Effect of light treatment on sleep and circadian rhythms in demented nursing home patients

OBJECTIVES: To determine whether fragmented sleep in nursing home patients would improve with increased exposure to bright light. DESIGN: Randomized controlled trial. SETTING: Two San Diego-area nursing homes. PARTICIPANTS: Seventy-seven (58 women, 19 men) nursing home residents participated. Mean age +/- standard deviation was 85.7 +/- 7.3 (range 60-100) and mean Mini-Mental State Examination was 12.8 +/- 8.8 (range 0-30). INTERVENTIONS: Participants were assigned to one of four treatments: evening bright light, morning bright light, daytime sleep restriction, or evening dim red light. MEASUREMENTS: Improvement in nighttime sleep quality, daytime alertness, and circadian activity rhythm parameters. RESULTS: There were no improvements in nighttime sleep or daytime alertness in any of the treatment groups. Morning bright light delayed the peak of the activity rhythm (acrophase) and increased the mean activity level (mesor). In addition, subjects in the morning bright light group had improved activity rhythmicity during the 10 days of treatment. CONCLUSION: Increasing exposure to morning bright light delayed the acrophase of the activity rhythm and made the circadian rhythm more robust. These changes have the potential to be clinically beneficial because it may be easier to provide nursing care to patients whose circadian activity patterns are more socially acceptable.     

No evidence for a phase delay in human circadian rhythms after a single morning melatonin administration

Although there is good consensus that a single administration of melatonin in the early evening can phase advance human circadian rhythms, the evidence for phase delay shifts to a single melatonin stimulus given in the early morning is sparse. We therefore carried out a double-blind randomized-order placebo-controlled study under modified constant routine (CR) conditions (58 hr bedrest under approximately 8 lux with sleep 23:00-07:00 hr) in nine healthy young men. A single (pharmacological) dose of melatonin (5 mg p.o.) or a placebo was administered at 07:00 hr on the first morning. Core body temperature (CBT) and heart rate (HR) were continuously recorded, and saliva was collected half-hourly for assay of melatonin. Neither the timing of the mid-range crossing times of temperature (MRCT) and HR rhythms, nor dim light melatonin onset (DLMOn) or offset (DLMOff) were phase shifted the day after melatonin administration compared with placebo. The only change was an altered wave form of the CBT rhythm: longer duration of higher-than-average temperature after melatonin administration. Under the same modified CR conditions we have previously demonstrated a clear phase advance of the above circadian rhythms following a single administration of 5 mg melatonin in the evening. This study's failure to find significant delays to a single administration does not negate other positive findings with multiple doses, which may be necessary for a 'weak zeitgeber'.     

Melatonin regulates circadian electroretinogram rhythms in a dose- and time-dependent fashion

The circadian rhythm of the chick electroretinogram (ERG) is regulated by the indoleamine hormone melatonin. To determine if the concentration of melatonin or the time at which it was administered would have differential effects on ERG parameters, we conducted experiments analyzing the effects of melatonin at different times of the day. Circadian rhythms of a- and b-wave implicit times and amplitudes were observed in both light:dark (LD) and in continuous darkness (DD). Intramuscular melatonin administration of 1 mg/kg and 100 ng/kg decreased a- and b-wave amplitudes and increased a- and b-wave implicit times. This effect was significantly greater than that observed for 1 ng/kg melatonin, which had little to no effect over the saline controls. The effect of 1 mg/kg and 100 ng/kg melatonin on a- and b-wave amplitude in LD and on b-wave amplitude in DD was greater during the night (ZT/CT 17) than during the day (ZT/CT 5). The fold change in b-wave implicit time over that of controls was greater during the day (ZT/CT 5) than during the night (ZT/CT 17). These data indicate that melatonin may play a role in regulating a day and night functional shift in the retina, and that it does so via regulation of a retinal clock.     

Dim light in the evening causes coordinated realignment of circadian rhythms,sleep, and short-term memory

Light provides the primary signal for entraining circadian rhythms to the day/night cycle. In addition to rods and cones, the retina contains a small population of photosensitive retinal ganglion cells (pRGCs) expressing the photopigment melanopsin (OPN4). Concerns have been raised that exposure to dim artificial lighting in the evening (DLE) may perturb circadian rhythms and sleep patterns, and OPN4 is presumed to mediate these effects. Here, we examine the effects of 4-h, 20-lux DLE on circadian physiology and behavior in mice and the role of OPN4 in these responses. We show that 2 wk of DLE induces a phase delay of ∼2 to 3 h in mice, comparable to that reported in humans. DLE-induced phase shifts are unaffected in Opn4^−/− mice, indicating that rods and cones are capable of driving these responses in the absence of melanopsin. DLE delays molecular clock rhythms in the heart, liver, adrenal gland, and dorsal hippocampus. It also reverses short-term recognition memory performance, which is associated with changes in preceding sleep history. In addition, DLE modifies patterns of hypothalamic and cortical cFos signals, a molecular correlate of recent neuronal activity. Together, our data show that DLE causes coordinated realignment of circadian rhythms, sleep patterns, and short-term memory process in mice. These effects are particularly relevant as DLE conditions―due to artificial light exposure―are experienced by the majority of the populace on a daily basis.

Light exerts profound effects on physiology and behavior, synchronizing biological rhythms to the light/dark cycle (LD) as well as directly modulating alertness and sleep (1, 2). In mammals, light detected by the eye is the primary time cue synchronizing circadian rhythms of activity and rest, a process termed entrainment. Exposure to light at dawn and dusk plays a key role, adjusting the phase of the master circadian clock in the hypothalamic suprachiasmatic nuclei (SCN) (3–5). Studies on the photoreceptors mediating circadian entrainment led to the identification of a distinct photoreceptor system consisting of a subset of photosensitive retinal ganglion cells (pRGCs) expressing the photopigment melanopsin (OPN4) (6, 7). These cells have a peak sensitivity at ∼480 nm (8, 9), hence differing from the classical visual system, which in humans is most sensitive to light at ∼555 nm, corresponding to the red and green cones of the fovea (10). In addition to modulating image-forming responses via local retinal circuitry, OPN4-expressing pRGC axons project to the SCN and different brain areas, setting the circadian clock and driving nonvisual responses to light (5, 7, 11).How does the mammalian brain adapt to changes in daylength? In humans, exposure to long-day photoperiods delays melatonin onset but advances melatonin offset, hence compressing the internal biological night, relative to short-day photoperiods; this is observed in laboratory studies (12, 13) as well as under naturalistic conditions (14, 15). In laboratory mice, the onset and offset of wheel-running activity change dynamically in response to daylength (16). Long-day photoperiods also cause functional reorganization in the SCN. In vivo multiunit recording in mice shows that 16-h light/8-h dark cycles (16:8 LD) weakens phase clustering of SCN neurons (17). Similarly, PERIOD2::LUCIFERASE bioluminescence signals in the mouse dorsal versus ventral SCN are dissociated after 20:4 LD (18). Weakened intercellular coupling in the SCN reflects a form of plasticity, enhancing adaptability of the circadian system to an increase in daylength (19). In addition, 19:5 LD reduces the number of dopamine neurons in the hypothalamus, increasing behavioral immobility and decreasing exploratory activity in rats (20) and mice (21); seasonal variation in photoperiod is also associated with changes in dopamine levels in the human midbrain (22). In the mouse hippocampus, molecular rhythms such as Per1,2 and Cry1,2 are blunted under 20:4 LD (23); however, the consequence is complex: it improves object and spatial discrimination in the spontaneous recognition memory task but disrupts context discrimination in the fear conditioning task (23).Aberrant lighting at night may lead to disrupted circadian rhythms and sleep, which are associated with many adverse health outcomes, including impaired concentration and performance, mood disturbances, metabolic diseases, cardiovascular and neurological disorders, and cancer (24–26). Numerous studies have characterized the disruptive effects of dim light at night (DLAN) on metabolic and mood-related processes in rodents. In these studies, animals were exposed to dim light for the entire night (27–35). As such, DLAN is highly relevant to conditions in which low-level light exposure continues throughout the night, such as light pollution. However, DLAN is somewhat different from exposure to artificial electrical lighting as experienced by the majority of the populace, who typically experience higher light levels during the day (though lower than natural daylight) but dim light for a short period in the evening (DLE) (14, 15, 36, 37). In humans, DLE exposure delays melatonin rhythms and sleep timing (14, 15, 37) and reduces alertness on the subsequent day (36); these phase-delaying effects of DLE on the circadian system are found under both natural summer (14) and winter photoperiods (15). As such, DLE combines features of both long-day photoperiods and DLAN. While similar to a long-day photoperiod, the extended light phase is of a lower light intensity and may exert different effects in comparison with the higher light levels during the day. Conversely, unlike DLAN, under DLE the evening light exposure only occurs at the start of the biological night when the circadian system is most sensitive to light-induced phase delays (38).Although the effects of long-day photoperiods (12–23) and DLAN (27–35) on circadian physiology and behavior have been extensively studied, the effects of DLE—as produced by artificial light exposure—have received less attention. Here, we investigate the effects of 2 wk of DLE in laboratory mice and the role of OPN4 in mediating these responses. Our choice of dim-light level and duration was based upon human studies conducted in nonlaboratory settings (14, 15, 36, 37), which reported that ∼3 to 4 h of ∼20 to 30 lx artificial lighting exposure increased alertness before bedtime, delayed melatonin timing and sleep onset, and increased sleepiness in the morning. Despite their nocturnality, the mouse phase response curve (PRC) is broadly similar to the human PRC: in both species, light presented during the early night delays circadian rhythms, whereas light presented later at night or early in the morning causes phase advances (5, 38, 39). Our DLE protocol comprises a 12-h light phase at 200 lx, a 4-h evening light period at 20 lx, and an 8-h dark phase. Here, we characterize the effects of 4-h, 20-lux DLE on a) locomotor activity rhythms, b) sleep patterns, c) molecular clocks in peripheral tissues, d) short-term memory process, and e) brain cFos signals.     

Classification of circadian pain rhythms and pain characteristics in chronic pain patients: An observational study

This study aimed to perform cluster analysis in patients with chronic pain to extract groups with similar circadian rhythms and compare neuropathic pain and psychological factors among these groups to identify differences in pain-related outcomes. A total of 63 community-dwellers with pain lasting at least 3 months and Numerical Rating Scale scores of ≥2 were recruited from 3 medical institutions. Their pain circadian rhythms were evaluated over 7 days by measuring pain intensity at 6-time points per day using a 10-cm visual analog scale. Cluster analysis was performed using 6 variables with standardized visual analog scale values at 6-time points for individual participants to extract groups with similar pain circadian rhythms. The results of the Neuropathic Pain Symptom Inventory and psychological evaluations in each group were compared using the Kruskal–Wallis test. The results revealed 3 clusters with different circadian rhythms of pain. The total and evoked pain subscale Neuropathic Pain Symptom Inventory scores differed among the 3 clusters. The results suggest that a thorough understanding of circadian pain rhythms in chronic pain patients may facilitate the performance of activities of daily living and physical exercise from the perspective of pain management.     

Influence of the pineal gland and circadian rhythms in circulating levels of thyroid hormones of male hamsters

Thyroxin (T4) and triiodothyronine (T3) were measured by radioimmunoassay in serum of hamsters sacrificed at 4-hr intervals throughout the daily light-dark cycle (14L/10D). Both T4 and T3 concentrations increased significantly during the L period of the daily cycle and decreased during the D period of the cycle; A.M. versus P.M. differences in free thyroxin indices (FTI) were also studied using the T4 and T3 uptake assays of Nuclear Medical Laboratories (Dallas, Texas). The free thyroxin index was significantly greater in serum samples of hamsters sacrificed at 7 P.M. than at 7 A.M. (lights on at 6:30 A.M.). Serum taken at 7 P.M. had less unsaturated binding sites than serum taken at 7 A.M. No significant A.M. versus P.M. differences in free thyroxin index were found in blind hamsters, although blind hamsters had significantly lower T4 and FTI than controls. Placing melatonin in the drinking water at a dose of 80 μg/ml did not significantly influence hormone levels. The greatest difference in hormone concentrations between control and blinded hamsters was found in P.M. samples. Blind hamsters had FTIs that were 48% of P.M. controls. Pinealectomy prevented the effects of blinding on T4 levels and FTIs.     

Circadian rhythms in the aged: a review

After a review of the fundamental concepts on chronobiology, the importance of circadian rhythms in the aged was examined on the basis of the data obtained in animals and humans, including personal observations on over 40 blood constituents. During ageing there are significant modifications of circadian rhythms, with frequent diminution of amplitude and a shift of acrophase. The biological, clinical and therapeutic implications of these findings are discussed.     

Microtubules modulate melatonin receptors involved in phase-shifting circadian activity rhythms: in vitro and in vivo evidence

Abstract:  MT1 melatonin receptors expressed in Chinese hamster ovary (CHO) cells remain sensitive to a melatonin re-challenge even following chronic melatonin exposure when microtubules are depolymerized in the cell, an exposure that normally results in MT1 receptor desensitization. We extended our findings to MT2 melatonin receptors using both in vitro and in vivo approaches. Using CHO cells expressing human MT2 melatonin receptors, microtubule depolymerization prevents the loss in the number of high potency states of the receptor when compared to melatonin-treated cells. In addition, microtubule depolymerization increases melatonin-induced PKC activity but not PI hydrolysis via Gi proteins similar to that shown for MT1Rs. Furthermore, microtubule depolymerization in MT2-CHO cells enhances the exchange of GTP on Gi-proteins using a photoaffinity analog of GTP. To test whether microtubules are capable of modulating melatonin-induced phase-shifts, microtubules are depolymerized specifically within the suprachiasmatic nucleus of the hypothalamus (SCN) of the Long Evans rat and the efficacy of melatonin to phase shift their circadian activity rhythms was assessed and compared to animals with intact SCN microtubules. We find that microtubule depolymerization in the SCN using either Colcemid or nocodazole enhances the efficacy of 10 p m melatonin to phase-shift the activity rhythms of the Long Evans rat. No enhancement occurs in the presence of β-lumicolchicine, the inactive analog of Colcemid. Taken together, these data suggest that microtubule dynamics can modulate melatonin-induced phase shifts of circadian activity rhythms which may explain, in part, why circadian disturbances occur in individuals afflicted with diseases associated with microtubule disturbances.     

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

Circadian rhythms and clock gene expressions are regulated by the suprachiasmatic nucleus in the hypothalamus, and melatonin is produced in the pineal gland. Although the brain detects the light through retinas and regulates rhythms and melatonin secretion throughout the body, the liver has independent circadian rhythms and expressions as well as melatonin production. Previous studies indicate the association between circadian rhythms with various liver diseases, and disruption of rhythms or clock gene expression may promote liver steatosis, inflammation, or cancer development. It is well known that melatonin has strong antioxidant effects. Alcohol drinking or excess fatty acid accumulation produces reactive oxygen species and oxidative stress in the liver leading to liver injuries. Melatonin administration protects these oxidative stress-induced liver damage and improves liver conditions. Recent studies have demonstrated that melatonin administration is not limited to antioxidant effects and it has various other effects contributing to the management of liver conditions. Accumulating evidence suggests that restoring circadian rhythms or expressions as well as melatonin supplementation may be promising therapeutic strategies for liver diseases. This review summarizes recent findings for the functional roles and therapeutic potentials of circadian rhythms and melatonin in liver diseases.     

Natural selection against a circadian clock gene mutation in mice

Circadian rhythms with an endogenous period close to or equal to the natural light–dark cycle are considered evolutionarily adaptive (“circadian resonance hypothesis”). Despite remarkable insight into the molecular mechanisms driving circadian cycles, this hypothesis has not been tested under natural conditions for any eukaryotic organism. We tested this hypothesis in mice bearing a short-period mutation in the enzyme casein kinase 1ε (tau mutation), which accelerates free-running circadian cycles. We compared daily activity (feeding) rhythms, survivorship, and reproduction in six replicate populations in outdoor experimental enclosures, established with wild-type, heterozygous, and homozygous mice in a Mendelian ratio. In the release cohort, survival was reduced in the homozygote mutant mice, revealing strong selection against short-period genotypes. Over the course of 14 mo, the relative frequency of the tau allele dropped from initial parity to 20%. Adult survival and recruitment of juveniles into the population contributed approximately equally to the selection for wild-type alleles. The expression of activity during daytime varied throughout the experiment and was significantly increased by the tau mutation. The strong selection against the short-period tau allele observed here contrasts with earlier studies showing absence of selection against a Period 2 (Per2) mutation, which disrupts internal clock function, but does not change period length. These findings are consistent with, and predicted by the theory that resonance of the circadian system plays an important role in individual fitness.Circadian clocks are a ubiquitous feature of life on earth, and serve to maintain synchrony of internal physiology with the external 24-h environment. Colin Pittendrigh, one of the founders of chronobiology, hypothesized that natural selection should favor circadian systems to operate in resonance with the external cycle (1, 2). A prediction from this hypothesis is that individuals exhibiting circadian rhythms with frequencies that are not in close resonance with the 24-h cycle should be selected against in nature. The hypothesis was initially supported by laboratory experiments in fly species that lived longer in a 24-h light–dark (LD) cycle than in non-24-h LD cycles (2–4). Stronger support emerged from dyadic competition experiments in batch cultures of cyanobacteria carrying single gene mutations affecting their circadian period (τ). Strains (either wild type or mutant) with a τ similar to the external LD cycle outcompeted strains with a τ different from the Zeitgeber (5, 6). Whether periods out of resonance with the external cycle entail a real fitness deficit in a natural setting has not been tested in any of these systems.The Ck1ε^tau (hereafter defined as the tau mutation) is a gain-of-function mutation (7) that accelerates the cellular dynamics of the circadian PERIOD protein (8, 9) and affects circadian behavior and physiology (10). It was first detected in Syrian hamsters (Mesocricetus auratus), where it causes τ to shorten with ∼2 h for each copy of the mutant allele (11). In mice, the same mutation shortens the circadian cycle to an almost identical extent (10). As a consequence of the accelerated circadian clockwork, both homozygote tau mice and hamsters are unable to entrain to 24-h LD cycles in the laboratory. Because its frequency deviates considerably from the natural 24-h cycle, the tau mutation provides an excellent model to study effects of deviant circadian periods on fitness in a natural setting. Here we report the consequences of deviant circadian rhythms in six replicate outdoor populations of mice. These populations were established with the release of mice, all born to two heterozygote parents, in identical enclosures, with ∼49% mutant tau alleles in a near Mendelian ratio in each pen. We used s.c. transponders to record each individual’s visits to feeders in each enclosure, which allowed us to quantify the rhythm of feeding activity and to keep track of each individual’s presence—and, hence, monitor lifespan, mortality, and the tau allele frequency in each population.