A pilot study of light exposure as a countermeasure for menstrual phase-dependent neurobehavioral performance impairment in women.

OBJECTIVE: To examine effects of menstrual phase and nighttime light exposure on subjective sleepiness and auditory Psychomotor Vigilance Task performance. METHODS: Twenty-nine premenopausal women (12 =Follicular; 17 =Luteal) completed a 6.5-hour nighttime monochromatic light exposure with varying wavelengths (420-620 nm) and irradiances (1.03-14.12 µW/cm2). Subjective sleepiness, reaction time, and attentional lapses were compared between menstrual phases in women with minimal (<33%) or substantial (≥33%) light-induced melatonin suppression. RESULTS: When melatonin was not suppressed, women in the follicular phase had significantly worse reaction time (mean difference=145.1 ms, 95% CI 51.8-238.3, p < .001, Cohen's D=1.9) and lapses (mean difference=12.9 lapses, 95% CI 4.37-21.41, p < .001, Cohen's D=1.7) compared to women in the luteal phase. When melatonin was suppressed, women in the follicular phase had significantly better reaction time (mean difference=152.1 ms, 95% CI 43.88-260.3, p < .001, Cohen's D=1.7) and lapses (mean difference=12.3 lapses, 95% CI 1.14-25.6, p < .01, Cohen's D=1.6) compared to when melatonin was not suppressed, such that their performance was not different (p > .9) from women in the luteal phase. Subjective sleepiness did not differ by menstrual phase (mean difference=0.6, p > .08) or melatonin suppression (mean difference=0.2, p > .4). CONCLUSIONS: Nighttime light exposure sufficient to suppress melatonin can also mitigate neurobehavioral performance deficits associated with the follicular phase. Despite the relatively small sample size, these data suggest that nighttime light may be a valuable strategy to help reduce errors and accidents in female shift workers.

The spectral sensitivity of human circadian phase resetting and melatonin suppression to light changes dynamically with light duration.

Human circadian, neuroendocrine, and neurobehavioral responses to light are mediated primarily by melanopsin-containing intrinsically-photosensitive retinal ganglion cells (ipRGCs) but they also receive input from visual photoreceptors. Relative photoreceptor contributions are irradiance- and duration-dependent but results for long-duration light exposures are limited. We constructed irradiance-response curves and action spectra for melatonin suppression and circadian resetting responses in participants exposed to 6.5-h monochromatic 420, 460, 480, 507, 555, or 620 nm light exposures initiated near the onset of nocturnal melatonin secretion. Melatonin suppression and phase resetting action spectra were best fit by a single-opsin template with lambdamax at 481 and 483 nm, respectively. Linear combinations of melanopsin (ipRGC), short-wavelength (S) cone, and combined long- and medium-wavelength (L+M) cone functions were also fit and compared. For melatonin suppression, lambdamax was 441 nm in the first quarter of the 6.5-h exposure with a second peak at 550 nm, suggesting strong initial S and L+M cone contribution. This contribution decayed over time; lambdamax was 485 nm in the final quarter of light exposure, consistent with a predominant melanopsin contribution. Similarly, for circadian resetting, lambdamax ranged from 445 nm (all three functions) to 487 nm (L+M-cone and melanopsin functions only), suggesting significant S-cone contribution, consistent with recent model findings that the first few minutes of a light exposure drive the majority of the phase resetting response. These findings suggest a possible initial strong cone contribution in driving melatonin suppression and phase resetting, followed by a dominant melanopsin contribution over longer duration light exposures.

Circadian lipid and hepatic protein rhythms shift with a phase response curve different than melatonin.

While studies suggest that light and feeding patterns can reset circadian rhythms in various metabolites, whether these shifts follow a predictable pattern is unknown. We describe the first phase response curves (PRC) for lipids and hepatic proteins in response to combined light and food stimuli. The timing of plasma rhythms was assessed by constant routine before and after exposure to a combined 6.5-hour blue light exposure and standard meal schedule, which was systematically varied by ~20° between in0000dividuals. We find that the rhythms shift according to a PRC, with generally greater shifts for lipids and liver proteins than for melatonin. PRC timing varies relative to the stimulus, with albumin and triglyceride PRCs peaking at a time similar to melatonin whereas the cholesterol and high-density lipoprotein PRCs are offset by ~12 h. These data have important implications for treating circadian misalignment in shiftworkers who consume meals and are exposed to light around the clock.

Modeling Neurocognitive Decline and Recovery During Repeated Cycles of Extended Sleep and Chronic Sleep Deficiency.

Study Objectives: Intraindividual night-to-night sleep duration is often insufficient and variable. Here we report the effects of such chronic variable sleep deficiency on neurobehavioral performance and the ability of state-of-the-art models to predict these changes. Methods: Eight healthy males (mean age ± SD: 23.9 ± 2.4 years) studied at our inpatient intensive physiologic monitoring unit completed an 11-day protocol with a baseline 10-hour sleep opportunity and three cycles of two 3-hour time-in-bed (TIB) and one 10-hour TIB sleep opportunities. Participants received one of three polychromatic white light interventions (200 lux 4100K, 200 or 400 lux 17000K) for 3.5 hours on the morning following the second 3-hour TIB opportunity each cycle. Neurocognitive performance was assessed using the psychomotor vigilance test (PVT) administered every 1-2 hours. PVT data were compared to predictions of five group-average mathematical models that incorporate chronic sleep loss functions. Results: While PVT performance deteriorated cumulatively following each cycle of two 3-hour sleep opportunities, and improved following each 10-hour sleep opportunity, performance declined cumulatively throughout the protocol at a more accelerated rate than predicted by state-of-the-art group-average mathematical models. Subjective sleepiness did not reflect performance. The light interventions had minimal effect. Conclusions: Despite apparent recovery following each extended sleep opportunity, residual performance impairment remained and deteriorated rapidly when rechallenged with subsequent sleep loss. None of the group-average models were capable of predicting both the build-up in impairment and recovery profile of performance observed at the group or individual level, raising concerns regarding their use in real-world settings to predict performance and improve safety.

Transcranial bright light treatment via the ear canals in seasonal affective disorder: a randomized, double-blind dose-response study.

BACKGROUND: Bright light treatment is effective for seasonal affective disorder (SAD), although the mechanisms of action are still unknown. We investigated whether transcranial bright light via the ear canals has an antidepressant effect in the treatment of SAD. METHODS: During the four-week study period, 89 patients (67 females; 22 males, aged 22-65, mean ± SD age: 43.2 ± 10.9 years) suffering from SAD were randomized to receive a 12-min daily dose of photic energy of one of three intensities (1 lumen/0.72 mW/cm(2); 4 lumens/2.881 mW/cm(2); 9 lumens/6.482 mW/cm(2)) via the ear canals. The light was produced using light-emitting diodes. The severity of depressive symptoms was assessed with the Hamilton Depression Rating Scale - Seasonal Affective Disorder (SIGH-SAD), the Hamilton Anxiety Rating Scale (HAMA), and the Beck Depression Inventory (BDI). Cognitive performance was measured by the Trail Making Test (TMT). The within-group and between-group changes in these variables throughout the study were analysed with a repeated measures analysis of variance (ANOVA), whereas gender differences at baseline within the light groups were analysed using Student's t-tests. RESULTS: Patients in all three groups showed significant decreases in their BDI, HAMA, and SIGH-SAD scores. Response rates, i.e., an at least 50% decrease of symptoms as measured by the BDI, were 74%-79% in the three treatment groups. Corresponding variations for the SIGH-SAD and the HAMA were 35-45% and 47-62%, respectively. No intensity-based dose-response relationships in the improvement of anxiety and depressive symptoms or cognitive performance between treatment groups were observed. Approximately one in four patients experienced mild adverse effects, of which the most common were headache, insomnia, and nausea. CONCLUSIONS: These results suggests that transcranial bright light treatment may have antidepressant and anxiolytic effect in SAD patients, as both self- and psychiatrist-rated depressive and anxiety symptoms decreased in all treatment groups. These improvements are comparable to findings of earlier bright light studies that used conventional devices. The lack of dose response may be due to a saturation effect above a certain light intensity threshold. Further studies on the effects of transcranial bright light with an adequate placebo condition are needed. TRIAL REGISTRATION: NCT01293409, ClinicalTrials.gov.

Transcranial bright light exposure via ear canals does not suppress nocturnal melatonin in healthy adults--a single-blind, sham-controlled, crossover trial.

We investigated whether transcranial bright light (TBL) affects nocturnal melatonin and cortisol secretion in sham-controlled crossover trial. Young healthy adults were exposed in random order to 24 minutes of TBL or sham exposure via ear canals at 01:10 h. Saliva and urine samples were collected hourly between 21 h-03 h and 06 h-09 h. There were no significant differences in melatonin or cortisol concentrations between TBL and sham exposures at any sampling point indicating that TBL via ear canals does not suppress nocturnal melatonin secretion. Thus, non-visual effects of TBL are mediated via a pathway not involving melatonin suppression.

Human phase response curve to a single 6.5 h pulse of short-wavelength light.

The photic resetting response of the human circadian pacemaker depends on the timing of exposure, and the direction and magnitude of the resulting shift is described by a phase response curve (PRC). Previous PRCs in humans have utilized high-intensity polychromatic white light. Given that the circadian photoreception system is maximally sensitive to short-wavelength visible light, the aim of the current study was to construct a PRC to blue (480 nm) light and compare it to a 10,000 lux white light PRC constructed previously using a similar protocol. Eighteen young healthy participants (18-30 years) were studied for 9-10 days in a time-free environment. The protocol included three baseline days followed by a constant routine (CR) to assess initial circadian phase. Following this CR, participants were exposed to a 6.5 h 480 nm light exposure (11.8 µW cm(-2), 11.2 lux) following mydriasis via a modified Ganzfeld dome. A second CR was conducted following the light exposure to re-assess circadian phase. Phase shifts were calculated from the difference in dim light melatonin onset (DLMO) between CRs. Exposure to 6.5 h of 480 nm light resets the circadian pacemaker according to a conventional type 1 PRC with fitted maximum delays and advances of -2.6 h and 1.3 h, respectively. The 480 nm PRC induced ∼75% of the response of the 10,000 lux white light PRC. These results may contribute to a re-evaluation of dosing guidelines for clinical light therapy and the use of light as a fatigue countermeasure.

Effects of circadian disruption on the cardiometabolic system.

The presence of day-night variations in cardiovascular and metabolic functioning is well known. However, only recently it has been shown that cardiovascular and metabolic processes are not only affected by the behavioral sleep/wake cycle but are partly under direct control of the master circadian pacemaker located in the suprachiasmatic nucleus (SCN). Heart rate, cardiac autonomic activity, glucose metabolism and leptin-involved in appetite control-all show circadian variation (i.e., under constant behavioral and environmental conditions). This knowledge of behavioral vs. circadian modulation of cardiometabolic function is of clinical relevance given the morning peak in adverse cardiovascular incidents observed in epidemiological studies and given the increased risk for the development of diabetes, obesity, and cardiovascular disease in shift workers. We will review the evidence for circadian control of cardiometabolic functioning, as well its sensitivity to light and melatonin, and discuss potential implication for therapy.

Time-of-day-dependent effects of bright light exposure on human psychophysiology: comparison of daytime and nighttime exposure.

Bright light can influence human psychophysiology instantaneously by inducing endocrine (suppression of melatonin, increasing cortisol levels), other physiological changes (enhancement of core body temperature), and psychological changes (reduction of sleepiness, increase of alertness). Its broad range of action is reflected in the wide field of applications, ranging from optimizing a work environment to treating depressed patients. For optimally applying bright light and understanding its mechanism, it is crucial to know whether its effects depend on the time of day. In this paper, we report the effects of bright light given at two different times of day on psychological and physiological parameters. Twenty-four subjects participated in two experiments (n = 12 each). All subjects were nonsmoking, healthy young males (18-30 yr). In both experiments, subjects were exposed to either bright light (5,000 lux) or dim light <10 lux (control condition) either between 12:00 P.M. and 4:00 P.M. (experiment A) or between midnight and 4:00 A.M. (experiment B). Hourly measurements included salivary cortisol concentrations, electrocardiogram, sleepiness (Karolinska Sleepiness Scale), fatigue, and energy ratings (Visual Analog Scale). Core body temperature was measured continuously throughout the experiments. Bright light had a time-dependent effect on heart rate and core body temperature; i.e., bright light exposure at night, but not in daytime, increased heart rate and enhanced core body temperature. It had no significant effect at all on cortisol. The effect of bright light on the psychological variables was time independent, since nighttime and daytime bright light reduced sleepiness and fatigue significantly and similarly.

Weak relationships between suppression of melatonin and suppression of sleepiness/fatigue in response to light exposure.

In this paper we examine the relationship between melatonin suppression and reduction of sleepiness through light by comparing three different data sets. In total 36 subjects participated in three studies and received 4 h of bright light either from midnight till 4:00 hours (experiments A and B) or from noon till 16:00 hours (experiment C). In experiment A (night-time light, partial illumination of the retina, pupil dilated) subjects were exposed to either 100 lx of ocular light on the temporal, 100 lx on the nasal part of the retina, or <10 lx of dim light on the whole retina. In experiments B (night-time light, whole retina, pupil not dilated) and C (daytime light, whole retina, pupil not dilated) subjects were exposed either to bright (5000 lx) or to dim light (<10 lx). Subjective sleepiness/fatigue and melatonin concentrations in saliva were assessed hourly in all three experiments. For experiment A, a significant suppression of melatonin due to nasal and temporal illumination of the retina was found, that was not accompanied by a detectable reduction of subjective sleepiness/fatigue. For experiment B we found a suppression of melatonin that was paralleled with a significant reduction in subjective sleepiness, but not in fatigue. During experiment C we found no melatonin suppression but a reduction of subjective sleepiness, but also no effect on fatigue. From these data we conclude that the effects of light on sleepiness/fatigue are not mediated by melatonin and that the influence of endogenous melatonin concentration on sleepiness/fatigue is restricted.

Nasal versus temporal illumination of the human retina: effects on core body temperature, melatonin, and circadian phase.

The mammalian retina contains both visual and circadian photoreceptors. In humans, nocturnal stimulation of the latter receptors leads to melatonin suppression, which might cause reduced nighttime sleepiness. Melatonin suppression is maximal when the nasal part of the retina is illuminated. Whether circadian phase shifting in humans is due to the same photoreceptors is not known. The authors explore whether phase shifts and melatonin suppression depend on the same retinal area. Twelve healthy subjects participated in a within-subjects design and received all of 3 light conditions--1) 10 lux of dim light on the whole retina, 2) 100 lux of ocular light on the nasal part of the retina, and 3) 100 lux of ocular light on the temporal part of the retina--on separate nights in random order. In all 3 conditions, pupils were dilated before and during light exposure. The protocol consisted of an adaptation night followed by a 23-h period of sustained wakefulness, during which a 4-h light pulse was presented at a time when maximal phase delays were expected. Nasal illumination resulted in an immediate suppression of melatonin but had no effect on subjective sleepiness or core body temperature (CBT). Nasal illumination delayed the subsequent melatonin rhythm by 78 min, which is significantly (p= 0.016) more than the delay drift in the dim-light condition (38 min), but had no detectable phase-shifting effect on the CBT rhythm. Temporal illumination suppressed melatonin less than the nasal illumination and had no effect on subjective sleepiness and CBT. Temporal illumination delayed neither the melatonin rhythm nor the CBT rhythm. The data show that the suppression of melatonin does not necessarily result in a reduction of subjective sleepiness and an elevation ofCBT. In addition, 100 lux of bright white light is strong enough to affect the photoreceptors responsible for the suppression of melatonin but not strong enough to have a significant effect on sleepiness and CBT. This may be due to the larger variability of the latter variables.

Acute and phase-shifting effects of ocular and extraocular light in human circadian physiology.

Light can influence physiology and performance of humans in two distinct ways. It can acutely change the level of physiological and behavioral parameters, and it can induce a phase shift in the circadian oscillators underlying variations in these levels. Until recently, both effects were thought to require retinal light perception. This view was challenged by Campbell and Murphy, who showed significant phase shifts in core body temperature and melatonin using an extraocular stimulus. Their study employed popliteal skin illumination and exclusively considered phase-shifting effects. In this paper, the authors explore both acute effects and phase-shifting effects of ocular as well as extraocular light. Twelve healthy males participated in a within-subject design and received all of three light conditions--(1) dim ocular light/no light to the knee, (2) dim ocular light/bright extraocular light to the knee, and (3) bright ocular light/no light to the knee--on separate nights in random order. The protocol consisted of an adaptation night followed by a 26-h period of sustained wakefulness, during which a 4-h light pulse was presented at a time when maximal phase delays were expected. The authors found neither immediate nor phase-shifting effects of extraocular light exposure on melatonin, core body temperature (CBT), or sleepiness. Ocular bright-light exposure reduced the nocturnal circadian drop in CBT, suppressed melatonin, and reduced sleepiness significantly. In addition, the 4-h ocular light pulse delayed the CBT rhythm by -55 min compared to the drift of the CBT rhythm in dim light. The melatonin rhythm shifted by -113 min, which differed significantly from the drift in the melatonin rhythm in the dim-light condition (-26 min). The failure to find immediate or phase-shifting effects in response to extraocular light in a within-subjects design in which effects of ocular bright light are confirmed strengthens the doubts raised by other labs of the impact of extraocular light on the human circadian system.