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Alternative TitleThe Supraspinal Mechanisms of Deep Brain Stimulation Produced Analgesia
Thesis Advisor罗非
Degree Grantor中国科学院研究生院
Place of Conferral北京
Degree Discipline心理学
Keyword深部脑刺激 急性痛 [慢性炎症痛 持续性疼痛 镇痛
Abstract实验室研究和临床试验发现深部脑刺激能够有效的缓解疼痛, 中脑导水管周围灰质(periaqueductal grey matter,  PAG)是深部脑刺激最常用的核团。但是目前PAG 刺激镇痛的机制还不是很清楚。以往的研究主要在脊髓水平探索 PAG 的镇痛机制,缺乏对脊髓上高级中枢的认识。本研究运用在体多通道同步记录技术记录内外侧疼痛通路的活动,探索腹外侧中脑导水管周围灰质(ventrolateral periaqueductal grey, vlPAG)刺激对急性痛、慢性炎症痛痛敏以及持续性疼痛调节的机制。在大鼠 vlPAG 埋置刺激电极,在内侧通路(前扣带回(anterior cingulate cortex, ACC)和背内侧丘脑(medial dorsal thalamus, MD)),外侧通路(初级躯体感觉皮层(primary  somatosensory cortex, SI)和腹后外侧丘脑(ventral posterior lateral nucleus of thalamus,VPL))埋置记录电极。运用辐射热刺激诱导急性痛,完全弗式佐剂(complete Freund's adjuvant, CFA)建立慢性炎症痛模型,福尔马林足底注射建立持续性疼痛模型。
(1)  vlPAG 刺激抑制辐射热刺激诱导的急性痛反应,电生理结果发现 vlPAG刺激全面降低疼痛内外侧通路对急性痛的兴奋性反应,包括 a) 在单个神经元水平,vlPAG 刺激降低 ACC、SI、MD 以及 VPL 对急性痛的加工,体现在抑制有反应神经元比例和反应强度;  b) vlPAG刺激抑制ACC、SI、MD 以及VPL神经元反应强度与抬脚潜伏期的相关。c) 在神经元群水平,vlPAG刺激降低ACC 到MD,SI到VPL,皮层到丘脑,丘脑到皮层,外侧通路到内侧通路以及内侧通路到外侧通路之间的功能连接。
(2) vlPAG刺激抑制CFA产生的炎症痛痛敏,镇痛强度超过 vlPAG刺激对健侧肢体的镇痛强度。vlPAG 刺激降低 ACC、SI、MD 以及 VPL 对炎症痛痛敏有反应神经元的比例,并降低这四个脑区神经元反应的强度。vlPAG刺激降低皮层到丘脑,内侧通路到外侧通路的信息流动,而不影响丘脑到皮层,外侧通路到内侧通路的信息流动量。
(3) 在福尔马林模型中,vlPAG刺激对 MD表现双重作用,即增加兴奋反应神经元数量,降低抑制反应神经元数量。对于 VPL,vlPAG刺激主要表现兴奋作用。在第一相,vlPAG刺激降低外侧通路到内侧通路的信息流动;在中间相和第二相,vlPAG刺激降低丘脑到皮层的信息流动;在第三相,vlPAG刺激增加皮层到丘脑的信息流动。
(4) vlPAG刺激增强四个脑区的神经元自发活动。
对于持续性疼痛,vlPAG刺激的机制更复杂。在神经元层面,对内侧通路发挥兴奋和抑制双重作用,对外侧通路发挥兴奋作用。在脑区功能连接层面, vlPAG刺激抑制外侧到内侧通路、丘脑到皮层的信息流动。
Other AbstractIt is well accepted that deep brain stimulation can produce an analgesic effect in animals with  experimental pain and patients with chronic pain. Periaqueductal gray matter (PAG) is the most common used brain area in deep brain stimulation. However, the neural basis underlying  PAG  stimulation  produced analgesia remains unclear. Although a number of studies have investigated morphine analgesia in spinal nervous tissue, less has been studied at the supraspinal level. In the present study, we recorded the neuronal activity within thalamocortical circuits in rats using a multichannel single unit recording technique. We specifically focused on four brain regions in the lateral and the medial pain systems, including the primary somatosensory cortex (SI), anterior cingulate cortex (ACC), medial dorsal thalamus (MD),  and ventral posterolateral thalamus (VPL),  to assess the effects of ventrolateral  PAG  (vlPAG) stimulation on the discharge of  single units as well as the functional connections between these regions. Some important findings emerged from this study:
(1) We found that vlPAG stimulation  inhibited the nociceptive responses  in the condition of noxious thermal-induced acute pain.  In the four recorded areas, vlPAG stimulation  inhibited  the nociceptive responses of single neurons by decreasing the neuronal response magnitude and reducing the fraction of responding neurons. vlPAG stimulation inhibited the correlation between response magnitude and paw withdrawal latency. Meanwhile,  vlPAG stimulation suppressed the pain-evoked changes in the information flow  from ACC to MD, from SI to VPL, between cortex and  thalamus, between lateral and medial pathways.
  (2)  Following inflammation,  vlPAG  stimulation significantly inhibited nociception in the inflamed paw, while had a weak inhibitory effect on the non-inflammed paw.  Following inflammation,  vlPAG stimulation had primary inhibitory effect on the the fraction of responding neurons and response magnitude. vlPAG stimulation significantly reduced the amount of information flow from cortex to thalamus, and  from medial to lateral pathway, while had no effect on the information flow from thalamus to cortex, and from lateral to medial pathway.
(3) After formalin injection, vlPAG stimulation produced significant changes in the neuronal activity, with primary activation in VPL while both inhibition and activation in MD. In phase 1, vlPAG stimulation decreased the amount of information flow from the lateral to medial pathway. vlPAG stimulation also decreased the amount of information flow from thalamus to cortex in the first hour after formalin injection, while increased the amount of information flow from cortex to thalamus in phase 3.
(4)  vlPAG stimulation significantly increased the spontaneous firing rates of neurons in both pain pathways.
In conclusion, vlPAG stimulation exerts analgesic effects on acute  and  chronic pain through suppressing both sensory and affective dimensions of pain. vlPAG had an excitatory and inhibitory effect on the neuronal activities while inhibitory effect on the  functiona
Subject Area认知神经科学
Document Type学位论文
Recommended Citation
GB/T 7714
苏园林. 深部脑刺激镇痛脊髓上电生理机制研究[D]. 北京. 中国科学院研究生院,2013.
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