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

TL;DR

Rare causes of disorders of consciousness affect the same brain circuits as common causes, supporting network-based models of consciousness.

Contribution

The paper identifies convergence of diverse rare conditions on shared brain circuits, validating and expanding network-based theories of consciousness.

Findings

Rare causes of coma and disorders of consciousness consistently target central thalamus and brainstem circuits.

Despite varied mechanisms, these conditions converge on similar anatomical networks linked to consciousness.

Findings highlight the need for therapies addressing both specific pathology and circuit-level dysfunction.

Abstract

Most foundational frameworks for understanding disorders of consciousness are based on common aetiologies 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 analyse a wide array of rare aetiologies—including genetic syndromes, parasitic and fungal infections, autoimmune encephalitides, amyloid and tau pathologies, toxic-metabolic states and haematological 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 aetiology-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.

Toker and Monti report that rare causes of disorders of consciousness—including infections, autoimmune conditions, genetic disorders and neurodegenerative diseases—target the same brain circuits as common causes: brainstem arousal systems, central thalamus, basal ganglia and distributed cortical networks. Their review validates network-based frameworks for understanding arousal and awareness.

Graphical Abstract

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