四川动物  2018, Vol. 37 Issue (5): 481-489

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文章信息

刘衍素, 范艳珠, 方光战
LIU Yansu, FAN Yanzhu, FANG Guangzhan
麻醉-觉醒周期中非洲爪蟾的大脑复杂度研究
Dynamics of Brain Complexity During Anesthesia-Awakening Cycle in Xenopus laevis
四川动物, 2018, 37(5): 481-489
Sichuan Journal of Zoology, 2018, 37(5): 481-489
10.11984/j.issn.1000-7083.20180073

文章历史

收稿日期: 2018-03-06
接受日期: 2018-06-07
麻醉-觉醒周期中非洲爪蟾的大脑复杂度研究
刘衍素1 , 范艳珠2 , 方光战2*     
1. 四川护理职业学院, 成都 610100
2. 中国科学院成都生物研究所, 成都 610041
摘要:全身麻醉是药物诱导下中枢神经系统的抑制状态,是长时间手术操作和有创实验顺利进行的保证。丘脑-皮层环路(特别是丘脑)可能在麻醉-觉醒调控中起着重要作用,但丘脑是否是最重要的调控脑区、调控时是否存在偏侧性尚不清楚。本研究以非洲爪蟾Xenopus laevis为动物模型,在其端脑、间脑、中脑左右两侧分别埋植电极,在鱼安定诱导下进行全身麻醉,连续记录动物在"麻醉前清醒-给药-恢复-麻醉后清醒"过程中的脑电信号,计算各时期的Lempel-Ziv复杂度(LZC)。结果显示:不同状态下的LZC值显著不同,清醒时最大,深度麻醉时最小;给药时长与各脑区LZC值间的显著相关性主要存在于右侧大脑,特别是右侧丘脑。说明LZC可以较好地刻画麻醉-觉醒周期,且右侧丘脑在麻醉-觉醒调控中可能起着重要作用。
关键词全身麻醉     脑电     丘脑     Lempel-Ziv复杂度     偏侧性     非洲爪蟾    
Dynamics of Brain Complexity During Anesthesia-Awakening Cycle in Xenopus laevis
LIU Yansu1 , FAN Yanzhu2 , FANG Guangzhan2*     
1. Sichuan Nursing Vocational College, Chengdu 610100, China;
2. Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
Abstract: General anesthesia is a situation with drug-induced inhibition of central nervous system which can be used for long-term operation procedures and invasive experiments. The thalamo-cortical loop, especially the thalamus, is supposed to play a role in anesthesia-awakening regulation, however, whether the thalamus is the most important brain region and this regulation is asymmetric remain unclear. The present study used the south African clawed frog (Xenopus laevis) as an animal model, and 6 cortical electrode pairs were implanted on the frog skull:both sides of the telencephalon, diencephalon and mesencephalon, respectively. The frogs were immersed in triciane methanesulfonate for general anesthesia and the electroencephalogram signals were recorded for the "pre-anesthesia, administration, recovery and post-anesthesia" cycle continuously. Lempel-Ziv complexity (LZC) was calculated for each stage. The results showed that LZC values differed significantly among various stages, and the highest values occurred during the awakening period and the lowest values occurred during the anesthesia period; and significant correlations were found exclusively between the duration of administration stage and LZC values for the right hemisphere, especially for the right thalamus. These results suggested that the anesthesia-awakening cycle could be reflected by LZC, and the right thalamus might play an important role in anesthesia-awakening regulation.
Keywords: general anesthesia     electroencephalogram     thalamus     Lempel-Ziv complexity     lateralization     Xenopus laevis    

全身麻醉是指药物诱导下中枢神经系统被抑制的状态,该状态能保证长时间的手术操作和有创实验研究的顺利进行(Antognini et al., 2005Goddard & Smith,2013)。全身麻醉以痛觉消失、静止不动和意识丧失为特征,是麻醉药品剂量和被麻醉对象意识状态之间的平衡(Pocock & Richards,1993Brown et al., 2010)。麻醉不充分可导致术中觉醒,而麻醉过量则增加并发症风险(Zhang et al., 2001Loepke & Soriano,2008)。因此,精确的麻醉深度监测对手术安全至关重要(Goddard & Smith,2013)。麻醉深度可用大脑活动的复杂度来刻画(Bruhn et al., 2000Zhang et al., 2001Ferenets et al., 2006Liang et al., 2015Hudetz et al., 2016):清醒时复杂度最高,而麻醉时复杂度最低。研究发现,不同脑区的大脑活动复杂度变化不尽相同;同时,与其他脑区相比,中脑网状结构、丘脑、顶叶联合皮层和额叶联合皮层等特定区域对麻醉药物更为敏感(Heinke & Koelsch,2005)。有研究认为,丘脑-皮层环路(特别是丘脑)可能在麻醉-觉醒调控中起着重要的调节作用(Ries & Puil,1999Franks,2008),但是在麻醉-觉醒过程中,丘脑活动复杂度的动态变化特征依然不够明确,同时尚不清楚丘脑是否为最重要的调控脑区。

大脑功能偏侧性普遍存在于动物中(Rogers & Vallortigara,2008Samara & Tsangaris,2011Sato et al., 2011Roussigne et al., 2012Salva et al., 2012Frasnelli,2013Rogers et al., 2013Rogers,2014Guo et al., 2016薛飞等,2016)。当信息传入大脑时,偏侧性可确保大脑左右半球并行处理信息,从而提高信息处理能力(Vallortigara & Rogers,2005Dadda et al., 2009Fang et al., 2014)。可见,偏侧性具有适应性意义,即通过提高动物感知信息和行为响应的效率来提高适合度。意识是大脑功能之一,所以麻醉-觉醒的调控(即意识的保持与恢复)可能亦存在偏侧性,但需实验证实。

脑电(electroencephalogram,EEG)是大量锥体细胞同步产生的突触后电位总和在大脑皮层或头皮表面的反映(Muthuswamy et al., 1996)。EEG是评估不同麻醉状态下大脑活动情况最直接的方法,但是通过传统的线性方法对原始EEG信号进行分析得到的结果往往难以解释大脑在不同麻醉状态下的各种特征(Billard et al., 1997Katoh et al., 1998Bruhn et al., 2006Mahon et al., 2008)。大脑通常表现出非线性和混沌行为(Bruhn et al., 2000Burioka et al., 2005),其特征可通过非线性参数加以描述;复杂度是众多非线性参数中的一种,与事物的本质特征有关,而与事物的大小、多少等物理量没有必然联系。Lempel-Ziv复杂度(Lempel-Ziv complexity,LZC)是用来度量信号复杂程度,算法简单快速且能有效刻画脑电信号复杂度的物理量(Zhang et al., 2001Abásolo et al., 2015),可用来研究大脑功能状态及麻醉剂对中枢神经系统的抑制作用(Schartner et al., 2015)。

从宏观解剖结构看,两栖类动物的大脑与爬行类、鸟类和哺乳类(含人类)相似,均分为端脑、间脑、中脑、后脑和延髓等部分(Wilczynski & Endepols,2007),其间脑由背侧的丘脑和腹侧的下丘脑组成,且直接位于颅骨下方,而不像其他高等动物被大脑皮层覆盖。这样的结构有利于电极植入,更有利于采集到高信噪比的丘脑活动信号。非洲爪蟾Xenopus laevis是两栖类中应用最广的动物模型,在发育、遗传和神经系统功能等研究领域有着广泛应用(Kay & Peng,1991Schultz & Dawson,2003Guénette et al., 2013)。鱼安定(triciane methanesulfonate,MS-222)是一种安全有效的水溶性麻醉剂,常用于鱼类和蛙类等变温动物的麻醉。

本研究以非洲爪蟾为对象,在其端脑、间脑、中脑左右两侧分别埋植电极,通过MS-222麻醉,连续记录动物在“麻醉前清醒-给药-恢复-麻醉后清醒”整个过程中的EEG信号。通过计算不同时期各脑区的LZC,探讨麻醉-觉醒过程中大脑活动复杂度的动态特征,及可能存在的麻醉-觉醒调控偏侧性。

1 实验材料和方法 1.1 实验动物

以14只成年非洲爪蟾(雌雄各半)为研究对象,按性别饲养于2个透明玻璃缸(长120 cm×宽50 cm×高60 cm)中,水深20 cm。每周投食、换水1次。养殖房室温20 ℃±1 ℃,光周期12L:12D(08:00开灯)。手术时动物体长为8.1 cm± 1.1 cm、体质量为67.1 g±22.2 g。所有手术及实验流程均符合中国科学院成都生物研究所动物福利伦理委员会的相关要求。

1.2 动物手术

将动物浸入3.5 g·L-1 MS-222溶液中进行麻醉,通过夹趾反应判断麻醉程度,无夹趾反应时立即停止麻醉。局部消毒,去除手术区皮肤,剥离头骨表面肌肉暴露头骨。根据图 1所示坐标,分别在左右端脑(LT和RT)、左右间脑(LD和RD)、左右中脑(LM和RM)埋植不锈钢电极(φ=0.8 mm),参考电极埋植在小脑上方(P)。LT和RT位于人字缝前方6.4 mm,旁开1 mm;LD和RD位于人字缝前方3.4 mm,旁开1 mm;LM和RM位于人字缝前方1.4 mm,旁开1 mm;P位于人字缝中线后1 mm处。电极拧入颅骨深度约1 mm,再用牙托水泥固定并覆盖整个手术创口,用局部消炎止痛药膏均匀涂抹创口。最后用自封膜包裹电极接插件以防水。术后,动物置于水深约10 cm的塑料盒中单独饲养,休息1 d后进行数据采集。

图 1 电极位置分布及相应的10 s脑电特征波形 Fig. 1 Electrode placements and corresponding typical electroencephalogram tracings of 10 s LT.左端脑,RT.右端脑,LD.左间脑,RD.右间脑,LM.左中脑,RM.右中脑,P.小脑上方;下同 LT and RT. the left and right telencephalon, LD and RD. the left and right diencephalon, LM and RM. the left and right mesencephalon, P. above the cerebellum; the same below
1.3 数据采集

在电磁屏蔽的隔音室(背景噪音24.3 dB±0.7 dB)内进行实验。将动物放在透明实验盒(底面积18 cm×11 cm,开口处20 cm×13 cm,高12 cm)内吸满水的海绵(厚度为1 cm、吸水量约150 mL)上,以保证动物皮肤湿润,实验盒上方加通气透明的盖子。光照和温度与养殖房一致。在实验盒上方约40 cm处安装具有运动侦测功能的红外摄像机,记录动物运动行为。

实验开始前,将动物连接至信号采集系统(RM6280,成都仪器厂),并设定采样频率为1 000 Hz,记录动物麻醉-觉醒周期的EEG和行为数据:(1)麻醉前清醒期(Stage Ⅰ):记录EEG 30 min,此时动物头部通常朝向实验盒一角并保持不动;(2)给药期(Stage Ⅱ):从将动物换入装有200 mL 3.5 g·L-1 MS-222溶液的、与实验盒同规格的塑料盒中进行麻醉开始,至无夹趾反应止;(3)恢复期(Stage Ⅲ):从将动物放入原记录盒开始,至轻触即出现自主运动止;(4)麻醉后清醒期(Stage Ⅳ):恢复期后连续记录30 min。实验结束后,通过过量麻醉对动物进行安乐死,并在电极的相应位点注射苏木精染料,检查电极位置是否与预期一致。

1.4 LZC

LZC是由Lempel和Ziv(1976)提出的一种时间序列复杂性测度分析方法,即先对时间序列进行符号化(粗粒化)处理后,通过计算其符号序列出现新模式的概率来表征时间序列的复杂度。计算步骤为:

(1) 对时间序列进行符号化(粗粒化)处理:对于时间序列xt(t=1,2,3,…,n),根据选取的阈值(大于阈值时取1,否则取0),将其转化成(0,1)符号序列,即St(t=1,2,3,…,n)。

(2) 令St(t=1,2,3,…,n)和Qt(t=1,2,3,…,m)为2个由(0,1)序列组成的字符串;SQ表示S和Q 2个字符串的级联,即SQ={S1,S2,…,Sn,Q1,Q2,…,Qm};SQπ表示把SQ中最后一个字符删去后所得的字符串,即SQπ=(S1,S2,…,Sn,Q1,Q2,…,Qm-1}。令V(SQπ)表示SQπ中所有不同子串的集合,并设C(n)为符号序列St的复杂度。

(3) 初始化:令C(n)=1,S={S1},Q={S2},则SQπ={S1}。

(4) 若Q∈V(SQπ),则表示Q中的字符串是S的子串,称为Q中的字符是可从S中复制的,此时把待求序列中的下一个字符级联到Q中,变成S={S1},Q={S2,S3};若Q∉V(SQπ),则Q中的字符串不是S的子串,称Q中字符为插入字符,这时应把Q级联到S,即S=SQ,并把Q清空,再将待求序列中的下一个字符添加到Q,此时S={S1,S2},Q={S3}。每次Q级联到S时,执行C(n)=C(n)+1。

(5) 重复步骤(4),直到待求序列中所有的字符被取完。这样就把符号序列St(t=1,2,3,…,n)分成了C(n)个不同的子串,即得到复杂度。

由于对任意足够长的序列,进行二进制符号化后所得的符号序列的复杂度趋向定值:

因此,复杂度可归一化为:LZC=C(n)/b(n)。LZC值为0~1,反映时间序列的复杂程度。LZC值越小,说明时间序列的规律性越明显;LZC值越大,则表示其复杂性越高,说明出现新模式的概率越高,即随机性越强。

1.5 数据处理

EEG信号经50 Hz陷波、0.5~45 Hz带通滤波和256 Hz降采样后,以2 s为长度对数据进行分段。若数据最大幅度大于100 μV,即视为伪迹剔除;由于中值对奇异值不敏感,所以对无伪迹数据段,取其中值为阈值对数据进行符号化(Abásolo et al., 2015);然后计算每段的LZC值;最后每只动物按时段和脑区对LZC值进行平均。后续统计分析均基于上述均值。

1.6 统计分析

用Shapiro-Wilk W检验和Levene's检验对LZC值进行正态性及方差齐性检验,采用三因素(时段、脑区和性别)重复测量ANOVA进行统计分析,同时检测主效应和交互效应。必要时使用Greehouse-Geisser校正;若存在交互效应则进行简单效应分析。利用最小显著性差异法(LSD)进行事后检验;效应度通过partial η2估计。利用Pearson相关分析计算各时段LZC值与给药时长的相关性。所有统计在SPSS 21.0中完成,显著性水平设置为α=0.05。

2 结果

在麻醉-觉醒过程中,不同脑区脑电LZC值的动态变化见图 2,在清醒阶段(Stages Ⅰ/Ⅳ),LZC值最大;给药时,LZC值急剧下降到最小;恢复时,LZC值逐渐上升。

图 2 在麻醉-觉醒过程中非洲爪蟾不同脑区的脑电Lempel-Ziv复杂度 Fig. 2 Lempel-Ziv complexity for different brain regions during the anesthesia-awakening cycle of Xenopus laevis Ⅰ.麻醉前清醒期,Ⅱ.给药期,Ⅲ.恢复期,Ⅳ.麻醉后清醒期;下同 Ⅰ. Stage Ⅰ (pre-anesthesia stage), Ⅱ. Stage Ⅱ (administration stage), Ⅲ. StageⅢ (recovery stage), Ⅳ. Stage Ⅳ (post-anesthesia stage); the same below
2.1 LZC值的统计结果

ANOVA分析结果显示(表 1),时段[F(2,24)=20.802,partial η2=0.634,P<0.001]和脑区[F(5,60)=21.115,ε=0.547,partial η2=0.638,P<0.001]的主效应极显著,而性别[F(1,12)=4.342,partial η2=0.266,P=0.059]无主效应,且时段和脑区交互效应显著[F(10,120)=3.506,ε=0.394,partial η2=0.226,P=0.014]。

表 1 Lempel-Ziv复杂度的ANOVA统计结果 Table 1 Results of ANOVA for Lempel-Ziv complexity
因素 方差分析ANOVA Greenhouse-Geisser校正的ε P partial η2效应度 最小显著性差异法LSD
时段 F2,24=20.802 NA <0.001 0.634 Ⅰ、Ⅳ>Ⅲ
性别 F1,12=4.342 NA 0.059 0.266 NA
脑区 F5,60=21.115 0.547 <0.001 0.638 LT、RT、LD、RD、RM>LM LT>LD、RD、RM RT>RD
时段*性别 F2,24=2.438 NA 0.109 0.169 NA
脑区*性别 F5,60=0.381 NA 0.860 0.031 NA
时段*脑区 F10,120=3.506 0.394 0.014 0.226 NA
时段*性别*脑区 F10,120=1.135 NA 0.342 0.086 NA
注:>表示其左侧相应条件下的LZC值大于右侧,同侧内无差异;NA.不适用;下同
Notes:> denotes that Lempel-Ziv complexity values for the given conditions on the left side are significantly larger than those on the right side,and no significant difference exists among the corresponding conditions on the same side;NA. not applicable;the same below

简单效应分析显示(表 2),麻醉-觉醒周期中左端脑的LZC值最大,并且清醒阶段(Stages Ⅰ/Ⅳ)端脑的LZC值极显著大于间脑[Stage Ⅰ:F(5,65)=36.252,ε=0.434,partial η2=0.736,P<0.001;Stage Ⅳ:F(5,65)=8.668,partial η2=0.400,P<0.001],但在恢复阶段,它们的差异无统计学意义。对于每个脑区而言,清醒阶段的LZC值均极显著大于恢复阶段[左端脑:F(2,26)=17.695,partial η2=0.576,P<0.001;右端脑:F(2,26)=20.450,partial η2=0.611,P<0.001;左间脑:F(2,26)=13.502,partial η2=0.509,P<0.001;右间脑:F(2,26)=12.980,partial η2=0.500,P<0.001;左中脑:F(2,26)=8.616,partial η2=0.399,P=0.001;右中脑:F(2,26)=16.977,partial η2=0.566,P<0.001]。

表 2 Lempel-Ziv复杂度的简单效应分析 Table 2 Simple effects analysis for Lempel-Ziv complexity
因素 方差分析ANOVA Greenhouse-Geisser校正的ε值 P partial η2效应度 最小显著性差异法LSD
时段 F5,65=36.252 0.434 <0.001 0.736 LT、RT、LD、RD、RM>LM LT>LD、RM RT>LD、RD、RM
F5,65=9.945 0.57 <0.001 0.433 LT、RT、LD、RD、RM>LM
F5,65=8.668 NA <0.001 0.400 LT、RT、LD、RD、RM>LM LT>LD、RD RT>RD
脑区 LT F2,26=17.695 NA <0.001 0.576 Ⅰ、Ⅳ>Ⅲ
RT F2,26=20.450 NA <0.001 0.611 Ⅰ、Ⅳ>Ⅲ
LD F2,26=13.502 NA <0.001 0.509 Ⅰ、Ⅳ>Ⅲ
RD F2,26=12.980 NA <0.001 0.500 Ⅰ、Ⅳ>Ⅲ
LM F2,26=8.616 NA 0.001 0.399 Ⅰ、Ⅳ>Ⅲ
RM F2,26=16.977 NA <0.001 0.566 Ⅰ、Ⅳ>Ⅲ
2.2 LZC相关性分析结果

相关性分析结果显示,在右端脑(r=0.665,P=0.009)和右间脑(r=0.625,P=0.017),Stage Ⅰ的LZC值与给药时长显著正相关;在右间脑(r=-0.542,P=0.045),Stage Ⅳ的LZC值与给药时长显著负相关(表 3)。

表 3 Lempel-Ziv复杂度与给药时长的相关性 Table 3 Correlation analysis between Lempel-Ziv complexity and the duration of administration stage
LT RT LD RD LM RM
r P r P r P r P r P r P
给药时长vs. LZC (Ⅰ) 0.384 0.176 0.665 0.009 0.322 0.261 0.625 0.017 0.273 0.345 0.443 0.113
给药时长vs. LZC (Ⅱ) 0.011 0.970 0.197 0.500 0.102 0.728 0.167 0.567 0.270 0.350 0.065 0.825
给药时长vs. LZC (Ⅲ) 0.076 0.795 -0.079 0.787 -0.053 0.858 -0.189 0.518 0.098 0.738 -0.140 0.634
给药时长vs. LZC (Ⅳ) -0.366 0.198 -0.181 0.535 -0.377 0.184 -0.542 0.045 -0.141 0.630 -0.322 0.261
3 讨论 3.1 LZC随麻醉-觉醒周期动态变化

通过计算非洲爪蟾“麻醉前清醒-给药-恢复-麻醉后清醒”整个周期中EEG信号的LZC值,发现全身麻醉能引起其显著改变:在麻醉前清醒期,LZC值处于较高水平;给药时,LZC值骤降;当动物处于深度麻醉时,LZC值最小;恢复阶段,LZC值逐渐恢复到原始清醒状态时的水平。这种大脑复杂度随着麻醉-觉醒周期动态变化的结果与非洲爪蟾在麻醉-觉醒过程中EEG信号的熵的动态变化相似(Fan et al., 2018),同时与人类病人在全身麻醉时大脑复杂度的动态变化类似(Bruhn et al., 2000),表明利用LZC值可以较好地刻画麻醉-觉醒周期大脑的动态变化和测量麻醉深度(Zhang et al., 2001Fan et al., 2011Schartner et al., 2015Hudetz et al., 2016)。统计结果显示,清醒期(麻醉前和麻醉后)的LZC值显著高于恢复期。LZC值越大,表明大脑系统复杂度越高,EEG信号更难预测;相反,LZC值越小,表明大脑系统复杂度越低,EEG信号变化具有更强的规律性和可预测性。清醒期LZC值的高水平与此时动物需不停采集外界信息并进行分析处理的功能需求一致(Heinke & Koelsch,2005);而在恢复期,大脑意识丧失,对外界刺激无响应,此时LZC值较低。由此可见,LZC值的变化与动物大脑功能状态的改变相对应,说明此方法适用于麻醉深度和大脑活动复杂度的监测。

3.2 右侧丘脑在麻醉-觉醒调控中可能起着关键作用

相关性分析显示,右端脑和右间脑(丘脑)在麻醉前清醒期的LZC值与给药时长正相关,说明右端脑和右侧丘脑在麻醉前清醒期越活跃,进入全身麻醉状态所需的时间就越长,这一结果与用近似熵和排列熵的分析结果类似(Fan et al., 2018)。另外,右侧丘脑在麻醉后清醒期的LZC值与给药时长呈负相关,说明给药时长越短,右侧丘脑在麻醉后清醒期就越活跃;反之,给药时间越长,右侧丘脑就越处于抑制状态。由于LZC值和给药时长的相关性主要出现在右侧丘脑,而且和清醒期相比,恢复期丘脑与端脑之间的LZC值差异无统计学意义,说明右侧丘脑在麻醉-觉醒调控中可能起着重要作用。这一推论与既往的研究结果一致:首先,脊椎动物不同脑区对麻醉剂的敏感程度不同(Heinke & Koelsch,2005);其次,大脑皮层、边缘系统和网状结构及皮层-丘脑环路在意识调控过程中起着关键作用(Heinke & Schwarzbauer,2002Heinke & Koelsch,2005),而丘脑是多种感觉信息投射到端脑的中继站(Sherman & Guillery,2002Béhuret et al., 2013),全身麻醉导致的无意识状态通常伴随着丘脑代谢或血流减少,提示丘脑起着意识开关的作用(Alkire et al., 1997Fiset et al., 1999)。当前结果进一步提示,右侧丘脑在麻醉-觉醒调控中可能起着更为重要的作用,即这种调控具有偏侧性,这一结论与包括人在内的所有脊椎动物的神经系统都具有结构和功能偏侧性这一事实相符(Fang et al., 2014Rogers,2014薛飞等,2016Vallortigara & Versace,2017)。总体上,端脑的LZC值最大,这与蛙类端脑具有高级认知和信息处理的功能相匹配(Fang et al., 2015Xue et al., 2016a, 2016bYue et al., 2017)。

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