See Fujita and Eidelberg (doi:10.1093/brain/awx305) for a scientific commentary on this article. Focal dystonias are the most common type of isolated dystonia. Although their causative pathophysiology remains unclear, it is thought to involve abnormal functioning of the basal ganglia-thalamo-cortical circuitry. We used high-resolution research tomography with the radioligand 11C-NNC-112 to examine striatal dopamine D1 receptor function in two independent groups of patients, writer’s cramp and laryngeal dystonia, compared to healthy controls. We found that availability of dopamine D1 receptors was significantly increased in bilateral putamen by 19.6–22.5% in writer’s cramp and in right putamen and caudate nucleus by 24.6–26.8% in laryngeal dystonia (all P ≤ 0.009). This suggests hyperactivity of the direct basal ganglia pathway in focal dystonia. Our findings paralleled abnormally decreased dopaminergic function via the indirect basal ganglia pathway and decreased symptom-induced phasic striatal dopamine release in writer’s cramp and laryngeal dystonia. When examining topological distribution of dopamine D1 and D2 receptor abnormalities in these forms of dystonia, we found abnormal separation of direct and indirect pathways within the striatum, with negligible, if any, overlap between the two pathways and with the regions of phasic dopamine release. However, despite topological disorganization of dopaminergic function, alterations of dopamine D1 and D2 receptors were somatotopically localized within the striatal hand and larynx representations in writer’s cramp and laryngeal dystonia, respectively. This finding points to their direct relevance to disorder-characteristic clinical features. Increased D1 receptor availability showed significant negative correlations with dystonia duration but not its severity, likely representing a developmental endophenotype of this disorder. In conclusion, a comprehensive pathophysiological mechanism of abnormal basal ganglia function in focal dystonia is built upon upregulated dopamine D1 receptors that abnormally increase excitation of the direct pathway, downregulated dopamine D2 receptors that abnormally decrease inhibition within the indirect pathway, and weakened nigro-striatal phasic dopamine release during symptomatic task performance. Collectively, these aberrations of striatal dopaminergic function underlie imbalance between direct and indirect basal ganglia pathways and lead to abnormal thalamo-motor-cortical hyperexcitability in dystonia.

中文翻译：

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直接基底神经节通路在局灶性肌张力障碍中功能亢进。


有关本文的科学评论，请参阅 Fujita 和 Eidelberg (doi:10.1093/brain/awx305)。局灶性肌张力障碍是最常见的孤立性肌张力障碍类型。尽管其病因病理生理学尚不清楚，但据认为与基底神经节-丘脑-皮质回路的功能异常有关。我们使用放射性配体 11C-NNC-112 进行高分辨率研究性断层扫描，检查两组独立患者（书写痉挛和喉肌张力障碍）的纹状体多巴胺 D1 受体功能，并与健康对照进行比较。我们发现，书写痉挛时双侧壳核中多巴胺 D1 受体的可用性显着增加 19.6-22.5%，喉肌张力障碍时右侧壳核和尾状核中的多巴胺 D1 受体可用性显着增加 24.6-26.8%（所有 P ≤ 0.009）。这表明局灶性肌张力障碍中直接基底神经节通路过度活跃。我们的研究结果与通过间接基底神经节途径异常降低的多巴胺能功能以及作家痉挛和喉肌张力障碍中症状诱导的阶段性纹状体多巴胺释放减少相一致。当检查这些形式的肌张力障碍中多巴胺 D1 和 D2 受体异常的拓扑分布时，我们发现纹状体内直接和间接通路的异常分离，两条通路之间以及与阶段性多巴胺释放区域的重叠（如果有的话）可以忽略不计。然而，尽管多巴胺能功能存在拓扑紊乱，但在书写痉挛和喉肌张力障碍中，多巴胺 D1 和 D2 受体的改变分别位于手纹状体和喉部表征内。这一发现表明它们与疾病特征的临床特征直接相关。 D1 受体可用性的增加与肌张力障碍持续时间呈显着负相关，但与其严重程度无关，可能代表了这种疾病的发育内表型。总之，局灶性肌张力障碍中基底神经节功能异常的综合病理生理学机制是建立在上调的多巴胺 D1 受体（异常增加直接通路的兴奋）、下调的多巴胺 D2 受体（异常减少间接通路内的抑制）和减弱的黑质纹状体相性基础上的。症状性任务执行过程中多巴胺的释放。总的来说，纹状体多巴胺能功能的这些异常是直接和间接基底神经节通路之间失衡的基础，并导致肌张力障碍中丘脑运动皮质异常兴奋。