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Abstract

OBJECTIVE: Arousal, or wakefulness, is a fundamental brain process on which all cognitive functions rely, and which has important clinical applications. However, the neurobiology of arousal in humans remains incompletely characterized. The underlying neuroanatomy can be studied through focal lesions that induce coma, with evidence suggesting that such lesions commonly involve the pontine tegmentum. However, the precise location of the brainstem region critical for arousal remains unclear. Furthermore, the brainstem is thought to promote arousal through ascending projections to a distributed network, but the nodes of this network in humans are poorly defined. METHODS: To identify the brainstem region critical for arousal and its associated network in humans, we integrated a lesion overlap analysis with resting state functional connectivity MRI (rs-fcMRI). We collected 36 focal brainstem lesions: 12 lesions caused coma, and 24 control lesions caused motor deficits with preservation of consciousness/arousal. By overlapping the coma lesions and subtracting the control lesions, we identified a coma-specific region of the brainstem. We then used rs-fcMRI collected from 98 healthy individuals to identify the functionally connected network of this coma-specific region. RESULTS: The coma-specific region of the brainstem localized to the lateral pontine tegmentum, overlying the medial parabrachial nucleus (PB). The rs-fcMRI analysis revealed two functionally connected nodes: the agranular insula (AI) and anterior cingulate cortex (ACC). These regions exhibited significantly more connectivity to coma lesions than control lesions. Based on connectivity to the AI and ACC, the PB most closely resembled the coma-specific region, compared to other nearby nuclei. CONCLUSIONS: Coma-causing lesions appear to involve the PB, which exhibits connectivity to the AI and ACC in a three-node network. Damage to the PB region may therefore be integral to the pathophysiology of coma; as the PB is critical to arousal in non-human animals, our findings suggest a homologous neural system of arousal between animals and humans. The AI and ACC are the primary sites of Von Economo neurons, and have been implicated in conscious awareness in humans. Our findings therefore link a brainstem nucleus of arousal to cortical regions associated with human awareness, offering a neural basis for integration of these two processes.