Diverse but complementary methodologies are required to uncover the complex determinants and pathophysiology of freezing of gait. To develop future therapeutic avenues, we need a deeper understanding of the disseminated functional-anatomic network and its temporally associated dynamic processes. In this targeted review, we will summarize the latest advances across multiple methodological domains including clinical phenomenology, neurogenetics, multimodal neuroimaging, neurophysiology, and neuromodulation. We found that (i) locomotor network vulnerability is established by structural damage, e.g. from neurodegeneration possibly as result from genetic variability, or to variable degree from brain lesions. This leads to an enhanced network susceptibility, where (ii) modulators can both increase or decrease the threshold to express freezing of gait. Consequent to a threshold decrease, (iii) neuronal integration failure of a multilevel brain network will occur and affect one or numerous nodes and projections of the multilevel network. Finally, (iv) an ultimate pathway might encounter failure of effective motor output and give rise to freezing of gait as clinical endpoint. In conclusion, we derive key questions from this review that challenge this pathophysiological view. We suggest that future research on these questions should lead to improved pathophysiological insight and enhanced therapeutic strategies.

中文翻译：

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步态冻结：了解神秘现象的复杂性。

需要多种多样但互补的方法来揭示步态冻结的复杂决定因素和病理生理。为了开发未来的治疗途径，我们需要对散布的功能解剖网络及其在时间上相关的动态过程有更深入的了解。在这篇有针对性的综述中，我们将总结多个方法领域的最新进展，包括临床现象学，神经遗传学，多模式神经影像学，神经生理学和神经调节。我们发现（i）运动网络的脆弱性是由结构损伤所建立的，例如，可能由于遗传变异而导致的神经退行性病变，或由于脑损伤而造成的程度不同。这导致网络易感性增强，其中（ii）调制器可以增加或减小表示步态冻结的阈值。阈值降低的结果是，（iii）多级大脑网络的神经元整合失败将发生并影响多级网络的一个或多个节点和投影。最后，（iv）最终途径可能会遇到有效运动输出失败的情况，并导致步态冻结成为临床终点。总之，我们从本综述中得出了挑战这一病理生理学观点的关键问题。我们建议将来对这些问题的研究应导致改善的病理生理学见识和增强的治疗策略。（iv）最终途径可能会遇到有效运动输出失败的情况，并导致步态冻结为临床终点。总之，我们从本综述中得出了挑战这一病理生理学观点的关键问题。我们建议将来对这些问题的研究应导致改善的病理生理学见识和增强的治疗策略。（iv）最终途径可能会遇到有效运动输出失败的情况，并导致步态冻结为临床终点。总之，我们从本综述中得出了挑战这一病理生理学观点的关键问题。我们建议将来对这些问题的研究应导致改善的病理生理学见识和增强的治疗策略。