Anesthesia as Decoupling?

A cardinal effect of general anesthetics is loss of consciousness. However, disruption of consciousness may be a happy accident; that is, the fundamental common mechanism of anesthetic drug effect may have nothing to do with a special targeting of conscious processing, as opposed to a generic effect on all neurons. After all, anesthetic drugs effect a remarkably wide range of organisms, incapacitating vertebrates, slowing organ movements of plants, and even halting the environmental responsiveness of amoebae. As organisms become simpler, it is hard to argue these organisms even have a consciousness to be disrupted because we have difficulty with the very idea of such organisms having a subjective experience. But even these putatively nonconscious model organisms provide an opportunity to understand key features of the mechanisms of anesthetics. An emerging view is that the common effect of general anesthetics is to increase the modularity of communication networks—that is, anesthetics interrupt connections that normally exist between networks so that the networks are dominated by local activity—thereby disrupting the efficiency of information transfer through the organism and isolating the organism from its surroundings. In this issue of Anesthesiology, Awal et al. report the results of simultaneously recording neuronal activity in almost the entire head of the roundworm Caenorhabditis elegans at different depths of sevoflurane and isoflurane anesthesia. In so doing, the authors are able to address a question that is currently unfeasible in mammalian models: do general anesthetics equally disrupt relationships between all neurons, or are connections between particular functional networks critical vulnerable nodes that are responsible for the behavioral impact of general anesthetics? Imagine an organism had three neuronal networks: a sensory network that projects to a decision network that projects to a motor network. Severing any one of these connections would render the organism unresponsive to the environment as the networks become more modular. Or perhaps the effect of anesthetics on the nervous system is scrambled by the introduction of random fluctuations in all three networks, so that normal relationships between three populations are decoupled. Awal et al.’s study depends upon two technical advancements in neurobiology during the last decade. The first is the development of fluorescent readouts of neuronal activity, which make electrical activity visible in vivo. The second is the rapid imaging of a three-dimensional volume over time, which the authors addressed by utilizing light sheet microscopy. Light sheet microscopy is so named because it simultaneously illuminates and captures an entire plane of the specimen (the “sheet” of light) simultaneously, rather than sequentially scanning a focused laser over each region of the sample in order, as a confocal microscope does. By rapidly shifting the depth of the imaging plane, it becomes feasible to detect transient responses within a three-dimensional volume. Interest in this imaging approach has exploded since 2014 when it was reported that it could be used to optically section specimens in vivo. Awal et al. found that the neurons in unanesthetized worms demonstrate stable global activity states that occasionally shift between different confirmations. While the worm is engaged in behavior, it defines a state in the nervous system. Because most of the time most neurons in C. elegans have slow, graded activity (rather than the more familiar all-or-none action potentials), the unanesthetized worm demonstrates very low frequency shifts in fluorescence levels, as neurons settle on stable intracellular calcium concentrations that persist until