Abstract. Decisions concerning anesthetic dosing typically rely on population-based measures of drug potency. However, similar anesthetic doses have markedly different effects on distinct individuals. While some patients recover from anesthesia uneventfully, in others, recovery is complicated by postoperative delirium and cognitive dysfunction. Such complications are disproportionally prevalent in the elderly. It is presently unclear why some elderly patients exhibit these debilitating and costly complications. To answer this question, individual-based rather than population-based measures of drug effects must be developed. We create such measures for anesthetics in mice. Preliminary data indicate that standard population-based measures of anesthetic potency, such as half-maximal effective concentration (EC50), are insufficient to explain anesthetic responses in each individual. This is because at a fixed anesthetic concentration, the level of consciousness in each individual fluctuates. While fluctuations in the state of arousal occur spontaneously, there is an inertial tendency in each animal to resist state transitions. Hence, the response in each individual depends not just upon the anesthetic concentration, but also upon the individual’s previous state of arousal. Standard drug potency measures fail to account for this history-dependence. Thus, to adequately quantify individual-based responses to anesthetics, we develop two independent measures: personalized drug sensitivity and resistance to state transitions. We hypothesize that resistance to state transitions contributes to delayed restoration of cognitive function after anesthesia. We investigate age-dependence of resistance to state transitions in a first of a kind longitudinal study (Aim 1). To investigate a neurobiological basis of resistance to state transitions, we selectively decrease resistance to state transitions using chemogenetic activation of orexinergic neurons that are critically involved in stabilization of sleep and wakefulness (Aim 2). To determine whether resistance to state transitions is causally linked to restoration of cognition, we use a behavioral test of sustained attention (SA) performed immediately upon recovery after anesthesia. Our published results indicate that SA is dramatically disrupted after recovery from anesthesia in human volunteers. We determine if increased resistance to state transitions is associated with greater impairment on SA performance after emergence in mice. We attempt to restore normal SA performance by modulating resistance to state transitions using chemogenetic activation of orexinergic neurons (Aim 3). In summary, we develop a qualitatively novel measure of personalized, rather than population-based anesthetic responses: resistance to state transitions. We determine the neurobiological underpinnings of resistance to state transitions, and investigate its relationship to subsequent cognitive recovery. Thus, we offer a critical first s...