A mesoscopic modelling approach to anaesthetic action on brain electrical activity

While history records many instances in which various substances such as wine, hemp and opium were used to deaden sensibility to the pain of surgery, it was not until William Morton's public demonstration of the painless extraction of a tooth in 1846 using ether that the modern era of anaesthesia can be said to have begun. Within a few years of this demonstration chloroform, diethyl ether and nitrous oxide had all attained a widespread, and ardent, clinical following. While these initial agents were variously highly toxic (chloroform), combustible (diethyl ether, chloroform) or of insufficient potency (nitrous oxide), by the end of the 20th century a range of intravenous and volatile general anaesthetic agents (GAs) had been developed that had overcome all of these limitations. Anaesthesia is now among the safest of all routine clinical procedures, with the mortality attributable to anaes-thesia having fallen from 1 per 10,000 healthy patients in 1950 (when mortality rates began to be systematically assayed) to less than 1 per 250,000 (Kohn et al, 2000). However, the dramatic advances in the clinical certitude and confidence with which anaesthetic agents are administered have not been parallelled by a similar increase in our knowledge of the neural mechanisms responsible for their ability to remove consciousness. While the last three decades or so have seen an explosion in our knowledge regarding the molecular and cellular targets of anaesthetic agents (Franks, 2008; Ishizawa, 2007; Rudolph and Antkowiak, 2004; Grasshoff et al, 2005; Hemmings et al, 2005; Campagna et al, 2003; Franks and Lieb, 1994), we remain largely ignorant regarding the mechanisms by which these microscopic effects produce alterations in large scale neuronal network activity and hence behaviour. Modeling the large scale electrophysiological effects of anaesthetic agents may help to mechanistically unify the multiple cellular and molecular targets of anaesthetic agents that have been identified to date