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Objective: Irregular sleep-wake patterns are associated with poor health outcomes. However, factors that lead individuals to adopt more regular sleep-wake patterns are not well understood. This stu...

Misalignment of circadian timing in patients with depression has commonly been reported, but the underlying mechanisms are not known. Individual differences in the sensitivity of the circadian system to light affect how the biological clock synchronizes with the external environment and can lead to misalignment of rhythms. We investigated the sensitivity of the circadian system to light in unmedicated (for3 months) women with a current or previous diagnosis of major depression, and healthy controls.Baseline melatonin levels in dim light (1 lux) were assessed, followed by melatonin levels in normal indoor lighting of 100 lux in order to determine melatonin suppression.Patients currently experiencing a depressive episode showed significantly lower levels of melatonin suppression to light compared to remitted patients and controls, with large effect sizes. Remitted patients and controls showed similar suppression.The relatively small sample, and lack of long-term, within subject assessments, make it difficult to determine the potential causal role of reduced light sensitivity in the development of circadian disruption.We conclude that hyposensitivity of the circadian system to light may contribute to circadian misalignment in patients with depression. Interventions that increase sensitivity to light or provide stronger light cues may assist in normalizing circadian clock function.

Mood states in bipolar disorder appear to be closely linked to changes in sleep and circadian function. It has been suggested that hypersensitivity of the circadian system to light may be a trait vulnerability for bipolar disorder. Healthy persons with emotional-behavioural traits associated with bipolar disorder also appear to exhibit problems with circadian rhythms, which may be associated with individual differences in light sensitivity. This study investigated the melanopsin-driven post-illumination pupil response (PIPR) in relation to emotional-behavioural traits associated with bipolar disorder (measured with the General Behavior Inventory) in a non-clinical group (n = 61). An increased PIPR was associated with increased bipolar disorder-related traits. Specifically, the hypomania scale of the General Behavior Inventory was associated with an increased post-blue PIPR. Further, both the full hypomania and shortened ‘7 Up’ scales were significantly predicted by PIPR, after age, sex and depressive traits were controlled. These findings suggest that increased sensitivity to light may be a risk factor for mood problems in the general population, and support the idea that hypersensitivity to light is a trait vulnerability for, rather than symptom of, bipolar disorder.

Significance Electric lighting has fundamentally altered how the human circadian clock synchronizes to the day/night cycle. Exposure to light after dusk is pervasive in the modern world. We examined group-level sensitivity of the circadian system to evening light and the degree to which sensitivity varies between individuals. We found that, on average, humans are highly sensitive to evening light. Specifically, 50% suppression of melatonin occurred at 50-fold difference in sensitivity to evening light across individuals. Interindividual differences in light sensitivity may explain differential vulnerability to circadian disruption and subsequent impact on human health., Before the invention of electric lighting, humans were primarily exposed to intense (>300 lux) or dim (

Light improves mood. The amygdala plays a critical role in regulating emotion, including fear-related responses. In rodents the amygdala receives direct light input from the retina, and light may play a role in fear-related learning. A direct effect of light on the amygdala represents a plausible mechanism of action for light’s mood-elevating effects in humans. However, the effect of light on activity in the amygdala in humans is not well understood. We examined the effect of passive dim-to-moderate white light exposure on activation of the amygdala in healthy young adults using the BOLD fMRI response (3T Siemens scanner;n= 23). Participants were exposed to alternating 30s blocks of light (10 lux or 100 lux) and dark (

There is large interindividual variability in circadian timing, which is underestimated by mathematical models of the circadian clock. Interindividual differences in timing have traditionally been modeled by changing the intrinsic circadian period, but recent findings reveal an additional potential source of variability: large interindividual differences in light sensitivity. Using an established model of the human circadian clock with real-world light recordings, we investigated whether changes in light sensitivity parameters or intrinsic circadian period could capture variability in circadian timing between and within individuals. Healthy participants ( n = 12, aged 18-26 years) underwent continuous light monitoring for 3 weeks (Actiwatch Spectrum). Salivary dim-light melatonin onset (DLMO) was measured each week. Using the recorded light patterns, a sensitivity analysis for predicted DLMO times was performed, varying 3 model parameters within physiological ranges: (1) a parameter determining the steepness of the dose-response curve to light ( p), (2) a parameter determining the shape of the phase-response curve to light ( K), and (3) the intrinsic circadian period ( tau). These parameters were then fitted to obtain optimal predictions of the three DLMO times for each individual. The sensitivity analysis showed that the range of variation in the average predicted DLMO times across participants was 0.65 h for p, 4.28 h for K, and 3.26 h for tau. The default model predicted the DLMO times with a mean absolute error of 1.02 h, whereas fitting all 3 parameters reduced the mean absolute error to 0.28 h. Fitting the parameters independently, we found mean absolute errors of 0.83 h for p, 0.53 h for K, and 0.42 h for tau. Fitting p and K together reduced the mean absolute error to 0.44 h. Light sensitivity parameters captured similar variability in phase compared with intrinsic circadian period, indicating they are viable targets for individualizing circadian phase predictions. Future prospective work is needed that uses measures of light sensitivity to validate this approach.

The regular rise and fall of the sun resulted in the development of 24-h rhythms in virtually all organisms. In an evolutionary heartbeat, humans have taken control of their light environment with electric light. Humans are highly sensitive to light, yet most people now use light until bedtime. We evaluated the impact of modern home lighting environments in relation to sleep and individual-level light sensitivity using a new wearable spectrophotometer. We found that nearly half of homes had bright enough light to suppress melatonin by 50%, but with a wide range of individual responses (0–87% suppression for the average home). Greater evening light relative to an individual’s average was associated with increased wakefulness after bedtime. Homes with energy-efficient lights had nearly double the melanopic illuminance of homes with incandescent lighting. These findings demonstrate that home lighting significantly affects sleep and the circadian system, but the impact of lighting for a specific individual in their home is highly unpredictable.

STUDY OBJECTIVES: In patients with delayed sleep-wake phase disorder (DSWPD), the circadian clock may be more easily affected by light at night. This creates a potential vulnerability, whereby individuals with irregular schedules may have less stable circadian rhythms. We investigated the stability of circadian timing and regularity of sleep in patients with DSWPD and healthy controls. METHODS: Participants completed 2 dim-light melatonin onset (DLMO) assessments approximately 2 weeks apart while keeping their habitual sleep/wake schedule. After the second DLMO assessment, light sensitivity was assessed using the phase-resetting response to a 6.5-hour 150-lux stimulus. The change in DLMO timing (DLMO instability) was assessed and related to light sensitivity and the sleep regularity index. RESULTS: Relative to healthy controls, patients with DSWPD had later sleep rhythm timing relative to clock time, earlier sleep rhythm timing relative to DLMO, lower sleep regularity index, and greater DLMO instability. Greater DLMO instability was associated with increased light sensitivity across all participants, but not within groups. CONCLUSIONS: We find that circadian timing is less stable and sleep is less regular in patients with DSWPD, which could contribute to etiology of the disorder. Measures of light sensitivity may be informative in generating DSWPD treatment plans. CITATION: Watson LA, McGlashan EM, Hosken IT, Anderson C, Phillips AJK, Cain SW. Sleep and circadian instability in delayed sleep-wake phase disorder. J Clin Sleep Med. 2020;16(9):1431–1436.

KEY POINTS: This is the first study to demonstrate an altered circadian phase shifting response in a circadian rhythm sleep disorder. Patients with delayed sleep–wake phase disorder (DSWPD) demonstrate greater sensitivity of the circadian system to the phase‐delaying effects of light. Increased circadian sensitivity to light is associated with later circadian timing within both control and DSWPD groups. DSWPD patients had a greater sustained pupil response after light exposure. Treatments for DSWPD should consider sensitivity of the circadian system to light as a potential underlying vulnerability, making patients susceptible to relapse. ABSTRACT: Patients with delayed sleep–wake phase disorder (DSWPD) exhibit delayed sleep–wake behaviour relative to desired bedtime, often leading to chronic sleep restriction and daytime dysfunction. The majority of DSWPD patients also display delayed circadian timing in the melatonin rhythm. Hypersensitivity of the circadian system to phase‐delaying light is a plausible physiological basis for DSWPD vulnerability. We compared the phase shifting response to a 6.5 h light exposure (∼150 lux) between male patients with diagnosed DSWPD (n = 10; aged 20.8 ± 2.3 years) and male healthy controls (n = 11; aged 22.4 ± 3.3 years). Salivary dim light melatonin onset (DLMO) was measured under controlled conditions in dim light (

Disturbances of the circadian system are common in depression. Though they typically subside when depression is treated with antidepressants, the mechanism by which this occurs is unknown. Despite being the most commonly prescribed class of antidepressants, the effect of selective serotonin reuptake inhibitors (SSRIs) on the human circadian clock is not well understood. To examine the effect of the SSRI citalopram (30 mg) on the sensitivity of the human circadian system to light. This study used a double-blind, placebo-controlled, within-subjects, crossover design. Participants completed two melatonin suppression assessments in room level light (~ 100 lx), taking either a single dose of citalopram 30 mg or a placebo at the beginning of each light exposure. Melatonin suppression was calculated by comparing placebo and citalopram light exposure conditions to a dim light baseline. A 47% increase in melatonin suppression was observed after administration of an acute dose of citalopram, with all participants showing more suppression after citalopram administration (large effect, d = 1.54). Further, melatonin onset occurred later under normal room light with citalopram compared to placebo. Increased sensitivity of the circadian system to light could assist in explaining some of the inter-individual variability in antidepressant treatment responses, as it is likely to assist in recovery in some patients, while causing further disruption for others.

Light is a variable of key interest in circadian rhythms research, commonly measured using wrist-worn sensors. The GENEActiv Original is a cost-effective and practical option for assessing light in ambulatory settings. With increasing research on health and well-being incorporating sleep and circadian factors, the validity of wearable devices for assessing light environments needs to be evaluated. In this study, we tested the accuracy of the GENEActiv Original devices (n = 10) for recording light under a range of ecologically relevant lighting conditions, including LED, fluorescent, infrared, and outdoor lighting. The GENEActiv output had a strong linear relationship with photopic illuminance. However, the devices consistently under-reported photopic illuminance, especially below 100 lux. Accuracy below 100 lux depended on the light source, with lower accuracy and higher variability under fluorescent lighting. The device&rsquo, s accuracy was also tested using light sources of varying spectral composition, which indicated that the device tends to under-report photopic illuminance for green light sources and over-report for red light sources. Furthermore, measures of photopic illuminance were impacted by infrared light exposure. We conclude that the GENEActiv Original is suitable for mapping light patterns within an individual context, and can reasonably differentiate indoor vs. outdoor lighting, though the accuracy is variable at low light conditions. Given the human circadian system&rsquo, s high sensitivity to light levels below 100 lux, if using the GENEActiv Original, we recommend also collecting light source data to better understand the impact on the circadian system, especially where participants spend prolonged periods in dim lighting.

Studies on circadian timing in depression have produced variable results, with some investigations suggesting phase advances and others phase delays. This variability may be attributable to differences in participant diagnosis, medication use, and methodology between studies. This study examined circadian timing in a sample of unmedicated women with and without unipolar major depressive disorder. Participants were aged 18-28 years, had no comorbid medical conditions, and were not taking medications. Eight women were experiencing a major depressive episode, nine had previously experienced an episode, and 31 were control participants with no history of mental illness. Following at least one week of actigraphic sleep monitoring, timing of salivary dim light melatonin onset (DLMO) was assessed in light of

Introduction Existing models of the human circadian clock accurately predict phase at group-level but not at individual-level. Interindividual variability in light sensitivity is not currently accounted for in these models and may be a practical approach to improving individual-level predictions. Using the gold-standard predictive model, we (i) identified whether varying light sensitivity parameters produces meaningful changes in predicted phase in field conditions; and (ii) tested whether optimizing parameters can significantly improve accuracy of circadian phase prediction. Methods Healthy participants (n=12, 7 women, aged 18-26) underwent continuous light and activity monitoring for 3 weeks (Actiwatch Spectrum). Salivary dim light melatonin onset (DLMO) was measured each week. A model of the human circadian clock and its response to light was used to predict the three weekly DLMO times using the individual’s light data. A sensitivity analysis was performed varying three model parameters within physiological ranges: (i) amplitude of the light response [p]; (ii) advance vs. delay bias of the light response [K]; and (iii) intrinsic circadian period [tau]. These parameters were then fitted using least squares estimation to obtain optimal predictions of DLMO for each individual. Accuracy was compared between optimized parameters and default parameters. Results The default model predicted DLMO with mean absolute error of 1.02h. Sensitivity analysis showed the average range of variation in predicted DLMOs across participants was 0.65h for p, 4.28h for K and 3.26h for tau. Fitting parameters independently, we found mean absolute error of 0.85h for p, 0.71h for K and 0.75h for tau. Fitting p and K together reduced mean absolute error to 0.57h. Conclusion Light sensitivity parameters capture similar or greater variability in phase as intrinsic circadian period, indicating they are a viable option for individualising circadian phase predictions. Future prospective work is needed using measures of light sensitivity to validate this approach. Support N/A

Circadian disruption is associated with poor health outcomes, including sleep and mood disorders. The suprachiasmatic nucleus (SCN) of the anterior hypothalamus acts as the master biological clock in mammals, regulating circadian rhythms throughout the body. The clock is synchronized to the day/night cycle via retinal light exposure. The BOLD-fMRI response of the human suprachiasmatic area to light has been shown to be greater in the night than in the day, consistent with the known sensitivity of the clock to light at night. Whether the BOLD-fMRI response of the human suprachiasmatic area to light is related to a functional outcome has not been demonstrated. In a pilot study (n=10), we investigated suprachiasmatic area activation in response to light in a 30 second block-paradigm of lights on (100 lux) and lights off (

This study investigated the utility of the pupillary light reflex as a method of differentiating DSPD patients with delayed melatonin timing relative to desired/required sleep time (circadian type) and those with non-delayed melatonin timing (non-circadian type). All participants were young adults, with a total of 14 circadian DSPD patients (M = 28.14, SD = 5.26), 12 non-circadian DSPD patients (M = 29.42, SD = 11.51) and 51 healthy controls (M = 21.47 SD = 3.16) completing the protocol. All participants were free of central nervous system acting medications and abstained from caffeine and alcohol on the day of the assessment. Two pupillary light reflex measurements were completed by each participant, one with a 1s dim (~10 lux) light exposure, and one with a 1s bright (~1500 lux) light exposure. Circadian DSPD patients showed a significantly faster pupillary light reflex than both non-circadian DSPD patients and healthy controls. Non-circadian patients and healthy controls did not differ significantly. Receiver operating characteristic curves were generated to determine the utility of mean and maximum constriction velocity in differentiating the two DSPD phenotypes, and these demonstrated high levels of sensitivity (69.23–-100%) and specificity (66.67–91.67%) at their optimal cut offs. The strongest predictor of DSPD phenotype was the mean constriction velocity to bright light (AUC = 0.87). These results support the potential for the pupillary light reflex to clinically differentiate between DSPD patients with normal vs. delayed circadian timing relative to desired bedtime, without the need for costly and time-consuming circadian assessments.

Selective serotonin reuptake inhibitors (SSRIs) have a profound effect on the circadian system's response to environmental light, which may impact treatment outcomes for patients depending on their habitual light exposure patterns. Here, we investigated the relationship between time-of-day preference, depressive symptoms and self-reported antidepressant treatment response. Evening types reported having taken a higher number of antidepressant medications in the previous 5 years and lower SSRI efficacy than morning types. While undergoing SSRI treatment, evening types also reported more depressive symptoms and suicidality. It is concluded that time-of-day preference may prove informative in predicting SSRI treatment responses.