ON-OFF MOOD CHANGE IN PARKINSONS DISEASE

拟议的职业发展计划将构成一座桥梁， 申请人过去的临床和研究经验，以一个富有成效的研究 职业生涯专注于运动障碍的功能性神经解剖学。 这 被视为申请人先前研究的自然延伸 经验，以及他对运动障碍的长期临床兴趣 和神经精神病学 短期职业目标包括（1）持续 开发多巴胺介导的通路功能的体内测试，以及 将该试验应用于适当的临床人群。 (2)这将 提供重要的新的研究技能，导致独立研究， 正电子发射断层扫描（PET）。 (3)进一步的临床专业知识， 运动障碍是另一个短期目标。 长期目标包括： 将这种PET技术或类似的方法应用于其他 多巴胺能功能异常的神经精神疾病 拟议的研究为实现这些目标提供了天然的垫脚石。 职业发展计划的其他要素包括有限的、重点突出的、 临床工作，并定期举办PET方法、运动障碍和 神经药理学 这种情况发生的环境是 无与伦比 该实验室是国际公认的领导者， PET方法和应用，并配备齐全。 从字面上看， 在同一屋檐下是主要的研究和临床MRI设施。 的 导师具有丰富的经验，无论是在临床方面的运动 疾病和PET在其研究中的应用。 他还 为基础PET的开发和应用做出了重大贡献 方法. 此外，非正式和正式的 与本实验室的其他独立研究人员合作 在校园的其他地方，特别是在神经科， 神经生物学精神病学和放射学 拟议动物的目标 研究是为了进一步开发一种体内测试的敏感性， 特异性多巴胺介导的途径。 特定的局部效应 多巴胺受体激动剂对PET测量的脑血流量（rCBF）的影响， 用来表示神经元活动的变化。 虽然一个相当新颖的 在PET的应用中，这类似于众所周知的PET的“活化“。 视觉刺激或记忆任务的rCBF，以及放射自显影动物研究 多巴胺激动剂引起的代谢变化支持其有效性， 效用 帕金森病（PD）患者的初步数据 和狒狒，证明了这种方法的可行性。 拟议 临床PET研究将检查L-DOPA和特异性多巴胺 在一组具有明显多巴胺相关性的PD患者中， 情绪的变化（间歇期抑郁症），与仔细 配对组的PD患者无关断期抑郁。 本地化， 假设特定的组差异。 这 研究可能具有广泛的适用性，不仅对许多PD 患者与关期抑郁症，但也向其他临床定义 PD患者亚组以及特发性 抑郁症、肌张力障碍、精神分裂症和抽动秽语综合征。

The proposed career development plan will form a bridge from the applicant's past clinical and research experience to a productive research career focused on the functional neuroanatomy of movement disorders. This is seen as a natural extension of the applicant's prior research experience, and his longstanding clinical interests in movement disorders and neuropsychiatry. Short-term career goals include (1) continued development of an in vivo test of dopamine-mediated pathway function, and application of this test to a suitable clinical population. (2) This will provide important new research skills leading to independent research with positron emission tomography (PET). (3) Further clinical expertise with movement disorders is another short-term goal. Long-term goals include the application of this PET technique or similar methods to other neuropsychiatric illnesses with abnormal dopaminergic function; the proposed research provides a natural stepping stone to these goals. Additional elements of the career development plan include limited, focused clinical work, and regular seminars in PET methods, movement disorders, and neuropharmacology. The environment in which this will occur is unparalleled. This laboratory is internationally recognized as a leader in PET methodology and applications, and is fully equipped. Also literally under the same roof are major research and clinical MRI facilities. The mentor has extensive experience both in clinical aspects of movement disorders and in the application of PET to their study. He has also contributed substantially to the development and application of basic PET methods. In addition, significant opportunities for informal and formal collaboration exist with other independent investigators in this laboratory and elsewhere on campus, especially within the departments of neurology, neurobiology, psychiatry and radiology. The goal of the proposed animal research is to further develop an in vivo test of the sensitivity of specific dopamine-mediated pathways. The localized effects of specific dopamine agonists on cerebral blood flow (rCBF) measured with PET will be used to indicate changes in neuronal activity. Although a fairly novel application of PET, this is analogous to the well-known "activation " of rCBF by visual stimuli or memory tasks, and autoradiographic animal studies of metabolic changes due to dopamine agonists support its validity and utility. Preliminary data, both in patients with Parkinson's disease (PD) and baboons, demonstrate athe feasibility of this approach. The proposed clinical PET study will examine the effects of L-DOPA and specific dopamine agonists on rCBF in a group of PD patients with marked dopamine-related changes in mood (off-period depression), as compared to a carefully matched group of PD patients without off-period depression. Localized, pharmacologically specific group differences are hypothesized. This research potentially has wide applicability, not only to the many PD patients with off-period depression, but also to other clinically-defined subgroups of patients with PD, as well as patients affected by idiopathic major depression, dystonia, schizophrenia, and Tourette syndrome.