The photic blink reflex as an index of photophobia.

Two recent studies of eye closure triggered by intense luminance increase suggest that this behavior reflects the melanopsin-based retinal activity known to underlie photophobia, the pathological aversion to light (Kardon, 2012; Kaiser et al., 2021). Early studies of the photic blink reflex (PBR) are reviewed to help guide future research on this possible objective index of photophobia. Electromyographic recordings of the lid-closure muscle, orbicularis oculi, reveal distinct bursts with typical onset latencies of 50 and 80 ms, R50 and R80, respectively. The latter component appears to be especially sensitive to visual signals from intrinsically photosensitive retinal ganglion cells (ipRGCs) and to prior trigeminal nociceptive stimuli. The authors argue that the R80's function, in addition to protecting the eyeballs from physical contact, is to shape the upper and lower eyelids into a narrow slit to restrict incoming light. This serves to prevent retinal bleaching or injury, while allowing continued visual function.

A new method to quantify the human visual threshold from melanopsin sensitive ganglion cells.

Traditional photoreceptors utilize the chromophore retinal to absorb light coupled with a unique opsin protein to specify receptor spectral sensitivity. Light absorption triggers a cascade of events transducing light energy to neural signals beginning with graded potentials in receptors (rods and cones) and bipolar cells in outer and middle retina eventuating in action potentials at the inner retinal amacrine and ganglion cell levels. Unlike traditional photoreceptors, ganglion cells in the inner retina (intrinsically photosensitive retinal ganglion cells, ipRGCs) absorb short wavelength, blue light utilizing their photopigment melanopsin. Assessment across multiple species show that the ipRGCs mediate myriad visual and non-visual functions including photo-entrainment and circadian rhythms, the pupillary light reflex, sleep, alertness, cognition, mood, and even conscious visual perception. Some ipRGC functions can persist despite blindness in animal models and humans exemplifying their multidisciplinary control of visual and non-visual functions. In previous research we used selective chromatic adaptation (blue stimulus on a bright amber field) to suppress input from rods, red and green sensitive cones to identify retinal and cortical responses from ipRGCs. Herein we used a similar approach, coupled with a filter to block input from blue sensitive cones, to develop a clinically expedient method to measure the full-field, putative visual threshold from human ipRGCs. This metric may expand our ability to detect, diagnose and monitor ocular and neurologic disease and provide a global retinal metric of ipRGCs as a potential outcome measure for studies using gene therapy to arrest and/or improve vision in hereditary retinal diseases.

The Newborn's Reaction to Light as the Determinant of the Brain's Activation at Human Birth.

Developmental neuroscience research has not yet fully unveiled the dynamics involved in human birth. The trigger of the first breath, often assumed to be the marker of human life, has not been characterized nor has the process entailing brain modification and activation at birth been clarified yet. To date, few researchers only have investigated the impact of the extrauterine environment, with its strong stimuli, on birth. This 'hypothesis and theory' article assumes the role of a specific stimulus activating the central nervous system (CNS) at human birth. This stimulus must have specific features though, such as novelty, efficacy, ubiquity, and immediacy. We propose light as a robust candidate for the CNS activation via the retina. Available data on fetal and neonatal neurodevelopment, in particular with reference to retinal light-responsive pathways, will be examined together with the GABA functional switch, and the subplate disappearance, which, at an experimental level, differentiate the neonatal brain from the fetal brain. In this study, we assume how a very rapid activation of retinal photoreceptors at birth initiates a sudden brain shift from the prenatal pattern of functions to the neonatal setup. Our assumption implies the presence of a photoreceptor capable of capturing and transducing light/photon stimulus, transforming it into an effective signal for the activation of new brain functions at birth. Opsin photoreception or, more specifically, melanopsin-dependent photoreception, which is provided by intrinsically photosensitive retinal ganglion cells (ipRGCs), is considered as a valid candidate. Although what is assumed herein cannot be verified in humans based on knowledge available so far, proposing an important and novel function can trigger a broad range of diversified research in different domains, from neurophysiology to neurology and psychiatry.

Burning the candle at both ends: Intraretinal signaling of intrinsically photosensitive retinal ganglion cells.

Intrinsically photosensitive retinal ganglion cells (ipRGCs) are photoreceptors located in the ganglion cell layer. They project to brain regions involved in predominately non-image-forming functions including entrainment of circadian rhythms, control of the pupil light reflex, and modulation of mood and behavior. In addition to possessing intrinsic photosensitivity via the photopigment melanopsin, these cells receive inputs originating in rods and cones. While most research in the last two decades has focused on the downstream influence of ipRGC signaling, recent studies have shown that ipRGCs also act retrogradely within the retina itself as intraretinal signaling neurons. In this article, we review studies examining intraretinal and, in addition, intraocular signaling pathways of ipRGCs. Through these pathways, ipRGCs regulate inner and outer retinal circuitry through both chemical and electrical synapses, modulate the outputs of ganglion cells (both ipRGCs and non-ipRGCs), and influence arrangement of the correct retinal circuitry and vasculature during development. These data suggest that ipRGC function plays a significant role in the processing of image-forming vision at its earliest stage, positioning these photoreceptors to exert a vital role in perceptual vision. This research will have important implications for lighting design to optimize the best chromatic lighting environments for humans, both in adults and potentially even during fetal and postnatal development. Further studies into these unique ipRGC signaling pathways could also lead to a better understanding of the development of ocular dysfunctions such as myopia.

[Recent advances in the elucidation of migraine pathophysiology].

Three hypotheses have been proposed so far regarding the pathophysiology of migraine: one is the "vascular theory", which posits cerebral vascular dysfunction as the etiological factor. The second is the "neuronal theory", which suggests that migraine is triggered by cortical spreading depression. The third is the "trigemino-vascular theory", which postulates that migraine is triggered by inflammation of trigeminal nerves and vessels around trigeminal ganglion cells. Nowadays, the "trigemino-vascular theory" is widely accepted. However, recent advances in imaging analysis indicate that the origin of migraine lies in a premonitory phase which precedes the aura phase. Modern imaging techniques such as functional MRI and PET reveal high activity of the hypothalamic area during the premonitory phase of migraine. These findings suggest that hypothalamic activation might be a generator of a migraine attack. On the other hand, current analyses show that the photosensitivity of migraine (photophobia) could be caused by dysfunction of the newly discovered intrinsically photosensitive retinal ganglion cells (ipRGCs). In the absence of visual signaling from rods and cones, light activation of ipRGCs expressing melanopsin photopigment is sufficient to produce photophobia during migraine. The ipRGCs project to the hypothalamus; their activation might be the trigger for migraine attacks. Significant advances in molecular biology and imaging in recent years have clarified the previous hypotheses of migraine pathophysiology.

Electrophysiological responses from intrinsically photosensitive retinal ganglion cells are diminished in glaucoma patients.

PURPOSE: To record electroretinograms (ERGs) from intrinsically photosensitive retinal ganglion cells (ipRGCs) of glaucoma patients. METHODS: ERGs were recorded in 10 normal subjects and 15 patients with glaucoma. The ERG illumination system was built to achieve receptor-silent substitution, and comprised an optical diffuser and four-in-one light-emitting diodes. RESULTS: The ERG recordings of ipRGC from normal subjects showed an "on" response and an "off" response. The mean (±SD) implicit time for the on and off responses in normal subjects was 103.0±24.9 and 337.9±45.8ms, respectively, with corresponding amplitudes of 7.7±2.8 and 7.3±3.4µV, respectively. In glaucoma patients, the implicit time of the on and off responses was 135.0±28.9 and 368.2±17.3ms, respectively. The corresponding amplitudes of the on and off responses in these patients were 0.47±0.18 and 0.66±0.32µV, respectively. CONCLUSIONS: The results demonstrate successful ERG recording of ipRGCs from advanced glaucoma patients, with marked reductions in amplitude, although not implicit time, compared with normal subjects.

Temporal characteristics of melanopsin inputs to the human pupil light reflex.

Rods, cones and melanopsin containing intrinsically photosensitive retinal ganglion cells (ipRGCs) operate in concert to regulate pupil diameter. The temporal properties of intrinsic ipRGC signalling are distinct to those of rods and cones, including longer latencies and sustained signalling after light offset. We examined whether the melanopsin mediated post-illumination pupil response (PIPR) and pupil constriction were dependent upon the inter-stimulus interval (ISI) between successive light pulses and the temporal frequency of sinusoidal light stimuli. Melanopsin excitation was altered by variation of stimulus wavelength (464 nm and 638 nm lights) and irradiance (11.4 and 15.2 log photons cm(-2) s(-1)). We found that 6s PIPR amplitude was independent of ISI and temporal frequency for all melanopsin excitation levels, indicating complete summation. In contrast to the PIPR, the maximum pupil constriction increased with increasing ISI with high and low melanopsin excitation, but time to minimum diameter was slower with high melanopsin excitation only. This melanopsin response to briefly presented pulses (16 and 100 ms) slows the temporal response of the maximum pupil constriction. We also demonstrate that high melanopsin excitation attenuates the phasic peak-trough pupil amplitude compared to conditions with low melanopsin excitation, indicating an interaction between inner and outer retinal inputs to the pupil light reflex. We infer that outer retina summation is important for rapidly controlling pupil diameter in response to short timescale fluctuations in illumination and may occur at two potential sites, one that is presynaptic to extrinsic photoreceptor input to ipRGCs, or another within the pupil control pathway if ipRGCs have differential temporal tuning to extrinsic and intrinsic signalling.