Hiroo Kuwahara

Automatic real-time analysis of human sleep stages by an interval histogram method

A new interval histogram method for automatic, all-night sleep stage scoring, simulated on a digital computer, is described. The system consists of a 2-step analysis. The first step is recognition of elementary patterns in EEG, EOG and EMG, and the second step is the determination of sleep stages based on these parameters. Correlation of this method with power spectral analysis of the dominant EEG patterns during each sleep stage supported the reliability of the first step analysis. Overall agreement (89.1%) between the computer and human judges was only 3% less than the agreement (92.1%) among the scorers, indicating considerable reliability of the second step. The primary areas of disagreement that arose in the identification of sleep stages occurred with stages 1, 2 and REM. To improve scoring accuracy, the system may require epoch sequence information. The profile of the elementary parameters of the EEG signals clearly illustrated the cyclic nature of these activities throughout the night. The alpha and delta 2 waves clearly separated the awake state from sleep stages. Beta 2 can discriminate stages 1 and REM from stage 2, and the best indicator for distincting stage 1 from REM was muscle activity. Sigma and spindles were prominent during stage 2 sleep. Both delta 2 and high voltage delta waves distinguished stage 3 from stage 4. On the other hand, delta 1 was evenly distributed and seemed to be common to all sleep stages.

Effect of ceruletide on tardive dyskinesia: a pilot study of quantitative computer analyses on electromyogram and microvibration

Seven patients with bucco-lingual dyskinesia were treated with a single dose of ceruletide 0.8 μg/kg IM, a potent analogue of cholecystokinin octapeptide. Time-course effects of the drug were then followed up to 6 weeks after injection in the longest case. To assess changes in severity of dyskinesia objectively, electromyogram and microvibration were recorded. These data were subjected to the Fast Fourier Transform and an averaged power spectrum was computed. The effect of ceruletide on dyskinesia within 2 h after injection differed (three cases: inhibitory, two cases: facilitatory, two cases: no effect). It was notable that a long-lasting inhibitory effect of this peptide was observed in two severe irreversible cases. The present findings might contribute to further understanding of the physiopathophysiological role of cholecystokinin-like peptides in the brain and to practical treatment of tardive dyskinesia.

Efficacy and tolerability of ramelteon in a double-blind, placebo-controlled, crossover study in Japanese patients with chronic primary insomnia

The aim of this study was to evaluate the efficacy and safety of ramelteon 4, 8, 16 or 32 mg and placebo in Japanese patients with chronic insomnia using a randomized, double-blind, five-period crossover design. A total of 65 Japanese patients with chronic primary insomnia received ramelteon or placebo for two nights each in sleep laboratories. Changes in sleep parameters were assessed objectively by polysomnography and subjectively by postsleep questionnaires. Safety and tolerability was evaluated by assessment of the occurrence of adverse events, next-day residual effects and laboratory and ECG investigations. Ramelteon 8 and 32 mg significantly shortened the mean latency to persistent sleep in comparison with placebo, and there was a statistically significant trend for linear dose–response for this sleep parameter. Overall changes in sleep architecture were modest (<3% changes vs placebo), with increases in stage 1 and decreases in stage 3/4. Ramelteon was well tolerated, the most common adverse effect being somnolence, which was similar to placebo at doses up to 8 mg, but increased with higher doses. Next-day residual effects occurred no more frequently with ramelteon at any dose than with placebo. When compared with sleep latency data from a similarly-designed US study, there was no evidence of any ethnic differences in the efficacy of ramelteon between Japanese and US patients. Overall, ramelteon 8 mg showed the most favorable balance between sleep-promoting effects and tolerability. The unique efficacy profile of ramelteon, promoting sleep initiation without affecting other sleep parameters, may be due to its circadian shifting effect.

Effect of zolpidem on sleep architecture and its next-morning residual effect in insomniac patients: a randomized crossover comparative study with brotizolam.

This study was conducted to determine the effect of zolpidem (ZOL) 10 mg orally on the sleep architecture and the next-morning residual effect in patients with non-organic insomnia (ICD-10) as compared to the effect of brotizolam (BTM) 0.25 mg orally, a widely used short-acting benzodiazepine (BZD) hypnotic in Japan, in a randomized, crossover comparative study. Fourteen patients with non-organic insomnia (3 males and 11 females; mean age of 54.9+/-S.D. 8.9 years). First three nights with placebo, middle three nights with either ZOL 10 mg or BTM 0.25 mg, and last three nights again with placebo in each session (a total of two sessions). Primary endpoints were polysomnography findings of sleep stages, sleep parameters, and sleep latency (SL) in the morning to examine calculable sleepiness as a residual effect. Secondary endpoint was sleep quality assessed by self-assessment questionnaire. At 150 min after Tmax, both ZOL and BTM significantly increased stage 2 (S2), and ZOL showed significantly longer slow wave sleep (SWS; stage 3+4) as compared to BTM. Stage wake was significantly increased by ZOL at the first withdrawal night and by BTM at the second withdrawal night. ZOL did not affect SL after rising, whereas BTM showed significantly shorter SL. Both drugs reduced the number of nocturnal awakenings and improved subjective sleep quality. The common adverse drug reaction (ADR) was sleepiness (3 patients) in each treatment. All events were mild. No serious adverse events occurred. ZOL is as effective as BTM in improving subjective sleep quality in patients with psychophysiological insomnia (PPI). ZOL has advantages over BTM in having a unique profile of increasing SWS with less next-morning residual effect.

Decreased blood flow of the left thalamus during somnolent episodes in a case of recurrent hypersomnia

Abstract A 24‐year‐old male with recurrent hypersomnia associated with decreased blood flow in the thalamus on single photon emission computed tomography (SPECT) is reported. In the hypersomnolent period, the decrease of blood flow in the left thalamus was revealed in the SPECT and slow waves appeared sporadically or sometimes as a burst on the electroencephalogram (EEG). In a phase of insomnia in the convalescent period there were almost no slow waves in the resting EEG but many slow waves appeared on hyperventilation EEG and the power spectrum at this hyperventilation resembled the power spectrum at the resting EEG in the hypersomnolent period. In the remission period there was no abnormal data in these testings.

A randomized placebo-controlled polysomnographic study of eszopiclone in Japanese patients with primary insomnia

OBJECTIVES To evaluate the efficacy and dose-response effect of eszopiclone on sleep latency and sleep maintenance in Japanese patients with primary insomnia. METHODS In this randomized, double-blind, five-way crossover study, 72 patients received placebo, eszopiclone 1mg, 2mg, and 3mg, and zolpidem 10mg in random order for two consecutive nights with a washout period between treatments. Objective sleep measures from polysomnography (PSG) and subjective patient reports were collected. RESULTS All active treatments produced significant improvement in objective and subjective sleep latency compared with placebo (P<0.05 for all comparisons); linear dose-response relationships were observed for eszopiclone. PSG-determined wake time after sleep onset (WASO), sleep efficiency, and number of awakenings (NA), and patient-reported measures of WASO, NA, sleep quality, sleep depth, and daytime functioning significantly improved following treatment with eszopiclone 2mg and 3mg and zolpidem 10mg versus placebo (P<0.05). Eszopiclone at all doses increased total sleep time and stage 2 sleep time (P<0.001 for both comparisons), but did not alter REM or slow-wave sleep. Eszopiclone was generally well tolerated; the most frequently reported adverse event was mild dysgeusia. CONCLUSIONS In Japanese patients with primary insomnia, eszopiclone 2mg and 3mg significantly improved PSG-determined and patient-reported sleep latency and sleep maintenance relative to placebo.

Study on withdrawal of hypnotics: questionnaire on hypnotic use and its withdrawal.

To investigate the situation and problems contingent to hypnotic use and withdrawal, we conducted a questionnaire of outpatients. Only 41% of the patients were satisfied with their sleep and 53% of the patients took hypnotics. As regards the period, 83% of users had used them for more than 1 year and 19% had used them for more than 10 years. Although 90% of patients perceived efficacy of hypnotics, 67% felt more or less anxious about hypnotic use. Sixty‐seven per cent of patients had actually withdrawn from the drugs or decreased dosage before. More than half the patients’ conditions worsened after the withdrawal or reducing dosage.

Situation and problem of administration methods and the intermission of hypnotics

Abstract The results of a questionnaire survey suggested four problems that might prolong the administration of benzodiazepine hypnotics without suspending the medication. First, psychiatrists did not actively consider the necessity of suspension of medication with hypnotics. Second, the period between improvement of insomnia and initiation of dose reduction was long, whereas the period between initiation of dose reduction and discontinuation was short. Third, to suspend medication of a hypnotic, every‐other‐day administration was used for the very short‐acting and short‐acting types, and substitution of the intermediate‐acting or long‐action type for the drugs with a short half‐life were performed frequently. Finally, dose reduction and intermission of medication induced rebound insomnia, withdrawal symptoms, and recurrence of insomnia.

Distinguishing Acute and Tardive Akathisia by Monitoring Microvibration: A Pilot Study

Abstract: One acute and one tardive akathisia patients, respectively, and 10: neuroleptic‐treated schizophrenic patients were injected with biperiden 5: mg or saline and the response to anticholinergics was monitored by microvibration (MV) as an indicator of muscle tonus. These data were subjected to the Fast Fourier Transform and an averaged power spectrum was computed. The biperiden injection markedly reduced the power spectral values of MV in acute akathisia. In contrast with acute akathisia, the biperiden injection sigdlcantly increased the power spectral values of MV in tardive akathisia. The subjective feelings of akathisia patients were parallel to the power spectral values of MV. Control patients were not aflected by such treatment. The present findings show that the subjective symptoms of akathisia can be well defined by the objective, differential response to anticholinergics in a manner similar to the visible extrapyramidal symptoms (dystonia, dyskinesia) induced by neuroleptics.

Absence of Adverse Effects of Oseltamivir on Sleep: A Double‐Blind, Randomized Study in Healthy Volunteers in Japan

Influenza-associated neuropsychiatric symptoms include parasomnias such as sleepwalking which is a common sleep disturbance in childhood. Oseltamivir is a widely used antiviral drug for influenza. Recently, sleepwalking-like events have been reported in patients with influenza receiving oseltamivir. We investigated whether oseltamivir itself has effects on sleep. In this crossover study, healthy Japanese male volunteers were randomized into two treatment groups, each of which comprised two double-blind 4-day treatment periods. In the first period, group A received 75 mg oseltamivir (evening dose) on day 3, followed by 75 mg b.i.d. on day 4, and placebo in the second period. Group B received the same treatments, but in reverse order. Polysomnographic assessments were performed on all four nights of each treatment period. Pharmacokinetics were assessed during a 2-day open-label phase beginning on day 12. Thirty-one volunteers aged 20-24 years were enrolled. No volunteer had electroencephalographic abnormalities, and no abnormal behaviour was observed. Sleep parameters measured over the whole night and during early- and late sleep periods (first and last thirds of the night) were very similar for oseltamivir and placebo, although the amount of stage 2 sleep in the middle sleep period was slightly greater with oseltamivir. Pharmacokinetics for oseltamivir phosphate in groups A and B were very similar, but for oseltamivir carboxylate, AUC and C(max) values were higher in group B, probably because this group received oseltamivir on the evening of day 11. Oseltamivir was well tolerated. Oseltamivir did not produce clinically relevant changes on nocturnal polysomnographic variables in young Japanese men.