Mutation of the Human Circadian Clock Gene CRY1 in Familial Delayed Sleep Phase Disorder.

Patterns of daily human activity are controlled by an intrinsic circadian clock that promotes ∼24 hr rhythms in many behavioral and physiological processes. This system is altered in delayed sleep phase disorder (DSPD), a common form of insomnia in which sleep episodes are shifted to later times misaligned with the societal norm. Here, we report a hereditary form of DSPD associated with a dominant coding variation in the core circadian clock gene CRY1, which creates a transcriptional inhibitor with enhanced affinity for circadian activator proteins Clock and Bmal1. This gain-of-function CRY1 variant causes reduced expression of key transcriptional targets and lengthens the period of circadian molecular rhythms, providing a mechanistic link to DSPD symptoms. The allele has a frequency of up to 0.6%, and reverse phenotyping of unrelated families corroborates late and/or fragmented sleep patterns in carriers, suggesting that it affects sleep behavior in a sizeable portion of the human population.

Concentration-Response Modeling of ECG Data From Early-Phase Clinical Studies as an Alternative Clinical and Regulatory Approach to Assessing QT Risk - Experience From the Development Program of Lemborexant.

Lemborexant is a novel dual orexin receptor antagonist being developed to treat insomnia. Its potential to cause QT prolongation was evaluated using plasma concentration-response (CR) modeling applied to data from 2 multiple ascending-dose (MAD) studies. In the primary MAD study, placebo or lemborexant (2.5 to 75 mg) was administered for 14 consecutive nights. In another MAD study designed to "bridge" pharmacokinetic and safety data between Japanese and non-Japanese subjects (J-MAD), placebo or lemborexant (2.5, 10, or 25 mg) was administered for 14 consecutive nights. QT intervals were estimated using a high-precision measurement technique and evaluated using a linear mixed-effects CR model, for each study separately and for the pooled data set. When each study was analyzed separately, the slopes of the CR relationship were shallow and not statistically significant. In the pooled analysis, the slope of the CR relationship was -0.00002 milliseconds per ng/mL (90%CI, -0.01019 to 0.01014 milliseconds). The highest observed Cmax was 400 ng/mL, representing a margin 8-fold above exposures expected for the highest planned clinical dose. The model-predicted QTc effect at 400 ng/mL was 1.1 milliseconds (90%CI, -3.49 to 5.78 milliseconds). In neither the J-MAD study nor the pooled analysis was an effect of race identified. CR modeling of data from early-phase clinical studies, including plasma levels far exceeding those anticipated clinically, indicated that a QT effect >10 milliseconds could be excluded. Regulatory agreement with this methodology demonstrates the effectiveness of a CR modeling approach as an alternative to thorough QT studies.

Alterations in skin temperature and sleep in the fear of harm phenotype of pediatric bipolar disorder.

In children diagnosed with pediatric bipolar disorder (PBD), disturbances in the quality of sleep and wakefulness are prominent. A novel phenotype of PBD called Fear of Harm (FOH) associated with separation anxiety and aggressive obsessions is associated with sleep onset insomnia, parasomnias (nightmares, night-terrors, enuresis), REM sleep-related problems, and morning sleep inertia. Children with FOH often experience thermal discomfort (e.g. feeling hot, excessive sweating) in neutral ambient temperature conditions, as well as no discomfort during exposure to the extreme cold, and alternate noticeably between being excessively hot in the evening and cold in the morning. We hypothesized that these sleep- and temperature-related symptoms were overt symptoms of an impaired ability to dissipate heat, particularly in the evening hours near the time of sleep onset. We measured sleep/wake variables using actigraphy, and nocturnal skin temperature variables using thermal patches and a wireless device, and compared these data between children with PBD/FOH and a control sample of healthy children. The results are suggestive of a thermoregulatory dysfunction that is associated with sleep onset difficulties. Further, they are consistent with our hypothesis that alterations in neural circuitry common to thermoregulation and emotion regulation underlie affective and behavioral symptoms of the FOH phenotype.

Effects of a month-long napping regimen in older individuals.

OBJECTIVES: To examine the effects of a month-long nap regimen using one of two durations (45 minutes or 2 hours) on nighttime sleep and waking function in a group of healthy older participants and to assess the degree to which healthy older individuals are willing and able to adhere to such napping regimens. DESIGN: Three laboratory sessions, with 2-week at-home recording interspersed, using a between-participants approach. SETTING: Laboratory of Human Chronobiology at Weill Cornell Medical College and participants' homes. PARTICIPANTS: Twenty-two healthy men and women aged 50 to 88 (mean 70). MEASUREMENTS: Polysomnography (sleep electroencephalography), actigraphy, sleep diaries, neurobehavioral performance, sleep latency tests. RESULTS: With the exception of adherence to the protocol, there were few differences between short and long nap conditions. Napping had no negative effect on subsequent nighttime sleep quality or duration, resulting in a significant increase in 24-hour sleep amounts. Such increased sleep was associated with enhanced cognitive performance but had no effect on simple reaction time. Participants were generally able to adhere better to the 45-minute than the 2-hour nap regimen. CONCLUSION: A month-long, daily nap regimen may enhance waking function without negatively affecting nighttime sleep. Using 2-hour naps in such a regimen is unlikely to meet with acceptable adherence; a regimen of daily 1-hour naps may be more desirable for effectiveness and adherence.

Measuring melatonin in humans.

STUDY OBJECTIVES: To provide guidelines for collecting and analyzing urinary, salivary, and plasma melatonin, thereby assisting clinicians and researchers in determining which method of measuring melatonin is most appropriate for their particular needs and facilitating the comparison of data between laboratories. METHODS: A modified RAND process was utilized to derive recommendations for methods of measuring melatonin in humans. RESULTS: Consensus-based guidelines are presented for collecting and analyzing melatonin for studies that are conducted in the natural living environment, the clinical setting, and in-patient research facilities under controlled conditions. CONCLUSIONS: The benefits and disadvantages of current methods of collecting and analyzing melatonin are summarized. Although a single method of analysis would be the most effective way to compare studies, limitations of current methods preclude this possibility. Given that the best analysis method for use under multiple conditions is not established, it is recommended to include, in any published report, one of the established low threshold measures of dim light melatonin onset to facilitate comparison between studies.

Delayed sleep phase disorder in temporal isolation.

STUDY OBJECTIVES: This study sought to characterize sleep and the circadian rhythm of body core temperature of an individual with delayed sleep phase disorder (DSPD) in the absence of temporal cues and social entrainment and to compare those measures to age-matched normal control subjects studied under identical conditions. DESIGN: Polysomnography and body temperature were recorded continuously for 4 days in entrained conditions, followed immediately by 17 days in a "free-running" environment. SETTING: Temporal isolation facility in the Laboratory of Human Chronobiology, Weill Cornell Medical College. PARTICIPANTS: One individual who met criteria for delayed sleep phase disorder according to the International Classification of Sleep Disorders Diagnostic and Coding Manual (ICSD-2) and 3 age-matched control subjects. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: The DSPD subject had a spontaneous period length (tau) of 25.38 hours compared to an average tau of 24.44 hours for the healthy controls. The DSPD subject also showed an altered phase relationship between sleep/wake and body temperature rhythms, as well as longer sleep latency, poorer sleep efficiency, and altered distribution of slow wave sleep (SWS) within sleep episodes, compared to control subjects. CONCLUSIONS: Delayed sleep phase disorder may be the reflection of an abnormal circadian timing system characterized not only by a long tau, but also by an altered internal phase relationship between the sleep/wake system and the circadian rhythm of body temperature. The latter results in significantly disturbed sleep, even when DSPD patients are permitted to sleep and wake at their preferred times.

Vagus nerve stimulation in children with mitochondrial electron transport chain deficiencies.

We retrospectively investigated outcome data for vagus nerve stimulation (VNS) in children less than 12 years of age with intractable seizures and mitochondrial disease. Five children with a mitochondrial disease, due to electron transport chain deficiency, were studied. Information was collected from clinic visits prior to, and subsequent to, VNS implantation. Data were collected by type and frequency of seizures, encephalogram and neuroimaging findings, and medication history. Four of the children had predominantly myoclonic seizures, while the other child had focal seizures with secondary generalization and myoclonic seizures. All five children did not have significant reduction in seizure frequency with VNS. VNS may not be an effective method to control myoclonic seizures in children with electron transport chain disorders.

The nature of spontaneous sleep across adulthood.

The decline in sleep quality that often accompanies aging is thought to be the consequence of alterations in both circadian and homeostatic processes widely assumed to be responsible for sleep/wake regulation. A number of experimental approaches have been used to examine various aspects of age-related sleep changes, but none has examined spontaneous sleep across the entire 24-h day. Using the 'disentrainment' protocol, we studied such sleep in young, middle-aged and older adults. All subjects exhibited polyphasic sleep patterns, characterized by relatively short intervals of both sleep and waking. Whereas, the average duration of major nighttime sleep was significantly shorter in middle-aged and older subjects than in young adults, daytime napping was essentially unaffected by age. Comparisons of sleep and circadian variables between age groups suggest differential effects on sleep of the two regulatory processes, with changes in homeostatic drive preceding those of the circadian component. These findings add to a surprisingly scant literature on the longitudinal decline in sleep quality associated with aging.

Sex hormones, sleep, and core body temperature in older postmenopausal women.

STUDY OBJECTIVES: Assessment of relationships between polysomnographic sleep, sex hormones, and core body temperature in postmenopausal women. DESIGN AND PARTICIPANTS: Ten women aged 57 to 71 years, at least 5 years past menopause. SETTING: Laboratory of Human Chronobiology at Weill Cornell Medical College. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Lower estradiol (E2) and higher luteinizing hormone (LH) levels were significantly correlated with indices of poor sleep quality. Relationships between LH and polysomnographic variables were more robust than those for E2. Significant increases from basal LH levels (i.e., LH pulses) occurred more frequently after sleep onset than prior to sleep onset, and 30 of 32 of these LH pulses occurred prior to long awakenings from sleep. In addition, higher body core temperature prior to and during sleep was significantly correlated with poorer sleep efficiency and higher LH levels. CONCLUSIONS: Most investigations of relationships between sleep, sex hormones, and body temperature have focused on perimenopausal women, menopausal phenomena such as hot flashes, the role of declining estrogen, and treatment with exogenous estrogen. The current results suggest that altered levels of both sex steroids and gonadotropins may contribute to sleep disturbance in older women and confirm the results of previous studies indicating that higher body core temperature is associated with poorer sleep quality, even in women without vasomotor symptoms. The findings also raise the possibility of alternate treatment avenues for menopause- and age-related sleep disturbance that focus on altering LH levels.

Vagus nerve stimulation for intractable seizures in children.

Forty-three children less than 12 years of age having intractable seizures were treated with vagus nerve stimulation. Five children were monitored for <12 months, 16 children for 12 to 17 months, and 22 children for > or =18 months with overall median seizure reduction of 55%. Thirty-seven percent had at least 90% reduction. Vagus nerve stimulation was effective in children with generalized, mixed, and partial medically refractory seizures.

Effects of a nap on nighttime sleep and waking function in older subjects.

OBJECTIVES: To examine, in older subjects, the effect on waking function of increasing 24-hour sleep amounts by providing a nap opportunity; to assess what effects an afternoon nap may have on subsequent nighttime sleep quality and composition. DESIGN: Two-session, within-subject laboratory design. SETTING: The study was conducted in the Laboratory of Human Chronobiology at Weill Cornell Medical College. PARTICIPANTS: Thirty-two healthy men and women aged 55 to 85. MEASUREMENTS: Polysomnography (sleep electroencephalogram), cognitive and psychomotor performance, body core temperature. RESULTS: Napping had little effect on subsequent nighttime sleep quality or duration, resulting in a significant increase in 24-hour sleep amounts. Such increased sleep resulted in enhanced cognitive and psychomotor performance immediately after the nap and throughout the next day. CONCLUSION: A behavioral approach that adds daytime sleep to the 24-hour sleep quota seems worthy of consideration when presented with a situation in which physiological changes associated with aging may limit the duration of nighttime sleep.

Failure of timed bright light exposure to alleviate age-related sleep maintenance insomnia.

OBJECTIVES: To determine whether a twice-weekly maintenance schedule of evening bright light exposure is effective in alleviating sleep maintenance insomnia on a long-term basis, after the establishment of a more favorable phase relationship between the core body temperature (CBT) rhythm and sleep. DESIGN: Subjects underwent light treatment while living at home. Eleven to 13 consecutive days of acute light treatment (active) were followed by a 3-month maintenance light treatment period (active or control). Subjects completed five laboratory sessions: before and after the acute phase and once a month during the maintenance period. SETTING: Sleep laboratory and subjects' homes. PARTICIPANTS: Fifteen older subjects (seven women, eight men; aged 63-84) with chronic (>1 year) complaints of sleep maintenance insomnia. INTERVENTIONS: During the acute phase, all participants were exposed to evening bright light (approximately 9:00 p.m. to 11:00 p.m.;>4,000 lux). During the maintenance phase, light treatment was reduced to a twice-weekly schedule, in which the active group received bright light from approximately 9:00 p.m. to 11:00 p.m. and the control group received bright light from 3:00 p.m. to 5:00 p.m. MEASUREMENTS: During each laboratory session, polysomnographic sleep and CBT were measured. RESULTS: Bright light exposure during the acute treatment resulted in an average phase delay in the temperature rhythm (Tmin) of 94 minutes. Sleep quality was not improved. No significant differences between active and control subjects were found during the maintenance phase; in both groups, Tmin gradually reverted to the baseline phase position, and sleep efficiency remained unchanged. CONCLUSIONS: Although a significant phase shift in CBT was achieved during the acute treatment phase, no improvement in sleep quality was observed. Twice-weekly light exposure was not effective in maintaining the circadian phase shift over the subsequent 3 months. Issues of compliance and alternate etiologies for the sleep maintenance insomnia are discussed.

Technology transfer concerns of college graduates with disabilities: Profiles in transition from higher education to competitive careers.

The article describes the technology transfer concerns reported by a small sample (N=14) of recent college graduates with disabilities. In structured, in-depth interviews, researchers asked respondents to reflect on the extent to which they had utilized technology resources during their college years in preparation for the world of work. Results suggest that colleges and universities need to play a more active role in introducing students with disabilities to both generalized and assistive technology services.