Shadab A. Rahman

Diurnal spectral sensitivity of the acute alerting effects of light.

STUDY OBJECTIVES Previous studies have demonstrated short-wavelength sensitivity for the acute alerting response to nocturnal light exposure. We assessed daytime spectral sensitivity in alertness, performance, and waking electroencephalogram (EEG). DESIGN Between-subjects (n = 8 per group). SETTING Inpatient intensive physiologic monitoring unit. PARTICIPANTS Sixteen healthy young adults (mean age ± standard deviation = 23.8 ± 2.7 y). INTERVENTIONS Equal photon density exposure (2.8 × 10(13) photons/cm(2)/s) to monochromatic 460 nm (blue) or 555 nm (green) light for 6.5 h centered in the middle of the 16-h episode of wakefulness during the biological day. Results were compared retrospectively to 16 individuals who were administered the same light exposure during the night. MEASUREMENTS AND RESULTS Daytime and nighttime 460-nm light exposure significantly improved auditory reaction time (P < 0.01 and P < 0.05, respectively) and reduced attentional lapses (P < 0.05), and improved EEG correlates of alertness compared to 555-nm exposure. Whereas subjective sleepiness ratings did not differ between the two spectral conditions during the daytime (P > 0.05), 460-nm light exposure at night significantly reduced subjective sleepiness compared to 555-nm light exposure at night (P < 0.05). Moreover, nighttime 460-nm exposure improved alertness to near-daytime levels. CONCLUSIONS The alerting effects of short-wavelength 460-nm light are mediated by counteracting both the circadian drive for sleepiness and homeostatic sleep pressure at night, but only via reducing the effects of homeostatic sleep pressure during the day.

Clinical efficacy of dim light melatonin onset testing in diagnosing delayed sleep phase syndrome

BACKGROUND Delayed Sleep Phase Syndrome (DSPS) arises from biological clock desynchrony and accounts for 10% of chronic insomnia patients. Currently DSPS is diagnosed based on sleep/wake cycle disruptions rather than examining the underlying biological clock alterations. The objective of the study was to determine the sensitivity and specificity of the Dim Light Melatonin Onset (DLMO) Test in diagnosing DSPS in a clinical setting. METHODS Fifty-six patients (mean age 28 years) symptomatic of DSPS participated in the study. Following an initial assessment of DSPS using sleep diaries, participants underwent two consecutive nights of polysomnography (PSG), with an imposed sleep period on the second night to demonstrate the delay in the timing of habitual sleep period and to thereby confirm DSPS. Circadian phase delays were also measured using melatonin secretion profiles, and the efficacy of diagnosing DSPS using DLMO was compared to using sleep diaries and PSG. Melatonin secretion was assayed for each individual by ELISA using saliva samples. RESULTS Main outcome measures included the time of melatonin secretion onset, clinical sensitivity and specificity of the DLMO test. The time of melatonin secretion onset was significantly delayed in DSPS patients. Clinical sensitivity and specificity of the DLMO test in diagnosing DSPS were 90.3% and 84.0%, respectively. CONCLUSIONS The DLMO test is an accurate tool for differentiating between sleep disorder patients with or without underlying circadian rhythm disruption. It is effective for phase typing DSPS patients in a clinical setting.

Antidepressant action of melatonin in the treatment of Delayed Sleep Phase Syndrome

BACKGROUND Depression is a common problem in patients with Delayed Sleep Phase Syndrome (DSPS). This study used a randomized, double-blind, crossover, placebo-controlled approach to test the hypothesis that exogenous melatonin (5mg) can attenuate depressive symptomatology in DSPS patients. METHODS Twenty patients with an established diagnosis of DSPS were dichotomized into DSPS with depressive symptoms (Group I; n=8) and without depressive symptoms (Group II; n=12) based on structured clinical interviews and a score greater than 17 on Center for Epidemiologic Studies Depression Scale (CES-D). Both groups received melatonin and placebo treatment for 4 weeks with a 1-week washout period in between. Participants underwent a clinical interview and psychometric evaluation to assess depression, and overnight polysomnographic sleep studies were carried out at baseline and at the end of melatonin and placebo treatments. Furthermore, melatonin secretion rhythm as a circadian phase marker was assessed by measuring urinary 6-sulphatoxymelatonin levels. RESULTS Melatonin treatment significantly reduced depression scores in the depressed patients as measured by the CES-D and Hamilton Depression Rating Scale--17. Melatonin treatment improved sleep continuity in both groups compared to placebo and baseline conditions. Group I individuals showed marked alterations in melatonin rhythms compared to Group II individuals. CONCLUSION Exogenous melatonin treatment may be an effective treatment modality for individuals with circadian rhythm sleep disorders and associated comorbid depressive symptomatology.

Spectral modulation attenuates molecular, endocrine, and neurobehavioral disruption induced by nocturnal light exposure

The human eye serves distinctly dual roles in image forming (IF) and non-image-forming (NIF) responses when exposed to light. Whereas IF responses mediate vision, the NIF responses affect various molecular, neuroendocrine, and neurobehavioral variables. NIF responses can have acute and circadian phase-shifting effects on physiological variables. Both the acute and phase-shifting effects induced by photic stimuli demonstrate short-wavelength sensitivity peaking ≈450-480 nm. In the current study, we examined the molecular, neuroendocrine, and neurobehavioral effects of completely filtering (0% transmission) all short wavelengths <480 nm and all short wavelengths <460 nm or partially filtering (~30% transmission) <480 nm from polychromatic white light exposure between 2000 and 0800 in healthy individuals. Filtering short wavelengths <480 nm prevented nocturnal light-induced suppression of melatonin secretion, increased cortisol secretion, and disrupted peripheral clock gene expression. Furthermore, subjective alertness, mood, and errors on an objective vigilance task were significantly less impaired at 0800 by filtering wavelengths <480 nm compared with unfiltered nocturnal light exposure. These changes were not associated with significantly increased sleepiness or fatigue compared with unfiltered light exposure. The changes in molecular, endocrine, and neurobehavioral processes were not significantly improved by completely filtering <460 nm or partially filtering <480 nm compared with unfiltered nocturnal light exposure. Repeated light-dark cycle alterations as in rotating nightshifts can disrupt circadian rhythms and induce health disorders. The current data suggest that spectral modulation may provide an effective method of regulating the effects of light on physiological processes.

Endogenous circadian regulation of pro-inflammatory cytokines and chemokines in the presence of bacterial lipopolysaccharide in humans.

Various aspects of immune response exhibit 24-hour variations suggesting that infection susceptibility and treatment efficacy may vary by time of day. Whether these 24-hour variations are endogenous or evoked by changes in environmental or behavioral conditions is not known. We assessed the endogenous circadian control and environmental and behavioral influences on ex-vivo lipopolysaccharide stimulation of whole blood in thirteen healthy participants under 48 hours of baseline conditions with standard sleep-wake schedules and 40–50 hours of constant environmental and behavioral (constant routine; CR) conditions. Significant 24-hour rhythms were observed under baseline conditions in Monocyte Chemotactic Protein, Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin 8 but not Tumor Necrosis Factor alpha whereas significant 24-hour rhythms were observed in all four immune factors under CR conditions. The rhythm amplitudes, expressed as a percentage of mean, were comparable between immune factors and across conditions. In contrast, the acrophase time (time of the fitted peak) was different between immune factors, and included daytime and nighttime peaks and changes across behavioral conditions. These results suggest that the endogenous circadian system underpins the temporal organization of immune responses in humans with additional effects of external environmental and behavioral cycles. These findings have implications for understanding the adverse effects of recurrent circadian disruption and sleep curtailment on immune function.

Selectively Filtering Short Wavelengths Attenuates the Disruptive Effects of Nocturnal Light on Endocrine and Molecular Circadian Phase Markers in Rats

Various physiological processes exhibit a circadian rhythm synchronized to the geophysical light/dark cycle. Our study using a rat model demonstrated that exposure to light at night suppressed the expected nocturnal rise in melatonin, increased plasma corticosterone, and disrupted core clock gene expression in the hypothalamus and the adrenal gland. These effects were prevented by filtration of a 10-nm bandwidth of light between 470 and 480 nm, whereas filtration of light between 452 and 462 nm prevented the rise of corticosterone without restoring normal melatonin secretion or hypothalamic clock gene expression. This is the first demonstration of a wavelength dependency of glucocorticoid secretion and clock gene expression. Our results in an animal model suggest that filtering a narrow bandwidth of light from nocturnal lighting may efficiently attenuate overall disruption of circadian endocrine rhythms and clock gene expression in the hypothalamus and adrenal gland. Because a narrow bandwidth of light is filtered, the color distribution of the illumination source is not altered, and this may be of practical importance for potential future studies in shift workers.

Prevention of melatonin suppression by nocturnal lighting : relevance to cancer

The decreased melatonin production in humans and animals caused by environmental lighting, especially short wavelength lighting (between 470 and 525 nm) has been shown to be associated with an increased risk of cancer. The purpose of this study was to investigate whether blocking light in this wavelength range under bright light may prevent the suppression of melatonin, which could help to prevent cancer. Optical filter lenses were designed, allowing selective exclusion of all wavelengths below 530 nm. Salivary melatonin levels were measured under dim light (<5 lux), bright light (800 lux) and filtered light (800 lux) at hourly intervals between 2000 and 0800 h in 11 healthy young male participants (mean age 23.5±1.5 years). The measurements were taken during three nonconsecutive nights over a 2-week period. The Dim Light Melatonin Onset test was used as a marker of circadian phase. Nine of the 11 participants demonstrated preserved melatonin levels in filtered light similar to their dim light secretion profile. With filtered light, the participants had a mean relative amount of melatonin of 91.2 (P>0.05 between dim light and experimental condition). Unfiltered bright light drastically suppressed melatonin production with a mean relative amount of melatonin of 25.4 (P<0.05 between dim light and experimental condition). Preventing melatonin deficiencies using lenses that block light of low wavelength from reaching the retina presents a cost-effective, practical solution to the problem of increased malignancy rates in shift workers.

Effects of Filtering Visual Short Wavelengths During Nocturnal Shiftwork on Sleep and Performance

Circadian phase resetting is sensitive to visual short wavelengths (450–480 nm). Selectively filtering this range of wavelengths may reduce circadian misalignment and sleep impairment during irregular light-dark schedules associated with shiftwork. We examined the effects of filtering short wavelengths (<480 nm) during night shifts on sleep and performance in nine nurses (five females and four males; mean age ± SD: 31.3 ± 4.6 yrs). Participants were randomized to receive filtered light (intervention) or standard indoor light (baseline) on night shifts. Nighttime sleep after two night shifts and daytime sleep in between two night shifts was assessed by polysomnography (PSG). In addition, salivary melatonin levels and alertness were assessed every 2 h on the first night shift of each study period and on the middle night of a run of three night shifts in each study period. Sleep and performance under baseline and intervention conditions were compared with daytime performance on the seventh day shift, and nighttime sleep following the seventh daytime shift (comparator). On the baseline night PSG, total sleep time (TST) (p < 0.01) and sleep efficiency (p = 0.01) were significantly decreased and intervening wake times (wake after sleep onset [WASO]) (p = 0.04) were significantly increased in relation to the comparator night sleep. In contrast, under intervention, TST was increased by a mean of 40 min compared with baseline, WASO was reduced and sleep efficiency was increased to levels similar to the comparator night. Daytime sleep was significantly impaired under both baseline and intervention conditions. Salivary melatonin levels were significantly higher on the first (p < 0.05) and middle (p < 0.01) night shifts under intervention compared with baseline. Subjective sleepiness increased throughout the night under both conditions (p < 0.01). However, reaction time and throughput on vigilance tests were similar to daytime performance under intervention but impaired under baseline on the first night shift. By the middle night shift, the difference in performance was no longer significant between day shift and either of the two night shift conditions, suggesting some adaptation to the night shift had occurred under baseline conditions. These results suggest that both daytime and nighttime sleep are adversely affected in rotating-shift workers and that filtering short wavelengths may be an approach to reduce sleep disruption and improve performance in rotating-shift workers. (Author correspondence: casper@lunenfeld.ca)

Temporal Dynamics of Ocular Indicators of Sleepiness across Sleep Restriction

The current study characterized the temporal dynamics of ocular indicators of sleepiness during extended sleep restriction. Ten male participants (mean age ± SD = 23.3 ± 1.6 years) underwent 40 h of continuous wakefulness under constant routine (CR) conditions; they completed the Karolinska Sleepiness Scale (KSS) and a 10-min auditory psychomotor vigilance task (aPVT) hourly. Waking electroencephalography (EEG) and ocular measures were recorded continuously throughout the CR. Infrared-reflectance oculography was used to collect the ocular measures positive and negative amplitude-velocity ratio, mean blink duration, the percentage of eye closure, and a composite score of sleepiness levels (Johns Drowsiness Scale). All ocular measures, except blink duration, displayed homeostatic and circadian properties. Only circadian effects were detected in blink duration. Significant, phase-locked cross-correlations (p < 0.05) were detected between ocular measures and aPVT reaction time (RT), aPVT lapses, KSS, and EEG delta-theta (0.5-5.5 Hz), theta-alpha (5.0-9.0 Hz), and beta (13.0-20.0 Hz) activity. Receiver operating characteristic curve analysis demonstrated reasonable sensitivity and specificity of ocular measures in correctly classifying aPVT lapses above individual baseline thresholds (initial 16 h of wakefulness). Under conditions of sleep restriction, ocular indicators of sleepiness paralleled performance impairment and self-rated sleepiness levels, and demonstrated their potential to detect sleepiness-related attentional lapses. These findings, if reproduced in a larger sample, will have implications for the use of ocular-based sleepiness-warning systems in operational settings.

The effects of spectral tuning of evening ambient light on melatonin suppression, alertness and sleep

We compared the effects of bedroom-intensity light from a standard fluorescent and a blue- (i.e., short-wavelength) depleted LED source on melatonin suppression, alertness, and sleep. Sixteen healthy participants (8 females) completed a 4-day inpatient study. Participants were exposed to blue-depleted circadian-sensitive (C-LED) light and a standard fluorescent light (FL, 4100K) of equal illuminance (50lx) for 8h prior to a fixed bedtime on two separate days in a within-subject, randomized, cross-over design. Each light exposure day was preceded by a dim light (<3lx) control at the same time 24h earlier. Compared to the FL condition, control-adjusted melatonin suppression was significantly reduced. Although subjective sleepiness was not different between the two light conditions, auditory reaction times were significantly slower under C-LED conditions compared to FL 30min prior to bedtime. EEG-based correlates of alertness corroborated the reduced alertness under C-LED conditions as shown by significantly increased EEG spectral power in the delta-theta (0.5-8.0Hz) bands under C-LED as compared to FL exposure. There was no significant difference in total sleep time (TST), sleep efficiency (SE%), and slow-wave activity (SWA) between the two conditions. Unlike melatonin suppression and alertness, a significant order effect was observed on all three sleep variables, however. Individuals who received C-LED first and then FL had increased TST, SE% and SWA averaged across both nights compared to individuals who received FL first and then C-LED. These data show that the spectral characteristics of light can be fine-tuned to attenuate non-visual responses to light in humans.