Cortical regional differences of delta waves during all-night sleep in schizophrenia.

BACKGROUND: Delta sleep is mediated by thalamocortical circuits and is postulated to be abnormal in schizophrenia. Delta wave deficits during sleep have been observed in patients with schizophrenia. Negative symptoms have been reported to reflect frontal lobe dysfunction and to be associated with decreased delta wave sleep. This investigation was undertaken to identify cortical functional abnormalities in patients with schizophrenia shown on the electroencephalogram. METHODS: We compared seventeen male, medically treated or neuroleptic-naive outpatients with schizophrenia and 18 healthy male volunteers by all-night polysomnography and investigated cortical regional differences of delta waves. All-night sleep data was evaluated by period amplitude analyses. Delta waves during sleep were investigated in bilateral frontal, central, parietal, and occipital regions by computer analysis. The associations between delta waves in all regions and measures of clinical variables were also estimated. RESULTS: Patients with schizophrenia showed lower total delta wave counts during all-night sleep than did control subjects in all regions. Control subjects showed significantly higher delta wave counts in the right frontal and central region than in the left, which was not observed in patients with schizophrenia. Significant inverse correlations were observed between negative symptom scores and delta wave counts in all regions. Control subjects showed significant inverse correlations between delta wave counts and age, which were not identified in patients with schizophrenia. CONCLUSIONS: Delta wave deficits in all regions may reflect thalamocortical dysfunction in schizophrenia. Reduced right frontal and central delta wave dominance is suggested to be involved in the pathophysiology of schizophrenia.

Reduced frontal asymmetry of delta waves during all-night sleep in schizophrenia.

Delta wave deficits during sleep have been observed in patients with schizophrenia. Decreased slow-wave sleep is reported to be associated with negative symptoms. Frontal lobe dysfunction is also believed to underlie negative symptoms of schizophrenia. This study was designed to identify functional abnormalities in schizophrenia manifested on patients' electroencephalograms. Polysomnograph examinations were performed in 12 healthy male volunteers and 11 male outpatients with schizophrenia. We investigated the laterality of frontal cortical delta waves in patients with schizophrenia and in healthy control subjects. Laterality of frontal cortex delta wave counts during all-night sleep was investigated by computer analysis. Total delta wave counts were lower in patients with schizophrenia than in control subjects. Control subjects showed significantly higher delta wave counts in the right frontal cortex than in the left. This asymmetry was not observed in patients with schizophrenia. These findings suggest that reduced right frontal delta wave dominance is involved in the pathophysiology of schizophrenia.

Effect of benzodiazepine hypnotic triazolam on relationship of blood pressure and Paco2 to cerebral blood flow during human non-rapid eye movement sleep.

We sought to clarify the effect of short-acting benzodiazepine hypnotic on the relationship of arterial blood pressure and arterial partial pressure of carbon dioxide (Paco2) to regional cerebral blood flow (rCBF) during human non-rapid-eye-movement (non-REM) sleep. Nine young normal volunteers were treated in a randomized, crossover design with triazolam or placebo and underwent positron emission tomography at night. During wakefulness and stage 2 and slow wave (stages 3 and 4) sleep, we measured mean arterial blood pressure (MAP), Paco2, and absolute CBF. With triazolam compared to placebo, MAP reduced gradually. During stage 2 sleep, Paco2 increased and whole-brain mean CBF decreased. With triazolam, relative rCBF of the left orbital basal forebrain decreased more during stage 2 than slow wave sleep, whereas absolute CBF of the occipital cortex and cerebral white matter remained constant. During triazolam-induced stage 2 sleep, absolute CBF of the cerebral white matter correlated more strongly to both MAP and Paco2 than during placebo sleep and also correlated more strongly to both MAP and Paco2 than absolute CBF of the occipital cortex. In the frontal white matter, during triazolam-induced stage 2 sleep compared to wakefulness, absolute CBF was significantly better correlated to MAP, but not to Paco2. During triazolam-induced stage 2, the cerebral white matter may receive a modulated CBF regulation having the strengthened relationship of Paco2 to CBF and, more locally, the frontal white matter may depend precariously on CBF regulation.

Cerebral white matter blood flow is constant during human non-rapid eye movement sleep: a positron emission tomographic study.

This study aimed to identify brain regions with the least decreased cerebral blood flow (CBF) and their relationship to physiological parameters during human non-rapid eye movement (NREM) sleep. Using [(15)O]H(2)O positron emission tomography, CBF was measured for nine normal young adults during nighttime. As NREM sleep progressed, mean arterial blood pressure and whole brain mean CBF decreased significantly; arterial partial pressure of CO(2) and, selectively, relative CBF of the cerebral white matter increased significantly. Absolute CBF remained constant in the cerebral white matter, registering 25.9 +/- 3.8 during wakefulness, 25.8 +/- 3.3 during light NREM sleep, and 26.9 +/- 3.0 (ml.100 g(-1).min(-1)) during deep NREM sleep (P = 0.592), and in the occipital cortex (P = 0.611). The regression slope of the absolute CBF significantly differed with respect to arterial partial pressure of CO(2) between the cerebral white matter (slope 0.054, R = - 0.04) and frontoparietal association cortex (slope - 0.776, R = - 0.31) (P = 0.005) or thalamus (slope - 1.933, R = - 0.47) (P = 0.004) and between the occipital cortex (slope 0.084, R = 0.06) and frontoparietal association cortex (P = 0.021) or thalamus (P < 0.001), and, with respect to mean arterial blood pressure, between the cerebral white matter (slope - 0.067, R = - 0.10) and thalamus (slope 0.637, R = 0.31) (P = 0.044). The cerebral white matter CBF keeps constant during NREM sleep as well as the occipital cortical CBF, and may be specifically regulated by both CO(2) vasoreactivity and pressure autoregulation.

A missense variation in human casein kinase I epsilon gene that induces functional alteration and shows an inverse association with circadian rhythm sleep disorders.

Recent studies have shown that functional variations in clock genes, which generate circadian rhythms through interactive positive/negative feedback loops, contribute to the development of circadian rhythm sleep disorders in humans. Another potential candidate for rhythm disorder susceptibility is casein kinase I epsilon (CKIepsilon), which phosphorylates clock proteins and plays a pivotal role in the circadian clock. To determine whether variations in CKIepsilon induce vulnerability to human circadian rhythm sleep disorders, such as delayed sleep phase syndrome (DSPS) and non-24-h sleep-wake syndrome (N-24), we analyzed all of the coding exons of the human CKIepsilon gene. One of the variants identified encoded an amino-acid substitution S408N, eliminating one of the putative autophosphorylation sites in the carboxyl-terminal extension of CKIepsilon. The N408 allele was less common in both DSPS (p = 0.028) and N-24 patients (p = 0.035) compared to controls. When DSPS and N-24 subjects were combined, based on an a priori prediction of a common mechanism underlying both DSPS and N-24, the inverse association between the N408 allele and rhythm disorders was highly significant (p = 0.0067, odds ratio = 0.42, 95% confidence interval: 0.22-0.79). In vitro kinase assay revealed that CKIepsilon with the S408N variation was approximately 1.8-fold more active than wild-type CKIepsilon. These results indicate that the N408 allele in CKIepsilon plays a protective role in the development of DSPS and N-24 through alteration of the enzyme activity.

Deactivation by benzodiazepine of the basal forebrain and amygdala in normal humans during sleep: a placebo-controlled [15O]H2O PET study.

OBJECTIVE: The authors' goal was to identify differences in regional brain activity between physiological and benzodiazepine-induced sleep to clarify the brain structures involved in the drug's hypnotic effect. METHOD: Using positron emission tomography, they compared regional cerebral blood flow during non-REM sleep in nine volunteers treated with placebo or triazolam, a short-acting benzodiazepine, in a double-blind, crossover design. RESULTS: Blood flow in the basal forebrain and amygdaloid complexes was lower during non-REM sleep when subjects were given triazolam than when they were given placebo. CONCLUSIONS: The hypnotic effect of the benzodiazepines may be mediated mainly by deactivation of the forebrain control system for wakefulness and also by the anxiolytic effect induced by deactivation of the emotional center.

The psychological aspects of patients with delayed sleep phase syndrome (DSPS).

OBJECTIVE: The current study attempts to define the psychological features of patients with delayed sleep-phase syndrome (DSPS). METHOD: We administered the Yatabe-Guilford test (Y-G test), Minnesota Multiphasic Personality Inventory (MMPI), Picture-Frustration study (P-F study) and Rorschach test to two groups, one of patients with DSPS (case group) and the other of people without psychiatric symptoms or insomnia (control group). RESULTS: Overall, the results of the tests indicate that patients with DSPS showed emotional features such as nervousness, depression and lack of control of emotional expression. Specific personality traits included introspection, defensiveness, aspiration for intellectual attainment with compulsivity, overly abstract thinking, unawareness of impulsivity to immediate gratification, perseverance and reduced cognitive ability. In addition, the patients with DSPS showed psychopathological features similar to those of neurosis, hypochondriasis, depression, conversion hysteria and psychopathic deviate. CONCLUSIONS: There seems to exist a definite psychological profile for patients with DSPS. (1) an excessive defense mechanism that increases nervousness and develops neurosis; (2) a high level of intellectual aspiration with compulsivity that makes the patients feel self-defeated, powerless and disappointed; (3) a tendency to egocentric emotion, inhibition and perseverance. These characteristics may worsen social withdrawal, causing a loss of social cues in synchronizing their circadian rhythm. Thus, the phase shift becomes more difficult and a vicious circle is constituted.

Sleep and circadian rhythm disturbances in patients with delayed sleep phase syndrome.

STUDY OBJECTIVES: The objective of this study was to clarify sleep characteristics and pathophysiology in patients with delayed sleep phase syndrome (DSPS), which is a major circadian rhythm sleep disorder subtype. DESIGN: Polysomnography was performed for 2 consecutive nights and core body temperature was sampled for 7 consecutive days, including the polysomnography study period, in all subjects. Findings were compared and statistically analyzed between patients with DSPS and matched controls. SETTING: Sleep disorders unit in National Center Hospital. PARTICIPANTS: 11 DSPS patients and 11 age-matched healthy volunteers. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Sleep latency, total sleep time, wakefulness after sleep-onset, and the amount and percentage of Stage 1 sleep were greater in DSPS patients than in volunteers. Sleep efficiency and the amount and percentage of slow wave sleep were lower in DSPS patients than in volunteers. Compared with the healthy volunteers, DSPS patients showed a decreased number and different temporal distribution of high-voltage and low-frequency delta waves. The time of minimum body temperature appeared earlier in the sleep phase for the patients than for the volunteers. Significant correlation was found between the amount of slow wave sleep and the time from sleep onset to minimum body temperature and between the amount and percentage of slow wave sleep and time from minimum body temperature to sleep offset. CONCLUSIONS: Disturbances were found in the sleep structure of patients with DSPS, and these disturbances were related to the discrepancy between patients and controls in the phase relationship difference between sleep and core body temperature rhythms.

Physical symptoms under forced-phase advance treatment in a patient with delayed sleep phase syndrome: a case report.

The physical symptoms that are observed with forced waking in patients with delayed sleep phase syndrome (DSPS) often prevent the successful treatment of patients. Better understanding of these symptoms will assist in providing appropriate treatment in such patients. Herein, a 19-year-old female patient with DSPS is described, in whom headache, fatigue, and dizziness were observed under forced-phase advance treatment. Statistical analysis showed that her headache was dependent on the therapeutic week, and her fatigue was dependent on the period of the day. There was no association between dizziness and either factor. Experience with this patient indicates that the fatigue observed with forced waking is related to the circadian system. This relationship should be explored for other physical symptoms as well.

Napping predicts responsiveness to hypnotics in patients with primary circadian rhythm disorder.

It is hypothesized that one of the primary abnormalities of primary circadian rhythm disorder (PCRD) is the strong link between any episode of sleep and circadian rhythm. To test this hypothesis, the relationship between napping and responsiveness to hypnotics was examined in 12 patients with PCRD. A significant association was found (P = 0.04, chi2 test). Patients with PCRD who napped were all responders to hypnotics. The results suggest a strong link between episodes of sleep and circadian rhythm in some patients with PCRD, and might also suggest the heterogeneity of PCRD. Napping in patients with PCRD may be a predictor for responsiveness to hypnotics. In addition, napping and responsiveness to hypnotics might have a clinical value to differentiate PCRD from secondary CRD.

Mutation screening of the human Clock gene in circadian rhythm sleep disorders.

We tested whether the human Clock (hClock) gene, one of the essential components of the circadian oscillator, is implicated in the vulnerability to delayed sleep phase syndrome (DSPS) and non-24-hour sleep-wake syndrome (N-24). Screening in the entire coding region of the hClock gene with PCR amplification revealed three polymorphisms, of which two predicted the amino acid substitutions R533Q and H542R. The frequencies of the R533Q and H542R alleles in patients with DSPS or N-24 were very low and not significantly different from those in control subjects. A T3111C polymorphism in the 3'-untranslated region of hClock, which had been reportedly associated with morning or evening preference for activity, was also investigated; the results showed that the 3111C allele frequency decreased in DSPS. Polymorphisms in the coding region of the hClock gene are unlikely to play an important role in the development of DSPS or N-24. The possible contribution of the T3111C polymorphism to DSPS susceptibility should be studied further.