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Sleep Research

Physiological Levels of Melatonin Relate to Cognitive Function and Depressive Symptoms

http://www.ncbi.nlm.nih.gov/pubmed/26052727

J Clin Endocrinol Metab. 2015 Jun 8:jc20151859. [Epub ahead of print]
Physiological Levels of Melatonin Relate to Cognitive Function and Depressive Symptoms: The HEIJO-KYO Cohort.
Obayashi K1, Saeki K1, Iwamoto J1, Tone N1, Tanaka K1, Kataoka H1, Morikawa M1, Kurumatani N1.
Author information

1Department of Community Health and Epidemiology (K.O., K.S., N.K.), Center for Academic Industrial and Governmental Relations (N.T.), Department of Neurology (H.K.), Department of Psychiatry (M.M.), Nara Medical University School of Medicine, Nara, Japan. Department of Nursing (J.I.), Tenri Health Care University, Nara, Japan. Osaka City University Graduate School of Medicine (K.T.), Osaka, Japan. Mie Prefectural Mental Care Center (M.M.), Mie, Japan.
Abstract

CONTEXT:

In contrast with randomized controlled trials, observational studies have suggested that physiological levels of melatonin are reduced in patients with dementia or depression but the relationship has not been evaluated in large populations.

OBJECTIVE:

To determine the relationships between physiological levels of melatonin and cognitive function and depressive symptoms.

DESIGN AND PARTCIPANTS:

A cohort of 1105 community-dwelling elderly individuals was enrolled in this cross-sectional study (mean age, 71.8 ± 7.1 years).

MEASURES:

Urinary 6-sulfatoxymelatonin excretion (UME) and Mini-Mental State Examination (MMSE, n=935) and Geriatric Depression Scale (GDS, n=1097) scores were measured as indices of physiological melatonin levels, cognitive function, and depressive symptoms, respectively.

RESULTS:

With increases in UME quartiles, prevalence of cognitive impairment (MMSE score ≤26) and depressed mood (GDS score ≥6) significantly decreased (P for trend=0.003 and 0.012, respectively). In multivariate logistic regression models, after adjusting for confounders such as age, gender, socioeconomic status, physical activity, and sleep/wake cycles, higher UME levels were significantly associated with lower odds ratios (ORs) for cognitive impairment and depressed mood (ORs: Q1=1.00; Q2=0.88 and 0.76; Q3=0.66 and 0.85; Q4=0.67 and 0.53; P for trend=0.023 and 0.033, respectively). In addition, the highest UME group showed a significantly lower OR for depressed mood than the lowest UME group (Q4 vs. Q1: OR, 0.53, 95% confidence interval, 0.32-0.89, P=0.033). UME levels above the median value were significantly associated with a lower OR for cognitive impairment, even after further adjustment for depressive symptoms (OR=0.74; 95% confidence interval, 0.55-0.99; P=0.043).

CONCLUSIONS:

Significant associations of higher physiological melatonin levels with lower prevalence of cognitive impairment and depressed mood were revealed in a large general elderly population. The association between physiological melatonin levels and cognitive function was independent of depressive symptoms.

PMID: 26052727

Light Pollution: Adverse Health Effects of Nighttime Lighting

Light Pollution: Adverse Health Effects of Nighttime Lighting

The natural 24-hour cycle of light and dark helps maintain precise alignment of circadian biological rhythms, the general activation of the central nervous system and various biological and cellular processes, and entrainment of melatonin release from the pineal gland. Pervasive use of nighttime lighting disrupts these endogenous processes and creates potentially harmful health effects and/or hazardous situations with varying degrees of harm. The latter includes the generation of glare from roadway, property, and other artificial lighting sources that can create unsafe driving conditions, especially for older drivers. More direct health effects of nighttime lighting may be attributable to disruption of the sleep-wake cycle and suppression of melatonin release. Even low intensity nighttime light has the capability of suppressing melatonin release. In various laboratory models of cancer, melatonin serves as a circulating anticancer signal and suppresses tumor growth. Limited epidemiological studies support the hypothesis that nighttime lighting and/or repetitive disruption of circadian rhythms increases cancer risk; most attention in this arena has been devoted to breast cancer. Further information is required to evaluate the relative role of sleep versus the period of darkness in certain diseases or on mediators of certain chronic diseases or conditions including obesity. Due to the nearly ubiquitous exposure to light at inappropriate times relative to endogenous circadian rhythms, a need exists for further multidisciplinary research on occupational and environmental exposure to light-at-night, the risk of cancer, and effects on various chronic diseases.

Human melatonin and alerting response to blue-enriched light depend on a polymorphism in the clock gene PER3

Human melatonin and alerting response to blue-enriched light depend on a polymorphism in the clock gene PER3

J Clin Endocrinol Metab. 2012 Mar;97(3):E433-7. doi: 10.1210/jc.2011-2391. Epub 2011 Dec 21.
Human melatonin and alerting response to blue-enriched light depend on a polymorphism in the clock gene PER3.

Chellappa SL, Viola AU, Schmidt C, Bachmann V, Gabel V, Maire M, Reichert CF, Valomon A, Götz T, Landolt HP, Cajochen C.
Source

Centre for Chronobiology, Psychiatric Hospital of the University of Basel, Wilhelm Kleinstrasse 27, CH-4012 Basel, Switzerland.

Abstract

CONTEXT:

Light exposure, particularly at the short-wavelength range, triggers several nonvisual responses in humans. However, the extent to which the melatonin-suppressing and alerting effect of light differs among individuals remains unknown.

OBJECTIVE:

Here we investigated whether blue-enriched polychromatic light impacts differentially on melatonin and subjective and objective alertness in healthy participants genotyped for the PERIOD3 (PER3) variable-number, tandem-repeat polymorphism.

DESIGN, SETTING, AND PARTICIPANTS:

Eighteen healthy young men homozygous for the PER3 polymorphism (PER3(5/5)and PER3(4/4)) underwent a balanced crossover design during the winter season, with light exposure to compact fluorescent lamps of 40 lux at 6500 K and at 2500 K during 2 h in the evening.

RESULTS:

In comparison to light at 2500 K, blue-enriched light at 6500 K induced a significant suppression of the evening rise in endogenous melatonin levels in PER3(5/5) individuals but not in PER3(4/4). Likewise, PER3(5/5) individuals exhibited a more pronounced alerting response to light at 6500 K than PER3(4/4) volunteers. Waking electroencephalographic activity in the theta range (5-7 Hz), a putative correlate of sleepiness, was drastically attenuated during light exposure at 6500 K in PER3(5/5) individuals as compared with PER3(4/4).

CONCLUSIONS:

We provide first evidence that humans homozygous for the PER3 5/5 allele are particularly sensitive to blue-enriched light, as indexed by the suppression of endogenous melatonin and waking theta activity. Light sensitivity in humans may be modulated by a clock gene polymorphism implicated in the sleep-wake regulation.

PMID:
22188742

The impact of light from computer monitors on melatonin levels in college students.

Neuro Endocrinol Lett. 2011 Apr 9;32(2). [Epub ahead of print]

Source

The impact of light from computer monitors on melatonin levels in college students.

Lighting Research Center, Rensselaer Polytechnic Institute, Troy, NY, USA. figuem@rpi.edu.

Abstract

OBJECTIVES:

Self-luminous electronic devices emit optical radiation at short wavelengths, close to the peak sensitivity of melatonin suppression. Melatonin suppression resulting from exposure to light at night has been linked to increased risk for diseases. The impact of luminous cathode ray tube (CRT) computer monitors on melatonin suppression was investigated.

DESIGN:

Twenty-one participants experienced three test conditions: 1) computer monitor only, 2) computer monitor viewed through goggles providing 40 lux of short-wavelength (blue; peak ¦Ë ¡Ö 470 nm) light at the cornea from light emitting diodes (LEDs), and 3) computer monitor viewed through orange-tinted safety glasses (optical radiation <525 nm ¡Ö 0). The blue-light goggles were used as a “true-positive” experimental condition to demonstrate protocol effectiveness; the same light treatment had been shown in a previous study to suppress nocturnal melatonin. The orange-tinted glasses served as a “dark” control condition because the short-wavelength radiation necessary for nocturnal melatonin suppression was eliminated. Saliva samples were collected from subjects at 23:00, before starting computer tasks, and again at midnight and 01:00 while performing computer tasks under all three experimental conditions.

RESULTS:

Melatonin concentrations after exposure to the blue-light goggle experimental condition were significantly reduced compared to the dark control and to the computer monitor only conditions. Although not statistically significant, the mean melatonin concentration after exposure to the computer monitor only was reduced slightly relative to the dark control condition.

CONCLUSIONS:

Additional empirical data should be collected to test the effectiveness of different, brighter and larger screens on melatonin suppression.

PMID:
21552190
[PubMed – as supplied by publisher]

 

 

Exposure to Room Light before Bedtime Suppresses Melatonin Onset and Shortens Melatonin Duration in Humans.

J Clin Endocrinol Metab. 2011 Mar;96(3):E463-72. Epub 2010 Dec 30.

Exposure to Room Light before Bedtime Suppresses Melatonin Onset and Shortens Melatonin Duration in Humans.

Gooley JJ, Chamberlain K, Smith KA, Khalsa SB, Rajaratnam SM, Van Reen E, Zeitzer JM, Czeisler CA, Lockley SW.

Division of Sleep Medicine, Brigham and Women`s Hospital and Harvard Medical School,

221 Longwood Avenue, Boston, Massachusetts 02115

. gmsjjg@nus.edu.

Abstract

Context: Millions of individuals habitually expose themselves to room light in the hours before bedtime, yet the effects of this behavior on melatonin signaling are not well recognized. Objective: We tested the hypothesis that exposure to room light in the late evening suppresses the onset of melatonin synthesis and shortens the duration of melatonin production. Design: In a retrospective analysis, we compared daily melatonin profiles in individuals living in room light (<200 lux) vs. dim light (<3 lux). Patients: Healthy volunteers (n = 116, 18-30 yr) were recruited from the general population to participate in one of two studies. Setting: Participants lived in a General Clinical Research Center for at least five consecutive days. Intervention: Individuals were exposed to room light or dim light in the 8 h preceding bedtime. Outcome Measures: Melatonin duration, onset and offset, suppression, and phase angle of entrainment were determined. Results: Compared with dim light, exposure to room light before bedtime suppressed melatonin, resulting in a later melatonin onset in 99.0% of individuals and shortening melatonin duration by about 90 min. Also, exposure to room light during the usual hours of sleep suppressed melatonin by greater than 50% in most (85%) trials. Conclusions: These findings indicate that room light exerts a profound suppressive effect on melatonin levels and shortens the body`s internal representation of night duration. Hence, chronically exposing oneself to electrical lighting in the late evening disrupts melatonin signaling and could therefore potentially impact sleep, thermoregulation, blood pressure, and glucose homeostasis.

Using blue-green light at night and blue-blockers during the day to improves adaptation to night work: A pilot study.

Authors:Sasseville, Alexandre
H¨¦bert, Marc marc.hebert@crulrg.ulaval.caSource:Progress in Neuro-Psychopharmacology & Biological Psychiatry; Oct2010, Vol. 34 Issue 7, p1236-1242, 7pDocument Type:ArticleSubject Terms:*ADAPTABILITY (Psychology)
*NIGHT work
*LIGHTING
*WAVELENGTHS
*ACTIGRAPHY
*BEDTIME
*MELATONIN
*SHIFT systemsAuthor-Supplied Keywords:bed time ( BT )
light and dark cycle ( L/D )
morningness¨Ceveningness questionnaire ( MEQ )
sleep efficiency ( SE )
sleep latency ( SL )
time in bed ( TIB )
total slept time ( TST )
visual analogue scale ( VAS )NAICS/Industry Codes:335129 Other Lighting Equipment ManufacturingAbstract:Abstract: Background: Bright light at night paired with darkness during the day seem to facilitate adaptation to night work. Considering the biological clock sensitive to short wavelengths, we investigated the possibility of adaptation in shift workers exposed to blue-green light at night, combined with using blue-blockers during the day. Methods: Four sawmill shift workers were evaluated during two weeks of night shifts (control and experimental) and one week of day shifts. Throughout the experimental week, ambient light (¡Ö130lx) was supplemented with blue-green light (200lx) from 00:00h to: 05:00h on Monday and Tuesday, 06:00h on Wednesday and 07:00h on Thursday. Blue-blockers had to be worn outside from the end of the night shift until 16:00h. For circadian assessment, salivary melatonin profiles were obtained between 00:00h and 08:00h, before and after 4 experimental night shifts. Sleep was continuously monitored with actigraphy and subjective vigilance was measured at the beginning, the middle and the end of each night and day shifts. The error percentage in wood board classification was used as an index of performance. Results: Through experimental week, melatonin profiles of 3 participants have shifted by at least 2hours. Improvements were observed in sleep parameters and subjective vigilance from the third night (Wednesday) as performance increased on the fourth night (Thursday) from 5.14% to 1.36% of errors (p=0.04). Conclusions: Strategic exposure to short wavelengths at night, and/or daytime use of blue-blocker glasses, seemed to improve sleep, vigilance and performance. [Copyright &y& Elsevier]

Sleep Habits and Susceptibility to the Common Cold

Arch Intern Med. 2009 Jan 12;169(1):62-7.

Sleep habits and susceptibility to the common cold.

Cohen S, Doyle WJ, Alper CM, Janicki-Deverts D, Turner RB.

Department of Psychology, Carnegie Mellon University, Pittsburgh, PA 15213, USA. scohen@cmu.edu

BACKGROUND: Sleep quality is thought to be an important predictor of immunity and, in turn, susceptibility to the common cold. This article examines whether sleep duration and efficiency in the weeks preceding viral exposure are associated with cold susceptibility. METHODS: A total of 153 healthy men and women (age range, 21-55 years) volunteered to participate in the study. For 14 consecutive days, they reported their sleep duration and sleep efficiency (percentage of time in bed actually asleep) for the previous night and whether they felt rested. Average scores for each sleep variable were calculated over the 14-day baseline. Subsequently, participants were quarantined, administered nasal drops containing a rhinovirus, and monitored for the development of a clinical cold (infection in the presence of objective signs of illness) on the day before and for 5 days after exposure. RESULTS: There was a graded association with average sleep duration: participants with less than 7 hours of sleep were 2.94 times (95% confidence interval [CI], 1.18-7.30) more likely to develop a cold than those with 8 hours or more of sleep. The association with sleep efficiency was also graded: participants with less than 92% efficiency were 5.50 times (95% CI, 2.08-14.48) more likely to develop a cold than those with 98% or more efficiency. These relationships could not be explained by differences in prechallenge virus-specific antibody titers, demographics, season of the year, body mass, socioeconomic status, psychological variables, or health practices. The percentage of days feeling rested was not associated with colds. CONCLUSION: Poorer sleep efficiency and shorter sleep duration in the weeks preceding exposure to a rhinovirus were associated with lower resistance to illness.

Means to Avoid the Suppression of Melatonin by Artificial Light: The Bright Side of Darkness

ABSTRACT

 

Melatonin is an active sleep facilitating hormone and important cancer fighting antioxidant. Ordinarily it is produced by the pineal gland only when the eyes are in darkness. The use of artificial light at night decreases substantially the time people are in darkness and thus the time that melatonin is produced. This is considered by some to be one cause for the increasing incidence of breast and other cancers in industrialized countries. In addition, the availability of artificial lighting encourages poor sleep habits and/or sleep deprivation, which, in turn, can exacerbate various mood disorders. The fact that it is only the blue component of light that suppresses melatonin production provides a simple way to possibly reduce these and other health problems without radical changes of life style. This involves the use of devices, for example eyewear and specially coated lamps, that filter out light wavelengths below 530nm. The properties of such devices and some possible health effects resulting from their use are discussed.

 

Key words: melatonin, artificial light, sleep, mood disorders, cancer risk, bipolar disorder

  1. INTRODUCTION

Melatonin, the strong antioxidant and sleep facilitating hormone, until quite recently, was believed to be produced by the pineal gland only when the eyes are in darkness [1]. In the same way, darkness is assumed to control the circadean clock, which in turn, through melatonin and other hormones, controls many of the body’s activities. Some researchers have come to believe that the use of artificial lighting at night in industrialized countries, since it reduces the time that melatonin is produced by the pineal gland, may disturb the natural behavior of many bodily functions.

It was recently shown conclusively, however, that it is only the blue component of light reaching the eyes that suppresses melatonin production [2,3]. With this in mind, as lighting developers, we have devised techniques of providing “blueless” light to the eyes in the evening before bedtime. This is accomplished by using light bulbs with coatings that do not transmit the blue light that suppresses melatonin, or by having subjects wear eyeglasses that filter out only the offending blue light. In this way normal after dark activities may continue using the remaining colors of light. The following figures illustrate the characteristics of such devices. Fig. 1 Plots of the relative intensity vs. wavelength of an uncoated (upper curve) and an identical coated lamp.

Figure 2. Eyeglass transmission spectrum.

 

In Fig. 1, plots of the relative light output vs. wavelength of an uncoated and an identical coated incandescent lamp are shown. Note that at wavelengths below 530nm the intensities of the coated lamp are well below those of an identical uncoated lamp. The transmission vs. wavelength of our eyeglasses is shown in Fig. 2. Note that below 530nm the transmission coefficient is less than 0,01 while above 530nm it rises rapidly to about 0,9. These and other devices with similar characteristics may be used to help find solutions to several health related problems, as discussed briefly in the following sections.

  1. SLEEP PROBLEMS

It is obvious, as evidenced by the large number of sleep aids that are advertised and prescribed, that many people suffer from poor sleep habits. We have begun working with a sleep disorder specialist [4] who, in her own words, has seen “remarkable improvements” in the sleep of patients who are using our eyeglasses. Her patients, as well a large number of others who have used the eyeglasses, put them on one to two hours before bedtime. They also completely avoid exposing their eyes to unfiltered light before retiring in a well darkened room. Prior to retiring they are able to read, watch television, work on their computer, or take part in almost any after dark activity. Most of her patients, as well other users, report substantial improvement in their sleep habits after doing this for only three or four days. The assumption is that the start of the flow of melatonin is advanced in time [5], resulting in its being present in quantity at bedtime. This causes sleep to come quickly and deeply.

Studies have shown that sighted subjects kept in darkness and most blind people (effectively always in darkness) produce melatonin for 9 to 10 hours a night [6]. By wearing blue blocking eyeglasses for a few hours before bedtime and being in the dark while sleeping, the 9 to 10 hours of melatonin flow may be achieved by anyone. This means the flow of melatonin can continue for the full duration of sleep despite the fact that it started sooner. This results in sound sleep lasting throughout the night.

  1. SLEEPY STUDENT SYNDROME

Studies have shown that because of the early starting times of many high schools, many students are barely awake during the first classes [7]. Relatively large levels of melatonin, the sleep hormone, have been found in the blood of such students during the early morning. This may explain their inability to perform well.

This problem may be avoided by advancing the time when melatonin production begins. This is accomplished by preventing exposure of the students’ eyes to blue light a few hours before their frequently late bedtime. Several ways exist that can accomplish this goal. The most convenient is for the students to put on blue blocking eyeglasses such as ours. Alternatively the lighting may be changed to coated light bulbs. In the latter case, however, other sources of light such as TV and computer screens, need to be covered with filters that block blue light.

Within a few days of avoiding blue light after 8 or 9 P.M., the students’ melatonin production cycle will be advanced so that it is completed well before the start of school. The advance may be solidified by exposing the students’ eyes to bright light containing substantial blue light soon after waking in the morning. However, the use of only the light in the morning is not encouraged, since having melatonin present in the evening will encourage the students to go to sleep (which they need), and also possibly provide protection from the risk of cancer [8].

  1. BIPOLAR DISORDER

The combination of recent theorizing and results of clinical research studies has suggested a new approach to treating bipolar disorder. First, some have theorized that the root of the problem of bipolar disorder is the failure of the internal (circadian) clock to function normally. Melatonin production is controlled by the internal clock(s) but melatonin also helps to set the clocks via a feed-back process. Second, remarkable success has been obtained in treating bipolar disorder by subjecting patients to prolonged periods of darkness [9,10]. Third, as first clearly demonstrated [11], the use of goggles that block blue light is equivalent to exposure to darkness, as far as melatonin production is concerned]. With these three somewhat disparate factors in mind, a new form of treatment of bipolar disorder has been proposed and is under early testing [12].

Basically, the new treatment consists of having the patients initially wear blue blocking eyeglasses for a prolonged period, such that the time wearing them plus the time spent in darkness while sleeping exceeds 12 hours. The patients will be directed to develop a routine of going to sleep at a regular hour and awakening at a regular hour. For example, in the evening, the patients will put on the eyeglasses at about 7P.M. and go to bed in darkness at about 11:00 P.M. Soon after awakening at 7 A.M, exposure to bright light (preferable outdoors) will be encouraged. Obviously these times may be adjusted to fit the desired schedule of each patient.

As indicated in the previous two sections, the patients should avoid exposing their eyes during the night to light containing a blue component. Nightlights, such as coated incandescents or amber LEDs, should be used. The patients should avoid napping during the day and evening. Exposure to bright light (outdoors if possible) during periods of drowsiness is recommended. For the first week or two a low dose (3mg) of melatonin may be taken by mouth an hour or two before bedtime to help lock in the new setting of the internal clock. It is not necessary that the patients sleep the entire 8 hours as long as they stay in darkness or avoid blue light during that period. It may require several day for the internal clock to become well synchronized. Until then, the outlined schedule should be carefully followed. Once a patient’s clock is working properly, missing some part of the routine now and then should not be a problem. To verify that the clock is functioning properly, saliva samples may be taken at regular intervals for at least a 24 hours period, especially right before bedtime, upon awakening, and during the night if the patient awakens.

  1. CANCER RISK

There is a considerable body of knowledge [8] showing that using artificial light at night may increase the risk of cancer. This reduces the time spent in darkness and thus reduces the time that cancer fighting melatonin is produced.. Studies have shown that blind people have a lower cancer rate than sighted people [12[. As already mentioned, other studies have shown that blind people and sighted people kept in darkness produce melatonin for 9 or 10 hours a night [6]. Typically, people in industrialized countries are in darkness and produce melatonin for only 6 or 7 hours a night. The various techniques discussed in previous sections can increase the duration of the melatonin flow to the natural 9 to 10 hours, but without a major change in life style. Though it will take many years to establish that using these techniques may reduce the risk of breast and other cancers, it would seem well worthwhile to do begin such studies as soon as possible.

  1. CONCLUSION

Assuming that 9 to 10 hours of melatonin production may be required to solve a number of prevalent health problems, requiring people to spend 9 or 10 hours in darkness is not practical. The most convenient and simple way to accomplish this is to put on eyeglasses that block the blue light two or three hours before bedtime and to avoid exposing the eyes to blue light any time before arising. Night lights that either produce no blue light, e.g. amber LEDs, or filtered incandescent or fluorescent lamps for use in hallways and bathrooms, are recommended. As an alternative to wearing eyeglasses, the area where one spends the hours before bedtime should be equipped with lamps that do not produce the damaging blue light and blue blocking filters for TV and computer screens should be employed. Normal after dark activities may be conducted since the light remaining after removing the melatonin suppressing blue wavelengths can be made perfectly adequate for reading, watching television or working on a computer.

References

  1. CZEISLER, CA and WRIGHT, KP Jr., Influence of light on circadian rhythmicity in humans, Regulation of Sleep and Circadian Rhythms, ed: Turek F.W. & Zee P.C. New York: Marcel Dekker, 1999.
  2. BRAINARD, GC, HANIFIN, JP, GREESON, JM, BYRNE, B, GLICKMAN, G, GERNER, E, and   ROLLAG, MD, Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor, J. Neurosci., 16, 6405-6412, 2001.
  3. THAPAN, K, ARENDT, J, and SKENE, DJ, An action spectrum for melatonin suppression: evidence for a novel non-rod, non-cone photoreceptor system in humans, J Physiol .535, 261-267, 2001.
  4. Personal communication: Berta Briones, M.D., see “A Sleep Disorders Reference for Physicians”, sleep-eportal@mdeportal.com..
  5. SANTHI, N, DUFFY, JF, HOROWITZ, TS, and CZEISLER, CA, Scheduling of sleep/darkness affects the circadian phase of night shift workers, Neurosci. Lett.384, 316-320, 2005.
  6. KLERMAN, EB, ZEITZER, JM, KHALSA, SB and CZEISLER, CA, Absence of an increase in the duration of the circadian melatonin secretory episode in totally blind human subjects, J. Clin. Endocrinol. Metab., 86 3166-3170, 2001.
  7. CARSKAADON, MA, WOLFSON, AR, ACEBO, C, TZISCHINSKY, O, and SEIFER, R, Adolescent sleep patterns, circadian timing, and sleepiness at a transition to early school days, Sleep, 21, 871-881, 1998.
  8. JASSER, SA, BLASK, DE, BRAINARD, GC, Light during darkness and cancer: relationships in circadian photoreception and tumor biology, Cancer Causes and Control, 4, 515-523, 2006.
  9. WEHR, TA, TURNER, EH, SHIMADA, JM, LOWE. CH, BARKER, C. and LEIBENLUFT, E, Treatment of rapidly cycling bipolar patient by using extended bed rest and darkness to stabalize the timing and duration of sleep, Biol. Psychiatry, 43, 822-828, 1998.
  10. BARBINI, B, BENEDETTI, F, COLOMBO, C, BERNASCONI, A, CIGALA-FULGOSI, M, FLORITA, M, and SMERALDI, E, Dark therapy for mania: a pilot study, Bipolar Disord., 1, 98-101, 2005.
  11. KAYUMOV, L, CASSPER, RF, HAWA, RF, PERLMAN, B, CHUNG, SA, SOKALASKY, S, and SHAPIRO, CM, Blocking low-wavelength light prevents nocturnal melatonin suppression with no adverse effect on performance during simulated shift work, J. Clin. Endocrinol Metab., 90, 2755-2761, 2005.
  12. Personal Communication: James Phelps, MD. See “Dark Therapy for Rapid Cycling and Mania” in www.psycheducation.org.
  13. HAHN, RA, . Profound bilateral blindness and the incidence of breast cancer, Epidemiology, 3, 208-210, 1991.

 

 

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E.F. Carome, R.L. Hansler and V.E. Kubulins

Lighting Innovations Institute

John Carroll University

20700 North Park Blvd.

Cleveland, Ohio 44118, USA

carome@jcu.edu

Wavelength-dependent Effects of Evening Light Exposure on Sleep Architecture and Sleep EEG Power Density in Men.

Am J Physiol Regul Integr Comp Physiol.
2006 Jan 26

Munch M, Kobialka S, Steiner R, Oelhafen P, Wirz-Justice A, Cajochen C.

Psychiatric University Clinics, Centre for Chronobiology, CH-4025 Basel, Switzerland.

Light strongly influences the circadian timing system in humans via non-image-forming photoreceptors in the retinal ganglion cells. Their spectral sensitivity is highest in the short wavelength range of the visible light spectrum as demonstrated by melatonin suppression, circadian phase shifting, acute physiological responses and subjective alertness. Here we tested the impact of short wavelength light (460nm) on sleep EEG power spectra and sleep architecture. We hypothesized that its acute action on sleep is of similar magnitude as the reported effects for polychromatic light at higher intensities, and significantly stronger than longer wavelength light (550 nm). The sleep EEG of 8 young men was analyzed after a 2-h evening exposition to blue (460 nm) and green (550 nm) light of equal photon densities (2.8x(13) photons/cm(2)/s) and to dark (0 lux) under constant posture conditions. The time course of slow-wave activity (SWA; 0.75-4.5 Hz) across sleep cycles after blue light at 460 nm was changed such that SWA was slightly reduced in the first and significantly increased during the third sleep cycle in parietal and occipital brain regions. Moreover, blue light significantly shortened REM sleep duration during these two sleep cycles. Thus, the alterations in the dynamics of SWA and REM sleep durations were blue shifted relative to the three-cone visual photopic system and differently mediated by the circadian, non-image-forming visual system. Our results can be interpreted in terms of an induction of a circadian phase delay and/or repercussions of a stronger alerting effect after blue light persisting into the sleep episode.

Blocking low-wavelength light prevents nocturnal melatonin suppression with no adverse effect on performance during simulated shift work.

Munch M, Kobialka S, Steiner R, Oelhafen P, Wirz-Justice A, Cajochen C.

Psychiatric University Clinics, Centre for Chronobiology, CH-4025 Basel, Switzerland.

Light strongly influences the circadian timing system in humans via non-image-forming photoreceptors in the retinal ganglion cells. Their spectral sensitivity is highest in the short wavelength range of the visible light spectrum as demonstrated by melatonin suppression, circadian phase shifting, acute physiological responses and subjective alertness. Here we tested the impact of short wavelength light (460nm) on sleep EEG power spectra and sleep architecture. We hypothesized that its acute action on sleep is of similar magnitude as the reported effects for polychromatic light at higher intensities, and significantly stronger than longer wavelength light (550 nm). The sleep EEG of 8 young men was analyzed after a 2-h evening exposition to blue (460 nm) and green (550 nm) light of equal photon densities (2.8x(13) photons/cm(2)/s) and to dark (0 lux) under constant posture conditions. The time course of slow-wave activity (SWA; 0.75-4.5 Hz) across sleep cycles after blue light at 460 nm was changed such that SWA was slightly reduced in the first and significantly increased during the third sleep cycle in parietal and occipital brain regions. Moreover, blue light significantly shortened REM sleep duration during these two sleep cycles. Thus, the alterations in the dynamics of SWA and REM sleep durations were blue shifted relative to the three-cone visual photopic system and differently mediated by the circadian, non-image-forming visual system. Our results can be interpreted in terms of an induction of a circadian phase delay and/or repercussions of a stronger alerting effect after blue light persisting into the sleep episode.

 

Optimizing Light Spectrum for Long-Duration Space Flight

Munch M, Kobialka S, Steiner R, Oelhafen P, Wirz-Justice A, Cajochen C.

Psychiatric University Clinics, Centre for Chronobiology, CH-4025 Basel, Switzerland.

Light strongly influences the circadian timing system in humans via non-image-forming photoreceptors in the retinal ganglion cells. Their spectral sensitivity is highest in the short wavelength range of the visible light spectrum as demonstrated by melatonin suppression, circadian phase shifting, acute physiological responses and subjective alertness. Here we tested the impact of short wavelength light (460nm) on sleep EEG power spectra and sleep architecture. We hypothesized that its acute action on sleep is of similar magnitude as the reported effects for polychromatic light at higher intensities, and significantly stronger than longer wavelength light (550 nm). The sleep EEG of 8 young men was analyzed after a 2-h evening exposition to blue (460 nm) and green (550 nm) light of equal photon densities (2.8x(13) photons/cm(2)/s) and to dark (0 lux) under constant posture conditions. The time course of slow-wave activity (SWA; 0.75-4.5 Hz) across sleep cycles after blue light at 460 nm was changed such that SWA was slightly reduced in the first and significantly increased during the third sleep cycle in parietal and occipital brain regions. Moreover, blue light significantly shortened REM sleep duration during these two sleep cycles. Thus, the alterations in the dynamics of SWA and REM sleep durations were blue shifted relative to the three-cone visual photopic system and differently mediated by the circadian, non-image-forming visual system. Our results can be interpreted in terms of an induction of a circadian phase delay and/or repercussions of a stronger alerting effect after blue light persisting into the sleep episode.

 

Melatonin, sleep, and circadian rhythms: rationale for development of specific melatonin agonists.

Sleep Med. 2004 Nov;5(6):523-32.

Melatonin, sleep, and circadian rhythms: rationale for development of specific melatonin agonists.
Turek FW, Gillette MU.

Department of Neurobiology and Physiology, Center for Sleep and Circadian Biology, Northwestern University, 2205 Tech Drive, Hogan Hall 2-160, Evanston, IL 60208, USA. fturek@northwestern.edu

Circadian rhythm sleep disorders (CRSDs), whether chronic or transient, affect a broad range of individuals, including many elderly, those with severe visual impairments, shift workers, and jet travelers moving rapidly across many time zones. In addition, various forms of insomnia affect another large sector of the population. A feature common among CRSDs and some forms of insomnia is sensitivity to the hormone melatonin, which is secreted by the pineal gland. Accumulating evidence suggests that melatonin may regulate the circadian clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Although the light-dark cycle is the primary signal that entrains the circadian clock to environmental cycles, exogenous melatonin has been shown to entrain the clock in individuals with no light perception and free-running circadian rhythms. Furthermore, studies have reported beneficial effects of melatonin for treatment of certain insomnias. Together, these studies suggest that melatonin may be useful for treating some insomnias and CRSDs. In these contexts, use of melatonin as a supplement has been popular in the United States. Unfortunately, the therapeutic potential of melatonin has been difficult to realize in clinical trials, possibly owing to non-specific actions of the agent and its unfavorable pharmacokinetic properties when administered orally. In an attempt to take advantage of the therapeutic opportunities available through the brain`s melatonin system, researchers have developed several melatonin agonists with improved properties in comparison to melatonin. Some of these agents are now in clinical trials for treatment of insomnia or CRSDs.

Circadian rhythm disorders

Semin Neurol. 2004 Sep;24(3):315-25.

Circadian rhythm disorders.
Reid KJ, Zee PC.

Center for Sleep and Circadian Biology, Northwestern University, Evanston, Illinois, USA.

Circadian rhythm sleep disorders occur when individuals attempt to sleep at the wrong circadian time. The misalignment between the internal circadian timing system and the external environment is typically due to either an alteration in the functioning of the circadian timing system (e.g., delayed or advanced sleep phase syndrome) or to changes in the external environment (e.g., jet lag). However, the clinical presentation of most of the circadian rhythm sleep disorders is influenced by a combination of physiological, behavioral, and environmental factors. These disorders lead to complaints of insomnia and excessive daytime sleepiness, with impairment in important areas of functioning and quality of life. Current treatments primarily involve the use of circadian synchronizing agents, such as light, to realign the internal and external environment. These treatments are limited by the availability of adequate diagnostic tools and well-controlled clinical trials. A better understanding of the pathophysiology of these disorders is required to develop more effective treatments. 

Effects of evening light conditions on salivary melatonin of Japanese junior high school students.

J Circadian Rhythms. 2004 Aug 11;2(1):4.

Effects of evening light conditions on salivary melatonin of Japanese junior high school students.
Harada T.

Laboratory of Environmental Physiology, Faculty of Education, Kochi University, Kochi 780-8520, Japan. haratets@cc.kochi-u.ac.jp

BACKGROUND: In a previous study, when adult subjects were exposed to a level of 400 lux light for more than 30 min or a level of 300 lux light for more than 2 hours, salivary melatonin concentration during the night dropped lower than when the subjects were exposed to dim illumination. It was suggested that such light exposure in adolescents or children during the first half of subjective night in normal life might decrease the melatonin level and prevent the falling into sleep. However, there has been no actual study on the effects of light exposure in adolescents. METHODS: Effects of exposure to the bright light (2000 lux) from fluorescent light bulbs during a period of three hours from 19:30 to 22:30 in one evening were examined on evening salivary melatonin concentrations from 19:45 to 23:40. The control group was exposed to dim light (60 lux) during these three hours. Both the dim light control group [DLCG] and the bright light experimental group [BLEG] consisted of two female and three male adolescent participants aged 14-15 y. RESULTS: The salivary melatonin level increased rapidly from 3.00 pg/ml at 21:45 to 9.18 pg/ml at 23:40 in DLCG, whereas it remained at less than 1.3 pg/ml for the three hours in BLEG. Melatonin concentration by BLEG at 22:30 of the experimental day was lower than that at the same time on the day before the experimental day, whereas it was significantly higher in the experimental day than on the day before the experimental day in DLCG. CONCLUSIONS: Bright lights of 2000 lux and even moderate lights of 200-300 lux from fluorescent light bulbs can inhibit nocturnal melatonin concentration in adolescents. Ancient Japanese lighting from a traditional Japanese hearth, oil lamp or candle (20-30 lux) could be healthier for children and adolescents because rapid and clear increase in melatonin concentration in blood seems to occur at night under such dim light, thus facilitating a smooth falling into night sleep.

Adaptation of human pineal melatonin suppression by recent photic history.

J Circadian Rhythms. 2004 Aug 11;2(1):4.

Effects of evening light conditions on salivary melatonin of Japanese junior high school students.
Harada T.

Laboratory of Environmental Physiology, Faculty of Education, Kochi University, Kochi 780-8520, Japan. haratets@cc.kochi-u.ac.jp

BACKGROUND: In a previous study, when adult subjects were exposed to a level of 400 lux light for more than 30 min or a level of 300 lux light for more than 2 hours, salivary melatonin concentration during the night dropped lower than when the subjects were exposed to dim illumination. It was suggested that such light exposure in adolescents or children during the first half of subjective night in normal life might decrease the melatonin level and prevent the falling into sleep. However, there has been no actual study on the effects of light exposure in adolescents. METHODS: Effects of exposure to the bright light (2000 lux) from fluorescent light bulbs during a period of three hours from 19:30 to 22:30 in one evening were examined on evening salivary melatonin concentrations from 19:45 to 23:40. The control group was exposed to dim light (60 lux) during these three hours. Both the dim light control group [DLCG] and the bright light experimental group [BLEG] consisted of two female and three male adolescent participants aged 14-15 y. RESULTS: The salivary melatonin level increased rapidly from 3.00 pg/ml at 21:45 to 9.18 pg/ml at 23:40 in DLCG, whereas it remained at less than 1.3 pg/ml for the three hours in BLEG. Melatonin concentration by BLEG at 22:30 of the experimental day was lower than that at the same time on the day before the experimental day, whereas it was significantly higher in the experimental day than on the day before the experimental day in DLCG. CONCLUSIONS: Bright lights of 2000 lux and even moderate lights of 200-300 lux from fluorescent light bulbs can inhibit nocturnal melatonin concentration in adolescents. Ancient Japanese lighting from a traditional Japanese hearth, oil lamp or candle (20-30 lux) could be healthier for children and adolescents because rapid and clear increase in melatonin concentration in blood seems to occur at night under such dim light, thus facilitating a smooth falling into night sleep. 

Adaptation of human pineal melatonin suppression by recent photic history.

J Clin Endocrinol Metab. 2004 Jul;89(7):3610-4.

Erratum in:

  • J Clin Endocrinol Metab. 2005 Mar;90(3):1370.

Adaptation of human pineal melatonin suppression by recent photic history.
Smith KA, Schoen MW, Czeisler CA.

Division of Sleep Medicine, Brigham & Women`s Hospital, Harvard Medical School, 221 Longwood Suite 438, Boston, MA 02115, USA.

The human circadian pacemaker controls the timing of the release of the pineal hormone melatonin, which promotes sleep, decreases body temperature, and diminishes cognitive performance. Abnormal melatonin secretion has been observed in psychiatric and circadian disorders. Although melatonin secretion is directly suppressed by exposure to light in a nonlinear intensity-dependent fashion, little research has focused on the effect of prior photic history on this response. We examined eight subjects in controlled laboratory conditions using a within-subjects design. Baseline melatonin secretion was monitored under constant routine conditions and compared with two additional constant routines with a fixed light stimulus for 6.5 h of 200 lux (50 microW/cm(2)) after approximately 3 d of photic exposure during the subjective day of either about 200 lux (50 microW/cm(2)) or about 0.5 lux (0.15 microW/cm(2)). We found a significant increase in melatonin suppression during the stimulus after a prior photic history of approximately 0.5 lux compared with approximately 200 lux, revealing that humans exhibit adaptation of circadian photoreception. Such adaptation indicates that translation of a photic stimulus into drive on the human circadian pacemaker involves more complex temporal dynamics than previously recognized. Further elucidation of these properties could prove useful in potentiating light therapies for circadian and affective disorders. 

The relationship between the dim light melatonin onset and sleep on a regular schedule in young healthy adults.

Behav Sleep Med. 2003;1(2):102-14.

The relationship between the dim light melatonin onset and sleep on a regular schedule in young healthy adults.
Burgess HJ, Savic N, Sletten T, Roach G, Gilbert SS, Dawson D.

Biological Rhythms Research Laboratory, Rush-Presbyterian-St. Luke`s Medical Center, Chicago, IL 60612, USA. hburgess@rush.edu

The endogenous melatonin onset in dim light (DLMO) is a marker of circadian phase that can be used to appropriately time the administration of bright light or exogenous melatonin in order to elicit a desired phase shift. Determining an individual`s circadian phase can be costly and time-consuming. We examined the relationship between the DLMO and sleep times in 16 young healthy individuals who slept at their habitual times for a week. The DLMO occurred about 2 hours before bedtime and 14 hours after wake. Wake time and midpoint of sleep were significantly associated with the DLMO (r = 0.77, r = 0.68 respectively), but bedtime was not (r = 0.36). The possibility of predicting young healthy normally entrained people`s DLMOs from their sleep times is discussed. 

Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor.

J Neurosci. 2001 Aug 15;21(16):6405-12.

Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor.

Brainard GC, Hanifin JP, Greeson JM, Byrne B, Glickman G, Gerner E, Rollag MD.

Department of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. george.brainard@mail.tju.edu

The photopigment in the human eye that transduces light for circadian and neuroendocrine regulation, is unknown. The aim of this study was to establish an action spectrum for light-induced melatonin suppression that could help elucidate the ocular photoreceptor system for regulating the human pineal gland. Subjects (37 females, 35 males, mean age of 24.5 +/- 0.3 years) were healthy and had normal color vision. Full-field, monochromatic light exposures took place between and while subjects` pupils were dilated. Blood samples collected before and after light exposures were quantified for melatonin. Each subject was tested with at least seven different irradiances of one wavelength with a minimum of 1 week between each nighttime exposure. Nighttime melatonin suppression tests (n = 627) were completed with wavelengths from 420 to 600 nm. The data were fit to eight univariant, sigmoidal fluence-response curves (R(2) = 0.81-0.95). The action spectrum constructed from these data fit an opsin template (R(2) = 0.91), which identifies 446-477 nm as the most potent wavelength region providing circadian input for regulating melatonin secretion. The results suggest that, in humans, a single photopigment may be primarily responsible for melatonin suppression, and its peak absorbance appears to be distinct from that of rod and cone cell photopigments for vision. The data also suggest that this new photopigment is retinaldehyde based. These findings suggest that there is a novel opsin photopigment in the human eye that mediates circadian photoreception.

An action spectrum for melatonin suppression: evidence for a novel non-rod, non-cone photoreceptor system in humans.

J Physiol. 2001 Aug 15;535(Pt 1):261-7.

An action spectrum for melatonin suppression: evidence for a novel non-rod, non-cone photoreceptor system in humans.

Thapan K, Arendt J, Skene DJ.

Centre for Chronobiology, School of Biomedical and Life Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK.

1. Non-image forming, irradiance-dependent responses mediated by the human eye include synchronisation of the circadian axis and suppression of pineal melatonin production. The retinal photopigment(s) transducing these light responses in humans have not been characterised. 2. Using the ability of light to suppress nocturnal melatonin production, we aimed to investigate its spectral sensitivity and produce an action spectrum. Melatonin suppression was quantified in 22 volunteers in 215 light exposure trials using monochromatic light (30 min pulse administered at circadian time (CT) 16-18) of different wavelengths (lambda(max) 424, 456, 472, 496, 520 and 548 nm) and irradiances (0.7-65.0 microW cm(-2)). 3. At each wavelength, suppression of plasma melatonin increased with increasing irradiance. Irradiance-response curves (IRCs) were fitted and the generated half-maximal responses (IR(50)) were corrected for lens filtering and used to construct an action spectrum. 4. The resulting action spectrum showed unique short-wavelength sensitivity very different from the classical scotopic and photopic visual systems. The lack of fit (r(2) < 0.1) of our action spectrum with the published rod and cone absorption spectra precluded these photoreceptors from having a major role. Cryptochromes 1 and 2 also had a poor fit to the data. Fitting a series of Dartnall nomograms generated for rhodopsin-based photopigments over the lambda(max) range 420-480 nm showed that rhodopsin templates between lambda(max) 457 and 462 nm fitted the data well (r(2) > or =0.73). Of these, the best fit was to the rhodopsin template with lambda(max) 459 nm (r(2) = 0.74). 5. Our data strongly support a primary role for a novel short-wavelength photopigment in light-induced melatonin suppression and provide the first direct evidence of a non-rod, non-cone photoreceptive system in humans.

Photoperiodism in humans and other primates: evidence and implications.

J Biol Rhythms. 2001 Aug;16(4):348-64.

Photoperiodism in humans and other primates: evidence and implications.

Wehr TA.

Section on Biological Rhythms, National Institute of Mental Health, Bethesda, MD, USA.

Most of the anatomical and molecular substrates of the system that encodes changes in photoperiod in the duration of melatonin secretion, and the receptor molecules that read this signal, have been shown to be conserved in monkeys and humans, and the functions of this system appear to be intact from the level of the retina to the level of the melatonin-duration signal of change of season. While photoperiodic seasonal breeding has been shown to occur in monkeys, it remains unclear whether photoperiod and mediation of photoperiod`s effects by melatonin influence human reproduction. Epidemiological evidence suggests that inhibition of fertility by heat in men in summer contributes to seasonal variation in human reproduction at lower latitudes and that stimulation of fertility by lengthening of the photoperiod in spring contributes to the variation at higher latitudes. Parallels between the seasonality of human reproduction and seasonal affective disorder suggest that they may be governed by common biological processes. Historical and experimental evidence indicates that human responses to seasonal changes in the natural photoperiod may have been more robust prior to the Industrial Revolution and that subsequently they have been increasingly suppressed by alterations of the physical environment.

Melatonin and seasonal rhythms.

J Biol Rhythms.
1997 Dec;12(6):518-27.
Melatonin and seasonal rhythms.

Wehr TA.

Clinical Psychobiology Branch, National Institute of Mental Health, Bethesda, MD 20892-1390, USA.

The pineal hormone melatonin plays a ubiquitous role in biology as a chemical mediator of the effects of season on animal physiology and behavior. Seasonal changes in night length (scotoperiod) induce parallel changes in the duration of melatonin secretion (which occurs exclusively at night), so that it is longer in winter and shorter in summer. These changes in duration of nocturnal melatonin secretion, in turn, trigger seasonal changes in behavior. The retinohypothalamic-pineal (RHP) axis`s responses to light are highly conserved in humans. Like other animals, humans secrete melatonin exclusively at night, and they interrupt its secretion when they are exposed to light during the nocturnal period of its secretion. In many individuals, the RHP axis also is capable of detecting changes in the length of the night and making proportional adjustments in the duration of nocturnal melatonin secretion, producing the type of melatonin message that animals use to trigger seasonal changes in their behavior. This has been shown both in naturalistic studies in which melatonin profiles were compared in summer and winter and in experimental studies in which melatonin profiles were compared after chronic exposure to long and short artificial “nights.” Individuals who live in modern urban environments differ in the degree to which, or even whether, the intrinsic duration of melatonin secretion (the duration measured in constant dim light) responds to seasonal changes in the length of the solar night. Changes in the intrinsic duration of melatonin secretion that are induced by changes in the scotoperiod are highly correlated with changes in the intrinsic timing of the morning offset of secretion and are only weakly correlated with changes in the intrinsic timing of evening onset of secretion. This finding suggests that differences in the way in which individuals are exposed to, or process, morning light may explain differences in their responsiveness to changes in duration of natural and experimental scotoperiods. Although the human RHP axis clearly is capable of detecting changes in the length of the night and in producing the melatonin message that other animals use to trigger seasonal changes in their behavior, it is not yet known whether or how the human reproductive system or other systems respond to this message.

 

Melatonin Rhythm in Human Milk.

J Biol Rhythms.
1997 Dec;12(6):518-27.
Melatonin and seasonal rhythms.Wehr TA.Clinical Psychobiology Branch, National Institute of Mental Health, Bethesda, MD 20892-1390, USA.The pineal hormone melatonin plays a ubiquitous role in biology as a chemical mediator of the effects of season on animal physiology and behavior. Seasonal changes in night length (scotoperiod) induce parallel changes in the duration of melatonin secretion (which occurs exclusively at night), so that it is longer in winter and shorter in summer. These changes in duration of nocturnal melatonin secretion, in turn, trigger seasonal changes in behavior. The retinohypothalamic-pineal (RHP) axis`s responses to light are highly conserved in humans. Like other animals, humans secrete melatonin exclusively at night, and they interrupt its secretion when they are exposed to light during the nocturnal period of its secretion. In many individuals, the RHP axis also is capable of detecting changes in the length of the night and making proportional adjustments in the duration of nocturnal melatonin secretion, producing the type of melatonin message that animals use to trigger seasonal changes in their behavior. This has been shown both in naturalistic studies in which melatonin profiles were compared in summer and winter and in experimental studies in which melatonin profiles were compared after chronic exposure to long and short artificial “nights.” Individuals who live in modern urban environments differ in the degree to which, or even whether, the intrinsic duration of melatonin secretion (the duration measured in constant dim light) responds to seasonal changes in the length of the solar night. Changes in the intrinsic duration of melatonin secretion that are induced by changes in the scotoperiod are highly correlated with changes in the intrinsic timing of the morning offset of secretion and are only weakly correlated with changes in the intrinsic timing of evening onset of secretion. This finding suggests that differences in the way in which individuals are exposed to, or process, morning light may explain differences in their responsiveness to changes in duration of natural and experimental scotoperiods. Although the human RHP axis clearly is capable of detecting changes in the length of the night and in producing the melatonin message that other animals use to trigger seasonal changes in their behavior, it is not yet known whether or how the human reproductive system or other systems respond to this message. 
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