Biological Determinants of Impulsivity in Parkinson's Disease

项目总结 帕金森氏病(PD)的运动症状可以通过基于多巴胺的疗法有效地控制，但 患者的行为变化可能是意想不到的后果。症状的特点是 持续参与奖励驱动的活动会对患者和照顾者造成严重的发病率。这个 这些症状的描述性术语，冲动和强迫行为，捕捉到了异常的目标- 定向的决策现象学在这种临床条件下是典型的。症状范围从 性欲亢进到强迫性进食、赌博、购物和过度参与某些爱好。 冲动和强迫行为在接受多巴胺激动剂治疗的患者中更常见， 而行为可以通过减少或停止使用它们来减少。事实上，其他治疗干预措施， 包括脑深部刺激和左旋多巴，与不良适应行为的发生有关，以及 总体而言，这些症状似乎定位于中脑皮质边缘多巴胺功能失调或过量。 系统。这项建议将表征冲动和强迫行为的生物学决定因素 帕金森病，特别关注多巴胺激动剂治疗和中脑边缘多巴胺网络的作用。我们 提出一系列实验，以确定多巴胺对大脑功能的不同变化 有和没有冲动和强迫行为的患者使用激动剂。我们的首要目标是找出 多巴胺激动剂的脑血流动力学反应区分冲动和强迫症 行为。我们假设这些患者有夸大或增强的中脑边缘血流动力学。 对多巴胺激动剂治疗的反应。血流动力学变化将与神经认知评估联系起来 基于报酬的决策和风险偏好，强调生理大脑之间的一致性 药物的变化和行为反应。接下来，我们的目标是确定多巴胺疗法如何 不同程度改变易感患者的抑制性γ-氨基丁酸(GABA)神经传递 冲动和强迫行为。最后，我们将检验可释放的多巴胺储存在 中脑边缘多巴胺系统对这些行为易感的患者更大，从而将生物学联系起来 这些不良适应行为的发病机制。这项研究的完成将为该系统的使用铺平道路 未来目标验证研究和早期阶段所需的非侵入性、定量的PD结果 药物发现。此外，我们还将提供多巴胺治疗作用于纹状体外神经的直接证据。 网络，将神经活动的区域性变化与多巴胺诱导的GABA水平变化联系起来。这部作品 将推动该领域采用新的治疗靶点，这对有效治疗脉冲和 强迫行为。最终，这项工作将指导改进的、个性化的治疗方法的发展， 推进个体化用药的治疗目标，这对帕金森病患者至关重要。

PROJECT SUMMARY Motor symptoms in Parkinson's disease (PD) are effectively managed by dopamine-based therapies, yet behavioral changes in patients can arise as an unintended consequence. Symptoms characterized by persistent participation in reward-driven activities result in significant morbidity to patients and caregivers. The descriptive term for these symptoms, impulsive and compulsive behaviors, captures the aberrant, goal- directed, decision-making phenomenology typified in this clinical condition. Symptoms range from hypersexuality to compulsive eating, gambling, shopping, and excessive participation in certain hobbies. Impulsive and compulsive behaviors are more commonly manifest in patients taking dopamine agonist therapy, and behaviors can abate with reduction or discontinuation of their use. Indeed, other therapeutic interventions, including deep brain stimulation and levodopa, are associated with the genesis of maladaptive behaviors, and overall, these symptoms appear to localize to a dysfunctional, or `overdosed', mesocorticolimbic dopamine system. This proposal will characterize the biological determinants of impulsive and compulsive behaviors in PD, with specific focus on the role of dopamine agonist therapy and the mesolimbic dopamine network. We propose a series of experiments that will determine distinct functional brain changes in response to dopamine agonist use in patients with and without impulsive and compulsive behaviors. Our first aim is to identify how the cerebral hemodynamic response to dopamine agonists distinguishes patients with impulsive and compulsive behaviors. We hypothesize that these patients have an exaggerated, or increased, mesolimbic hemodynamic response to dopamine agonist therapy. Hemodynamic changes will be linked to neurocognitive assessments of reward-based decision making and risk preference, emphasizing the coherence between physiologic brain changes and the behavioral response to medication. Next, we aim to determine how dopamine therapy can differentially alter inhibitory gamma-aminobutyric acid (GABA) neurotransmission in patients susceptible to impulsive and compulsive behaviors. Finally, we will test the hypothesis that releasable dopamine stores in the mesolimbic dopamine system are greater in patients susceptible these behaviors, thus linking a biological mechanism the etiology of these maladaptive behaviors. Completion of this study will pave the way for the use of non-invasive, quantitative outcomes in PD necessary for future target validation studies and early-phase drug discovery. Also, we will provide direct evidence that dopamine therapy acts on extra-striatal neural networks, linking regional changes in neural activity to dopamine-induced alterations to GABA levels. This work will advance the field to engaging novel therapeutic targets essential to effective treatment of impulsive and compulsive behaviors. Ultimately, this work will guide the development of improved, individualized therapies, advancing the therapeutic goals of personalized medicine, which is vital for patients suffering from PD.