Relationship of Autonomic Nervous System Activity to Daytime Sleepiness and Prior Sleep

Transcription

1 Sleep 12(3): , Raven Press, Ltd., New York 1989 Association of Professional Sleep Societies Relationship of Autonomic Nervous System Activity to Daytime Sleepiness and Prior Sleep Mark R. Pressman and June M. Fry Sleep Disorders Center, Department of Neurology, The Medical College of Pennsylvania at Eastern Pennsylvania Psychiatric Institute, Philadelphia, Pennsylvania, U.S.A. Summary: Autonomic nervous system (ANS) measures have been used frequently as measures of activation or arousal. However, their relationship to standard measures of alertness-the Multiple Sleep Latency Test (MSL T) and Stanford Sleepiness Scale (SSS}-and to the quantity and quality of prior sleep has not been determined. In this study, the direct pupil light reflex (PLR) was measured with the MSL T and SSS to determine how ANS activity varies with daytime sleepiness and how all three measures were related to prior nocturnal sleep in a group of patients with obstructive sleep apnea. When the effects of age and time of day were partialed out, PLR data suggest that increased sleepiness as measured by MSL T is significantly correlated with increased parasympathetic activity (r = , p < 0.01) and not with decreased sympathetic activity (r = -0.24, not significant). These partial correlations were significantly different (p < 0.05). Increased sleepiness as measured by the SSS was significantly correlated with decreased sympathetic activity (r = , p < 0.05) and not with increased parasympathetic activity (r = -0.00, not significant). These partial correlations were significantly different (p < 0.02). In the group of sleep apnea patients, the PLR suggests that increased number of apneas and hypopneas (sleep fragmentation) was significantly correlated with both decreased sympathetic activity and increased parasympathetic activity. These findings suggest that ANS activity is related to daytime sleepiness and to the quality of prior sleep. Key Words: Sleepiness-Pupil light reflex Autonomic nervous system-sleep. Autonomic nervous system (ANS) activity is hypothesized to vary in intensity along a continuum from vigorous activity, intense emotion, and high alertness to calmness and sleep (1). Measures of ANS activity have been used extensively in the study of arousal and activation (2-6). However, the relationship of ANS activity to alertness and to prior sleep has never been directly tested using current measurement techniques such as polysomnography (PSG), the Multiple Sleep Latency Test (MSLT), or the Stanford Sleepiness Scale (SSS) (7,8). Address correspondence and reprint requests to Dr. M. R. Pressman at Sleep Disorders Center, Department of Neurology, The Medical College of Pennsylvania at EPPI, 3200 Henry Avenue, Philadelphia, PA 19129, U.S.A. 239

2 240 M. R. PRESSMAN AND J. M. FRY The pupil, controlled by the ANS, is sensitive to changes in alertness. It is generally large during alertness, small and unstable during sleepiness, and miotic or fissurated during sleep (9-11). Baseline changes of pupil size and activity have been used as measures of fatigue and for the diagnosis and treatment of narcolepsy (12-14). A prior study suggested that daytime sleepiness and nocturnal sleep disruption may be the cause of senile miosis (15). Another method of recording pupil behavior, the direct pupil light reflex (PLR), appears to be better suited for the study of ANS function and alertness (16). The PLR consists of pupillary changes evoked by a flash of light. The hypothetical dynamics of the PLR and the derived origins of the PLR components are based largely on anatomical studies in the cat and rat. The efferent pathway of the PLR begins in a group of parasympathetic pupiloconstrictor neurons in the area of the Edinger-Westphal nucleus in the midbrain (17,18). These pupiloconstrictor neurons fire autochthonously if not actively inhibited (19). Putatively sympathetic neurons in the cortex, hypothalamus, and/or reticular-activating formation are thought to provide supranuclear inhibition (16). A brief flash of light transiently removes this inhibition so that the parasympathetic pupiloconstrictor neuron activity increases and the pupil constricts (20,21). The constriction phase of the PLR is thought to reflect purely parasympathetic activity (17,18,22,23). The rate of constriction, assuming sympathetic activity is completely inhibited, reflects the rate and number ofpupiloconstrictor neurons firing (20,21). With the termination of the light flash, supranuclear inhibition returns, constriction of the pupil slows and stops, and the pupil redilates. The mechanisms controlling the rate of redilation are not known but probably reflect the number and rate of firing of sympathetic neurons. The PLR thus will permit independent measurement of parasympathetic and sympathetic components of the ANS and not just the balance between them. This study is a first step in determining if waking ANS activity, as measured by the PLR, is related to the quantity and quality of prior sleep, and to alertness as measured by MSLT and SSS, the standard techniques for the measurement of sleepiness. Preliminary results of this study have been previously reported (24). METHODS Subjects were 16 men and three women, with a mean age of 50.2 years, selected from 29 consecutive patients being evaluated for a complaint of excessive daytime sleepiness. The 19 subjects were selected because they were free of central nervous system drugs that might affect the PLR and had a clinical sleep disorder that reduced the quantity or quality of sleep. These disorders included; obstructive sleep apnea (15 subjects), periodic leg movements in sleep (nocturnal myoclonus) (three subjects), and insufficient sleep (one subject) (25). Protocol All subjects had one night of clinical polysomnography including electroencephalography (EEG) (CCA 1, A 2 ), electrooculography (right and left outer canthi), chin electromyography (EMG) (bilateral mentalis muscle), leg EMG (right and left anterior tibialis muscles), electrocardiography (ECG), airflow measurement (right and left nares and mouth), respiratory effort measurement (intercostal EMG), and oximetry. During the following day, all subjects had a 4-nap MSLT beginning 2 h after arising and continuing at 2-h intervals (8). For each nap opportunity, the subject was put to bed in

3 ANS ACTIVITY AND SLEEPINESS 241 a darkened room and instructed to try to fall asleep. During this time EEG (C 4 -A 1, A 2 ), electrooculogram (right and left outer canthi), and chin EMG (bilateral mentalis muscle) were continuously recorded. Testing was terminated -10 min after sleep onset or after 20 min.of recording time without sleep. Due to the fragmentation of sleep by apneas and hypopneas during the nap opportunity, sleep onset was defined as the first 10 s of sleep. All subjects gave informed consent. The PLR was done prior to the second or third MSLT nap opportunity. Subjects first indicated their current level of subjective alertness using the SSS (7). The SSS consists of seven statements indicating level of alertness. A score of 1 indicates maximum alertness, and a score of 7 indicates maximum sleepiness. They were then seated in front of the pupillometer (Iriscorder C2515; Hamamatsu Corp., Bridgewater, NJ) with their chin on the chin rest. Following 3 min of dark adaptation, they were instructed to focus on a dim asterix visible in the camera lens via a reflex mirror system. A light of -1 foot candle intensity was flashed for 1/4 s using the same reflex mirror system, and pupil area was measured for 6 s. Mter an additional minute of darkness, a light of -17 foot candle intensity was flashed for 1/4 s and pupil area was measured for 6 s. Following each light flash, pupil area was analyzed on line and graphed on paper. Prior to PLR measurement, the subject was instructed not to blink for 6 s after the light flash. Data analysis The PSG was analyzed using standard techniques and total sleep time, total wake time, and the total number of apneas, hypopneas, or periodic leg movements determined (26-28). The sleep latency was determined for each nap in the MSLT and a mean MSLT score computed. The PLR was analyzed and the following component variables extracted: (a) initial pupil area, (b) extent of constriction, (c) constriction velocity, and (d) redilation velocity (Fig. O. Statistical procedures The distribution of all variables was initially examined for skew and kurtosis. Partial residual scatterplots of correlated variables were generated to examine possible nonlinearity. N 60 E 50 E 0 40 Initial pupil area + + CI)... «light 30 flash 0. ::l CL 20 ~l..,,", " I constriction con- t ~ striction phose redilalion phose o 2 Seconds FIG. 1. Pupil light reflex. 3 4

4 242 M. R. PRESSMAN AND J. M. FRY Partial correlation coefficients were computed for components of the PLR with the mean MSLT latency and SSS controlling for time of day of the PLR and subject age for all 19 subjects. Age of all subjects was controlled for because of reports that pupil diameter decreases significantly with age (29). Pupil test time was controlled for because of reports that the PLR may show circadian variation (30). Partial correlation coefficients were computed for each PLR component, mean MSLT latency, and SSS with total sleep time, total wake time, and total number of apneas plus hypopneas for the 15 subjects with obstructive sleep apnea while controlling for age and the test time of the PLR and SSS. MSL T test time was not controlled for because mean MSLT latency represents sleepiness across an 8-h period. RESULTS Of all the variables examined for possible skew and kurtosis, only the SSS exhibited significant skew (skew = 1.338, Z = 2.55). This was not considered sufficient to affect the correlations. None of the variables exhibited significant kurtosis. Partial residual scatterplots of correlated variables were examined, and nonlinear relationships were judged to be absent. Table 1 shows the partial correlation coefficients for PLR components with the MSLT and SSS. The MSLT was significantly correlated with constriction velocity, a measure of parasympathetic activity. The SSS was significantly correlated with redilation velocity, a measure of supranuclear inhibition or putative sympathetic activity. The SSS was not significantly correlated with the mean MSLT (r = 0.13, ns). The difference between the two partial correlation coefficients-mslt and constriction velocity versus MSL T and redilation velocity-was tested and found to be significant (I = , p < 0.05). Additionally, the difference between the two partial correlation coefficients-sss and constriction velocity versus SSS and redilation velocity-was also found to be significant (t = 2.64, p < 0.02). Table 2 shows the partial correlation coefficients for the PLR components and mean MSLT sleep latency with total sleep time, total wake time, and the number of apneas plus hypopneas in the 15 subjects with obstructive sleep apnea. An increase in the total number of apneas plus hypopneas was correlated with a decrease in supranuclear inhibition or sympathetic activity and an increase in parasympathetic activity. Table 3 contains the sleep data for the 15 subjects with sleep apnea. Pupil light reflex data for the entire group are shown in Table 4. TABLE 1. Partial correlation coefficients for pupil light reflex components with the mean sleep latency of the MSLT and SSS controlling for age and time of day of pupil testing (n = 19) PLR components Initial pupil area Extent of constriction Constriction velocity Redilation velocity Mean MSLT ** a SSS O.OOb -0.46* * p < ** p < a Partial correlations (-0.60 versus -0.24) significantly different, p < b Partial correlations (-0.00 versus -0.46) significantly different, p < on 03 September Sleep, Vol , No.3, 1989

5 ANS ACTIVITY AND SLEEPINESS 243 TABLE 2. Partial correlation coefficients for components of the direct PLR and mean sleep latency of the MSLT with nocturnal sleep variables controlling for age and time of pupillary testing (n = 15). Partial correlation coefficients for the MSLT with nocturnal sleep variables are provided controlling for age alone Initial pupil area Extent of constriction Constriction velocity Redilation velocity Mean MSLT * p < ** p < Total sleep time Total wake time Apneas + hypopneas * 0.58** * DISCUSSION These findings suggest that ANS activity as measured by the PLR is sensitive to changes in prior sleep and is related to current levels of daytime sleepiness when the effects of age and time of day are removed. The significant correlations of the MSLT and SSS with different components of the PLR suggests that the neurophysiological mechanisms associated with objectively (MSLT) and subjectively (SSS) measured sleepiness may be different in patients with disorders of excessive daytime sleepiness secondary to fragmented or insufficient sleep. Sleepiness as measured by the MSLT is associated with an increase in parasympathetic activity as indicated by an increased constriction velocity. An increase in subjectively measured sleepiness, on the other hand, is associated with a decrease in supranuclear inhibition or sympathetic activity as measured by the decreased redilation velocity. The mean sleep latency of the MSLT did not show a significant correlation with the SSS in this group of patients. A lack of correlation between objectively and subjectively measured daytime sleepiness has been previously reported and attributed to a changing frame of reference as to what constitutes alertness (31). These findings suggest that this difference may be secondary to differences in parasympathetic and sympathetic activity. PLR components also correlated significantly with the number of apneas plus hypopneas during the prior night's sleep, as did the MSLT. The PLR data indicated that an increase in the number of apneas plus hypopneas is associated with an increase in TABLE 3. Sleep data for 15 subjects with sleep apnea Time in bed (min) Total sleep time (min) Sleep efficiency (%) Stage 1 (min) Stage 2 (min) Stage 3 (min) Stage 4 (min) REM (min) Latency to stage 1 (min) Wake after sleep onset (min) Respiratory events (apneas + hypopneas) Respiratory event index (events per hour of sleep) Mean MSLT Mean SD ± ± ± ± ± ± ± ± ± ± ± ± ± 3.9 Range

6 244 M. R. PRESSMAN ANDJ. M. FRY TABLE 4. PLR data Initial pupil area (mm 2 ) Extent of constriction (mm 2 ) Constriction velocity (mm2/sec) Redilation velocity (mm2/sec) Mean SO 34.5 ± ± ± ± 2.0 Range parasympathetic activity and a decrease in supranuclear inhibition. Neither the PLR or the MSLT showed any correlation with total sleep time or total wake time. This lack of correlation may be due to the inaccurate determination of wake time by standard sleep staging techniques when sleep is severely fragmented by apneas and hypopneas. Typically, total sleep time is overscored, because the intrusions of wakefulness, though frequent, are too short to be scored. Other researchers have stated that although the MSLT may measure the intensity of sleepiness, it is not useful in characterizing the quality or etiology of sleepiness (32). The mean sleep latency measurement of the MSLT does not differentiate between sleepiness of sleep deprivation, obstructive sleep apnea, or narcolepsy (33). The high correlation of PLR components with the MSLT and SSS suggests that measurement of ANS activity may prove to be a useful adjunct to current techniques in providing additional information about the quality or etiology of sleepiness. However, this remains to be substantiated with further research. These data suggest that ANS activity as measured by the PLR does vary with the level of daytime sleepiness as measured by current techniques and with the quality of prior sleep. Thus, as predicted by classical theories of arousal, ANS activity does appear to reflect activity along the continuum from deep sleep to high alertness. Acknowledgment: This research was supported in part by the Department of Public Welfare, Commonwealth of Pennsylvania. We gratefully acknowledge the loan of the Iriscorder, Model C2515 by the Hamamatsu Corporation, Bridgewater, NJ and the technical assistance of Mark A. DiPhillipo, R.PSG.T. and Rosemary Durante, R.PSG.T. REFERENCES I. Thayer RE. Toward a psychological theory of multidimensional activation (arousal). Motivation and Emotion 1978;2: Gale A, Edwards J. Introduction. In: Gale A, Edwards J, eds. Physiological correlates of human behavior (Vol. 2, attention and performance). New York: Academic Press, 1983: Duffy E. Activation and behavior. New York: Wiley, Malmo RB. Activation: a neuropsychological dimension. Psychol Rev 1959;66: Parasuraman R. Vigilance, arousal and the brain. In: Gale A, Edwards J, eds. Physiological correlates of human behavior (Vol. 2, attention and performance). New York: Academic Press, 1983: Thayer RE. Activation states as assessed by verbal report and four psychophysiological variables. Psychophysiology 1970;7: Hoddes E, Zarcone V, Smithe H, Phillips R, Dement WC. Quantification of sleepiness: a new approach. Psychophysiology 1973;10: Mitler MM. The multiple sleep latency test as an evaluation for excessive somnolence. In: Guilleminault C, ed, Sleeping and waking disorders: indications and techniques.. Menlo Park, California: Addison Wesley Publish Co., 1982: Duke-Elder, S. System of ophthalmology, vol. XII. Kimpton, London: Berlucchi G, Moruzzi G, Salvi G, Strada P. Pupil behavior and ocular movements during synchronized and de synchronized sleep. Arch Ital Bioi 1964;102: Pressman MR, Spielman AJ, Korczyn A, Rubinstein A, Pollak CP, Weitzman ED. Patterns of daytime sleepiness in narcoleptics and normals: a pupillometric study. Electroencephalogr Clin Neurophysiol 1984;57:

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