疼痛感受变异性的神经基础：电生理研究

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	疼痛感受变异性的神经基础：电生理研究
其他题名	Neural correlates of pain variability: electrophysiological studies
	郭一飞
	2016-05
摘要	疼痛是一种具有高度变异性的感知觉，这可以体现在不同的层面上。首先，同一个体对完全相同的伤害性刺激可以随时间的变化而产生非常不同的体验，即表现出个体内的变异性。其次，相同的伤害性刺激在不同的个体中引起的知觉与行为反应可以非常不同，即表现出个体间的变异性。第三，当疼痛从急性状态转变为慢性状态，即发生了疼痛的慢性化时，疼痛本身的意义及它对个体身心状态的影响可能发生巨大改变。对疼痛变异性相关脑机制的理解将可极大地促进人们对痛知觉的产生与调节机制的认识，并有可能帮助人们实现对疼痛感受的客观预测。本论文运用大鼠行为学与神经电生理学研究手段，围绕疼痛变异性与自发及诱发脑活动的关系这一核心问题，在个体内、个体间、以及急性痛与慢性痛之间这三种不同的层面上探索疼痛变异性相关的神经机制。在第一项研究中，我们首先利用时频分析方法第一次完整地刻画了伤害性刺激在大鼠皮层引发的脑电响应。其中既包括锁相响应 (LEP-1 和LEP-2，与事件相关电位对应)，也包括非锁相响应 (事件相关去同步化反应 -ERD-1 和-ERD-2，以及事件相关同步化反应 -ERS-1、-ERS-2 和-ERS-3)。结果显示，被先前研究忽视的伤害性刺激引发的大鼠皮层非锁相响应在大鼠的疼痛加工活动中占有相当的比例。更重要的是，我们首次采用多维度的视角分别揭示了对疼痛的感觉运动反应以及情绪反应的动态变化与上述皮层响应的关系。在刺激客观强度一致的情况下，对疼痛的感觉运动反应涌现与否与锁相反应LEP-2 (发生于刺激后250-350 ms，3-11 Hz) 以及非锁相反应-ERS-2 (发生于刺激后250-450 ms，53-95 Hz) 和-ERS-3 (发生于刺激后500-1400 ms，53-75 Hz) 的幅度相关。在感觉运动反应稳定发生的前提下，疼痛情绪反应涌现与否与非锁相反应-ERS-2 和-ERS-3 的幅度进一步相关。结果显示，大鼠疼痛反应的动态变化不仅像前人研究中所报告的那样与皮层的锁相响应相关，同时也与皮层的非锁相响应具有极大的关联。我们推测LEP-2 可能直接与意识知觉的产生相关联；-ERS-2 不仅与意识知觉相关，且可能进一步体现刺激后个体的觉知程度和脑对伤害性刺激的加工程度，进而对应着个体的主观疼痛强度和行为反应；-ERS-3 则可能反映了与注意相关的知觉后加工过程。在第二项研究中，我们首次揭示了静息态大鼠皮层自发振荡活动对疼痛行为反应个体差异的预测价值，并首次将静息态脑功能与个体的痛感觉和痛情绪特质分别建立联系。我们发现对疼痛的感觉运动反应和情绪反应特质分别与皮层自发振荡活动的不同空间-频率特征相关联。个体对疼痛的感觉运动反应与静息态下后部皮层自发的beta 与mid-gamma 振荡的强度呈正相关关系，与额部自发的high-gamma 振荡的强度呈负相关关系。回归模型显示两个位置的振荡成分为预测提供了独立而互补的信息，二者联合预测的效果优于单独预测。个体的情绪反应则可由静息态下额中区位置自发的mid-gamma 以及high-gamma 振荡在左右皮层的不对称分布情况所预测。在观察的基础上，我们提出一种决定个体对伤害性刺激的感觉反应性的脑自发活动功能组织模型，其中沿脑前后轴分布的两个组分发挥相互拮抗的作用。后部组分介导对环境变化 (特别是威胁性信息) 的持续监测，促进感觉觉知并驱动适应性行为反应；前部组分表征在无特定任务状态下占用一定认知资源的自发心理过程并可能干扰外部感觉刺激诱发的反应。在第三项研究中，为辨别疼痛的急性状态和慢性状态，我们提出一种全新的策略，即以疼痛对非伤害性感觉加工的跨模态调节作用的变化来指示疼痛本身的状态变化。利用大鼠疼痛模型，我们考察了在急性痛和慢性痛背景下以听觉诱发电位为代表的大鼠皮层听觉加工活动。研究发现急性痛和慢性痛对皮层听觉加工活动具有相反的调节作用。与无痛对照组相比，急性痛大鼠的听觉诱发电位中的N100 成分显著增强，慢性痛大鼠的N100 则显著减弱，表明急性痛对皮层听觉加工的促进作用以及慢性痛的抑制作用。这种相反的调节作用与急性痛和慢性痛个体对外部环境信息所具有的不同警觉状态相吻合，并具有其各自的适应性意义——急性痛作为外界威胁的警示信号促进个体对环境信息的警觉与加工，而慢性痛使个体更多关注自身内部的变化并因此削弱个体对外部环境中与疼痛无关的刺激的警觉与加工。这种相反的调节作用的存在，提示疼痛对听觉加工的跨模态调节的脑表征 (即疼痛背景下听觉诱发电位的改变) 有可能成为一种有助于区分急性和慢性疼痛相关脑状态的指标。综上，本论文在个体内动态变化、个体间差异、以及急性痛与慢性痛之间的转变这三个方面揭示了与疼痛变异性相关的脑活动。我们希望这些结果能够促进人们对复杂多变的痛感受及痛行为的神经机制的理解。
其他摘要	Pain is a highly variable perception. The variations in pain experience may exist (1) at the intra-individual level where the perception of identical nociceptive stimuli varies from time to time even in the same individual, (2) at the inter-individual level where the same nociceptive input can elicit different responses in different individuals, and (3) during the transition from acute pain to chronic pain, which is accompanied by considerable changes in the individual’s physiological and psychological state. Investigations on the neural correlates of pain variations may facilitate the understanding of the mechanisms generating and modulating pain perception and may help achieve a reliable pain prediction from brain signatures. Focusing on the relationships between variations in pain responses and stimulus-elicited/spontaneous brain activities, the present thesis utilized behavioral and neuroelectrophysiological methods in rat models to explore the brain mechanisms underlying pain variability at the above three levels. In the first study, by using time-frequency analysis, we provided the first comprehensive description of nociceptive laser-elicited EEG responses in rats, which comprised both phase-locked responses (LEP-1 and LEP-2) corresponding to laser-evoked potentials and non-phase-locked responses including event-related desynchronization of beta activities (-ERD-1 and -ERD-2) and event-related synchronization of gamma activities (-ERS-1, -ERS-2, and -ERS-3). This result indicates that the laser-induced non-phased-locked responses in rats, which were largely ignored in the previous literature, actually represent a significant fraction of cortical pain processing in rats. More importantly, we showed that the laser-elicited cortical responses were associated with intra-individual variations in the sensorimotor and affective aspects of pain behaviors. In particular, when the objective stimulus intensity was maintained at a constant level, the emergence of sensorimotor response (as indicated by pain-elicited withdrawal behavior) was associated with the enhancement of LEP-2 (occurred at latencies of 250-350 ms and in a frequency range of 3-11 Hz), -ERS-2 (250-450 ms, 53-95 Hz), and -ERS-3 (500-1400 ms, 53-75 Hz), while when the sensorimotor response could be reliably observed, the further emergence of emotional response (as indicated by pain-induced vocalization) was associated with the further enhancement of -ERS-2 and -ERS-3. These findings indicate that the intra-individual variations in rats’ pain behaviors were not only related to the phaselocked cortical responses as previously reported, but also closely related to the non-phaselocked cortical responses. We speculate that LEP-2 might be particularly related to conscious perception, -ERS-2 might be related to both conscious perception and degree to which the stimulus is further processed, while -ERS-3 might reflect attention-related post-perceptual processes. In the second study, by directly linking individual resting-state cortical oscillations recorded before any nociceptive stimuli to individual sensorimotor and affective responses to pain in rats, we demonstrated the predictive value of resting-state cortical oscillations for pain traits. We found that individual differences in the sensorimotor and affective dimensions of pain were associated with distinct spatial-spectral patterns of spontaneous cortical oscillations. In particular, individual sensorimotor response was positively correlated with the power of resting-state posterior beta to mid-gamma oscillations and negatively correlated with the power of resting-state frontal high-gamma oscillations. Regression analyses revealed that the above two predictors together performed significantly better than either single predictor and may provide independent and complementary information for predicting individual differences in the behavioral responses prompted by the sensory aspect of pain. In contrast, individual differences in the affective aspect could be predicted from asymmetrical distributions of resting-state midand high-gamma oscillations at fronto-central regions. Based on our findings, we proposed a theoretical functional framework of intrinsic brain activities within which two components organized along the anterior-posterior axis of the brain making antagonistic contributions in determining individual sensory responsiveness to nociceptive information: an anterior component supports internally-oriented processes that possibly interfere with sensory-evoked responses, while a posterior component supports monitoring of environmental changes and facilitates sensory awareness. In the third study, we proposed a new strategy to differentiate acute and chronic pain states, that is, monitoring the crossmodal modulatory effect of pain on non-nociceptive sensory processing instead of investigating the pain system per se. Using rat pain models, we found opposite influences of acute and chronic pain on cortical responses to auditory inputs. In particular, compared to no-pain controls, the N100 wave of the rat auditoryevoked potentials was significantly enhanced in rats with acute pain but significantly reduced in rats with chronic pain, indicating that acute pain facilitated cortical processing of auditory information while chronic pain exerted an inhibitory effect. These findings could be justified by the fact that individuals suffering from acute or chronic pain would have different vigilance states: acute pain signals actual or potential threats in the environment and may increase an individual’s vigilance to external changes, whereas chronic pain may lead to excessive attention to an individual’s internal state and a decreased level of vigilance to pain-irrelevant, external signals. Since the cortical processing of auditory information could be modulated by acute and chronic pain in opposite directions, brain representation for the crossmodal modulation of auditory processing by pain (i.e., altered auditory-evoked potential) might be used as a signature to differentiate the brain states related to acute and chronic pain. To sum up, in the present thesis we identified neural correlates of pain variability within individuals, between individuals, and between acute and chronic pain. We hope that our findings could potentially lead to a better understanding of the brain mechanisms underlying the complex and dynamic pain experience and related behaviors.
学科领域	认知神经科学
关键词	个体内变异性个体间变异性急性痛慢性痛动物模型
学位类型	博士
语种	中文
学位专业	心理学
学位授予单位	中国科学院研究生院
学位授予地点	北京
文献类型	学位论文
条目标识符	http://ir.psych.ac.cn/handle/311026/19818
专题	认知与发展心理学研究室
作者单位	中国科学院心理研究所
推荐引用方式 GB/T 7714	郭一飞. 疼痛感受变异性的神经基础：电生理研究[D]. 北京. 中国科学院研究生院,2016.

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