Local field potentials reveal reward processing and impulse control disorders in Parkinson’s disease

项目摘要/摘要 这项应用试图描述奖赏过程中基底节的电生理活动。 帕金森氏病(PD)合并和不合并冲动控制障碍(ICD)患者的处理。 ICD包括过度和不可控制的行为，包括性欲亢奋、病态赌博、酗酒 进食、强迫性购买、打赌(重复简单的活动)和多巴胺调节失调综合症。他们 影响多达三分之一的帕金森病患者，并显著影响生活质量。尽管ICD以前是 帕金森病的另一个医源性病因是脑深部刺激，归因于多巴胺替代疗法。 丘脑底核(STN)或苍白球内核(GPI)-两个FDA批准的常规- 使用DBS靶点治疗严重或药物不耐受的帕金森病。源于缺乏 从病理生理学的角度来看，目前还没有可靠的策略来抑制帕金森病患者的这些行为。因此， 如今，帕金森病患者的ICDS治疗仍然是一个未得到满足的医疗需求。尽管ICD的机械基础 在帕金森病中并不完全清楚，有大量证据表明奖赏加工功能障碍与这两种情况有关 帕金森病的亚临床和临床诊断的冲动性。也就是说，患有ICD的人表现出 对奖励敏感，对损失不敏感。我们的目标是识别电生理标记物 在STN和GPI中的奖赏处理，以表征这些皮质下核团在贡献时所起的作用 致ICDS。为此，我们在PD DBS期间成功管理了一个奖励处理游戏，同时 同时使用植入的STN或GPI DBS电极作为记录装置；我们发现了事件- 特异性局部场电位(LFP)(神经元群体水平活动)的相关和振荡变化 在STN和GPI中奖励。这一提议的中心假设是STN和GPI参与 奖励处理--可通过LFP测量--可用于区分有无的个体 ICDS。在目标1中，我们将检查STN和GPI中的LFP在觉醒，行为中的奖励处理游戏中 接受星展神经外科手术的帕金森病患者。在目标2中，我们将确定是否存在临床诊断的 ICD在奖励处理过程中会影响STN和GPI中测量的LFP。这项工作意义重大，因为它 将通过特定的LFP变化牵涉到临床上显著的奖赏加工中的基底节。这 这项工作的创新之处在于它将同时揭示帕金森病的ICD机制并激发新的 这些疾病的治疗策略，特别是接受DBS植入物的患者。

Project Summary/Abstract This application seeks to characterize the electrophysiological activity of the basal ganglia during reward processing in people with Parkinson’s disease (PD) with and without comorbid impulse control disorders (ICDs). ICDs encompass excessive and uncontrollable behaviors including hypersexuality, pathological gambling, binge eating, compulsive buying, punding (repeating simple activities), and dopamine dysregulation syndrome. They affect up to one-third of PD patients and significantly impact quality of life. Although ICDs were previously attributed to dopamine replacement therapies in PD, an additional iatrogenic etiology is deep brain stimulation (DBS) of the subthalamic nucleus (STN) or globus pallidus internus (GPi) – two FDA-approved and routinely- used DBS targets for the treatment of severe or medication-intolerant PD. Stemming from a lack of pathophysiological insight, there are no reliable strategies to curb these behaviors in PD. Therefore, the treatment of ICDs in PD today remains an unmet medical need. Although the mechanistic underpinnings of ICDs in PD are not fully known, there is a large body of evidence linking dysfunction in reward processing to both subclinical and clinically diagnosed impulsivity in PD. Namely, individuals with ICDs demonstrate a hypersensitivity to reward and a hyposensitivity to loss. Our objective is to identify electrophysiological markers of reward processing in the STN and GPi to characterize the role of these subcortical nuclei as they contribute to ICDs. To that end, we have successfully administered a reward processing game during PD DBS while simultaneously using the implanted STN or GPi DBS electrode as a recording device; we have discovered event- related and oscillatory changes in local field potentials (LFPs) (neuronal population-level activity) specific to reward in the STN and GPi. The central hypothesis of this proposal is that the STN and GPi participate in reward processing – measurable through LFPs – which can be used to differentiate individuals with and without ICDs. In Aim 1, we will examine LFPs in the STN and GPi during a reward processing game in awake, behaving PD patients undergoing DBS neurosurgery. In Aim 2, we will determine if the presence of clinically diagnosed ICDs affects LFPs measured in the STN and GPi during reward processing. This work is significant because it will implicate the basal ganglia in clinically significant reward processing through specific LFP changes. This work is innovative in that it will simultaneously uncover mechanisms of ICDs in PD and motivate novel therapeutic strategies for these disorders, particularly for patients receiving DBS implants.