Deciphering Freezing of Gait: What Neuropathology Reveals About an Episodic Phenomenon

Freezing of gait (FoG) is an episodic, debilitating motor phenomenon defined as paroxysmal episodes wherein there is an inability to step effectively, despite attempting to do so. Although FoG is most commonly associated with Parkinson's disease, it manifests across a spectrum of progressive neurodegenerative and potentially transient non-neurodegenerative conditions that affect overlapping locomotor circuits. The episodic nature of FoG implies transient disruptions of a distributed locomotor network rather than fixed structural lesions, rendering its neuropathological basis particularly challenging to define. This review synthesizes current knowledge of the structural, neurochemical and proteinopathic substrates that precondition and precipitate FoG. The principal disease categories implicated in FoG are reviewed, including Lewy body diseases, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration and argyrophilic grain disease, as well as non-neurodegenerative conditions such as cerebrovascular disease and metabolic encephalopathy. Mixed and overlapping pathologies are common. Across these disorders, different disease stages and phases, and their frequent combinations, interact with selective vulnerability of distinct neuronal and glial populations, giving rise to a complex pathophysiological landscape. It is proposed that this convergence results in heightened network susceptibility, whereby cumulative damage to cortical, subcortical and brainstem locomotor nodes progressively lowers the threshold for episodic circuit failure. Understanding these multilevel neuropathological determinants is essential for developing targeted therapeutic strategies aimed at stabilizing the locomotor network and reducing FoG burden.