Examples

The Effects of Short-term (1 week) Partial Sleep Deprivation on Sleepiness and Cytokine Secretion

Student

Heather Follett, class of 2002
Student Box 29
717-832-3672
hnf102@psu.edu

Faculty Advisor

Alexandros Vgontzas, M.D., Department of Psychiatry
717-531-7278
axv3@psu.edu

Research Period

September 24, 2001 to February 15, 2002

Objectives

Hypothesis

Short-term sleep curtailment causes increased sleepiness and increased daytime plasma IL-6 and TNF-a levels, but does not increase daytime cortisol levels.

Specific aim

Evaluate the effects of short-term (one week) partial sleep deprivation on sleepiness and plasma IL-6, TNF-a and cortisol levels in young (age 20-40 years), healthy, non-obese (BMI<27.8 for men and <27.3 for women) subjects.

Background

A lack of sufficient sleep is a chronic problem for many people in today's society. Such sleep loss has been shown to cause a deterioration in a person's ability to function effectively and can lead to uncontrolled sleep attacks. The effects of total sleep deprivation are well documented. Specifically, total sleep deprivation, in addition to increasing a subject's subjective perception of daytime sleepiness, has been shown to significantly increase the percentage of slow wave (stages three and four) sleep during the post-sleep deprivation recovery night (Vgontzas et al. 1999). Sleep latency, which is the amount of time it takes for a subject to fall asleep after going to bed, was also significantly decreased post-sleep deprivation in the same study. The effects of partial sleep loss are not well studied. In fact, some sleep researchers have suggested that some sleep, such as stage two sleep, is "optional" and therefore unnecessary for the functioning and well-being of humans.

IL-6 and tumor necrosis factor-alpha (TNF-a) are cytokines which are involved in the acute phase response of inflammation, which involves a number of early systemic responses to infection or tissue damage (Spath - Schwalbe et al. 1998). Both cytokines have a circadian pattern of secretion. Plasma TNF-a levels peak during the night, and IL-6 levels peak in the early evening and early morning. TNF-a has been shown to be elevated in patients with sleep apnea and narcolepsy, while IL-6 has been shown to be elevated in patients with sleep apnea only. These results suggest that these cytokines may play a significant role in mediating sleepiness and fatigue in these sleep disorders (Vgontzas et al. 1997). While no studies have been done which measure the effects of sleep deprivation on TNF-a levels, total sleep deprivation has been shown to alter the pattern of circadian IL-6 secretion in young, healthy male subjects. In a study by Vgontzas et al., the total amount of IL-6 over a twenty-four hour period did not change, but there was a shift in the major peak, such that IL-6 levels were elevated during the day and decreased during the recovery night post-sleep deprivation (1999). Furthermore, a negative correlation was found between the difference in interleukin-6 (IL-6) levels pre- and post- sleep deprivation and the baseline percentage of slow wave sleep, suggesting that greater amounts of slow wave sleep render subjects resistant to the effects of total sleep deprivation (Vgontzas et al. 1999). We suspect that there will be a similar shift in the IL-6 peaks and troughs after partial sleep deprivation, and that IL-6 and TNF-a levels may play a role in mediating sleepiness experienced by our subjects.

The effects of sleep deprivation on the hypothalamic-pituitary-adrenal axis have been studied in the past, but the results have been inconsistent. Sleep deprivation in healthy subjects was associated with no change in urinary glucocorticoid excretion in studies by Poland et al. (1972) and Kant et al. (1984). However, Akerstedt et al. demonstrated a decrease in urinary glucocorticoid excretion in their 1980 study. Other studies involving subjects with major depression have shown an increase in cortisol secretion during the night of sleep deprivation (Baumgartner et al., 1990; Bouhuys et al., 1990), while another study showed no change in plasma cortisol levels the morning after sleep deprivation (Ebert et al., 1994). Leproult et al. found elevated cortisol levels after both partial and total sleep deprivation in healthy young men (1997). Vgontzas et al. found a significant decrease in plasma cortisol levels for twenty-four hours following total sleep deprivation in young, healthy male subjects (1999). Theirs was the only study to extend the measure of plasma cortisol levels to include the recovery night. We anticipate that partial sleep deprivation will have a similar effect on plasma cortisol levels.

Methods

Young (age 20-40 years), healthy, non-obese (BMI<27.8 for men and <27.3 for women) subjects participated in a twelve-day sleep laboratory experiment. For two weeks prior to the study, the subjects recorded their sleep schedule in a log book and wore actigraphy watches on their non-dominant hands to confirm that they were receiving adequate sleep time and following regular sleep schedules. The subjects were also screened for drug use prior to the study.

During the first four nights in the sleep laboratory, the subjects were allowed to sleep for eight hours, from 2300 to 0700. The subjects were awakened two hours earlier (0500) on the subsequent seven nights so that they only received six hours of sleep. Finally, on the twelfth night, the subjects were allowed to sleep for eight hours again. Throughout the study, the subjects were instructed to avoid naps, to continue their normal daily activities and to maintain their normal diets, including the use of caffeinated beverages. They continued to wear actigraphy watches on their non-dominant hands throughout the study to assess compliance with the instructions to avoid naps.

The subjects were instructed to complete a ten-centimeter visual analogue sleepiness scale and the Stanford sleepiness scale every hour while awake on days four and twelve of the study, and at 1700, 1800 and 1900 during the other days of the study. On the fourth and twelfth days, the subjects' blood was sampled every thirty minutes over a twenty-four hour period to measure TNF-a and IL-6 plasma levels. During the two days of blood sampling, the subjects were recorded with hypno-polygrams according to a modified multiple sleep latency test (MSLT) procedure at 0900, 1200, 1500, 1700, 1900 and 2100 for an objective measure of daytime sleepiness; the subjects were given twenty minutes to attempt to fall asleep, and the sleep latency was measured. Subjects were immediately woken after entering sleep stage one. Psychomotor vigilance testing (PVT), which is a simple, ten-minute computerized test of alertness, was also done every hour on the blood sampling days.

The study was approved by the IRB, and each subject signed a consent form prior to participating in the study.

Student's Responsibilities

  1. Assistance in the collection of data (e.g. overnight blood draws and performance of MSLT).
  2. Organization and analysis of IL-6, TNF-a, and cortisol levels, MSLT and PVT data.
  3. Literature research of sleep deprivation and its relationship to hormonal parameters, cytokine levels, sleepiness and changes in the sleep cycle.
  4. Preparation and submission of research paper. 

Sponsor's Responsibilities

  1. Facilitation of data analysis.
  2. Evaluation and critique of research paper. 

References

Akerstedt, T., Palmblad, J., de la Torre, B., Marana, R. and Gillberg, M. (1980) Adrenocortical and gonadal steroids during sleep deprivation. Sleep 3 (1): 23-30.

Baumgartner, A., Garf, K., Kurten, I., Meinhold, H. and Scholz, P. (1990) Neuroendocrinological investigations during sleep deprivation in depression I. Early morning levels of thyrotropin, TH, cortisol, prolactin, LH, FSH, estradiol, and testosterone. Biological Psychiatry 28: 556-568.

Bouhuys, A.L., Flentge, F. and Van den Hoofdakker, R.H. (1990) Effects of total sleep deprivation on urinary cortisol, self-rated arousal, and mood in depressed patients. Psychiatry Research 34: 149-162.

Ebert, D., Kaschka, W.P., Loew, T. and Beck, G. (1994) Cortisol and beta-endorphin responses to sleep deprivation in major depression-the hyperarousal theories of sleep deprivation. Neuropsychobiology 29: 64-68.

Kant, G.J., Genser, S.G., Thorne, D.R., Pfalser, J.L. and Mougey, E.H. (1984) Effects of 72 hour sleep deprivation on urinary cortisol and indices of metabolism. Sleep 7 (2): 142-146.

Leproult, R., Copinschi, G., Buxton, O., and Van Cauter, E. (1997) Sleep loss results in an elevation of cortisol levels the next evening. Sleep. 20: 865-870.

Poland, R.E., Rubin, R.T., Clark, B.R. and Gouin, P.R. (1972) Circadian patterns of urine 17-OHC and VMA excretion during sleep deprivation. Diseases of the Nervous System 33: 456-458.

Spath-Schwalbe, E, Hansen K, Schmidt F, et al. (1998) Acute effects of recombinant human interleukin-6 on endocrine and central nervous sleep functions in healthy men. Journal of Clinical Endocrinology and Metabolism 83:1578-1579.

Vgontzas, A., Papanicolaou, D., Bixler, E., et al. (1997) Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity. Journal of Clinical Endocrinology and Metabolism 82: 1313-1316.

Vgontzas, A., Papanicolaou, D, Bixler, E, et al. (1999) Circadian interleukin-6 secretion and quantity and depth of sleep. Journal of Clinical Endocrinology and Metabolism 84: 2603-2607.

Vgontzas, A., Mastorakos, G., Bixler E., et al. (1999) Sleep deprivation effects on the activity of the hypothalamic-pituitary-adrenal and growth axes: potential clinical implications. Clinical Endocrinology. 51: 205-215.

Heather Follett Alexandros Vgontzas, MD