Decrease In Rapid Eye Movement Sleep Research Articles

Tumor Necrosis Factor Antagonism Normalizes Rapid Eye Movement Sleep in Alcohol Dependence

In alcohol dependence, markers of inflammation are associated with increases in rapid eye movement (REM) sleep, which is thought to be a prognostic indicator of alcohol relapse. This study was undertaken to test whether blockade of biologically active tumor necrosis factor-alpha (TNF-alpha) normalizes REM sleep in alcohol-dependent adults. In a randomized, placebo-controlled, double-blind, crossover trial, 18 abstinent alcohol-dependent male adults received a single dose of etanercept (25 mg) versus placebo in a counterbalanced order. Polysomnographic sleep was measured at baseline and for 3 nights after the acute dose of etanercept or placebo. Compared with placebo, administration of etanercept produced significant decreases in the amount and percentage of REM sleep. Decreases in REM sleep were robust and approached low levels typically found in age-comparable control subjects. Individual differences in biologically active drug as indexed by circulating levels of soluble tumor necrosis factor receptor II negatively correlated with the percentage of REM sleep. Pharmacologic neutralization of TNF-alpha activity is associated with significant reductions in REM sleep in abstinent alcohol-dependent patients. These data suggest that circulating levels of TNF-alpha may have a physiologic role in the regulation of REM sleep in humans.

Potentiating effect of diltiazem on pentobarbital-induced hypnosis is augmented by serotonergic system: The TMN and VLPO as key elements in the pathway

To investigate the mechanism by which L-type Ca 2+ channel blockers exerted potentiating effects on pentobarbital-induced hypnosis, the present study was undertaken to determine if the interaction of diltiazem and serotonergic system influences the architecture of pentobarbital sleep in rats and examined c-Fos expression in the ventrolateral preoptic nucleus (VLPO) and the tuberomammillary nucleus (TMN). The polysomnogram consisting of EEG and EMG was recorded for analyzing sleep architecture. The results showed that diltiazem (2.0 and 5.0 mg/kg, p.o.) increased both total pentobarbital sleep and slow wave sleep (SWS), but decreased rapid eye movement (REM) sleep. These effects were potentiated by 5-hydroxytryptophan (5-HTP), a precursor of serotonin, but abolished by p-chlorophenylalanine (PCPA), an inhibitor of tryptophan hydroxylase. Diltiazem (1 mg/kg, p.o.) or 5-HTP (2 mg/kg, i.p.) alone did not change the architecture of pentobarbital sleep and pentobarbital-induced c-Fos expression in the VLPO and the TMN, but co-administration of them significantly increased both total pentobarbital sleep and SWS, whereas decreased REM sleep, with increasing c-Fos expression in the VLPO and concomitantly decreasing c-Fos expression in the TMN. These findings indicate that the serotonergic system may be involved in the augmentative effect of diltiazem on pentobarbital sleep and the VLPO–TMN neuronal circuit may play a key role.

Theta and Gamma Coordination of Hippocampal Networks during Waking and Rapid Eye Movement Sleep

Rapid eye movement (REM) sleep has been considered a paradoxical state because, despite the high behavioral threshold to arousing perturbations, gross physiological patterns in the forebrain resemble those of waking states. To understand how intrahippocampal networks interact during REM sleep, we used 96 site silicon probes to record from different hippocampal subregions and compared the patterns of activity during waking exploration and REM sleep. Dentate/CA3 theta and gamma synchrony was significantly higher during REM sleep compared with active waking. In contrast, gamma power in CA1 and CA3-CA1 gamma coherence showed significant decreases in REM sleep. Changes in unit firing rhythmicity and unit-field coherence specified the local generation of these patterns. Although these patterns of hippocampal network coordination characterized the more common tonic periods of REM sleep (approximately 95% of total REM), we also detected large phasic bursts of local field potential power in the dentate molecular layer that were accompanied by transient increases in the firing of dentate and CA1 neurons. In contrast to tonic REM periods, phasic REM epochs were characterized by higher theta and gamma synchrony among the dentate, CA3, and CA1 regions. These data suggest enhanced dentate processing, but limited CA3-CA1 coordination during tonic REM sleep. In contrast, phasic bursts of activity during REM sleep may provide windows of opportunity to synchronize the hippocampal trisynaptic loop and increase output to cortical targets. We hypothesize that tonic REM sleep may support off-line mnemonic processing, whereas phasic bursts of activity during REM may promote memory consolidation.

The developmental decrease in REM sleep: the role of transmitters and electrical coupling.

This mini-review considers certain factors related to the developmental decrease in rapid eye movement (REM) sleep, which occurs in favor of additional waking time, and its relationship to developmental factors that may influence its potential role in brain development. Specifically, we discuss some of the theories proposed for the occurrence of REM sleep and agree with the classic notion that REM sleep is, at the least, a mechanism that may play a role in the maturation of thalamocortical pathways. The developmental decrease in REM sleep occurs gradually from birth until close to puberty in the human, and in other mammals it is brief and coincides with eye and ear opening and the beginning of massive exogenous activation. Therefore, the purported role for REM sleep may change to involve a number of other functions with age. We describe recent findings showing that morphologic and physiologic properties as well as cholinergic, gamma amino-butyric acid, kainic acid, n-methyl-d-aspartic acid, noradrenergic, and serotonergic synaptic inputs to mesopontine cholinergic neurons, as well as the degree of electrical coupling between mostly noncholinergic mesopontine neurons and levels of the neuronal gap-junction protein connexin 36, change dramatically during this critical period in development. A novel mechanism for sleep-wake control based on well-known transmitter interactions, as well as electrical coupling, is described. We hypothesize that a dysregulation of this process could result in life-long disturbances in arousal and REM sleep drive, leading to hypervigilance or hypovigilance such as that observed in a number of disorders that have a mostly postpubertal age of onset.

Quantity and Quality of Sleep in the Surgical Intensive Care Unit: Are Our Patients Sleeping?

The lack of adequate sleep during intensive care unit (ICU) admission is a frequently overlooked complication. Disrupted sleep is associated with immune system dysfunction, impaired resistance to infection, as well as alterations in nitrogen balance and wound healing. The effects of surgical ICU admission on patients' sleep quality and architecture remain poorly defined. The purpose of this study was to describe the quantity and quality of sleep as well as sleep architecture, as defined by polysomnography (PSG), in patients cared for in the surgical ICU. A prospective observational cohort study was performed at our urban Level I trauma center. A convenience sample of surgical or trauma ICU patients underwent continuous PSG for up to 24 hours to evaluate sleep patterns. A certified sleep technician performed, monitored, and scored all PSG recordings. A single neurologist trained in PSG interpretation reviewed all PSG recordings. chi goodness-of-fit analysis was performed to detect differences in the proportion of time spent in stages 1 and 2 (superficial stages), stages 3 and 4 (deep stages), or rapid eye movement (REM) sleep between study patients and healthy historical controls. All PSG recordings were performed greater than 24 hours after the administration of a general anesthetic. Patients with traumatic brain injury were excluded. Sixteen patients were selected to undergo PSG recordings. Median age was 37.5 years (range, 20-83), 81.3% were male patients, 62.5% were injured, and 31.3% were mechanically ventilated. Total PSG recording time was 315 hours (mean, 19.7 hours per patient), total sleep time captured by PSG was 132 hours (mean, 8.28 hours per patient), and there were 6.2 awakenings per hour of sleep measured. ICU patients had an increase in the proportion of time spent in the superficial stages of sleep, and a decrease in the proportion of time spent in the deeper stages of sleep as well as a decrease in REM sleep compared with healthy controls (p < 0.001). Patients do achieve measurable sleep while cared for in a surgical ICU setting. However, sleep is fragmented and the quality of sleep is markedly abnormal with significant reductions in stages 3 and 4 and REM, the deeper restorative stages of sleep. Further studies on the effects of a strategy to promote sleep during ICU care are warranted.

Selective Blockade of 5-Hydroxytryptamine (5-HT)7Receptors Enhances 5-HT Transmission, Antidepressant-Like Behavior, and Rapid Eye Movement Sleep Suppression Induced by Citalopram in Rodents

Evidence has accumulated supporting a role for 5-hydroxytryptamine (5-HT)7 receptors in circadian rhythms, sleep, and mood disorders, presumably as a consequence of the modulation of 5-HT-mediated neuronal activity. We hypothesized that a selective 5-HT7 receptor antagonist, (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]-pyrrolidine (SB-269970), should increase activity of 5-HT neurons and potentiate the effect of selective serotonin reuptake inhibitors (citalopram). In rats, administration of 3 mg/kg s.c. citalopram alone increased the extracellular concentration of 5-HT. This effect of citalopram on extracellular 5-HT concentration was significantly enhanced by an ineffective dose of SB-269970. Combining this dose of SB-269970 with a low dose of citalopram also resulted in a significant increase in extracellular concentration of 5-HT, suggesting a potentiation of neurochemical effects. In mice, citalopram and SB-269970 dose-dependently decreased immobility time in the tail suspension test. The dose-effect curve of citalopram was shifted leftward by coadministration of an effective dose of SB-269970. Furthermore, combining ineffective doses of citalopram and SB-269970 also resulted in a significant decrease of immobility time in the tail suspension test, suggesting potentiation of antidepressant-like effects. In rats, SB-269970 potentiated the increase of rapid eye movement (REM) latency and the REM sleep decrease induced by citalopram. SB-269970 also reversed the increase in sleep fragmentation induced by citalopram. Rat plasma and brain concentrations of citalopram were not affected by coadministration of SB-269970, arguing for a pharmacodynamic rather than a pharmacokinetic mechanism. Overall, these results indicate that selective blockade of 5-HT7 receptors may enhance the antidepressant efficacy of citalopram and may provide a novel therapy to alleviate sleep disturbances associated with depression.

The effect of placebo administration on the first-night effect in healthy young volunteers

The first-night effect is a well-known phenomenon that is considered to result from a subject's lack of adaptation to the unfamiliar environment of a sleep laboratory and to the technical equipment used for polysomnography. The effect has been explored as a laboratory model for transient insomnia. The main characteristics of this effect are short total sleep time (TST) and rapid eye movement (REM) sleep, a lower sleep efficiency index, and longer REM sleep latency. Previous studies have reported that personality traits (such as trait anxiety) are a potential cause of the first-night effect and that the placebo effect is closely related to the anxiety levels of the subjects. To the best of our knowledge, there are no reports regarding the effects of a placebo on first-night sleep. This omission can be explained by the fact that the polysomnographic recordings obtained during the first night of a study are generally excluded from the analysis in order to avoid the inclusion of the first-night effect. In the present study, 8 male university students were subjected to polysomnographic examinations during drug-free, placebo-administration, and benzodiazepine-administration conditions in order to clarify the placebo effect on sleep during consecutive nights, particularly on the first night. The recordings for each condition were conducted for 4 consecutive nights. A placebo or 5 mg nitrazepam was administered at 2230 h using a double-blind crossover design, while no drug was administered during the drug-free condition. There was a 10-day interval between the examination of each condition. Polysomnographic recording was started at 2300 h and continued until the natural awakening of the subjects on the next morning. Subsequently, the subjects were requested to fill in a rating scale that is used to evaluate the subjective perception of sleep. An increase in stage-2 sleep associated with the first-night effect was observed on the first night during the drug-free and placebo-administration conditions. However, REM sleep reduction associated with the first-night effect was detected on the first night during the drug-free condition; this decrease in REM sleep was counteracted by the placebo during the placebo-administration condition. The nitrazepam, but not the placebo, decreased both slow-wave sleep (SWS) and REM sleep. The values for the tendency to fall asleep, feeling refreshed upon awakening in the morning, and the tension upon awakening in the morning were improved to a greater extent by the placebo and nitrazepam administrations than when no drug was administered. These results demonstrate the possibility that placebo administration may have a hypnotic/anxiolytic effect and may improve transient insomnia without causing SWS and REM sleep reductions.

Evidence for Electrical Coupling in the SubCoeruleus (SubC) Nucleus

SubCoeruleus (SubC) neurons, which are thought to modulate rapid-eye-movement (REM) sleep, were recorded in brain stem slices from 7- to 20-day rats and found to manifest spikelets, indicative of electrical coupling. Spikelets occurred spontaneously or could be induced by superfusion of the cholinergic agonist carbachol. Whole cell recordings revealed that carbachol induced membrane oscillations and spikelets in the theta frequency range in SubC neurons in the presence of fast synaptic blockers. Electrical coupling in neurons is mediated by the gap junction protein connexin 36 (Cx 36). We found that Cx 36 gene expression and protein in the mesopontine tegmentum decreased during development. Cx 36 protein levels specifically in the SubC decreased in concert with the developmental decrease in REM sleep. The presence of electrical coupling in the SubC introduces a novel potential mechanism of action for the regulation of sleep-wake states.

Muscarinic and nicotinic responses in the developing pedunculopontine nucleus (PPN)

The pedunculopontine nucleus (PPN), the cholinergic arm of the reticular activating system (RAS), is known to modulate waking and rapid eye movement (REM) sleep. REM sleep decreases between 10 and 30 days postnatally in the rat, with the majority occurring between 12 and 21 days. We investigated the possibility that changes in the cholinergic, muscarinic and/or nicotinic, input to PPN neurons could explain at least part of the developmental decrease in REM sleep. We recorded intracellularly from PPN neurons in 12–21 day rat brainstem slices maintained in artificial cerebrospinal fluid (aCSF) and found that application of the nicotinic agonist 1,1-dimethyl-4-phenyl-piperazinium iodide (DMPP) depolarized PPN neurons early in development, then hyperpolarized PPN neurons by day 21. Most of the effects of DMPP persisted following application of the sodium channel blocker tetrodotoxin (TTX), and in the presence of glutamatergic, serotonergic, noradrenergic and GABAergic antagonists, but were blocked by the nicotinic antagonist mecamylamine (MEC). The mixed muscarinic agonist carbachol (CAR) hyperpolarized all type II (A current) PPN cells and depolarized all type I (low threshold spike-LTS current) and type III (A + LTS current) PPN cells, but did not change effects during the period known for the developmental decrease in REM sleep. The effects of CAR persisted in the presence of TTX but were mostly blocked by the muscarinic antagonist atropine (ATR), and the remainder by MEC. We conclude that, while the nicotinic inputs to the PPN may help modulate the developmental decrease in REM sleep, the muscarinic inputs appear to modulate different types of cells differentially.

Sleep apnea syndrome and erectile dysfunction

Erectile dysfunction (ED), defined as the consistent inability to obtain and/or maintain penile erection sufficient for satisfactory sexual relations, is associated with a variety of medical, psychological, and lifestyle risk factors. Estimates for ED incidence in the United States range from 20% to 50%, depending on the epidemiologic study consulted. Sleep apnea syndrome (SAS) affects an estimated 4% of men between the ages of 30 and 60 years. This syndrome is characterized by recurrent episodes of upper airway obstruction during sleep, and it is usually associated with loud snoring and increased daytime sleepiness. It also results in marked sleep fragmentation and decreased rapid eye movement (REM) sleep. This decrease in REM sleep leads to a decrease in nocturnal erectile activity. Due to the loss of protective erections during REM sleep, some researchers have suggested that SAS may be a risk factor for ED. Both ED and SAS affect millions of men. Both diseases have a significant negative impact upon quality of life and interpersonal relationships. Sleep apnea syndrome represents a risk factor for ED, and the severity of both conditions shows a correlation.

Ambient temperature related sleep changes in rats neonatally treated with capsaicin

Ambient temperature related sleep changes in rats neonatally treated with capsaicin. PHYSIOL BEHAV 00(0) 000-000, 2004. The study was conducted on adult male Wistar rats, neonatally treated with capsaicin to destroy the peripheral warm receptors. The sleep-wakefulness was recorded for 5 h at an ambient temperature ( T amb) of 18, 24, 30 and 33 °C on different days. The rectal temperatures ( T r) of the rats were studied on exposure to 6 and 37 °C for 2 h to assess their thermoregulatory ability. The changes in the behavioral thermoregulation were assessed by noting the thermal preference of rats when they were placed in an environmental chamber with 3 interconnected compartments maintained at 24, 27 and 30 °C. Slow wave (SWS) and rapid eye movement (REM) sleep were decreased at 18 °C and increased at 30 °C, in control rats. There was a decrease in REM sleep and no change in SWS when T amb was raised from 30 to 33 °C. However, in neonatally capsaicin treated rats, sleep was increased even at 33 °C, though there was no significant change in sleep when T amb was increased from 18 to 24 °C. Capsaicin treated rats showed thermoregulatory deficiency at 37 °C but the thermal preference was unaltered in these rats. The results suggest that the central warm receptors can produce alteration in sleep at different T amb, even in absence of peripheral warm receptors. The behavioral thermoregulation was unaffected in these rats, though their ability to defend the body temperature in warm environment was affected.

Dyssomnia in children diagnosed with attention deficit hyperactivity disorder: a critical review

Objective: Studies prior to 1999 reported prevalent sleep disturbances in children diagnosed with attention deficit hyperactivity disorder (ADHD). However, these reports were largely inconclusive and inconsistent in their findings, hence the current review based on studies published thereafter. Method: An online research of the National Library of Medicine and the Cochrane Library was conducted using the terms ‘attention deficit hyperactivity disorder’, ‘sleep’, ‘human’, and ‘English language’. Results: Sixteen articles met the search criteria with 10 reporting objective measures of sleep characteristics (i.e. polysomnography, actigraphy, and/or video recording). These studies confirm an increase of rapid eye movement (REM) sleep latency and a proportional decrease of REM sleep in children diagnosed with ADHD. Stimulant treatment appears to have little effect on sleep quality while parent's reports of poor sleep in their ADHD-diagnosed offspring was largely inconsistent with the objective measures. Conclusions: The review demonstrated a link between disturbances in sleep architecture and ADHD. Whether this is of an intrinsic or extrinsic cause remains debateable, as both behavioural (parental reporting) and physiological (objective differences in sleep architecture) factors are indicated. The effect of stimulant medication on sleep also requires further research, as current evidence is limited by study design.

Dyssomnia in Children Diagnosed with Attention Deficit Hyperactivity Disorder: A Critical Review

Studies prior to 1999 reported prevalent sleep disturbances in children diagnosed with attention deficit hyperactivity disorder (ADHD). However, these reports were largely inconclusive and inconsistent in their findings, hence the current review based on studies published thereafter. An online research of the National Library of Medicine and the Cochrane Library was conducted using the terms 'attention deficit hyperactivity disorder', 'sleep', 'human', and 'English language'. Sixteen articles met the search criteria with 10 reporting objective measures of sleep characteristics (i.e. polysomnography, actigraphy, and/or video recording). These studies confirm an increase of rapid eye movement (REM) sleep latency and a proportional decrease of REM sleep in children diagnosed with ADHD. Stimulant treatment appears to have little effect on sleep quality while parent's reports of poor sleep in their ADHD-diagnosed offspring was largely inconsistent with the objective measures. The review demonstrated a link between disturbances in sleep architecture and ADHD. Whether this is of an intrinsic or extrinsic cause remains debateable, as both behavioural (parental reporting) and physiological (objective differences in sleep architecture) factors are indicated. The effect of stimulant medication on sleep also requires further research, as current evidence is limited by study design.

Analysis of the first night effect and sleep parameters in medically refractory epilepsy patients

Objectives To assess the first night effect (FNE) and compare sleep stage proportions to normative values in a sample of medically refractory epilepsy patients. Patients and methods Sleep parameters of 53 epilepsy patients, ages (18–56, mean: 34±12, 25 females 28 men), who underwent two consecutive nights of polysomnography (PSG) were compared. Non-rapid eye movement (NREM) stage 3 and NREM stage 4 were combined as slow wave sleep (SWS). Sleep efficiency, sleep latency, rapid eye movement (REM) latency, number of stage shifts, total minutes and proportion of total sleep time for stage 1, stage 2, SWS, and REM sleep were compared between the 2 nights. Results SWS was the only parameter that differed between nights 1 and 2 for both total minutes ( P=0.02) and proportion of total sleep time ( P=0.01), although the means for both nights were within the normative range. Comparing sleep proportions to normative values indicates that our patients had increased NREM stage 1 and decreased REM sleep. Conclusions We observed a minimal FNE in this sample of epilepsy patients manifested by reduced SWS. Multiple PSGs to accommodate the FNE may not be necessary in this population.

Developmental decrease in REM sleep: the shift to kainate receptor regulation

We found a shift in the responsiveness of pedunculopontine neurons from N-methyl-D-aspartic acid (NMDA) to kainic acid (KA) regulation around 15 days of age. While rapid eye movement (REM) sleep in humans decreases from 50 to 15% of sleep time between birth and the end of puberty, a similar decrease in the rat occurs from 10 to 30 days postnatally. Intracellularly recorded type II cholinergic PPN neurons, known to modulate waking and REM sleep, showed a gradual decrease in responsiveness to NMDA, and an increase in responsiveness to KA, during this period. Non-cholinergic PPN neurons did not show a developmental-dependent change in responsiveness. These results do not help explain if KA and NMDA control the developmental decrease in REM sleep, however, the data indicate that the shift at ∼15 days suggests that REM sleep becomes selectively modulated by KA receptors in the adult. Therefore, given development of appropriate compounds, KA receptor antagonism may become an effective treatment for disorders that manifest increased REM sleep drive and produce frequent nocturnal arousals and awakenings, e.g. schizophrenia, anxiety, insomnia, etc.

Developmental decrease in REM sleep: the shift to kainate receptor regulation

We found a shift in the responsiveness of pedunculopontine neurons from N-methyl- d-aspartic acid (NMDA) to kainic acid (KA) regulation around 15 days of age. While rapid eye movement (REM) sleep in humans decreases from 50 to 15% of sleep time between birth and the end of puberty, a similar decrease in the rat occurs from 10 to 30 days postnatally. Intracellularly recorded type II cholinergic PPN neurons, known to modulate waking and REM sleep, showed a gradual decrease in responsiveness to NMDA, and an increase in responsiveness to KA, during this period. Non-cholinergic PPN neurons did not show a developmental-dependent change in responsiveness. These results do not help explain if KA and NMDA control the developmental decrease in REM sleep, however, the data indicate that the shift at ∼15 days suggests that REM sleep becomes selectively modulated by KA receptors in the adult. Therefore, given development of appropriate compounds, KA receptor antagonism may become an effective treatment for disorders that manifest increased REM sleep drive and produce frequent nocturnal arousals and awakenings, e.g. schizophrenia, anxiety, insomnia, etc.

Development of REM sleep drive and clinical implications.

Rapid eye movement (REM) sleep in the human declines from approximately 50% of total sleep time ( approximately 8 h) in the newborn to approximately 15% of total sleep time (approximately 1 h) in the adult, and this decrease takes place mainly between birth and the end of puberty. We hypothesize that without this developmental decrease in REM sleep drive, lifelong increases in REM sleep drive may ensue. In the rat, the developmental decrease in REM sleep occurs 10-30 days after birth, declining from >70% of total sleep time in the newborn to the adult level of approximately 15% of sleep time during this period. Rats at 12-21 days of age were anesthetized with ketamine and decapitated, and brain stem slices were cut for intracellular recordings. We found that excitatory responses of pedunculopontine nucleus (PPN) neurons to N-methyl-D-aspartic acid decrease, while responses to kainic acid increase, over this critical period. During this developmental period, inhibitory responses to serotonergic type 1 agonists increase but responses to serotonergic type 2 agonists do not change. The results suggest that as PPN neurons develop, they are increasingly activated by kainic acid and increasingly inhibited by serotonergic type 1 receptors. These processes may be related to the developmental decrease in REM sleep. Developmental disturbances in each of these systems could induce differential increases in REM sleep drive, accounting for the postpubertal onset of a number of different disorders manifesting increases in REM sleep drive. Examination of modulation by PPN projections to ascending and descending targets revealed the presence of common signals modulating ascending arousal-related functions and descending postural/locomotor-related functions.

The developmental decrease in REM sleep

This mini-review considers certain factors related to the developmental decrease in rapid eye movement (REM) sleep, including its timing, its relationship to other developmental changes, factors that may influence its progress and its potential role in brain development. Specifically, we discuss some of the theories proposed for its occurrence and agree with the classic notion that REM sleep is, at least, an active mechanism that may play a role in the maturation of the central nervous system (CNS), specifically contributing to the maturation of thalamocortical pathways. The developmental decrease in REM sleep occurs gradually from birth until after puberty in the human, but in other mammals it is brief and coincides with eye and ear opening and the beginning of massive exogenous activation. This purported role for REM sleep may change to involve a number of other functions with age. We describe recent findings showing that intrinsic morphological and physiological properties as well as serotonergic, n-methyl-D-aspartic acid (NMDA) and kainic acid (KA) synaptic inputs to mesopontine cholinergic neurons change dramatically at this critical period in development, perhaps driving what has been proposed as a REM sleep inhibitory process (RIP). We hypothesize that a dysregulation of this process could result in life-long disturbances in REM sleep drive, leading to hypervigilance or hypovigilance such as that observed in a number of disorders which have a mostly postpubertal age of onset. Finally, we also hypothesize that the role of normal cyclic increases in vigilance, observable during both sleep and waking, may be related, at least in part, to cortical blood flow.

The developmental decrease in REM sleep

This mini-review considers certain factors related to the developmental decrease in rapid eye movement (REM) sleep, including its timing, its relationship to other developmental changes, factors that may influence its progress and its potential role in brain development. Specifically, we discuss some of the theories proposed for its occurrence and agree with the classic notion that REM sleep is, at least, an active mechanism that may play a role in the maturation of the central nervous system (CNS), specifically contributing to the maturation of thalamocortical pathways. The developmental decrease in REM sleep occurs gradually from birth until after puberty in the human, but in other mammals it is brief and coincides with eye and ear opening and the beginning of massive exogenous activation. This purported role for REM sleep may change to involve a number of other functions with age. We describe recent findings showing that intrinsic morphological and physiological properties as well as serotonergic, n-methyl- d-aspartic acid (NMDA) and kainic acid (KA) synaptic inputs to mesopontine cholinergic neurons change dramatically at this critical period in development, perhaps driving what has been proposed as a REM sleep inhibitory process (RIP). We hypothesize that a dysregulation of this process could result in life-long disturbances in REM sleep drive, leading to hypervigilance or hypovigilance such as that observed in a number of disorders which have a mostly postpubertal age of onset. Finally, we also hypothesize that the role of normal cyclic increases in vigilance, observable during both sleep and waking, may be related, at least in part, to cortical blood flow.

Effects of trazodone and imipramine on the biological rhythm: an analysis of sleep EEG and body core temperature.

Depression commonly involves abnormalities of the sleep-wake rhythm, the temperature rhythm, and other biological rhythms. The changes of these biological rhythms are caused in remission by medications. However, it has yet to be clarified whether the biological rhythms are changed as a result of recovery from depression or from the direct pharmacological effects of the antidepressants. Therefore, we have undertaken a study on the direct effects of the antidepressants trazodone and imipramine on the biological rhythms of healthy volunteers. The study involved 12 healthy male volunteers (ages 21 approximately 28 years, mean age 23.9+/-1.7 years) who had given written informed consent. Placebo, trazodone, and imipramine were each administered in a single blind manner four times a day, during the three-day study period. The total daily dosage of trazodone was 100 mg (50 mg in one subject), and of imipramine 40 mg (20 mg in one subject). Subjects were submitted to polysomnography (PSG) and body core temperature (rectal temperature) measurements during the study period. We compared the data concerning the antidepressants to those of the placebo. The results show that, with regard to the sleep rhythm, trazodone significantly increased slow wave sleep (SWS), but no changes were observed in REM (rapid eye movement) sleep. Imipramine significantly decreased REM sleep and prolonged the REM cycle. With regard to the temperature rhythm, trazodone showed a tendency to advance the appearance time of the minimal temperature. Imipramine significantly lowered the maximal temperature and decreased the difference between the maximal and the minimal temperature, but no changes in the phases were observed. Neither antidepressant had any effect on the temperature cycle. Trazodone and imipramine showed different effects on PSG. Furthermore, they had different effects on the temperature rhythm. The changes of the sleep-wake rhythm were greater than those of the temperature rhythm. Although the two antidepressants had different mechanisms of action, it is worthy of note that both directly influenced the biological rhythms of healthy volunteers.