Abstract:
The association between idiopathic Parkinson\'s disease, a paradigmatic dopamine-deficiency syndrome, and problems in the estimation of time has been studied experimentally for decades. I review that literature, which raises a question about whether and if dopamine deficiency relates not only to the motor slowness that is an objective and cardinal parkinsonian sign, but also to a compromised neural substrate for time perception. Why does a clinically (motorically) significant deficiency in dopamine play a role in the subjective perception of time\'s passage? After a discussion of a classical conception of basal ganglionic control of movement under the influence of dopamine, I describe recent work in healthy mice using optogenetics; the methodology visualizes dopaminergic neuronal firing in very short time intervals, then allows for correlation with motor behaviors in trained tasks. Moment-to-moment neuronal activity is both highly dynamic and variable, as assessed by photometry of genetically defined dopaminergic neurons. I use those animal data as context to review a large experimental experience in humans, spanning decades, that has examined subjective time perception mainly in Parkinson\'s disease, but also in other movement disorders. Although the human data are mixed in their findings, I argue that loss of dynamic variability in dopaminergic neuronal activity over very short intervals may be a fundamental sensory aspect in the pathophysiology of parkinsonism. An important implication is that therapeutic response in Parkinson\'s disease needs to be understood in terms of short-term alterations in dynamic neuronal firing, as has already been examined in novel ways-for example, in the study of real-time changes in neuronal network oscillations across very short time intervals. A finer analysis of a treatment\'s network effects might aid in any effort to augment clinical response to either medications or functional neurosurgical interventions in Parkinson\'s disease.
摘要:
特发性帕金森病,典型的多巴胺缺乏综合征,时间估计问题已经在实验上研究了几十年。我回顾了那些文献,这引发了一个问题,即多巴胺缺乏是否以及是否不仅与运动缓慢有关,这是一个客观和基本的帕金森标志,而且还有时间感知的受损神经基质。为什么临床上(运动性)多巴胺的显着缺乏在时间流逝的主观感知中起作用?在讨论了多巴胺影响下的基底神经节运动控制的经典概念之后,我描述了使用光遗传学在健康小鼠中的最新工作;该方法在非常短的时间间隔内可视化多巴胺能神经元放电,然后允许与训练任务中的运动行为相关。时刻到时刻的神经元活动是高度动态和可变的,通过基因定义的多巴胺能神经元的光度测定进行评估。我用这些动物数据作为背景来回顾人类的大量实验经验,跨越几十年,主要研究帕金森病的主观时间知觉,还有其他运动障碍。尽管人类数据在他们的发现中混杂,我认为,在很短的时间间隔内,多巴胺能神经元活动的动态变化的丧失可能是帕金森病病理生理学的基本感觉方面。一个重要的意义是,帕金森病的治疗反应需要从动态神经元放电的短期变化的角度来理解,正如已经以新颖的方式研究过的那样——例如,在非常短的时间间隔内研究神经元网络振荡的实时变化。对治疗的网络效应进行更精细的分析可能有助于增强帕金森病患者对药物治疗或功能性神经外科干预的临床反应。