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

描述(由申请人提供)：90%的帕金森氏病(PD)患者出现言语和吞咽障碍，吸入性肺炎是该患者群体的主要死亡原因。虽然目前的药物和手术干预措施在缓解帕金森病的一般肢体运动症状方面是有效的，但它们未能对大脑皮质球束控制的脑运动功能(如言语和吞咽)提供显著的好处。这表明帕金森病患者的颅运动和肢体运动障碍是由不同的潜在神经病理机制引起的，然而这些差异的本质目前还不清楚。这项建议的中心目标是在帕金森病动物模型中调查调节皮质球损伤和皮质脊髓损伤的神经机制的差异。使用皮质内微刺激和由颅脑运动和肢体运动任务组成的综合行为测试组，拟议的研究将：(1)确定单侧和双侧纹状体多巴胺耗竭对颅脑和肢体运动功能以及皮质球和皮质脊髓回路的不同影响；(2)确定帕金森病患者对靶向运动康复和多巴胺替代治疗的颅和肢体运动功能的不同反应；(3)确定靶向运动康复和多巴胺替代疗法对皮质球和皮质脊髓回路完整性的不同影响。这一结果有可能指导神经生物学知情疗法的发展，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。更有效的帕金森病患者颅运动功能障碍的治疗策略将提高患者的生活质量，降低个体医疗费用，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：这一结果将为帕金森病患者调节口腔运动障碍的神经机制提供直接的见解，并对开发专门针对帕金森病患者颅运动障碍的新型、有效和神经生物学知情的治疗方法具有明确的意义。对帕金森病患者的言语和吞咽功能障碍采取更好的治疗策略将提高生活质量，降低个人医疗保健成本、总经济负担、照顾者负担、吸入性肺炎，并最终降低这种疾病人群的死亡率。

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.