Neuroanatomic Connectivity of the Human Ascending Arousal System Critical to Consciousness and Its Disorders

TLDR

The ascending reticular activating system (ARAS) mediates arousal, and its lesions cause coma, yet its neuroanatomic connectivity remains poorly understood due to methodological limitations, with evidence suggesting structural specializations that underlie distinct functional characteristics of human arousal. The study aimed to elucidate the structural connectivity of the human ARAS using high angular resolution diffusion imaging (HARDI) in three adult brains, including two postmortem cases. High angular resolution diffusion imaging (HARDI) tractography was employed to map ARAS pathways in three adult brains, with two postmortem specimens, integrating histological guidance. HARDI tractography revealed both known animal ARAS connections and novel human pathways linking the brainstem to the thalamus, hypothalamus, and basal forebrain, with distinct neurotransmitter‑specific fiber distributions, providing initial evidence of human‑specific ARAS pathways and demonstrating that HARDI tractography can advance the study of consciousness and its disorders.

Abstract

The ascending reticular activating system (ARAS) mediates arousal, an essential component of human consciousness. Lesions of the ARAS cause coma, the most severe disorder of consciousness. Because of current methodological limitations, including of postmortem tissue analysis, the neuroanatomic connectivity of the human ARAS is poorly understood. We applied the advanced imaging technique of high angular resolution diffusion imaging (HARDI) to elucidate the structural connectivity of the ARAS in 3 adult human brains, 2 of which were imaged postmortem. High angular resolution diffusion imaging tractography identified the ARAS connectivity previously described in animals and also revealed novel human pathways connecting the brainstem to the thalamus, the hypothalamus, and the basal forebrain. Each pathway contained different distributions of fiber tracts from known neurotransmitter-specific ARAS nuclei in the brainstem. The histologically guided tractography findings reported here provide initial evidence for human-specific pathways of the ARAS. The unique composition of neurotransmitter-specific fiber tracts within each ARAS pathway suggests structural specializations that subserve the different functional characteristics of human arousal. This ARAS connectivity analysis provides proof of principle that HARDI tractography may affect the study of human consciousness and its disorders, including in neuropathologic studies of patients dying in coma and the persistent vegetative state.