Different diseases, same circuits: lessons from rare and overlooked causes of disorders of consciousness

Most foundational frameworks for understanding disorders of consciousness are based on common etiologies such as traumatic brain injury, stroke, or hypoxic-ischemic insult. From these, the mesocircuit hypothesis has emerged as a leading model, proposing that consciousness depends on a distributed network of brainstem arousal systems, central thalamic hubs, and cortico-subcortical loops. However, rare and underrecognized causes of coma and prolonged disorders of consciousness offer a unique opportunity to test, refine, and expand these models. In this review, we analyze a wide array of rare etiologies—including genetic syndromes, parasitic and fungal infections, autoimmune encephalitides, amyloid and tau pathologies, toxic-metabolic states, and hematological disorders—that are often excluded from mainstream consciousness research. Despite their diverse mechanisms, these conditions converge on a consistent set of anatomical targets: the central thalamus, brainstem reticular activating system, deep white matter “bridging zones,” basal ganglia, and distributed cortical networks. This convergence not only provides powerful external validation of network-based frameworks such as the mesocircuit hypothesis, but also underscores the clinical need for therapeutic approaches that address both etiology-specific pathology and distributed circuit-level dysfunction. However, evidence quality varies considerably across these rare conditions, with many findings based on limited case reports or small series, necessitating cautious interpretation of proposed anatomical frameworks.