Measuring and using light in the melanopsin age
Authors: Robert J. Lucas, Stuart N. Peirson, David M. Berson, Timothy M. Brown, Howard M. Cooper, Charles A. Czeisler, Mariana G. Figueiro, Paul D. Gamlin, Steven W. Lockley, John B. O’Hagan, Luke L.A. Price, Ignacio Provencio, Debra J. Skene, George C. Brainard
Journal: Trends in Neurosciences (2013)

•Photoreceptive retinal ganglion cells (ipRGCs) regulate behavior and physiology.•ipRGCs use melanopsin-dependent intrinsic light responses and rod/cone inputs.•The relative contribution of each photoreceptor to evoked responses is not fully understood.•A method for quantifying light is presented that accounts for complex photoreceptive inputs.•Guidance for those designing architectural and therapeutic lighting is provided. Light is a potent stimulus for regulating circadian, hormonal, and behavioral systems. In addition, light therapy is effective for certain affective disorders, sleep problems, and circadian rhythm disruption. These biological and behavioral effects of light are influenced by a distinct photoreceptor in the eye, melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs), in addition to conventional rods and cones. We summarize the neurophysiology of this newly described sensory pathway and consider implications for the measurement, production, and application of light. A new light-measurement strategy taking account of the complex photoreceptive inputs to these non-visual responses is proposed for use by researchers, and simple suggestions for artificial/architectural lighting are provided for regulatory authorities, lighting manufacturers, designers, and engineers. Light is a potent stimulus for regulating circadian, hormonal, and behavioral systems. In addition, light therapy is effective for certain affective disorders, sleep problems, and circadian rhythm disruption. These biological and behavioral effects of light are influenced by a distinct photoreceptor in the eye, melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs), in addition to conventional rods and cones. We summarize the neurophysiology of this newly described sensory pathway and consider implications for the measurement, production, and application of light. A new light-measurement strategy taking account of the complex photoreceptive inputs to these non-visual responses is proposed for use by researchers, and simple suggestions for artificial/architectural lighting are provided for regulatory authorities, lighting manufacturers, designers, and engineers. During the past three decades, empirical evidence has demonstrated that many aspects of human physiology and behavior are influenced by retinal illumination [1Aschoff J. Biological Rhythms (Handbook of Behavioral Neurobiology No. 4). Plenum, 1981Google Scholar, 2Wurtman R.J. et al.The Medical and Biological Effects of Light. The New York Academy of Sciences, 1985Google Scholar, 3Wetterberg L. Light and Biological Rhythms in Man. Pergamon Press, 1993Google Scholar, 4Lam R.W. Beyond Seasonal Affective Disorder: Light Treatment for SAD and non-SAD Disorders. American Psychiatric Press, 1996Google Scholar]. Such responses originate in the eye but are separate from other aspects of vision insofar as they are unrelated to particular spatial patterns of light exposure, and can survive even in some blind subjects. Consequently, these types of light responses have been commonly referred to as non-image-forming or non-visual. These catch-all terms encompass a wide array of response types. The most influential is light-induced phase resetting of endogenous circadian clocks. Because circadian rhythmicity is a feature of nearly every physiological, metabolic, and behavioral system, this phenomenon brings a wide array of biological processes under indirect retinal control. Beyond this, the term non-visual response has come to encompass a growing list of more acute effects of light that together ensure a day-like physiological state. Thus, for example, light constricts the pupil, suppresses pineal melatonin production, increases heart rate and core body temperature, stimulates cortisol production, and acts as a neurophysiological stimulant (increasing subjective and objective measures of alertness and psychomotor reaction time, and reducing lapses of attention). Appreciation of this basic biology has led to the development of a number of therapeutic applications. Light has been shown to have anti-depressant properties, particularly in the treatment of seasonal affective disorder (SAD) and its subclinical variant sSAD [3Wetterberg L. Light and Biological Rhythms in Man. Pergamon Press, 1993Google Scholar, 4Lam R.W. Beyond Seasonal Affective Disorder: Light Treatment for SAD and non-SAD Disorders. American Psychiatric Press, 1996Google Scholar]. Appropriately timed light exposure has also been developed as therapy for circadian-rhythm sleep disorders and circadian disruption associated with jetlag, shift work, and space flight. Finally, light has been explored as a treatment for non-seasonal depression, menstrual-cycle-related problems, bulimia nervosa, and cognitive and fatigue problems associated with senile dementia, chemotherapy, and traumatic brain injury [3Wetterberg L. Light and Biological Rhythms in Man. Pergamon Press, 1993Google Scholar, 4Lam R.W. Beyond Seasonal Affective Disorder: Light Treatment for SAD and non-SAD Disorders. American Psychiatric Press, 1996Google Scholar, 5Tuunainen A. et al.Light therapy for non-seasonal depression.Cochrane Database Syst. Rev. 2004; 2: 1-83Google Scholar, 6J. Biol. Rhythms. 2005; 20: 279-386Crossref PubMed Scopus (177) Google Scholar]. These effects of light on physiology and behavior evolved over millennia in which environmental illumination provided a reliable indicator of time of day. The advent of electrical lighting has disrupted this relationship, with patterns of light exposure now also reflecting personal tastes and social pressures. It is important therefore that non-visual effects of light are incorporated into considerations for lighting design. Thus, for example, one might ask to what extent a given architectural lighting replicates the biological effects of natural daylight; how lighting could be employed to minimize the deleterious effects of shiftwork while promoting alertness and safety; or how light therapy could be optimized. The lighting industry and academic researchers have started to address these problems [7CIE Ocular Lighting Effects on Human Physiology and Behaviour. 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A radiometer quantifies radiant power over a defined bandwidth of electromagnetic energy. Photometry is a specialized branch of radiometry that takes into account the fact that biological photoreceptors are not equally sensitive to light at all wavelengths. A photometer is a radiometer that uses filters to weight the detector response to different wavelengths according to the spectral sensitivity of an aspect of human vision. Most commercially available photometers use a weighting function termed the photopic luminous efficiency function (or Vλ), which reflects the spectral sensitivity of long- and middle-wavelength-sensitive cones [11CIE Commission Internationale de l'Éclairage Proceedings, 1924, Cambridge University Press1926Google Scholar]. Depending on the geometric properties of interest, luminous intensity (units of lumens/sr or candelas, cd), luminance (cd/m2), or illuminance (lm/m2 or lux) can be determined from the output of these devices. Between 1980 and 2000, the great majority of studies on human circadian, endocrine, behavioral, and therapeutic responses to light quantified stimuli in terms of photopic illuminance (lux) [1Aschoff J. Biological Rhythms (Handbook of Behavioral Neurobiology No. 4). Plenum, 1981Google Scholar, 2Wurtman R.J. et al.The Medical and Biological Effects of Light. The New York Academy of Sciences, 1985Google Scholar, 3Wetterberg L. Light and Biological Rhythms in Man. Pergamon Press, 1993Google Scholar]. During that time, lux meters were readily available and inexpensive because they were the tool of choice in the lighting and photographic professions. Two related branches of investigation have since shown that this practice is inadequate. First, during the last decade it was discovered that whereas the photoreceptive capacity of the retina is dominated by rods and cones, a few of the retinal output neurons (retinal ganglion cells) are also directly photosensitive [12Berson D.M. et al.Phototransduction by retinal ganglion cells that set the circadian clock.Science. 2002; 295: 1070-1073Crossref PubMed Scopus (2514) Google Scholar, 13Hattar S. et al.Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity.Science. 2002; 295: 1065-1070Crossref PubMed Scopus (1935) Google Scholar]. These intrinsically photoreceptive retinal ganglion cells (ipRGCs) achieve this photoreceptive capacity through expression of melanopsin, an opsin photopigment [14Provencio I. et al.Melanopsin: an opsin in melanophores, brain, and eye.Proc. Natl. Acad. Sci. U.S.A. 1998; 95: 340-345Crossref PubMed Scopus (746) Google Scholar, 15Provencio I. et al.A novel human opsin in the inner retina.J. 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Unfortunately, to date there is no established replacement. This omission has important practical consequences. For researchers, the absence of a suitable and agreed method of light measurement makes it difficult to compare findings or replicate experimental conditions. It also represents a significant barrier to relating laboratory findings to lighting applications, and makes it difficult for the lighting industry and regulators to predict the impact of different lighting regimes on behavioral and physiological systems. The fundamental problem in addressing this need has been the difficulty in determining a spectral weighting function (equivalent to Vλ) suitable for non-visual responses. To understand this challenge it is first necessary to review the basic neurophysiology of ipRGCs. Melanopsin, the photopigment of ipRGCs, is structurally and phylogenetically more closely related to the opsins of invertebrate rhabdomeric photoreceptors than to rod and cone opsins [46Borges R. et al.The role of gene duplication and unconstrained selective pressures in the melanopsin gene family evolution and vertebrate circadian rhythm regulation.PLoS ONE. 2012; 7: e52413Crossref PubMed Scopus (20) Google Scholar, 47Nasi E. del Pilar Gomez M. Melanopsin-mediated light-sensing in amphioxus: a glimpse of the microvillar photoreceptor lineage within the deuterostomia.Commun. Integr. Biol. 2009; 2: 441-443Crossref PubMed Scopus (13) Google Scholar]. In common with such invertebrate rhodopsins, the phototransduction cascade engaged by melanopsin results in cellular depolarization [48Hughes S. et al.Melanopsin phototransduction: slowly emerging from the dark.Prog. Brain Res. 2012; 199: 19-40Crossref PubMed Scopus (67) Google Scholar]. 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This sensitivity highlights an important feature of this photoreceptive system: ipRGCs receive input from the outer retina (Figure 1A) . Thus, ipRGC dendrites are targets for synaptic input from bipolar and amacrine cells, as well as being sites for melanopsin-driven phototransduction. As a result, the ipRGC firing pattern is a composite, integrated signal consisting of the intrinsic light response (melanopsin photoreception) and incoming rod- and cone-driven signals [36Dacey D.M. et al.Melanopsin-expressing ganglion cells in primate retina signal colour and irradiance and project to the LGN.Nature. 2005; 433: 749-754Crossref PubMed Scopus (981) Google Scholar]. This arrangement greatly extends the range of stimuli that can elicit circadian and neurophysiological responses, and explains why animals that are genetically null for melanopsin continue to exhibit non-image-forming responses to light [16Lucas R.J. et al.Diminished pupillary light reflex at high irradiances in melanopsin-knockout mice.Science. 2003; 299: 245-247Crossref PubMed Scopus (660) Google Scholar, 54Panda S. et al.Melanopsin (Opn4) requirement for normal light-induced circadian phase shifting.Science. 2002; 298: 2213-2216Crossref PubMed Scopus (672) Google Scholar, 55Ruby N.F. et al.Role of melanopsin in circadian responses to light.Science. 2002; 298: 2211-2213Crossref PubMed Scopus (528) Google Scholar]. At its very origin, the signal driving physiological and behavioral light responses (ipRGC firing) is defined by the combined influence of multiple photoreceptive processes: the melanopsin-driven phototransduction mechanism within the ipRGC itself, and remote photoreception in rods and cones (Figure 1B). Each of these mechanisms of light detection has a distinct spectral sensitivity, defined by the spectral efficiency of the photopigment expressed and the spectral transmission properties of the ocular media.(i)Rods. Rod opsin, the photopigment of rod photoreceptors, shows peak sensitivity (λmax) at approximately 500 nm in all mammalian species. Pre-receptoral filtering shifts this towards somewhat longer wavelength in the standard human observer (507 nm).(ii)Cones. Mammalian genomes typically contain several genes encoding spectrally distinct cone opsins. Humans, and other old world primates, have three types of cones. Human S cones express a short-wavelength-sensitive cone opsin (cyanolabe), maximally sensitive to wavelengths at ∼420 nm; M cones contain a different cone opsin (chlorolabe; peak sensitivity ∼535 nm); L cones contain a red-shifted cone opsin (erythrolabe; peak sensitivity ∼565 nm [56Stockman A. Sharpe L.T. Spectral sensitivities of the middle- and long-wavelength sensitive cones derived from measurements in observers of known genotype.Vision Res. 2000; 40: 1711-1737Crossref PubMed Scopus (561) Google Scholar]). Other mammals lack the chlorolabe/erythrolabe distinction, and have a single cone opsin maximally sensitive in the middle of the human visible spectrum. There are also important species differences in the spectral sensitivity of the cyanolabe pigments. For example, many rodent retinas have a photopigment that is maximally sensitive to near-ultraviolet radiation [57Jacobs G.H. et al.Retinal receptors in rodents maximally sensitive to ultraviolet light.Nature. 1991; 353: 655-657Crossref PubMed Scopus (338) Google Scholar]. In humans, pre-receptoral filtering shifts peak sensitivity of short- and medium-wavelength cones to longer wavelength (∼440 and 545 nm, respectively).(iii)Melanopsin. 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In either event, studies on mice indicate that this factor does not significantly impact the spectral response properties of melanopsin under practical lighting regimes [69Enezi J. et al.A 'melanopic' spectral efficiency function predicts the sensitivity of melanopsin photoreceptors to polychromatic lights.J. Biol. Rhythms. 2011; 26: 314-323Crossref PubMed Scopus (178) Google Scholar, 70Brown T.M. et al.The melanopic sensitivity function accounts for melanopsin-driven responses in mice under diverse lighting conditions.PLoS ONE. 2013; 8: e53583Crossref PubMed Scopus (29) Google Scholar]. The firing rate of ipRGCs may thus be influenced by five (or four in the case of non-primates) spectrally distinct photoreceptors (Figure 1B). It follows that the spectral sensitivity of down