Relationship Between Cortical Acetylcholine, Neurophysiologic Complexity, and the Level of Consciousness

Abstract

Contemporary theories have argued that the level of consciousness can be approximated by cortical complexity or the strength of frontoparietal connectivity. In support of this, studies have demonstrated suppressed brain state repertoire and frontoparietal connectivity during loss of consciousness. Comparatively little focus has been placed on understanding the neurobiological mechanisms relating to these computational measures of consciousness, leaving their relationship to underlying neurochemical processes unknown. Levels of acetylcholine in the cortex have been shown to relate to the capacity for consciousness, but a relationship between cortical acetylcholine and cortical dynamics such as neurophysiologic complexity has not been investigated. We therefore tested the hypothesis that cortical cholinergic tone would correlate with neurophysiologic complexity. A prior study from our laboratory assessed the effects of cholinergic or noradrenergic stimulation of the prefrontal or parietal cortices in anesthetized rats, finding that only cholinergic stimulation of the prefrontal cortex restored wakefulness during anesthesia. While only prefrontal cholinergic neurotransmission was implicated in regulating the level of consciousness, all stimulation cohorts displayed an activated electroencephalogram (EEG) and elevations in cortical acetylcholine relative to the pre-stimulation anesthetized state. Therefore, in our first data chapter we used EEG data from Pal et al. 2018 to test if prefrontal cholinergic neurotransmission regulates the level of consciousness through changes in neurophysiologic complexity and frontoparietal connectivity. As expected, sevoflurane anesthesia suppressed neurophysiologic complexity and corticocortical connectivity relative to wakefulness. Unexpectedly, however, the strength of frontoparietal connectivity remained suppressed in all cohorts following stimulation, notwithstanding the presence or absence of wakefulness. In contrast, complexity was elevated in all cohorts, correlating instead with spectral features such as EEG activation and periods of elevated cortical acetylcholine. We conclude that prefrontal cholinergic neurotransmission does not regulate the level of consciousness through frontoparietal connectivity, and that neurophysiologic complexity may instead index EEG activation or cortical acetylcholine. In our next data chapter, we explored the relationship between EEG complexity, spectral contents of the signal, and the level of consciousness by contrasting the effects of ketamine and propofol anesthesia over three bandwidths (0.5-175 Hz, 65-175 Hz, and 0.5-55 Hz). We demonstrate bandwidth-dependent properties of both ketamine and propofol on complexity, demonstrating that ketamine anesthesia suppresses complexity in the 65-175 Hz bandwidth, while propofol does not. Using a normalization method to average out spectral influence on the signal, we demonstrate comparable effects of ketamine and propofol anesthesia on 0.5-175 Hz and 0.5-55 Hz complexity that are dissociable from spectral EEG properties. In our final data chapter, we leveraged the dose-dependent properties of the dissociative anesthetics ketamine and nitrous oxide to characterize the relationship between cortical acetylcholine levels, neurophysiologic complexity, and frontoparietal connectivity (25-55 Hz, 85-125 Hz, 125-175 Hz). During subanesthetic ketamine and nitrous oxide induction, we report periods of elevated prefrontal and parietal cortical cholinergic tone, neurophysiologic complexity, and frontoparietal connectivity in the 125-175 Hz bandwidth. During nitrous oxide sedation, cortical acetylcholine levels and neurophysiologic complexity were concomitantly suppressed with the level of arousal. Our findings demonstrate a correlation between cortical acetylcholine levels, neurophysiologic complexity, and frontoparietal connectivity in the high gamma bandwidth. In sum, our findings establish acetylcholine as a neurochemical correlate of cortical dynamics purported to relate to consciousness. While future causal studies are necessary, we offer preliminary evidence suggesting a role for cortical cholinergic neurotransmission in supporting neurophysiologic complexity and the capacity for consciousness.