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Background: The aim of this study was to identify the acute effects of ethanol on the relationship between sleep and heart rate variability (HRV) during sleep. Methods: Ten healthy male university students were enrolled in this study. An alcoholic beverage was given to each subject at a dosage of 0 (control), 0.5 (low dose: LD), or 1.0 g (high dose: HD) of pure ethanol/kg of body weight. All experiments were performed at 3-week intervals. On the day of the experiment, a Holter electrocardiogram was attached to the subject for a 24-hour period, and the subject was instructed to drink the above-described dosage of alcoholic beverage 100 minutes before going to bed; polysomnography was then performed for 8 hours. Power spectral analysis of the HRV was performed using the maximum entropy method, and the low- (LF: 0.04 to 0.15 Hz) and high-frequency (HF: 0.15 to 0.4 Hz) components along with LF/HF ratio were calculated. Results: As alcohol consumption increased, the heart rate increased and the spectral power of HRV measured at each frequency range decreased. Higher doses of ethanol also increased the LF/HF ratio compared with the measured ratio of the control group. Conclusions: Acute ethanol intake inhibits parasympathetic nerve activity and results in predominance of sympathetic nerve activity during sleep, in a dosage-dependent manner. The results of this study suggest that ethanol interferes with the restorative functions of sleep.

Study objectives Cerebrospinal fluid (CSF) hypocretin-1 levels and their relationship with the clinical characteristics of narcolepsy without cataplexy have not been well elucidated. Our aim was to examine whether clinical characteristics vary with CSF hypocretin-1 levels among narcoleptic patients without cataplexy. Design Clinical features, variables on the multiple sleep latency test, and results of HLA typing were correlated with CSF hypocretin-1 levels. Setting University-based sleep laboratories and a sleep disorders center. Patients Seventeen patients (5 male, 12 female) who fulfilled the diagnostic criteria of narcolepsy without cataplexy according to the International Classification of Sleep Disorders. INERVENTIONS: Patients underwent lumbar puncture for CSF sampling. Measurements and results Five patients showed a markedly decreased CSF hypocretin-1 level, whereas the remaining 12 patients showed almost normal levels. The mean rapid eye movement (REM) latency was significantly shorter and the age at onset was significantly earlier in the low CSF hypocretin-1 group compared with the normal CSF hypocretin-1 group. HLA-DR2 was positive in all of the patients with low CSF hypocretin-1, whereas only 33.3% of patients with normal CSF hypocretin-1 were DR2 positive. Conclusions Some narcoleptic patients without cataplexy have low CSF hypocretin-1 levels. In patients who have narcolepsy without cataplexy, short mean REM latency, younger age at onset, and HLA-DR2 are associated with CSF hypocretin-1 deficiency. Markedly decreased CSF hypocretin-1 levels could be a significant marker for identifying subgroups of narcolepsy patients without cataplexy.

Objective This study investigated the sleep-promoting, thermoregulatory, and circadian phase-shifting actions of passive body heating (PBH) in elderly insomniac patients (IPs) with mild-to-moderate vascular dementia. Methods Thirteen elderly IPs with vascular dementia (mean age 76.9 years; male/female ratio 2/11) were subjected to a PBH trial session. This session comprised a 3-day baseline period, 2-day PBH period, and 1-day post-PBH period. In the PBH period, the subjects received PBH (immersion in hot water about 40.0°C to mid-thorax level) for 30 minutes beginning 2 hours before bedtime. Sleep–waking, estimated by actigraph, core body temperature (cBT), and heart rate variability were continuously monitored. Dim-light melatonin-onset time (DLMO) was determined in the baseline and post-PBH periods. Results PBH significantly improved subjects' sleep quality; sleep latency decreased; sleep efficiency increased; and wake time after sleep onset decreased. These trends were more prominent in the latter half of the sleep time. PBH induced a rapid cBT elevation of approximately 0.80°C, on average, followed by enhanced heat loss (ΔcBT: difference in cBT between just after the PBH and bedtime), lasting 1.5 hours before sleep. There was a significantly positive correlation between ΔcBT and sleep latency. PBH induced no significant phase shift in DLMO. Heart-rate variability data showed that PBH induced parasympathomimetic action during sleep time in the subjects. Conclusion PBH may have a sleep-promoting effect by intervening in the thermoregulatory and autonomic systems in elderly IPs with vascular dementia.

In spite of the accumulation of knowledge regarding the neuropharmacological action of benzodiazepines (Bz), the physiological process by which their sedative/hypnotic effects are induced remains poorly understood. We conducted a single-blind, crossover trial to evaluate the role of the thermoregulatory process in sleepiness and impaired psychomotor performance induced by a standard Bz, diazepam (DZP). Each of the eight healthy young male volunteers (mean age, 19.75 years; range, 18-23 years) was given a single oral dose of either 5 or 10 mg of DZP or placebo 12 h after his average sleep onset time. Changes in plasma DZP concentration, proximal body temperature (p-BT), distal body temperature (d-BT), subjective sleepiness measured by the Visual Analog Scale and Stanford Sleepiness Scale, and psychomotor performance measured by Choice Reaction Time were monitored under a modified constant routine condition in which various factors affecting thermoregulation, alertness, and psychomotor performances were strictly controlled. Orally administered DZP induced a significant transient decrease in p-BT and psychomotor performance as well as an increase in d-BT and subjective sleepiness. Distal-p-BT gradient (DPG; difference between d-BT and p-BT), which is an indicator of blood flow in distal skin regions, showed a strong positive correlation with the plasma DZP concentration, indicating that DZP in clinical doses promotes heat loss in a dose-dependent manner. The DPG also correlated positively with the magnitude of subjective sleepiness and impaired psychomotor performance. These findings indicate that the sedative/hypnotic effects of Bz could be due, at least in part, to changes in thermoregulation, especially in the process of heat loss, in humans.

The symptoms of narcolepsy can occur during the course of other neurological conditions (i.e. symptomatic narcolepsy). We define symptomatic narcolepsy as cases that meet the International Sleep Disorders Narcolepsy Criteria, which are also associated with a significant underlying neurological disorder that accounts for excessive daytime sleepiness (EDS) and temporal associations. By 2005, we have counted 116 symptomatic cases of narcolepsy reported in the literature. As several authors previously reported, inherited disorders (n = 38), tumors (n = 33), and head trauma (n = 19) are the three most frequent causes for symptomatic narcolepsy. A review of these cases (especially those with brain tumors), illustrates a clear picture that the hypothalamus is most often involved. Reduced CSF orexin-A levels were seen in most symptomatic narcolepsy cases of EDS, with various etiologies including brain tumors, head trauma, and immune-mediated neurological conditions, such as neuromyelitis optica (NMO), and EDS in these cases is sometimes reversible with an improvement of the causative neurological disorder and an improvement of orexin status. It is also noted that some symptomatic EDS cases (with Parkinson diseases and the thalamic infarction) were observed,, but were not linked with orexin ligand deficiency. In this chapter, we first provide an overview of cases of symptomatic narcolepsy and EDS and then extend our discussions to the roles of the orexin system in EDS disorders associated with various neurological conditions.

A 5-year-old girl suffering from hypersomnia due to acute disseminated encephalomyelitis (ADEM) is reported. Brain CT revealed a large low-density lesion involving the lentiform nucleus, posterior limb of the internal capsule, thalamus, posterior hypothalamus and midbrain in the left side. She was treated with intravenous dexamethazone. After the initial dose of dexamethazone, hypersomnia was dramatically and rapidly improved. A later brain CT study disclosed that the lesion in the brain disappeared. The brain lesion in this case involved the waking center in the brain, which was described by Von Economo. We concluded that hypersomnia in this case was due to ADEM involving the neural mechanism for maintaing wakefulness, probably in the thalamus and posterior hypothalamus. Repeat all night polysomnograpy in this case disclosed prolonged total sleep time and increased amount of stage 3–4 sleep in the hypersomniac state.

The pineal hormone melatonin has some circadian regulatory effects and is assumed to have a close relation with sleep initiation and maintenance. Many previous reports have described age-related decreases in melatonin levels, especially in elderly insomniacs (EIs), which may act as causal or exacerbating factors in sleep disturbances in the elderly. Ten elderly residents with psychophysiological insomnia (mean age, 74.2 yr), 10 healthy residents of the same home [elderly control (EC) group; mean age, 72.7 yr], and 10 healthy young control subjects (mean age, 20.9 yr) living at home participated in this study. The elderly persons, especially the EIs, were exposed to significantly less environmental light and simultaneously suffered from significantly diminished nocturnal melatonin secretion. Supplementary exposure to 4 h (1000 to 1200 h, 1400 to 1600 h) of midday bright light in the EI group significantly increased melatonin secretion to levels similar to those in the young control group without circadian phase-shifting. There was a tendency for the magnitude of the increase in nocturnal melatonin secretion stimulated by bright light to parallel amelioration of sleep disturbances in these subjects. The present findings suggest that we need to pay attention to elderly individuals who suffer under conditions of poor environmental light resulting in disorganized circadian rhythms, including the sleep-wake cycle.

Increased daytime napping, early morning awakening, frequent nocturnal sleep interruptions, and lowered amplitude and phase advance of the circadian sleep-wake rhythm are characteristic features of sleep-waking and chronobiological changes associated with aging. Especially in elderly patients with dementia, severely fragmented sleep-waking patterns are observed frequently and are associated with disorganized circadian rhythm of various physiological functions. Functional and/or organic deterioration of the suprachiasmatic nucleus (SCN), decreased exposure to time cues such as insufficient social interaction and reduced environmental light, lowered sensitivity of sensory organs to time cues, and reduced ability of peripheral effector organs to express circadian rhythms may cause these chronobiological changes. In many cases of dementia, the usual treatments for insomnia do not work well, and the development of an effective therapy is an important concern for health care practitioner and researchers. Recent therapeutical trials of supplementary administration of artificial bright light and the pineal hormone melatonin, a potent synchronizer for mammalian circadian rhythm, have indicated that these treatments are useful tools for demented elderly insomniacs. Both bright light and melatonin simultaneously ameliorate disorganized thermoregulatory and neuroendocrine systems associated with disrupted sleep-waking times, suggesting a new, potent therapeutic means for insomnia in the demented elderly. Future studies should address the most effective therapeutic design and the most suitable types of symptoms for treatment and investigate the use of these tools in preventive applications in persons in early stages of dementia.

We examined the effects of an L-type Ca2+ channel blocker, nilvadipine (0.5 and 2.0 mg/kg), and that of a T-type Ca2+ channel blocker, flunarizine (10.0 and 40.0 mg/kg), on the hypnotic potency of both a benzodiazepine (BZ)-hypnotic, triazolam (1.0 mg/kg), and a non-BZ hypnotic, zolpidem (20.0 mg/kg), in rats. The polysomnogram was recorded for 6 h after administration of the vehicle solution alone, or after one of the Ca2+ channel blockers, with or without one of the hypnotics. Both Ca2+ channel blockers prolonged the increased total time of non-rapid eye movement (non-REM) sleep induced by either hypnotic. In the case of triazolam, however, the non-REM sleep-enhancing effect induced by nilvadipine was greater than that induced by flunarizine. These findings indicate that the hypnotic action of triazolam is potentiated more strongly by an L-type Ca2+ channel blocker than by a T-type Ca2+ channel blocker.

Background: There is growing evidence that the dysregulation of circadian rhythms may play an important role in irregular sleep–waking in demented elderly. In this study, we investigated daily variation of the pineal hormone melatonin, which has been reported to possess hypnogenic and synchronizing effects, in patients with senile dementia of Alzheimer’s type. Methods: Serum melatonin secretion rhythms in inpatients with senile dementia of Alzheimer’s type (SDAT group, n = 10, average age = 75.7 years) with disturbed sleep–waking and nondemented elderly (ND group, n = 10, age = 78.3 years) without clinical sleep disorders in the same facility were monitored under a dim light condition without excessive physical exercise. Results: The SDAT group showed a significantly higher degree of irregularities in actigraphically recorded rest–activity (R-A) rhythm during the 7-day baseline period compared with the ND group. The SDAT group simultaneously showed significantly reduced amplitude, larger variation of peak times, and diminished amount of total secretion in the melatonin secretion rhythm compared with the ND group. There were significantly positive correlations between the severity of R-A rhythm disorder and the reduced amplitude as well as diminished amount of total melatonin secretion. Conclusions: The SDAT patients with disturbed sleep–waking possessed melatonin secretion rhythm disorders that may play an important role in irregular sleep–waking in demented elderly.

In order to investigate the relative efficacy and safety of zopiclone and zolpidem, we compared the effects of higher doses of zopiclone and zolpidem on the frequency of hippocampal theta activity and sleep structure with that of triazolam. Rats were divided into triazolam treatment group (1 mg/kg, 5 mg/kg), zopiclone treatment group (20 mg/kg, 100 mg/kg) and zolpidem treatment group (20 mg/kg, 100 mg/kg). Rats were injected intraperitoneally with these drugs or their vehicle. Polygraphic sleep recording and visual frequency analysis of the hippocampal EEG activity in REM sleep were carried out for 6 h after each injection. Zolpidem, unlike triazolam and zopiclone, had a much milder reducing-effect on the frequency of hippocampal theta activity and suppressing-effect on REM sleep. These results suggest that zolpidem may prove to be a safer hypnotic drug which has fewer or milder side effects than are benzodiazepine and cyclopyrrolone hypnotics.

1. 1. The effect of electroconvulsive shock (ECS) on the extracellular concentration of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) was examined in the frontal cortex of rats with the use of in vivo microdialysis. 2. 2. The extracellular concentration of DOPAC, HVA and 5-HIAA was largely increased after the first ECS treatment. The increase after the eighth ECS treatment tended to be attenuated or was significantly attenuated as compared to that after the first ECS treatment. The baseline concentration of DOPAC and 5-HIAA was significantly increased after repeated ECS, though that of DA and HVA did not show any significant change after repeated ECS. 3. 3. These results suggest that the activating effect of repeated ECT on 5-hydroxytryptaminergic (5-HT) and DA neurotransmission, (especially on 5-HT neurotransmission), is significant in improving depression both in patients with Parkinson's disease (PD) and in those who do not suffer from PD.

The authors compared the therapeutic effect of morning bright and dim light exposure on rest-activity (R-A) rhythm disorders in patients with vascular dementia (VD) and patients with dementia of Alzheimer's type (DAT). Participants in this study were 12 patients with VD (M/F = 5/7; average age = 81 years) and 10 patients with DAT (M/F = 4/6; average age = 78 years). They were exposed to 2 weeks of bright light (BL; 5000-8000 lux) and 2 weeks of dim light (DL; 300 lux) in the morning (09:00-11:00) in a randomized crossover design in which the 2-week treatment period took place between pretreatment (1 week) and posttreatment (1 week) periods. Continuous R-A monitoring was performed at 1-minute intervals throughout the study using an actigraph around the nondominant wrist. The BL exposure for 2 weeks induced a significant reduction in both nighttime activity and percentages of nighttime activity to total activity compared with the pretreatment period, as well as compared with the DL condition in the VD group, but not in the DAT group. These findings support the assumption that the therapeutic efficacies of morning BL exposure are prominent in VD patients and are mainly due to its photic effect rather than nonphotic effects such as the intensification of social interaction accompanying light therapy.

STUDY OBJECTIVES Cyclic alternating pattern (CAP) is frequently followed by changes in heart rate (HR) and blood pressure (BP), but the sequential associations between CAP and autonomic nerve activity have not been studied. The study aimed to reveal the precise changes in heart rate variability (HRV) during phase A of the CAP cycle. DESIGN Polysomnography was recorded according to the CAP Atlas (Terzano, 2002), and BP and electrocardiogram were simultaneously recorded. The complex demodulation method was used for analysis of HRV and evaluation of autonomic nerve activity. SETTING Academic sleep laboratory. PARTICIPANTS Ten healthy males. MEASUREMENTS AND RESULTS The increase in HR (median [first quartile - third quartile]) for each subtype was as follows: A1, 0.64 (-0.30 to 1.69), A2, 1.44 (0.02 to 3.79), and A3, 6.24 (2.53 to 10.76) bpm (A1 vs. A2 P < 0.001, A1 vs. A3 P < 0.001, A2 vs. A3 P < 0.001). The increase in BP for each subtype was as follows: A1, 1.23 (-2.04 to 5.75), A2, 1.76 (-1.46 to 9.32), and A3, 12.51 (4.75 to 19.94) mm Hg (A1 vs. A2 P = 0.249, A1 vs. A3 P < 0.001, A2 vs. A3 P < 0.001). In all of phase A, the peak values for HR and BP appeared at 4.2 (3.5 to 5.4) and 8.4 (7.0 to 10.3) seconds, respectively, after the onset of phase A. The area under the curve for low-frequency and high-frequency amplitude significantly increased after the onset of CAP phase A (P < 0.001) and was higher in the order of subtype A3, A2, and A1 (P < 0.001). CONCLUSIONS All phase A subtypes were accompanied with increased heart rate variability, and the largest heart rate variability was seen in subtype A3, while a tendency for less heart rate variability was seen in subtype A1.

It has been reported that platelet-derived growth factor B-chains homodimer (PDGF-BB) improves learning function of mice, and that sugar chain structure Lewis-X of N-glycosylated glycoprotein promotes PDGF-BB secretion from platelets. Based on these findings, we assumed that learning dysfunction in some patients with mental retardation might be due to abnormality in PDGF-BB metabolism and/or Lewis-X structure. No difference in the reactivity of PDGF-BB and Lewis-X was found between the serum of patients with mental retardation and that of normals. But sialic acid reactivity of the Lewis-X fraction in some patients was remarkably higher than that in other patients and in normals. These findings suggest that sialic acids in the Lewis-X fraction may have a relation to one of the causes of learning dysfunction in these patients.

Using an actigraph and a long-term body temperature (BT) monitoring system, we simultaneously monitored rest-activity (R-A) and BT rhythms in patients with senile dementia of Alzheimer's type (SDAT; n = 20) or multi-infarct dementia (MID; n = 21) for 5-7 consecutive days. The SDAT group exhibited a well-organized BT rhythm with significantly higher amplitude compared with the MID group. The SDAT group also showed significant positive correlation between the total daily activity as well as percentage of nighttime activity and the degree of dementia, while no such tendency was observed in the MID group. The different properties of the biological rhythm disorders among the SDAT and MID groups possibly underlie their sleep and behavioral disorders.

Thalidomide is a sedative hypnotic that was widely used in the 1950s but was withdrawn due to its teratogenic properties. The compound has recently been reintroduced as an immune modulating agent. Thalidomide significantly aggravates canine cataplexy, a pathological manifestation of rapid eye movement (RFM) sleep atonia seen in narcolepsy. This compound also increases REM sleep and slow wave sleep in these animals. In vitro receptor binding and enzyme assays demonstrate that thalidomide does not bind to or enzymatically modulate the neurotransmitter systems reported to be involved in the regulation of cataplexy. Thalidomide may therefore affect cataplexy through its immune modulation properties. Further studies on the mechanisms of action of thalidomide should increase our understanding of the pathophysiology of this disabling disorder.

Summary The majority of patients with narcolepsy-cataplexy were reported to have very low cerebrospinal fluid (CSF) hypocretin-1 (orexin-A) levels. The hypocretin-1 levels of secondary excessive daytime sleepiness (EDS) disorders are not known. In this study, we found that CSF hypocretin levels in the patients with obstructive sleep apnea syndrome were within the control range. The low hypocretin levels seem to reflect only the presence of cataplexy and DR2 positive in narcoleptics but not EDS itself.

Muscle sympathetic nerve activity (MSNA) was recorded from peroneal from peroneal nerve in 4 OSAS patients during sleep. During apneic episode, MSNA was enhanced, but it did not increase progressively toward the end of the apneic episode. MSNA remained at a stable level in the later part of an apneic episode. A surge of MSNA took place just preceding or just at the end of an apneic episode and it was followed by a transient marked blood pressure elevation.

The treatment of depression in senile patients with dementia is difficult with the drugs used formerly. The effects of a new anxiolytic drug, tandospirone, were investigated on depression symptoms in nine senile patients with dementia using Hamilton Depression Rating Scale (HAM-D) items. Tandospirone improved the symptoms, especially the depressive mood, agitation and anxiety, although a slight gastrointestinal symptom was found in one patient. The findings in the present study may suggest that tandospirone is a useful and comparatively safe drug for depression symptoms in senile patients with dementia.

The aim of this study was to identify the acute effects of ethanol on the relationship between sleep and heart rate variability (HRV) during sleep.Ten healthy male university students were enrolled in this study. An alcoholic beverage was given to each subject at a dosage of 0 (control), 0.5 (low dose: LD), or 1.0 g (high dose: HD) of pure ethanol/kg of body weight. All experiments were performed at 3-week intervals. On the day of the experiment, a Holter electrocardiogram was attached to the subject for a 24-hour period, and the subject was instructed to drink the above-described dosage of alcoholic beverage 100 minutes before going to bed; polysomnography was then performed for 8 hours. Power spectral analysis of the HRV was performed using the maximum entropy method, and the low- (LF: 0.04 to 0.15 Hz) and high-frequency (HF: 0.15 to 0.4 Hz) components along with LF/HF ratio were calculated.As alcohol consumption increased, the heart rate increased and the spectral power of HRV measured at each frequency range decreased. Higher doses of ethanol also increased the LF/HF ratio compared with the measured ratio of the control group.Acute ethanol intake inhibits parasympathetic nerve activity and results in predominance of sympathetic nerve activity during sleep, in a dosage-dependent manner. The results of this study suggest that ethanol interferes with the restorative functions of sleep.

The symptoms of narcolepsy can occur during the course of other neurologic conditions (ie, symptomatic narcolepsy). Inherited disorders, tumors, and head trauma were the three most frequent causes for symptomatic narcolepsy. Other causes include multiple sclerosis (MS), vascular disorders, and encephalitis. Cerebrospinal fluid hypocretin-1 measures were carried out in some recent cases with symptomatic narcolepsy, and moderate decreases in hypocretin levels were seen in a large majority of these cases. Excessive daytime sleepiness (EDS) in these symptomatic cases was sometimes reversible with an improvement of the causative neurologic disorder and with an improvement of the hypocretin (orexin) status. Recently, we found that several symptomatic narcoleptic cases with MS show unique bilateral symmetric hypothalamic lesions associated with significant hypocretin ligand deficiency. In addition, these patients often share the clinical characteristics of neuromyelitis optica (NMO) and the detection of NMO-IgG (or anti-aquaporin-4 [AQP4] antibodies), suggesting a new clinical entity. Further studies of the involvement of the hypocretin system in symptomatic narcolepsy and EDS are helpful to understand the pathophysiologic mechanisms for occurrence of EDS and cataplexy.

Slow vertex response (SVR) to sound stimuli was used as an index to assess whether cortical reactivity in REM sleep with tonic mentalis EMG activity (stage 1-REM) corresponds to that in REM sleep or rather to that in stage 1 of NREM sleep. In 11 young adult subjects 3 night polygraphic records were made after administration of 25 or 50 mg of clomipramine or non-active placebo. Stage 1-REM was observed in the drug night in 8 of the 11 subjects. N 1 -P 2 and P 2 -N 2 amplitudes of SVR were markedly smaller in stage 1-REM than in stage 1, but were virtually of the same height in stage 1-REM and in stage REM. This indicates that cortical reactivity in stage 1-REM closely resembles the counterpart in stage REM. This findings corresponds well with the frequent emergence of vivid dreams in stage 1-REM, indicating that stage 1-REM observed in the present subjects probably represents REM sleep without muscle atonia.

SUMMARY Muscle nerve sympathetic activity (MSA) was recorded from the peroneal nerve during wakefulness and in different sleep states in healthy young adults. The burst rate (BR) of MSA significantly decreased in NREM, but not in REM sleep, compared with that during wakefulness. Transient increases of MSA frequently appeared in association with rapid eye movements during REM sleep. K-complexes in Stage 2 were almost always accompanied by a burst of MSA, and were followed by a transient elevation of arterial blood pressure. Auditory stimuli applied in sleep induced a burst of MSA followed by a transient increase of arterial blood pressure, only when they elicited an arousal response in the EEG, such as a K-complex, transient EEG desynchronization, or a short train of alpha waves. The same stimuli applied during wakefulness did not induce such changes in MSA and in arterial blood pressure. KEYWORDS arousal response, K-complex microneurography

We compared the sleep characteristics of seven healthy elderly people complaining of nocturnal somnambulism-like behaviors with those of 14 age-matched healthy elderly people who had never shown such behavior. Polysomnographic data revealed the appearance of “Stage 1-REM with tonic electromyographic (EMG) activity” sometimes accompanied by abnormal behavior in the first group, but the sleep architecture and parameters showed no significant difference between the two groups except for higher REM density in the first group. “Stage 1-REM with tonic EMG,” observed in the first group was considered equivalent to REM sleep without muscle atonia. It is suggested that both reduced activity of tonic phenomena (muscle atonia) and increased activity of phasic phenomena (higher REM density) of REM sleep are essential for the induction of somnambulism-like behaviors during sleep in healthy elderly subjects.

The symptoms of narcolepsy can occur during the course of other neurological conditions (i.e., symptomatic narcolepsy). We define symptomatic narcolepsy as cases that meet the International Sleep Disorders Narcolepsy Criteria, which are also associated with a significant underlying neurological disorder that accounts for excessive daytime sleepiness (EDS) and temporal associations. By 2005, we have counted 116 symptomatic cases of narcolepsy reported in the literature. As several authors previously reported, inherited disorders (n = 38), tumors (n = 33), and head trauma (n = 19) are the three most frequent causes for symptomatic narcolepsy. A review of these cases (especially those with brain tumors), illustrates a clear picture that the hypothalamus is most often involved.

Nocturnal sleep was examined in 12 patients with degenerative diseases involving the brain stem and in 2 patients with late cerebellar cortical atrophy (LCCA). A peculiar sleep state, characterized by the concomitant appearance of a low-voltage mixed frequency EEG, rapid eye movements (REMs) and tonic EMG in mental muscles, repeatedly appeared during nocturnal sleep in all of the 12 patients with degenerative diseases involving the brain stem and it was called stage 1-REM after Tachibana et al.32 In 8 of the 12 patients, delirious or oneiric behavior appeared during, or soon after, the episodes of stage 1-REM. Inner experiences reported by one of the subjects well corresponded to his behavior during the episode of stage 1-REM. Stage 1-REM was not observed during nocturnal sleep of the patients with LCCA. These results indicate that a degenerative lesion in the brain stem induced stage 1-REM and delirious behavior during nocturnal sleep through abolishing muscle atonia of REM sleep and causing dissociation of the functional components characterizing REM sleep.

Vitamin B12 (VB12) was administered to two patients suffering for many years from different sleep-wake rhythm disorders. One patient was a 15-year-old blind girl suffering from a free-running sleep-wake rhythm (hypernychthemeral syndrome) with a period of about 25 h. In spite of repeated trials to entrain her sleep-wake cycle to the environmental 24-h rhythm, her free-running rhythm persisted for about 13 years. When she was 14 years old, administration of VB12 per os was started at the daily dose of 1.5 mg t.i.d. Shortly thereafter, her sleep-wake rhythm was entrained to the environmental 24-h rhythm, and her 24-h sleep-wake rhythm was maintained while she was on the medication. Within 2 months of the withholding of VB12, her free-running sleep-wake rhythm reappeared. The VB12 level in the serum was within the normal range both before and after treatment. The other patient was a 55-year-old man suffering from delayed sleep phase syndrome since 18 years of age. After administration of VB12 at the daily doses of 1.5 mg, his sleep-wake rhythm disorder was improved. The good therapeutic effect lasted for more than 6 months while he was on the medication.

Polysomnography was used to assess the effect of thalidomide on human sleep. This compound significantly increased the time spent in REM and stage 3-4 sleep as compared with placebo. On the other hand, thalidomide significantly decreased the time spent in stage 1, while the time spent in stage 2 was unchanged. The effect of thalidomide on REM and stage 3-4 sleep is unique as compared with other hypnotics. Although the mode of action of this compound is unknown, further studies on thalidomide should help in our understanding of the mechanisms of sleep regulation.

The present study was performed in order to determine whether spontaneous K-complex are induced by sensory stimuli. Electroencephalogram (EEG) segments in stage 2 sleep containing an evoked K-complex or spontaneous K-complex were separately averaged with respect to the peak of N300, one of the main components constituting the K-complex. Small negative and positive components were found immediately before the main components of spontaneous K-complex in averaged EEG. These two components were judged to correspond to N100 and P200 induced by the sound stimulus. The present findings suggest that the spontaneous K-complex is not a spontaneous phenomenon but that it is induced by sensory stimuli.

A suddenly occurring episode characterized by perceptual alteration (SEPA), mainly of visual and/or auditory modalities, which repeatedly occurred in three schizophrenic patients on long-term neuroleptic medication, is described. Perceptual alteration showed some distinct features that were different from acute symptoms of schizophrenia, and was accompanied by mood changes such as severe anxiety and agitation and, in one of the patients, also by extrapyramidal symptoms. Perceptual alteration, as well as mood changes and extrapyramidal symptoms, responded well to an anticholinergic drug, biperiden. Recent studies have shown that SEPA occurred not only in schizophrenic patients but also in patients on long-term neuroleptic medication for treating other mental disorders. These findings suggest that SEPA is associated with dopaminergic hypoactivity in the brain, which is induced by long-term neuroleptic medication.

To evaluate the effect of bright light on the sympathetic nervous system in human, muscle sympathetic nerve activity (MSNA) was recorded from the peroneal nerve in five healthy subjects. Each subject was exposed to bright light of 5000 lx for 20 min. After the bright light exposure, MSNA became significantly enhanced. The heart rate increased transiently only during the bright light exposure. The blood pressure did not change significantly during and after the bright light exposure. This result is the first direct evidence showing that bright light modulates the activity of the sympathetic nervous system in normal human.

It is reported that high-dose methamphetamine (8 mg/kg) induces stereotyped behavior in ddY mice in an open field, but it is still not certain that low-dose methamphetamine (less than 2 mg/kg) can induce the stereotyped behavior in ddY mice in a narrow space. In order to investigate the problem, we evaluated the quantity of stereotyped behavior of ddY mice by using a mouse wheel-running apparatus. In this method, we have come to recognize an increase in the stereotyped behavior depending on the dose of methamphetamine and the reverse-tolerance phenomenon as a decrease in the wheel-revolution counts. The present findings indicate that low-dose methamphetamine can promote stereotyped behavior in ddY mice under conditions in which the ambulation is restricted to a narrow wheel space.

Whether elderly people suffer from age-related changes in pharmacokinetics and/or pharmacodynamics with administration of benzodiazepines is still a matter of controversy. We investigated the course of brain function and thermoregulation after oral administration of a standard benzodiazepine, diazepam (DZP), in 8 healthy young men (mean age, 19.8 years; range, 18 to 23 years) and 8 healthy middle-aged and older men (mean age, 60.9 years; range, 53 to 71 years). Placebo or DZP was administered in a single-blind crossover manner to the young men (placebo, 5-mg, 10-mg DZP) and to the older men (placebo, 5-mg DZP), and plasma DZP concentration, choice reaction time, proximal body temperature, and distal body temperature were monitored with high time resolution under a modified constant routine condition to exclude masking effects. Whereas there was no evidence of age-related alterations in pharmacokinetics between the 2 groups, the older subjects, in comparison to the young subjects, showed a more delayed choice reaction time in response to the same plasma DZP level, suggesting that hypersensitivity is related to increased age. DZP at 5 mg in the older subjects induced acute and transient hypothermia to the same degree as that induced by DZP at 10 mg in the young subjects. The distal-proximal body temperature gradient (difference between distal body temperature and proximal body temperature), an indicator of blood flow in distal skin regions, showed strong positive correlation with the delay in choice reaction time in both groups. These findings suggest that hypersensitivity to benzodiazepine in older persons may be due, at least in part, to age-related changes in thermoregulation, especially in the heat loss process.

Study Objectives: Sleep deprivation has a profound effect on cardiovascular regulation through the autonomic nervous system. This study examined the effect of 24-hour total sleep deprivation on muscle sympathetic nerve activity (MSNA), which is a direct measurement of the postganglionic sympathetic efferent innervating the vascular bed in the skeletal muscle and other circulatory structures. Design: The study was performed on 6 young healthy men. The factors exerting influence on MSNA, such as aging, obesity, body posture, activity, intensity of illumination, and food and beverage consumption were strictly controlled. Burst rate and burst incidence were used as parameters of MSNA. The burst rate, burst incidence, heart rate, and systolic and diastolic blood pressure were measured after total sleep deprivation and control sleep. To perform a linear regression analysis of arterial baroreflex (ABR), the incidence of MSNA bursts corresponding to a given diastolic blood pressure (%MSNA) was examined. Measurement and Results: The diastolic blood pressure was significantly higher after total sleep deprivation than after control sleep (66.5 ± 1.7 vs 57.4 ± 3.3 mm Hg). The burst rate (9.6 ± 1.8 vs 13.3 ± 2.7 bursts/min) and burst incidence (21.6 ± 4.5 vs 30.3 ± 8.9 bursts/100 heart beats) of MSNA were significantly lower after total sleep deprivation than after control sleep (P < .05). Analysis of the ABR disclosed a significant linear regressive relation between %MSNA and diastolic blood pressure in every subject after both total sleep deprivation and control sleep. This result implies that the ABR regulates the occurrence of MSNA bursts under different diastolic blood pressure conditions. The threshold (X-axis intercept) of the blood pressure regression line (ie, an indicator of the ABR set point) shifted by 12 ± 4.3 mm Hg toward a higher blood pressure level after total sleep deprivation (P < .05). The ABR sensitivity, or the slope of the regression line, tended to be less steep after total sleep deprivation than after control sleep, although it was not statistically significant (P = .09). Conclusions: The diastolic blood pressure increased and both burst rate and burst incidence of MSNA decreased after total sleep deprivation. The results show that resetting of the ABR toward a higher blood pressure level occurred after total sleep deprivation. This ABR resetting probably brings about an increase in arterial blood pressure after total sleep depri

Aging is often associated with decreased ability of sleep maintenance. It has been hypothesized that the elderly experience a delayed timing of sleep period relative to the circadian phase of various sleep-promoting physiological functions, possibly causing decreased sleep propensity in the latter part of their nocturnal sleep. We evaluated the relationship between the sleep timing and circadian phase of melatonin secretion, which is known as a possible human sleep modulator as well as a stable marker of biological clock phase (BCP). Actigraph sleep recordings were performed, followed by the evaluation of melatonin phase under dim light in 42 healthy elderly volunteers (mean age, 68.8 yr; male/female ratio, 16/26) and 27 healthy young male volunteers (22.5 yr). Elderly subjects showed remarkable clock time advances in both the midpoint of BCP and sleep timing, with a significant decrease in sleep maintenance ability. However, they showed no significant age-related changes in the sleep timing against the midpoint of BCP, suggesting that early morning awakening in the elderly appeared in a BCP for which sleep propensity remained sufficient to sustain sleep. The present findings do not support the hitherto known hypothesis that age-related delay in the sleep timing against the BCP induces the deterioration in sleep maintenance in the elderly.

The relationship between antidepressant effects and plasma levels of milnacipran was studied in 49 cases of major depression without psychotic features during 6 weeks of milnacipran treatment. The daily dose of milnacipran was 50 mg/day for the first week, and up to 100 mg/day thereafter. Depressive symptoms were evaluated by the Montgomery and Asberg depression rating scale (MADRS) before treatment and at 1, 2, 4 and 6 weeks after the beginning of this study. Thirty-four patients (69.4%) were responders (defined as a 50% or greater decrease in the baseline MADRS score). Significant differences of MADRS scores were seen from 1 week after the beginning of this study (p=0.004, unpaired t-test) between responders and nonresponders. The mean plasma milnacipran level of responders, 82.0 +/- 29.4 ng/ml, was similar to that of non-responders, 78.6+/-23.1 ng/ml; there was no significant difference between responders and nonresponders. Neither a significant linear nor a curvilinear relationship was obtained between the final MADRS score and the plasma levels of milnacipran. Although there was no significant relationship between the plasma levels of milnacipran and the antidepressant response, milnacipran should be considered an efficacious agent in the treatment of major depressive patients.

Study objectives To investigate the effects of one night's total sleep deprivation (TSD) on NK cell activity, with rigorous control of circadian phase of sampling points as well as physical exercise level in association with sleep deprivation. Design The mean sleep onset time of each subject before starting the study was defined as his 0000 h. This study was composed of a Sleep-Sleep session (sleep times, 00:00 h - 08:00 h and 24:00 h - 32:00 h) and a Sleep-Wake session (sleep time, 00:00 h - 08:00 h) with TSD (24:00 h - 32:00 h) placed in a cross-over design with 2-week interval between each session. In each session, the subjects were rested in the supine position under dim light from - 06:00 h to 36:00 h (for 42 hours). Setting University-based sleep and chronobiology laboratory Participants 10 healthy adult men (mean age, 20.9 y; age range, 19-23 y) Interventions NA. Measurements and results NK cell activity was measured every 4 hours from 12:00 h. NK cell activity during TSD (at 28:00 h) has been revealed to significantly increase (p=0.01) compared with the corresponding value in the Sleep-Sleep session. This effect was weaker at their usual waking time 32:00 h (p=0.07), and disappeared until 36:00 h (4 hours after awakening). The circadian rhythm phases (dim light melatonin onset time) were coincident between the 2 sessions. Conclusions The present findings suggest that one night TSD induces an acute and transient increase in NK cell activity that is not influenced by the effects of circadian rhythm or the amount of physical exercise undertaken during TSD.

We have newly found that interleukin-2 (IL-2) increases mouse voluntary running 24 hours, but not 30 minutes, after the injection. We suspected that IL-2 induced a substance increasing the voluntary running for 24 hours after injection. Serum obtained from mice 24 hours after the IL-2 treatment was fractioned with the use of an ion-exchanger and an ultra-filtration method, and the amino acid sequence analysis indicated that the substance purified from the effective fraction was a fragment of mouse complement 3a (C3a) lacking the primary 9 amino acids. The 20 amino acid peptide synthesized according to the fragment showed the activity increasing the voluntary running, but the 20 amino acid peptide synthesized according to the C3a itself did not. The effect of the synthesized peptide was demuted by haloperidol but not by a specific dopamine 2 antagonist (−)sulpiride. The present findings clearly indicate that IL-2 produces the C3a fragment lacking the primary 9 amino acids which directly promotes the voluntary running, and that the effect of the fragment is mediated by an activity of haloperidol on the neurons, except for the dopamine 2 antagonism.

Panic attacks meeting the diagnostic criteria for panic disorder (DSM-III-R) were found in nine (20%) of 45 patients suffering chronic schizophrenia for more than 5 years. The scores of the Hamilton Depression Rating Scale and the Simpson Angus Scale were significantly higher in the group of patients with panic attacks. They also tended to be taking neuroleptics in larger doses than in the other group. The present report suggests that long-term treatment with neuroleptics is closely related to the manifestation of panic attacks in chronic schizophrenia. It also suggests that when panic attacks are seen frequently in patients taking high doses of neuroleptics, dose reduction of neuroleptics should be considered.

Behavior of event related potential (ERP) components in the drowsy state was examined in nine subjects using oddball paradigm. A component with peak latency of 300 msec, N300, was superimposed on ERP in the drowsy state. N300 appeared also in stage 1 of NREM sleep and closely resembled vertex sharp wave evoked by sound stimulation in both scalp distribution and peak latency. It was suggested that N300 recorded in the drowsy state and vertex sharp wave recorded in stage 1 of NREM sleep are generated by the identical synchronizing mechanism in the brain.

We studied the prevalence of sleep-related respiratory disorders (SRRD) in 101 schizophrenic inpatients (64 men and 37 women) and in 48 healthy volunteers (control group: 22 men and 26 women) using ambulatory pulse-oximetric devices. Those with a desaturation index (DI) > or = 5 were classified as having SRRD. The prevalence of SRRD in the schizophrenic patients (men 21.9%, women 13.5%) was not higher than that in the control group (men 30.7%, women 13.6%). Gender difference in the prevalence of SRRD was not observed in schizophrenic group. This was probably because the schizophrenic women took an increased amount of sleeping pills. Neuroleptics were shown to be least effected on SRRD.

We recorded muscle sympathetic nerve activity (MSNA) from the peroneal nerve during sleep iii three OSAS patients who showed three kinds of apnea. During central apneas and central component of mixed apnea, bursts of MSNA appeared in high probability with almost each heart beat. During obstructive apneas and the obstructive component of mixed apneas, bursts of MSNA appeared in a cluster after the end of each inspiratory effort. Burst rate of MSNA during apnea were higher in central apneas and the central component of mixed apnea than in obstructive apneas and the obstructive component of mixed apneas. These findings indicate that activity in the sympathetic nervous system is enhanced not only in obstructive apnea but also in central and mixed apnea.

Six healthy male volunteers (average age = 22.5 years) received orally melatonin (MLT; 3 mg or 9 mg) or placebo at 0930 hours in a randomized, single-blind, cross-over study. Both doses of exogenously administered melatonin (ex-MLT) induced transient, significant suppression of core body temperature (BT) compared to the placebo condition. There was no significant difference in the degree of BT suppression among the two MLT conditions in spite of significantly higher levels of serum MLT with the close of 9 mg, suggesting that there may be a threshold level of ex-MLT inducing the hypothermic action. Daytime administered ex-MLT also induced a significant sleep-inducing effect only in the 9 mg condition, while 3 mg ex-MLT failed to produce statistical significance. These findings suggest that the sleep-inducing action of ex-MLT occurs only at relatively high doses, and this action is probably not due to its BT lowering action. The present study led us to assume that ex-MLT produce its therapeutic effect for circadian rhythm sleep disorders through induction of circadian phase-shifting preceded by an acute, transient hypothermic action rather than light entrainment after setting sleep time by induction of sleep propensity.

1. 1. The effect of electroconvulsive shock (ECS) on extracellular concentration of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) was examined with the use of in vivo microdialysis in rat striatum. 2. 2. Extracellular concentration of DA was markedly increased up to 183% after single ECS, and that of DOPAC, HVA and 5-HIAA was also significantly increased. The increase after the eighth ECS was attenuated compared to their increase soon after the first ECS. After repeated ECS, baseline concentration of DOPAC, HVA and 5-HIAA was significantly increased, and baseline DA concentration tended to increase. 3. 3. These results suggested that single and repeated ECS activated metabolism of DA and 5-hydroxytryptamine in rat striatum. Activated metabolism of DA may be responsible for the clinical effect of electroconvulsive therapy for parkinsonism.