James F. Cheeseman

General anesthesia alters time perception by phase shifting the circadian clock

Following general anesthesia, people are often confused about the time of day and experience sleep disruption and fatigue. It has been hypothesized that these symptoms may be caused by general anesthesia affecting the circadian clock. The circadian clock is fundamental to our well-being because it regulates almost all aspects of our daily biochemistry, physiology, and behavior. Here, we investigated the effects of the most common general anesthetic, isoflurane, on time perception and the circadian clock using the honeybee (Apis mellifera) as a model. A 6-h daytime anesthetic systematically altered the time-compensated sun compass orientation of the bees, with a mean anticlockwise shift in vanishing bearing of 87° in the Southern Hemisphere and a clockwise shift in flight direction of 58° in the Northern Hemisphere. Using the same 6-h anesthetic treatment, time-trained bees showed a delay in the start of foraging of 3.3 h, and whole-hive locomotor-activity rhythms were delayed by an average of 4.3 h. We show that these effects are all attributable to a phase delay in the core molecular clockwork. mRNA oscillations of the central clock genes cryptochrome-m and period were delayed by 4.9 and 4.3 h, respectively. However, this effect is dependent on the time of day of administration, as is common for clock effects, and nighttime anesthesia did not shift the clock. Taken together, our results suggest that general anesthesia during the day causes a persistent and marked shift of the clock effectively inducing “jet lag” and causing impaired time perception. Managing this effect in humans is likely to help expedite postoperative recovery.

Way-finding in displaced clock-shifted bees proves bees use a cognitive map

Significance The question of the computational capacities of the brains of widely separated genera of animals is of interest to behavioral biologists, comparative psychologists, computational neuroscientists, philosophers of mind, and—we believe—much of the scientific community. Half a century ago, the claim that any nonhuman animal had a cognitive map was deeply controversial. If true, it greatly favored a computational theory of mind, as opposed to an antirepresentational behaviorist theory. Now that it is well established by behavioral and neurobiological evidence that rodents have a metric cognitive map, the question of whether insects do is a frontier question, the answer to which has broad implications in several disciplines. Mammals navigate by means of a metric cognitive map. Insects, most notably bees and ants, are also impressive navigators. The question whether they, too, have a metric cognitive map is important to cognitive science and neuroscience. Experimentally captured and displaced bees often depart from the release site in the compass direction they were bent on before their capture, even though this no longer heads them toward their goal. When they discover their error, however, the bees set off more or less directly toward their goal. This ability to orient toward a goal from an arbitrary point in the familiar environment is evidence that they have an integrated metric map of the experienced environment. We report a test of an alternative hypothesis, which is that all the bees have in memory is a collection of snapshots that enable them to recognize different landmarks and, associated with each such snapshot, a sun-compass–referenced home vector derived from dead reckoning done before and after previous visits to the landmark. We show that a large shift in the sun-compass rapidly induced by general anesthesia does not alter the accuracy or speed of the homeward-oriented flight made after the bees discover the error in their initial postrelease flight. This result rules out the sun-referenced home-vector hypothesis, further strengthening the now extensive evidence for a metric cognitive map in bees.

A simulation design for research evaluating safety innovations in anaesthesia

It is notoriously difficult to obtain evidence from clinical randomised controlled trials for safety innovations in healthcare. We have developed a research design using simulation for the evaluation of safety initiatives in anaesthesia. We used a standard and a modified scenario in a human‐patient simulator, involving a potentially life‐threatening problem requiring prompt attention – either a cardiac arrest or a failure in oxygen supply. The modified scenarios involved distractions such as loud music, a demanding and uncooperative surgeon, telephone calls and frequent questions from a medical student. Twenty anaesthetics were administered by 10 anaesthetists. A mean (SD) of 11.3 (2.8) errors per anaesthetic were identified in the oxygen failure scenarios, compared with 8.0 (3.4) in the cardiac arrest scenarios (ANOVA: p = 0.04). The difference between the combined standard scenarios and the combined modified scenarios was not significant. The mean rate of errors overall was 9.7 per simulation, with a pooled SD of 4.46, so in future studies 21 subjects would provide 80% statistical power to show a reduction in error rate of 30% from baseline with p≤0.05. Our research design will facilitate the evaluation of safety initiatives in anaesthesia.

Circadian rhythms and their development in children: implications for pharmacokinetics and pharmacodynamics in anesthesia.

The influence of time‐of‐day on the action and toxicity of drugs may be an important factor in the design of pharmacokinetic (PK) and pharmacodynamic (PD) studies, and the interpretation of data resulting from these studies. Time‐of‐day can have a profound influence on the action of drugs. In some settings (e.g. cancer chemotherapy), the timing of drug administration has been utilized to maximize therapeutic effect and minimize toxicity. Time‐of‐day variation in the action of anesthetic drugs has been clearly demonstrated in adults. For example, local anesthetic action is longest during the afternoon, and neuromuscular blockade by rocuronium lasts one‐third longer in the morning than the afternoon. Circadian rhythms develop over the first months and years of life. Robust rhythms in hormone production (e.g. melatonin and cortisol) are seen at approximately 3 months of age, but it remains unclear as to when daily rhythms in drug PK and PD first appear. Here, we review the evidence for time‐of‐day effects in anesthetic drugs in adults and children and outline the potential influence this has on pediatric anesthesia.

Circadian-Related Sleep Disorders and Sleep Medication Use in the New Zealand Blind Population: An Observational Prevalence Survey

Study Objectives To determine the prevalence of self-reported circadian-related sleep disorders, sleep medication and melatonin use in the New Zealand blind population. Design A telephone survey incorporating 62 questions on sleep habits and medication together with validated questionnaires on sleep quality, chronotype and seasonality. Participants Participants were grouped into: (i) 157 with reduced conscious perception of light (RLP); (ii) 156 visually impaired with no reduction in light perception (LP) matched for age, sex and socioeconomic status, and (iii) 156 matched fully-sighted controls (FS). Sleep Habits and Disturbances The incidence of sleep disorders, daytime somnolence, insomnia and sleep timing problems was significantly higher in RLP and LP compared to the FS controls (p<0.001). The RLP group had the highest incidence (55%) of sleep timing problems, and 26% showed drifting sleep patterns (vs. 4% FS). Odds ratios for unconventional sleep timing were 2.41 (RLP) and 1.63 (LP) compared to FS controls. For drifting sleep patterns, they were 7.3 (RLP) and 6.0 (LP). Medication Use Zopiclone was the most frequently prescribed sleep medication. Melatonin was used by only 4% in the RLP group and 2% in the LP group. Conclusions Extrapolations from the current study suggest that 3,000 blind and visually impaired New Zealanders may suffer from circadian-related sleep problems, and that of these, fewer than 15% have been prescribed melatonin. This may represent a therapeutic gap in the treatment of circadian-related sleep disorders in New Zealand, findings that may generalize to other countries.

Reply to Cheung et al.: The cognitive map hypothesis remains the best interpretation of the data in honeybee navigation

Cheung et al. (1) criticize two points of our study, both of which are unfounded. The first is that general anesthesia is not shifting the clock controlling sun compass orientation in bees. This is clearly wrong. We show that sun compass orientation and food anticipatory behavior are systematically shifted by anesthesia. This effect results from anesthesia shifting the underlying molecular circadian clock of the bee (2).

The effect of time of day on the duration of neuromuscular blockade elicited by rocuronium

In a prospective, observational trial, we investigated the influence of time of day on the duration of neuromuscular blockade (NMB) elicited by rocuronium. Forty‐nine patients scheduled for surgery between 08:00 and 02:00 were enrolled after giving written informed consent. Time to neuromuscular recovery was measured following three doses: (1) a fat‐free‐mass (FFM) related induction dose (0.6 mg.kg−1: n = 47); (2) a maintenance dose (20% of the induction dose: n = 42); and (3) a standard 10‐mg dose (n = 35). The extent of NMB was dependent on the time of administration (p = 0.038 General Linear Model Analysis). The maximum effect of 50 min (95% CI 41–59 min) was elicited between 08:00 and 11:00 and the minimum duration of 29 min (95% CI 23–35 min) between 14:00 and 17:00 (p = 0.005). A similar pattern was observed for the maintenance dose. The duration of action of rocuronium is influenced by time of day and this effect is of potential clinical significance and practical relevance to research.

Validating the use of wrist-level light monitoring for in-hospital circadian studies.

This clinical methods comparison study describes the difference between light levels measured at the wrist (Actiwatch-L) and at the eye (Daysimeter) in a postoperative in-patient population. The mean difference between the two devices was less than 10 lux at light levels less than 5000 lux. Agreement between the devices was found to decrease as eye-level light exposure increased. Measurements at eye level of 5000 lux or more corresponded to a difference between the devices of greater than 100 lux. Agreement between the eye- and wrist-level light measurements also appears to be influenced by time of day. During the day, the measurement differences were on average 50 lux higher at eye level, whereas at night they were on average 50 lux lower. Although the wrist-level monitor was found to underestimate light exposure at higher light levels, it was well tolerated by participants in the clinical setting. In contrast, the eye-level monitor was cumbersome and uncomfortable for the patients to wear. This study provides light-exposure data on patients in real conditions in the clinical environment. The results show that wrist-level monitoring provides an adequate estimate of light exposure for in-hospital circadian studies. (Author correspondence: g.warman@auckland.ac.nz)

A Honey Bee (Apis mellifera) Light Phase Response Curve

The authors report a phase response curve (PRC) for individual honey bees (Apis mellifera) to single 1-h light pulses (1000 lux) using an Aschoff Type 1 protocol (n = 134). The bee PRC is a weak (Type 1) PRC with a maximum advance of 1.5 h between circadian time (CT) 18 and 3 and a maximum delay of 1.5 h between CT 12 and 18. This is the first published honey bee light PRC and provides an important resource for chronobiologists and honey bee researchers. It may also have practical applications for what is an economically important species frequently transported across different time zones. (Author correspondence: G.warman@auckland.ac.nz)

The effects of the general anaesthetic isoflurane on the honey bee (Apis mellifera) circadian clock

ABSTRACT General anaesthesia administered during the day has previously been shown to phase shift the honey bee clock. We describe a phase response curve for honey bees (n=105) to six hour isoflurane anaesthesia. The honey bee isoflurane PRC is “weak” with a delay portion (maximum shift of –1.88 hours, circadian time 0 – 3) but no advance zone. The isoflurane-induced shifts observed here are in direct opposition to those of light. Furthermore, concurrent administration of light and isoflurane abolishes the shifts that occur with isoflurane alone. Light may thus provide a means of reducing isoflurane–induced phase shifts.