Neurotransmitter Systems Underlying Freezing of Gait (FOG) in Parkinson's Disease

Freezing of gait (FOG) is a common and debilitating symptom of Parkinson's disease (PD). Despite its significant clinical impact, the underlying pathophysiological mechanisms of FOG remain poorly understood. Given the clinical heterogeneity of FOG and its occurrence in various disorders, not only dopaminergic dysfunction but also multiple nondopaminergic neurotransmitter systems play a role in this phenomenon. In this review, we offer a comprehensive overview of current evidence regarding the contributions of various neurotransmitters to FOG, including dopamine, acetylcholine, norepinephrine, serotonin, glutamate, and gamma-aminobutyric acid (GABA). While dopaminergic dysfunction is particularly relevant in levodopa-responsive forms of FOG, the occurrence of paradoxical ON-state freezing and levodopa-unresponsive FOG underscores dopamine's limited and nonlinear role in gait control. Degeneration of the cholinergic system has been linked to impaired gait automaticity, attentional control, and postural stability, thereby exacerbating freezing, especially in cognitively triggered and levodopa-unresponsive FOG. Additionally, noradrenergic dysfunction may impair attentional and adaptive control of gait, making locomotor networks more susceptible to freezing under stress or cognitive load. Although evidence is limited, the serotonergic system is also thought to be involved in FOG. An imbalance between glutamatergic excitation and GABAergic inhibition within cortico-basal ganglia-brainstem circuits may destabilize locomotor network dynamics and contribute to freezing, as supported by neuroimaging and pharmacological studies. The ways in which these neurotransmitter systems contribute to FOG are multifactorial and involve complex interactions within distributed locomotor networks.