Dissociating the Neural Substrates of Cranial and Limb Motor Impairment in an Ani

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，吸入性肺炎是该患者人群的主要死因。虽然目前的药物和手术干预在缓解PD的一般肢体运动症状方面是有效的，但它们未能为皮质延髓束控制的颅运动功能（如言语和吞咽）提供显著益处。这表明颅运动和肢体运动缺陷是由PD中不同的潜在神经病理介导的，然而这些差异的性质目前尚不清楚。这个建议的中心目标是调查的差异，在神经机制介导皮质延髓与皮质脊髓损伤的PD动物模型。采用皮质内微刺激和包括颅运动和肢体运动任务的综合行为测试组合，拟议的研究将（1）确定单侧与双侧纹状体多巴胺耗竭对颅和肢体运动功能以及皮质延髓和皮质脊髓回路的不同影响;（2）确定PD患者的颅和肢体运动功能对靶向运动康复和多巴胺替代治疗的不同反应;和（3）确定靶向运动康复和多巴胺替代疗法对皮质延髓和皮质脊髓回路完整性的不同影响。这些结果有可能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颅运动障碍。PD患者颅运动功能障碍的更有效治疗策略将改善患者的生活质量，降低个人医疗保健成本，减少吸入性肺炎，并最终降低该疾病人群的发病率。 公共卫生相关性：这些结果将提供直接的洞察力的神经机制介导的PD口腔运动障碍，并有明确的意义，为开发新的，有效的和神经生物学的治疗，特别是针对颅运动障碍的PD。PD患者言语和吞咽功能障碍的更好治疗策略将改善生活质量，降低个人医疗保健费用、总经济负担、护理人员负担、吸入性肺炎，并最终降低该疾病人群的死亡率。

DESCRIPTION (provided by applicant): Speech and swallowing impairments occur in 90% of individuals with Parkinson's Disease (PD) and aspiration pneumonia constitutes the leading cause of death in this patient population. While current pharmacological and surgical interventions are effective in alleviating general limb motor symptoms of PD, they have failed to provide significant benefit for cranial motor functions controlled by corticobulbar tracts such as speech and swallowing. This suggests that cranial motor and limb motor deficits are mediated by different underlying neural pathologies in PD, however the nature of these differences are not currently understood. The central goal of this proposal is to investigate differences in the neural mechanisms mediating corticobulbar versus corticospinal impairments in an animal model of PD. Using intracorticial microstimulation and a comprehensive behavioral testing battery consisting of both cranial motor and limb motor tasks, the proposed studies will (1) determine the differential effects of unilateral versus bilateral striatal dopamine depletion on cranial and limb motor function and corticobulbar and corticospinal circuits; (2) determine the differential responses of cranial and limb motor function in PD to targeted motor rehabilitation and dopamine replacement therapy; and (3) determine the differential effects of targeted motor rehabilitation and dopamine replacement therapy on the integrity of corticobulbar and corticospinal circuits. The results have the potential to guide the development of neurobiologically informed therapies that specifically target cranial motor impairment that can be translated to the human patient population. More effective treatment strategies of cranial motor dysfunction in PD will improve patient quality of life; reduce individual health care cost, aspiration pneumonia and ultimately morbidity in this disease population. PUBLIC HEALTH RELEVANCE: The results will provide direct insight into the neural mechanisms mediating oral motor impairments in PD and have clear implications for the development of novel, effective and neurobiologically informed treatments that specifically target cranial motor impairment in PD. Better treatment strategies for speech and swallowing dysfunction in PD will lead to improvements in quality of life and reductions in individual health care costs, total economic burden, caregiver burden, aspiration pneumonia and ultimately mortality in this disease population.