Studies in non-human primates (NHPs) have led to major advances in our understanding of the function of the basal ganglia and of the pathophysiologic mechanisms of hypokinetic movement disorders such as Parkinson's disease and hyperkinetic disorders such as chorea and dystonia. Since the brains of NHPs are anatomically very close to those of humans, disease states and the effects of medical and surgical approaches, such as deep brain stimulation (DBS), can be more faithfully modeled in NHPs than in other species. According to the current model of the basal ganglia circuitry, which was strongly influenced by studies in NHPs, the basal ganglia are viewed as components of segregated networks that emanate from specific cortical areas, traverse the basal ganglia, and ventral thalamus, and return to the frontal cortex. Based on the presumed functional domains of the different cortical areas involved, these networks are designated as 'motor', 'oculomotor', 'associative' and 'limbic' circuits. The functions of these networks are strongly modulated by the release of dopamine in the striatum. Striatal dopamine release alters the activity of striatal projection neurons which, in turn, influences the (inhibitory) basal ganglia output. In parkinsonism, the loss of striatal dopamine results in the emergence of oscillatory burst patterns of firing of basal ganglia output neurons, increased synchrony of the discharge of neighboring basal ganglia neurons, and an overall increase in basal ganglia output. The relevance of these findings is supported by the demonstration, in NHP models of parkinsonism, of the antiparkinsonian effects of inactivation of the motor circuit at the level of the subthalamic nucleus, one of the major components of the basal ganglia. This finding also contributed strongly to the revival of the use of surgical interventions to treat patients with Parkinson's disease. While ablative procedures were first used for this purpose, they have now been largely replaced by DBS of the subthalamic nucleus or internal pallidal segment. These procedures are not only effective in the treatment of parkinsonism, but also in the treatment of hyperkinetic conditions (such as chorea or dystonia) which result from pathophysiologic changes different from those underlying Parkinson's disease. Thus, these interventions probably do not counteract specific aspects of the pathophysiology of movement disorders, but non-specifically remove the influence of the different types of disruptive basal ganglia output from the relatively intact portions of the motor circuitry downstream from the basal ganglia. Knowledge gained from studies in NHPs remains critical for our understanding of the pathophysiology of movement disorders, of the effects of DBS on brain network activity, and the development of better treatments for patients with movement disorders and other neurologic or psychiatric conditions.

译文

对非人类灵长类动物 (NHPs) 的研究在我们对基底节的功能以及运动不足性疾病 (如帕金森氏病) 和运动亢进性疾病 (如舞蹈病和肌张力障碍) 的病理生理机制的理解方面取得了重大进展。由于NHPs的大脑在解剖学上与人类的大脑非常接近,因此与其他物种相比,疾病状态以及医学和外科手术方法 (例如深部脑刺激 (DBS)) 的影响可以在NHPs中更忠实地建模。根据受NHPs研究强烈影响的当前基底神经节回路模型,基底神经节被视为分离网络的组成部分,这些网络来自特定的皮质区域,穿过基底神经节和腹侧丘脑,然后返回额叶皮层。根据所涉及的不同皮质区域的假定功能域,这些网络被指定为 “运动”,“眼动”,“关联” 和 “边缘” 电路。这些网络的功能受到纹状体中多巴胺释放的强烈调节。纹状体多巴胺的释放会改变纹状体投射神经元的活性,进而影响 (抑制性) 基底神经节的输出。在帕金森氏病中,纹状体多巴胺的丧失导致基底神经节输出神经元放电的振荡爆发模式的出现,相邻基底神经节神经元放电的同步性增加以及基底神经节输出的总体增加。在帕金森氏症的NHP模型中,在丘脑底核 (基底神经节的主要组成部分之一) 水平上的运动回路失活的抗帕金森氏效应的证明了这些发现的相关性。这一发现也有力地促进了手术干预治疗帕金森氏病患者的复兴。虽然消融程序最初是为此目的使用的,但现在已被丘脑下核或苍白球内部节段的DBS所取代。这些程序不仅可有效治疗帕金森氏症,而且可有效治疗多动性疾病 (例如舞蹈病或肌张力障碍),这些疾病是由与帕金森氏病不同的病理生理变化引起的。因此,这些干预措施可能不会抵消运动障碍的病理生理学的特定方面,而是非特异性地消除了基底神经节下游运动电路相对完整部分中不同类型的破坏性基底神经节输出的影响。从NHPs研究中获得的知识对于我们了解运动障碍的病理生理学,DBS对脑网络活动的影响以及为运动障碍和其他神经或精神疾病患者开发更好的治疗方法仍然至关重要。

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