The importance of intrinsically photosensitive retinal ganglion cells and implications for lighting design

Impact on health

A normal ipRGC function is important for normal biological, physiological activities and health. IpRGCs are found to be important for several non-retinal diseases, such as sleep disorders, seasonal affective disorder, mood disorders, and migraines [20]. One of the critical mechanisms for ipRGCs affect health is their photic input to the circadian system.

In a simple configuration, the central circadian system can be conceptualized as having three components: (1) the central clock, which generates the rhythms, (2) input pathways that provide signals to synchronize the central clock, and (3) output pathways that convey the central clock signal to other regulatory systems in the brain and body (Fig. 2). The central circadian clock exists in the SCN, a tiny region located in the hypothalamus, sitting right above the optic chiasm. There are three major neural input pathways to the SCN: (1) retinal photoreceptors that transmit the light signal to the SCN via the retinohypothalamic tract, (2) neuronal projections from the raphe nuclei, which provide non-photic inputs, and (3) neuronal projections from the intergeniculate leaflet (IGL), which also receives inputs from the retina and raphe nuclei. The output pathways are implicated in the control of the endocrine system (such as melatonin release), and other brain and body regions controlling various behaviors such as sleep/wake [21, 22].

The correct timing of the central circadian clock relative to the environment is essential for optimal sleep, waking functions and health. In humans, the central circadian clock has an average endogenous period slightly greater than 24 h (~24.2 h) [23]. Daily input signals are required to shift the clock earlier (phase advance) to synchronize the clock’s timing to the external 24-h solar day, and light is the strongest zeitgeber (“time giver”) to the central circadian clock. In humans, light in the evening or first part of the night causes the clock to shift rhythms later (phase delay) and light in the morning shift the clock earlier (phase advance). Thus morning light is essential for producing corrective daily phase advances in humans, while evening light can produce phase delays, which exacerbate the human clock’s endogenous tendency to drift later and promote circadian misalignment. Circadian misalignment can lead to difficulty in falling asleep, maintaining sleep, excessive daytime sleepiness lower quality of life, worsen mood and well-being, worsen depression, reduce cognitive performance and increase rates of myocardial infarction and cancer [20, 21, 24–28].

IpRGCs can not only influence health through their photic input to the circadian system, but also provide direct information to brain areas that are important for sleep, cognition, and mood [35]. In addition, ipRGCs are found to be related to retinal diseases such as glaucoma and age-related macular degeneration [29]. Thus, ipRGCs exerts a major influence on circadian timing, which in turn impacts mental and physical health.

Impact on pupil responses

IpRGCs send photic signals to the OPN to control pupil light responses [10]. Pupil size variation produces a number of changes in retinal stimulation to affect visual functions, including retinal illuminance (the amount of light falling into the retina), the ratio of rod/cone stimulation, spectral sensitivity and spatial resolution [30]. In fact, the melanopsin spectral sensitivity function estimated from in vivo post-illumination pupil response (PIPR) in humans or macaques [31] is almost identical to that measured from in vitro ipRGC recording in macaques (peak at 482 nm) [3]. Therefore, pupil light reflex measurement can be used as a functional marker of ipRGC response. We now know that tonic pupil responses are driven preferentially by melanopsin activation, while rod and cones are combined to signal phasic pupil responses [5, 32]. Further, compared with cone-mediated PIPR, the melanopsin-mediated PIPR has long integration duration [33] and large spatial summation area [34].

Impact on visual perception

Compared with rod or cone photopigment, melanopsin phototransduction is extremely sluggish [35]. In addition, ipRGCs are rare (~3,000, only ~0.2 % of total number of RGCs in the primate or human retina) with large cell bodies, dendrite trees and large receptive fields (least 5–10 times more extensive than those for classical RGCs) [3]. It is proposed that ipRGCs sacrifice spatiotemporal resolution to reliably signal ambient illumination levels [35]. However, emerging evidences have shown that melanopsin activation in ipRGCs contributes to visual perception directly or indirectly.

IpRGCs act as a photon counter in the same way than a light meter in a camera [3, 36]. This unique capability, not shared by other photoreceptors, could serve as a reference for the visual system to optimize light adaptation. Indeed, melanopsin has been found to regulate cone electroretinograms (ERGs) in mice [37] or humans [38]. More recently, it is reported that melanopsin activation level can modulate the spatial/temporal tuning patterns of visual network [36].

Melanopsin activation can affect visual perception directly. It has been reported that humans lacking an outer retina [39] or animals with rods and cones ablated genetically [40] can preserve some light detection functions. In people with normal retinas, melanopsin activation could contribute to brightness discrimination [40], chromatic discrimination [41], color perception [42, 43] and contrast sensitivity [4, 44]. However, the mechanisms for melanopsin activation affecting conscious visual perception are not well-understood.

Visual perception in primates and humans is mediated by three primary visual pathways that transfer visual information from the retina to different layers of the LGN and then subsequently to the visual cortex, including the magnocellular (MC-), parvocellular (PC-), and koniocellular (KC-) pathways [45, 46]. These pathways combine differential long (L-), middle (M-) and short (S-) wavelength sensitive cone signals. The MC-pathway processes summed L- and M-cone excitations to signal luminance information. The PC-pathway uses the difference in L- and M-cone excitations to mediate the “red-green” chromatic signal. The KC-pathway processes the responses of S-cones opposed to the sum of L- and M-cones to signal the “blue-yellow” chromatic information. However, we have no direct knowledge about how signals arising from melanopsin contribute to the three primary visual pathways to alter visual perception. Using principal component analyses based on the excitations of the melanopsin, rods, S-, M- and L-cones for 9 hyperspectral natural images under 21 natural illuminants, we analyzed the contribution of melanopsin activation to the three primary visual pathways, namely the MC-, PC- and KC- pathways. With only cone excitations considered, the principal components revealed were consistent with the patterns of cone combinations in the MC-, PC- and KC-pathways [47]. Further analysis indicated that melanopsin contributed strongly to the MC- and KC-pathways and weakly to the PC-pathway [5]. It is known that red-green color vision mediated by the PC pathways was evolved much later than the MC- and KC-pathways [48], therefore from an evolution perspective, it makes senses that melanopsin activation has a weaker input to the PC-pathway.

Implications in lighting design

Traditionally, lighting industry guidelines followed several scientific principles for efficacy (energy efficiency), light quantity (illumination levels), light quality (color temperature, color rendition, glare, etc.) and lighting uses (ambient, task or accent lighting). The discovery of ipRGCs introduces a new dimension of considerations for lighting or display designs: that is, how to minimize the adverse effect of artificial lights, via ipRGC phototransduction, on mental and physical health while maximize visual functions and energy efficiency (Fig. 3).

Biological adaptation to the sun has evolved over millions of years, however, people in modern society spend a large portion of their time in environments illuminated by artificial lights, working in front of computer displays, watching TV, or interacting with smartphones/tablets for reading, internet surfing, social networking, or video gaming etc. Compared with natural sunlight, the artificial illuminants or display lights are substantially dimmer than daylight, and have different spectral compositions (thus different melanopsin activation levels). Our computation indicated that the artificial illuminants (5 LEDs, 5 High Pressure Sodium lamps, and 27 fluorescents) have significantly lower melanopsin activation level than 25 CIE D natural daylights ([7], Fig. 4). Therefore, indoor workers would experience substantially lower melanopsin excitations compared with outdoor daylight. On the other hand, the artificial lights can be turned on at any time, such as nighttime thus replacing the natural light–dark transition. These abrupt state-light changes will potentially disrupt normal biological and physiological functions, causing various adverse health effects, such as circadian rhythm disruption, sleep disorders, mood disorders, and even cancer [20, 21, 24–28]. For example, a latest study demonstrated that evening use of light-emitting-eReaders impaired sleep, circadian timing and next-morning alertness [49], although the real impact of evening use of eReaders on circadian rhythm will depend on prior light exposure history [50, 51]. Therefore, lighting (ambient and occupational lighting or display lighting) has become a public health issue [52]. To improve human quality of life and health, how to design artificial lights to optimize NIF functions (which are important for physical and mental health) as well as image-forming functions (which are important for normal daily function and life quality) has become an important issue. Additionally, primate ipRGCs responds excitatory to melanopsin activation, rod, L- and M-cone inputs but inhibitory to S-cone inputs [3]. This unique characteristic of its receptive field was shown to appear in pupillary recordings [4, 53]. This chromatic opponency of ipRGCs may also be evolved to signal the large spectral changes, from bluish to orangish, produced at dawn and dusk to set the biological clock more precisely [3] and effectively [54]. Artificial lighting with unvaried chromaticities cannot trigger ipRGCs’ responses as natural sunlight. However, more research is needed to fully understand how ipRGCs impact health and provide scientific guidelines for lighting design.

Finally, the discovery of ipRGCs will have great implication of light specification and regulation. Currently, regulations for lighting industry are based on photometry units (i.e. lux for illuminance or cd/m² for luminance). These units consider a particular visual function, the combination of L- and M-cone in the magnocellular pathway. Although many other visual functions could be considered, this function produces the additive photopic spectral-luminosity function V_λ, which is suitable for use in lighting industry [55]. However, melanopsin spectral sensitivity function is shifted to shorter wavelengths with respect to the overwhelmingly used V_λ. Therefore traditional photopic units cannot reflect the state of melanopsin activation that is important for health and perception. Recently, new approaches were proposed to cope with this issue by considering melanopsin activation [56, 57].