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

• 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
• 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

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）患者出现语言和吞咽障碍，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在缓解PD的一般运动症状方面是有效的，主要由皮质脊髓束控制，但它们未能为皮质延髓束控制的功能（如言语和吞咽）提供显著益处。这表明PD患者的口腔运动和上肢缺陷是由不同的潜在神经病理介导的。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差异影响控制舌与前肢功能的神经回路。这导致了一种假设，即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。本研究的目的是分离不同的行为和神经变化介导的恢复口腔运动与上肢功能的PD。具体而言，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治疗的不同反应，2）确定运动康复和多巴胺替代治疗对运动皮层内口腔运动与上肢运动表征的不同影响。本研究首先对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，60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）口服运动疗法; 2）口服运动疗法+左旋多巴; 3）上肢疗法; 4）上肢疗法+左旋多巴; 5）左旋多巴疗法;或6）无康复，持续8周。这些治疗的影响将在治疗后相同的运动任务组合中进行评估。然后将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来确定纹状体多巴胺耗竭的水平。本研究整合了一个全面的行为测试电池与皮质内微刺激，以确定特定的神经基质介导的口腔运动障碍和恢复在PD。 公共卫生相关性：这些结果将指导神经生物学信息疗法的发展，这些疗法专门针对可以转化为人类患者群体的口腔运动障碍。更有效的PD口腔运动功能障碍的治疗策略将提高患者的生活质量，降低个人医疗费用，并最终降低PD相关死亡率。

项目成果

Targeted motor rehabilitation dissociates corticobulbar versus corticospinal dysfunction in an animal model of Parkinson's disease.

有针对性的运动康复在帕金森病动物模型中分离皮质延髓与皮质脊髓功能障碍。

• DOI: 10.1177/1545968313498648
• 发表时间: 2014
• 期刊: Neurorehabilitation and neural repair
• 影响因子: 4.2
• 作者: Plowman,EmilyK;Maling,Nicholas;Thomas,NaghemeJ;Fowler,StephenC;Kleim,JeffreyA
• 通讯作者: Kleim,JeffreyA