Sleep Enhancement Research Articles

A Music Therapy Strategy for Depressed Older Adults in the Community

A music therapy strategy for depressed older adults involves eight music-listening programs facilitated by a music therapist for use in the home environment. Body relaxation, imagery, stimulation, and sleep enhancement are included in these programs that use music to cue relaxation and positive thinking. Four case studies describing successful application of this approach to older adults with depression and/or anxiety offer encouragement for this type of programming.

Panax ginseng extract modulates sleep in unrestrained rats

The amount of wakefulness and slow wave sleep (SWS) during the 12-h light period slightly but significantly decreased and increased, respectively, in freely behaving rats after continued 1-week intake of Panax ginseng extract through drinking water (15 mg/day). Paradoxical sleep was little affected. No sleep parameters were modulated by the treatment during the dark period. The diurnal SWS enhancement disappeared and recovered to the baseline level after 2 weeks of continued treatment. It is speculated that the well known health-improving effect of the ginseng may be, at least in part, related to an enhancement of sleep.

Exercice physique et sommeil en climat tropical sec: étude préliminaire chez trois sujets africains

Resume Trois sujets africains sedentaires (âge moyen: 25 ± 1,7 ans) ont participe a l'etude des effets d'un entrainement physique progressif sur les etats de sommeil en periode fraiche et en periode chaude de la saison seche du climat sahelien. L'entrainement a consiste en un exercice en creneaux repete 3 fois par semaine pendant 6 semaines (plateaux de 4 min a puissance sous-maximale, pic a puissance maximale la cinquieme minute). Le nombre de creneaux a ete augmente de 5 la premiere semaine a 7 la deuxieme semaine puis a 9 les 4 semaines suivantes et la puissance developpee a ete accrue progressivement lors des 3 dernieres semaines. L'amelioration des performances physiques a ete estimee par une epreuve triangulaire realisee avant l'entrainement, et apres les troisieme et sixieme semaines d'exercice. Le programme d'entrainement a ete realise en periode fraiche et repete en periode chaude apres 2 mois 1/2 sans exercice physique. Les examens polygraphiques du sommeil ont ete realises avant l'entrainement (3 nuits consecutives) et pendant les quatrieme et sixieme semaines (2 nuits consecutives). La periode de controle en saison fraiche a ete consideree comme periode de reference, chaque sujet constituant son propre temoin. L'efficacite du sommeil a ete amelioree par l'entrainement, avec surtout une augmentation du nombre de phases de sommeil delta (stades 3 et 4), conduisant a un accroissement de cet etat. Ces changements ont ete plus importants en periode chaude. Au contraire, le sommeil paradoxal n'a pas varie avec les conditions climatiques, mais avec l'intensite de l'exercice. Il a diminue lors de la sixieme semaine par rapport a la quatrieme. En conclusion, l'augmentation du sommeil delta est en rapport avec la charge thermique supportee par le sujet, le sommeil paradoxal etant sensible au stress lie a l'intensite de l'exercice pratique.

REM sleep enhancement induced by sensory stimulation is prevented by kainic acid lesion of the pontine reticular formation

It has been shown that auditory or somatic stimulation during rapid eye movement (REM) sleep is capable of producing a significant increase in ponto-geniculo-occipital (PGO) spike density as well as in REM sleep duration. The purpose of this study was to determine the role of the medial pontine reticular formation (PRF) in mediating such increase of REM sleep duration. After a baseline recording whereby on the same recording day the control and the stimulus (auditory or somatic) alternated with each REM, a group of cats was lesioned with kainic acid in the PRF. The sleep-wake cycle was recorded again on days 15, 30 and 45 it post-lesion, following the same procedure. The results showed no changes in REM sleep duration and PGO spike density in the lesioned animals. However, when sensory stimulation was applied it was ineffective in producing REM sleep enhancement, although it was able to increase PGO spike density. These findings suggest that the effects of sensory stimulation on REM sleep duration are accomplished through the PRF, probably by inducing an increase in the excitability levels of such neurons, and further suggests that PGO spike density and REM duration are independent of each other.

Enhancement of sleep by microinjection of triazolam into the medial preoptic area.

A growing literature suggests that the basal forebrain may contain structures involved in the regulation of sleep. As part of a series of studies designed to locate the site(s) of hypnotic action of benzodiazepines, we have injected triazolam into the medial preoptic area (MPA) of the hypothalamus of rats. Total sleep time was increased, due primarily to an increase in non-rapid eye movement (non-REM) sleep and a trend toward a decrease in intermittent waking time. A previous study from this laboratory reported that injections into the raphe nucleus decreased sleep, whereas injections at adjacent sites were without effect. These studies indicate the selectivity with which different brain regions respond to triazolam in terms of actions on sleep.

Satiety and sleep: the effects of bombesin

Our recently proposed ischymetric hypothesis of the control of feeding and sleep predicts that both of these phenomena must be closely related. Whether food was available or not, peripherally administered bombesin produced an enhancement of total sleep by specifically increasing the duration of slow wave sleep but not the duration of paradoxical sleep. In all experimental situations, paradoxical sleep latency was increased. The data suggest an active role for endogenous bombesin-like peptides in the regulation of satiety and sleep.

Enhancement of quiet sleep in rabbit neonates by muramyl dipeptide.

Muramyl peptides that induce excess slow-wave sleep have been isolated from urine and brain. A synthetic analogue to those substances, muramyl dipeptide (MDP, N-acetylmuramyl-L-alanyl-D-isoglutamine), was found to induce prolonged increases in slow-wave sleep and to increase electroencephalographic (EEG) delta-wave activity. MDP is also pyrogenic, although this activity can be separated from its somnogenic activity. To further investigate the somnogenic actions of MDP, neonatal rabbits were used in the present study. Intraperitoneal injection of 100 micrograms/kg MDP induced differential somnogenic and pyrogenic effects; from postnatal days 7-9, MDP increased duration of quiet sleep (QS, the precursor of adult slow-wave sleep) and decreased active sleep (AS) as judged by behavioral criteria. These animals were not febrile during the period of enhanced QS, nor did MDP alter EEG delta-wave activity at this age. From postnatal days 10-15, MDP induced prolonged (6 h) increases in duration of QS; both behavioral and EEG criteria were used at this age to determine duration of QS and AS. Maximum MDP-induced effects occurred during the 2nd h, with a parallel increase in amplitudes of EEG delta-wave activity. At this age, MDP also elicited monophasic fevers and inhibition of AS, with maximum effects observed during hours 3-4 postinjection. After postnatal day 16, MDP-induced somnogenic and febrile responses were similar to those observed in adult rabbits. We conclude that the mechanisms responsible for behavioral sleep states are responsive to a sleep-promoting substance early in ontogenesis.

Sleep improvement in dogs after oral administration of mioflazine, a nucleoside transport inhibitor.

Mioflazine, a nucleoside transport inhibitor, was given PO to dogs at doses of 0.04-10 mg/kg. Sixteen hour polygraphic sleep recordings were made and analysis and sleep stage classification was done by computer. Mioflazine decreased wakefulness and increased slow wave sleep, but did not affect the latencies of either REM sleep or slow wave sleep. This increased sleep was due to an increase in the number of light and deep slow wave sleep epochs. The effect lasted for about 8 h. The decreased wakefulness and increased slow wave sleep could be antagonized by the adenosine antagonist caffeine (2.5 and 10 mg/kg, PO); however, there was not a pure antagonistic effect. It might be that the enhancement of slow wave sleep is due to an activation of brain adenosine receptors. This is the first report of a drug acting on adenosine that given orally improves sleep. Mioflazine might be the prototype of substances worth considering for the treatment of a variety of sleep disorders.

Bacterial peptidoglycans as modulators of sleep. II. Effects of muramyl peptides on the structure of rabbit sleep

Sleep-promoting substances derived from human urine and rabbit brain were identified as muramyl peptides (MPs). We report in the accompanying paper that in the molecular structure of MPs, the 1,6-anhydro muramic acid moiety of MPs is important for enhancement of slow-wave sleep (SWS) in rabbits. Here, we document more extensively the effects of one MP: 1,6-anhydro-muramyl-alanyl-glutamyl-diamophenyl-alanine (AMTP for anhydro-muramyl tetrapeptide) on sleep structure of rabbits. AMTP significancantly increased percent of time spent in SWS but its effects on rapid eye movement (REM) sleep were dose-dependent. Brain temperatures were significantly elevated but continued to fluctuate with sleep and wake state transitions indistinguishably from control. Sleep was episodic and animals could be easily aroused. AMTP increased number of SWS episodes and decreased number of REM episodes. There was a shift in the distribution of sleep-wake episode durations: longer waking and REM episodes were decreased, thus increased the proportion of shorter episodes. Increased duration of SWS resulted from a larger number of SWS episodes longer than 8 min. We conclude that AMTP amplifies the SWS compenent of physiological sleep.

Alimentary sleep satiety in suckling rats

Sleep/wake states were investigated in rat pups at 12–13 days of age following deprivation of milk and their dam for 9–12 hr. Early in the deprivation period each pup was equipped with bipolar stainless steel electrodes for electroencephalographic (EEG) and electromyographic (EMG) recordings. Four groups of pups were tested using anesthetized dams. The pups were either (a) allowed to root in the dam's fur, but were not allowed to attach to a nipple; (b) allowed to root after receiving a gut load of rat's milk; (c) allowed to attach and suck a nipple without receiving milk; or (d) allowed to attach and suck a nipple following a gut load of rat's milk. The results indicate that sucking elicits sleep, especially slow-wave sleep. Milk in the gut enhanced paradoxical sleep, primarily in the context of sucking. This experiment confirms that the types of sleep can be affected separately by specific internal and external events. The shift in the sleep/wake condition to slow-wave sleep in the suckling situation suggests one type of satiety. Furthermore, the selective enhancement of paradoxical sleep following the gut load of milk suggests postingestive satiety.

Enhancement of slow-wave sleep by endotoxin and lipid A.

Some muramyl peptides derived from bacterial peptidoglycan enhance slow-wave sleep (SWS). The purpose of this study was to test whether another cell wall component, lipopolysaccharide (LPS), and its lipid A moiety also have an effect on sleep. When injected intravenously, both LPS and lipid A enhanced the duration of SWS, increased electroencephalogram delta-wave amplitudes, suppressed rapid eye movement (REM) sleep, and induced biphasic fevers. The effects of intravenously administered lipid A and LPS on SWS were present primarily during the first 3 h postinjection. Intraventricular lipid A administration enhanced SWS, did not suppress REM, and induced a monophasic fever; the SWS effect had a 3-h latency, whereas temperature started to rise during the second hour. Regardless of the route of administration, within the dose range used here, sleep was normal by the following criteria: sleep was episodic, animals could be easily aroused, and brain temperature, although elevated to "febrile" levels, continued to fluctuate during sleep-state transitions indistinguishably from control conditions. We conclude that LPS and lipid A are capable of modulating sleep.

Neurotoxicity and metabolism of methyl bromide in rats

Changes in locomotor activity, body temperature, and body weight gain, and the enhancement of thiopental-induced sleep were investigated inrats as indices of the functional changes in the CNS caused by methyl bromide (CH 3Br) exposure. The correlations of these behavioral changes with CH 3Br metabolism are discussed. The LC50 value and its 95% confidence limits for an 8-hr exposure of CH 3Br was 302 ppm (267–340) ppm. Effects were examined following exposure to 63, 125, 188, or 250 ppm CH 3Br for 8 hr. CH 3Br concentrations as low as 63 ppm remarkably enhanced the sleep-inducing potency of thiopental, but CH 3Br exerted no effect on thiopental metabolism. The body temperature and body weight gain were decreased at exposure to concentrations of 125 ppm or higher, and locomotor activity was reduced at 188 ppm or higher. These effects were reversible and, at 24 hr after the exposure, locomotor activity and body temperature were almost the same as in control rats. In a time-course study of CH 3Br, bromine, and methyl alcohol, CH 3Br was rapidly eliminated from rat tissues following the cessation of exposure, with a half-life of about 30 min in the early post-exposure period. In contrast, the elimination rate of bromine was very slow, with a half-life about 5 days. The methanol amount was below that reported to induce the changes in CNS functions. These results suggest that the CNS depression caused by CH 3Br exposure may be due to the CH 3Br molecule or the methyl moiety incorporated into tissues and may not be attribuatable to bromine or methanol. A linear relationship was obtained between bromine amounts in blood and the exposure concentration or duration. This result suggests the possibility that the extent of CH 3Br exposure may be estimated from the bromine quantities in blood.

Enhancement of desynchronized sleep signs after pontine microinjection of the muscarinic agonist bethanechol

The question of which brainstem neuronal receptors can mediate cholinergic REM sleep induction was investigated by injecting the pure muscarinic agonist bethanechol via glass micropipettes in the pontine tegmentum of cats. The REM sleep enhancement was observed to be equally potent, equally dose-dependent and its appearance equally site-dependent as that previously observed with carbachol, a mixed muscarinic/nicotinic agonist. The results suggest that the pharmacological activation of muscarinic receptors in pontine neurons is sufficient to trigger REM sleep.

Effect of ambient temperature on the 24-hour sleep-wake cycle in normal and capsaicin-treated rats

The 24-hour sleep-wake cycle of untreated, normal rats and of capsaicin-treated rats was continuously recorded by telemetry. Recordings were made on two baseline days at 22°C, two days at 29°C, and two final days at 22°C. In untreated animals the daily amount of waking was reduced by the elevated ambient temperature and nonREM sleep was enhanced. This effect was mainly due to the frequent interruption of the dark-time waking episodes by sleep. In capsaicin-treated animals, raising the ambient temperature did not significantly enhance sleep. However, in both groups of rats the slow wave sleep (SWS) fraction of nonREM sleep was increased after elevating the temperature to 29°C. REM sleep showed a minor increase which was significant only for the capsaicin-treated group. The results suggest that a moderate increase of ambient temperature has two effects: (1) It causes an enhancement of sleep by a reduction in the duration of waking episodes, an effect that may represent a heat-defense response. The attenuation of this response in capsaicin-treated rats may be a consequence of the impairment of warm-receptors. (2) It favors the occurrence of SWS and REM sleep.

EEG and behavioral effects of gamma-hydroxybutyrate in the rabbit

The effects of gamma-hydroxybutyrate (GHB) upon sleep wakefulness patterns and quantified nuchal muscle activity were examined in the rabbit in a dose-response paradigm (25–1,000 mg/kg). Relative to control (saline) values, there was no facilitation of sleep onset or epileptogenic activity at any of the dosages studied. However, at the higher GHB concentrations, slow wave sleep and tonic muscle activity were enhanced and a high amplitude, slow activity was superimposed on background EEG patterns. The highest concentration of GHB (1,000 mg/kg) was associated with depression of motor activity. An enhancement of paradoxical sleep observed at lower GHB levels in other species occured in attenuated form in the rabbit. The results indicate dose-related effects on both sleep and motor activation in the rabbit, but the absence of seizure activity for the concentrations of GHB studied.

Enhancement of hexobarbital-induced sleep by lysine and its metabolites

Lysine has been shown to be metabolized in the rat brain to pipecolic acid which is a precursor of piperidine. Lysine and its proposed metabolites in this pathway were studied for the first time for their effect on the sleeping time induced by hexobarbital in the rat. Only L -lysine and D -lysine were found to prolong sleeping time significantly without toxic effect. A 3-day pretreatment with L -lysine produced an even more profound sleep prolongation. In most cases sleep enhancement was accompanied by a significant shortening of the time of sleep onset. Quantification of brain hexobarbital levels in the control and treated rats indicates that prolongation of sleeping time was not produced by inhibition of hexobarbital metabolism. The sleep prolonging effect of lysine, therefore, may be a direct action of lysine, or the metabolite(s) derived in vivo from lysine, on the central nervous system.

Inhibition of ethanol and acetate metabolism in mice by chlordimeform and related compounds

1. Since chlordimeform or N′-(4-chloro- o-toly l)- N, N-dimethylformamidine and certain of its mammalian metabolites prolong ethanol induced sleep in mice, their effect on ethanol and acetate metabolism was examined. 2. Intraperitoneal treatment of mice with chlordimeform (50 mg/kg) and demethylchlordimeform or N′-(4-chloro- o-tolyl)- N-methylformamidine (50 mg/kg), the two most potent sleep inducers, appreciably inhibited the metabolism of ethanol to 14CO 2. Another metabolite, 4-chloro- to-formotoluidide (100 mg/kg), a very weak sleep inducer, also markedly inhibited ethanol metabolism. 3. Chlordimeform, demethylchlordimeform, and 4-chloro- o-formotoluidide inhibited the conversion of ethanol to 14CO 2 and the conversion of acetate to 14CO 2 in vitro by mouse liver preparations. 4. The potency of 4-chloro- o-formotoluidide as an inhibitor of acetate metabolism in vitro compared favorably with that of SKF-525A, a known inhibitor of microsomal mixed function oxidases. 5. At a concentration of 1 × 10 −3 M, demethylchlordimeform yielded 27.4% inhibition of yeast alcohol dehydrogenase as compared to 46.3% for thiourea, a known inhibitor of this enzyme. The other compounds gave little, if any, inhibition of yeast alcohol or aldehyde dehydrogenase. 6. Although it is not possible to explain the mechanism for ethanol sleep enhancement in mice by chlordimeform and its metabolite demethylchlordimeform, inhibition of the alcohol dehydrogenase by demethylchlordimeform may be significant in this connection. 7. The decrease in ethanol metabolism apparently was due in large part to the activity of chlordimeform, demethylchlordimeform and especially 4-chloro- o-formotoluidide as inhibitors of microsomal mixed function oxidases.

Enhancement of ethanol-induced sleep by whole oil of nutmeg.

In young chickens, the whole oil of nutmeg (200 mg/kg) increased the duration of sleep induced by ethanol (1--4 g/kg), particularly deep sleep. Iproniazid (50-400 mg/kg), a monoamine oxidase inhibitor, did not mimic this effect.

Enhancement of paradoxical sleep by short light periods in the golden hamster

In hamsters exposed to short light-dark (LD) cycles, paradoxical sleep (PS) predominated during the light periods, whereas slow wave sleep (SWS) was not affected by the lighting conditions. Thus a selective effect of lighting conditions on paradoxical sleep which so far has been documented only for the rat, occurs in a further rodent species.

The brain as a dream state generator: an activation-synthesis hypothesis of the dream process

Recent research in the neurobiology of dreaming sleep provides new evidence for possible structural and functional substrates of formal aspects of the dream process. The data suggest that dreaming sleep is physiologically determined and shaped by a brain stem neuronal mechanism that can be modeled physiologically and mathematically. Formal features of the generator processes with strong implications for dream theory include periodicity and automaticity of forebrain activation, suggesting a preprogrammed neural basis for dream mentation in sleep; intense and sporadic activation of brain stem sensorimotor circuits including reticular, oculomotor, and vestibular neurons, possibly determining spatiotemporal aspects of dream imagery; and shifts in transmitter ratios, possibly accounting for dream amnesia. The authors suggest that the automatically activated forebrain synthesizes the dream by comparing information generated in specific brain stem circuits with information stored in memory.