的干预效果进行评价。采用两种经 典抑郁模型：慢性皮质酮注射及慢性束缚动物模型，利用ANY-MAZE软件分 析40Hz频闪光对慢性应激小鼠抑郁行为和认知功能的影响。结果显示(图1-2)： 40Hz频闪光刺激能有效改善不同慢性应激小鼠抑郁行为及认知功能障碍。
光生物调节技术作为一种无创性的物理治疗手段，具备有效、安全、副作 用低等优点，通过发光装置产生不同波长和强度的光线，刺激自主神经和脑干 网状结构，调节血液循环和内分泌功能，改善症状。目前国内光疗技术主要用 于新生儿黄疸、皮肤病等治疗，在精神疾病及神经退行性疾病中的治疗尚不多 见；且照射光源比较单一，针对脑电波同步的光调节技术运用不足，特别是基 于视觉频闪光在精神障碍治疗中的作用尚未见报道。因此，本发明提供一种新 的视觉频闪光技术在慢性应激障碍治疗中的作用及用途，本技术方法可以有效 改善慢性应激诱导抑郁症的抑郁行为和认知功能障碍，达到治疗效果。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细， 但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的 普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改 进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权 利要求为准。
Claims (4)
1.一种用于治疗有需要的受试者中的应激相关障碍的方法，其特征在于，所述方法包括以下步骤：非侵入性地向所述受试者递送具有20～40Hz的频闪光。
2.根据权利要求1所述用于治疗有需要的受试者中的应激相关障碍的方法，其特征在于，所述频闪光与γ振荡脑电波同步,采用节律性视觉振荡的方式治疗或改善应激相关情绪障碍和认知功能。
3.根据权利要求2所述用于治疗有需要的受试者中的应激相关障碍的方法，其特征在于，所述节律性视觉振荡的方式为：每日早、晚各1小时,持续7-28天。
4.根据权利要求1所述用于治疗有需要的受试者中的应激相关障碍的方法，其特征在于，所述频闪光采用方波电流信号驱动发光二极管的阵列产生。
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