Center for the Study of Movement, Cognition and Mobility, Neurological Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
J Neurol. 2021 Feb;268(2):658-668. doi: 10.1007/s00415-020-10089-x. Epub 2020 Sep 9.
The "levodopa-overdose hypothesis" posits that dopaminergic replacement therapy (1) increases performance on tasks that depend on the nigrostriatal-pathway (e.g., motor-control circuits), yet (2) decreases performance on tasks that depend upon the mesocorticolimbic-pathway (e.g., prefrontal cortex, PFC). Previous work in Parkinson's disease (PD) investigated this model while focusing on cognitive function. Here, we evaluated whether this model applies to gait in patients with PD and freezing of gait (FOG). Forty participants were examined in both the OFF anti-Parkinsonian medication state (hypo-dopaminergic) and ON state (hyper-dopaminergic) while walking with and without the concurrent performance of a serial subtraction task. Wireless functional near-infrared spectroscopy measured PFC activation during walking. Consistent with the "overdose-hypothesis", performance on the subtraction task decreased (p = 0.027) after dopamine intake. Moreover, the effect of walking condition on PFC activation depended on the dopaminergic state (i.e., interaction effect p = 0.001). Gait significantly improved after levodopa administration (p < 0.001). Nonetheless, PFC activation was higher (p = 0.013) in this state than in the OFF state during usual-walking. This increase in PFC activation in the ON state suggests that dopamine treatment interfered with PFC functioning. Otherwise, PFC activation, putatively a reflection of cognitive compensation, should have decreased. Moreover, in contrast to the OFF state, in the ON state, PFC activation failed to increase (p = 0.313) during dual-tasking, perhaps due to a "ceiling effect". These findings extend the "levodopa-overdose hypothesis" and suggest that it also applies to gait in PD patients. While dopaminergic therapy improves certain aspects of motor performance, optimal treatment should consider the "double-edged sword" of levodopa.
“左旋多巴过量假说”认为，多巴胺替代疗法 (1) 会提高依赖黑质纹状体通路（例如运动控制回路）的任务表现，然而 (2) 会降低依赖中脑边缘通路（例如前额叶皮层，PFC）的任务表现。之前在帕金森病 (PD) 中的研究主要集中在认知功能方面，探讨了该模型。在这里，我们评估了该模型是否适用于 PD 患者的步态和冻结步态 (FOG)。40 名参与者在停用抗帕金森药物（低多巴胺能）和使用抗帕金森药物（高多巴胺能）状态下，分别在不进行和进行连续减法任务的情况下进行行走测试。无线功能近红外光谱测量了行走过程中 PFC 的激活情况。与“过量假说”一致，在摄入多巴胺后减法任务的表现下降（p=0.027）。此外，行走条件对 PFC 激活的影响取决于多巴胺状态（即交互效应 p=0.001）。左旋多巴给药后步态明显改善（p<0.001）。然而，与停用药物状态相比，在正常行走状态下，该状态下 PFC 的激活更高（p=0.013）。这种在 ON 状态下 PFC 激活增加表明，多巴胺治疗干扰了 PFC 的功能。否则，PFC 激活，推测是认知补偿的反映，应该会降低。此外，与停用药物状态相比，在 ON 状态下，PFC 激活在双重任务期间没有增加（p=0.313），可能是由于“天花板效应”。这些发现扩展了“左旋多巴过量假说”，并表明它也适用于 PD 患者的步态。虽然多巴胺治疗改善了某些运动表现方面，但最佳治疗应考虑左旋多巴的“双刃剑”效应。
