Anaesthesia and saccadic eye movements - Wiley Online Library

Anaesthesia, 2000, 55, pages 877±882 ................................................................................................................................................................................................................................................

R E V I E W A RT I C L E

Anaesthesia and saccadic eye movements O. A. Khan,1 S. R. J. Taylor1 and J. G. Jones2 1 Senior House Officer, and 2 Professor of Anaesthesia, University Department of Anaesthesia, Addenbrooke's Hospital, Box 93, Hills Road, Cambridge CB2 2QQ, UK Summary

During the last 10 years, there has been a vast increase in day-case surgery under general anaesthesia, but this has not been accompanied by research into the residual cognitive and motor effects during recovery from anaesthesia. Part of the explanation for this phenomenon is the lack of a suitable biophysical monitor of anaesthetic sedation. This review discusses one of the most commonly used of these biophysical monitors ± namely saccadic eye movements. In particular, the efficacy of peak saccadic velocity as a monitor of sedation will be evaluated. In addition, the physiology and pharmacology of saccadic eye movements will be discussed within the context of developing other parameters of saccadic eye movements as novel biophysical monitors of anaesthetic sedation. Keywords

Monitor, biophysical: saccadic eye movement. Sedation. Anaesthesia: recovery.

................................................................................................. Correspondence to: Professor J. G. Jones Accepted: 15 November 1999

The ocular motor system has been investigated by physiologists as a model for the somatic motor system. The principal attraction is that it has easily definable neural inputs, with no appreciable stretch reflex (as compared with the highly specialised muscle spindle apparatus seen in voluntary muscle), together with an output consisting of a limited repertoire of stereotypical, easily recordable movements. Moreover, the system is capable of producing movements which are modulated by a number of `higher executive' cortical inputs, and these inputs themselves appear to be structured in a hierarchical fashion. These features make the ocular motor system an ideal tool for investigating not only the motor system, but also the impairment of higher neural control systems. Not surprisingly, these characteristics have meant that the performance of ocular motor system has also been used as a psychophysiological monitor of both the effects of low-dose anaesthetic agents and recovery from anaesthesia. This review aims to discuss the best characterised of these movements, namely saccadic eye movements, and summarise the known effects of anaesthetic agents on various parameters of these movements, as well the dose dependency of these relationships. In addition, the probable mode of action of these anaesthetics will be discussed in the context of neurophysiological models of q 2000 Blackwell Science Ltd

oculomotor function. Finally, the utility of previously unexamined oculomotor monitors of anaesthesia will be evaluated. Classification of eye movements

Eye movements can be divided physiologically into two main classes: 1 Gaze-holding movements: These refer to reflex movements which prevent retinal slip during head movements. In humans, two such reflex movements have been characterised, namely the vestibuloocular reflex (VOR) and the opto-kinetic reflex (OKR). These reflexes differ with respect to the mechanism by which head movement is sensed, and have been the focus of much research in the investigation of cerebellar function. 2 Gaze-shifting movements: Of these, the best characterised are saccades, which will be the focus of this review. These refer to rapid, semivoluntary conjugate, gaze-shifting movements designed to centre a target of interest onto the fovea. Experimentally, these movements can be produced by instructing a subject to follow a target which is made to jump horizontally and instantaneously from one point to 877

O. A. Khan et al. Anaesthesia and saccadic eye movements Anaesthesia, 2000, 55, pages 877±882 ................................................................................................................................................................................................................................................

another. Of all the eye movements, saccades best exemplify the importance of higher cognitive centres on primitive eye movements, and as such have been of interest to a number of researchers. The exact mechanism by which saccades are controlled will be discussed later in this review. In contrast, smooth pursuit movements are tracking movements which match retinal slip velocity to the velocity of moving targets, and are entirely voluntary. Finally, vergence movements are disconjugate eye movements, which adjust the eyes for viewing different distances in depth, and are closely related to accommodation. Analysis of the performance of the oculomotor system is aided by the fact that, as outlined above, most eye movements are `goal-focused'. Hence, by identifying and standardising a particular visual stimulus known to elicit a particular eye movement, it is possible to experiment on the effects of drugs on consistent, comparable parameters of these movements (such as velocity, duration, accuracy and reaction time). Measurement of eye movements

The development of electronics and computer technology have greatly aided the generation of appropriate visual stimuli, and in particular the recording of eye movements themselves. Though many techniques for recording these movements have been described, only two have extensively been used in humans, namely: 1 Electro-oculography (EOG) [1, 2]. This technique relies on detecting changes in the ocular electrical field, which occur as a consequence of a change in eye displacement.

2 Infrared oculometry. This technique measures eye movement by detecting infrared reflection from the scleral±limbic junction. Although the EOG is more widely used than infrared reflection, there are in fact several practical and theoretical reasons why infrared recording should be the preferred method of oculometry. First, this technique is less invasive than the EOG; and perhaps more importantly, there is some evidence that it may also allow higher resolution recording [1]. Another potential advantage in utilising infrared reflection recording techniques is the possibility that drugs, and in particular anaesthetic agents, may affect the sensitivity of the EOG by altering the ocular electrical field; surprisingly, this phenomenon has yet to be investigated. Generation of appropriate visual stimuli has been revolutionised by advances in computer technology. For example, in the case of saccadic eye movements, typically, a target dot is projected by the computer onto a monitor, and made to jump instantaneously horizontally. However, this experimental arrangement has in the past been cumbersome, and hence has not been used outside a laboratory setting. This lack of portability is clearly an impediment to developing saccadic eye movements as a practical measure of anaesthetic sedation for postoperative patients. We have recently been using a new mobile saccade monitoring system (SPIC) [3]; this is shown in Fig. 1. As can be seen, the visual stimuli are displayed on a compact LED display, and the eye movements themselves are monitored through an infrared oculometer. The inputs to the LED, as well as the analysis of the data from the oculometer, are carried out by a laptop computer. This system is highly portable and hence may in fact prove to be of practical use in a clinical setting.

Figure 1 An example of the apparatus used

by our laboratory to record saccadic eye movements.

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Anaesthesia, 2000, 55, pages 877±882 O. A. Khan et al. Anaesthesia and saccadic eye movements ................................................................................................................................................................................................................................................

Saccadic eye movements

Given that saccadic eye movements have been shown to be the fastest movement the body musculature is capable of making [4], it is not surprising that peak saccadic velocity is the parameter most commonly used to quantify saccadic performance. Aschoff [5] was the first to illustrate the depression of saccadic peak velocity following administration of diazepam; since then many groups have shown similar effects with a variety of drugs, including chlorpromazine [6], ethanol [7] and carbamazepine [8]. However, the first attempt to quantify the effects of anaesthetic agents was undertaken by Gao et al. [9], who showed that peak saccadic velocity varied linearly with the log10 of propofol concentration. Further work by this group using inhalation anaesthetics [10] showed that low concentrations of isoflurane depressed peak saccadic velocity (a relationship which was later characterised as being dose dependent for concentrations up to 10% MAC [11]), whilst equi-MAC concentrations of nitrous oxide had no effect on peak saccadic velocity. Subsequent work by Yoshizumi et al. [12] showed that dose-equivalent concentrations of both halothane and cyclopropane both decreased peak saccadic velocity in a dose-related fashion, but that cyclopropane had significantly less efficacy than halothane. Moreover, Gao et al. [9] have shown that nitrous oxide has no effect on the value of the peak saccadic velocity for concentrations up to 10% MAC. Quite why nitrous oxide and cyclopropane do not have a significant effect on saccadic velocity is unclear. Yoshizumi et al. [12] have suggested that this phenomenon is a consequence of the stimulatory effect of these two agents on the sympathetic nervous system; however, no study has demonstrated a significant role for the sympathetic system in controlling saccadic eye movements, making this explanation somewhat tendentious. Moreover, it appears that thiopental, in contrast to all the anaesthetic agents previously discussed, does depress saccadic velocity, but not in a dose dependent manner [13]. Indeed, the unpredictable effect of many anaesthetic agents on saccadic velocity is more likely to be a consequence of the nonspecific nature of these agents on receptor systems rather than idiosyncrasies in saccade generation. Three questions are of interest in reviewing this information: 1 How well does peak saccadic velocity compare with other psychological monitors of anaesthetic sedation? 2 How well does peak saccadic velocity compare with other physiological monitors of anaesthetic sedation? 3 What other saccadic parameters have been tested as monitors of anaesthetic sedation? The answer to the first question is fairly clear-cut: certainly peak saccadic velocity has been shown to be q 2000 Blackwell Science Ltd

superior to psychological monitors of anaesthetic sedation. Yoshizumi et al. [12] showed that self-evaluation of subjective criteria such as headache, nausea and odour detection, as well as more detailed visual analogue scoring (where volunteers were asked to rate their level of sleepiness on a scale of 1±10), failed to differentiate the effects of inhalation of halothane or cyclopropane from air. In addition, Paut et al. [14] showed that visual analogue scoring for a battery of psychological and physiological monitors were a poorer monitor of recovery from anaesthesia following injection of 0.15 mg.kg21 of midazolam than peak saccadic velocity. However, the evidence of the superiority of peak saccadic velocity over physiological monitors of anaesthetic sedation is less clear. Indeed, it was initially proposed [15] that changes in critical flicker fusion threshold (namely the frequency at which a flickering light gives rise to the subjective sensation of steady light) was the best psychometric test for monitoring sedation. However, recent studies have cast serious doubts on this suggestion. For example, Griffiths [16] has shown that peak saccadic velocity is altered by far smaller doses of midazolam than the critical flicker fusion threshold. More recently, Yoshizumi et al. [11] detected only a nominal reduction in critical flicker fusion threshold at 15% MAC concentration of isoflurane ± at this concentration the peak saccadic velocity is reduced by 30%. The situation is yet more unclear with regard to another traditional physiological measure of sedation ± the choice reaction test (CRT). In this test, a subject scans an array of lights which are randomly illuminated, and the recognition time of the subject is recorded. Tedeschi et al. [17] has shown that whilst meptazinol reduces peak saccadic velocity, it has no effect on CRT, suggesting that peak saccadic velocity is a more sensitive monitor of sedation. However, the validity of this observation with regard to volatile anaesthetics was challenged by Yoshizumi et al. [11], who concluded that CRT was a better measure of depth of sedation than peak saccadic velocity for isoflurane concentrations greater than 10% MAC. More confusingly, this group also concluded in the same experiments that peak saccadic velocity is a more sensitive measure of recovery from the effects of low-dose isoflurane. This raises the prospect that the sedation states which occur during induction and recovery from anaesthesia are in fact two quantitatively distinct states which can be monitored separately by different biophysical measures. To date, there has been no real attempt to investigate this possibility ± Paut et al. [14] have recently shown that peak saccadic velocity is more sensitive than CRT in measuring recovery from midazolam injection (in keeping with the observations of Yoshizumi et al.) but 879


no attempt was made to compare CRT and peak saccadic velocity as a monitor of sedation during induction. The answer to the final question, i.e. what is the role of other saccadic parameters as a measure of depth of anaesthesia, is interesting and merits some detailed discussion. Unfortunately, most research has concentrated on peak saccadic velocity, almost to the exclusion of any other saccadic characteristic; indeed, the only other saccadic parameter that has been investigated to any degree is saccadic latency. Even so, to date, there have only been two studies which assessed the utility of latency as a monitor of benzodiazepine-induced sedation. Paut et al. [14] showed that saccadic latency is a useful monitor of recovery from anaesthesia following administration of midazolam, but that it is a less sensitive monitor than peak saccadic velocity. In contrast, Padoan et al. [13] have shown that though saccadic latency and peak saccadic velocity are both affected by diazepam, neither appears to be affected in a dose-dependent manner. To date, there has been no study to assess the role of latency as a monitor of sedation by volatile agents ± we have recently shown that isoflurane does increase latency, but we have yet to characterise the dose dependency of this response [18]. In terms of the remaining saccadic parameters, there is, unfortunately, virtually no evidence as to their utility as monitors of anaesthetic sedation. Yoshizumi et al. [11] have looked at saccadic error and concluded that this is a more sensitive monitor of sedation than peak saccadic velocity at concentrations of isoflurane greater than 10% MAC; however, no group has attempted to replicate these results with other volatile or nonvolatile agents. We have recently been investigating the effects of isoflurane on a hitherto untested saccadic parameter ± namely the ability of subjects to inhibit saccades. Though we have demonstrated that isoflurane does alter this ability [18, 19], we have not, as yet, characterised the dose±response of this relationship, and hence we are unable to compare the sensitivity of this parameter with peak saccadic velocity.

Anaesthetic mechanisms of action

Given the nonspecific nature of most anaesthetic agents, it is difficult to ascribe a precise physiological and pharmacological site for their mode of action on saccadic eye movements. However, advances in the elucidation of the physiological basis of saccade generation and control have led to development of various theoretical models [20], within whose constructs one can attempt to ascertain the effect of a particular anaesthetic agent. A highly simplified model of saccadic generation is shown in Fig. 2. As shown, the process of saccadic generation may divided into several stages: 1 The retina detects a possible target outside the fovea. 2 A decision is made to centre the fovea on this target position, i.e. a decision is made to generate a saccade. 3 A particular motor programme is selected depending on a variety of inputs, including superior colliculus, basal ganglia, cerebellum, thalamus and cortex. 4 Enaction of this motor programme to produce a saccade is accomplished through the simultaneous stimulation of a population of burst neurones and inhibition of pause neurones (which are believed to exert a tonic inhibitory effect on saccadic eye movements [21]). 5 Impulses are sent to the extra-ocular muscles to perform a saccade; this mechanical system is heavily damped. Within this model of saccade generation, it is possible to draw some conclusions as to the likely action of drugs which reduce the peak saccadic velocity. From a purely theoretical point of view, this reduction must be the consequence of either a `central effect' (in other words, a change in the selection of motor program) or a `peripheral effect' (directly affecting either the burst neurone firing pattern or the extra-ocular muscles). Several lines of evidence seem to suggest that it is changes to the `central' mechanism which is predominantly responsible for anaesthetic-mediated peak saccadic velocity depression. For example, it has long been observed that a subjective reduction in alertness causes a reduction

Figure 2 A model of saccade generation

based on the Robinson model [20].

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Anaesthesia, 2000, 55, pages 877±882 O. A. Khan et al. Anaesthesia and saccadic eye movements ................................................................................................................................................................................................................................................

in peak saccadic velocity, and some researchers have drawn analogies between this effect and that of drug depression of peak saccadic velocity. Moreover, it has been shown that memory specified saccades (where the subject makes a saccade to a target which has disappeared shortly after an initial presentation) show a reduced peak saccadic velocity [22]. It has therefore been postulated that visual targets enhance cellular firing in the superior colliculus, tending to alter the selection of motor program to one with increased saccadic velocity. This would imply that the reduction in peak saccadic velocity seen in anaesthetic sedation may simply be a consequence of a reduction in visual attention towards a target. However, this view is by no means universal ± Padoan et al. [13] have suggested that the depression in peak saccadic velocity seen following diazepam administration may be due to both the specific action of this agent on brain stem neurones (presumably the burst neurones) as well as a `central' sedative effect of this agent. Indeed, given the apparently idiosyncratic action of certain anaesthetic agents on peak saccadic velocity, it is likely that peak saccadic velocity reductions are mediated by both these mechanisms, with various agents having differing effects on each of these mechanisms. The issue of ascribing a site of action to an anaesthetic agent that prolongs saccadic latency is more complex. At a basic level, the prolongation of latency must be due to either: 1 An increase in the time taken to select an appropriate motor program. 2 The time taken to execute this program. An increase in the time taken to execute the motor program could be due to increased stimulation of the pause cells, reduced stimulation of the burst cells or indeed a slowing of neural transmission itself. However, there is as yet no direct evidence that any of these mechanisms does occur. If we consider the selection process, it is clear that any change would have to act at the level of the cortical and subcortical inputs influencing the motor program library. In fact, Robinson [20] proposed that the basal ganglia provide the most important input, acting so as to facilitate or block potential saccades. Interestingly, work by several groups has shown that saccadic latency is increased by a variety of conditions including Parkinson's disease [23], human MPTP-induced parkinsonian syndrome [24] and Alzheimer's disease [25], and that in each of these conditions, degenerative changes are seen in the basal ganglia. It is possible that anaesthetic agents which do increase latency act in an analogous fashion to these degenerative diseases, temporarily impairing basal ganglia function. If this is indeed the mechanism of action of anaesthetic q 2000 Blackwell Science Ltd

agents, this raises an interesting point. The high latency associated with normal saccadic generation has been said by some researchers to be due to saccadic procrastination [26], i.e. there is a long delay between the generation and execution of a saccade during which inhibition may occur, allowing the cancellation of unnecessary saccades to inappropriate targets. By increasing latency, anaesthetic agents may allow a longer `cancellation period', hence aiding voluntary inhibition of saccades. We have recently tested this hypothesis using isoflurane, with mixed results [18, 19]. This may possibly be due to isoflurane affecting the cancellation process itself in addition to its effects on latency, with the two effects cancelling each other out. Our laboratory is still investigating these effects. Given the nonspecific nature of anaesthetic agents, it seems likely that the time taken to select a motor program and the time taken to execute it are both affected. In order to evaluate which of the two mechanisms is predominantly responsible for the prolongation of latency following administration of a particular anaesthetic agent, the statistics of latency distribution need to be studied in more detail. It is appropriate at this stage to briefly discuss the effects of anaesthetic agents on the other classes of eye movements. Unfortunately, in comparison with the wealth of data accumulated on the effects of anaesthetic agents on saccadic eye movements, there is a paucity of information on the effects of these agents on these other classes of eye movements. Indeed, in the case of both vergence movements and the opto-kinetic reflex, there has, to date, been no attempt to quantify the effects of anaesthetic sedation on these movements. In the case of smooth pursuit, however, Padoan et al. [13] have shown that diazepam and thiopental both reduce the gain of the tracking movements of the eye. Similarly, Schalen et al. [27] have shown that intravenous administration of these two agents reduce the gain of the vestibulo-ocular reflex. Nonetheless, even with these two classes of eye movement, there has not been enough work done on a large enough number of anaesthetic agents for any definitive conclusion to be drawn as to their utility as monitors of anaesthetic sedation. Conclusions

It is clear that saccadic eye movements do provide a useful system for the evaluation of both induction and recovery from anaesthetic sedation. Though there is certainly good evidence that peak saccadic velocity is a sensitive monitor of benzodiazepine-induced sedation, the situation with regard to volatile agents is more equivocal. Whilst saccadic latency has shown some initial promise as a monitor of 881


benzodiazepine-induced sedation, there is not as yet enough evidence to draw any conclusions as to their role in monitoring the effects of volatile agents. Moreover, the utility of other saccadic parameters such as saccadic error and saccadic inhibition is only now being evaluated, and research in this field may not only assess their efficacy as monitors of sedation but may also provide some insight into the mechanisms of actions of anaesthetics on the neural substrates of saccade generation. Indeed, until further research is carried out in this area, it is impossible to make a definitive statement as to which of all the saccadic parameters is the most sensitive measure of anaesthetic-induced sedation.

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