Slovin H, Abeles M, Vaadia E, Haalman I, Prut Y, Bergman H
Department of Physiology, Hadassah Medical School, The Hebrew University, Jerusalem 91120, Israel.
J Neurophysiol. 1999 Feb;81(2):858-74. doi: 10.1152/jn.1999.81.2.858.
There is considerable overlap between the cognitive deficits observed in humans with frontal lobe damage and those described in patients with Parkinson's disease. Similar frontal impairments have been found in the 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) primate model of Parkinsonism. Here we provide quantitative documentation of the cognitive, oculomotor, and skeletomotor dysfunctions of monkeys trained on a frontal task and treated with low-doses (LD) of MPTP. Two rhesus monkeys were trained to perform a spatial delayed-response task with frequent alternations between two behavioral modes (GO and NO-GO). After control recordings, the monkeys were treated with one placebo and successive LD MPTP courses. Monkey C developed motor Parkinsonian signs after a fourth course of medium-dose (MD) MPTP and later was treated with combined dopaminergic therapy (CDoT). There were no gross motor changes after the LD MPTP courses, and the average movement time (MT) did not increase. However, reaction time (RT) increased significantly. Both RT and MT were further increased in the symptomatic state, under CDoT. Self-initiated saccades became hypometric after LD MPTP treatments and their frequency decreased. Visually triggered saccades were affected to a lesser extent by the LD MPTP treatments. All saccadic parameters declined further in the symptomatic state and improved partially during CDoT. The number of GO mode (no-response, location, and early release) errors increased after MPTP treatment. The monkeys made more perseverative errors while switching from the GO to the NO-GO mode. Saccadic eye movement patterns suggest that frontal deficits were involved in most observed errors. CDoT had a differential effect on the behavioral errors. It decreased omission errors but did not improve location errors or perseverative errors. Tyrosine hydroxylase immunohistochemistry showed moderate ( approximately 70-80%) reduction in the number of dopaminergic neurons in the substantia nigra pars compacta after MPTP treatment. These results show that cognitive and motor disorders can be dissociated in the LD MPTP model and that cognitive and oculomotor impairments develop before the onset of skeletal motor symptoms. The behavioral and saccadic deficits probably result from the marked reduction of dopaminergic neurons in the midbrain. We suggest that these behavioral changes result from modified neuronal activity in the frontal cortex.
额叶损伤的人类所观察到的认知缺陷与帕金森病患者所描述的认知缺陷之间存在相当大的重叠。在帕金森病的1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）灵长类动物模型中也发现了类似的额叶损伤。在此，我们提供了对接受额叶任务训练并接受低剂量（LD）MPTP治疗的猴子的认知、动眼神经和骨骼运动功能障碍的定量记录。两只恒河猴接受训练以执行空间延迟反应任务，在两种行为模式（执行和不执行）之间频繁交替。在对照记录后，猴子接受一次安慰剂和连续的低剂量MPTP疗程。猴子C在接受第四疗程的中剂量（MD）MPTP后出现运动性帕金森病体征，随后接受联合多巴胺能治疗（CDoT）。低剂量MPTP疗程后没有明显的运动变化，平均运动时间（MT）没有增加。然而，反应时间（RT）显著增加。在CDoT治疗下的症状状态下，RT和MT均进一步增加。在低剂量MPTP治疗后，自主发起的扫视运动幅度变小，其频率降低。视觉触发的扫视运动受低剂量MPTP治疗的影响较小。在症状状态下，所有扫视运动参数进一步下降，在CDoT治疗期间部分改善。执行模式（无反应、定位和提前释放）错误的数量在MPTP治疗后增加。猴子在从执行模式转换到不执行模式时出现更多的持续性错误。扫视眼动模式表明，大多数观察到的错误都涉及额叶缺陷。CDoT对行为错误有不同的影响。它减少了遗漏错误，但没有改善定位错误或持续性错误。酪氨酸羟化酶免疫组织化学显示，MPTP治疗后黑质致密部多巴胺能神经元数量中度减少（约减少70 - 80%）。这些结果表明，在低剂量MPTP模型中，认知和运动障碍可以分离，并且认知和动眼神经损伤在骨骼运动症状出现之前就已发生。行为和扫视缺陷可能是由于中脑多巴胺能神经元的显著减少所致。我们认为这些行为变化是由额叶皮质中神经元活动的改变引起的。
