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获得对人类多巴胺系统功能的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）发明、植入和成功长期使用深部脑刺激电极（DBS）治疗晚期帕金森病患者，（2）开发多巴胺能功能的计算模型，该模型现已在多巴胺神经元的单个单位活动水平、靶结构处的多巴胺释放水平和人类受试者的功能成像实验（fMRI）水平上得到验证，（3）证明可以使用功能磁共振成像和简单的条件反射和决策任务跟踪帕金森病患者中被认为是由多巴胺传递编码的学习信号，以及（4）开发生物相容性电极，能够在学习和决策任务期间对细胞外多巴胺进行亚秒级测量。该项目将对人类大脑中多巴胺系统的功能产生前所未有的洞察力，并应证明对涉及多巴胺能功能的一系列问题（包括成瘾和各种形式的精神疾病）是非常宝贵的。帕金森氏病（PD）的主要身体缺陷是80-90%的多巴胺神经元的损失，因此该提议寻求使用DBS电极植入的急性期来获得对悲惨地折磨疾病患者的病理学的新见解。

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.