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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.

Background: Causative role of encephalitis in major psychotic features, dyskinesias (particularly orofacial), seizures, and autonomic and respiratory changes has been recently emphasized. These symptoms often occur in young females with ovarian teratomas and are frequently associated with serum and CSF autoantibodies to the NMDA receptor (NMDAR)., Methods: The study included a total of 61 patients from age 15 to 61 and was carried out between January 1, 2005, and Dec 31, 2010. The patients were divided into the following three clinical groups for comparison. Group A; Patients with typical clinical characteristics of anti-NMDAR encephalitis. Group B; Patients with narcolepsy with severe psychosis. Group C; Patients with schizophrenia or schizo-affective disorders., Results: Ten out of 61 cases were anti-NMDAR antibody positive in typical encephalitis cases (group A: 3 of 5 cases) and cases in a broader range of psychiatric disorders including narcolepsy (group B: 3 of 5 cases) and schizophrenia (group C: 4 of 51 cases)., Conclusion: In addition to 3 typical cases, we found 7 cases with anti-NMDAR antibody associated with various psychotic and sleep symptoms, which lack any noticeable clinical signs of encephalitis (seizures and autonomic symptoms) throughout the course of the disease episodes; this result suggest that further discussion on the nosology and pathophysiology of autoimmune-mediated atypical psychosis and sleep disorders is required.

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., (Copyright © 2011 by the Research Society on Alcoholism.)

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.

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 degrees 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 degrees C, on average, followed by enhanced heat loss (DeltacBT: difference in cBT between just after the PBH and bedtime), lasting 1.5 hours before sleep. There was a significantly positive correlation between DeltacBT 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.

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 deprivation.

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., (Copyright 2003 John Wiley & Sons, Ltd.)

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 process of heat loss has been shown to be a key pathway regulating sleepiness in humans. The influence of physical exercise with its attending heat production on subjective sleepiness and performance levels during total sleep deprivation (SD) was assessed in eight healthy young volunteers (mean age 21.1 years). Each subject participated in a SD cross-over study in which sleepiness and performance levels were tested under exercise and non-exercise conditions. The exercise entailed 15 min walking/h (3.0 Kcal/kg per h caloric consumption). Physical exercise significantly alleviated subjective sleepiness depending on the magnitude of the core body temperature elevation. This indicates that suppressing heat loss could prevent progression of subjective sleepiness during the nighttime. We found a strong positive correlation between increased sleepiness and decreased performance levels in each of the two experimental sessions. However, ANCOVA revealed a significant difference in the slope of the regression lines representing two sessions, indicating less subjective sleepiness with physical exercise despite the same decrease in performance. The present findings alert us to the possibility that increased physical activity during extended wakefulness could increase the dissociation between subjective evaluation of sleepiness and actual brain function, resulting in increased risk of human error.

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., (Copyright 2002 John Wiley & Sons, Ltd.)