Steven W. Lockley

Comparison between subjective and actigraphic measurement of sleep and sleep rhythms

Sleep is often assessed in circadian rhythm studies and long‐term monitoring is required to detect any changes in sleep over time. The present study aims to investigate the ability of the two most commonly employed methods, actigraphy and sleep logs, to identify circadian sleep/wake disorders and measure changes in sleep patterns over time. In addition, the study assesses whether sleep measured by both methods shows the same relationship with an established circadian phase marker, urinary 6‐sulphatoxymelatonin. A total of 49 registered blind subjects with different types of circadian rhythms were studied daily for at least four weeks. Grouped analysis of all study days for all subjects was performed for all sleep parameters (1062–1150 days data per sleep parameter). Good correlations were observed when comparing the measurement of sleep timing and duration (sleep onset, sleep offset, night sleep duration, day‐time nap duration). However, the methods were poorly correlated in their assessment of transitions between sleep and wake states (sleep latency, number and duration of night awakenings, number of day‐time naps). There were also large and inconsistent differences in the measurement of the absolute sleep parameters. Overall, actigraphs recorded a shorter sleep latency, advanced onset time, increased number and duration of night awakenings, delayed offset, increased night sleep duration and increased number and duration of naps compared with the subjective sleep logs. Despite this, there was good agreement between the methods for measuring changes in sleep patterns over time. In particular, the methods agreed when assessing changes in sleep in relation to a circadian phase marker (the 6‐sulphatoxymelatonin (aMT6s) rhythm) in both entrained (n= 30) and free‐running (n= 4) subjects.

Measuring and using light in the melanopsin age

Light is a potent stimulus for regulating circadian, hormonal, and behavioral systems. In addition, light therapy is effective for certain affective disorders, sleep problems, and circadian rhythm disruption. These biological and behavioral effects of light are influenced by a distinct photoreceptor in the eye, melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs), in addition to conventional rods and cones. We summarize the neurophysiology of this newly described sensory pathway and consider implications for the measurement, production, and application of light. A new light-measurement strategy taking account of the complex photoreceptive inputs to these non-visual responses is proposed for use by researchers, and simple suggestions for artificial/architectural lighting are provided for regulatory authorities, lighting manufacturers, designers, and engineers.

Meeting Report: The Role of Environmental Lighting and Circadian Disruption in Cancer and Other Diseases

Light, including artificial light, has a range of effects on human physiology and behavior and can therefore alter human physiology when inappropriately timed. One example of potential light-induced disruption is the effect of light on circadian organization, including the production of several hormone rhythms. Changes in light–dark exposure (e.g., by nonday occupation or transmeridian travel) shift the timing of the circadian system such that internal rhythms can become desynchronized from both the external environment and internally with each other, impairing our ability to sleep and wake at the appropriate times and compromising physiologic and metabolic processes. Light can also have direct acute effects on neuroendocrine systems, for example, in suppressing melatonin synthesis or elevating cortisol production that may have untoward long-term consequences. For these reasons, the National Institute of Environmental Health Sciences convened a workshop of a diverse group of scientists to consider how best to conduct research on possible connections between lighting and health. According to the participants in the workshop, there are three broad areas of research effort that need to be addressed. First are the basic biophysical and molecular genetic mechanisms for phototransduction for circadian, neuroendocrine, and neurobehavioral regulation. Second are the possible physiologic consequences of disrupting these circadian regulatory processes such as on hormone production, particularly melatonin, and normal and neoplastic tissue growth dynamics. Third are effects of light-induced physiologic disruption on disease occurrence and prognosis, and how prevention and treatment could be improved by application of this knowledge.

Efficacy of melatonin treatment in jet lag, shift work, and blindness.

Melatonin has chronobiotic properties in humans. It is able to phase shift strongly endogenous rhythms, such as core temperature and its own endogenous rhythm, together with the sleep-wake cycle. Its ability to synchronize free-running rhythms has not been fully investigated in humans. There is evidence for synchronization of the sleep-wake cycle, but the available data suggest that it is less effective with regard to endogenous melatonin and core temperature rhythms. When suitably timed, most studies indicate that fast release preparations are able to hasten adaptation to phase shift in both field and simulation studies of jet lag and shift work. Both subjective and objective measures support this statement. However, not all studies have been successful. Careful evaluation of the effects on work-related performance is required. When used to alleviate the non-24-h sleep-wake disorder in blind subjects, again most studies report a successful outcome using behavioral measures, albeit in a small number of individuals. The pres suggest, however, that although leep-wake can be stabilized to 24 h, entrainment of other rhythms is exceptionally rare.

Spectral Responses of the Human Circadian System Depend on the Irradiance and Duration of Exposure to Light

Light resets the circadian clock through a non–image-forming receptor system—or so it was thought; now, cone photoreceptors are shown to also participate. Retinal Receptors Conspire to Keep Us Awake Even without an intervening miracle, some blind people can see. When confronted by light, their pupils can constrict, their circadian clocks remain in rhythm, and their blood melatonin is suppressed. Although these people do not detect images of their surroundings—usually conveyed through their missing rods and cones—light still falls on their remaining retina, including special cells that contain a pigment (melanopsin) that receives and transfers blue light, allowing some light-regulated processes to function normally. But new evidence collected by Gooley et al. shows that the distinction between image-forming and non–image-forming sight is more complicated than we have appreciated. The authors carefully examined the light sensitivity of two functions: melatonin suppression and circadian phase control. To this end, they exposed normal individuals to two different wavelengths of light, one designed to be detected by the visual image-forming system and the other by the blue-light receptor melanopsin system. Rather than the expected result—that the non–image-forming responses were induced only by blue-light melanopsin cells—they saw that, at the beginning of the illumination period and at low light levels, the visual system could also drive the non–image-forming endpoints. These findings fit with neuroanatomy; cells that contain the blue-light receptors receive input from cones, which are integral parts of the image-forming system. Furthermore, these findings suggest that we have more to learn about how to optimally activate our light receptors. Indeed, advocates of blue-light therapy for sleep disorders or other ailments will need to rethink their views, as white light may work just as well. And technology addicts beware: The authors suggest that low-light exposure from our computers or indoor lighting late at night may be interfering with our circadian rhythms, making it even harder to get up in the morning. In humans, modulation of circadian rhythms by light is thought to be mediated primarily by melanopsin-containing retinal ganglion cells, not rods or cones. Melanopsin cells are intrinsically blue light–sensitive but also receive input from visual photoreceptors. We therefore tested in humans whether cone photoreceptors contribute to the regulation of circadian and neuroendocrine light responses. Dose-response curves for melatonin suppression and circadian phase resetting were constructed in subjects exposed to blue (460 nm) or green (555 nm) light near the onset of nocturnal melatonin secretion. At the beginning of the intervention, 555-nm light was equally effective as 460-nm light at suppressing melatonin, suggesting a significant contribution from the three-cone visual system (λmax = 555 nm). During the light exposure, however, the spectral sensitivity to 555-nm light decayed exponentially relative to 460-nm light. For phase-resetting responses, the effects of exposure to low-irradiance 555-nm light were too large relative to 460-nm light to be explained solely by the activation of melanopsin. Our findings suggest that cone photoreceptors contribute substantially to nonvisual responses at the beginning of a light exposure and at low irradiances, whereas melanopsin appears to be the primary circadian photopigment in response to long-duration light exposure and at high irradiances. These results suggest that light therapy for sleep disorders and other indications might be optimized by stimulating both photoreceptor systems.

Short-Wavelength Light Sensitivity of Circadian, Pupillary, and Visual Awareness in Humans Lacking an Outer Retina

Summary As the ear has dual functions for audition and balance, the eye has a dual role in detecting light for a wide range of behavioral and physiological functions separate from sight [1–11]. These responses are driven primarily by stimulation of photosensitive retinal ganglion cells (pRGCs) that are most sensitive to short-wavelength (∼480 nm) blue light and remain functional in the absence of rods and cones [8–10]. We examined the spectral sensitivity of non-image-forming responses in two profoundly blind subjects lacking functional rods and cones (one male, 56 yr old; one female, 87 yr old). In the male subject, we found that short-wavelength light preferentially suppressed melatonin, reset the circadian pacemaker, and directly enhanced alertness compared to 555 nm exposure, which is the peak sensitivity of the photopic visual system. In an action spectrum for pupillary constriction, the female subject exhibited a peak spectral sensitivity (λmax) of 480 nm, matching that of the pRGCs but not that of the rods and cones. This subject was also able to correctly report a threshold short-wavelength stimulus (∼480 nm) but not other wavelengths. Collectively these data show that pRGCs contribute to both circadian physiology and rudimentary visual awareness in humans and challenge the assumption that rod- and cone-based photoreception mediate all “visual” responses to light.

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

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 bodys 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.

The 3111 Clock gene polymorphism is not associated with sleep and circadian rhythmicity in phenotypically characterized human subjects

Mutations in clock genes are associated with abnormal circadian parameters, including sleep. An association has been reported previously between a polymorphism (3111C), situated in the 3′‐untranslated region (3′‐UTR) of the circadian gene Clock and evening preference. In the present study, this polymorphism was assessed in: (1) 105 control subjects with defined diurnal preference, (2) 26 blind subjects with free‐running circadian rhythms and characterized with regard to circadian period (τ) and (3) 16 delayed sleep phase syndrome patients. The control group was chosen from a larger population (n = 484) by Horne‐Östberg questionnaire analysis, from which three subgroups were selected (evening, intermediate and morning preference). Data from sleep diaries completed by 90% of these subjects showed a strong correlation between preferred and estimated timings of sleep and wake. The mean timings of activities for the evening group were at least 2 h later than the morning group. Genetic analysis showed that, in contrast with the previously published finding, there was no association between 3111C and eveningness. Neither was there an association between 3111C and τ, nor a significant difference in 3111C frequency between the normal and delayed sleep phase syndrome groups. To assess the effect of this polymorphism on messenger RNA (mRNA) translatability, luciferase reporter gene constructs containing the two Clock polymorphic variants in their 3′‐UTR were transfected into COS‐1 cells and luciferase activity measured. No significant difference was observed between the two variants. These results do not support Clock 3111C as a marker for diurnal preference, τ, or delayed sleep phase syndrome in humans.

Sleep Disorders, Health, and Safety in Police Officers

CONTEXT Sleep disorders often remain undiagnosed. Untreated sleep disorders among police officers may adversely affect their health and safety and pose a risk to the public. OBJECTIVE To quantify associations between sleep disorder risk and self-reported health, safety, and performance outcomes in police officers. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional and prospective cohort study of North American police officers participating in either an online or an on-site screening (n=4957) and monthly follow-up surveys (n=3545 officers representing 15,735 person-months) between July 2005 and December 2007. A total of 3693 officers in the United States and Canada participated in the online screening survey, and 1264 officers from a municipal police department and a state police department participated in the on-site survey. MAIN OUTCOME MEASURES Comorbid health conditions (cross-sectional); performance and safety outcomes (prospective). RESULTS Of the 4957 participants, 40.4% screened positive for at least 1 sleep disorder, most of whom had not been diagnosed previously. Of the total cohort, 1666 (33.6%) screened positive for obstructive sleep apnea, 281 (6.5%) for moderate to severe insomnia, 269 (5.4%) for shift work disorder (14.5% of those who worked the night shift). Of the 4608 participants who completed the sleepiness scale, 1312 (28.5%) reported excessive sleepiness. Of the total cohort, 1294 (26.1%) reported falling asleep while driving at least 1 time a month. Respondents who screened positive for obstructive sleep apnea or any sleep disorder had an increased prevalence of reported physical and mental health conditions, including diabetes, depression, and cardiovascular disease. An analysis of up to 2 years of monthly follow-up surveys showed that those respondents who screened positive for a sleep disorder vs those who did not had a higher rate of reporting that they had made a serious administrative error (17.9% vs 12.7%; adjusted odds ratio [OR], 1.43 [95% CI, 1.23-1.67]); of falling asleep while driving (14.4% vs 9.2%; adjusted OR, 1.51 [95% CI, 1.20-1.90]); of making an error or safety violation attributed to fatigue (23.7% vs 15.5%; adjusted OR, 1.63 [95% CI, 1.43-1.85]); and of exhibiting other adverse work-related outcomes including uncontrolled anger toward suspects (34.1% vs 28.5%; adjusted OR, 1.25 [95% CI, 1.09-1.43]), absenteeism (26.0% vs 20.9%; adjusted OR, 1.23 [95% CI, 1.08-1.40]), and falling asleep during meetings (14.1% vs 7.0%; adjusted OR, 1.95 [95% CI, 1.52-2.52]). CONCLUSION Among a group of North American police officers, sleep disorders were common and were significantly associated with increased risk of self-reported adverse health, performance, and safety outcomes.

Relationship between napping and melatonin in the blind

Daytime sleepiness is a common complaint in blind subjects. Abnor mally timed melatonin has been invoked as a possible cause of both daytime sleepiness and nighttime awakening. In free-running blind individuals, there is an opportunity to assess the relationship between endogenous melatonin rhythms and subjective sleepiness and naps. The aim of this study was to characterize melatonin rhythms and simultaneously to evaluate subjective nap ping. A total of 15 subjects with no conscious light perception (NPL) were studied for 1 month. Prior to the study, sleep disorders were assessed using the Pittsburgh Sleep Quality Index. Cosinor and regression analysis revealed that 9 of the 15 NPL subjects had free-running 6-sulphatoxymelatonin (aMT6s) rhythms (period [τ] range = 24.34 to 24.79 h), 3 were entrained with an abnormal phase, and 3 were normally entrained. Most of the subjects (13 of 15) had daytime naps; the 2 individuals who did not made conscious efforts not to do so. Subjects with abnormal aMT6s rhythms had more naps of a longer duration than did those with normal rhythms. Free-running nap rhythms occurred only in subjects with free-running aMT6s rhythms. The 2 abnormally entrained subjects who napped did so at times that coincided with high levels of aMT6s (mean aMT6s acrophase [phi] ± SD = 14.30 ± 1.08 h, 20.30 ± 0.62 h; mean nap time ± SD = 14.01 ± 3.60 h, 18.23 ± 3.20 h, respectively). Regardless of aMT6s rhythm abnormality, signifi cantly more naps occurred within a 4-h period before and after the estimated aMT6s acrophase. In 4 free-running subjects, aMT6s acrophase (phi) passed through an entire 24-h period. When aMT6s was in a normal phase position (24:00 to 06:00 h), night-sleep duration tended to increase with a significant reduction in the number and duration of naps. Sleep onset and offset times tended to advance and delay as the aMT6s rhythms advanced and delayed. Our results show a striking relationship between the timing of daytime production of melatonin and the timing of daytime naps. This suggests that abnormally timed endogenous melatonin may induce sleepiness in blind subjects.