Parkinson’s Disease as a Disorder of Spatial–Temporal Symmetry

Parkinson’s disease (PD) is traditionally defined by dopaminergic loss in the substantia nigra, yet its heterogeneous phenotypes and prodromal trajectories challenge a linear, dopamine-centered model. The α-synuclein origin and connectome (SOC) model proposes two major trajectories: a brain-first pathway, with the pathology initiating in limbic and brainstem structures and spreading ipsilaterally to the nigrostriatal system, and a body-first pathway, with the pathology originating in enteric and peripheral autonomic nerves before ascending to the brain. In this review, we integrate the SOC model into a broader framework, reconceptualizing PD as a progressive disorder of spatial–temporal symmetry. Spatial symmetry encompasses left–right and cranio-caudal balance of neural and musculoskeletal systems, whereas temporal symmetry denotes the coherence of biological rhythms from circadian and autonomic cycles, coupled with metabolic health and mitochondrial function, to sub-second timing governed by dopaminergic and basal ganglia–cortical network dynamics. We outline how systemic insulin resistance and mitochondrial stress erode temporal symmetry, while cranio-cervical malalignment and temporomandibular disorders perturb spatial symmetry. We discuss the neurobiological implementation of these symmetry axes via large-scale networks and dopaminergic modulation of spatial–temporal sensorimotor dynamics, framing PD as a multiscale symmetry-breaking process, and explore the implications for symmetry-oriented biomarkers, subtyping, and future interventions.