Biological Determinants of Impulsivity in Parkinson's Disease

帕金森病冲动的生物决定因素

基本信息

批准号：
9486009
负责人：
Daniel Oliver Claassen
金额：
$ 52.86万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9486009
关键词：
Abate Acute Address Behavior Behavioral Binding Binge Eating Biological Biological Markers Biological Neural Networks Biophysics Blood flow Brain Caregivers Cerebrovascular Circulation Cerebrum Clinical Cognitive Compulsive Behavior Corpus striatum structure Data Decision Making Deep Brain Stimulation Development Dextroamphetamine Dopamine Dopamine Agonists Dopamine D2 Receptor Dorsal Equilibrium Etiology Future Gambling Goals Hobbies Image Impairment Impulsive Behavior Impulsivity Levodopa Link Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Measurement Measures Mediating Medical History Methods Molecular Morbidity - disease rate Motor Multimodal Imaging Nature Neurocognitive Neurotransmitters Outcome Overdose Parkinson Disease Pathway interactions Patients Perfusion Pharmaceutical Preparations Phase Phenotype Physiological Placebos Positron-Emission Tomography Predisposition Prevalence Preventive therapy Quality of Care Research Personnel Rewards Risk Risk-Taking Role Series Severities Structure Symptoms Synapses Techniques Testing Thalamic structure Therapeutic Therapeutic Intervention Ventral Striatum Weight Gain Withdrawal Work anxiety symptoms base behavior change behavior measurement behavioral response cerebral hemodynamics curative treatments disabling symptom dopamine system drug discovery effective therapy exhaustion experience experimental study gamma-Aminobutyric Acid hemodynamics high risk imaging approach improved indexing individualized medicine innovation insight mesolimbic system motor symptom neurobiological mechanism neurochemistry neurotransmission new therapeutic target novel novel therapeutic intervention patient subsets personalized medicine phenomenological models preference putamen receptor receptor binding relating to nervous system response sexual encounter symptomatology targeted treatment treatment response trend validation studies

项目摘要

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.

项目摘要帕金森氏病（PD）中的运动症状有效地通过基于多巴胺的疗法来管理患者的行为改变可能是意外的结果。症状为特征持续参与奖励驱动的活动会导致患者和看护人的显着发病率。这这些症状，冲动和强迫性行为的描述性术语捕获了异常，目标指导的，决策现象学在这种临床状况下典型。症状范围从强迫性饮食，赌博，购物和过度参与某些爱好的过度性。冲动性和强迫性行为更常见于接受多巴胺激动剂治疗的患者，行为可以减少或停止使用它们的使用。确实，其他治疗干预措施，包括深脑刺激和左旋多巴，与适应不良行为的起源有关，以及总体而言，这些症状似乎本地化为功能障碍或“剂量过量”，中质胶质糖多巴胺系统。该建议将表征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疗法和中唇多巴胺网络的作用。我们提出了一系列实验，这些实验将决定多巴胺的响应中不同的功能性大脑变化在有或没有冲动和强迫性行为的患者中使用激动剂。我们的第一个目的是确定如何对多巴胺激动剂的脑血液动力学反应区分了冲动和强迫性的患者行为。我们假设这些患者夸张或增加了中唇血流动力学对多巴胺激动剂疗法的反应。血液动力学变化将与神经认知评估有关基于奖励的决策和风险偏好，强调生理大脑之间的连贯性变化和对药物的行为反应。接下来，我们旨在确定多巴胺疗法如何差异改变了抑制性γ-氨基丁酸（GABA）神经传递的患者冲动和强迫性行为。最后，我们将测试以下假设在易感这些行为的患者中，中唇多巴胺系统较大，从而将生物学联系起来机理这些不良适应行为的病因。这项研究的完成将为使用铺平道路未来目标验证研究所需的PD中的无创，定量结果药物发现。此外，我们将提供直接证据表明多巴胺治疗作用于肤色外神经网络，将神经活动的区域变化与多巴胺诱导的改变与GABA水平联系起来。这项工作将使该领域成为有效治疗脉冲治疗至关重要的新型治疗靶标强迫行为。最终，这项工作将指导开发改进的个性化疗法，促进个性化医学的治疗目标，这对于患有PD的患者至关重要。