The hypocretin neurotransmission system in myotonic dystrophy type 1.

BACKGROUND: Patients with myotonic dystrophy type 1 (DM1) frequently have symptoms of excessive daytime sleepiness (EDS). Some patients with DM1 show sleep-onset REM, similar to that observed in narcolepsy. Narcolepsy is characterized by impaired hypocretin (Hcrt) neurotransmission. OBJECTIVE: To test for dysregulation of Hcrt neurotransmission in a prospective cohort of patients with DM1. METHODS: Hcrt levels in CSF were measured by radioimmunoassay. Sleep physiology was assessed by overnight polysomnography (PSG) and a multiple sleep latency test (MSLT). Splicing of Hcrt receptor 1 and 2 (HcrtR1 and HcrtR2) mRNA was examined in postmortem samples of temporal cortex. RESULTS: Seventeen of 38 patients with DM1 reported symptoms of EDS. Among patients with DM1 with EDS who underwent PSG/MSLT, 7 of 13 showed reduced sleep latency, sleep-onset REM, or both. However, CSF Hcrt levels in DM1 (mean 277 pg/mL, n = 38) were not different from controls (mean 277 pg/mL, n = 33). Also, splicing of HcrtR1 and HcrtR2 mRNA in patients with DM1 was similar to controls. CONCLUSIONS: Excessive daytime sleepiness and dysregulation of REM sleep occur frequently in patients with myotonic dystrophy type 1 (DM1). However, the pathophysiologic basis is distinct from narcolepsy, as patients with DM1 do not have a consistent defect of Hcrt release or receptor splicing.

A comparison of placebo and no-treatment during a hypnotic clinical trial.

OBJECTIVE: Sleep parameters commonly improve during placebo treatment in insomnia clinical trials. We examined whether the improvement seen with placebo was related to taking pills or other non-specific factors. METHOD: 95 insomniacs took either a placebo pill (pill+) or no pill (pill-) on nights of their choosing over 12 weeks. RESULTS: Pills were consumed on about half of the nights. Consistent improvement was seen with reduced reported sleep latency, wakefulness after sleep onset, number of awakenings, and total sleep time over the 12 weeks for both the pill+ and pill condition. A difference between pill+ and pill- was detected only for total sleep time, and this difference favored pill+. CONCLUSIONS: This study suggests that improvement seen during placebo treatment is more related to non-specific factors of participating in clinical trial than to pill taking behavior.

Generalized covariance-adjusted canonical correlation analysis with application to psychiatry.

The lack of control over covariates in practice motivates the need for their adjustment when measuring the degree of association between two sets of variables, for which canonical correlation is traditionally used. In most studies however, there is also a lack of control over the attributes of responses for the sets of variables of interest. In particular, a portion of the response variable may be continuous and the other discrete. For such settings, the traditional partial canonical correlation approach is restrictive, since a covariate-adjustment for a set of continuous variables is assumed. By ignoring the assumption of continuous variates and proceeding with a partial canonical correlation analysis in the presence of continuous and discrete variates, results in canonical correlation estimates that are not consistent. In this paper we generalize the traditional partial canonical correlation approach to covariate-adjustment by allowing the response variables to contain continuous, as well as discrete, variates. The methodology is illustrated with a psychiatric application for examining which sleep variables relate to which depressive symptoms, as measured by commonly used constructs that presents with both continuous and discrete outcomes.

The mesograde amnesia of sleep may be attenuated in subjects with primary insomnia.

In this study, we pilot tested one of the more controversial components of the Neurocognitive Model of Insomnia; the proposition that subjects with chronic primary insomnia are better able to recall and/or recognize information from sleep onset intervals than good sleeper controls. Nine subjects participated in this pilot study, five of whom had a complaint of insomnia. The remaining four subjects were self-reported good sleeper controls. Subjects were matched for age, sex, and body mass. All subjects spent two nights in the sleep laboratory. The first night served as an adaptation night. The second night served as the experimental night during which a forced awakening and memory task was deployed. In this procedure, subjects were played single-word stimuli across four time periods: at natural sleep onset (Trial 1) and at the sleep onset transitions following three forced awakenings (Trials 2-4 from Stage 2 sleep). All subjects were awakened after about 6 h had elapsed from lights out and were tested for free recall and recognition memory for the word stimuli. The insomnia subjects, tended to identify more of the word stimuli on the recognition task (average for the four trials) and recognized significantly more of the words that were presented at sleep onset proper (Trial 1). This finding suggests that the natural mesograde amnesia of sleep may be attenuated in subjects with insomnia.

Behavioral treatment of insomnia: treatment outcome and the relevance of medical and psychiatric morbidity.

Recently, we undertook a case series study and found that behavior therapy for insomnia was effective as plied in the clinic setting and that the findings were similar to those in the "clinical trial" literature. In the present study, we evaluate a second set of case series data to assess (1) the replicability of our original findings, (2) if our treatment outcomes are statistically comparable to those in the literature, and (3) if medical and psychiatric morbidity influence treatment outcome. It was found that patients who completed four or more sessions of cognitive behavioral therapy for insomnia (CBT) were, on average, 33% improved. This average corresponded to a 56% reduction in wake time after sleep onset, a 34% reduction in sleep latency, a 29% increase in total sleep time, and a 13% decrease in number of awakenings per night. These findings are not significantly different from those reported in literature for both CBT and pharmacotherapy interventions. Medical and psychiatric comorbidity did not influence treatment outcome.

Temporal and stagewise distribution of high frequency EEG activity in patients with primary and secondary insomnia and in good sleeper controls.

In the present study, we evaluate the temporal and stagewise distribution of high frequency EEG activity (HFA) in primary and secondary insomnia. Three groups (n=9 per group) were compared: primary insomnia (PI), Insomnia secondary to major depression (MDD), and good sleeper controls (GS). Groups were matched for age, sex and body mass. Average spectral profiles were created for each sleep epoch. Grand averages were created for each NREM cycle and each stage of sleep after removing waking and movement epochs and epochs containing micro or miniarousals. It was found that HFA (in terms of relative power) tends to increase across NREM cycles, occurs maximally during stage 1 and during REM sleep, and that both these effects are exaggerated in patients with PI. In addition, HFA was found to be inversely associated with Delta activity and the three groups in our study appear to exhibit characteristic Delta/Beta patterns. Our data are consistent with the perspective that HFA is related to CNS arousal to the extent that Beta/Gamma activity occurs maximally during shallow stages of sleep and maximally in subjects with PI.

Presleep cognitions in patients with insomnia secondary to chronic pain.

This study had two primary objectives: (1) characterize the content of presleep cognitions of chronic pain patients and (2) evaluate the association between presleep cognitions and sleep disturbance. Thirty-one outpatients with benign chronic pain completed the Beck Depression Inventory, pain and sleep diaries and participated in an in vivo, presleep thought sampling procedure for 1 week in their homes. The three most frequently reported presleep cognitions were general pain-related thoughts (36%), thoughts about the experimental procedure (27%), and negative sleep-related thoughts (26%). Stepwise multiple regression analyses found the presleep thoughts pertaining to pain and environmental stimuli were significantly associated with sleep continuity, independent from the effects of depression and nightly pain severity. Pain severity was found to be positively associated with Wake After Sleep Onset Time. These results are consistent with cognitive-behavioral models of primary insomnia and suggest the content of presleep cognitive arousal may contribute to sleep disturbance secondary to pain.

Beta/Gamma EEG activity in patients with primary and secondary insomnia and good sleeper controls.

STUDY OBJECTIVE: Several studies have shown that patients with insomnia exhibit elevated levels of Beta EEG activity (14-35 Hz) at or around sleep onset and during NREM sleep. In this study, we evaluated 1) the extent to which high frequency EEG activity is limited to the 14-32 Hz domain, 2) whether high frequency EEG activity (HFA) is associated with discrepancies between subjective and PSG measures of sleep continuity, and 3) the extent to which high frequency EEG activity occurs in patients with primary, as opposed to secondary, insomnia. DESIGN: Three groups (n=9 per group) were compared: Primary Insomnia, Insomnia secondary to Major Depression, and Good Sleeper Controls. Groups were matched for age, sex and body mass. Average spectral profiles were created for each NREM cycle after removing waking and movement epochs and epochs containing micro- or mini-arousals. SETTING: Sleep Research Laboratory PATIENTS OR PARTICIPANTS: Patients with primary and secondary insomnia INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Subjects with Primary Insomnia exhibited more average NREM activity for Beta-1 (14-20Hz), Beta-2 (20-35Hz) and Gamma activity (35-45Hz) than the other two groups (p.<.01). Group differences were also suggestive for Omega activity (45.0-125Hz) (p.<.10), with MDD subjects tending to exhibit more activity than the other groups. Correlational analyses revealed that average NREM Beta-1 and Beta-2 activity tended to be negatively correlated with subjective-objective discrepancy measures for total sleep time and sleep latency. CONCLUSIONS: Our results confirm that Beta activity is increased in Primary Insomnia. In addition, our data suggest that high frequency activity in patients with Primary Insomnia is limited to the Beta/Gamma range (14-45 Hz), and is negatively associated with the perception of sleep.

Improving compliance with nasal CPAP and vigilance in older adults with OAHS.

The present study examined the efficacy of a cognitive-behavioral intervention at improving compliance with CPAP and vigilance in older adults with obstructive sleep apnea/hypopnea syndrome (OSAHS). Participants included 12 subjects who were randomized into one of two groups controlling for age, education, disease severity, and vigilance. The experimental group received two 45-min sessions designed to educate subjects on the consequences of OSAHS and the efficacy of CPAP. The control group received the same extent of therapist contact but did not receive information on OSAHS or CPAP. All subjects were administered a test of vigilance both before and after the study. Compliance data were collected using CPAP devices with internal microprocessors at were read at 1, 4, and 12 weeks after treatment initiation. The results showed that the experimental condition did not enhance compliance after 1 week of treatment but did so by the 12-week follow-up. Subjects in the experimental condition had a run time of 3.2-h per night longer than did those in the control group. Those using CPAP more regularly at 12 weeks also showed greater improvement on vigilance at follow-up. Performance on vigilance testing before the introduction of CPAP was predictive of CPAP use at 12 weeks. In conclusion, a modest cognitive-behavioral intervention may substantially increase CPAP use and vigilance in older adults.

The diagnosis of primary insomnia and treatment alternatives.

This review provides information about the diagnosis and treatment of primary insomnia. Several treatment strategies are reviewed including the use of hypnotics, naturopathic remedies and behavioral interventions. We suggest that nonpharmacologic interventions are likely to be the most safe and effective.

Behavioral treatment of insomnia: a clinical case series study.

There is substantial experimental evidence that behavioral treatment of insomnia produces significant clinical improvement and that treatment gains tend to be maintained over time. Less clear is whether behavioral treatment is effective as it is plied in clinical settings. In this clinical case series study, we evaluated 47 patients with primary insomnia. It was found that patients were, on average, 43% improved. This average corresponded to a 65% reduction in sleep latency, a 46% decrease in number of awakenings per night, a 48% reduction in wake time after sleep onset, and a 13% increase in total sleep time. These results suggest that behavioral treatment for insomnia is as effective in clinical settings as it is as under clinical trial conditions.

Sleep quality and presleep arousal in chronic pain.

This study was designed (1) to characterize the extent and nature of sleep complaints of chronic pain patients and (2) to examine the factors that predict sleep quality. A heterogeneous sample of 51 outpatients with benign, chronic pain was recruited from newspaper and pain clinic advertisements. Patients completed a variety of self-report instruments including the Multidimensional Pain Inventory, the Pittsburgh Sleep Quality Index, the Pre-Sleep Arousal Scale, and the Beck Depression Inventory. Sleep complaints were reported by 88% of the sample. Presleep cognitive arousal, rather than pain severity, was found to be the primary predictor of sleep quality.

Behavioral sleep medicine. An emerging subspecialty in health psychology and sleep medicine.

As the knowledge base in sleep disorders medicine has broadened, a subspecialty that we will refer to as "behavioral sleep medicine" area is emerging. This article will define this subspecialty area, provide some historical context for its emergence, review issues related to specialty training and clinical practice, and suggest needs for future research.The term "behavioral sleep medicine" was selected because it clearly denoted the two fields from which our subspecialty emerged (health psychology/behavioral medicine and sleep disorders medicine). It suggests much about our approach to training, clinical practice, and research, and it appropriately implies that the field is open to PhD sleep specialists, MD sleep specialists, and other health care providers with the relevant training. Formally, behavioral sleep medicine refers to the branch of clinical sleep medicine and health psychology that: (1) focuses on the identification of the psychological (e.g. cognitive and/or behavioral) factors that contribute to the development and/or maintenance of sleep disorders and (2) specializes in developing and providing empirically validated cognitive, behavioral, and/or other nonpharmacologic interventions for the entire spectrum of sleep disorders.

EEG sleep in African-American patients with major depression: a historical case control study.

This study was designed to evaluate the effect of race, specifically African-American, on electroencephalographic (EEG) sleep and clinical symptom profile in unipolar major depression. A clinical research database was used to identify appropriate subjects and a double-matched historical case-control design was implemented. African-American depression patients were double matched within protocol to Euro-American depressed patients. Age, sex, and protocol of origin were matching variables. African-American depressed patients had less total sleep, less slow wave sleep, more stage 2 sleep, longer rapid eye movement (REM) sleep latency, less REM sleep, and lower REM density than Euro-American depressed patients. African-American depressed patients did not differ from Euro-American patients in symptom severity, age of onset, number of episodes, socio-economic status, and, as planned, did not differ in age and sex distribution. Depressive symptom constellation also did not distinguish the two groups. African-American depressed patients demonstrated differences in EEG sleep profile, with less total sleep, overall lighter nonREM sleep, and relatively preserved REM sleep, despite a clinical symptom profile that did not differ from Euro-American depressed patients. The sleep profile appeared to be consonant with the sleep findings in chronic insomnia. The pathological implications of these differences remained to be explored in careful prospective studies of African-American depressed patients and in well-characterized, racially matched normal control comparisons.

Which depressive symptoms are related to which sleep electroencephalographic variables?

Sleep complaints and electroencephalographic (EEG) sleep abnormalities are associated with risk for new onset depression, illness severity, treatment outcome, and vulnerability for recurrence of depression. The aim of this study was to evaluate the strength of association between EEG sleep measures and depression symptoms, and to identify the variables that account for the majority of the association. Depression ratings from the Hamilton Rating Scale for Depression and the Beck Depression Inventory and polysomnographic measures were examined in 361 adult outpatients with major depressive disorder. Canonical correlation and serial multiple regression analyses were used to determine the associations between depressive symptoms and sleep measures. Canonical correlation showed a unidimensional relationship between depressive symptoms and sleep measures (R = .55, p < .05). Fifteen depression items and nine sleep measures accounted for 95% of the correlation. Depression variables encompassed a core set of mood, neurovegetative, and cognitive symptoms. Sleep variables were primarily related to delta EEG activity, and this may be reflective of impaired sleep "drive" or heightened arousal during sleep.

Psychophysiological insomnia: the behavioural model and a neurocognitive perspective.

A number of paradoxes are apparent in the assessment and treatment of psychophysiological insomnia and sleep state misperception. Three of these paradoxes exist as discrepancies between polysomnographic (PSG) measures and the subjective impressions regarding sleep quality and quantity. The remaining incongruity exists largely within the objective domain. In the case of subjective-objective discrepancies, patients with insomnia: (1) frequently identify themselves as having been awake when awakened from PSG defined sleep; (2) tend to overestimate sleep latency and underestimate total sleep time as compared with PSG measures; (3) appear to derive more benefit from pharmacotherapy that can be explained by objective gains. The remaining paradox pertains to the observation that hypnotic medications, by and large, do not normalize sleep architecture or produce a more 'sleep-like' EEG. In this paper, we review possible explanations for these various paradoxes, introduce a new perspective and suggest possible research avenues. The model introduced is based on the observation that beta and/or gamma activity (which have been found to be associated with cognitive processes) is enhanced in insomnia at or around sleep onset. We propose that this kind of high frequency EEG activity may interfere with the normal establishment of sleep onset-related mesograde amnesia. As a result, the patient with insomnia maintains a level of information and/or memory processing that blurs the phenomenological distinction between sleep and wakefulness and influences retrospective judgments about sleep initiation and duration.

Longitudinal sleep EEG power spectral analysis studies in adolescents with minor head injury.

Power spectral analysis (PSA) was used to evaluate the longitudinal overnight electroencephalographic (EEG) sleep recordings of eight subjects, between the ages of 15 and 19 years, who had sustained a minor head injury (MHI). Recordings occurred within 72 h, 6 weeks, and 12 weeks following MHI. A conditioning night preceded the first study night during which EEG electrodes were in place and subjects slept at least 7.5 h with a mean sleep efficiency of 91%. PSA was performed on four channels of EEG data recorded from fronto-temporal (F3-T3, F4-T4), and temporal (T3-T5, T4-T6) electrodes. The three waveforms associated with sleep, Delta, Theta, and Alpha-1 were all significantly elevated within 72 h post-MHI. Over time all wave forms decreased in mean log power. Theta in rapid eye movement (REM) sleep Cycle 1 decreased significantly within 6 weeks postinjury. The greatest number of significant changes, over the 12-week period were recorded during the non-REM (NREM) sleep. Changes included (1) significant decreases in mean log power of Theta and Alpha-1 in Cycle 1 from fronto-temporal leads; (2) significant decreases in Delta, Theta, and Alpha-1 in Cycle 2 from fronto-temporal leads, and (3) significant decreases in Delta and Theta for consistency during Cycle 2 from temporal leads. The intrusion of Theta into the first REM cycle within 6 weeks and its subsequent decrease within 6 weeks suggested the initiation of recovery toward baseline values. This was followed by decreased levels of Theta power during NREM Cycles 1 and 2, and Delta power in Cycle 2, both of which approached their lowest levels within 12 wks. The decrease in Alpha-1 power occurred last. Alpha-1 remained elevated through both Cycles 1 and 2 of the 6th week and then showed a precipitous decrease between the sixth and twelfth week. These findings suggested that following MHI, the brain has a specific sequence of recovery as illustrated by Delta, Theta, and Alpha-1 powers requiring different time frames to reach their lowest levels.

Sleep complaints in chronic postconcussion syndrome.

This study was designed to identify the incidence of sleep complaints in 39 patients with chronic postconcussion syndrome compared to those of a control group of 27 patients with orthopedic injuries. Patients with orthopedic injuries were selected as a comparison group to control for the effects of traumatic injury or chronic pain. There were no differences in age, sex distribution, or time from injury between the patient groups. Type and frequency of sleep disturbances in a mean two-year postinjury period were evaluated. Patients with chronic postconcussion syndrome reported more difficulty in initiating and maintaining sleep at night and greater difficulty with sleepiness during the day.

Alpha sleep and information processing, perception of sleep, pain, and arousability in fibromyalgia.

This study examined the relationship between alpha sleep and information processing during sleep, perception of sleep, musculoskeletal pain, and arousability in patients with fibromyalgia. Patients (n = 20) were allowed to sleep undisturbed for the first 60 minutes of the study to assess amount of alpha sleep and were classified as high or low alpha generators based on quantitative analyses of alpha activity during this period. The groups were compared for performance on two memory tasks, perceptions of polysomnographically-defined sleep and EEG arousals in response to auditory stimuli. Correlations between symptoms of fibromyalgia and alpha activity were also examined. Alpha activity during sleep in fibromyalgic patients was associated with the perception of shallow sleep and an increased tendency to arouse in relation to auditory stimuli. Alpha activity was not associated with increased memory for auditory stimuli presented during sleep, sleep state misperception, or with myalgia symptoms. Alpha sleep appears to be, electrophysiologically, a shallow form of sleep. Our results suggest that it is perceived as such phenomenologically and that it is also associated with increased arousability.