Post-illumination Pupil Response Research Articles

0688 Post-illumination Pupillary Response (PIPR) Is Attenuated in Patients with REM-sleep Behaviour Disorder

0688 Post-illumination Pupillary Response (PIPR) Is Attenuated in Patients with REM-sleep Behaviour Disorder

Circadian photoentrainment varies by season and depressed state: associations between light sensitivity and sleep and circadian timing.

Altered light sensitivity may be an underlying vulnerability for disrupted circadian photoentrainment. The photic information necessary for circadian photoentrainment is sent to the circadian clock from melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs). The current study tested whether the responsivity of ipRGCs measured using the post-illumination pupil response (PIPR) was associated with circadian phase, sleep timing, and circadian alignment, and if these relationships varied by season or depression severity. Adult participants (N = 323, agem = 40.5, agesd = 13.5) with varying depression severity were recruited during the summer (n = 154) and winter (n = 169) months. Light sensitivity was measured using the PIPR. Circadian phase was assessed using Dim Light Melatonin Onset (DLMO) on Friday evenings. Midsleep was measured using actigraphy. Circadian alignment was calculated as the DLMO-midsleep phase angle. Multilevel regression models covaried for age, gender, and time since wake of PIPR assessment. Greater light sensitivity was associated with later circadian phase in summer but not in winter (β = 0.23; p = 0.03). Greater light sensitivity was associated with shorter DLMO-midsleep phase angles (β = 0.20; p = 0.03) in minimal depression but not in moderate depression (SIGHSAD < 6.6; Johnson-Neyman region of significance). Light sensitivity measured by the PIPR was associated with circadian phase during the summer but not in winter, suggesting ipRGC functioning in humans may affect circadian entrainment when external zeitgebers are robust. Light sensitivity was associated with circadian alignment only in participants with minimal depression, suggesting circadian photoentrainment, a possible driver of mood, may be decreased in depression year-round, similar to decreased photoentrainment in winter.

Dysregulated 24 h melatonin secretion associated with intrinsically photosensitive retinal ganglion cell function in diabetic retinopathy: a cross-sectional study.

The aim of this study was to explore whether diabetic retinopathy is associated with alterations of the circadian system, and to examine the role of reduced intrinsically photosensitive retinal ganglion cell (ipRGC) function. Participants with type 2 diabetes, with diabetic retinopathy (n=14) and without diabetic retinopathy (n=9) underwent 24 h blood sampling for melatonin and cortisol under controlled laboratory conditions. ipRGC function was inferred from the post-illumination pupil response (PIPR). Habitual sleep duration, efficiency and variability were assessed by actigraphy. Participants with diabetic retinopathy compared to participants without diabetic retinopathy had smaller PIPR (p=0.007), lower 24 h serum melatonin output (p=0.042) and greater day-to-day sleep variability (p=0.012). By contrast, 24 h cortisol profiles, sleep duration and efficiency were similar in both groups. Six individuals with diabetic retinopathy had no detectable dim-light melatonin onset. PIPR correlated with 24 h mean melatonin levels (r=0.555, p=0.007). ipRCG dysfunction in diabetic retinopathy is associated with disruptions of the 24 h melatonin rhythm, suggesting circadian dysregulation in diabetic retinopathy.

Melanopsin-mediated post-illumination pupillary response (PIPR) correlated with sleep timing, chronotype and overnight urinary 6-sulphatoxymelatonin in older individuals

Melanopsin-mediated post-illumination pupillary response (PIPR) correlated with sleep timing, chronotype and overnight urinary 6-sulphatoxymelatonin in older individuals

Chromatic pupillometry for evaluating melanopsin retinal ganglion cell function in Alzheimer's disease and other neurodegenerative disorders: a review.

The evaluation of pupillary light reflex (PLR) by chromatic pupillometry may provide a unique insight into specific photoreceptor functions. Chromatic pupillometry refers to evaluating PLR to different wavelengths and intensities of light in order to differentiate outer/inner retinal photoreceptor contributions to the PLR. Different protocols have been tested and are now established to assess in-vivo PLR contribution mediated by melanopsin retinal ganglion cells (mRGCs). These intrinsically photosensitive photoreceptors modulate the non-image-forming functions of the eye, which are mainly the circadian photoentrainment and PLR, via projections to the hypothalamic suprachiasmatic and olivary pretectal nucleus, respectively. In this context, chromatic pupillometry has been used as an alternative and non-invasive tool to evaluate the mRGC system in several clinical settings, including hereditary optic neuropathies, glaucoma, and neurodegenerative disorders such as Parkinson's disease (PD), idiopathic/isolated rapid eye movement sleep behavior disorder (iRBD), and Alzheimer's disease (AD). The purpose of this article is to review the key steps of chromatic pupillometry protocols for studying in-vivo mRGC-system functionality and provide the main findings of this technique in the research setting on neurodegeneration. mRGC-dependent pupillary responses are short-wavelength sensitive, have a higher threshold of activation, and are much slower and sustained compared with rod- and cone-mediated responses, driving the tonic component of the PLR during exposure to high-irradiance and continuous light stimulus. Thus, mRGCs contribute mainly to the tonic component of the post-illumination pupil response (PIPR) to bright blue light flash that persists after light stimulation is switched off. Given the role of mRGCs in circadian photoentrainment, the use of chromatic pupillometry to perform a functional evaluation of mRGcs may be proposed as an early biomarker of mRGC-dysfunction in neurodegenerative disorders characterized by circadian and/or sleep dysfunction such as AD, PD, and its prodromal phase iRBD. The evaluation by chromatic pupillometry of mRGC-system functionality may lay the groundwork for a new, easily accessible biomarker that can be exploited also as the starting point for future longitudinal cohort studies aimed at stratifying the risk of conversion in these disorders.

Vigilance and circadian function in daytime and nocturnal epilepsy compared to controls

BackgroundPeople with epilepsy often experience daytime vigilance problems and fatigue. This may be related to disturbed sleep due to nocturnal seizures. AimTo compare subjective and objective markers of vigilance and circadian function in adults with epilepsy with nocturnal seizures to those with daytime seizures and healthy controls and to identify determinants of impaired daytime vigilance in epilepsy in an explorative study. MethodsWe included 30 adults with epilepsy (15 with daytime seizures and 15 with nocturnal seizures), and 15 healthy controls. All participants filled out the Epworth sleepiness scale (ESS), fatigue severity scale (FSS), Pittsburgh sleep quality index (PSQI) and the Munich chronotype questionnaire (MCTQ). Each participant performed two trials of the sustained attention to response task (SART) as a measure of vigilance, and had a post-illumination pupil response (PIPR) assessment as a marker for the circadian function. ResultsBoth epilepsy groups reported more fatigue on the FSS than healthy controls (p < .001) and had higher SART error scores (p = .026). The poorer FSS and SART scores were most prominent among those with nocturnal seizures. The ESS, PSQI, MCTQ and the primary PIPR outcome did not differ between groups. Having nocturnal seizures (p = .010) and using more antiseizure medications (p = .004) were related to increased SART error scores. ConclusionsNocturnal epilepsy is associated with poorer vigilance, indicating lower quality of wake time. We could not relate this to circadian dysfunction. Further studies should focus on vigilance problems in people with nocturnal epilepsy and explore interventions to improve the quality of wake time.

THU315 Sleep And Circadian Regulation, And Intrinsically Photosensitive Retinal Ganglion Cells Function In Diabetic Retinopathy

Abstract Disclosure: S. Reutrakul: None. J.J. McAnany: None. J.C. Park: None. F.Y. Chau: None. K.K. Danielson: None. P. Bharati: None. S. Pannain: None. E. Van Cauter: None. E.C. Hanlon: None. Background: Diabetic retinopathy (DR) is associated with a dysfunction of intrinsically photosensitive retinal ganglion cells (ipRGCs), a crucial component of the entrainment of the circadian system and of the photic entrainment of melatonin secretion. We explored ipRGC function, sleep, 24-h melatonin and cortisol profiles in patients with and without DR. Methods: Type 2 diabetes patients with DR (n=10) and without DR (n=7,) participated. ipRGC function was inferred from the post illumination pupil response (PIPR). Sleep was assessed by 14-day actigraphy. Serum was sampled at hourly intervals for 24hrs for melatonin and cortisol measurement. Results: Mean (SD) age (53.8 (8.1) vs (54.0 (8.6) yr) and mean A1C (7.5 (1.7) vs. 7.1 (0.9)%) did not differ between DR and no-DR patients. PIPR was significantly smaller in DR than no-DR patients (0.14 (0.16) vs. 0.33 (0.10), p=0.001). Nightly sleep duration and efficiency were similar, but sleep variability (standard deviation of daily sleep duration over 7 nights) tended to be larger in DR than no-DR patients (84.1 (29.8) vs. 59.5 (21.8) minutes), p=0.08. Twenty four-hour serum melatonin output was significantly lower in DR than no-DR patients (103.1 (95.4) pg/ml vs. 231.1 (131.3) pg/ml, p=0.034). All no-DR patients exhibited the classical 24-h profile of melatonin with consistently low levels during the day time and a clear nocturnal rise peaking around the middle of the night. In contrast, a normal melatonin rhythm was observed only in 3 of the 10 patients with DR. Six DR patients had 24-h mean melatonin level under 3 pg/ml, five without any evident day-night pattern. One DR patient had a shift in melatonin timing. There was a significant correlation between PIPR and 24-h melatonin output, r= 0.726, p&amp;lt;0.001, but not with sleep variability. In contrast, mean 24-h cortisol profiles and levels, however, were not significantly different between the two groups (mean levels DR 6.18 (1.23) vs no-DR 6.18 (0.73) μg/dL), Conclusion: DR is associated with ipRCGs dysfunction, irregular sleep, and with major disruptions of the 24-hour melatonin rhythm while cortisol rhythm was maintained, suggesting circadian dysfunction in those with type 2 diabetes and retinopathy. Whether melatonin supplementation is beneficial in type 2 diabetes with DR should be explored. Presentation: Thursday, June 15, 2023

Post-Illumination Pupil Response and Sleep Quality in Patients With Glaucoma: The LIGHT Study.

This study aimed to investigate whether intrinsically photosensitive retinal ganglion cell function evaluated using post-illumination pupil response (PIPR) in patients with glaucoma is associated with sleep quality. This cross-sectional study measured the PIPR in 138 patients with glaucoma (mean age, 70.3 years) using pupil diameter after red and blue light exposure. The net PIPR change was classified into three groups according to tertiles (i.e., low, intermediate, and high groups), with lower net PIPR change indicating lower intrinsically photosensitive retinal ganglion cell (ipRGC) function. Subjective and objective sleep qualities were assessed using the Pittsburgh Sleep Quality Index (PSQI) questionnaire and actigraphy, respectively, with a total PSQI score of ≥6 indicating sleep disturbance. The prevalence of subjective sleep disturbance significantly increased with decreasing tertile groups of net PIPR change (P = 0.036). Subgroup analysis obtained the same results in the severe glaucoma group (P = 0.004) but not in the non-severe glaucoma group. In the severe glaucoma group, multivariable logistic regression analysis adjusted for potential confounders showed a higher odds ratio for subjective sleep disturbance in the low-tertile group of net PIPR compared with the high-tertile group (odds ratio = 6.22; 95% confidence interval, 1.76-21.90; P = 0.004). Significant associations between PIPR and objective sleep quality (total sleep time, sleep efficiency, and wake after sleep onset) were found in the severe glaucoma group (P = 0.015, P = 0.013, and P = 0.015, respectively). The PIPR in patients with glaucoma was significantly associated with decreased sleep quality, independent of potential confounders.

Handheld chromatic pupillometry can reliably detect functional glaucomatous damage in eyes with high myopia

Background/aimsTo assess pupillary light responses (PLRs) in eyes with high myopia (HM) and evaluate the ability of handheld chromatic pupillometry (HCP) to identify glaucomatous functional loss in eyes with HM.MethodsThis...

Chromatic pupillometry isolation and evaluation of intrinsically photosensitive retinal ganglion cell-driven pupillary light response in patients with retinitis pigmentosa.

The pupil light response (PLR) is driven by rods, cones, and intrinsically photosensitive retinal ganglion cells (ipRGCs). We aimed to isolate ipRGC-driven pupil responses using chromatic pupillometry and to determine the effect of advanced retinitis pigmentosa (RP) on ipRGC function. A total of 100 eyes from 67 patients with advanced RP and 18 healthy controls (HCs) were included. Patients were divided into groups according to severity of visual impairment: no light perception (NLP, 9 eyes), light perception (LP, 19 eyes), faint form perception (FFP, 34 eyes), or form perception (FP, 38 eyes). Pupil responses to rod-weighted (487 nm, -1 log cd/m2, 1 s), cone-weighted (630 nm, 2 log cd/m2, 1 s), and ipRGC-weighted (487 nm, 2 log cd/m2, 1 s) stimuli were recorded. ipRGC function was evaluated by the postillumination pupil response (PIPR) and three metrics of pupil kinetics: maximal contraction velocity (MCV), contraction duration, and maximum dilation velocity (MDV). We found a slow, sustained PLR response to the ipRGC-weighted stimulus in most patients with NLP (8/9), but these patients had no detectable rod- or cone-driven PLR. The ipRGC-driven PLR had an MCV of 0.269 ± 0.150%/s and contraction duration of 2.562 ± 0.902 s, both of which were significantly lower than those of the rod and cone responses. The PIPRs of the RP groups did not decrease compared with those of the HCs group and were even enhanced in the LP group. At advanced stages, ipRGC responses gradually became the main component of the PLR. Chromatic pupillometry successfully isolated an ipRGC-driven PLR in patients with advanced RP. This PLR remained stable and gradually became the main driver of pupil contraction in more advanced cases of RP. Here, we present baseline data on ipRGC function; we expect these findings to contribute to evaluating and screening candidates for novel therapies.

Evaluation of the Glaucomatous Macular Damage by Chromatic Pupillometry.

This study aimed to examine the performance of binocular chromatic pupillometry for the objective and rapid detection of primary open-angle glaucoma (POAG), and to explore the association between pupillary light response (PLR) features and structural glaucomatous macular damage. Forty-six patients (mean age 41.00 ± 13.03years) with POAG and 23 healthy controls (mean age 42.00 ± 11.08years) were enrolled. All participants underwent sequenced PLR tests of full-field, superior/inferior quadrant-field chromatic stimuli using a binocular head-mounted pupillometer. The constricting amplitude, velocity, and time to max constriction/dilation, and the post-illumination pupil response (PIPR) were analyzed. The inner retina thickness and volume measurements were determined by spectral domain optical coherence tomography. In the full-field stimulus experiment, time to pupil dilation was inversely correlated with perifoveal thickness (r = -0.429, P < 0.001) and perifoveal volume (r = -0.364, P < 0.001). Dilation time (AUC 0.833) showed good diagnostic performance, followed by the constriction amplitude (AUC 0.681) and PIPR (AUC 0.620). In the superior quadrant-field stimulus experiment, time of pupil dilation negatively correlated with inferior perifoveal thickness (r = -0.451, P < 0.001) and inferior perifoveal volume (r = -0.417, P < 0.001). The dilation time in response to the superior quadrant-field stimulus showed the best diagnostic performance (AUC 0.909). In the inferior quadrant-field stimulus experiment, time to pupil dilation (P < 0.001) correlated well with superior perifoveal thickness (r = -0.299, P < 0.001) and superior perifoveal volume (r = -0.304, P < 0.001). The use of chromatic pupillometry offers a patient-friendly and objective approach to detect POAG, while the impairment of PLR features may serve as a potential indicator of structural macular damage.

Blue-light stimulation of the blind-spot constricts the pupil and enhances contrast sensitivity.

Short- and long-wavelength light can alter pupillary responses differently, allowing inferences to be made about the contribution of different photoreceptors on pupillary constriction. In addition to classical retinal photoreceptors, the pupillary light response is formed by the activity of melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGC). It has been shown in rodents that melanopsin is expressed in the axons of ipRGCs that bundle at the optic nerve head, which forms the perceptual blind-spot. Hence, the first aim of this study was to investigate if blind-spot stimulation induces a pupillary response. The second aim was to investigate the effect of blind-spot stimulation by using the contrast sensitivity tests. Fifteen individuals participated in the pupil response experiment and thirty-two individuals in the contrast sensitivity experiment. The pupillary change was quantified using the post-illumination pupil response (PIPR) amplitudes after blue-light (experimental condition) and red-light (control condition) pulses in the time window between 2 s and 6 s post-illumination. The contrast sensitivity was assessed using two different tests: the Freiburg Visual Acuity Test and Contrast Test and the Tuebingen Contrast Sensitivity Test, respectively. Contrast sensitivity was measured before and 20 minutes after binocular blue-light stimulation of the blind-spot at spatial frequencies higher than or equal to 3 cycles per degree (cpd) and at spatial frequencies lower than 3 cpd (control condition). Blue-light blind-spot stimulation induced a significantly larger PIPR compared to red-light, confirming a melanopsin-mediated pupil-response in the blind-spot. Furthermore, contrast sensitivity was increased after blind-spot stimulation, confirmed by both contrast sensitivity tests. Only spatial frequencies of at least 3 cpd were enhanced. This study demonstrates that stimulating the blind-spot with blue-light constricts the pupil and increases the contrast sensitivity at higher spatial frequencies.

0648 Retinal responsivity is associated with light and season-related cognitions in older adults with seasonal depression

Abstract Introduction Maladaptive cognitions associated with lower light availability in winter and the changing of the seasons are elevated in winter depression and are treatment targets in psychotherapy. Mechanisms underlying the development of SAD-specific cognitions may be related to seasonal variation in melanopsin-driven retinal responsivity to light. Prior work has shown reduced retinal responsivity to light during the winter in seasonal depression. We hypothesized maladaptive seasonal cognitions would be associated with reduced retinal responses to light. We also tested whether age moderated this relationship, hypothesizing that this learned association may only appear in older individuals who have experienced a greater number of seasonal depressive episodes. Methods Participants ages 19-65 (M=36.13, SD=12.81) with seasonal depression (n=37) and non-depressed controls (n=32) completed assessments in winter months (21st December to 21st March). Maladaptive seasonal cognitions were measured by the Seasonal Beliefs Questionnaire (SBQ). Melanopsin-driven retinal responsivity was assessed using the post illumination pupil response (PIPR). Net PIPR as a percent of baseline was averaged across the 10-30 seconds post-stimulus for use in analyses. Using multiple regression, we tested (1) if seasonal beliefs predict the PIPR and (2) if an interaction between seasonal beliefs and age predicts the PIPR, controlling for gender, the pupillary light reflex (PLR), and circadian time of testing from Dim Light Melatonin Onset. Results Seasonal beliefs were not associated with the PIPR (b= -0.86e-5, SE=0.27e-3, p=0.98). There was a significant interaction between seasonal beliefs and age on the PIPR (b= -0.56e-4, SE=0.23e-4, p=0.02), in which greater seasonal beliefs were associated with reduced PIPR in older individuals but not younger individuals. The Johnson-Neyman interval indicated that in participants above age 49, greater seasonal beliefs were significantly associated with lower retinal responsivity (PIPR; p&amp;lt; 0.05). Conclusion Greater seasonal beliefs were associated with reduced retinal responsivity, but only in older adults with seasonal depression. It is possible that reduced retinal responsivity creates learned maladaptive schemas regarding seasonal changes that are reinforced with annually recurring winter depressive episodes. However, longitudinal data focused on changes in seasonal beliefs resulting from reduced retinal sensitivity is necessary to test whether retinal responsivity is a mechanism in the formation of these seasonal-specific cognitions. Support (if any)

0628 Retinal responsivity increases after light therapy and is associated with improved depression: Preliminary findings from a RCT

Abstract Introduction Light therapy is a first line treatment for seasonal depression but is not effective for everyone. Understanding mechanisms of light therapy may help predict who will successfully respond to treatment. Individual differences in the retina’s responsivity to light may underlie differences in treatment response given prior work linking reduced retinal responsivity in seasonal depression. This study tested if retinal responsivity changed across a light therapy intervention and whether changes in retinal responsivity were associated with improved depression. Methods Participants diagnosed with Major Depressive Disorder, With Seasonal Pattern were randomized to 6 weeks of light therapy or cognitive behavioral therapy for seasonal affective disorder (CBT-SAD). Participants in the light therapy group (N=52) were on average 41.9 years (SD=14.8) and predominantly women (72%). Retinal responsivity was assessed using the post-illumination pupil response (PIPR), measured mid-day in winter pre- and post-treatment. The net PIPR (red minus blue) was calculated as a percent of baseline 10-30 seconds post stimulus. Depression severity was measured using the Structured Interview Guide for the Hamilton Depression Rating Scale – Seasonal Affective Disorder version (SIGH-SAD). Using multilevel models, we tested 1) if the PIPR changed from pre- to post-treatment and 2) if changes in the PIPR predicted improvements in depression. All analyses included a random intercept of participant ID and controlled for age, gender, time of testing, and the pupillary light reflex (PLR). Results There was a significant main effect of time on the PIPR, such that PIPR increased from pre- to post-light treatment (b=0.29; SE=0.13; p=0.03). There was a significant negative association between changes in PIPR and changes in depression, such that increases in PIPR were associated with decreases in depression symptom severity (b= -0.18; SE=0.06; p=0.01). Conclusion Retinal responsivity increased across a light therapy intervention and increases in retinal responsivity were associated with improved depression. It is possible an upregulation in retinal responsivity drives antidepressant effects of light therapy, either through direct or circadian pathways. However, changes in retinal responsivity measured throughout treatment are required to discern whether these changes are mechanistic. Support (if any)

0653 The effects of light exposure on retinal responsivity in seasonal affective disorder

Abstract Introduction Seasonal affective disorder (SAD) is characterized as patterned depressed mood that emerges during the fall/winter and enters remission during the spring/summer. Retinal responsivity is lower in SAD in the winter and may contribute to the seasonal pattern of mood disruption (Roecklein et al., 2021). Light exposure in the month prior has been shown to influence retinal responsivity (Kawasaki et al., 2018). No work to date has investigated how more proximal prior light history may influence retinal responsivity differently in individuals with SAD versus controls. This study sought to examine group differences in how environmental blue light exposure impacts retinal responsivity in the 2 hours prior. Methods Participants included 19 never depressed controls (Mean Age = 33, SD = 11), and 17 individuals diagnosed with SAD (Mean Age = 36, SD = 10). SAD episode criteria were assessed using the SCID-5 and SIGH-SAD. Retinal responsivity was measured using the Post-Illumination Pupil Response (PIPR) in the winter months. The PIPR was calculated as percent of baseline difference between the blue and red stimuli from 10-30 secs. Light exposure was measured using the Phillips Actiwatch blue light levels in photon flux in 30-second epochs for 2 hours before the PIPR. Means were calculated and cube transformed to account for right skew. Covariates included circadian time of PIPR testing, calculated from DLMO, and Pupil Light Reflex as a measure of retinal irradiance. Results Multiple regressions were performed for the SAD and control groups, separately. Results indicated that the mean blue-light exposure 2-hours before the PIPR did not significantly predict PIPR in either group (Control group: b = -13e-7, p = 0.31/ SAD group: b = -12e-7, p = 0.13). Conclusion This is the first study to find that light exposure within the prior 2 hours does not influence retinal responsivity in SAD or control participants. Future studies should evaluate different light exposure parameters, such as a longer duration of light exposure before the PIPR, variation in light exposure across different timeframes, and circadian time of light exposure. Support (if any)

Pupillometry to differentiate idiopathic hypersomnia from narcolepsy type 1.

Idiopathic hypersomnia is poorly diagnosed in the absence of biomarkers to distinguish it from other central hypersomnia subtypes. Given that light plays a main role in the regulation of sleep and wake, we explored the retinal melanopsin-based pupil response in patients with idiopathic hypersomnia and narcolepsy type 1, and healthy subjects. Twenty-seven patients with narcolepsy type 1 (women 59%, 36 ± 11.5 years old), 36 patients with idiopathic hypersomnia (women 83%, 27.2 ± 7.2 years old) with long total sleep time (> 11/24 hr), and 43 controls (women 58%, 30.6 ± 9.3 years old) were included in this study. All underwent a pupillometry protocol to assess pupil diameter, and the relative post-illumination pupil response to assess melanopsin-driven pupil responses in the light non-visual input pathway. Differences between groups were assessed using logistic regressions adjusted on age and sex. We found that patients with narcolepsy type 1 had a smaller baseline pupil diameter as compared with idiopathic hypersomnia and controls (p < 0.05). In addition, both narcolepsy type 1 and idiopathic hypersomnia groups had a smaller relative post-illumination pupil response (respectively, 31.6 ± 13.9% and 33.2 ± 9.9%) as compared with controls (38.7 ± 9.7%), suggesting a reduced melanopsin-mediated pupil response in both types of central hypersomnia (p < 0.01). Both narcolepsy type 1 and idiopathic hypersomnia showed a smaller melanopsin-mediated pupil response, and narcolepsy type 1, unlike idiopathic hypersomnia, also displayed a smaller basal pupil diameter. Importantly, we found that the basal pupil size permitted to well discriminate idiopathic hypersomnia from narcolepsy type 1 with a specificity=66.67% and a sensitivity=72.22%. Pupillometry may aid to multi-feature differentiation of central hypersomnia subtypes.

The melanopsin-mediated pupil response is reduced in idiopathic hypersomnia with long sleep time

Idiopathic hypersomnia (IH), characterized by an excessive day-time sleepiness, a prolonged total sleep time on 24 h and/or a reduced sleep latency, affects 1 in 2000 individuals from the general population. However, IH remains underdiagnosed and inaccurately treated despite colossal social, professional and personal impacts. The pathogenesis of IH is poorly known, but recent works have suggested possible alterations of phototransduction. In this context, to identify biomarkers of IH, we studied the Post-Illumination Pupil Response (PIPR) using a specific pupillometry protocol reflecting the melanopsin-mediated pupil response in IH patients with prolonged total sleep time (TST > 660 min) and in healthy subjects. Twenty-eight patients with IH (women 86%, 25.4 year-old ± 4.9) and 29 controls (women 52%, 27.1 year-old ± 3.9) were included. After correction on baseline pupil diameter, the PIPR was compared between groups and correlated to sociodemographic and sleep parameters. We found that patients with IH had a lower relative PIPR compared to controls (32.6 ± 9.9% vs 38.5 ± 10.2%, p = 0.037) suggesting a reduced melanopsin response. In addition, the PIPR was not correlated to age, chronotype, TST, nor depressive symptoms. The melanopsin-specific PIPR may be an innovative trait marker of IH and the pupillometry might be a promising tool to better characterize hypersomnia.

0199 Iris color predicts melanopsin-driven retinal responses in older but not younger individuals

Abstract Introduction The retina contains melanopsin-containing retinal ganglion cells, which underlie non-image forming responses to light. The Post-Illumination Pupil Response (PIPR) can assess melanopsin cell responsivity, with applications for sleep disorders, mood disorders, and circadian entrainment. Lighter pigmented irises allow more light to pass through the retina. The present study tested an association between the PIPR and iris pigmentation. Methods Participants (N=49) included seasonal depression (n=26) and never-depressed controls (n=23). Photos of participants’ irises were rated using both the Franssen (2008) scale, a set of 24 standardized iris photos, and the Mackey (2011) scale, a 9-category rating system. Red and blue stimuli 13.5 log photons/cm2/s were presented, and infrared pupillometry measured pupil diameter for 40 seconds. We used multilevel regression with a random intercept of participant to predict the PIPR from each iris rating system separately, controlling for age, gender, and circadian time of testing determined from Dim Light Melatonin Onset. Results Agreement between raters, calculated using Cohen's κ, was moderate for both scales (Franssen, κ=0.57, 95% CI: 0.42 to 0.71, p&amp;lt;0.001; Mackey, κ=0.67, 95% CI: 0.53 to 0.81, p&amp;lt;0.001). Bivariate correlations showed age was inversely associated with iris color: older individuals had lighter iris pigmentation. Analyses were therefore stratified by age (older &amp;gt;=31 years: n=24; younger &amp;lt;31 years, n=25). Greater retinal responsivity was associated with lighter iris pigmentation in the older sample (Mackey: unstandardized b=-0.016; SE=0.005; p=0.002; Franssen: unstandardized b=-0.006; SE=0.002, p=0.002), but not the younger sample (Mackey: unstandardized b=-0.0008; SE=0.003; p=0.770; Franssen: unstandardized b=-0.0009; SE=0.002, p=0.619). There was no effect of iris color on PIPR in the whole sample (p’s &amp;gt;0.13). Conclusion Iris color explained ~8% of variance in the PIPR, indicating that PIPR studies should recruit samples with similar distributions of iris pigmentation across conditions and ages, as this finding was only seen in the older sample with more individuals with lighter iris pigmentation. Future studies will test iris pigmentation by light exposure interactions on the PIPR. Light stimuli focused to a point on the pupil (i.e., Maxwellian) would eliminate variation in the amount of light incident on the retina due to iris pigmentation. Support (If Any) NIMH K.A.R. MH103303

0196 Retinal responsivity is associated with circadian phase and circadian alignment but not sleep timing

Abstract Introduction Light entrains the central circadian clock, with projections from the retina to the SCN through melanopsin-containing retinal ganglion cells (ipRGCs). Altered responsivity to light reflects ipRGC functioning and may be a physiological vulnerability for disrupted photoentrainment. Understanding how retinal responsivity relates to sleep and circadian timing may inform who might most benefit from sleep and circadian interventions. Methods 64 participants (85 observations) ages 20-66 years old were recruited during winter (n=35) and summer months (n=50), and included individuals with seasonal depression (n=33) and nonseasonal, never depressed controls (n=31). The post-illumination pupil response (PIPR) to red and blue light was used to measure the responsivity of ipRGCs (average 1:30pm; 10am-7pm). Circadian phase was assessed using Dim Light Melatonin Onset (DLMO), collected every 30-minutes on Friday evenings. Midsleep timing was measured using actigraphy (average number nights=4), and circadian alignment was calculated as the DLMO-midsleep phase angle. We performed a multilevel regression to determine the relationship between PIPR and markers of sleep and circadian timing, accounting for repeated seasonal assessments with a random intercept of participant. Covariates included age, gender, diagnostic group, and circadian time of PIPR assessments. We ran sensitivity analyses including photoperiod length on the day of PIPR assessment to account for potential light exposure on the PIPR. Results Greater retinal responsivity was associated with later DLMO (b=4.45; partially standardized b=0.28; SE=1.84; p=0.03), and shorter DLMO-midsleep phase angle (b= -7.33; partially standardized b= -0.32; SE=2.51; p=0.004), but not midsleep (b= -3.44; partially standardized b= -0.14; SE=2.35; p&amp;gt;0.05). Individuals with later DLMO had PIPR assessments at earlier circadian times (b= -0.12; SE=0.04; p=0.01). Older participants (b= -0.04; SE=0.02; p=0.04) and controls (b= -0.95; SE=0.44; p=0.04) had earlier sleep midpoints, but covariates were not associated with circadian markers. The association between circadian timing and PIPR became nonsignificant (b=4.15; partially standardized b=0.26; SE=1.88; p=0.06) when including photoperiod. Conclusion Retinal responsivity was associated with circadian but not behavioral sleep timing, suggesting ipRGC functioning may have downstream effects on circadian entrainment. Assessing circadian variation of retinal responsivity remains a crucial next step prior to testing whether retinal responsivity impacts response to circadian-focused interventions. Support (If Any) NIMH K.A.R.MH103303

0212 Habitual Heavy Alcohol Drinking in Healthy Adults is Associated With Reduced Circadian Photoreceptor Responsivity to Light

Abstract Introduction Habitual alcohol consumption and circadian timing are interconnected. Numerous studies have reported that heavy alcohol use is associated with eveningness. Only two studies have assessed the dim light melatonin onset (DLMO) in the context of habitual alcohol use, and both reported a shorter DLMO-midsleep interval was associated with heavier alcohol consumption. A gap in this research is the potential impact of alcohol use on the primary circadian photoreceptor, the intrinsically photosensitive retinal ganglion cells (ipRGCs), which influence circadian timing. This study aimed to compare sleep, circadian timing, and photoreceptor responsivity between light and heavy alcohol drinkers. Methods Participants were healthy (average age 27 years) and included 28 light (average 2.6 drinks/week) and 50 heavy (average 17.9 drinks/week) drinkers. They participated in an 8-day study protocol: 1 week of adlib sleep monitored with wrist actigraphy, followed by a 9-hour laboratory session with a photoreceptor responsivity (post-illumination pupil response, PIPR) and circadian phase assessment. Participants passed a breathalyzer test at the start of the laboratory session. Results Both drinking groups were good sleepers with minimal mood disturbance. Consistent with earlier studies, the heavy drinkers had more eveningness (p=0.029), and a trend for a shorter DLMO-midsleep interval (p=0.059) as compared to the light drinkers. The PIPR in the heavy drinkers was significantly smaller than in the light drinkers (p=0.006), suggesting reduced circadian photoreceptor responsivity in the heavy drinkers. In the light drinkers, a larger PIPR in the evening, reflecting greater sensitivity to phase-delaying light, was significantly associated with a later DLMO (r=0.42, p=0.028). However, this relationship was absent in the heavy drinkers (r=-0.07, p=0.68). Conclusion The findings replicate previous work examining the relationship between chronotype, DLMO, and habitual alcohol consumption. For the first time, circadian photoreceptor responsivity was examined, and found to be significantly reduced in heavy alcohol drinkers as compared to light alcohol drinkers. This finding is consistent with prior rodent studies that found reduced phase shifts to light with acute or chronic alcohol consumption, and suggests that habitual heavy alcohol use may impair the circadian response to light in humans. Support (If Any) Grant awarded from NIAAA R01 AA023839.