Restless legs syndrome (RLS) is traditionally conceptualized as a dopamine-responsive sensorimotor disorder; however, new evidence suggests a more complex and heterogeneous neurobiological basis. Findings from neuroimaging, genetic studies, circadian biology, and clinical research indicate that dopaminergic dysfunction occurs within a broader context of neuromodulatory imbalance involving iron metabolism, adenosinergic signalling, glutamatergic excitability, and, potentially, noradrenergic pathways. In parallel, quantitative susceptibility mapping and related approaches have provided indirect evidence of altered brain iron distribution, although results remain variable across studies. Clinically, RLS extends beyond nocturnal discomfort and is associated with sleep fragmentation, impaired quality of life, and neuropsychiatric comorbidity, as well as treatment-related complications such as augmentation. However, current diagnostic frameworks remain predominantly phenomenological, and available biomarkers lack sufficient validation for routine clinical use. In this narrative review, the available clinical, genetic, and neuroimaging evidence is synthesized to propose an integrative, network-based model in which iron-dependent neuromodulatory processes influence excitability across cortico–striatal–thalamo–limbic circuits. This framework is intended as a hypothesis-generating model rather than a definitive explanation of disease mechanisms. Substantial heterogeneity across studies, together with variability in clinical presentation and limited reproducibility of candidate biomarkers, underscores the need for standardized methodologies and longitudinal, multimodal investigations. Future work should aim to test this model empirically, refine biological stratification, and determine whether network-informed approaches can improve diagnosis and therapeutic targeting in RLS.
Oscar Arias-Carrión (Wed,) studied this question.