Dopaminergic activity and release during DBS implantation in humans

描述（由申请人提供）：4项独立创新的融合揭示了对人类多巴胺系统功能获得前所未有的见解的可能性。认知、学习、决策和行动选择的许多方面都依赖于完整的多巴胺能功能，这使得这个机会变得重要、及时和令人兴奋。这四项创新是：(1)在晚期帕金森患者中发明、植入并成功地长期使用深部脑刺激电极（DBS），(2)多巴胺能功能计算模型的发展，目前已在多巴胺神经元的单个单位活动水平上得到验证，多巴胺在目标结构上的释放，以及人类受试者的功能成像实验（fMRI）。(3)利用功能磁共振成像（fMRI）和简单的条件反射和决策任务，可以跟踪帕金森患者被认为由多巴胺传递编码的学习信号；(4)开发出能够在学习和决策任务中进行亚秒级细胞外多巴胺测量的生物相容性电极。这个项目将对人类大脑中多巴胺系统的功能产生前所未有的深入了解，并对包括成瘾和各种形式的精神疾病在内的一系列涉及多巴胺能功能的问题证明是无价的。帕金森病（PD）的主要生理缺陷是80-90%多巴胺神经元的损失，因此本研究旨在利用DBS电极植入的急性期来获得新的见解，以确切了解这种疾病患者的悲惨病理。

DESCRIPTION (provided by applicant): The convergence of 4 separate innovations has exposed the possibility of gaining unprecedented insights into the function of dopamine systems in humans. The many aspects of cognition, learning, decision-making, and action selection that depend on intact dopaminergic function make this opportunity important, timely, and exciting. The four innovations are (1) the invention, implantation, and successful chronic use of deep brain stimulation electrodes (DBS) in late stage Parkinson's patients, (2) the development of computational models of dopaminergic function that have now been validated at the level of single unit activity in dopamine neurons, dopamine release at target structures, and functional imaging experiments (fMRI) in human subjects, (3) the demonstration that learning signals thought to be encoded by dopamine delivery can be tracked in Parkinson's patients using fMRI and simple conditioning and decision-making tasks, and (4) the development of biocompatible electrodes capable of making sub-second measurements of extracellular dopamine during learning and decision-making tasks. This project will yield unprecedented insight into the function of dopamine systems in the human brain and should prove invaluable to a range of problems involving dopaminergic function including addiction and various forms of mental illness. The primary physical deficit in Parkinson's disease (PD) is the loss of 80-90% of dopamine neurons and so this proposal seeks to use the acute phase of DBS electrode implantation to gain new insights into exactly the pathology that tragically afflicts sufferers of the disease.