Bright Light Increases Alertness and Not Cortisol in Healthy Men: A Forced Desynchrony Study Under Dim and Bright Light (I).

Light-induced improvements in alertness are more prominent during nighttime than during the day, suggesting that alerting effects of light may depend on internal clock time or wake duration. Relative contributions of both factors can be quantified using a forced desynchrony (FD) designs. FD designs have only been conducted under dim light conditions (<10 lux) since light above this amount can induce non-uniform phase progression of the circadian pacemaker (also called relative coordination). This complicates the mathematical separation of circadian clock phase from homeostatic sleep pressure effects. Here we investigate alerting effects of light in a novel 4 × 18 h FD protocol (5 h sleep, 13 h wake) under dim (6 lux) and bright light (1300 lux) conditions. Hourly saliva samples (melatonin and cortisol assessment) and 2-hourly test sessions were used to assess effects of bright light on subjective and objective alertness (electroencephalography and performance). Results reveal (1) stable free-running cortisol rhythms with uniform phase progression under both light conditions, suggesting that FD designs can be conducted under bright light conditions (1300 lux), (2) subjective alerting effects of light depend on elapsed time awake but not circadian clock phase, while (3) light consistently improves objective alertness independent of time awake or circadian clock phase. Reconstructing the daily time course by combining circadian clock phase and wake duration effects indicates that performance is improved during daytime, while subjective alertness remains unchanged. This suggests that high-intensity indoor lighting during the regular day might be beneficial for mental performance, even though this may not be perceived as such.

Bright Light Decreases Peripheral Skin Temperature in Healthy Men: A Forced Desynchrony Study Under Dim and Bright Light (II).

Human thermoregulation is strictly regulated by the preoptic area of the hypothalamus, which is directly influenced by the suprachiasmatic nucleus (SCN). The main input pathway of the SCN is light. Here, thermoregulatory effects of light were assessed in humans in a forced desynchrony (FD) design. The FD experiment was performed in dim light (DL, 6 lux) and bright white light (BL, 1300 lux) in 8 men in a semi-randomized within-subject design. A 4 × 18 h FD protocol (5 h sleep, 13 h wake) was applied, with continuous core body temperature (CBT) and skin temperature measurements at the forehead, clavicles, navel, palms, foot soles and toes. Skin temperature parameters indicated sleep-wake modulations as well as internal clock variations. All distal skin temperature parameters increased during sleep, when CBT decreased. Light significantly affected temperature levels during the wake phase, with decreased temperature measured at the forehead and toes and increased navel and clavicular skin temperatures. These effects persisted when the lights were turned off for sleep. Circadian amplitude of CBT and all skin temperature parameters decreased significantly during BL exposure. Circadian proximal skin temperatures cycled in phase with CBT, while distal skin temperatures cycled in anti-phase, confirming the idea that distal skin regions reflect heat dissipation and proximal regions approximate CBT. In general, we find that increased light intensity exposure may have decreased heat loss in humans, especially at times when the circadian system promotes sleep.

Bright Light During Wakefulness Improves Sleep Quality in Healthy Men: A Forced Desynchrony Study Under Dim and Bright Light (III).

Under real-life conditions, increased light exposure during wakefulness seems associated with improved sleep quality, quantified as reduced time awake during bed time, increased time spent in non-rapid eye movement (NREM) sleep, or increased power of the electroencephalogram delta band (0.5-4 Hz). The causality of these important relationships and their dependency on circadian phase and/or time awake has not been studied in depth. To disentangle possible circadian and homeostatic interactions, we employed a forced desynchrony protocol under dim light (6 lux) and under bright light (1300 lux) during wakefulness. Our protocol consisted of a fast cycling sleep-wake schedule (13 h wakefulness-5 h sleep; 4 cycles), followed by 3 h recovery sleep in a within-subject cross-over design. Individuals (8 men) were equipped with 10 polysomnography electrodes. Subjective sleep quality was measured immediately after wakening with a questionnaire. Results indicated that circadian variation in delta power was only detected under dim light. Circadian variation in time in rapid eye movement (REM) sleep and wakefulness were uninfluenced by light. Prior light exposure increased accumulation of delta power and time in NREM sleep, while it decreased wakefulness, especially during the circadian wake phase (biological day). Subjective sleep quality scores showed that participants rated their sleep quality better after bright light exposure while sleeping when the circadian system promoted wakefulness. These results suggest that high environmental light intensity either increases sleep pressure buildup during wakefulness or prevents the occurrence of micro-sleep, leading to improved quality of subsequent sleep.

Gold, silver or bronze: circadian variation strongly affects performance in Olympic athletes.

The circadian system affects physiological, psychological, and molecular mechanisms in the body, resulting in varying physical performance over the day. The timing and relative size of these effects are important for optimizing sport performance. In this study, Olympic swim times (from 2004 to 2016) were used to determine time-of-day and circadian effects under maximal motivational conditions. Data of athletes who made it to the finals (N = 144, 72 female) were included and normalized on individual levels based on the average swim times over race types (heat, semifinal, and final) per individual for each stroke, distance and Olympic venue. Normalized swim times were analyzed with a linear mixed model and a sine fitted model. Swim performance was better during finals as compared to semi-finals and heats. Performance was strongly affected by time-of-day, showing fastest swim times in the late afternoon around 17:12 h, indicating 0.32% improved performance relative to 08:00 h. This study reveals clear effects of time-of-day on physical performance in Olympic athletes. The time-of-day effect is large, and exceeds the time difference between gold and silver medal in 40%, silver and bronze medal in 64%, and bronze or no medal in 61% of the finals.

Circadian phase resetting in response to light-dark and dark-light transitions.

Phase shifting of circadian systems by light has been attributed both to parametric effects on angular velocity elicited by a tonic response to the luminance level and to nonparametric instantaneous shifts induced by a phasic response to the dark-light (D>L) and light-dark (L>D) transitions. Claims of nonparametric responses are partly based on "step-PRCs," that is, phase response curves derived from such transitions. Step-PRCs in nocturnal mammals show mostly delays after lights-on and advances after lights-off, and therefore appear incompatible with phase delays generated by light around dusk and advances by light around dawn. We have pursued this paradox with 2 experimental protocols in mice. We first use the classic step-PRC protocol on wheel running activity, using the center of gravity as a phase marker to minimize the masking effects of light. The experiment was done for 3 different light intensities (1, 10, and 100 lux). D>L transitions evoke mostly delays and L>D transitions show no clear tendency to either delay or advance. Overall there is little or no circadian modulation. A 2nd protocol aimed to avoid the problem of masking by assessing phase before and after the light stimuli, both in DD. Light stimuli consisted of either a slow light intensity increase over 48 h followed by abruptly switching off the light, or an abrupt switch on followed by a slow decrease toward total darkness during 48 h. If the abrupt transitions were responsible for phase shifting, we expected large differences between the 2 stimuli. Both light stimuli yielded similar PRCs characterized by delays only with circadian modulation. The results can be adequately explained by a model in which all PRCs evoked by steps result in fact from tonic responses to the light following a step-up or preceding a step-down. In this model only the response reduction of tonic velocity change after the 1st hour is taken into account. The data obtained in both experiments are thus compatible with tonic velocity responses. Contrary to standard interpretation of step-PRCs, nonparametric responses to the transitions are unlikely since they would predict delays in response to lights-off, advances in response to lights-on, while the opposite was found. Although such responses cannot be fully excluded, parsimony does not require invocation of a role for transitions, since all the data can readily be explained by tonic velocity (parametric) effects, which must exist because of the dependence of tau on light intensity.

Circadian response reduction in light and response restoration in darkness: a "skeleton" light pulse PRC study in mice (Mus musculus).

Entrainment may involve responses to dawn, to dusk, and to the light in between these transitions. Previous studies showed that the circadian system responds to only 2 light pulses, one at the beginning and one at the end of the day, in a similar way as to a full photoperiod, as long as the photoperiod is less than approximately 1/2 tau. The authors used a double 1-h light pulse protocol with different intervals of darkness in between (1, 2, 4, 7, 10, and 16 h) to study the phase responses of mice. The phase response curves obtained were compared to full light pulse PRCs of corresponding durations. Up to 6 hours, phase responses induced by double light pulses are virtually the same as by a corresponding full light pulse. The authors made a simple phase-only model to estimate the response reduction due to light exposure and response restoration due to dark exposure of the system. In this model, they assumed a 100% contribution of the first 1-h light pulse and fitted the reduction factor for the second light pulse to yield the best fit to the observations. The results suggest that after 1 h of light followed by less than 4 h of darkness, there is a considerable reduction in response to the second light pulse. Full response restoration requires more than 10 h of darkness. To investigate the influence of the duration of light on the response saturation, the authors performed a second series of experiments where the duration of the 2 light pulses was varied from 4 to 60 min each with a fixed duration of the stimulus (4 h). The response to 2 light pulses saturates when they are between 30 and 60 min long. In conclusion, double pulses replace single full light pulses of a corresponding duration of up to 6 h due to a response reduction during light, combined with response restoration during darkness. By the combined response reduction and response restoration, mice can maintain stable entrainment to the external LD cycle without being continuously exposed to it.

Integration of color and intensity increases time signal stability for the human circadian system when sunlight is obscured by clouds.

The mammalian circadian system encodes both absolute levels of light intensity and color to phase-lock (entrain) its rhythm to the 24-h solar cycle. The evolutionary benefits of circadian color-coding over intensity-coding per se are yet far from understood. A detailed characterization of sunlight is crucial in understanding how and why circadian photoreception integrates color and intensity information. To this end, we continuously measured 100 days of sunlight spectra over the course of a year. Our analyses suggest that circadian color-coding may have evolved to cope with cloud-induced variation in light intensity. We proceed to show how an integration of intensity and spectral composition reduces day-to-day variability in the synchronizing signal (Zeitgeber). As a consequence, entrained phase angle of the circadian clock will be more stable, which will be beneficial for the organism. The presented characterization of sunlight dynamics may become important in designing lighting solutions aimed at minimizing the detrimental effects of light at night in modern societies.

Phase and period responses of the circadian system of mice (Mus musculus) to light stimuli of different duration.

To understand entrainment of circadian systems to different photoperiods in nature, it is important to know the effects of single light pulses of different durations on the free-running system. The authors studied the phase and period responses of laboratory mice (C57BL6J//OlaHsd) to single light pulses of 7 different durations (1, 3, 4, 6, 9, 12, and 18 h) given once per 11 days in otherwise constant darkness. Light-pulse duration affected both amplitude and shape of the phase response curve. Nine-hour light pulses yielded the maximal amplitude PRC. As in other systems, the circadian period slightly lengthened following delays and shortened following advances. The authors aimed to understand how different parts of the light signal contribute to the eventual phase shift. When PRCs were plotted using the onset, midpoint, and end of the pulse as a phase reference, they corresponded best with each other when using the mid-pulse. Using a simple phase-only model, the authors explored the possibility that light affects oscillator velocity strongly in the 1st hour and at reduced strength in later hours of the pulse due to photoreceptor adaptation. They fitted models based on the 1-h PRC to the data for all light pulses. The best overall correspondence between PRCs was obtained when the effect of light during all hours after the first was reduced by a factor of 0.22 relative to the 1st hour. For the predicted PRCs, the light action centered on average at 38% of the light pulse. This is close to the reference phase yielding best correspondence at 36% of the pulses. The result is thus compatible with an initial major contribution of the onset of the light pulse followed by a reduced effect of light responsible for the differences between PRCs for different duration pulses. The authors suggest that the mid-pulse is a better phase reference than lights-on to plot and compare PRCs of different light-pulse durations.

Treatment of depression with low-strength transcranial pulsed electromagnetic fields: A mechanistic point of view.

BACKGROUND: Mood disorders constitute a high burden for both patients and society. Notwithstanding the large arsenal of available treatment options, a considerable group of patients does not remit on current antidepressant treatment. There is an urgent need to develop alternative treatment strategies. Recently, low-strength transcranial pulsed electromagnetic field (tPEMF) stimulation has been purported as a promising strategy for such treatment-resistant depression (TRD). The mode of action of this new technique is however largely unknown. METHODS: We searched PubMed for literature reports on the effects of tPEMF and for information regarding its working mechanism and biological substrate. RESULTS: Most studies more or less connect with the major hypotheses of depression and concern the effects of tPEMF on brain metabolism, neuronal connectivity, brain plasticity, and the immune system. Relatively few studies paid attention to the possible chronobiologic effects of electromagnetic fields. LIMITATIONS: We reviewed the literature of a new and still developing field. Some of the reports involved translational studies, which inevitably limits the reach of the conclusions. CONCLUSION: Weak magnetic fields influence divergent neurobiological processes. The antidepressant effect of tPEMF may be specifically attributable to its effects on local brain activity and connectivity.

EEG power density during nap sleep: reflection of an hourglass measuring the duration of prior wakefulness.

The relation between the duration of prior wakefulness and EEG power density during sleep in humans was assessed by means of a study of naps. The duration of prior wakefulness was varied from 2 to 20 hr by scheduling naps at 1000 hr, 1200 hr, 1400 hr, 1600 hr, 1800 hr, 2000 hr, and 0400 hr. In contrast to sleep latencies, which exhibited a minimum in the afternoon, EEG power densities in the delta and theta frequencies were a monotonic function of the duration of prior wakefulness. The data support the hypothesis that EEG power density during non-rapid eye movement sleep is only determined by the prior history of sleep and wakefulness and is not determined by clock-like mechanisms.

Melatonin suppression by light in humans is maximal when the nasal part of the retina is illuminated.

This study investigated whether sensitivity of the nocturnal melatonin suppression response to light depends on the area of the retina exposed. The reason to suspect uneven spatial sensitivity distribution stems from animal work that revealed that retinal ganglion cells projecting to the suprachiasmatic nuclei (SCN) are unequally distributed in several species of mammals. Four distinct areas of the retinas of 8 volunteers were selectively exposed to 500 lux between 1:30 a.m. and 3:30 a.m. Saliva samples were taken before, during, and after light exposure in 1-h intervals. A significant difference in sensitivity was found between exposure of the lateral and nasal parts of the retinas, showing that melatonin suppression is maximal on exposure of the nasal part of the retina. The results imply that artificial manipulation of the circadian pacemaker to alleviate jet lag, to improve alertness in shift workers, and possibly to treat patients suffering from seasonal affective disorder should encompass light exposure of the nasal retina.

Accuracy of circadian entrainment under fluctuating light conditions: contributions of phase and period responses.

The accuracy with which a circadian pacemaker can entrain to an environmental 24-h zeitgeber signal depends on (a) characteristics of the entraining signal and (b) response characteristics and intrinsic stability of the pacemaker itself. Position of the sun, weather conditions, shades, and behavioral variations (eye closure, burrowing) all modulate the light signal reaching the pacemaker. A simple model of a circadian pacemaker allows researchers to explore the impact of these factors on pacemaker accuracy. Accuracy is operationally defined as the reciprocal value of the day-to-day standard deviation of the clock times at which a reference phase (0) is reached. For the purpose of this exploration, the authors used a model pacemaker characterized solely by its momentary phase and momentary velocity. The average velocity determines the time needed to complete one pacemaker cycle and, therefore, is inversely proportional to pacemaker period. The model pacemaker responds to light by shifting phase and/or changing its velocity. The authors assumed further that phase and velocity show small random fluctuations and that the velocity is subject to aftereffects. Aftereffects were incorporated mathematically in a term allowing period to contract exponentially to a stable steady-state value, with a time constant of 69 d in the absence of light. The simulations demonstrate that a pacemaker reaches highest accuracy when it responds to light by simultaneous phase shifts and changes of its velocity. Phase delays need to coincide with slowing down and advances with speeding up; otherwise, no synchronization to the zeitgeber occurs. At maximal accuracy, the changes in velocity are such that the average period of the pacemaker under entrained conditions equals 24 h. The results suggest that during entrainment, the pacemaker adjusts its period to 24 h, after which daily phase shifts to compensate for differences between the periods of the zeitgeber and the clock are no longer necessary. On average, phase shifts compensate for maladjustments of phase and velocity changes compensate for maladjustments of period.

Accuracy of human circadian entrainment under natural light conditions: model simulations.

The patterns of light intensity to which humans expose their circadian pacemakers in daily life are very irregular and vary greatly from day to day. The circadian pacemaker can adjust to such irregular exposure patterns by daily phase shifts, such as summarized in a phase response curve. It is demonstrated in this paper on the basis of computer simulations applying actually recorded human light exposure patterns that the pacemaker can substantially improve its accuracy by an additional response to light: For that purpose, it should additionally change its angular velocity (and consequently its period tau) in response to light. Reductions of tau in response to light in the morning and increases of tau in response to light in the evening can lead to an increase in entrained pacemaker accuracy with about 25%. Circadian pacemakers have evolved as accurate internal representations of external time, and investigated diurnal mammals all seem to respond to light by changing the period of their circadian pacemaker (in addition to shifting phase). The authors suggest that also human circadian systems take advantage of this possibility and that their pacemakers respond to light by shifting phase and changing period. As a consequence of this postulated mechanism, the simulations demonstrate that the period of the pacemaker under normally entrained conditions is 24 h. The maximum accuracy corresponds to a day-to-day standard deviation of the time of phase 0 of circa 15 min. This is considerably more accurate than the light signal humans usually perceive.

Testing the hypothesis of a circadian phase disturbance underlying depressive mood in nonseasonal depression.

In a crossover design, 8 nonseasonal depressed subjects, selected on the presence of diurnal mood variations, and 8 sex- and age-matched controls were exposed to dim light (< 10 lux) in the evening (18:00-21:00 h) and bright light (2500 lux) in the morning (ML, 6:00-9:00 h), to dim light in the morning and bright light in the evening (EL), or to dim light both in the evening and in the morning (DL) during 3 consecutive days in each of these conditions. There were no initial phase differences between depressed and healthy subjects in the timing of dim light melatonin onset, sleep termination, and body temperature. The phase shifts after EL and ML in both healthy and depressed subjects were as expected on the basis of a human phase response curve. On average, there was no therapeutic effect of the light exposure in the depressed patients. Two patients improved, but these effects do not seem to be related to shifts in the circadian system.

Prophylactic treatment of seasonal affective disorder (SAD) by using light visors: bright white or infrared light?

BACKGROUND: Thirty-eight patients with SAD participated in a light visor study addressing two questions. 1. Can the development of a depressive episode be prevented by daily exposure to bright light started before symptom onset in early fall and continued throughout the winter? 2. Does the light have to be visible in order to have beneficial effects? METHODS: Three groups participated in the study: I (n = 14) received bright white light (2500 lux); II, (n = 15) received infrared light (0.18 lux); III (n = 9, control group) did not receive any light treatment at all. RESULTS: Infrared light is just as effective as bright white light. Both are more effective than the control condition. CONCLUSIONS: Light visors can be effectively used to prevent the development of SAD. The fact that exposure to infrared light was as effective as exposure to bright white light questions the specific role of visible light in the treatment of SAD.

Body temperature and mood variations during forced desynchronization in winter depression: a preliminary report.

BACKGROUND: It has been suggested that certain abnormalities (e.g., in phase or amplitude) of the circadian pacemaker underlie seasonal affective disorder. METHODS: One male seasonal affective disorder patient (blind to the study design) participated in two 120-hour forced desynchrony experiments and was subjected to six 20-hour days, once during a depressive episode and once after recovery. Core body temperature was continuously measured. During wakefulness, the Adjective Mood Scale was completed at 2-hour intervals. RESULTS: Sleep-wake as well as pacemaker-related variations of mood were found, both when the subject was depressed and when he was euthymic. Compared with recovery, during the depressive episode the circadian temperature minimum and the circadian mood variation showed phase delays of approximately 1 and 2 hours, respectively. CONCLUSIONS: The data of this first seasonal affective disorder patient, participating in forced desynchrony experiments, may indicate a phase delay of the circadian pacemaker during a seasonal affective disorder episode.

The prevalence of seasonal affective disorder in The Netherlands: a prospective and retrospective study of seasonal mood variation in the general population.

BACKGROUND: The aim of the present study was to assess the prevalence of seasonal affective disorder (SAD) in The Netherlands. METHODS: The subjects (n = 5356), randomly selected from community registers, were given the Seasonal Pattern Assessment Questionnaire and the Centre for Epidemiological Studies Depression Scale over a period of 13 months. The response rate was 52.6%. RESULTS: Three percent of the respondents met the criteria for winter SAD, 0.1% for summer SAD. The criteria for subsyndromal SAD, a milder form of SAD, were met by 8.5%, 0.3% of whom showed a summer pattern. Younger women received a diagnosis of SAD more often than men or older women. CONCLUSIONS: SAD subjects were significantly more often unemployed or on sick leave than other subjects. Respondents who met winter SAD criteria were significantly more depressed than healthy subjects, in both winter and summer. Finally, month of completion had no influence on the number of subjects meeting the SAD criteria.

Extraocular light therapy in winter depression: a double-blind placebo-controlled study.

BACKGROUND: It has been hypothesized that the circadian pacemaker is phase delayed in seasonal affective disorder, (SAD) winter type, and that the phase advance resulting from morning ocular light accounts for the efficacy of light therapy. Extraocular light has been reported to produce phase-shifts of the human circadian pacemaker. This allows a double-blind, placebo-controlled study of light therapy in SAD. METHODS: Twenty-nine SAD patients participated. Clinical state was measured on days 1, 8, and 15 of the protocol. From days 4 through 8, 15 patients (4 M, 11 F) received extraocular light by fiberoptic illumination, and 14 (4 M, 10 F) placebo (no light) in the popliteal fossae, from 8 AM to 11 AM. In the evenings of days 3 and 8, the salivary dim light melatonin onset (DLMO) was assessed. Patients completed daily self-ratings on mood, alertness, and sleep. RESULTS: Both conditions showed a progressive improvement of clinical state over time. Between conditions, no significant differences were observed in clinical scores, the self-ratings on mood and alertness, and in timing of the DLMO before and directly after treatment. CONCLUSIONS: The response to extraocular light therapy in SAD patients did not exceed its placebo effect. Extraocular light did not induce a phase shift of the circadian pacemaker.

All night spectral analysis of EEG sleep in young adult and middle-aged male subjects.

The sleep EEGs of 9 young adult males (age 20-28 years) and 8 middle-aged males (42-56 years) were analyzed by visual scoring and spectral analysis. In the middle-aged subjects power density in the delta, theta and sigma frequencies were attenuated as compared to the young subjects. In both age groups power density in the delta and theta frequencies declined from NREM period 1 to 3. In the sigma frequencies, however, no systematic changes in power density were observed over the sleep episode. In both age groups the decay of EEG power (0.75-7.0 Hz) over successive NREM-REM cycles and the time course of EEG power during NREM sleep was analyzed. The decay rate of both EEG power density over successive NREM-REM cycles and EEG power density during NREM sleep was smaller in the middle-aged subjects than in the young subjects. It is concluded that the age-related differences in human sleep EEG power spectra are not identical to the changes in EEG power spectra observed in the course of the sleep episode. Therefore age-related differences in EEG power spectra cannot be completely explained by assuming a reduced need for sleep in older subjects. The smaller decay rate of EEG power during NREM sleep in the middle-aged subjects is interpreted as a reduced sleep efficiency. The results are discussed in the frame work of the two-process model of sleep regulation.

Sex differences in the sleep EEG of young adults: visual scoring and spectral analysis.

Baseline sleep of 13 men (mean age of 23.5 years) and 15 women (21.9 years) was analyzed. Visual scoring of the electroencephalograms (EEGs) revealed no significant differences between the sexes in the amounts of slow-wave sleep and rapid-eye-movement (REM) sleep. Spectral analysis, however, detected significantly higher power densities during non-REM sleep over a wide frequency range (0.25-11.0 Hz) in the female versus male subjects. Also, during REM sleep, power densities were higher in the females. Analysis of the time course of EEG power density during sleep revealed that the differences between males and females persisted throughout the sleep episode. Comparison of these differences with published data on the effects of sleep deprivation on EEG power spectra did not suggest a common mechanism underlying sleep deprivation effects and the sex difference in sleep EEGs. It is concluded that sex differences in EEG power spectra are not likely to be caused by sex differences in sleep regulatory mechanisms but may, for instance, be caused by sex differences in skull characteristics.