Investigating light sensitivity in bipolar disorder (HELIOS-BD).

Many people with bipolar disorder have disrupted circadian rhythms. This means that the timing of sleep and wake activities becomes out-of-sync with the standard 24-hour cycle. Circadian rhythms are strongly influenced by light levels and previous research suggests that people with bipolar disorder might have a heightened sensitivity to light, causing more circadian rhythm disruption, increasing the potential for triggering a mood switch into mania or depression. Lithium has been in clinical use for over 70 years and is acknowledged to be the most effective long-term treatment for bipolar disorder. Lithium has many reported actions in the body but the precise mechanism of action in bipolar disorder remains an active area of research. Central to this project is recent evidence that lithium may work by stabilising circadian rhythms of mood, cognition and rest/activity. Our primary hypothesis is that people with bipolar disorder have some pathophysiological change at the level of the retina which makes them hypersensitive to the visual and non-visual effects of light, and therefore more susceptible to circadian rhythm dysfunction. We additionally hypothesise that the mood-stabilising medication lithium is effective in bipolar disorder because it reduces this hypersensitivity, making individuals less vulnerable to light-induced circadian disruption. We will recruit 180 participants into the HELIOS-BD study. Over an 18-month period, we will assess visual and non-visual responses to light, as well as retinal microstructure, in people with bipolar disorder compared to healthy controls. Further, we will assess whether individuals with bipolar disorder who are being treated with lithium have less pronounced light responses and attenuated retinal changes compared to individuals with bipolar disorder not being treated with lithium. This study represents a comprehensive investigation of visual and non-visual light responses in a large bipolar disorder population, with great translational potential for patient stratification and treatment innovation.

Temporal Sensitivity for Achromatic and Chromatic Flicker across the Visual Cortex.

The retinal ganglion cells (RGCs) receive different combinations of L, M, and S cone inputs and give rise to one achromatic and two chromatic postreceptoral channels. The goal of the current study was to determine temporal sensitivity across the three postreceptoral channels in subcortical and cortical regions involved in human vision. We measured functional magnetic resonance imaging (fMRI) responses at 7 T from three participants (two males, one female) viewing a high-contrast, flickering, spatially uniform wide field (∼140°). Stimulus flicker frequency varied logarithmically between 2 and 64 Hz and targeted the L + M + S, L - M, and S - (L + M) cone combinations. These measurements were used to create temporal sensitivity functions of the primary visual cortex (V1) across eccentricity and spatially averaged responses from the lateral geniculate nucleus (LGN), and the V2/V3, hV4, and V3A/B regions. fMRI responses reflected the known properties of the visual system, including higher peak temporal sensitivity to achromatic versus chromatic stimuli and low-pass filtering between the LGN and V1. Peak temporal sensitivity increased across levels of the cortical visual hierarchy. Unexpectedly, peak temporal sensitivity varied little across eccentricity within area V1. Measures of adaptation and distributed pattern activity revealed a subtle influence of 64 Hz achromatic flicker in area V1, despite this stimulus evoking only a minimal overall response. The comparison of measured cortical responses to a model of the integrated retinal output to our stimuli demonstrates that extensive filtering and amplification are applied to postretinal signals.

Power Analysis for Human Melatonin Suppression Experiments.

In humans, the nocturnal secretion of melatonin by the pineal gland is suppressed by ocular exposure to light. In the laboratory, melatonin suppression is a biomarker for this neuroendocrine pathway. Recent work has found that individuals differ substantially in their melatonin-suppressive response to light, with the most sensitive individuals being up to 60 times more sensitive than the least sensitive individuals. Planning experiments with melatonin suppression as an outcome needs to incorporate these individual differences, particularly in common resource-limited scenarios where running within-subjects studies at multiple light levels is costly and resource-intensive and may not be feasible with respect to participant compliance. Here, we present a novel framework for virtual laboratory melatonin suppression experiments, incorporating a Bayesian statistical model. We provide a Shiny web app for power analyses that allows users to modify various experimental parameters (sample size, individual-level heterogeneity, statistical significance threshold, light levels), and simulate a systematic shift in sensitivity (e.g., due to a pharmacological or other intervention). Our framework helps experimenters to design compelling and robust studies, offering novel insights into the underlying biological variability in melatonin suppression relevant for practical applications.

The Impact of Pupil Constriction on the Relationship Between Melanopic EDI and Melatonin Suppression in Young Adult Males.

The pupil modulates the amount of light that reaches the retina. Not only luminance but also the spectral distribution defines the pupil size. Previous research has identified steady-state pupil size and melatonin attenuation to be predominantly driven by melanopsin, which is expressed by a unique subgroup of intrinsically photosensitive retinal ganglion cells (ipRGCs) that are sensitive to short-wavelength light (~480 nm). Here, we aimed to selectively target the melanopsin system during the evening, while measuring steady-state pupil size and melatonin concentrations under commonly experienced evening light levels (<90 lx). Therefore, we used a five-primary display prototype to generate light conditions that were matched in terms of L-, M-, and S-cone-opic irradiances, but with high and low melanopic irradiances (~3-fold difference). Seventy-two healthy, male participants completed a 2-week study protocol. The volunteers were assigned to one of the four groups that differed in luminance levels (27-285 cd/m2). Within the four groups, each volunteer was exposed to a low melanopic (LM) and a high melanopic (HM) condition. The two 17-h study protocols comprised 3.5 h of light exposure starting 4 h before habitual bedtime. Median pupil size was significantly smaller during HM than LM in all four light intensity groups. In addition, we observed a significant correlation between melanopic weighted corneal illuminance (melanopic equivalent daylight illuminance [mEDI]) and pupil size, such that higher mEDI values were associated with smaller pupil size. Using pupil size to estimate retinal irradiance showed a qualitatively similar goodness of fit as mEDI for predicting melatonin suppression. Based on our results here, it remains appropriate to use melanopic irradiance measured at eye level when comparing light-dependent effects on evening melatonin concentrations in healthy young people at rather low light levels.

Selecting, implementing and evaluating control and placebo conditions in light therapy and light-based interventions.

Introduction: Light profoundly influences human physiology, behaviour and cognition by affecting various functions through light-sensitive cells in the retina. Light therapy has proven effective in treating seasonal depression and other disorders. However, designing appropriate control conditions for light-based interventions remains a challenge.Materials and methods: This article presents a novel framework for selecting, implementing and evaluating control conditions in light studies, offering theoretical foundations and practical guidance. It reviews the fundamentals of photoreception and discusses control strategies such as dim light, darkness, different wavelengths, spectral composition and metameric conditions. Special cases like dynamic lighting, simulated dawn and dusk, complex interventions and studies involving blind or visually impaired patients are also considered.Results: The practical guide outlines steps for selection, implementation, evaluation and reporting, emphasizing the importance of α-opic calculations and physiological validation.Conclusion: In conclusion, constructing effective control conditions is crucial for demonstrating the efficacy of light interventions in various research scenarios.

Temporal sensitivity for achromatic and chromatic flicker across the visual cortex.

The retinal ganglion cells (RGCs) receive different combinations of L, M, and S cone inputs and give rise to one achromatic and two chromatic post-receptoral channels. Beyond the retina, RGC outputs are subject to filtering and normalization along the geniculo-striate pathway, ultimately producing the properties of human vision. The goal of the current study was to determine temporal sensitivity across the three post-receptoral channels in subcortical and cortical regions involved in vision. We measured functional magnetic resonance imaging (MRI) responses at 7 Tesla from three participants (two males, one female) viewing a high-contrast, flickering, spatially-uniform wide field (~140°). Stimulus flicker frequency varied logarithmically between 2 and 64 Hz and targeted the L+M+S, L-M, and S-[L+M] cone combinations. These measurements were used to create temporal sensitivity functions of primary visual cortex (V1) across eccentricity, and spatially averaged responses from lateral geniculate nucleus (LGN), V2/V3, hV4, and V3A/B. Functional MRI responses reflected known properties of the visual system, including higher peak temporal sensitivity to achromatic vs. chromatic stimuli, and low-pass filtering between the LGN and V1. Peak temporal sensitivity increased across levels of the cortical visual hierarchy. Unexpectedly, peak temporal sensitivity varied little across eccentricity within area V1. Measures of adaptation and distributed pattern activity revealed a subtle influence of 64 Hz achromatic flicker in area V1, despite this stimulus evoking only a minimal overall response. Comparison of measured cortical responses to a model of integrated retinal output to our stimuli demonstrates that extensive filtering and amplification is applied to post-retinal signals.

Effects of calibrated blue-yellow changes in light on the human circadian clock.

Evening exposure to short-wavelength light can affect the circadian clock, sleep and alertness. Intrinsically photosensitive retinal ganglion cells expressing melanopsin are thought to be the primary drivers of these effects. Whether colour-sensitive cones also contribute is unclear. Here, using calibrated silent-substitution changes in light colour along the blue-yellow axis, we investigated whether mechanisms of colour vision affect the human circadian system and sleep. In a 32.5-h repeated within-subjects protocol, 16 healthy participants were exposed to three different light scenarios for 1 h starting 30 min after habitual bedtime: baseline control condition (93.5 photopic lux), intermittently flickering (1 Hz, 30 s on-off) yellow-bright light (123.5 photopic lux) and intermittently flickering blue-dim light (67.0 photopic lux), all calibrated to have equal melanopsin excitation. We did not find conclusive evidence for differences between the three lighting conditions regarding circadian melatonin phase delays, melatonin suppression, subjective sleepiness, psychomotor vigilance or sleep.The Stage 1 protocol for this Registered Report was accepted in principle on 9 September 2020. The protocol, as accepted by the journal, can be found at https://doi.org/10.6084/m9.figshare.13050215.v1 .

An inventory of human light exposure behaviour.

Light exposure is an essential driver of health and well-being, and individual behaviours during rest and activity modulate physiologically relevant aspects of light exposure. Further understanding the behaviours that influence individual photic exposure patterns may provide insight into the volitional contributions to the physiological effects of light and guide behavioural points of intervention. Here, we present a novel, self-reported and psychometrically validated inventory to capture light exposure-related behaviour, the Light Exposure Behaviour Assessment (LEBA). An expert panel prepared the initial 48-item pool spanning different light exposure-related behaviours. Responses, consisting of rating the frequency of engaging in the per-item behaviour on a five-point Likert-type scale, were collected in an online survey yielding responses from a geographically unconstrained sample (690 completed responses, 74 countries, 28 time zones). The exploratory factor analysis (EFA) on an initial subsample (n = 428) rendered a five-factor solution with 25 items (wearing blue light filters, spending time outdoors, using a phone and smartwatch in bed, using light before bedtime, using light in the morning and during daytime). In a confirmatory factor analysis (CFA) performed on an independent subset of participants (n = 262), we removed two additional items to attain the best fit for the five-factor solution (CFI = 0.95, TLI = 0.95, RMSEA = 0.06). The internal consistency reliability coefficient for the total instrument yielded McDonald's Omega = 0.68. Measurement model invariance analysis between native and non-native English speakers showed our model attained the highest level of invariance (residual invariance CFI = 0.95, TLI = 0.95, RMSEA = 0.05). Lastly, a short form of the LEBA (n = 18 items) was developed using Item Response Theory on the complete sample (n = 690). The psychometric properties of the LEBA indicate the usability for measuring light exposure-related behaviours. The instrument may offer a scalable solution to characterise behaviours that influence individual photic exposure patterns in remote samples. The LEBA inventory is available under the open-access CC-BY license. Instrument webpage: https://leba-instrument.org/ GitHub repository containing this manuscript: https://github.com/leba-instrument/leba-manuscript .

ENLIGHT: A consensus checklist for reporting laboratory-based studies on the non-visual effects of light in humans.

BACKGROUND: There is no consensus on reporting light characteristics in studies investigating non-visual responses to light. This project aimed to develop a reporting checklist for laboratory-based investigations on the impact of light on non-visual physiology. METHODS: A four-step modified Delphi process (three questionnaire-based feedback rounds and one face-to-face group discussion) involving international experts was conducted to reach consensus on the items to be included in the checklist. Following the consensus process, the resulting checklist was tested in a pilot phase with independent experts. FINDINGS: An initial list of 61 items related to reporting light-based interventions was condensed to a final checklist containing 25 items, based upon consensus among experts (final n = 60). Nine items were deemed necessary to report regardless of research question or context. A description of each item is provided in the accompanying Explanation and Elaboration (E&E) document. The independent pilot testing phase led to minor textual clarifications in the checklist and E&E document. INTERPRETATION: The ENLIGHT Checklist is the first consensus-based checklist for documenting and reporting ocular light-based interventions for human studies. The implementation of the checklist will enhance the impact of light-based research by ensuring comprehensive documentation, enhancing reproducibility, and enabling data aggregation across studies. FUNDING: Network of European Institutes for Advanced Study (NETIAS) Constructive Advanced Thinking (CAT) programme; Sir Henry Wellcome Postdoctoral Fellowship (Wellcome Trust, 204686/Z/16/Z); Netherlands Organisation for Health Research and Development VENI fellowship (2020-09150161910128); U.S. Department of Defense Grant (W81XWH-16-1-0223); National University of Singapore (NUHSRO/2022/038/Startup/08); and National Research Foundation Singapore (NRF2022-THE004-0002).

Usability and Acceptability of a Corneal-Plane α-Opic Light Logger in a 24-h Field Trial.

Introduction: Exposure to light fundamentally influences human physiology and behaviour by synchronising our biological clock to the external light-dark cycle and controlling melatonin production. In addition to well-controlled laboratory studies, more naturalistic approaches to examining these "non-visual" effects of light have been developed in recent years. As naturalistic light exposure is quite unlike well-controlled stimulus conditions in the laboratory, it is critical to measure light exposure in a person-referenced way, the "spectral diet." To this end, light loggers have been developed to capture personalised light exposure. As an alternative to light sensors integrated into wrist-worn actimeters, pendants, or brooch-based light loggers, a recently developed wearable light logger laterally attached to spectacle frames enables the measurement of biologically relevant quantities in the corneal plane. Methods: Here, we examine the usability and acceptability of using the light logger in an undergraduate student sample (n = 18, mean±1SD: 20.1 ± 1.7 years; 9 female; Oxford, UK) in real-world conditions during a 24-h measurement period. We probed the acceptability of the light logger using rating questionnaires and open-ended questions. Results: Our quantitative results show a modest acceptability of the light logger. A thematic analysis of the open-ended questions reveals that the form factor of the device, in particular, size, weight, and stability, and reactions from other people to the wearer of the light logger, were commonly mentioned aspects. Conclusion: In sum, the results indicate the miniaturisation of light loggers and "invisible" integration into extant everyday objects as key areas for future technological development, facilitating the availability of light exposure data for developing personalised intervention strategies in both research, clinical and consumer contexts.

Light exposure behaviors predict mood, memory and sleep quality.

Ample research has shown that light influences our emotions, cognition, and sleep quality. However, little work has examined whether different light exposure-related behaviors, such as daytime exposure to electric light and nighttime usage of gadgets, especially before sleep, influence sleep quality and cognition. Three-hundred-and-one Malaysian adults (MeanAge±SD = 28 ± 9) completed the Light Exposure Behavior Assessment tool that measured five light exposure behaviors. They also completed the Morningness-Eveningness Questionnaire, Positive and Negative Affect Schedule, Pittsburgh Sleep Quality Index, and single items assessing trouble in memory and concentration. A partial least square structural equation model, showing 72.72% predictive power, revealed that less use of wearable blue filters outdoors during the day and more within one hour before sleep predicted early peak time (direct effect = -0.25). Increased time spent outdoors predicted a positive affect (direct effect = 0.33) and a circadian phase advancement (direct effect: rising time = 0.14, peak time = 0.20, retiring time = 0.17). Increased use of mobile phone before sleep predicted a circadian phase delay (direct effect: retiring time = -0.25; rising time = -0.23; peak time = -0.22; morning affect = -0.12), reduced sleep quality (direct effect = 0.13), and increased trouble in memory and concentration (total effect = 0.20 and 0.23, respectively). Increased use of tunable, LED, or dawn-simulating electric light in the morning and daytime predicted a circadian phase advancement (direct effect: peak time = 0.15, morning affect = 0.14, retiring time = 0.15) and good sleep quality (direct effect = -0.16). The results provide valuable insights into developing a healthy light diet to promote health and wellness.

The impact of Alzheimer's disease risk factors on the pupillary light response.

Alzheimer's disease (AD) is the leading cause of dementia, and its prevalence is increasing and is expected to continue to increase over the next few decades. Because of this, there is an urgent requirement to determine a way to diagnose the disease, and to target interventions to delay and ideally stop the onset of symptoms, specifically those impacting cognition and daily livelihood. The pupillary light response (PLR) is controlled by the sympathetic and parasympathetic branches of the autonomic nervous system, and impairments to the pupillary light response (PLR) have been related to AD. However, most of these studies that assess the PLR occur in patients who have already been diagnosed with AD, rather than those who are at a higher risk for the disease but without a diagnosis. Determining whether the PLR is similarly impaired in subjects before an AD diagnosis is made and before cognitive symptoms of the disease begin, is an important step before using the PLR as a diagnostic tool. Specifically, identifying whether the PLR is impaired in specific at-risk groups, considering both genetic and non-genetic risk factors, is imperative. It is possible that the PLR may be impaired in association with some risk factors but not others, potentially indicating different pathways to neurodegeneration that could be distinguished using PLR. In this work, we review the most common genetic and lifestyle-based risk factors for AD and identify established relationships between these risk factors and the PLR. The evidence here shows that many AD risk factors, including traumatic brain injury, ocular and intracranial hypertension, alcohol consumption, depression, and diabetes, are directly related to changes in the PLR. Other risk factors currently lack sufficient literature to make any conclusions relating directly to the PLR but have shown links to impairments in the parasympathetic nervous system; further research should be conducted in these risk factors and their relation to the PLR.

PySilSub: An open-source Python toolbox for implementing the method of silent substitution in vision and nonvisual photoreception research.

The normal human retina contains several classes of photosensitive cell-rods for low-light vision, three cone classes for daylight vision, and intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing melanopsin for non-image-forming functions, including pupil control, melatonin suppression, and circadian photoentrainment. The spectral sensitivities of the photoreceptors overlap significantly, which means that most lights will stimulate all photoreceptors to varying degrees. The method of silent substitution is a powerful tool for stimulating individual photoreceptor classes selectively and has found much use in research and clinical settings. The main hardware requirement for silent substitution is a spectrally calibrated light stimulation system with at least as many primaries as there are photoreceptors under consideration. Device settings that will produce lights to selectively stimulate the photoreceptor(s) of interest can be found using a variety of analytic and algorithmic approaches. Here we present PySilSub (https://github.com/PySilentSubstitution/pysilsub), a novel Python package for silent substitution featuring flexible support for individual colorimetric observer models (including human and mouse observers), multiprimary stimulation devices, and solving silent substitution problems with linear algebra and constrained numerical optimization. The toolbox is registered with the Python Package Index and includes example data sets from various multiprimary systems. We hope that PySilSub will facilitate the application of silent substitution in research and clinical settings.

Melanopic irradiance defines the impact of evening display light on sleep latency, melatonin and alertness.

Evening light-emitting visual displays may disrupt sleep, suppress melatonin and increase alertness. Here, we control melanopic irradiance independent of display luminance and colour, in 72 healthy males 4 h before habitual bedtime and expose each of them to one of four luminance levels (i.e., dim light, smartphone, tablet or computer screen illuminance) at a low and a high melanopic irradiance setting. Low melanopic light shortens the time to fall asleep, attenuates evening melatonin suppression, reduces morning melatonin, advances evening melatonin onset and decreases alertness compared to high melanopic light. In addition, we observe dose-dependent increases in sleep latency, reductions in melatonin concentration and delays in melatonin onset as a function of melanopic irradiance-not so for subjective alertness. We identify melanopic irradiance as an appropriate parameter to mitigate the unwanted effects of screen use at night. Our results may help the many people who sit in front of screens in the evening or at night to fall asleep faster, feel sleepier, and have a more stable melatonin phase by spectrally tuning the visual display light without compromising the visual appearance.

Light on Shedding: A Review of Sex and Menstrual Cycle Differences in the Physiological Effects of Light in Humans.

The human circadian system responds to light as low as 30 photopic lux. Furthermore, recent evidence shows that there are huge individual differences in light sensitivity, which may help to explain why some people are more susceptible to sleep and circadian disruption than others. The biological mechanisms underlying the differences in light sensitivity remain largely unknown. A key variable of interest in understanding these individual differences in light sensitivity is biological sex. It is possible that in humans, males and females differ in their sensitivity to light, but the evidence is inconclusive. This is in part due to the historic exclusion of women in biomedical research. Hormonal fluctuations across the menstrual cycle in women has often been cited as a confound by researchers. Attitudes, however, are changing with funding and publication agencies advocating for more inclusive research frameworks and mandating that women and minorities participate in scientific research studies. In this article, we distill the existing knowledge regarding the relationship between light and the menstrual cycle. There is some evidence of a relationship between light and the menstrual cycle, but the nature of this relationship seems dependent on the timing of the light source (sunlight, moonlight, and electric light at night). Light sensitivity may be influenced by biological sex and menstrual phase but there might not be any effect at all. To better understand the relationship between light, the circadian system, and the menstrual cycle, future research needs to be designed thoughtfully, conducted rigorously, and reported transparently.

Optimizing Light Flash Sequence Duration to Shift Human Circadian Phase.

Unlike light input for forming images, non-image-forming retinal pathways are optimized to convey information about the total light environment, integrating this information over time and space. In a variety of species, discontinuous light sequences (flashes) can be effective stimuli, notably impacting circadian entrainment. In this study, we examined the extent to which this temporal integration can occur. A group of healthy, young (n = 20) individuals took part in a series of 16-day protocols in which we examined the impact of different lengths of light flash sequences on circadian timing. We find a significant phase change of -0.70 h in response to flashes that did not differ by duration; a 15-min sequence could engender as much change in circadian timing as 3.5-h sequences. Acute suppression of melatonin was also observed during short (15-min) exposures, but not in exposures over one hour in length. Our data are consistent with the theory that responses to light flashes are mediated by the extrinsic, rod/cone pathway, and saturate the response of this pathway within 15 min. Further excitation leads to no greater change in circadian timing and an inability to acutely suppress melatonin, indicating that this pathway may be in a refractory state following this brief light stimulation.

Melatonin suppression does not automatically alter sleepiness, vigilance, sensory processing, or sleep.

Presleep exposure to short-wavelength light suppresses melatonin and decreases sleepiness with activating effects extending to sleep. This has mainly been attributed to melanopic effects, but mechanistic insights are missing. Thus, we investigated whether two light conditions only differing in the melanopic effects (123 vs. 59 lx melanopic EDI) differentially affect sleep besides melatonin. Additionally, we studied whether the light differentially modulates sensory processing during wakefulness and sleep. Twenty-nine healthy volunteers (18-30 years, 15 women) were exposed to two metameric light conditions (high- vs. low-melanopic, ≈60 photopic lx) for 1 h ending 50 min prior to habitual bed time. This was followed by an 8-h sleep opportunity with polysomnography. Objective sleep measurements were complemented by self-report. Salivary melatonin, subjective sleepiness, and behavioral vigilance were sampled at regular intervals. Sensory processing was evaluated during light exposure and sleep on the basis of neural responses related to violations of expectations in an oddball paradigm. We observed suppression of melatonin by ≈14% in the high- compared to the low-melanopic condition. However, conditions did not differentially affect sleep, sleep quality, sleepiness, or vigilance. A neural mismatch response was evident during all sleep stages, but not differentially modulated by light. Suppression of melatonin by light targeting the melanopic system does not automatically translate to acutely altered levels of vigilance or sleepiness or to changes in sleep, sleep quality, or basic sensory processing. Given contradicting earlier findings and the retinal anatomy, this may suggest that an interaction between melanopsin and cone-rod signals needs to be considered. Clinical Trial Registry: German Clinical Trials Register, DRKS00023602, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00023602.