ment (REM) sleep and the activities of the hypothalamic-pituitary- adrenal axis and ... period (REM latency), and percentage of slow wave (stages 3 and 4) sleep.
0021-972X/97/$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1997 by The Endocrine Society
Vol. 82, No. 10 Printed in U.S.A.
Rapid Eye Movement Sleep Correlates with the Overall Activities of the Hypothalamic-Pituitary-Adrenal Axis and Sympathetic System in Healthy Humans ALEXANDROS N. VGONTZAS, EDWARD O. BIXLER, DIMITRIS A. PAPANICOLAOU, ANTHONY KALES, CONSTANTINE A. STRATAKIS, ANTONIO VELA-BUENO, PHILIP W. GOLD, AND GEORGE P. CHROUSOS Sleep Research and Treatment Center, Department of Psychiatry, Pennsylvania State University (A.N.V., E.O.B., A.K., A.V.-B.), Hershey, Pennsylvania 17033; and the Developmental Endocrinology Branch, National Institute of Child Health and Human Development (D.A.P., C.A.S., G.P.C.), and the Clinical Neuroendocrinology Branch, National Institute of Mental Health (P.W.G.), National Institutes of Health, Bethesda, Maryland 20892 ABSTRACT To assess the association of the overall amount of rapid eye movement (REM) sleep and the activities of the hypothalamic-pituitaryadrenal axis and sympathetic system, we performed polysomnography and measured 24-h urinary free cortisol and catecholamine excretion in 21 healthy adults. After an adaptation night, each subject was recorded in the sleep laboratory for 3 consecutive nights while 24-h urine specimens were collected. Urinary free cortisol, epinephrine, dihydroxyphenylglycol, and dihydroxyphenylacetic acid levels
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APID EYE movement (REM) sleep is a state of central nervous system activation that resembles unconscious wakefulness (paradoxical sleep). In healthy humans, REM sleep, cortisol secretion, and sympathetic system activity are increased during the latter part of the night (1, 2). In patients with melancholic depression, there are both REM sleep alterations, including reduced REM latency and increased amount of REM sleep and density during the first sleep cycle (3), and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) (4, 5). These data suggest that the activity of the HPA axis and that of the sympathetic system might increase during REM sleep. However, several studies based on serial, every 10 –30 min measurements of plasma cortisol reported that REM sleep was mostly present when cortisol concentrations were decreased (6, 7) and that there was a reduction of sympathetic system activity during REM sleep (8, 9). The goal of our study was to examine the relationship of the overall amount of REM sleep and other sleep stages to integrative measures of HPA axis and SNS system activity, i.e. 24-h urinary free cortisol (UFC) and catecholamine excretion. Received April 29, 1997. Revision received June 24, 1997. Accepted June 27, 1997. Address all correspondence and requests for reprints to: Alexandros N. Vgontzas, M.D., Sleep Research and Treatment Center, Department of Psychiatry, Pennsylvania State University, 500 University Drive, Hershey, Pennsylvania 17033.
were significantly and positively correlated with the average values of percent REM sleep (P , 0.05). There were no correlations between hormone values and REM latency, other variables of REM distribution, or REM density, an index of phasic activity during REM sleep. The positive correlations between stress system activity and REM sleep are consistent with hormonal and sleep alterations in melancholic depression, a state characterized by increased cortisol and catecholamine secretion. (J Clin Endocrinol Metab 82: 3278 –3280, 1997)
Subjects and Methods Subjects Twenty-one subjects [17 men and 4 women; 21–52 yr of age (mean 6 se, 33.6 6 2.3 yr); body mass index, 26.6 6 1.0 kg/m2] were recruited from the community and from the medical and technical staff and students of Hershey Medical Center. They were in good general health, had no sleep complaints, had normal sleep laboratory findings, and were not taking any medications.
Sleep laboratory recordings Subjects were studied in the sleep laboratory for 4 consecutive nights. The first night allowed for screening for sleep apnea and nocturnal myoclonus and adaptation to the new sleeping environment and was not included in the analysis. On each night of the study, subjects were continuously monitored with electroencephalogram, electromyogram, and electrooculogram for 8 h. All sleep recordings were scored according to standardized criteria (10). Sleep efficiency parameters assessed from the sleep recordings included sleep induction (sleep latency), sleep maintenance [wake time after sleep onset (WTASO) and number of awakenings], total wake time (the sum of sleep latency and WTASO), and percentage of sleep time. In addition, a number of sleep stage parameters were evaluated, including REM sleep and stages 1, 2, 3, and 4, number of REM periods, interval from sleep onset to the first REM period (REM latency), and percentage of slow wave (stages 3 and 4) sleep. Finally, REM density was calculated by counting the number of 2-s epochs within a REM period that included at least one eye movement.
Hormone measurements During 3 consecutive days of the study (days 2– 4), subjects were asked to collect complete 24-h urine specimens. After the total volume of the 24-h urine collections was measured, 20-mL aliquots were frozen at 220 C (cortisol) or 270 C (catecholamines) until assay. Creatinine was measured to confirm the completeness of each collection. Eighteen sub-
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STRESS SYSTEM AND REM SLEEP jects had complete urine collections for all 3 days, two for 2 days, and one for 1 day. Cortisol was determined by RIA of urine samples (11). The sensitivity of the assay was 0.4 pg/dL, and the intraassay coefficient of variation was less than 10%. Urinary catecholamines, including norepinephrine (NE), epinephrine (E), dopamine (DA), its precursor dihydroxyphenylalanine (DOPA), and their metabolites, dihydroxyphenylacetic acid (DOPAC) and dihydroxyphenylglycol (DHPG), were measured by high performance liquid chromatography with electrochemical detection (12). The sensitivity for catecholamines was 5 pg/mL, with the exception of dopamine, which was 25 pg/mL. The intraassay variability for catecholamines was less than 13%.
Statistical analysis The mean values of the sleep efficiency and sleep stage variables from nights 2– 4 were correlated to the mean values of UFC and urinary catecholamines for days 2– 4 using Pearson’s product-moment correlation. Also, single 24-h urinary hormone concentrations were correlated to the corresponding single night sleep variables. The UFC and urinary catecholamine values are expressed as micrograms per 24 h. All values are expressed as the mean 6 se.
Results
The subjects demonstrated an average sleep latency of 24.2 6 4.0 min, WTASO of 51.1 6 8.1 min, total wake time of 75.3 6 9.7 min, and percentage of sleep time of 84.3 6 2.0. Also, the mean distribution of sleep stages was as follows: stage 1, 10.6 6 1.3%; stage 2, 63.9 6 1.1%; SWS, 2.8 6 0.7%; and REM, 22.7 6 1.1%. The REM latency was 80.3 6 5.0 min, and the average REM density index (number of 2-s epochs with eye movements in a 40-s REM epoch) was 3.1 6 0.3.
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distribution, or REM density. Also, there was no correlation between amount of 24-h UFC and other sleep stages or sleep efficiency measures. Polysomnographic measures of sleep and 24-h urinary catecholamines
The average values of the 3-day urinary collections for catecholamines were as follows: NE, 35.3 6 2.4 mg/24 h; E, 6.8 6 0.5 mg/24 h; DA, 253.0 6 19.9 mg/24 h; DOPA, 36.4 6 5.3 mg/24 h; DHPG, 59.8 6 3.6 mg/24 h; and DOPAC, 964.8 6 73.3 mg/24 h. There were positive correlations between 3-day individual mean values and percentage of REM sleep, and 3-day urinary average concentrations of E (rxy 5 0.60; P , 0.01), DHPG (rxy 5 0.44; P , 0.05), and DOPAC (rxy 5 0.47; P , 0.05; Fig. 2). NE, DA, and DOPA were positively, but nonsignificantly, correlated with the percentage of REM sleep. None of these relationships was influenced by age, sex, or BMI. There were no correlations between 24-h urinary catecholamine levels and REM latency, other variables of REM distribution, or REM density. Also, there was no correlation between 24-h urinary catecholamine levels and other sleep stages or sleep efficiency measures. Discussion
The mean value for the 3-day 24-h UFC measurement was 89.6 6 12.0 mg/24 h. Increased amounts of the 3-day individual mean values of percentage of REM sleep were correlated with higher 3-day individual mean values of UFC (rxy 5 0.51; P , 0.05; Fig. 1). This relationship was not affected by age, whereas it was strengthened when we controlled for BMI (rxy 5 0.66; P , 0.01). There were no correlations between 24-h UFC and REM latency, other variables of REM
Our primary finding is that in healthy, normal sleepers, the amount of REM sleep is positively correlated with 24-h UFC and catecholamine excretion. Variables related to REM distribution and REM density were not correlated with the hormonal values. The positive correlations between the percentage of REM sleep and the integrated measures of activity of the HPA axis and sympathetic system are consistent with the known central nervous system activation during REM sleep and the coexistence of stress system activation and REM sleep increases in patients with melancholic depression (3–5). An early study showed that urinary 17-hydroxycorticoids were increased during REM epochs in catheterized urolog-
FIG. 1. Correlation of 24-h UFC excretion with percentage of REM sleep.
FIG. 2. Correlation of 24-h urinary epinephrine with percentage of REM sleep.
Polysomnographic measures of sleep and 24-h UFC
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ical patients (13). In contrast, several more recent studies reported decreasing levels of plasma cortisol during REM sleep (6, 7), whereas the administration of CRH, which is an arousal-inducing peptide, was paradoxically associated with increased slow wave sleep (14). The authors of these studies concluded that REM sleep had an inhibitory effect on adrenal secretion. The discrepancy between these findings and our results based on integrative measures may mean that individuals with increased amounts of REM have a higher cortisol secretion, but not necessarily during the REM period. Our finding of a positive correlation between REM sleep and catecholamine excretion is consistent with the results of another study that measured sympathetic nerve activity using microneurography during sleep in normal subjects (15), with the caveats that the correlation in this case would only reflect norepinephrine and that we do not know whether microneurographic activity reflects phasic or tonic events during REM sleep. Our study did not demonstrate any association between HPA axis or SNS activity and REM density, which is a reflection of the phasic activity of REM sleep. This agrees with earlier reports of dissociation between REM density and the amount of REM sleep (16) or REM sleep timing (17) and of the reduction in the amount of REM sleep, but not REM density, induced by exogenous hydrocortisone (18). It also agrees with results from patients with major depression, in whom REM density was higher than in normal controls, but not significantly different between patients with and without HPA axis alterations, as assessed by a dexamethasone suppression test (19). Our findings combined with the results of these studies suggest that HPA axis and SNS activity are related to the tonic, rather than the phasic, component of REM sleep, and that different neuroanatomical and neurochemical substrates control these two phenomena. References 1. Williams RL, Agnew Jr HW, Webb WB. 1964 Sleep patterns in young adults: an EEG study. Electroencephalogr Clin Neurophysiol. 17:376 –381.
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