Melanopsin-dependent phototransduction is impaired in delayed sleep–wake phase disorder and sighted non–24-hour sleep–wake rhythm disorder

Abstract

Study Objectives The circadian system must perform daily adjustments to align sleep-wake and other physiologic rhythms with the environmental light-dark cycle: this is mediated primarily through melanopsin containing intrinsically photosensitive retinal ganglion cells. Individuals with delayed sleep-wake phase disorder (DSWPD) exhibit a delay in sleep-wake timing relative to the average population, while those with sighted non-24-hour sleep-wake rhythm disorder (N24SWD) exhibit progressive delays. An inability to maintain appropriate entrainment is characteristic of both disorders. In this study, we test the hypothesis that individuals with DSWPD exhibit alteration in melanopsin dependent retinal photo-transduction as measured with the post-illumination pupil response (PIPR). Methods Twenty-one control and 29 participants with DSWPD were recruited from the community and clinic. Of the 29 DSWPD participants, 17 reported a history of N24SWD. A pupillometer was used to measure the post-illumination pupil response (PIPR) in response to a bright 30s blue or red-light stimulus. The PIPR was calculated as the difference in average pupil diameter at baseline and 10-40s after light stimulus offset. Results The PIPR was significantly reduced in the DSWPD group when compared to the control group (1.26±1.11 mm vs. 2.05±1.04 mm, p&0.05, t-test). The PIPR was significantly reduced in the sighted N24SWD subgroup when compared to individuals with history of only DSWPD (0.88±0.58 mm vs 1.82±1.44 mm, p&0.05, ANOVA) or controls (0.88±0.58 mm vs 2.05±1.04 mm, p&0.01, ANOVA). Conclusions These results indicate that reduced melanopsin dependent retinal photo-transduction may be a novel mechanism involved in the development of DSWPD and sighted N24SWD.

Workshop report. Circadian rhythm sleep–wake disorders: gaps and opportunities

“…within the retina or SCN) may be tested. For example, if a phase disorder is determined to be largely the result of altered light sensitivity [ 13 ] driven by altered function of ipRGCs (which mediate nonvisual responses to light) [ 14 ], or altered downstream processing of ipRGC responses, then novel treatments directly targeting ipRGC response to mitigate the altered physiology may be useful as an adjunct to, or in place of, conventional light therapy and/or melatonin supplementation. Current treatments have a high failure rate, and it is often unclear whether that is due to lack of efficacy or to lack of adherence on the part of the patient.…”

“…Etiology and pathophysiology of ASWPD and DSWPD are poorly understood, but the few studies that have been carried out point to shorter circadian period related to family mutations in ASWPD, and longer circadian period, delayed phase, altered sleep–wake homeostatic responses, and changes in light sensitivity [ 13 ] as potential underlying mechanisms for DSWPD.…”

“…There is no known genetic marker or trigger for N24SWD (with the exception noted later [ 72 ]). Potential etiologies for N24SWD include a long intrinsic period, alterations in light sensitivity [ 13 ], and/or altered rates of buildup of homeostatic pressure, all potentially exacerbated by decreased structured social and physical activity [ 36 ]. In addition, there are case reports of N24SWD induced through chronotherapy [ 72 ], after the treatment strategy of purposefully delaying sleep–wake rhythms as a treatment for DSWPD [ 73 ].…”

“…Comparing results from sighted individuals with and without N24SWD may help determine which zeitgebers are essential for entrainment, and the period length that limits the ability to entrain to a 24-h day. In addition, if it is determined that sighted individuals with N24SWD do not respond appropriately to the common treatments of timed artificial bright light [ 13 ] or exogenous melatonin administration, research on other treatments could be pursued. Further study of entrainment strategies in blind individuals with N24SWD may lead to improved understanding of human circadian entrainment to non-photic zeitgebers in the general population.…”

Human circadian variations

“…Prevalence estimates for DSWPD range by definition and age but are 7%-16% in adolescents and young adults (79). Artificial light in the evening, lack of natural light, an intrinsic period longer than 24 hours, altered phase angle of entrainment, and possibly differential phototransduction to the SCN contribute to this higher prevalence of delayed sleep phase (80). Additional factors include school and work schedules that make sleeping later challenging.…”