Eus J. W. Van Someren

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 Melatonin also increased withdrawn behavior by 1.02 points (95% CI, 0.18-1.86) on the Multi Observational Scale for Elderly Subjects scale, although this effect was not seen if given in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.

Indirect bright light improves circadian rest-activity rhythm disturbances in demented patients

Light is known to be an important modulator of circadian rhythms. We tested the hypothesis than an enduring increase in the daytime environmental illumination level improves rest-activity rhythm disturbances in demented patients. Actigraphy was performed before, during, and after 4 weeks of increased illumination in the living rooms of 22 patients with dementia clinically diagnosed as probable Alzheimers disease, multi-infarct dementia, dementia associated with alcoholism, or normal pressure hydrocephalus. The results indicated that during increased illumination, the stability of the rest-activity rhythm increased in patients with intact vision, but not in visually impaired patients.

Daily nighttime melatonin reduces blood pressure in male patients with essential hypertension.

Abstract—Patients with essential hypertension have disturbed autonomic cardiovascular regulation and circadian pacemaker function. Recently, the biological clock was shown to be involved in autonomic cardiovascular regulation. Our objective was to determine whether enhancement of the functioning of the biological clock by repeated nighttime melatonin intake might reduce ambulatory blood pressure in patients with essential hypertension. We conducted a randomized, double-blind, placebo-controlled, crossover trial in 16 men with untreated essential hypertension to investigate the influence of acute (single) and repeated (daily for 3 weeks) oral melatonin (2.5 mg) intake 1 hour before sleep on 24-hour ambulatory blood pressure and actigraphic estimates of sleep quality. Repeated melatonin intake reduced systolic and diastolic blood pressure during sleep by 6 and 4 mm Hg, respectively. The treatment did not affect heart rate. The day–night amplitudes of the rhythms in systolic and diastolic blood pressures were increased by 15% and 25%, respectively. A single dose of melatonin had no effect on blood pressure. Repeated (but not acute) melatonin also improved sleep. Improvements in blood pressure and sleep were statistically unrelated. In patients with essential hypertension, repeated bedtime melatonin intake significantly reduced nocturnal blood pressure. Future studies in larger patient group should be performed to define the characteristics of the patients who would benefit most from melatonin intake. The present study suggests that support of circadian pacemaker function may provide a new strategy in the treatment of essential hypertension.

Circadian rest—activity rhythm disturbances in alzheimer's disease

Previous studies showed circadian rhythm disturbances in patients with Alzheimers disease. Rest-activity rhythm disturbances manifest themselves through a fragmentation of the rhythm, a weak coupling with Zeitgebers, and high levels of activity during the night. The aim of the present study was to investigate which factors contribute to the presence of these disturbances. Therefore, several rest-activity rhythm, constitutional, and environmental variables were assessed in a heterogeneous group of 34 patients with Alzheimers disease, including presenile and senile patients living at home or in a nursing home, as well as in 11 healthy controls. Circadian rest-activity rhythm disturbances were most prominent in institutionalized patients. Regression analyses showed the involvement of the following variables. First stability of the rest-activity rhythm is associated with high levels of daytime activity and high levels of environmental light resulting from seasonal effects as well as from indoor illumination. Presenile onset contributed to instability of the rhythm. Second, fragmentation of periods of activity and rest is associated with low levels of daytime activity, and is most prominent in moderately severe dementia. Third, night-time activity level is higher during the times of the year when the days are getting shorter and lower when the days are growing longer. These findings indicate that rest-activity rhythm disturbances may improve by increasing environmental light and daytime activity, an assumption for which empirical evidence has recently been published.

MORE THAN A MARKER: INTERACTION BETWEEN THE CIRCADIAN REGULATION OF TEMPERATURE AND SLEEP, AGE-RELATED CHANGES, AND TREATMENT POSSIBILITIES

The neurobiological mechanisms of both sleep and circadianregulation have been unraveled partly in the last decades. A network of brainstructures, rather than a single locus, is involved in arousal state regulation,whereas the suprachiasmatic nucleus (SCN) has been recognized as a key structurefor the regulation of circadian rhythms. Although most models of sleep regulationinclude a circadian component, the actual mechanism by which the circadiantiming system promotes—in addition to homeostatic pressure—transitionsbetween sleep and wakefulness remains to be elucidated. Little more can bestated presently than a probable involvement of neuronal projections and neurohumoralfactors originating in the SCN. This paper reviews the relation among bodytemperature, arousal state, and the circadian timing system and proposes thatthe circadian temperature rhythm provides an additional signaling pathwayfor the circadian modulation of sleep and wakefulness. A review of the literatureshows that increased brain temperature is associated with a type of neuronalactivation typical of sleep in some structures (hypothalamus, basal forebrain),but typical of wakefulness in others (midbrain reticular formation, thalamus).Not only local temperature, but also skin temperature are related to the activationtype in these structures. Warming of the skin is associated with an activationtype typical of sleep in the midbrain reticular formation, hypothalamus, andcerebral cortex (CC). The decreasing part of the circadian rhythm in coretemperature is mainly determined by heat loss from the skin of the extremities,which is associated with strongly increased skin temperature. As such, alterationsin core and skin temperature over the day could modulate the neuronal activationstate or “preparedness for sleep” in arousal-related brain structures.Body temperature may thus provide a third signaling pathway, in addition tosynaptic and neurohumoral pathways, for the circadian modulation of sleep.A proposed model for the effects of body temperature on sleep appears to fitthe available data better than previous hypotheses on the relation betweentemperature and sleep. Moreover, when the effects of age-related thermoregulatoryalterations are introduced into the model, it provides an adequate descriptionof age-related changes in sleep, including shallow sleep and awakening closerto the nocturnal core temperature minimum. Finally, the model indicates thatappropriately timed direct (passive heating) or indirect (bright light, melatonin,physical activity) manipulation of the nocturnal profile of skin and coretemperature may be beneficial to disturbed sleep in the elderly. Althoughsuch procedures could be viewed by researchers as merely masking a markerfor the endogenous rhythm, they may in fact be crucial for sleep improvementin elderly subjects. (Chronobiology International,17(3), 313–354, 2000)The neurobiological mechanisms of both sleep and circadian regulation have been unraveled partly in the last decades. A network of brain structures, rather than a single locus, is involved in arousal state regulation, whereas the suprachiasmatic nucleus (SCN) has been recognized as a key structure for the regulation of circadian rhythms. Although most models of sleep regulation include a circadian component, the actual mechanism by which the circadian timing system promotes—in addition to homeostatic pressure—transitions between sleep and wakefulness remains to be elucidated. Little more can be stated presently than a probable involvement of neuronal projections and neurohumoral factors originating in the SCN. This paper reviews the relation among body temperature, arousal state, and the circadian timing system and proposes that the circadian temperature rhythm provides an additional signaling pathway for the circadian modulation of sleep and wakefulness. A review of the literature shows that increased brain temperature is associated with a type of neuronal activation typical of sleep in some structures (hypothalamus, basal forebrain), but typical of wakefulness in others (midbrain reticular formation, thalamus). Not only local temperature, but also skin temperature are related to the activation type in these structures. Warming of the skin is associated with an activation type typical of sleep in the midbrain reticular formation, hypothalamus, and cerebral cortex (CC). The decreasing part of the circadian rhythm in core temperature is mainly determined by heat loss from the skin of the extremities, which is associated with strongly increased skin temperature. As such, alterations in core and skin

Sleep benefits subsequent hippocampal functioning

Sleep before learning benefits memory encoding through unknown mechanisms. We found that even a mild sleep disruption that suppressed slow-wave activity and induced shallow sleep, but did not reduce total sleep time, was sufficient to affect subsequent successful encoding-related hippocampal activation and memory performance in healthy human subjects. Implicit learning was not affected. Our results suggest that the hippocampus is particularly sensitive to shallow, but intact, sleep.

Sleep, Cognition, and Behavioral Problems in School-Age Children: A Century of Research Meta-Analyzed

Clear associations of sleep, cognitive performance, and behavioral problems have been demonstrated in meta-analyses of studies in adults. This meta-analysis is the first to systematically summarize all relevant studies reporting on sleep, cognition, and behavioral problems in healthy school-age children (5-12 years old) and incorporates 86 studies on 35,936 children. Sleep duration shows a significant positive relation with cognitive performance (r = .08, confidence interval [CI] [.06, .10]). Subsequent analyses on cognitive subdomains indicate specific associations of sleep duration with executive functioning (r = .07, CI [.02, .13]), with performance on tasks that address multiple cognitive domains (r = .10, CI = [.05, .16]), and with school performance (r = .09, CI [.06, .12]), but not with intelligence. Quite unlike typical findings in adults, sleep duration was not associated with sustained attention and memory. Methodological issues and brain developmental immaturities are proposed to underlie the marked differences. Shorter sleep duration is associated with more behavioral problems (r = .09, CI [.07, .11]). Subsequent analyses on subdomains of behavioral problems showed that the relation holds for both internalizing (r = .09, CI [.06, .12]) and externalizing behavioral problems (r = .08, CI [.06, .11]). Ancillary moderator analyses identified practices recommended to increase sensitivity of assessments and designs in future studies. In practical terms, the findings suggest that insufficient sleep in children is associated with deficits in higher-order and complex cognitive functions and an increase in behavioral problems. This is particularly relevant given societys tendency towards sleep curtailment.

Melatonin and Bright-Light Treatment for Rest–Activity Disruption in Institutionalized Patients with Alzheimer’s Disease

OBJECTIVES: To test whether the addition of melatonin to bright‐light therapy enhances the efficacy in treating rest–activity (circadian) disruption in institutionalized patients with Alzheimers disease (AD).

Idiopathic chronic sleep onset insomnia in attention-deficit/hyperactivity disorder: a circadian rhythm sleep disorder

To investigate whether ADHD‐related sleep‐onset insomnia (SOI) is a circadian rhythm disorder, we compared actigraphic sleep estimates, the circadian rest‐activity rhythm, and dim light melatonin onset (DLMO) in ADHD children having chronic idiopathic SOI with that in ADHD children without sleep problems. Participants were 87 psychotropic-medication-naïve children, aged 6 to 12 yrs, with rigorously diagnosed ADHD and SOI (ADHD‐SOI) and 33 children with ADHD without SOI (ADHD‐noSOI) referred from community mental health institutions and pediatric departments of non‐academic hospitals in The Netherlands. Measurements were 1 wk, 24 h actigraphy recordings and salivary DLMO. The mean (±SD) sleep onset time was 21:38±0:54 h in ADHD‐SOI, which was significantly (p<0.001) later than that of 20:49±0:49 h in ADHD‐noSOI. DLMO was significantly later in ADHD‐SOI (20:32±0:55 h), compared with ADHD‐noSOI (19:47±0:49 h; p<0.001). Wake‐up time in ADHD‐SOI was later than in ADHD‐noSOI (p=0.002). There were no significant between‐group differences in sleep maintenance, as estimated by number of wake bouts and activity level in the least active 5 h period, or inter‐ and intradaily rhythm variability. We conclude that children with ADHD and chronic idiopathic sleep‐onset insomnia show a delayed sleep phase and delayed DLMO, compared with ADHD children without SOI.

Reduced Orbitofrontal and Parietal Gray Matter in Chronic Insomnia: A Voxel-Based Morphometric Study

BACKGROUND Brain mechanisms of chronic insomnia, a highly prevalent condition, have barely been investigated. We demonstrate here a decrease in orbitofrontal gray matter (GM) volume that strongly correlates with the severity of complaints. METHODS In a case-control study, optimized voxel-based morphometry was used to compare the regional brain volumes of 24 medication-free chronic primary insomnia patients (age range 52-74 years, 17 women), carefully selected to exclude psychiatric comorbidity, with those of 13 matched control subjects without sleep problems (age range 50-76 years, 9 women). Additionally, the correlation of regional volumes with insomnia severity was investigated. RESULTS Patients had a smaller volume of GM in the left orbitofrontal cortex, strongly correlating (r = -.71) with the subjective severity of insomnia. Furthermore, reduced GM volume was found in the anterior and posterior precuneus. Patients did not show increased GM volume in any area. No group differences were found for white matter volume. CONCLUSIONS This is the first voxel-based morphometry study showing structural brain correlates of insomnia and their relation with insomnia severity. Functional roles of the affected areas in decision-making and stimulus processing might better guide future research into the poorly understood condition of insomnia.