Effects of hypnotics on the sleep EEG of healthy young adults: new data and psychopharmacologic implications
Introduction
Both period-amplitude analysis (PAA) and power spectral analysis have shown that classical benzodiazepine (BZ) hypnotics strongly affect the EEG of non-rapid eye movement (NREM) sleep in three frequency bands. BZs reduce delta (0.3–3 Hz) but increase spindle (12–15 Hz) and beta (15–23 Hz) activity (Gaillard et al., 1973, Johnson et al., 1976, Johnson et al., 1979, Feinberg et al., 1978, Feinberg et al., 1979, Borbely et al., 1985; and many subsequent reports). Interestingly, these three bands show strong and interrelated oscillations across sleep. Sigma and delta oscillate inversely in NREM but both decline to their lowest levels in REM (Uchida et al., 1991); beta and delta oscillate inversely across both NREM and REM sleep (Uchida et al., 1992).
This study compared the effects of zolpidem, triazolam and temazepam on visually scored sleep stages and computer-measured NREM EEG. Although the functional significance of hypnotic-induced changes in sleep architecture and EEG is unknown, these changes are of considerable biological interest. This is particularly the case for the delta frequencies, which are thought to be correlates of the homeostatic (restorative) processes of sleep (Feinberg et al., 1974, Borbely 1982). While there is no general agreement on the functional significance of spindle and beta frequencies, their oscillatory relationships with delta make them of interest. An important additional source of interest in the pharmacology of spindle and delta EEG is the strong effect of human brain maturation and aging on these frequencies. The goals of the present studies were (1) to determine whether the non-benzodiazepine GABAergic hypnotic zolpidem produces the same changes in NREM delta, sigma and beta as those induced by two “classical” benzodiazepines, triazolam and temazepam; and (2) to explore with period amplitude analysis the effects of these drugs on the amplitude, incidence and across-night trends of the waves in these three frequencies. Spectral power, and its period-amplitude equivalent, integrated amplitude, are composite measures that reflect the number and amplitude of the waves in an EEG frequency band. Period-amplitude analysis, but not spectral analysis, can determine the separate contributions of wave amplitude and incidence. While there have been several studies (Trachsel et al., 1990, Brunner et al., 1991) of the effects of recently developed non-benzodiazepine GABAergic hypnotics on spectral power, no previous study compared the effects of zolpidem and classical GABAergic hypnotics on the amplitude and incidence of waves in NREM delta, sigma and beta frequencies.
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Subjects
Subjects (Ss) were paid volunteers, 10 male and six female students at UC Davis between the ages of 19 and 26 years inclusive. Females were non-pregnant and, if sexually active, used contraception throughout the period of study. All were non-smokers, within 25% of the desirable weight for their height (by Metropolitan Life Insurance Table), and in good health according to medical and psychiatric evaluations and laboratory (including drug) screen. The drug screen was repeated randomly during the
Results
Since the treatments were administered in different sequences to groups of four Ss, a preliminary ANOVA was performed to test for order effects. None of these F values approached significance and Ss were grouped by drug for further analyses.
Discussion
In considering these findings, the reader should be aware of two relevant analyses of the same data that will soon be published. Tan et al. (2000b) examined the internight reliability of PAA measures and spectral power for NREM delta, sigma and beta frequencies in baseline sleep. Reliability was extremely high: for most variables, a single night's measurement provided a correlation >0.90 with the 5-night mean. In addition, the reliability across successive individual nights was excellent for
Acknowledgements
Lorex Pharmaceuticals and the Research Service of the Department of Veterans Affairs supported this research. Preparation of this manuscript was supported by PHS grants R01MH50741 and R01MH57928. The authors have no relationship with Lorex that would cause a conflict of interest with the content of this manuscript. We thank the technicians who helped with this project: Jon Marrs, Dolores White, Hanson Quon, and Mike Minimiji. We also thank the subjects who participated in the study.
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2019, Journal of Neuroscience MethodsCitation Excerpt :In a series of studies that investigated the role of sleep spindles for hippocampal-dependent memory consolidation, our group compared zolpidem, a GABAA receptor agonist shown to enhance sigma activity, and sodium oxybate, which interacts with the GABAB receptor and has conversely been shown to decrease sigma activity. Initially, we conducted a dose-response study of zolpidem (5 mg and 10 mg) and sodium oxybate (2.5 g and 3 g) to determine the optimal dose of zolpidem for increasing the density of N2 sleep spindles (Brunner et al., 1991; Feinberg et al., 2000), and sodium oxybate for decreasing the density of N2 sleep spindles in an early morning nap (Mednick et al., 2013). The nap occurred at 8:30 AM to capitalize on circadian fluctuations in REM sleep (highest in the morning) and maximize differences in sleep stages between the drug and placebo conditions.
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2016, International Journal of PsychophysiologyCitation Excerpt :However, one limitation of spectral analysis is that the technique is not able to distinguish the specific morphological change(s) in slow waves that account for alterations in spectral power (i.e., whether changes in SWA are due to reductions in the number of incident waves and/or amplitude of the waveform). Using period amplitude analyses, which allows for the detection and subsequent morphological characterization of slow waves, benzodiazepines have been shown to decrease the amplitude of detected waves (Feinberg et al., 1977; Feinberg et al., 2000; Johnson et al., 1979; Wright et al., 1986). However, changes in the incidence of slow waves have been less consistent among studies, with both reductions (Feinberg et al., 1977; Feinberg et al., 2000; Johnson et al., 1979) and increases (Wright et al., 1986) demonstrated.