Biological Determinants of Impulsivity in Parkinson's Disease

项目摘要 帕金森病（PD）的运动症状可通过基于多巴胺的治疗有效控制，但 患者的行为变化可能会产生意想不到的后果。症状特征为 持续参与奖励驱动的活动导致患者和护理人员的严重发病率。的 这些症状的描述性术语，冲动和强迫行为，捕捉了异常的，目标- 在这种临床条件下，有针对性的，决策现象学是典型的。症状包括 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受体激动剂治疗的患者中更常见， 并且行为可以随着其使用的减少或停止而减轻。事实上，其他治疗干预， 包括脑深部电刺激和左旋多巴，与适应不良行为的发生有关， 总的来说，这些症状似乎局限于中皮质边缘多巴胺功能障碍或“过量” 系统这项建议将描述冲动和强迫行为的生物决定因素， PD，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 我提出了一系列实验，以确定多巴胺对大脑功能的不同影响。 在有和没有冲动和强迫行为的患者中使用激动剂。我们的第一个目标是确定 多巴胺受体激动剂的脑血流动力学反应可区分冲动型和强迫型患者 行为。我们假设这些患者有夸大的，或增加，中脑血流动力学 多巴胺受体激动剂治疗的反应。血流动力学变化将与神经认知评估相关， 基于奖励的决策和风险偏好，强调生理大脑之间的一致性 变化和对药物的行为反应。接下来，我们的目标是确定多巴胺治疗如何 差异性改变易受以下疾病影响的患者的抑制性γ-氨基丁酸（GABA）神经传递 冲动和强迫行为。最后，我们将测试可释放的多巴胺储存在大脑中的假设。 中脑边缘多巴胺系统在易受这些行为影响的患者中更大，从而将生物学 这些适应不良行为的病因机制。这项研究的完成将为使用 PD的非侵入性定量结果对于未来的目标验证研究和早期阶段研究是必要的 药物发现。此外，我们将提供直接的证据表明，多巴胺治疗作用于纹状体外神经元， 网络，连接区域神经活动的变化，多巴胺诱导的GABA水平的改变。这项工作 将推动该领域的参与新的治疗目标至关重要的有效治疗冲动和 强迫性行为最终，这项工作将指导改进的个性化治疗的发展， 推进个性化医疗的治疗目标，这对PD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.