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Melatonin Entrains Free‐running Blind People According to a Physiological Dose‐response Curve
Abstract
The specific circadian role proposed for endogenous melatonin production was based on a study of sighted people who took low pharmacological doses (500 microg) of this chemical signal for the "biological night": the magnitude and direction of the induced phase shifts were dependent on what time of day exogenous melatonin was administered and were described by a phase-response curve that turned out to be the opposite of that for light. We now report that lower (physiological) doses of up to 300 microg can entrain (synchronize) free-running circadian rhythms of 10 totally blind subjects that would otherwise drift later each day. The resulting log-linear dose-response curve in the physiological range adds support for a circadian function of endogenous melatonin in humans. Efficacy of exogenous doses in the physiological range are of clinical significance for totally blind people who will need to take melatonin daily over their entire lifetimes in order to remain entrained to the 24 h day. Left untreated, their free-running endocrine, metabolic, behavioral, and sleep/wake cycles can be almost as burdensome as not having vision.
... In fact, this has been observed. Studies in blind individuals revealed that relatively small amounts of melatonin (0.5 or 0.3 mg) were effective, whereas higher doses such as 10 mg failed to entrain [31][32][33]. Notably, these findings are well in accordance with the low doses of melatonin required for sleep initiation [19]. Although the sleep latency reduction and circadian resetting are mechanistically different, the common property is the requirement of an only short action at a low dose. ...
... This is Sleep Vigilance (2018) 2:5- 11 7 typically followed by a delay part, thereafter a transition phase in which the system switches from delays to advances, and an advance part (Fig. 1). In humans, PRCs for melatonin have been obtained under various conditions and in different populations, including blind people [32,[36][37][38]. Under these premises, it is entirely obvious that entrainment can be only achieved when melatonin is given in suitable parts of the PRC. ...
... A typical case for this would be blindness in those individuals who do not possess melanopsin-containing RGCs and are, therefore, not sensitive to a light/dark cycle. In many cases, such persons have been successfully treated by melatonin [23,31,32,37,[40][41][42]. Visual blindness in patients possessing these RGCs does not require additional synchronizing time cues, provided that their period length is in the range of entrainment. ...
Purpose
This review summarizes the conditions under which sleep promotion by melatonin or other melatonergic drugs can be successfully achieved or not. Importantly, the chronobiological rules are outlined which have to be followed in cases in which an etiology of circadian deviations is responsible for sleep difficulties.
Dose and Duration of Action
Sleep initiation is already possible with low doses (below 1 mg) of immediate-release melatonin. Prolonged actions have only caused moderate improvements of sleep maintenance. At elevated doses, melatonin may occasionally cause sleep fragmentation in some patients. Low doses (below 1 mg) of short-acting melatonin are also suitable for entraining and readjusting circadian rhythms, because circadian oscillators are particularly sensitive to nonparametric synchronizing signals.
Phase Response Curve
Successful entrainment of circadian rhythms is only possible if the phase response curve (PRC) is considered, which consists of phases of a silent zone with poor resetting, a delay and an advance part. Notably, the dim light melatonin onset (DLMO) is still in the silent zone.
Conclusions
For purposes of melatonergic treatment, the knowledge of synchronization-sensitive phases within the circadian cycle is helpful in correcting circadian rhythm sleep disorders, otherwise poorly entrainable rhythms, e.g., in blind people, and mood disorders with circadian etiology. The disregard of the PRC leads to false conclusions on inefficacy of melatonin or other melatonergic drugs. Correcting actions by melatonin should not be inhibited by other drugs. For instance, attempts of shortening a circadian oscillation by well-timed melatonin should not be counteracted by period-lengthening drugs, such as lithium.
... Further study demonstrated that doses as low as 0.02 mg can successfully entrain people with non-24 and that melatonin acts according to a log-linear dose response curve across a range of 0.02-0.3 mg [66]. These low doses of melatonin may have been effective because of the additional resetting effects of non-photic time cues (possibly physical activity, caloric intake, and/or sleep itself) [30,35]. ...
... It has been shown that when people with non-24 and free-running periods greater than 24 h are entrained with melatonin, the DLMO typically occurs 0-5 h after the time of melatonin administration [66,68]. Consequently, if melatonin (0.5 mg) was given at the same clock time each day, around bedtime, and entrainment was achieved, the DLMO could occur after bedtime (as in Fig. 2b), by as much as 5 h. ...
... A large number of trials have shown that melatonin is effective in entraining the circadian clock [34,[62][63][64][65][66]. The initial studies were double-blind placebo-controlled trials [34,62], while many later single-blind non-placebo-controlled trials sought to address questions related to dose and timing [63][64][65][66]68] as discussed above. ...
Non-24-h sleep-wake disorder (non-24) is a circadian rhythm disorder occurring in 55-70% of totally blind individuals (those lacking conscious light perception) in which the 24-h biological clock (central, hypothalamic, circadian pacemaker) is no longer synchronized, or entrained, to the 24-h day. Instead, the overt rhythms controlled by the biological clock gradually shift progressively earlier or later (free run) in accordance with the clock's near-24-h period, resulting in a recurrent pattern of daytime hypersomnolence and night-time insomnia. Orally administered melatonin and the melatonin agonist tasimelteon have been shown to entrain (synchronize) the circadian clock, resulting in improvements in night-time sleep and daytime alertness. We review the basic principles of circadian rhythms necessary to understand and treat non-24. The time of melatonin or tasimelteon administration must be considered carefully. For most individuals, those with circadian periods longer than 24 h, low-dose melatonin should be administered about 6 h before the desired bedtime, while in a minority, those with circadian periods shorter than 24 h (more commonly female individuals and African-Americans), melatonin should be administered at the desired wake time. Small doses (e.g., 0.5 mg of melatonin) that are not soporific would thus be preferable. Administration of melatonin or tasimelteon at bedtime will entrain individuals with non-24 but at an abnormally late time, resulting in continued problems with sleep and alertness. To date, tasimelteon has only been administered 1 h before the target bedtime in patients with non-24. Issues of cost, dose accuracy, and purity may figure into the decision of whether tasimelteon or melatonin is chosen to treat non-24. However, there are no head-to-head studies comparing efficacy, and studies to date show comparable rates of treatment success (entrainment).
... However, it has also been demonstrated that daily administration of appropriately timed melatonin can synchronize the circadian clock [62][63][64][65][66] in patients with sleep disorders; its use is even recommended by the Standards of Practice Committee of the American Academy of Sleep Medicine [67]. The phase-shifting effects of melatonin are essentially opposite to those of light. ...
... The former includes circadian rhythm control and sleep regulation. There is a considerable body of evidence of melatonin regulating sleep in various sleep disorders [7,[62][63][64][65][66]. ...
Background
The medical community is beginning to recognize that retinitis pigmentosa (RP), due to its disabling progression, eventually leads to a reduction in the patient´s quality of life, a direct economic impact, and an increase in the burden on the health care system. There is no curative treatment for the origin of the disease, and most of the current interventions fail in reducing the associated negative psychological states, such as anxiety and depression, which lead to increased variability of vision and pose a continuous threat to the patient’s independence.
Objective
The aim of this study is to assess the effect of oral melatonin (OM) administration alone and combined with short-wavelength light (SWL)–blocking filters on patients with RP and test their effectiveness in improving the level of stress and sleep problems in many of these patients.
Methods
We have developed a low-cost therapy protocol for patients with RP with sleep disorders and negative psychological stress. Patients will be randomized to receive a combined intervention with SWL-blocking filters and OM, SWL-blocking filters alone, or OM alone. There will also be a nonintervention arm as a control group. This study will be conducted across 2 retinal units in patients with RP with sleep disorders and high perceived stress and anxiety score reports. Patients will be assessed in the preintervention period, weekly during the 4 weeks of intervention, and then at 6 months postintervention. The primary outcomes are the differences in changes from baseline to postintervention in hormone release (α-amylase, cortisol, and melatonin) and sleep quality, as measured with the visual analog scale. Secondary outcome measures include clinical macular changes, as measured with optical coherence tomography and optical coherence tomography angiography; retinal function, as measured using the visual field and best-corrected visual acuity; sleep data collected from personal wearables; and several patient-reported variables, such as self-recorded sleep diaries, quality of life, perceived stress, and functional status.
Results
This project is still a study protocol and has not yet started. Bibliographic research for information for its justification began in 2020, and this working group is currently seeking start-up funding. As soon as we have the necessary means, we will proceed with the registration and organization prior to the preliminary phase.
Conclusions
In this feasibility randomized clinical controlled trial, we will compare the effects of SWL blocking alone, administration of OM alone, and a combined intervention with both in patients with RP. We present this study so that it may be replicated and incorporated into future studies at other institutions, as well as applied to additional inherited retinal dystrophies. The goal of presenting this protocol is to aid recent efforts in reducing the impact of sleeping disorders and other psychological disorders on the quality of life in patients with RP and recovering their self-autonomy. In addition, the results of this study will represent a significant step toward developing a novel low-cost therapy for patients with RP and validating a novel therapeutic target.
International Registered Report Identifier (IRRID)
PRR1-10.2196/49196
... The PRC typically contains delay and advance parts and, in between, silent zones in which no substantial changes are achieved. The PRC for melatonin has been determined in the human (Figure 1), for sighted and blind subjects [19,[54][55][56]. When closely looking at the details of the PRC, one will state that the frequently read recommendation for melatonin intake about half an hour before bedtime can remain insufficient for resetting. ...
... Under condition (3), light-insensitive nonentrained blind people can, of course, be easily treated by melatonin in any desired phase that is suitable for resetting. The usefulness of melatonin has been demonstrated in several cases [54,55,62,118]. Again, low doses are sufficient and, as mentioned in Section 2, elevated doses such as 10 mg are less efficient than lower ones [62], presumably because of overlaps of different sections of the PRC. ...
Melatonin has been used preclinically and clinically for different purposes. Some applications are related to readjustment of circadian oscillators, others use doses that exceed the saturation of melatonin receptors MT1 and MT2 and are unsuitable for chronobiological purposes. Conditions are outlined for appropriately applying melatonin as a chronobiotic or for protective actions at elevated levels. Circadian readjustments require doses in the lower mg range, according to receptor affinities. However, this needs consideration of the phase response curve, which contains a silent zone, a delay part, a transition point and an advance part. Notably, the dim light melatonin onset (DLMO) is found in the silent zone. In this specific phase, melatonin can induce sleep onset, but does not shift the circadian master clock. Although sleep onset is also under circadian control, sleep and circadian susceptibility are dissociated at this point. Other limits of soporific effects concern dose, duration of action and poor individual responses. The use of high melatonin doses, up to several hundred mg, for purposes of antioxidative and anti-inflammatory protection, especially in sepsis and viral diseases, have to be seen in the context of melatonin’s tissue levels, its formation in mitochondria, and detoxification of free radicals.
... 17 Of note, although the aforementioned melatonin dose recommendations may be adhered to, lower and more physiological doses (0.3 mg) have been demonstrated to assist in synchronizing a 24-hour circadian rhythm in persons with visual impairment. 60 However, in our own practice, some NPL VI athletes have reported positive experiences in response to a larger, albeit tapered, dosing regimen wherein doses start large (eg, an initial 7-8 mg dose) then reduce (eg, 5 mg for days 1-3). Thus, the precise melatonin dose for NPL VI athletes to alleviate the effects of jet lag is currently unknown, and it is advised that athletes, in conjunction with health care professionals and dietitians, ascertain individual dosages that optimally support their physiological requirements. ...
Purpose : Transmeridian travel is common for elite athletes participating in competitions and training. However, this travel can lead to circadian misalignment wherein the internal biological clock becomes desynchronized with the light–dark cycle of the new environment, resulting in performance decrement and potential negative health consequences. Existing literature extensively discusses recommendations for managing jet lag, predominantly emphasizing light-based interventions to synchronize the internal clock with the anticipated time at the destination. Nevertheless, visually impaired (VI) athletes may lack photoreceptiveness, diminishing or nullifying the effectiveness of this therapy. Consequently, this invited commentary explores alternative strategies for addressing jet lag in VI athletes. Conclusions : VI athletes with light perception but reduced visual acuity or visual fields may still benefit from light interventions in managing jet lag. However, VI athletes lacking a conscious perception of light should rely on gradual shifts in behavioral factors, such as meal timing and exercise, to facilitate the entrainment of circadian rhythms to the destination time. Furthermore, interventions like melatonin supplementation may prove useful during and after travel. In addition, it is recommended that athlete guides adopt phase-forward or phase-back approaches to synchronize with the athlete, aiding in jet-lag management and optimizing performance.
... Sleep and circadian disorders are common among blind individuals, with severity depending on the degree of light perception [182,183]. Many visually impaired individuals have a free-running circadian rhythm with periods lasting longer than 24 h [184], while those with complete loss of ocular perception of light have a greater concentration of daily plasma melatonin compared to sighted individuals, due to reduced nighttime suppression of melatonin [185]. Individuals with limited light perception have an abnormal circadian rhythm, which has been treated with daily administration of melatonin [182,183]. ...
Light is an essential part of many life forms. The natural light–dark cycle has been the dominant stimulus for circadian rhythms throughout human evolution. Artificial light has restructured human activity and provided opportunities to extend the day without reliance on natural day–night cycles. The increase in light exposure at unwanted times or a reduced dynamic range of light between the daytime and nighttime has introduced negative consequences for human health. Light exposure is closely linked to sleep–wake regulation, activity and eating patterns, body temperature, and energy metabolism. Disruptions to these areas due to light are linked to metabolic abnormalities such as an increased risk of obesity and diabetes. Research has revealed that various properties of light influence metabolism. This review will highlight the complex role of light in human physiology, with a specific emphasis on metabolic regulation from the perspective of four main properties of light (intensity, duration, timing of exposure, and wavelength). We also discuss the potential influence of the key circadian hormone melatonin on sleep and metabolic physiology. We explore the relationship between light and metabolism through circadian physiology in various populations to understand the optimal use of light to mitigate short and long-term health consequences.
... A number of studies have been conducted in non-sighted individuals with timed administration of melatonin to entrain the circadian rhythm [132][133][134][135][136]. Melatonin at doses of 0.5 mg or 10 mg at 21:00 or 1 h before bedtime for 4 to 12 weeks led to the entrainment of 67% of non-sighted individuals with Non-24 [2]. ...
Circadian rhythms oscillate throughout a 24-h period and impact many physiological processes and aspects of daily life, including feeding behaviors, regulation of the sleep-wake cycle, and metabolic homeostasis. Misalignment between the endogenous biological clock and exogenous light–dark cycle can cause significant distress and dysfunction, and treatment aims for resynchronization with the external clock and environment. This article begins with a brief historical context of progress in the understanding of circadian rhythms, and then provides an overview of circadian neurobiology and the endogenous molecular clock. Various tools used in the diagnosis of circadian rhythm sleep–wake disorders, including sleep diaries and actigraphy monitoring, are then discussed, as are the therapeutic applications of strategically timed light therapy, melatonin, and other behavioral and pharmacological therapies including the melatonin agonist tasimelteon. Management strategies towards each major human circadian sleep–wake rhythm disorder, as outlined in the current International Classification of Sleep Disorders – Third Edition, including jet lag and shift work disorders, delayed and advanced sleep–wake phase rhythm disorders, non-24-h sleep–wake rhythm disorder, and irregular sleep–wake rhythm disorder are summarized. Last, an overview of chronotherapies and the circadian dysregulation of neurodegenerative diseases is reviewed.
... In accordance with our findings, Irina et al. observed that lower-dose melatonin (0.3 mg, p.o.) was sufficient to restore the nocturnal physiological level of melatonin in insomnia patients; it also provided the most significant effect on sleep improvement compared to a pharmacological dose (3 mg, p.o.) [77]. Similarly, Lewy et al. reported that lower doses of melatonin, 20-300 µg, were sufficient to reach the physiological level and synchronize the free-running circadian rhythm in blind subjects [78]. Our i.t. ...
Opioids are commonly prescribed for clinical pain management; however, dose-escalation, tolerance, dependence, and addiction limit their usability for long-term chronic pain. The associated poor sleep pattern alters the circadian neurobiology, and further compromises the pain management. Here, we aim to determine the correlation between constant light exposure and morphine tolerance and explore the potential of melatonin as an adjuvant of morphine for neuropathic pain treatment.
Methods:
Wistar rats were preconditioned under constant light (LL) or a regular light/dark (LD) cycle before neuropathic pain induction by chronic constriction injury. An intrathecal (i.t.) osmotic pump was used for continued drug delivery to induce morphine tolerance. Pain assessments, including the plantar test, static weight-bearing symmetry, and tail-flick latency, were used to determine the impact of the light disruption or exogenous melatonin on the morphine tolerance progression.
Results:
constant light exposure significantly aggravates morphine tolerance in neuropathic rats. Continued infusion of low-dose melatonin (3 μg/h) attenuated morphine tolerance in both neuropathic and naïve rats. This protective effect was independent of melatonin receptors, as shown by the neutral effect of melatonin receptors inhibitors. The transcriptional profiling demonstrated a significant enhancement of proinflammatory and pain-related receptor genes in morphine-tolerant rats. In contrast, this transcriptional pattern was abolished by melatonin coinfusion along with the upregulation of the Kcnip3 gene. Moreover, melatonin increased the antioxidative enzymes SOD2, HO-1, and GPx1 in the spinal cord of morphine-tolerant rats.
Conclusion:
Dysregulated circadian light exposure significantly compromises the efficacy of morphine's antinociceptive effect, while the cotreatment with melatonin attenuates morphine tolerance/hyperalgesia development. Our results suggest the potential of melatonin as an adjuvant of morphine in clinical pain management, particularly in patients who need long-term opioid treatment.
... MLT supplementation treatment significantly inhibits sepsis and neuroinflammation. MLT is effectively used to treat sleep disorders and phase shift of circadian rhythms, depressive disorders, and improve learning and memory [201][202][203]. Studies demonstrated that MLT protects against neurodegeneration, apoptosis, and I/R injury by the mechanism of freeradical-scavenging properties [204,205]. ...
Melatonin (MLT) is a powerful chronobiotic hormone that controls a multitude of circadian rhythms at several levels and, in recent times, has garnered considerable attention both from academia and industry. In several studies, MLT has been discussed as a potent neuroprotectant, anti-apoptotic, anti-inflammatory, and antioxidative agent with no serious undesired side effects. These characteristics raise hopes that it could be used in humans for central nervous system (CNS)-related disorders. MLT is mainly secreted in the mammalian pineal gland during the dark phase, and it is associated with circadian rhythms. However, the production of MLT is not only restricted to the pineal gland; it also occurs in the retina, Harderian glands, gut, ovary, testes, bone marrow, and lens. Although most studies are limited to investigating the role of MLT in the CNS and related disorders, we explored a considerable amount of the existing literature. The objectives of this comprehensive review were to evaluate the impact of MLT on the CNS from the published literature, specifically to address the biological functions and potential mechanism of action of MLT in the CNS. We document the effectiveness of MLT in various animal models of brain injury and its curative effects in humans. Furthermore, this review discusses the synthesis, biology, function, and role of MLT in brain damage, and as a neuroprotective, antioxidative, anti-inflammatory, and anticancer agent through a collection of experimental evidence. Finally, it focuses on the effect of MLT on several neurological diseases, particularly CNS-related injuries.
... A good candidate to treat rhythm disturbances is me- latonin. This is known to have chronobiotic properties, and has been used to treat circadian desynchrony in blind people, circadian disorders of sleep and mood, and mal- adaptation to shift work and to trans-meridian air trav- el (Arendt, Skene 2005; Lewy et al. 2005;Redfern et al. 1994;Sack, Lewy 1997). Lewy and coworkers ( Lewy et al. 1992) were the first to show that orally administered me- latonin shifts circadian rhythms in humans according to a phase-response curve (for further references, see Lewy et al. 2004). ...
The aim of the present review is to characterize the circadian body temperature rhythm of humans, a well-established marker of the circadian system and its origins. Some results of experiments on animals are also mentioned as they show general biological principles. The relevance of the circadian body temperature rhythm for health and wellbeing is described together with examples of its distinct alterations in association with certain pathologies. Since the circadian body temperature rhythm varies depending on stages of individual development, ontogenetic and age-dependent changes, their causes and consequences are also considered. Finally, some ways to prevent or minimize consequences of disruptions of the circadian body temperature rhythm are discussed.
... Another, assessing its use for secondary sleep disorders with no requirement for circadian desynchrony, found little effect but did consider that it was efficacious in advancing phase in delayed-sleep phase syndrome (DSPS) [124]. Its use in free-running sleep wake disorder (non-24) in the blind has not been meta-analysed, but to the author's knowledge there are no unsuccessful studies (see below for use of the agonists in the blind) [106,120,[125][126][127][128][129][130][131]. The American Academy of Sleep Medicine recommends melatonin for DSPS, non-24 and jet lag [98]. ...
For many years now a treatment mitigating the debilitating effects of jet lag has been sought. Rapid travel across time zones leads, in most people, to temporary symptoms, in particular poor sleep, daytime alertness and poor performance. Mis-timed circadian rhythms are considered to be the main factor underlying jet-lag symptoms, together with the sleep deprivation from long haul flights. Virtually all aspects of physiology are rhythmic, from cells to systems, and circadian rhythms are coordinated by a central pacemaker or clock in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN adapts slowly to changes in time zone, and peripheral clocks or oscillators adapt at different rates, such that the organism is in a state of desynchrony from the external environment and internally. Light exposure is the main factor controlling the circadian system and needs to be considered together with any pharmacological interventions. This review covers the relatively new chronobiotic drugs, which can hasten adaptation of the circadian system, together with drugs directly affecting alertness and sleep propensity. No current treatment can instantly shift circadian phase to a new time zone; however, adaptation can be hastened. The melatoninergic drugs are promising but larger trials in real-life situations are needed. For short stopovers it is recommended to preserve sleep and alertness without necessarily modifying the circadian system. New research suggests that modification of clock function via genetic manipulation may one day have clinical applications.
... Melatonin is an essential component of the circadian system and is the "internal zeitgeber" of its functioning (Lewy et al., 2005), and has also been implicated in AD (Cardinali et al., 2002;Lee et al., 2009). Therefore, it is important to study the mechanisms of melatonin synthesis in human and suitable animal models. ...
Neurodegenerative diseases are the most frequent cause of dementia, representing a burden for public health systems (especially in middle and middle-high income countries). Although most research on this issue is concentrated in first-world centers, growing efforts in South America are affording important breakthroughs. This emerging agenda poses new challenges for the region but also new opportunities for the field. This book aims to integrate the community of experts across the globe and the region, and to establish new challenges and developments for future investigation. We present research focused on neurodegenerative research in South America. We introduce studies assessing the interplay among genetic, neural, and behavioral dimensions of these diseases, as well as articles on vulnerability factors, comparisons of findings from various countries, and works promoting multicenter and collaborative networking. More generally, our book covers a broad scope of human-research approaches (behavioral assessment, neuroimaging, electromagnetic techniques, brain connectivity, peripheral measures), animal methodologies (genetics, epigenetics, proteomics, metabolomics, other molecular biology tools), species (all human and non-human animals, sporadic, and genetic versions), and article types (original research, review, and opinion papers). Through this wide-ranging proposal, we hope to introduce a fresh approach to the challenges and opportunities of research on neurodegeneration in South America.
... Melatonin is an essential component of the circadian system and is the "internal zeitgeber" of its functioning (Lewy et al., 2005), and has also been implicated in AD (Cardinali et al., 2002;Lee et al., 2009). Therefore, it is important to study the mechanisms of melatonin synthesis in human and suitable animal models. ...
Alzheimer's disease (AD) is a multifactorial progressive neurodegenerative disease. Despite decades of research, no disease modifying therapy is available and a change of research objectives and/or development of novel research tools may be required. Much AD research has been based on experimental models using animals with a short lifespan that have been extensively genetically manipulated and do not represent the full spectrum of late-onset AD, which make up the majority of cases. The aetiology of AD is heterogeneous and involves multiple factors associated with the late-onset of the disease like disturbances in brain insulin, oxidative stress, neuroinflammation, metabolic syndrome, retinal degeneration and sleep disturbances which are all progressive abnormalities that could account for many molecular, biochemical and histopathological lesions found in brain from patients dying from AD. This review is based on the long-lived rodent Octodon degus (degu) which is a small diurnal rodent native to South America that can spontaneously develop cognitive decline with concomitant phospho-tau, β-amyloid pathology and neuroinflammation in brain. In addition, the degu can also develop several other conditions like type 2 diabetes, macular and retinal degeneration and atherosclerosis, conditions that are often associated with aging and are often comorbid with AD. Long-lived animals like the degu may provide a more realistic model to study late onset AD.
... The SCN is also sensitive to feedback from the pineal melatonin rhythm which impinges on the SCN through its melatonin receptors (Pevet and Challet, 2011). Exogenous melatonin can phase-shift and entrain the SCN, but its effects depend on the circadian phase of melatonin administration (Lewy et al., 2005). ...
Diagnosis and treatment of circadian rhythm sleep-wake disorders both require assessment of circadian phase of the brain’s circadian pacemaker. The gold-standard univariate method is based on collection of a 24-hr time series of plasma melatonin, a suprachiasmatic nucleus-driven pineal hormone. We developed and validated a multivariate whole-blood mRNA-based predictor of melatonin phase which requires few samples. Transcriptome data were collected under normal, sleep-deprivation and abnormal sleep-timing conditions to assess robustness of the predictor. Partial least square regression (PLSR), applied to the transcriptome, identified a set of 100 biomarkers primarily related to glucocorticoid signaling and immune function. Validation showed that PLSR-based predictors outperform published blood-derived circadian phase predictors. When given one sample as input, the R² of predicted vs observed phase was 0.74, whereas for two samples taken 12 hr apart, R² was 0.90. This blood transcriptome-based model enables assessment of circadian phase from a few samples.
DOI: http://dx.doi.org/10.7554/eLife.20214.001
... While the underlying mechanism for the anxiolytic outcome is yet to be elucidated, our study provides insight into the pivotal role of ventral subiculum in regulating stress and anxiety. Patients suffering from seasonal affective disorders experience recurrent episodes of depression and anxiety, starting in the fall or winter and have been successfully treated with light therapy [62,63]. In addition to entraining the circadian system, light therapy and melatonin supplementation have been shown to improve activity rhythms and sleep efficiency in AD and dementia patients [64][65][66]. ...
Neurodegeneration of hippocampal structures is implicated in Alzheimer's disease (AD). Patients with AD exhibit ‘sundown syndrome’ featuring mood swings and anxiety. Although there are studies demonstrating circadian rhythm disruption associated with sundown phenomenon, the mechanisms underlying the emotional disturbances remain elusive. In the present study, we examined the relationship between subiculum (a key hippocampal output structure) and anxiety. Our study demonstrates that bilateral ventral subicular lesion (VSL) leads to anxiogenic behavior. In the elevated plus maze test, VSL rats made less number of entries into the open arms and spent significantly more time in the closed arms. Similarly, in the light–dark exploration test, VSL rats spent significantly more time in the dark chamber and made fewer entries into the light chamber. VSL also produced significant neurodegeneration in the paraventricular, suprachiasmatic and dorsomedial nuclei of the hypothalamus. Exposing VSL rats to a short photoperiod regime (SPR; 06/18 h light–dark cycle) for 21 days ameliorated the anxiety-like behavior. VSL rats on SPR also exhibited increased food consumption and higher core body temperature. Our study supports the hypothesis that the ventral subiculum regulates anxiety-like behavior and that SPR helps in the alleviation of such behavior. Even though the mechanisms underlying anxiolytic effects of light–dark cycle manipulation are yet to be elucidated, such non-pharmacological strategies can help to mitigate anxiety-like behavior. A proper understanding of the effectiveness of photoperiod manipulation will help in developing strategies in the management of emotional disturbances associated with affective and neurodegenerative disorders including AD.
... У слепых людей, не имеющих возможности воспринимать свет, часто наблюдаются несинхронизированные эндокринные, метаболические, поведенческие процессы и циклы сна -бодрствования на протяжении всей жизни, за исключением случаев, когда проводится лечение десинхроноза, которое оказывается эффективным [8]. Организм входит в состояние сна легче всего, когда температура тела находится на своем самом низком уровне, в сочетании с повышением уровня секреции мелатонина. ...
Traveling by plane is a big part of high-level athletes’ life. As training and competitions often take part in different countries and sometimes even on different continents, athletes are forced to fly by plane across several time zones. As a result, jet lag can occur. Jet lag is the cause of changes in sleep-wake cycle, sickness, and bad mood. That may result in a decrease of sports performance and competition results. The aim of this paper was an assessment of the latest information about the mechanisms of jet lag development, and the latest results of clinical investigations of its treatment and prevention, based on scientific periodicals publications. Jet lag is a relevant problem for frequent-flying athletes. Its treatment and prevention is an important part of team physician routine. Jet lag treatment method depends on a number of changed time zones, estimated duration of stay in the new time zone, presence and severity of Jet lag symptoms, and athlete’s individual capacity to adapt.
jet lag; phototherapy; melatonin; ramelteon; armodafinil.
... 92 Doses of 0.5 mg or less appear optimal with respect to achievement of maximal chronobiotic effect. 99 Complicating matters, however, is the fact that pediatric patients and/or their caregivers are frequently reluctant recipients of this supplement because of concerns related to adverse effects on reproductive function and regulation of growth hormone. [100][101][102] Reflective of the above, a long-term outcome study of adolescents with delayed sleep phase disorder demonstrated that the majority (66%) pursued treatment for a median duration of only 2-5 months, and only 17% of subjects were treated for 1 year or longer. ...
Bhanu P Kolla,1,2 R Robert Auger,1,2 Timothy I Morgenthaler11Mayo Center for Sleep Medicine, 2Department of Psychiatry and Psychology, Mayo Clinic College of Medicine, Rochester, MN, USAAbstract: Misalignment between endogenous circadian rhythms and the light/dark cycle can result in pathological disturbances in the form of erratic sleep timing (irregular sleep–wake rhythm), complete dissociation from the light/dark cycle (circadian rhythm sleep disorder, free-running type), delayed sleep timing (delayed sleep phase disorder), or advanced sleep timing (advanced sleep phase disorder). Whereas these four conditions are thought to involve predominantly intrinsic mechanisms, circadian dysrhythmias can also be induced by exogenous challenges, such as those imposed by extreme work schedules or rapid transmeridian travel, which overwhelm the ability of the master clock to entrain with commensurate rapidity, and in turn impair approximation to a desired sleep schedule, as evidenced by the shift work and jet lag sleep disorders. This review will focus on etiological underpinnings, clinical assessments, and evidence-based treatment options for circadian rhythm sleep disorders. Topics are subcategorized when applicable, and if sufficient data exist. The length of text associated with each disorder reflects the abundance of associated literature, complexity of management, overlap of methods for assessment and treatment, and the expected prevalence of each condition within general medical practice.Keywords: circadian rhythm sleep disorders, assessment, treatment
... Note on draft transcript, 29 January 2014.59 Lockley et al. (2000);Sack et al. (2000);Lewy et al. (2005).60 Professor Josephine Arendt added: 'Incidentally I am aware that Stuart Checkley successfully treated a registered blind lady for SAD with light -but she may have had some residual light perception or indeed retained hypothalamic light perception.' ...
... Apart from light, other time cues (known as "zeitgebers") exist that entrain the circadian clock; these include regular cycles in temperature (Rensing and Ruoff, 2002), food availability (Stephan, 2002), exercise (Yamanaka et al., 2006), and intake of pharmacological agents such as melatonin (Lewy et al., 2005). The presence of light is by far the strongest zeitgeber, and this dissertation focuses on the photic entrainment of mammals. ...
Animals have intrinsic circadian periods of around 24 hours. In order to synchronize to the 24-hour day, circadian rhythms entrain to photic time cues and establish a consistent daily rhythm. The maintenance of a stable phase relationship between circadian rhythms and the light-dark (LD) cycle is necessary for entrainment to occur. It is commonly thought that there is a fixed relationship between the phase angle of entrainment and the intrinsic free-running period, where a smaller phase angle reflects a shorter period. Furthermore, it was thought that individuals with smaller phase angles would adjust faster to advance shift of the LD cycle, and slower to delay shift of the LD cycle. This dissertation reevaluated these relationships in rats using long-term in vivo pineal microdialysis to carefully monitor melatonin secretion rhythm. The studies presented in this dissertation examined both the interindividual differences between outbred rats, as well as differences in melatonin rhythms of inbred rats entrained to different photoperiods. Under long photoperiod (short night), melatonin rhythm has smaller phase angles and shorter durations; the opposite is true for short photoperiods. The phase angle variation, natural as well as manipulated, did not correlate with the free-running period variation in rats. Furthermore, individuals with smaller phase angles reentrained faster in both the advance and delay direction. To gain a greater understanding of the role of photoperiod in melatonin phase angle, the adjustment of the melatonin rhythm to an expansion or compression of dark period was studied by altering the dark period symmetrically or unidirectionally. While reentrainment to an 8h night resulted in very similar melatonin profiles regardless of how the dark period was altered, reentrainment to a 16h night depend significantly on whether the dark period was expanded symmetrically or by morning or evening expansion. These findings demonstrate that the relationship between period, phase, and pattern of reentrainment are quite different than is currently believed, and new analysis may be necessary to understand the underlying biology of the circadian timing system.
Late in the twentieth century, interest intensified regarding the involvement of the circadian system in the aetiology and treatment of Parkinson's disease (PD). It has been envisaged that this approach might provide relief beyond the limited benefits and severe side effects achieved by dopamine (DA) replacement. In the first clinical article, published in 1996, polychromatic light was used to shift the circadian clock as it is considered to be the most powerful zeitgeber (time keeper) that can be implemented to realign circadian phase. Since that time, 11 additional articles have implemented light treatment (LT) in various forms as an adjuvant to DA replacement. In spite of the growing interest in this area, the systematic exploration of LT in PD has been stymied by several methodological factors. Such factors include time of LT presentation, duration of studies undertaken, frequency of light employed, dose of light prescribed and relevance of experimental design to the prolonged course of the illness. On this basis, it is the purpose of this review to provide an in-depth examination of these papers, and the underlying preclinical work, to provide critique, thereby giving direction for future studies in therapeutic applications of LT for PD. Consideration of this collective work may serve to carve a path for future research and thereby improve the lives of those suffering from this debilitating disorder.
Misalignment between the environment and one’s circadian system is a common phenomenon (e.g., jet lag) which can have myriad negative effects on physical and mental health, mental and physiological performance, and sleep. Absent any intervention, the circadian system adjusts only 0.5-1.0 h per day to a shifted light-dark and sleep-wake schedule. Bright light facilitates circadian adjustment, but in field studies, bright light is only modestly better than no stimulus. Evidence indicates that exercise and melatonin can be combined with bright light to elicit larger shifts but no study has combined all of these stimuli or administered them at the times that are known to elicit the largest effects on the circadian system. The aims of this study are to compare the effects of different treatments on circadian adjustment to simulated jet lag in a laboratory. Following 2 weeks of home recording, 36 adults will spend 6.5 consecutive days in the laboratory. Following an 8 h period of baseline sleep recording on the participant’s usual sleep schedule on Night 1 (e.g., 0000-0800 h), participants will undergo a 26 h circadian assessment protocol involving 2 h wake intervals in dim light and 1 h of sleep in darkness, repeated throughout the 26 h. During this protocol, all urine voidings will be collected; mood, sleepiness, psychomotor vigilance, and pain sensitivity will be assessed every 3 h, forehead temperature will be assessed every 90 min, and anaerobic performance (Wingate test) will be tested every 6 h. Following, the circadian assessment protocol, the participant’s sleep-wake and light dark schedule will be delayed by 8 h compared with baseline (e.g., 0800-1400 h), analogous to travelling 8 times zones westward. This shifted schedule will be maintained for 3 days. During the 3 days on the delayed schedule, participants will be randomized to one of 3 treatments: (1) Dim Red Light + Placebo Capsules, (2) Bright Light Alone, (3) Bright Light + Exercise + Melatonin. During the final 26 h, all conditions and measures of the baseline circadian protocol will be repeated. Acclimatization will be defined by shifts in circadian rhythms of aMT6s, psychomotor vigilance, Wingate Anaerobic performance, mood, and sleepiness, and less impairments in these measures during the shifted schedule compared with baseline. We posit that Bright Light Alone and Bright Light + Exercise + Melatonin will elicit greater shifts in circadian rhythms and less impairments in sleep, mood, performance, and sleepiness compared with Dim Red Light + Placebo Capsules. We also posit that Bright Light + Exercise + Melatonin will elicit greater shifts and less impairments than Bright Light Alone.
The neurohormone melatonin facilitates entrainment of biological rhythms to environmental light-dark conditions as well as phase-shifts of circadian rhythms in constant conditions via activation of the MT1 and/or MT2 receptors expressed within the suprachiasmatic nucleus of the hypothalamus. The efficacy of melatonin and related agonists to modulate biological rhythms can be assessed using two well-validated mouse models of rhythmic behaviors. These models serve as predictive measures of therapeutic efficacy for treatment of circadian phase disorders caused by internal (e.g., clock gene mutations, blindness, depression, seasonal affective disorder) or external (e.g., shift work, travel across time zones) causes in humans. Here we provide background and detailed protocols for quantitative assessment of the magnitude and efficacy of melatonin receptor ligands in mouse circadian phase-shift and re-entrainment paradigms. The utility of these models in the discovery of novel therapeutics acting on melatonin receptors will also be discussed.Key words
Melatonin
Melatonin receptorsPhase-shiftEntrainmentJet lagRhythmic behaviors
This article focuses on melatonin and other melatonin receptor agonists and summarizes their circadian phase shifting and sleep-enhancing properties, along with their associated possible safety concerns. The circadian system and circadian rhythm sleep-wake disorders are described, along with the latest American Academy of Sleep Medicine recommendations for the use of exogenous melatonin in treating them. In addition, the practical aspects of using exogenous melatonin obtainable over the counter in the United States, consideration of the effects of concomitant light exposure, and assessing treatment response are discussed.
Between 10 and 30% of workers carry out night work at least once a month and 12–13% are working on rotating or regular night shifts. These atypical work schedules cause irregular, fragmented sleep patterns, as well as alertness and performance impairments at night. Atypical work schedules result in circadian misalignment, a state of desynchronization between the endogenous circadian system and the environment. Working at night also produces a state of internal desynchronization between several levels of the circadian system. Circadian adaptation to a night-oriented schedule is a gradual process requiring extended, consistent, and regular exposure to the altered work-rest cycle. There is a high degree of variability in the capacity of individuals to adapt to night schedules and it is estimated only 1 out of 4 workers is able to do so without specific interventions to facilitate circadian phase shifts. As light is the must powerful synchronizer of human circadian rhythms, countermeasures based on strategic light-dark interventions can favor circadian adaptation to atypical work schedules or modulate the secretion of melatonin at night. Melatonin, a hormone secreted by the pineal gland at night can also be administered exogenously to promote sleep in the daytime and shift human circadian rhythms. Most of our knowledge on the resetting and melatonin suppressive effects of light are based on the study of non-shift working populations in highly controlled laboratory conditions. In the field, exogenous melatonin proved useful to extend daytime sleep, although, still today, its resetting effects of shift workers' circadian rhythms remain unclear. The aim of this article is to review the latest scientific evidence on the usefulness of strategic light-dark interventions and on the use of melatonin and melatonin agonists prior to daytime sleep periods in shift working populations.
The circadian rhythm sleep–wake disorders consist of several disorders in which an individual's circadian clock, often best observed through rest-activity patterns, is not appropriately aligned with the surrounding environment, or their social and work demands. This article will provide an overview of general circadian biology, followed by a discussion of each of the circadian rhythm sleep–wake disorders, focused on their history, pathophysiology and current treatment recommendations.
Melatonin has not only to be seen as a regulator of circadian clocks. In addition to its chronobiotic functions, it displays other actions, especially in cell protection. This includes antioxidant, anti-inflammatory and mitochondria protecting effects. Although protection is also modulated by the circadian system, the respective actions of melatonin can be distinguished and differ with regard to dose requirements in therapeutic settings. It is the aim of this article to outline these differences in terms of function, signaling and dosage. Focus has been placed on both the nexus and the dissecting properties between circadian and non-circadian mechanisms. This has to consider details beyond the classic view of melatonin's role, such as widespread synthesis in extrapineal tissues, formation in mitochondria, effects on the mitochondrial permeability transition pore, and secondary signaling, e.g., via upregulation of sirtuins and by regulating noncoding RNAs, especially miRNAs. The relevance of these findings, the differences and connections between circadian and non-circadian functions of melatonin shed light on the regulation of inflammation including macrophage/microglia polarization, damage-associated molecular patterns, avoidance of cytokine storms and mitochondrial functions, with numerous consequences to antioxidative protection, i.e., aspects of high actuality with regard to deadly viral and bacterial diseases.
Growing understanding of the finely orchestrated and integrated mechanisms governing sleep and wakefulness allow for new insights into sleep disorders and their pharmacological treatments. While sleep related conditions are many and diverse, this chapter focuses on the common ailments of insomnia and circadian rhythm disorders. We provide a brief overview of these conditions followed by a review of current pathophysiologic understandings for these conditions, which provide context to the subsequent medication review. While an in-depth review of the pharmacologic options is provided, section summaries and tables are included to allow for ease of accessibility and retrieval of the information.
There is conflicting evidence on the clinical efficacy of exogenous melatonin for the treatment of sleep disorders. This may be due to differences in the pharmacokinetic (PK) properties of melatonin formulations used in clinical trials. The aim of this systematic review was to understand the relationship between melatonin formulations and PK parameters and, where possible, the effects on sleep outcomes. To this purpose, we conducted a systematic review and nineteen papers were included. The studies included three melatonin transdermal formulation, thirteen oral formulations, one topical, two buccal, two intravenous and two nasogastric formulations. Seven studies investigated the effect of the melatonin formulation on sleep and six of them found a significant improvement in one or more sleep parameters. The potential for an improved controlled release formulation that delays maximum concentration (Cmax) was identified. The different formulations and doses affect melatonin PK, suggesting that treatment efficacy maybe affected. Based on the current evidence, we are unable to provide recommendations of specific melatonin formulations and PK parameters for specific sleep disorders. Future studies should systematically investigate how different PK parameters of melatonin formulations affect efficacy treatment of sleep as well as circadian disorders.
Objective
There is a growing interest in psychiatry regarding melatonin use both for its soporific and chronobiotic effects. This study aimed to evaluate factors impacting the daily-dose.
Methods
In a university department of psychiatry in Paris (France), we conducted a posteriori naturalistic observational study from April 03, 2017 to January 31, 2018. We assessed links between sociodemographic and clinical characteristics and daily dose of melatonin (the daily-dose of melatonin initiation and the daily-dose at Hospital discharge). A survey of drug interactions was performed regarding metabolic inducers and inhibitors of the cytochrome P450 1A2.
Results
Forty patients were included and treated with immediate-release melatonin. For patients with no history of melatonin use, the initiation dose of was 2 or 4 mg, with no effects of age, weight, BMI, melatonin indication, cause of hospitalization. We found that higher discharge dose was associated with higher BMI (P = 0.036) and more reevaluations of melatonin dose (P = 0.00019). All patients with a moderate inducer (n = 3, here lansoprazole) were significantly more associated with the discontinuation melatonin group (P = 0.002).
Conclusion
The BMI and the number of reevaluations impact the daily dose of melatonin. Two mechanisms may explain that BMI may need higher doses: (i) melatonin diffuses into the fat mass, (ii) the variant 24E on melatonin receptor MT2, more frequent in obese patients, leads to a decrease of the receptor signal.
Human circadian timing—most visibly, the sleep-wake cycle—is constantly calibrated to match changing environmental conditions, through a complex system that responds mainly to ambient light. For psychiatrists, the most familiar clinical manifestations of disordered circadian timing are sleep disorders, that is, impaired intrinsic circadian cycling or a persistent mismatch between an individual’s sleep timing and societal expectations, and this chapter discusses their psychopathology. However, the physiological significance of circadian functions extends far beyond sleep, to include mood, hormonal function, and metabolism. We will also discuss how techniques to directly influence circadian timing can be used by psychiatrists to treat mood disorders.
Non-24-hour sleep/wake rhythm disorder (non-24) most commonly presents in totally blind individuals and results from the loss of synchronization (entrainment) of the hypothalamic circadian pacemaker to the 24-hour day. The etiology of the disorder in the sighted is likely distinct from that in the blind and has yet to be definitively demonstrated. Diagnosis of this disorder is based on the patient’s report of relapsing and remitting symptoms of daytime hypersomnolence and/or nighttime insomnia as well as sleep/wake timing that can drift progressively later or earlier each day as documented by sleep diaries or wrist actigraphy. Both melatonin and the melatonin agonist tasimelteon have been shown to successfully entrain the circadian pacemaker in placebo-controlled trials and thereby treat the disorder. The clinician must carefully consider both the time and dose of melatonin administration to achieve the optimal clinical result. Controlled trials of light or melatonin are lacking in the treatment of non-24 among the sighted, but the use of both may be effective when the patients’ self-selected light/dark schedules are taken into account.
This article focuses on melatonin and other melatonin receptor agonists, and specifically their circadian phase shifting and sleep-enhancing properties. The circadian system and circadian rhythm sleep-wake disorders are briefly reviewed, followed by a summary of the circadian phase shifting, sleep-enhancing properties, and possible safety concerns associated with melatonin and other melatonin receptor agonists. The recommended use of melatonin, including dose and timing, in the latest American Academy of Sleep Medicine Clinical Practice Guidelines for the treatment of intrinsic circadian rhythm disorders is also reviewed. Lastly, the practical aspects of treatment and consideration of clinical treatment outcomes are discussed.
Melatonin and melatonin agonists offer novel treatments for sleep and mood disorders, particularly where circadian misalignment is also present. The therapies offer both phase-shifting and sleep-promoting effects and have shown potential to treat advanced and delayed sleep-wake phase disorder, non-24-h sleep-wake cycle, jetlag, shift work disorder, insomnia, seasonal affective disorder and major depressive disorder.
Sleep disorders can occur in any child, but the impact of inadequate, disrupted, or disturbed sleep is more common and frequently more consequential in individuals with neurodevelopmental disabilities. The interactions between the underlying disorders can be specific and predictable, such as obstructive apnea in Down syndrome or an inverted sleep-wake cycle in Smith-Magenis syndrome. It can also be generic such as the impact of medication, as in sleep-onset insomnia and periodic movement disorder associated with ADHD, sedating anti-seizure drugs or boredom – induced daytime naps leading to shortened and/or disrupted nocturnal sleep in wheelchair-bound students in special education. This chapter will focus on medication treatment for specific sleep disorders associated with developmental disabilities as well as the current status of medical treatment for sleep disorders in all children – including insomnia, parasomnias, and excessive daytime sleepiness – but with an emphasis on the evidence concerning those with developmental disabilities.
La dépression est associée à de nombreuses anomalies circadiennes au sein des rythmes biologiques mais également à des perturbations du cycle veille-sommeil. Toutefois, Les mécanismes qui permettent d’expliquer le lien entre les troubles du rythme circadien et la dépression ne sont pas encore connus à ce jour. Certains modèles proposent une explication chronobiologique à l’apparition des symptômes dépressifs, c’est le cas de l’hypothèse de la désynchronisation interne. Par ailleurs, de plus en plus d’auteurs suggèrent l’existence d’un oscillateur externe, capable d’entrainer les rythmes biologiques et le rythme veille-sommeil. Parmi les anomalies rythmiques constatées chez le sujet dépressif, les perturbations de l’axe corticotrope sont les plus fréquentes. Or, le cortisol semble jouer un rôle primordial à la fois dans la régulation de l’humeur et dans le système circadien. Cette revue de la littérature a pour but de présenter les mécanismes neurophysiologiques et chronobiologiques qui soustendent ce rôle. Les preuves de l’implication de cette hormone dans la physiopathologie de la dépression y sont également discutées, via l’étude de la Cortisol Awakening Response (CAR) lors de l’épisode dépressif et au cours d’épreuves de désynchronisation interne. Enfin, cet article s’attardera sur l’effet de différentes stratégies antidépressives, à la fois sur les rythmes circadiens et sur la régulation de l’axe corticotrope. Bien qu’il existe des liens évidents entre la régulation de l’axe corticotrope, le cycle veille-sommeil et l’humeur, la cascade d’évènement qui conduit à l’apparition des symptômes dépressifs devra faire l’objet d’études ultérieures, afin de confirmer cette hypothèse chronobiologique.
Study objectives:
To report the diagnostic and treatment challenges of sighted non-24-hour sleep-wake disorder (N24SWD).
Methods:
We report a series of seven sighted patients with N24SWD clinically evaluated by history and sleep diaries, and when available wrist actigraphy and salivary melatonin levels, and treated with timed melatonin and bright light therapy.
Results:
Most patients had a history of a delayed sleep-wake pattern prior to developing N24SWD. The typical sleep-wake pattern of N24SWD was seen in the sleep diaries (and in actigraphy when available) in all patients with a daily delay in midpoint of sleep ranging 0.8 to 1.8 hours. Salivary dim light melatonin onset (DLMO) was evaluated in four patients but was missed in one. The estimated phase angle from DLMO to sleep onset ranged from 5.25 to 9 hours. All six patients who attempted timed melatonin and bright light therapy were able to entrain their sleep-wake schedules. Entrainment occurred at a late circadian phase, possibly related to the late timing of melatonin administration, though the patients often preferred late sleep times. Most did not continue treatment and continued to have a non-24-hour sleep-wake pattern.
Conclusions:
N24SWD is a chronic debilitating disorder that is often overlooked in sighted people and can be challenging to diagnose and treat. Tools to assess circadian pattern and timing can be effectively applied to aid the diagnosis. The progressive delay of the circadian rhythm poses a challenge for determining the most effective timing for melatonin and bright light therapies. Furthermore, once the circadian sleep-wake rhythm is entrained, long-term effectiveness is limited because of the behavioral and environmental structure that is required to maintain stable entrainment.
Insomnia is a prevalent sleep complaint in the general population and in clinical practice. Chronic insomnia carries significant burden for the individual and for society at large. It is associated with negative health outcomes including increased risk for role impairments, work disability, depression, and hypertension. Despite its high prevalence and negative consequences, insomnia is often under-recognized and undertreated. Treatment options currently available include basic sleep hygiene education, cognitive behavioral therapies, various classes of prescribed medications, and several complementary and alternative therapies. Of these, only two therapeutic approaches, cognitive behavioral therapies and benzodiazepine receptor agonists, have adequate data supporting both their safety and efficacy. These therapies have been shown effective for improving sleep continuity, but neither approach produces optimal therapeutic outcome. Medication is particularly effective on a short-term basis, but there is limited data about benefits once medication is discontinued or about long-term outcomes with prolonged treatment. Cognitive behavioral therapies are effective for chronic insomnia, and while more time-consuming initially, they produce sleep improvements that are well sustained over time. As no single treatment is effective for all forms of insomnia or acceptable to all patients, additional research is needed to examine optimal treatment algorithms using sequential or combination therapies. Clinical practice guidelines are still much needed.
Mood disorders are wide spread with estimates that one in seven of the population are affected at some time in their life (Kessler et al., 2012). Many of those affected with severe depressive disorders have cognitive deficits which may progress to frank neurodegeneration. There are several peripheral markers shown by patients who have cognitive deficits that could represent causative factors and could potentially serve as guides to the prevention or even treatment of neurodegeneration. Circadian rhythm misalignment, immune dysfunction and oxidative stress and circadian rhythm misalignment are key pathologic processes implicated in neurodegeneration and cognitive dysfunction in depressive disorders. Novel treatments targeting these pathways may therefore potentially improve patient outcomes whereby the primary mechanism of action is outside of the monoaminergic system. Moreover, targeting immune dysfunction, oxidative stress and circadian rhythm misalignment (rather than primarily the monoaminergic system) may hold promise for truly disease modifying treatments that may prevent neurodegeneration rather than simply alleviating symptoms with no curative intent. Further research is required to more comprehensively understand the contributions of these pathways to the pathophysiology of depressive disorders to allow for disease modifying treatments to be discovered.
Biologische Prozesse sind zeitlich strukturiert, wobei gerichtete und zyklische Komponenten unterschieden werden können. Die gerichteten Prozesse sind zumeist irreversibel, auf ein bestimmtes Ziel gerichtet und damit in der Regel auch zeitbegrenzt. Es handelt sich um Differenzierungs- und Wachstumsprozesse sowie Anpassungsvorgänge an veränderte Umweltbedingungen. Ziel sowie Zeitdauer sind weitgehend genetisch fixiert und nur in bestimmten Grenzen exogen beeinflussbar. Aus der Zielstellung ergibt sich die biologische Relevanz.
Human sleep alternates between periods of non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Sleep and wakefulness are modulated by homeostatic and circadian regulatory mechanisms. Like most physiological systems, sleep and wakefulness are also governed by a circadian oscillator located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Patients with sleep disorders often benefit from a general medical evaluation to investigate contributing factors. Fatigue and sleepiness may be associated with endocrine disorders such as hypothyroidism. The major symptom of Insomnia Disorder is dissatisfaction with the quantity or quality of sleep. Insomnia is associated with a wide variety of medical disorders, including pulmonary, cardiovascular, and metabolic disorder. Breathing-Related Sleep Disorders (BRSD) encompasses three entities: Obstructive Sleep Apnea Hypopnea (OSAH), Central Sleep Apnea (CSA), and Sleep-Related Hypoventilation (SRH).
Chronobiological disorders and syndromes include seasonal affective disorder (SAD), total blindness, advanced and delayed sleep phase syndrome, jet lag, and shift work maladaptation. These disorders are treated by adjusting circadian phase, using appropriately timed bright light exposure and melatonin administration (at doses of 0.5 mg or less). In some cases, it may be necessary to measure internal circadían phase, using the time when endogenous melatonin levels rise.
The pineal gland hormone melatonin may play a role in synchronization of rat circadian rhythms. Free-running activity rhythms
of the rat were entrained by a daily melatonin injection, with entrainment occurring when the onset of activity coincided
with the time of daily injections. When injections were stopped, activity rhythms became free-running again. Thus in pharmacological
experiments, the time of day of melatonin administration is crucial.
Bright artificial light suppressed nocturnal secretion of melatonin in six normal human subjects. Room light of less intensity,
which is sufficient to suppress melatonin secretion in other mammals, failed to do so in humans. In contrast to the results
of previous experiments in which ordinary room light was used, these findings establish that the human response to light is
qualitatively similar to that of other mammals.
In mammals, ocular photoreceptors mediate an acute inhibition of pineal melatonin by light. The effect of rod and cone loss on this response was assessed by combining the rd mutation with a transgenic ablation of cones (cl) to produce mice lacking both photoreceptor classes. Despite the loss of all known retinal photoreceptors, rd/rd cl mice showed normal suppression of pineal melatonin in response to monochromatic light of wavelength 509 nanometers. These data indicate that mammals have additional ocular photoreceptors that they use in the regulation of temporal physiology.
Most totally blind people have circadian rhythms that are "free-running" (i.e., that are not synchronized to environmental time cues and that oscillate on a cycle slightly longer than 24 hours). This condition causes recurrent insomnia and daytime sleepiness when the rhythms drift out of phase with the normal 24-hour cycle. We investigated whether a daily dose of melatonin could entrain their circadian rhythms to a normal 24-hour cycle.
We performed a crossover study involving seven totally blind subjects who had free-running circadian rhythms. The subjects were given 10 mg of melatonin or placebo daily, one hour before their preferred bedtime, for three to nine weeks. They were then given the other treatment. The timing of the production of endogenous melatonin was measured as a marker of the circadian time (phase), and sleep was monitored by polysomnography.
At base line, the subjects had free-running circadian rhythms with distinct and predictable cycles averaging 24.5 hours (range, 24.2 to 24.9). These rhythms were unaffected by the administration of placebo. In six of the seven subjects the rhythm was entrained to a 24.0-hour cycle during melatonin treatment (P<0.001). After entrainment, the subjects spent less time awake after the initial onset of sleep (P=0.05) and the efficiency of sleep was higher (P=0.06). Three subjects subsequently participated in a trial in which a 10-mg dose of melatonin was given daily until entrainment was achieved. The dose was then reduced to 0.5 mg per day over a period of three months; the entrainment persisted, even at the lowest dose.
Administration of melatonin can entrain circadian rhythms in most blind people who have free-running rhythms.
The master circadian oscillator in the hypothalamic suprachiasmatic nucleus is entrained to the day/night cycle by retinal photoreceptors. Melanopsin (Opn4), an opsin-based photopigment, is a primary candidate for photoreceptor-mediated entrainment. To investigate the functional role of melanopsin in light resetting of the oscillator, we generated melanopsin-null mice (Opn4-/-). These mice entrain to a light/dark cycle and do not exhibit any overt defect in circadian activity rhythms under constant darkness. However, they display severely attenuated phase resetting in response to brief pulses of monochromatic light, highlighting the critical role of melanopsin in circadian photoentrainment in mammals.
Most research papers published in Chronobiology International report the findings of investigations conducted on laboratory animals and human beings. The Journal, its editors and the publication committee endorse the compliance of investigators to the principles of the Declaration of Helsinki of the World Medical Association relating to the conduct of ethical research on human beings and the Guide for the Care and Use of Laboratory Animals of the Institute for Laboratory Animal Research of the National Research Council relating to the conduct of ethical research on laboratory and other animals. Chronobiology International requires that submitted manuscripts reporting the findings of human and animal research conform to the respective policy and mandates of the Declaration of Helsinki and the Guide for the Care and Use of Laboratory Animals. The peer review of manuscripts will thus include judgment of whether or not the involved research methods conform to the standards of good research practice. This article outlines the basic expectations for the methods of human and animal biological rhythm research, both from the perspective of the fundamental criteria necessary for quality chronobiology investigation and from the perspective of humane and ethical research on human beings and animals.
The hormone melatonin phase shifts circadian rhythms generated by the mammalian biological clock, the suprachiasmatic nucleus (SCN) of the hypothalamus, through activation of G protein-coupled MT2 melatonin receptors. This study demonstrated that pretreatment with physiological concentrations of melatonin (30-300 pM or 7-70 pg/mL) decreased the number of hMT2 melatonin receptors heterologously expressed in mammalian cells in a time and concentration-dependent manner. Furthermore, hMT2-GFP melatonin receptors heterologously expressed in immortalized SCN2.2 cells or in non-neuronal mammalian cells were internalized upon pretreatment with both physiological (300 pM or 70 pg/mL) and supraphysiological (10 nM or 2.3 ng/mL) concentrations of melatonin. The decrease in MT2 melatonin receptor number induced by melatonin (300 pM for 1 h) was reversible and reached almost full recovery after 8 h; however, after treatment with 10 nM melatonin full recovery was not attained even after 24 h. This recovery process was partially protein synthesis dependent. Furthermore, exposure to physiological concentrations of melatonin (300 pM) for a time mimicking the nocturnal surge (8 h) desensitized functional responses mediated through melatonin activation of endogenous MT2 receptors, i.e., stimulation of protein kinase C (PKC) in immortalized SCN2.2 cells and phase shifts of circadian rhythms of neuronal firing in the rat SCN brain slice. We conclude that in vivo the nightly secretion of melatonin desensitizes endogenous MT2 melatonin receptors in the mammalian SCN thereby providing a temporally integrated profile of sensitivity of the mammalian biological clock to a melatonin signal.
In the mammalian retina, besides the conventional rod-cone system, a melanopsin-associated photoreceptive system exists that conveys photic information for accessory visual functions such as pupillary light reflex and circadian photo-entrainment. On ablation of the melanopsin gene, retinal ganglion cells that normally express melanopsin are no longer intrinsically photosensitive. Furthermore, pupil reflex, light-induced phase delays of the circadian clock and period lengthening of the circadian rhythm in constant light are all partially impaired. Here, we investigated whether additional photoreceptive systems participate in these responses. Using mice lacking rods and cones, we measured the action spectrum for phase-shifting the circadian rhythm of locomotor behaviour. This spectrum matches that for the pupillary light reflex in mice of the same genotype, and that for the intrinsic photosensitivity of the melanopsin-expressing retinal ganglion cells. We have also generated mice lacking melanopsin coupled with disabled rod and cone phototransduction mechanisms. These animals have an intact retina but fail to show any significant pupil reflex, to entrain to light/dark cycles, and to show any masking response to light. Thus, the rod-cone and melanopsin systems together seem to provide all of the photic input for these accessory visual functions.
Melatonin has been implicated in several neurotropic effects, but few studies have investigated the bioavailability of melatonin in the brain. The discovery of periventricular sites of action adjacent to the third ventricle forced us to investigate the dynamics of cerebrospinal fluid (CSF) melatonin release and the source of this melatonin. Our first study demonstrated unequivocally that third ventricle CSF melatonin, like jugular plasma melatonin, accurately reflects the duration of the night and is rapidly suppressed by light. However, third ventricle CSF melatonin levels are 20-fold higher than nocturnal plasma concentrations. A further study showed that melatonin increased in plasma before third ventricle CSF, raising the possibility that melatonin is taken up from the blood after recirculation through the Galen vein. However, a final experiment suggested strongly that CSF melatonin is released directly into the third ventricle, as melatonin levels in the lateral ventricle were 7-fold lower than those...
In mammals, ocular photoreceptors mediate an acute inhibition of pineal melatonin by light. The effect of rod and cone loss
on this response was assessed by combining the rd mutation with a transgenic ablation of cones (cl) to produce mice lacking both photoreceptor classes. Despite the loss of all known retinal photoreceptors, rd/rd cl mice showed normal suppression of pineal melatonin in response to monochromatic light of wavelength 509 nanometers. These
data indicate that mammals have additional ocular photoreceptors that they use in the regulation of temporal physiology.
A physiological dose of orally administered melatonin shifts circadian rhythms in humans according to a phase-response curve (PRC) that is nearly opposite in phase with the PRCs for light exposure: melatonin delays circadian rhythms when administered in the morning and advances them when administered in the afternoon or early evening. The human melatonin PRC provides critical information for using melatonin to treat circadian phase sleep and mood disorders, as well as maladaptation to shift work and transmeridional air travel. The human melatonin PRC also provides the strongest evidence to date for a function of endogenous melatonin and its suppression by light in augmenting entrainment of circadian rhythms by the light-dark cycle.
1 Phase response curves for 15′ bright light pulses of four species of nocturnal rodents are described. All show delay phase shifts early in the subjective night, advance shifts in the late subjective night, and relative insensitivity during the subjective day. 2 The broad scatter in measured phase-shifts is largely due to error of measurement: the response of the pacemakers to light stimuli is more accurate than we observe. 3. Indications are found that the response to a resetting stimulus at a given phase of the rhythm is correlated with the individual {Mathematical expression} (freerunning period). Fast pacemakers (short {Mathematical expression}) tend to be more delayed or less advanced by the light than slow pacemakers (long {Mathematical expression}). 4. Within individual mice (Mus musculus) the circadian pacemaker adjusts its resetting response to variations in its frequency: when τ is long (induced as after-effect of prior light treatment) light pulses at a defined phase of the oscillation (ct 15) produce smaller delay phase shifts than when τ is short. 5. Among species there are conspicuous differences in the shape of the phase response curve: where {Mathematical expression} is long, advance phase shifts are large and delay phase shifts small (Mesocricetus auratus); where {Mathematical expression} is short, advance shifts are small, and delay shifts are large (Mus musculus;Peromyscus maniculatus). 6. The functional meaning of the interrelationships of τ and PRC is briefly discussed.
1.
In thefirst part of the paper, the model of non-parametric entrainment of circadian pacemakers is tested for the case of nocturnal rodents. The model makes use of the available data on freerunning period ([`(t)]\bar \tau
is close to 24 h. Thus the verycircadian nature of these pacemakers helps to conserve[`(t)]\bar \tau
=24 h. The effect of-instability is further reduced by entrainment with 2 pulses (dawn and dusk), made possible by the PRC's having both an advance and a delay section.
8.
To analyze the contributions to-conservation with seasonally changing photoperiod, we have assumed that it is of functional significance to conserve the phase of activity with respect to dusk (nocturnal animals) or to dawn (diurnal animals). We distinguish three contributions of nocturnal pacemaker behaviour to this type of-conservation: increased amplitude of the PRC (i), asymmetry in the PRC, such that the slope of the delay-part is steeper than the slope of the advance-part (ii), and a short freerunning period in DD (iii).
9.
A further contribution must derive from parametric effects of light, which are not traceable by the model, but certainly effective in preventing in complete photoperiods the-jump which is seen in skeleton photoperiods. The existence of parametric effects is further demonstrated by the change of with light intensity in LL, described by Aschoff's Rule, which presumably reflects differences in PRC-shape between nocturnal and diurnal animals (Daan and Pittendrigh, 1976b).
10.
The paper concludes with an attempt to distinguish the features of circadian clocks that are analytically necessary for entrainment to occur (i), or have functional meaning, either in the measurement of the lapse of time (ii) or in the identification of local time (iii).
The pineal enzyme, serotonin N-acetyltransferase, exhibits a circadian rhythm of activity with nocturnal levels 15–30 times greater than those observed during a light period in the rat. This rhythm has been shown to be under visual control mediated by the sympathetic innervation to the pineal. The present study examined the participation of visual pathways and other central mechanisms in the regulation of pineal serotonin N-acetyltransferase activity. Following destruction of all visual pathways by blinding, the rhythm in enzyme activity is no longer controlled by the pattern of diurnal lighting and becomes free-running. Destruction of the primary optic tracts, the accessory optic tracts, or both of these components of the central retinal projection together, does not alter visual entrainment of the enzyme rhythm. In the absence of these pathways the only central retinal projection known to exist is a retinohypothalamic pathway branching directly off the optic chiasm to terminate bilaterally in the suprachiasmatic hypothalamic nuclei. Selective ablation of these nuclei, sparing the optic chiasm, abolishes the circadian rhythm in pineal serotonin N-acetyltransferase. This effect is mimicked by a knife cut across the medial hypothalamus caudal to the suprachiasmatic nuclei and by bilateral lesions transecting the medial forebrain bundle within the lateral hypothalamus, but a hypothalamic knife cut just rostral to the nuclei has no effect upon the rhythm. It is concluded that the retinohypothalamic projection to the suprachiasmatic nuclei is essential for maintaining the entrainment to light of the circadian rhythm in pineal serotonin N-acetyltransferase activity in the rat. In addition, the observations presented here suggest that the suprachiasmatic nuclei represent a central rhythm generator having projections directed caudally into the medial hypothalamus and into the medial forebrain bundle in the lateral hypothalamus.
Three techniques have been used to measure human plasma melatonin: bioassay, radioimmunoassay, and gas chromatography--mass spectrometry (GC-MS). GC-MS is theoretically capable of the greatest specificity, but in general suffers from insufficient sensitivity. Negative chemical ionization, a new technique, provides a 150-fold increase in GC-MS sensitivity for electron-capturing compounds. Negative chemical ionization GC-MS permits routine measurement in human plasma of melatonin at a concentration as low as 1 picogram per milliliter.
A physiological dose of orally administered melatonin shifts circadian rhythms in humans according to a phase-response curve (PRC) that is nearly opposite in phase with the PRCs for light exposure: melatonin delays circadian rhythms when administered in the morning and advances them when administered in the afternoon or early evening. The human melatonin PRC provides critical information for using melatonin to treat circadian phase sleep and mood disorders, as well as maladaptation to shift work and transmeridional air travel. The human melatonin PRC also provides the strongest evidence to date for a function of endogenous melatonin and its suppression by light in augmenting entrainment of circadian rhythms by the light-dark cycle.
Previous work in our laboratory has shown that daily injection of large doses of the pineal hormone melatonin entrains the free-running locomotor rhythms of rats held in constant darkness and synchronizes the disrupted patterns of rats maintained in constant bright light. The present experiments determined the dose-response characteristics of entrainment to daily melatonin injections and made preliminary biochemical estimates of blood melatonin levels and half-lives after two critical doses of the hormone. The data indicated that the median effective dose for melatonin as an entraining agent in free-running rats was 5.45 +/- 1.33 micrograms/kg, considerably lower than doses previously employed and lower than doses employed in reproductive and metabolic studies in rats and hamsters. The data further indicated that the response to melatonin was quantal; rats either entrained to melatonin or they did not. No "partial entrainment" was evident, nor were there differences in phase angle, activity, or period among all effective doses. Biochemical estimates of blood melatonin after either 1 mg/kg or 1 microgram/kg of melatonin indicated that all effective doses resulted in supraphysiological levels of blood melatonin, although doses of 1 microgram/kg resulted in blood levels that were within one order of magnitude of normal nighttime values. Together, the data suggest that the rat circadian system is sensitive to the pineal hormone melatonin at or below doses required to effect rodent reproduction. Whether this sensitivity reflects a role for the pineal gland in rat circadian organization, however, still remains to be determined.
To determine whether effects of light pulses on the photoperiodic time measuring system involve changes in pineal gland function, melatonin profiles were determined in groups of ewes maintained under 10-h light, 14-h dark (10L:14D) or 10L:10D:1L:3D. Ewes exposed to 10L:14D had a significantly (P less than 0.01) longer duration of melatonin secretion (15.0 +/- 0.4 h, mean +/- SE) than ewes under 10L:10D:1L:3D (9.0 +/- 0.4 h). The 1-h pulse of light therefore acted as a dawn signal in the latter group. During a period of extended darkness imposed to study endogenous control of melatonin release, there was no change in the duration of elevated melatonin in control ewes (16.1 +/- 0.5 h), but a significant (P less than 0.05) lengthening occurred in pulsed ewes (13.2 +/- 1.4 h). PRL responses to a bolus iv injection of TRH (50 ng/kg BW) were significantly (P less than 0.01) smaller in control ewes (478 +/- 134 ng/ml) compared with pulsed ewes (1578 +/- 175 ng/ml), with responses in the latter group resembling those observed in ewes on long days. A 1-h pulse of light late in the dark phase, therefore, resulted in a melatonin pattern normally observed under long days in ewes, and this was associated with other endocrine functions also characteristic of sheep on long days. It is concluded that pulses of light modify activity of the pineal gland which in turn interacts with the photoperiodic time-measuring system via melatonin. The increase in duration of melatonin secretion observed in pulsed ewes under extended darkness suggests that the melatonin rhythm is under the control of two oscillators coupled to dusk and dawn, and that these oscillators interact more strongly when compressed by an interrupted dark phase.
Previous work has shown that daily injections of the pineal hormone melatonin (N-acetyl, 5-methoxytryptamine) entrain the free-running locomotor rhythms of rats held in constant darkness (with a median effective dose [ED50] of 5.45 +/- 1.33 micrograms/kg) and in constant bright light. The present experiments determined the dose-response characteristics of entrainment and phase shifting to daily and single melatonin injections in both sham-operated (SHAM) and pinealectomized (PINX) rats. The data indicated an ED50 of 332 +/- 53 ng/kg and 121 +/- 22 ng/kg for SHAM and PINX rats, respectively, during the entrainment experiment. The ED50's for the entrainment experiment were considerably lower than doses previously employed, and much lower than doses employed in reproductive and metabolic studies in rats and hamsters. The data indicated that no partial entrainment occurred; nor were there differences in phase angle, length of activity, or period among all effective doses. Next, a single injection of 1 mg/kg melatonin has previously been shown to cause a phase advance of approximately 45 min when administered at about circadian time (CT) 10. We found that both SHAM and PINX animals phase-advanced, in a dose-dependent manner to a single melatonin injection given at CT 10. The data for the phase-shifting experiment indicated an ED50 of 8.19 +/- 0.572 micrograms/kg and 2.16 +/- 0.326 micrograms/kg for SHAM and PINX animals, respectively, with an average phase advance of 40 min for both groups. Together, the data suggest that the presence of the pineal gland is not necessary for the effects of melatonin on the rat circadian system, and that PINX animals are marginally more sensitive to melatonin than their SHAM controls.
Melatonin is able to phase-shift the endogenous circadian clock and can induce acute temperature suppression. It is possible that there is a direct relationship between these phenomena. In a double-blind, placebo-controlled crossover study, 6 healthy volunteers maintained a regular sleep/wake cycle in a normal environment. From dusk until 24:00 h on days (D) 1-4 subjects remained in dim artificial lighting (< 50 lux) and darkness (< 1 lux) from 24:00-08:00 h. At 17:00 h on D3 either melatonin (0.05 mg, 0.5 mg or 5 mg) or placebo was administered. Melatonin treatment induced acute, dose-dependent temperature suppression and decrements in alertness and performance efficiency. On the night of D3, earlier sleep onset, offset and better sleep quality were associated with increasing doses of melatonin. The following day, a significant dose-dependent phase-advance in the plasma melatonin onset time and temperature nadir (D4-5) was observed with a trend for the alertness rhythm to phase-advance. A significant dose-response relationship existed between the dose of oral melatonin, the magnitude of temperature suppression and the degree of advance phase shift in the endogenous melatonin and temperature rhythms, suggesting that acute changes in body temperature by melatonin may be a primary event in phase-shifting mechanisms.
A number of researchers have suggested that the phase (timing) of circadian rhythms in depressed patients is abnormal. Longitudinal studies could help to elucidate the relationship between circadian phase and mood. Such studies would be facilitated by the development of a noninvasive method for measuring circadian phase. In normal volunteers, the concentration of salivary melatonin measurements has been shown to be significantly correlated with those obtained in plasma; however, it is unknown whether salivary melatonin measurements can reliably detect the unmasked time of onset of nocturnal melatonin secretion (a measure of circadian phase). In addition, the relationship between salivary and plasma melatonin measurements in medicated psychiatric patients is unknown. We measured plasma and salivary melatonin simultaneously in a sample of 12 medicated patients with rapid cycling bipolar disorder. The intraclass correlation coefficient between plasma and salivary measures of the dim light melatonin onset (DLMO) was 0.93. We therefore conclude that salivary melatonin can be used to determine the time of the DLMO in this population.
There are many situations in which it would be useful to know the phase state of the biological clock. It is recognized that measurement of melatonin levels can provide this information, but traditionally blood has been used for the analysis, and there are many problems in extending the measurements into the home or field situations. The aim of this study was to develop and validate a salivary melatonin radioimmunoassay and to compare results obtained against a plasma assay for determining the onset of melatonin secretion. The assay developed was sensitive (4.3 pM) and required only 200 microliters of sample. A rhythm in melatonin was detected in saliva, peaking at approximately 120 pM or 30% of the plasma levels. Using an objective criterion for determining the onset of secretion (mean +/- 2 standard deviations of three daytime samples), the time of onset was shown to exhibit low intraindividual variability (coefficient of variation = 1.5%-4.3%). The time of onset determined using saliva was significantly correlated with the plasma onset (r = .70, p < .05). The onsets determined were 22:30 h +/- 22 min for the saliva and 21:50 h +/- 16 min for plasma for 17 subjects. Similarly, the acrophases of the saliva and plasma melatonin rhythms were significantly correlated. Neither posture alone nor changes in posture affected the calculation of the onset of melatonin secretion using the saliva approach. Very high saliva flow rates induced by citric acid resulted in lower melatonin concentrations compared to the gentle chewing on parafin film. These results firmly establish the use of salivary melatonin measurements for phase typing of the melatonin rhythm in humans.
Melatonin's timekeeping function is undoubtedly related to the fact that it is primarily produced during nighttime darkness; that is, melatonin and light occur at opposite times. The human phase response curve (PRC) to melatonin appears to be about 12h out of phase with the PRC to light. These striking complementarities, together with light's acute suppressant effect on melatonin production, suggest that a function for endogenous melatonin is to augment entrainment of the circadian pacemaker by the light-dark cycle. The melatonin PRC also indicates correct administration times for using exogenous melatonin to treat circadian phase disorders.
In a double-blind placebo-controlled cross-over study, 30 patients with Delayed Sleep Phase Syndrome (DSPS) were included, of whom 25 finished the study. Melatonin 5 mg was administered during two weeks in a double-blind setting and two weeks in an open setting successively or interrupted by two week of placebo. The study's impact was assessed by measurements of the 24-h curves of endogenous melatonin production and rectal temperature (n = 14), polysomnography (n = 22), actigraphy (n = 13), sleep log (n = 22), and subjective sleep quality (n = 25). Mean dim light melatonin onset (DLMO) (+/- SD), before treatment, occurred at 23.17 hours (+/- 138 min). Melatonin was administered five hours before the individual DLMO. After treatment, the onset of the nocturnal melatonin profile was significantly advanced by approximately 1.5 hour. Body temperature trough did not advance significantly. During melatonin use, actigraphy showed a significant advance of sleep onset and polysomnography, a significant decreased sleep latency. Sleep architecture was not influenced. During melatonin treatment patients felt significantly more refreshed in the morning. These results show that analysis of DLMO of patients suffering from DSPS is important both for diagnosis and therapy. These results are discussed in terms of the biochemistry of the pineal.
The circadian secretion of melatonin by the pineal gland and retinae is a direct output of circadian oscillators and of the circadian system in many species of vertebrates. This signal affects a broad array of physiological and behavioral processes, making a generalized hypothesis for melatonin function an elusive objective. Still, there are some common features of melatonin function. First, melatonin biosynthesis is always associated with photoreceptors and/or cells that are embryonically derived from photoreceptors. Second, melatonin frequently affects the perception of the photic environment and has as its site of action structures involved in vision. Finally, melatonin affects overt circadian function at least partially via regulation of the hypothalamic suprachiasmatic nucleus (SCN) or its homologues. The mechanisms by which melatonin affects circadian rhythms and other downstream processes are unknown, but they include interaction with a class of membrane-bound receptors that affect intracellular processes through guanosine triphosphate (GTP)-binding protein second messenger systems. Investigation of mechanisms by which melatonin affects its target tissues may unveil basic concepts of neuromodulation, visual system function, and the circadian clock.
Several circadian rhythms have been used to assess the phase of the endogenous circadian pacemaker (ECP). However, when more than one marker rhythm is measured, results do not always agree. Questions then inevitably arise. Are there multiple oscillators? Are some markers more reliable than others? Masking is a problem for all marker rhythms. Masking of melatonin is minimized by sampling under dim light. The dim-light melatonin onset (DLMO) is particularly convenient since it can usually be obtained before sleep. However, assessing the DLMO in low melatonin producers may be problematic, particularly with the commonly used operationally defined threshold of 10 pg/ml. This study evaluates various circadian phase markers provided by the plasma melatonin profile in 14 individuals, several of whom are low melatonin producers. The amount (amplitude) of melatonin production appears to influence the phase of many points on the melatonin profile. Accordingly, when low producers are in a data set, we now prefer a lower DLMO threshold than the one previously recommended (10 pg/ml). Indeed, there are some low producers who never exceed this threshold at any time. Radioimmunoassays are now available that have the requisite sensitivity and specificity to support the use of a lower threshold. Nevertheless, the dim-light melatonin offset (DLMOff), even when operationally defined at thresholds less than 10 pg/ml, appears to be confounded by amplitude in this study; in such cases, it may be preferable to use the melatonin synthesis offset (SynOff) because it is not confounded by amplitude and because, theoretically, it is temporally closer to the endogenous mechanism signaling the offset of production. The question of whether the termination mechanism of melatonin synthesis is related to an interval timer or to a second oscillator loosely coupled to the onset oscillator is probably best answered using the SynOff rather than the DLMOff. It is hoped that these findings will make a useful contribution to the debate on the best ways to use points on the melatonin profile to assess circadian phase position in humans.
The purpose of the study was to induce in two different ways, a phase-angle difference between the circadian pacemaker and the imposed sleep-wake cycle in humans, we intended to: (i) shift the circadian pacemaker by exposure to bright light and keep the timing of the sleep-wake cycle fixed; and (ii) keep the timing of the circadian pacemaker fixed by a constant light-dark cycle and displace sleep. We monitored dim light melatonin onset (DLMO), core body temperature and sleep. DLMO was delayed significantly after 3 days of a 3-h delayed sleep-phase when compared with 3 days of sleep at a normal or 3-h advanced sleep-phase. The shifts in DLMO were not accompanied by shifts in body temperature, changes in waking-up time or by a change in the duration of the first rapid eye movement (REM) sleep episode. Three days of light exposure in the morning or evening resulted in shifts in DLMO of similar magnitude, but this was accompanied by shifts in the rhythm of body temperature, changes in waking-up time and in the duration of the first REM sleep episode. We conclude that the changes observed after light exposure reflect shifts in the circadian pacemaker. In contrast, we propose that the changes observed in DLMO after sleep displacement are not mediated by the circadian pacemaker. These results raise some doubts about the reliability of DLMO as a marker of circadian phase in cases of sleep disturbances. Finally, we initiate a search for changes in sleep that might be responsible for the unexpected effects on DLMO.
Melatonin has been implicated in several neurotropic effects, but few studies have investigated the bioavailability of melatonin in the brain. The discovery of periventricular sites of action adjacent to the third ventricle forced us to investigate the dynamics of cerebrospinal fluid (CSF) melatonin release and the source of this melatonin. Our first study demonstrated unequivocally that third ventricle CSF melatonin, like jugular plasma melatonin, accurately reflects the duration of the night and is rapidly suppressed by light. However, third ventricle CSF melatonin levels are 20-fold higher than nocturnal plasma concentrations. A further study showed that melatonin increased in plasma before third ventricle CSF, raising the possibility that melatonin is taken up from the blood after recirculation through the Galen vein. However, a final experiment suggested strongly that CSF melatonin is released directly into the third ventricle, as melatonin levels in the lateral ventricle were 7-fold lower than those in the third ventricle. Our study raises the possibility that there may be two compartments of melatonin affecting physiological functioning: the first in plasma acting on peripheral organs, and the second in the CSF affecting neurally mediated functions at a much higher concentration of this pineal indoleamine.
Older people typically exhibit poor sleep efficiency and reduced nocturnal plasma melatonin levels. The daytime administration of oral melatonin to younger people, in doses that raise their plasma melatonin levels to the nocturnal range, can accelerate sleep onset. We examined the ability of similar, physiological doses to restore nighttime melatonin levels and sleep efficiency in insomniac subjects over 50 yr old. In a double-blind, placebo-controlled study, subjects who slept normally (n = 15) or exhibited actigraphically confirmed decreases in sleep efficiency (n = 15) received, in randomized order, a placebo and three melatonin doses (0.1, 0.3, and 3.0 mg) orally 30 min before bedtime for a week. Treatments were separated by 1-wk washout periods. Sleep data were obtained by polysomnography on the last three nights of each treatment period. The physiologic melatonin dose (0.3 mg) restored sleep efficiency (P < 0.0001), acting principally in the midthird of the night; it also elevated plasma melatonin levels (P < 0.0008) to normal. The pharmacologic dose (3.0 mg), like the lowest dose (0.1 mg), also improved sleep; however, it induced hypothermia and caused plasma melatonin to remain elevated into the daylight hours. Although control subjects, like insomniacs, had low melatonin levels, their sleep was unaffected by any melatonin dose.
We have recently shown that six of seven totally blind people (who had free-running circadian rhythms with periods longer than 24 h) could be entrained (synchronized) to a nightly dose of 10 mg melatonin. After treatment discontinuation and re-entrainment to the 10 mg dose, we further found in three of these subjects that the dose could be gradually reduced to 0.5 mg without loss of effect. The question then arose: can a de novo (starting) dose of 0.5 mg initially capture free-running rhythms? Following withdrawal of the stepped-down 0.5 mg dose and consequent release into a free-run, the same three individuals were given 0.5 mg of melatonin de novo. All entrained within a few weeks.
The circadian pacemaking system of birds comprises three major components: (i) the pineal gland, which rhythmically synthesizes and secretes melatonin; (ii) a hypothalamic region, possibly equivalent to the mammalian suprachiasmatic nuclei; and (iii) the retinae of the eyes. These components jointly interact, stabilize and amplify each other to produce a highly self-sustained circadian output. Their relative contribution to overt rhythmicity appears to differ between species and the system may change its properties even within an individual depending, for example, on its state in the annual cycle or its photic environment. Changes in pacemaker properties are partly mediated by changes in certain features of the pineal melatonin rhythm. It is proposed that this variability is functionally important, for instance, for enabling high-Arctic birds to retain synchronized circadian rhythms during the low-amplitude zeitgeber conditions in midsummer or for allowing birds to adjust quickly their circadian system to changing environmental conditions during migratory seasons. The pineal melatonin rhythm, apart from being involved in generating the avian pacemaking oscillation, is also capable of retaining day length information after isolation from the animal. Hence, it appears to participate in photoperiodic after-effects. Our results suggest that complex circadian clocks have evolved to help birds cope with complex environments.
In a previous report, we were unable to entrain one out of seven totally blind people with free-running endogenous melatonin rhythms to 10 mg of exogenous melatonin. This person had the longest circadian period (24.9 h) of the group. We now find that this person can be entrained to 0.5 mg of melatonin, but not to 20 mg. These results are consistent with the idea that too much melatonin may spill over onto the wrong zone of the melatonin phase-response curve.
Time in the biological sense is measured by cycles that range from
milliseconds to years. Circadian rhythms, which measure time on a scale of
24 h, are generated by one of the most ubiquitous and well-studied
timing systems. At the core of this timing mechanism is an intricate molecular
mechanism that ticks away in many different tissues throughout the body.
However, these independent rhythms are tamed by a master clock in the brain,
which coordinates tissue-specific rhythms according to light input it receives
from the outside world.
The brains of nonmammalian vertebrates contain populations of photoreceptive cells that are important for establishing the
circadian rhythms of physiology and behavior. Do mammals, which evolved from strictly nocturnal ancestors, contain such photoreceptive
cells? As
Menaker
explains in his Perspective, new work (including
Lucas
et al. and
Van Gelder
et al.) establishes that the mammalian retina contains photoreceptive ganglion cells carrying the photopigment melanopsin, which
contribute to the entrainment of circadian rhythms to the light-dark cycle.
The human circadian pacemaker, with an intrinsic period between 23.9 and 24.5 hr, can be reset by low levels of light. Biomathematical models of the human clock predict that light-dark cycles consisting of only approximately 3.5 lux during 16 hr of wakefulness and 0 lux during 8 hr of sleep should entrain approximately 45% of the population. However, under real-life conditions, sleep-wake schedules and the associated light-dark exposures are often irregular. It remains unclear whether the phase of the pacemaker would remain stable under such conditions. We investigated the stability of the circadian phase in dim light by assessing the plasma melatonin rhythm during nine consecutive circadian cycles. Ten subjects were scheduled to sleep for 8 hr (0.03 lux) and to be awake for 16 hr (5-13 lux) during all days except on days 4 and 8, during which the subjects were sleep deprived for 40 hr (5-13 lux), either in a sitting/standing or supine body posture. In all subjects, the phase of the melatonin rhythm occurred at a later clock time on day 9 than on day 2 (average delay: 1.4 hr). Largest delays in the melatonin onset were observed in subjects with low amplitude melatonin rhythms. The area under the curve during active melatonin secretion was significantly reduced when subjects were sleep deprived in the 40-hr supine body posture condition compared with either the 40-hr sitting/standing sleep deprivation (SD) or the ambulatory condition under non-SD conditions. Posture differences did not significantly affect the relative phase position of the melatonin profiles. The data indicate that under conditions of reduced zeitgeber strength, the phase of the human circadian pacemaker, using plasma melatonin as a marker, can be phase delayed by one night of SD and the associated dim light exposure.
Four blind individuals who were thought to be entrained at an abnormal circadian phase position were reset to a more normal phase using exogenous melatonin administration. In one instance, circadian phase was shifted later. A fifth subject who was thought to be entrained was monitored over four years and eventually was shown to have a circadian period different from 24 h. These findings have implications for treating circadian phase abnormalities in the blind, for distinguishing between abnormally entrained and free-running blind individuals, and for informing the debate over zeitgeber hierarchy in humans.
Exogenous melatonin (0.5-10 mg) has been shown to entrain the free-running circadian rhythms of some blind subjects. The aim of this study was to assess further the entraining effects of a daily dose of 0.5 mg melatonin on the cortisol rhythm and its acute effects on subjective sleep in blind subjects with free-running 6-sulphatoxymelatonin (aMT6s) rhythms (circadian period [tau] 24.23-24.95 h). Ten subjects (9 males) were studied, aged 32 to 65 years, with no conscious light perception (NPL). In a placebo-controlled, single-blind design, subjects received 0.5 mg melatonin or placebo p.o. daily at 2100 h (treatment duration 26-81 days depending on individuals' circadian period). Subjective sleep was assessed from daily sleep and nap diaries. Urinary cortisol and aMT6s were assessed for 24 to 48 h weekly and measured by radioimmunoassay. Seven subjects exhibited an entrained or shortened cortisol period during melatonin treatment. Of these, 4 subjects entrained with a period indistinguishable from 24 h, 2 subjects continued to free run for up to 25 days during melatonin treatment before their cortisol rhythm became entrained, and 1 subject appeared to exhibit a shortened cortisol period throughout melatonin treatment. The subjects who entrained within 7 days did so when melatonin treatment commenced in the phase advance portion of the melatonin PRC (CT6-18). When melatonin treatment ceased, cortisol and aMT6s rhythms free ran at a similar period to before treatment. Three subjects failed to entrain with initial melatonin treatment commencing in the phase delay portion of the PRC. During melatonin treatment, there was a significant increase in nighttime sleep duration and a reduction in the number and duration of daytime naps. The positive effect of melatonin on sleep may be partly due to its acute soporific properties. The findings demonstrate that a daily dose of 0.5 mg melatonin is effective at entraining the free-running circadian systems in most of the blind subjects studied, and that circadian time (CT) of administration of melatonin may be important in determining whether a subject entrains to melatonin treatment. Optimal treatment with melatonin for this non-24-h sleep disorder should correct the underlying circadian disorder (to entrain the sleep-wake cycle) in addition to improving sleep acutely.
About 15% of the legally blind completely lack light perception. Most of these individuals have abnormally phased circadian rhythms and many free-run. Light treatment is not an option for them. However, melatonin treatment can be highly effective. A daily dose of 0.5 mg of melatonin usually results in entrainment. It has been suggested that treatment in individuals with circadian periods > 24 h should be initiated on the advance zone of the melatonin phase response curve, which was based on findings in which melatonin initiated on the delay zone were less likely to result in entrainment, even though treatment continued across all circadian phases. In the present study, 7 totally blind people started low-dose melatonin treatment (0.5 mg; 1 person was given 0.05 mg) on the delay zone. All entrained as circadian phase free-ran and the advance zone of the melatonin phase response curve coincided with the time of melatonin administration. These results are consistent with studies in other mammals. It does not appear that low-dose melatonin treatment needs to be initiated on the advance zone to induce eventual entrainment in blind people with free-running rhythms > 24 h. Therefore, it is not essential that circadian phase be ascertained before starting low-dose melatonin treatment of blind people.
Light is the primary synchronizer of the human biological clock. In more than half of those blind individuals who completely lack light perception, the absence of photic input to the hypothalamic circadian pacemaker results in rhythms that free-run (blind free-runners [BFRs]) with a period typically greater than 24 h. The remainder are entrained, although sometimes at an abnormal phase angle. It is presumed that weak as-yet-to-be-identified time cues provide the necessary resetting stimulus in these entrained individuals. These weak zeitgebers might be expected to modulate the observed circadian period in blind people who are not actually entrained by them. The authors report here the results from 5 BFRs (average linear regression period +/-SD of 24.31 +/- 0.06 h) who had high-resolution (many and frequent) phase assessments. All 5 subjects demonstrated a similar and reproducible pattern of changes in observed period (period response curves) indicative of relative coordination. The precise shape of the period response curve to weak zeitgebers has implications for the entrainment of BFRs using exogenous melatonin administration or other nonphotic stimuli. Sighted individuals may also be affected by such weak zeitgebers, which may be obscured by the stronger light/dark cycle.
Assays for measuring the dim light melatonin onset (DLMO) in human plasma
- A J Lewy
- R L Sack
- R S Boney
- A A Clemons
- N R Anderson
- S D Pen
- V K Bauer
- N L Cutler
- C T Harker
Lewy, A.J., Sack, R.L., Boney, R.S., Clemons, A.A., Anderson, N.R., Pen, S.D., Bauer, V.K., Cutler, N.L., Harker, C.T. (1997). Assays for measuring the dim light melatonin onset (DLMO) in human plasma. Sleep Res. 26:733.
The endogenous melatonin profile as a marker for circadian phase position
- A J Lewy
- N L Cutler
- R L Sack
Coordination of circadian timing in mammals
- S M Reppert
- D R Weaver
- Zhdanova I. V.
- Lewy A. J