Neural Substrates of Oral Motor Dysfunction in Parkinson's Disease

帕金森病口腔运动功能障碍的神经基质

基本信息

批准号：
7912217
负责人：
Emily Kate Plowman
金额：
$ 4.12万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-01 至 2010-09-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7912217
关键词：
Affect Aftercare Animal Model Animals Aspiration Pneumonia Behavioral Cause of Death Corpus striatum structure Corticobulbar Tracts Corticospinal Tracts Deglutition Development Dopamine Forelimb Functional disorder Goals Health Care Costs Human Immunohistochemistry Impairment Individual Injection of therapeutic agent Lead Levodopa Long-Evans Rats Maps Measures Mediating Motor Motor Cortex Movement Operative Surgical Procedures Oxidopamine Parkinson Disease Pathology Patients Quality of life Recovery Rehabilitation therapy Replacement Therapy Speech Symptoms Tongue Training Translating Upper Extremity behavior test effective therapy improved jaw movement male microstimulation mortality motor impairment neural circuit oral motor patient population public health relevance relating to nervous system response treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Speech and swallowing impairments occur in 90% of Parkinson's Disease (PD) patients and aspiration pneumonia is the leading cause of death. While current pharmacological and surgical interventions are effective in alleviating general motor symptoms of PD, largely controlled by corticospinal tracts, they have failed to provide significant benefit for functions controlled by corticobulbar tracts such as speech and swallowing. This suggests that oral motor and upper extremity deficits in PD are mediated by different underlying neural pathologies. Our newly developed animal model of oral motor impairment in PD suggests that striatal dopamine depletion does indeed differentially affect the neural circuits controlling lingual versus forelimb function. This has lead to the hypothesis that improvements in oral motor function in PD may require treatments different from those used to treat upper extremity function. The goal of the proposed study is to dissociate the different behavioral and neural changes mediating recovery of oral motor versus upper extremity function in PD. Specifically, this study will 1) determine the differential responses of oral motor and upper extremity function to motor rehabilitation and dopamine replacement therapy and 2) determine the differential effects of motor rehabilitation and dopamine replacement therapy on oral motor versus upper extremity movement representations within the motor cortex. This study involves first training 90 male Long Evans rats on an extensive battery of motor tasks to establish a baseline measure of upper extremity and oral motor function. Striatal dopamine will be depleted bilaterally in sixty of the animals via localized 6-Hydroxydopamine injections. One month following each injection, motor impairments will be assessed. Animals will then receive either 1) oral motor therapy; 2) oral motor therapy + levodopa; 3) upper extremity therapy; 4) upper extremity therapy + levodopa; 5) levodopa therapy; or 6) no rehabilitation for eight weeks. The impact of these treatments will be assessed on the same battery of motor tasks post treatment. Intracortical microstimulation will then be used to derive motor maps of forelimb, tongue and jaw movements and the level of striatal dopamine depletion will be determined using immunohistochemistry. This study integrates a comprehensive behavioral test battery with intracortical microstimulation to determine the specific neural substrates mediating oral motor impairment and recovery in PD. PUBLIC HEALTH RELEVANCE: The results will guide the development of neurobiologically informed therapies that specifically target oral motor impairment that can be translated to the human patient population. More effective treatment strategies of oral motor dysfunction in PD will improve patient quality of life, reduce individual health care cost and ultimately reduce PD related mortality.

描述（由申请人提供）：90% 的帕金森病 (PD) 患者会出现言语和吞咽障碍，吸入性肺炎是导致死亡的主要原因。虽然目前的药物和手术干预可有效缓解帕金森病的一般运动症状（主要由皮质脊髓束控制），但未能对皮质延髓束控制的功能（例如言语和吞咽）提供显着的益处。这表明帕金森病中的口腔运动和上肢缺陷是由不同的潜在神经病理学介导的。我们新开发的 PD 口腔运动障碍动物模型表明，纹状体多巴胺耗竭确实对控制舌功能和前肢功能的神经回路产生不同的影响。这导致了这样的假设：PD 患者口腔运动功能的改善可能需要与治疗上肢功能不同的治疗方法。本研究的目的是区分帕金森病患者口腔运动恢复与上肢功能恢复的不同行为和神经变化。具体来说，本研究将 1) 确定口腔运动和上肢功能对运动康复和多巴胺替代疗法的差异反应，2) 确定运动康复和多巴胺替代疗法对口腔运动与运动内上肢运动表征的差异影响皮质。这项研究首先对 90 只雄性 Long Evans 大鼠进行一系列广泛的运动任务训练，以建立上肢和口腔运动功能的基线测量。通过局部注射 6-羟基多巴胺，六十只动物的双侧纹状体多巴胺将被耗尽。每次注射后一个月，将评估运动障碍。然后动物将接受 1) 口腔运动治疗； 2）口腔运动疗法+左旋多巴； 3）上肢治疗； 4）上肢治疗+左旋多巴； 5)左旋多巴治疗；或 6) 八周内没有康复。这些治疗的影响将在治疗后对同一组运动任务进行评估。然后使用皮质内微刺激来获得前肢、舌头和下颌运动的运动图，并使用免疫组织化学测定纹状体多巴胺消耗水平。本研究将综合行为测试组与皮质内微刺激相结合，以确定介导 PD 口腔运动障碍和恢复的特定神经基质。公共健康相关性：研究结果将指导神经生物学疗法的开发，这些疗法专门针对口腔运动障碍，可以转化为人类患者群体。更有效的 PD 口腔运动功能障碍治疗策略将改善患者的生活质量，降低个人医疗保健成本，并最终降低 PD 相关死亡率。