Compression of the optic chiasm is associated with reduced photoentrainment of the central biological clock.

Objective: Pituitary tumours that compress the optic chiasm are associated with long-term alterations in sleep-wake rhythm. This may result from damage to intrinsically photosensitive retinal ganglion cells (ipRGCs) projecting from the retina to the hypothalamic suprachiasmatic nucleus via the optic chiasm to ensure photoentrainment (i.e. synchronisation to the 24-h solar cycle through light). To test this hypothesis, we compared the post-illumination pupil response (PIPR), a direct indicator of ipRGC function, between hypopituitarism patients with and without a history of optic chiasm compression. Design: Observational study, comparing two predefined groups. Methods: We studied 49 patients with adequately substituted hypopituitarism: 25 patients with previous optic chiasm compression causing visual disturbances (CC+ group) and 24 patients without (CC- group). The PIPR was assessed by chromatic pupillometry and expressed as the relative change between baseline and post-blue-light stimulus pupil diameter. Objective and subjective sleep parameters were obtained using polysomnography, actigraphy, and questionnaires. Results: Post-blue-light stimulus pupillary constriction was less sustained in CC+ patients compared with CC- patients, resulting in a significantly smaller extended PIPR (mean difference: 8.1%, 95% CI: 2.2-13.9%, P = 0.008, Cohen's d = 0.78). Sleep-wake timing was consistently later in CC+ patients, without differences in sleep duration, efficiency, or other rest-activity rhythm features. Subjective sleep did not differ between groups. Conclusion: Previous optic chiasm compression due to a pituitary tumour in patients with hypopituitarism is associated with an attenuated PIPR and delayed sleep timing. Together, these data suggest that ipRGC function and consequently photoentrainment of the central biological clock is impaired in patients with a history of optic chiasm compression.

A network analysis of self-reported sleep bruxism in the Netherlands sleep registry: its associations with insomnia and several demographic, psychological, and life-style factors.

OBJECTIVES: To investigate the association between self-reported sleep bruxism and insomnia and their potential risk factors (eg, depression and anxiety), and to construct a network model with all these factors. METHODS: We recruited 2251 participants from the Netherlands Sleep Registry. All participants completed questionnaires on self-reported sleep bruxism, insomnia, depression, anxiety, smoking frequency, and alcohol and caffeine consumption. The associations between self-reported sleep bruxism and other variables were analyzed by univariate analysis, multivariate logistic regression, and network analysis. RESULTS: Although univariate analysis showed that there was a positive association between sleep bruxism and insomnia (P < 0.001), this association disappeared in the multivariate logistic regression model (P = 0.258). However, multivariate logistic regression did show an association between self-reported sleep bruxism and anxiety (OR = 1.087, 95% CI 1.041-1.134). The network model showed that there was no direct link between self-reported sleep bruxism and insomnia. However, there was an indirect link between self-reported sleep bruxism and insomnia via anxiety. CONCLUSIONS: Although self-reported sleep bruxism has no direct association with insomnia, anxiety is a bridging factor between these variables.

Light Therapy for Cancer-Related Fatigue in (Non-)Hodgkin Lymphoma Survivors: Results of a Randomized Controlled Trial.

PURPOSE: To evaluate the short- and long-term effects of light therapy on fatigue (primary outcome) and sleep quality, depression, anxiety, quality of life, and circadian rhythms (secondary outcomes) in survivors of (non-)Hodgkin lymphoma presenting with chronic cancer-related fatigue. METHODS: We randomly assigned 166 survivors (mean survival 13 years) to a bright white light intervention (BWL) or dim white light comparison (DWL) group. Measurements were completed at baseline (T0), post-intervention (T1), at three (T2), and nine (T3) months follow-up. A mixed-effect modeling approach was used to compare linear and non-linear effects of time between groups. RESULTS: There were no significant differences between BWL and DWL in the reduction in fatigue over time. Both BWL and DWL significantly (p < 0.001) improved fatigue levels during the intervention followed by a slight reduction in this effect during follow-up (EST0-T1 = -0.71; EST1-T3 = 0.15). Similar results were found for depression, sleep quality, and some aspects of quality of life. Light therapy had no effect on circadian rhythms. CONCLUSIONS: BWL was not superior in reducing fatigue compared to DWL in HL and DLBCL survivors. Remarkably, the total sample showed clinically relevant and persistent improvements on fatigue not commonly seen in longitudinal observational studies in these survivors.

High prevalence of parent-reported sleep problems in pediatric patients with acute lymphoblastic leukemia after induction therapy.

OBJECTIVE: To assess sleep problems (prevalence and predictors) in pediatric patients with acute lymphoblastic leukemia (ALL) after the most intensive phase of therapy (induction). METHODS: Patients (≥2 years) treated according to the Dutch ALL-11 protocol were included. Sleep was measured using parent-reports and self-reports (Children's Sleep Habits Questionnaire; CSHQ) and actigraphy. Parental sleep (Medical Outcome Study Sleep Scale) and distress and parenting problems (Distress Thermometer for Parents) were assessed with questionnaires. Z-scores were calculated for total CSHQ scores using age-appropriate scores of healthy Dutch children. The prevalence of sleep problems (defined as a Z-score > 1) in patients with ALL was compared to healthy children (chi-square tests). Actigraphic sleep estimates were collected in healthy Dutch children (n = 86, 2-18 years) for comparison with patients (linear regression). Determinants of parent-reported child sleep (total CSHQ Z-score) were identified with regression models. RESULTS: Responses were collected for 124 patients (response rate 67%), comprising 123 parent-reports, 34 self-reports, and 69 actigraphy assessments. Parents reported sleep problems in 38.0% of the patients compared to 15.2% in healthy children (P < .001). Patients reported fewer sleep problems themselves: 12.1% compared to 15.8% in healthy children (P = .33). Total time in bed (B (95% CI): 22.89 (9.55-36.22)) and total sleep time (B (95% CI):16.30 (1.40-31.19)), as derived from actigraphy, were significantly longer in patients. More parent-reported child sleep problems were predicted by parenting problems, more parental sleep problems, bedroom sharing, and child's sleep medication use (explained variance: 27.4%). CONCLUSIONS: Systematic monitoring of child and parental sleep and implementation of effective interventions may be a gateway to improve quality of survival in pediatric ALL.

Sleep-wake rhythm disruption is associated with cancer-related fatigue in pediatric acute lymphoblastic leukemia.

STUDY OBJECTIVES: To compare sleep-wake rhythms, melatonin, and cancer-related fatigue in pediatric patients with acute lymphoblastic leukemia (ALL) to healthy children and to assess the association between sleep-wake outcomes and cancer-related fatigue. METHODS: A national cohort of ALL patients (2-18 years) was included. Sleep-wake rhythms were measured using actigraphy and generated the following variables: Interdaily stability (IS): higher IS reflects higher stability; intradaily variability (IV): lower IV indicates less fragmentation; L5 and M10 counts: activity counts during the five least and 10 most active hours, respectively; and relative amplitude (RA): the ratio of L5 and M10 counts (higher RA reflects a more robust rhythm). The melatonin metabolite, 6-sulfatoxymelatonin (aMT6s), was assessed in urine. Cancer-related fatigue was assessed with the PedsQL Multidimensional Fatigue Scale. Using regression models sleep-wake rhythms, aMT6s, and cancer-related fatigue were compared to healthy children and associations between sleep-wake outcomes and cancer-related fatigue were assessed in ALL patients. RESULTS: In total, 126 patients participated (response rate: 67%). IS, RA, and M10 counts were lower in patients compared to healthy children (p < 0.001). aMT6s levels were comparable to healthy children (p = 0.425). Patients with ALL were more fatigued compared to healthy children (p < 0.001). Lower IS, RA and M10 counts and higher IV were significantly associated with more parent-reported cancer-related fatigue. Associations between sleep-wake rhythms and self-reported cancer-related fatigue were not statistically significant. CONCLUSIONS: Sleep-wake rhythm impairment is associated with more cancer-related fatigue in pediatric ALL patients. Interventions aimed to improve sleep hygiene and encourage physical activity may reduce cancer-related fatigue.

Light rescues circadian behavior and brain dopamine abnormalities in diurnal rodents exposed to a winter-like photoperiod.

Seasonal affective disorder (SAD), beyond mood changes, is characterized by alterations in daily rhythms of behavior and physiology. The pathophysiological conditions of SAD involve changes in day length and its first-line treatment is bright light therapy. Animal models using nocturnal rodents have been studied to elucidate the neurobiological mechanisms of depression, but might be ill suited to study the therapeutic effects of light in SAD since they exhibit light-aversive responses. Here Arvicanthis ansorgei, a diurnal rodent, was used to determine behavioral, molecular and brain dopamine changes in response to exposure to a winter-like photoperiod consisting of a light-dark cycle with 8 h of light, under diminished light intensity, and 16 h of darkness. Furthermore, we evaluated whether timed-daily bright light exposure has an effect on behavior and brain physiology of winter-like exposed animals. Arvicanthis under a winter-like condition showed alterations in the synchronization of the locomotor activity rhythm to the light-dark cycle. Moreover, alterations in day-night activity of dopaminergic neurotransmission were revealed in the nucleus accumbens and the dorsal striatum, and in the day-night clock gene expression in the suprachiasmatic nucleus. Interestingly, whereas dopamine disturbances were reversed in animals exposed to daily light at early or late day, altered phase of the daily rhythm of locomotion was reverted only in animals exposed to light at the late day. Moreover, Per2 gene expression in the SCN was also affected by light exposure at late day in winter-like exposed animals. These findings suggest that light induces effects on behavior by mechanisms that rely on both circadian and rhythm-independent pathways influencing the dopaminergic circuitry. This last point might be crucial for understanding the mechanisms of non-pharmacological treatment in SAD.

Insomnia heterogeneity: Characteristics to consider for data-driven multivariate subtyping.

Meta-analyses and systematic reviews have reported surprisingly few consistent insomnia-characteristics with respect to cognitions, mood, traits, history of life events and family history. One interpretation of this limited consistency is that different subtypes of insomnia exist, each with its own specific multivariate profile of characteristics. Because previously unrecognized subtypes will be differentially represented in individual studies and dilute effect sizes of subtype-dependent characteristics of importance, they are unlikely to be reported consistently in individual studies, let alone in meta-analyses. This review therefore aims to complement meta-analyses by listing previously reported psychometric characteristics of insomnia, irrespective of the degree of consistency over studies. The review clearly indicates that characteristics of insomnia may not be limited to sleep. Reports suggest that at least some individuals with insomnia may deviate from people without sleep complaints with respect to demographics, mental and physical health, childhood trauma, life events, fatigue, sleepiness, hyperarousal, hyperactivity, other sleep disorders, lifetime sleep history, chronotype, depression, anxiety, mood, quality of life, personality, happiness, worry, rumination, self-consciousness, sensitivity, dysfunctional beliefs, self-conscious emotion regulation, coping, nocturnal mentation, wake resting-state mentation, physical activity, food intake, temperature perception and hedonic evaluation. The value of this list of characteristics is that 1) internet has now made it feasible to asses them all in a large sample of people suffering from insomnia, and 2) statistical methods like latent class analysis and community detection can utilize them for a truly bottom-up data-driven search for subtypes. The supplement to this review provides a blueprint of this multivariate approach as implemented in the Sleep registry platform (www.sleepregistry.nl), that allows for bottom-up subtyping and fosters cross-cultural comparison and worldwide collaboration on insomnia subtype finding - and beyond.

Genome-wide association analysis of insomnia complaints identifies risk genes and genetic overlap with psychiatric and metabolic traits.

Persistent insomnia is among the most frequent complaints in general practice. To identify genetic factors for insomnia complaints, we performed a genome-wide association study (GWAS) and a genome-wide gene-based association study (GWGAS) in 113,006 individuals. We identify three loci and seven genes associated with insomnia complaints, with the associations for one locus and five genes supported by joint analysis with an independent sample (n = 7,565). Our top association (MEIS1, P < 5 × 10-8) has previously been implicated in restless legs syndrome (RLS). Additional analyses favor the hypothesis that MEIS1 exhibits pleiotropy for insomnia and RLS and show that the observed association with insomnia complaints cannot be explained only by the presence of an RLS subgroup within the cases. Sex-specific analyses suggest that there are different genetic architectures between the sexes in addition to shared genetic factors. We show substantial positive genetic correlation of insomnia complaints with internalizing personality traits and metabolic traits and negative correlation with subjective well-being and educational attainment. These findings provide new insight into the genetic architecture of insomnia.

Effectiveness of internet-supported cognitive behavioral and chronobiological interventions and effect moderation by insomnia subtype: study protocol of a randomized controlled trial.

BACKGROUND: DSM-V criteria for insomnia disorder are met by 6 to 10% of the adult population. Insomnia has severe consequences for health and society. One of the most common treatments provided by primary caregivers is pharmacological treatment, which is far from optimal and has not been recommended since a 2005 consensus report of the National Institutes of Health. The recommended treatment is Cognitive Behavioral Therapy for Insomnia. Effectiveness, however, is still limited. Only a few studies have evaluated the effectiveness of chronobiological treatments, including the timed application of bright light, physical activity and body warming. Another opportunity for optimization of treatment is based on the idea that the people suffering from insomnia most likely represent a heterogeneous mix of subtypes, with different underlying causes and expected treatment responses. The present study aims to evaluate the possibility for optimizing insomnia treatment along the principles of personalized and stratified medicine. It evaluates the following: 1. The relative effectiveness of internet-supported cognitive behavioral therapy, bright light, physical activity and body warming; 2. Whether the effectiveness of internet-supported cognitive behavioral therapy for insomnia can be augmented by simultaneous or prior application of bright light, physical activity and body warming; and 3. Whether the effectiveness of the interventions and their combination are moderated by the insomnia subtype. METHODS/DESIGN: In a repeated measures, placebo-controlled, randomized clinical trial that included 160 people diagnosed with insomnia disorder, we are evaluating the relative effectiveness of 4 intervention weeks. Primary outcome is subjective sleep efficiency, quantified using a sleep diary. Secondary outcomes include other complaints of sleep and daytime functioning, health-related cost estimates and actigraphic objective sleep estimates. Compliance will be monitored both subjectively and objectively using activity, light and temperature sensors. Insomnia subtypes will be assessed using questionnaires. Mixed effect models will be used to evaluate intervention effects and moderation by insomnia subtype ratings. DISCUSSION: The current study addresses multiple opportunities to optimize and personalize treatment of insomnia disorder. TRIAL REGISTRATION: Netherlands National Trial Register NTR4010, 4 June 2013.

Stability and fragmentation of the activity rhythm across the sleep-wake cycle: the importance of age, lifestyle, and mental health.

The rhythms of activity across the 24-h sleep-wake cycle, determined in part by the circadian clock, change with aging. Few large-scale studies measured the activity rhythm objectively in the general population. The present population-based study in middle-aged and elderly persons evaluated how activity rhythms change with age, and additionally investigated sociodemographics, mental health, lifestyle, and sleep characteristics as determinants of rhythms of activity. Activity rhythms were measured objectively with actigraphy. Recordings of at least 96 h (138 ± 14 h, mean ± SD) were collected from 1734 people (age: 62 ± 9.4 yrs) participating in the Rotterdam Study. Activity rhythms were quantified by calculating interdaily stability, i.e., the stability of the rhythm over days, and intradaily variability, i.e., the fragmentation of the rhythm relative to its 24-h amplitude. We assessed age, gender, presence of a partner, employment, cognitive functioning, depressive symptoms, body mass index (BMI), coffee use, alcohol use, and smoking as determinants. The results indicate that older age is associated with a more stable 24-h activity profile (ß = 0.07, p = 0.02), but also with a more fragmented distribution of periods of activity and inactivity (ß = 0.20, p < 0.001). Having more depressive symptoms was related to less stable (ß = -0.07, p = 0.005) and more fragmented (ß = 0.10, p < 0.001) rhythms. A high BMI and smoking were also associated with less stable rhythms (BMI: ß = -0.11, p < 0.001; smoking: ß = -0.11, p < 0.001) and more fragmented rhythms (BMI: ß = 0.09, p < 0.001; smoking: ß = 0.11, p < 0.001). We conclude that with older age the 24-h activity rhythm becomes more rigid, whereas the ability to maintain either an active or inactive state for a longer period of time is compromised. Both characteristics appear to be important for major health issues in old age.

Arginine vasopressin immunoreactivity is decreased in the hypothalamic suprachiasmatic nucleus of subjects with suprasellar tumors.

Suprasellar tumors with compression of the optic chiasm are associated with an impaired sleep-wake rhythm. We hypothesized that this reflects a disorder of the biological clock of the human brain, the suprachiasmatic nucleus (SCN), which is located just above the optic chiasm. In order to test this hypothesis, we investigated the expression of two key neuropeptides of the SCN, that is, arginine vasopressin (AVP) and vasoactive intestinal peptide (VIP), as assessed by quantitative immunocytochemistry in post-mortem hypothalamic tissue of patients with a suprasellar tumor inducing permanent visual field defects. Post-mortem hypothalamic tissue of 5 patients with a suprasellar tumor inducing permanent visual field defects (acromegaly n = 2, nonfunctioning macro-adenoma n = 1, macroprolactinoma n = 1, infundibular metastasis of a colorectal adenocarcinoma n = 1) and 15 age- and gender-matched controls was obtained from the Netherlands Brain Bank. Total AVP immunoreactivity in the SCN was lower in patients with a suprasellar tumor than in controls (P = 0.03). By contrast, total VIP immunoreactivity was not different between patients and controls (P = 0.44). Suprasellar tumors leading to permanent visual field defects are associated with reduced AVP, but not VIP immunoreactivity, in the SCN. These findings raise the possibility that selective impairment of the SCN contributes to sleep-wake disturbances in these patients.

Associations between sleep characteristics, seasonal depressive symptoms, lifestyle, and ADHD symptoms in adults.

OBJECTIVE: The authors explored associations between ADHD symptoms, seasonal depressive symptoms, lifestyle, and health. METHOD: Adult ADHD patients (n = 202) and controls (n = 189) completed the ASESA questionnaire involving lifestyle, eating pattern, and physical and psychological health, and validated measures on ADHD and sleep. ASESA is the Dutch acronym for inattention, sleep, eating pattern, mood, and general health questionnaire. RESULTS: Indication for delayed sleep phase syndrome (DSPS) was 26% in patients and 2% in controls (p < .001). Patients reported shorter sleep, longer sleep-onset latency, and later midsleep. Shorter (R (2) = .21) and later (R (2) = .27) sleep were associated with hyperactivity, male gender, younger age, and seasonal depressive symptoms. Seasonal depressive symptoms were related to hyperactivity, female gender, unemployment, and late sleep (pseudo R (2) = .28). Higher body mass index (BMI) was associated with shorter sleep in patients (ρ = -.16; p = .04) and controls (ρ = -.17; p = .02). Longer sleep showed lower odds for indication of metabolic syndrome (OR = -0.17; p = .053). CONCLUSION: DSPS is more prevalent in ADHD and needs further investigation to establish treatment to prevent chronic health issues.

Medical history of optic chiasm compression in patients with pituitary insufficiency affects skin temperature and its relation to sleep.

The hypothalamus is crucially involved in the circadian timing of the sleep-wake rhythm, yet also accommodates the most important thermoregulatory neuronal network. We have shown before that adults with pituitary insufficiency and history of chiasm compression due to a tumor with suprasellar extension fall asleep later and sleep shorter than those without such history and presumed hypothalamic involvement. To solidify the hypothesized link between vigilance and thermoregulation by the hypothalamus, we aimed to test the hypothesis that the presumed hypothalamic impairment in these patients also affects skin temperature and its association with sleep onset. In a case-control study of 50 patients (54.7 ± 14.5 yrs of age, 30 males) with pituitary insufficiency, 33 of whom had a history of chiasm compression, ambulatory distal and proximal skin temperatures were assessed continuously for 24 h. Sleep parameters were assessed via questionnaire. Group differences in mean skin temperature, calculated over the wake and sleep periods separately, and group differences in the strength of association between pre-sleep skin temperature and sleep onset latency were compared. Results showed that patients with a medical history of chiasm compression had lower proximal skin temperature during the day (34.1°C ± .7°C vs. 34.6°C ± .7°C, p = .045). Additionally, the typical association between sleep onset latency and pre-sleep distal-to-proximal skin temperature gradient was absent in these patients (r = -.01, p = .96), whereas it was unimpaired in those without chiasm compression (r = -.61, p = .02). Thus, patients with history of chiasm compression show impaired skin temperature regulation in association with disturbed sleep. The findings support the hypothesis that a medical history of chiasm compression affects hypothalamic regulation of both vigilance and temperature, possibly by chronically affecting relevant nuclei, including the ventrolateral preoptic area and anterior hypothalamic preoptic area.

A new automated method for rat sleep deprivation with minimal confounding effects on corticosterone and locomotor activity.

The function of sleep in physiology, behaviour and cognition has become a primary focus of neuroscience. Its study inevitably includes experimental sleep deprivation designs. However, concerns exist regarding confounds like stress, increased locomotor activity levels, and decreased motivation to perform operant tasks induced by the methods employed. We here propose a novel procedure for sleep deprivation in rats and evaluate how it affects sleep, corticosterone concentration profiles, locomotor activity levels, and motivation to perform an operant task. Before, during and after 12h of total sleep deprivation by means of gradually increasing the rotation variability and the speed of a novel automated, two-compartment sleep deprivation device, sleep-wake states were assessed by electroencephalography (n=21), brain extracellular corticosterone concentrations using microdialysis (n=11), locomotor activity by infrared measurements (n=8), and operant performance using a fixed-interval-fixed-ratio task (n=16). Sleep was effectively prevented during the procedure; rats on average slept less than 1% of the time (0.8±0.2%, mean±standard error). Brain corticosterone concentrations were mildly increased during the procedure, but did not exceed normal peak concentrations. Locomotor activity was not only increased during the procedure, but also did not exceed the peak levels found during undisturbed wakefulness. Food restriction to 12 g/rat/day prevented sleep deprivation from reducing the motivation to perform an operant task. This novel procedure can be applied to sleep deprive rats in a highly effective way, while keeping corticosterone and locomotor activity within the normal range.

Bright light treatment in elderly patients with nonseasonal major depressive disorder: a randomized placebo-controlled trial.

CONTEXT: Major depressive disorder (MDD) in elderly individuals is prevalent and debilitating. It is accompanied by circadian rhythm disturbances associated with impaired functioning of the suprachiasmatic nucleus, the biological clock of the brain. Circadian rhythm disturbances are common in the elderly. Suprachiasmatic nucleus stimulation using bright light treatment (BLT) may, therefore, improve mood, sleep, and hormonal rhythms in elderly patients with MDD. OBJECTIVE: To determine the efficacy of BLT in elderly patients with MDD. DESIGN: Double-blind, placebo-controlled randomized clinical trial. SETTING: Home-based treatment in patients recruited from outpatient clinics and from case-finding using general practitioners' offices in the Amsterdam region. PARTICIPANTS: Eighty-nine outpatients 60 years or older who had MDD underwent assessment at baseline (T0), after 3 weeks of treatment (T1), and 3 weeks after the end of treatment (T2). Intervention Three weeks of 1-hour early-morning BLT (pale blue, approximately 7500 lux) vs placebo (dim red light, approximately 50 lux). MAIN OUTCOME MEASURES: Mean improvement in Hamilton Scale for Depression scores at T1 and T2 using parameters of sleep and cortisol and melatonin levels. RESULTS: Intention-to-treat analysis showed Hamilton Scale for Depression scores to improve with BLT more than placebo from T0 to T1 (7%; 95% confidence interval, 4%-23%; P = .03) and from T0 to T2 (21%; 7%-31%; P = .001). At T1 relative to T0, get-up time after final awakening in the BLT group advanced by 7% (P < .001), sleep efficiency increased by 2% (P = .01), and the steepness of the rise in evening melatonin levels increased by 81% (P = .03) compared with the placebo group. At T2 relative to T0, get-up time was still advanced by 3% (P = .001) and the 24-hour urinary free cortisol level was 37% lower (P = .003) compared with the placebo group. The evening salivary cortisol level had decreased by 34% in the BLT group compared with an increase of 7% in the placebo group (P = .02). CONCLUSIONS: In elderly patients with MDD, BLT improved mood, enhanced sleep efficiency, and increased the upslope melatonin level gradient. In addition, BLT produced continuing improvement in mood and an attenuation of cortisol hyperexcretion after discontinuation of treatment. TRIAL REGISTRATION: clinicaltrials.gov Identifier NCT00332670.

The role of environmental light in sleep and health: effects of ocular aging and cataract surgery.

Environmental illumination profoundly influences human health and well-being. Recently discovered photoreceptive retinal ganglion cells (pRGCs) are primary mediators of numerous circadian, neuroendocrine and neurobehavioral responses. pRGCs provide lighting information to diverse nonvisual (non-image-forming) brain centers including the suprachiasmatic nuclei (SCN) which serve as the body's master biological clock. The SCN exert functional control over circadian aspects of physiology. The timing and strength (amplitude) of SCN rhythmic signals are affected by light exposure. Light deficiency may attenuate SCN function and its control of physiological and hormonal rhythms which in turn can result in a cascade of adverse events. Inadequate pRGC photoreception cannot be perceived consciously, but may aggravate many common age-associated problems including insomnia, depression and impaired cognition. In this review we (1) summarize circadian physiology, emphasizing light's critical role as the most important geophysical timing cue in humans; (2) analyze evidence that typical residential lighting is insufficient for optimal pRGC requirements in youth and even more so with advancing age; (3) show how ocular aging and cataract surgery impact circadian photoreception; and (4) review some of the diverse morbidities associated with chronodisruption in general and those which may be caused by light deficiency in particular.

Sleep during a regular week night: a twin-sibling study.

Previous genetic investigations of variation in normal sleep have focused on measures that describe sleep over longer periods of time. We undertook a study with the aim of evaluating whether heritability can be found in single-night sleep traits. A classical twin study design of monozygotic and dizygotic twins, enriched with siblings of twins was employed. The study included adult twin pairs and their siblings (N = 813 subjects from 342 families). A subsample of 66 individuals participated twice. For a single night, bedtime, awakening time and subjective sleep quality were assessed using a diary. The diary also assessed smoking, alcohol and coffee consumption, and the subjective evaluation of stress. Resemblance between family members was used to estimate the heritability of bedtime, awakening time, sleep problems and sleep quality as a function of sex. Most sleep measures showed familial clustering, but results differed for men and women. Heritability for bedtime and sleep problems was seen in women; and for awakening time in men. We conclude that heritability can be demonstrated for bedtime and subjective evaluation of even a single night of sleep. The contribution of the genetic make-up is sex specific. In women variance in awakening time is so affected by environmental circumstances, that the genetic contribution to the variance becomes negligible. In contrast, for males, variance in the evening bedtime is so affected by environmental circumstances, that the genetic contribution to the variance becomes negligible.

Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: a randomized controlled trial.

CONTEXT: Cognitive decline, mood, behavioral and sleep disturbances, and limitations of activities of daily living commonly burden elderly patients with dementia and their caregivers. Circadian rhythm disturbances have been associated with these symptoms. OBJECTIVE: To determine whether the progression of cognitive and noncognitive symptoms may be ameliorated by individual or combined long-term application of the 2 major synchronizers of the circadian timing system: bright light and melatonin. DESIGN, SETTING, AND PARTICIPANTS: A long-term, double-blind, placebo-controlled, 2 x 2 factorial randomized trial performed from 1999 to 2004 with 189 residents of 12 group care facilities in the Netherlands; mean (SD) age, 85.8 (5.5) years; 90% were female and 87% had dementia. INTERVENTIONS: Random assignment by facility to long-term daily treatment with whole-day bright (+/- 1000 lux) or dim (+/- 300 lux) light and by participant to evening melatonin (2.5 mg) or placebo for a mean (SD) of 15 (12) months (maximum period of 3.5 years). MAIN OUTCOME MEASURES: Standardized scales for cognitive and noncognitive symptoms, limitations of activities of daily living, and adverse effects assessed every 6 months. RESULTS: Light attenuated cognitive deterioration by a mean of 0.9 points (95% confidence interval [CI], 0.04-1.71) on the Mini-Mental State Examination or a relative 5%. Light also ameliorated depressive symptoms by 1.5 points (95% CI, 0.24-2.70) on the Cornell Scale for Depression in Dementia or a relative 19%, and attenuated the increase in functional limitations over time by 1.8 points per year (95% CI, 0.61-2.92) on the nurse-informant activities of daily living scale or a relative 53% difference. Melatonin shortened sleep onset latency by 8.2 minutes (95% CI, 1.08-15.38) or 19% and increased sleep duration by 27 minutes (95% CI, 9-46) or 6%. However, melatonin adversely affected scores on the Philadelphia Geriatric Centre Affect Rating Scale, both for positive affect (-0.5 points; 95% CI, -0.10 to -1.00) and negative affect (0.8 points; 95% CI, 0.20-1.44). Melatonin also increased withdrawn behavior by 1.02 points (95% CI, 0.18-1.86) on the Multi Observational Scale for Elderly Subjects scale, although this effect was not seen if given in combination with light. Combined treatment also attenuated aggressive behavior by 3.9 points (95% CI, 0.88-6.92) on the Cohen-Mansfield Agitation Index or 9%, increased sleep efficiency by 3.5% (95% CI, 0.8%-6.1%), and improved nocturnal restlessness by 1.00 minute per hour each year (95% CI, 0.26-1.78) or 9% (treatment x time effect). CONCLUSIONS: Light has a modest benefit in improving some cognitive and noncognitive symptoms of dementia. To counteract the adverse effect of melatonin on mood, it is recommended only in combination with light. TRIAL REGISTRATION: controlled-trials.com/isrctn Identifier: ISRCTN93133646.

Live to the rhythm, slave to the rhythm.

Circadian rhythms in health and disease have most often been described in terms of their phases and amplitudes, and how these respond to a single exposure to stimuli denoted as zeitgebers. The present paper argues that it is also important to consider the 24-h regularity in the repeated occurrence of the zeitgebers. The effect of the regularity of stimulation by light, melatonin, physical activity, body temperature, corticosteroids and feeding on synchronization within and between the central circadian clock and peripheral oscillators is discussed. In contrast to the phase shifts that can be recorded acutely after a single zeitgeber pulse, the effects of irregularly versus regularly timed zeitgeber can be studied only in long-term protocols and may develop slowly, which is a possible reason why they have received relatively little attention. Several observations indicate a reciprocal relation between the robustness of the endogenous circadian timing system and its dependency on regularly timed zeitgebers. Especially at old age and in disease, proper functioning of the circadian timing system may become more dependent on regularly timed exposure to zeitgeber stimuli. in such conditions, regularly timed exposure to zeitgeber appears to be highly important for health. After a concise introduction on inputs to the central and peripheral oscillators of the circadian timing system, the paper discusses the responses of the circadian timing system and health to (1) a chronic lack of zeitgeber stimuli; (2) fragmented or quasi-ultradian stimuli and (3) repeated phase shifts in stimuli. Subsequently, the specific relevance to aging is discussed, followed by an overview of the effects of experimentally imposed regularly timed stimuli. Finally, a possible mechanism for the gradually evolving effects of repeated regularly timed stimuli on the circadian timing system is proposed.

Evaluation of wireless determination of skin temperature using iButtons.

Measurements of skin temperatures are often complicated because of the use of wired sensors. This is so in field studies, but also holds for many laboratory conditions. This article describes a wireless temperature system for human skin temperature measurements, i.e. the Thermochron iButton DS1291H. The study deals with validation of the iButton and its application on the human skin, and describes clinical and field measurements. The validation study shows that iButtons have a mean accuracy of -0.09 degrees C (-0.4 degrees C at most) with a precision of 0.05 degrees C (0.09 degrees C at most). These properties can be improved by using calibration. Due to the size of the device the response time is longer than that of conventional sensors, with a tau in water of 19 s. On the human skin under transient conditions the response time is significantly longer, revealing momentary deviations with a magnitude of 1 degrees C. The use of iButtons has been described in studies on circadian rhythms, sleep and cardiac surgery. With respect to circadian rhythm and sleep research, skin temperature assessment by iButtons is of significant value in laboratory, clinical and home situations. We demonstrate that differences in laboratory and field measurements add to our understanding of thermophysiology under natural living conditions. The advantage of iButtons in surgery research is that they are easy to sterilize and wireless so that they do not hinder the surgical procedure. In conclusion, the application of iButtons is advantageous for measuring skin temperatures in those situations in which wired instruments are unpractical and fast responses are not required.