Figure 1.

Schematic representation of the complex systems regulating cortical arousal and controlling the sleep-wake cycle. Each assembly of neurons interacts with a series of other nuclei through complex excitatory and inhibitory projections (which are not all drawn for the sake of clarity). The final outputs of this complex network are ascending arousal-promoting or arousal-inhibiting cortical projections. Top-down cortical control of the activity of the subcortical structures also occurs. Stars indicate structures the activity of which is thought to be influenced by the administration of anaesthetic agents. For example, agents with a predominant gamma-aminobutyric acid (GABA)ergic effect (propofol or halogenated vapours; red star) potentiate the inhibition of cortical pyramidal neurons by inhibitory interneurons, boost the inhibitory effect of TR neurons on the cortex, and increase the inhibition of cortical arousal-promoting nuclei by the Vl and MPo, including the histaminergic Tm, the noradrenergic LC, the serotonergic DR, and the cholinergic BF, Pp, and LdT. The effects of ketamine (green star) are complex, and dose dependent. Through N-methyl-D-aspartate (NMDA) glutamate receptor antagonism, ketamine is known to inhibit GABAergic inhibitory interneurons at the cortical level, producing a hyper-glutamatergic state and the activation of specific cortical regions (anterior cingulate, medial prefrontal cortex, insula, and precuneus), the limbic system, and the hippocampus.^{65 66} This inhibitory interneuron inhibition also promotes cholinergic, dopaminergic, and other aminergic neurotransmission emerging from subcortical nuclei (e.g. TM, BF, Pp, and LdT). Aside from these effects, ketamine also inhibits excitatory-to-excitatory coupling in the cortex, provoking the inhibition of specific cortical regions.⁶⁸ Alpha2-adrenergic agonists such as dexmedetomidine block the release of norepinephrine by LC. This has a direct inhibitory effect on cortical arousal-promoting nuclei such as BF and IL, or promotes the inhibition of other arousal-promoting nuclei (e.g. Tm, DR, PeF, Pp, and LdT) by Vl and MPo.⁵⁵ Inspired by Moody and colleagues⁴⁸ and from Purdon and colleagues.⁶⁴ Drawn with BioRender. AAN, ascending arousal network; BF, basal forebrain; DR, dorsal raphe; IL, intralaminar nucleus of the thalamus; LC, locus coeruleus; LH, lateral hypothalamus; LHb, lateral habenula; Pb, parabrachial nucleus; PeF, perifornical area; Pp and LdT, pedunculo-pontine and latero-dorsal tegmentum nuclei; ReF, reticular formation; RmT, rostro-medial tegmental nucleus; So, supra-optic nucleus; Tm, tubero-mamillary nucleus; TR, thalamic reticular nucleus; Vl and MPo, ventro-lateral and median preoptic nuclei; VTA, ventral tegmental area.