Several general anesthetics produce their sedative effect by activating endogenous sleep pathways. We propose that general anesthesia is a two‐step process targeting sleep circuits at low doses, and synaptic release mechanisms across the entire brain at the higher doses required for surgery. Our hypothesis synthesizes data from a variety of model systems, some which require sleep (e.g. rodents and adult flies) and others that probably do not sleep (e.g. adult nematodes and cultured cell lines). Non‐sleeping systems can be made insensitive (...) (or hypersensitive) to some anesthetics by modifying a single pre‐synaptic protein, syntaxin1A. This suggests that the synaptic release machinery, centered on the highly conserved SNARE complex, is an important target of general anesthetics in all animals. A careful consideration of SNARE architecture uncovers a potential mechanism for general anesthesia, which may be the primary target in animals that do not sleep, but a secondary target in animals that sleep. (shrink)

Frontoparietal connectivity has been suggested to be important in conscious processing and its interruption is thought to be one mechanism of general anesthesia. Data in animals demonstrate that feedforward processing of information may persist during the anesthetized state, while feedback processing is inhibited. We investigated the directionality and functional organization of frontoparietal connectivity in 10 human subjects anesthetized with propofol on two separate occasions. Multichannel electroencephalography and a computational method of assessing directed functional connectivity were employed. We demonstrate that directed (...) feedback connectivity is diminished with loss of consciousness and returns with responsiveness to verbal command. We also applied the Dendrogram classification method to assess the global organization of directed functional connectivity during consciousness and anesthesia. We demonstrate a state-specific hierarchy and subject-specific subhierarchy in functional organization. These data support the hypothesis that specific states of human consciousness are defined by specific states of frontoparietal connectivity. (shrink)