Thin-film optical notch filter spectacle coatings for the treatment of migraine and photophobia

Previous evidence suggests optical treatments hold promise for treating migraine and photophobia. We designed an optical notch filter, centered at 480 nm to reduce direct stimulation of intrinsically photosensitive retinal ganglion cells. We used thin-film technology to integrate the filter into spectacle lenses. Our objective was to determine if an optical notch filter, designed to attenuate activity of intrinsically photosensitive retinal ganglion cells, could reduce headache impact in chronic migraine subjects. For this randomized, double-masked study, our primary endpoint was the Headache Impact Test (HIT-6; GlaxoSmithKline, Brentford, Middlesex, UK). We developed two filters: the therapeutic filter blocked visible light at 480 nm; a 620 nm filter was designed as a sham. Participants were asked to wear lenses with one of the filters for 2 weeks; after 2 weeks when no lenses were worn, they wore lenses with the other filter for 2 weeks. Of 48 subjects, 37 completed the study. Wearing either the 480 or 620 nm lenses resulted in clinically and statistically significant HIT-6 reductions. However, there was no significant difference when comparing overall effect of the 480 and 620 nm lenses. Although the 620 nm filter was designed as a sham intervention, research published following the trial indicated that melanopsin, the photopigment in intrinsically photosensitive retinal ganglion cells, is bi-stable. This molecular property may explain the unexpected efficacy of the 620 nm filter. These preliminary findings indicate that lenses outfitted with a thin-film optical notch filter may be useful in treating chronic migraine.     

Visual responses in the lateral geniculate evoked by Cx36-independent rod pathways

Emerging evidence indicates rods can communicate with retinal ganglion cells (RGCs) via pathways that do not involve gap-junctions. Here we investigated the significance of such pathways for central visual responses, using mice lacking a key gap junction protein (Cx36^−/−) and carrying a mutation that disrupts cone phototransduction (Gnat2^cpfl3). Electrophysiological recordings spanning the lateral geniculate revealed rod-mediated ON and OFF visual responses in virtually every cell from all major anatomical sub-compartments of this nucleus. Hence, we demonstrate that one or more classes of RGC receive input from Cx36-independent rod pathways and drive extensive ON and OFF responses across the visual thalamus.     

Impact of age and retinal degeneration on the light input to circadian brain structures

Aging causes anatomical and functional changes in visual and circadian systems. In wild type mice rods, cones, and photosensitive retinal ganglion cells (pRGCs) decline with age. In rd/rd cl mice, the early loss of rods and cones is followed by protracted transneuronal loss of inner retinal neurons as well as the pRGCs. Here we use Fos induction to study the light input pathway to the suprachiasmatic nuclei (SCN), the intergeniculate leaflets (IGL) and ventral lateral geniculate nuclei (vLGN) of old (∼700 days) and young (∼150 days) wild type and rd/rd cl mice. Cholera toxin tracing was used in parallel to study the anatomy of this pathway. We find that aging rather than retinal degeneration is a more important factor in reducing light input to the SCN, causing both a reduction in Fos expression and retinal afferents. Furthermore, we show light-induced Fos within the vLGN and IGL is predominantly subserved by rods and cones, and once again aging reduces the amplitude of this response.     

Disturbed sleep/wake rhythms and neuronal cell loss in lateral hypothalamus and retina of mice with a spontaneous deletion in the ubiquitin carboxyl-terminal hydrolase L1 gene

Many neurodegenerative disorders including Parkinson's disease (PD) and Alzheimer's disease (AD) are associated with sleep disturbances with presumably multifactorial etiology. Ubiquitin C-terminal hydrolase L1 (UCH-L1) is involved in the pathophysiology of PD and AD. In the present study, we analyzed locomotor rhythms, orexin A-immunoreaction (Ir) in the lateral hypothalamus (LH) and melanopsin-Ir in the retina of gracile axonal dystrophy (gad) mice with a spontaneous deletion in the Uch-l1 gene. In constant darkness, gad mice showed circadian rhythms in locomotor activity, indicating the integrity of the endogenous circadian rhythm generator. However, gad mice showed an increased activity during subjective day and a decreased number of orexin A-immunoreactive neurons in the LH compared with the wild type (WT). In addition, gad mice showed increased locomotor activity in the light period when kept in a standard photoperiod and entrainment to phase shifts was significantly slower than in WT. Moreover, melanopsin-Ir was significantly reduced in the retina of gad mice, suggesting an impairment of circadian light perception in gad mice.     

Pupillary correlates of light-evoked melanopsin activity in humans

We investigated whether cones are the only photosensitive process mediating the photopic pupillary light reflex. New analyses were performed on previously published recordings, focusing on those evoked by the onset of photopically equated short- and long-wavelength stimuli. Comparisons between responses revealed contraction differences that slowly grew to a peak and gradually declined. The late contraction was associated with short wavelengths and appeared mostly at the higher stimulus intensities. We conclude that cones are not the only photoreception process mediating the photopic ON-reflex and infer that melanopsin is another. Melanopsin contributes to the steady-state pupil size in daylight illumination.     

Human and macaque pupil responses driven by melanopsin-containing retinal ganglion cells

Melanopsin, a novel photopigment, has recently been localized to a population of retinal ganglion cells that display inherent photosensitivity. During continuous light and following light offset, primates are known to exhibit sustained pupilloconstriction responses that resemble closely the photoresponses of intrinsically-photoreceptive ganglion cells. We report that, in the behaving macaque, following pharmacological blockade of conventional photoreceptor signals, significant pupillary responses persist during continuous light and following light offset. These pupil responses display the unique spectral tuning, slow kinetics, and irradiance coding of the sustained, melanopsin-derived ganglion cell photoresponses. We extended our observations to humans by using the sustained pupil response following light offset to document the contribution of these novel ganglion cells to human pupillary responses. Our results indicate that the intrinsic photoresponses of intrinsically-photoreceptive retinal ganglion cells play an important role in the pupillary light reflex and are primarily responsible for the sustained pupilloconstriction that occurs following light offset.     

Optogenetics for visual restoration: From proof of principle to translational challenges

Degenerative retinal disorders are a diverse family of diseases commonly leading to irreversible photoreceptor death, while leaving the inner retina relatively intact. Over recent years, innovative gene replacement therapies aiming to halt the progression of certain inherited retinal disorders have made their way into clinics. By rendering surviving retinal neurons light sensitive optogenetic gene therapy now offers a feasible treatment option that can restore lost vision, even in late disease stages and widely independent of the underlying cause of degeneration.Since proof-of-concept almost fifteen years ago, this field has rapidly evolved and a detailed first report on a treated patient has recently been published. In this article, we provide a review of optogenetic approaches for vision restoration. We discuss the currently available optogenetic tools and their relative advantages and disadvantages. Possible cellular targets will be discussed and we will address the question how retinal remodelling may affect the choice of the target and to what extent it may limit the outcomes of optogenetic vision restoration. Finally, we will analyse the evidence for and against optogenetic tool mediated toxicity and will discuss the challenges associated with clinical translation of this promising therapeutic concept.     

The influence of intrinsically-photosensitive retinal ganglion cells on the spectral sensitivity and response dynamics of the human pupillary light reflex

Historically, it was assumed that the light-evoked neural signals driving the human pupillary light reflex (PLR) originated exclusively from rod and cone photoreceptors. However, a novel melanopsin-containing photoreceptive cell class has recently been discovered in the mammalian retina. These intrinsically-photosensitive retinal ganglion cells (ipRGCs) project to the pretectum, the retinorecipient area of the brain responsible for the PLR. This study was therefore designed to examine the relative contribution of rod, cone and the melanopsin photoresponses of ipRGCs to the human PLR. We establish that the melanopsin photoresponse of ipRGCs contributes significantly to the maintenance of half maximal pupilloconstriction in response to light stimuli of 30 s or longer, even at low photopic irradiances. Furthermore, we show that the melanopsin photoresponse contributes significantly to three-quarter maximal pupilloconstriction in response to light stimuli as short as 2 s. We also demonstrate that cone photoresponses driving pupilloconstriction adapt considerably and contribute little after 30 s, but rod photoresponses adapt less and contribute significantly to the maintenance of pupilloconstriction in response to steady-state light stimuli at irradiance levels which are below the threshold of the melanopsin photoresponse.     

Optic enucleation eliminates circadian rhythm shifts induced by stimulating the intergeniculate leaflet in Syrian hamsters

The intergeniculate leaflet (IGL) is a region of the lateral geniculate complex that is part of the circadian system. It receives direct innervation by specialized retinal ganglion cells involved in circadian rhythm entrainment and is also reciprocally connected to the suprachiasmatic nucleus (SCN), which is the principal circadian pacemaker. Electrical stimulation in the IGL results in shifts of circadian rhythms with a pattern of phase dependence that resembles that elicited by periods of darkness. IGL stimulation also increases levels of c-Fos in the dorsolateral part of the caudal SCN. A previous study showed that optic enucleation prevents increases in c-Fos in the SCN, suggesting the hypothesis that this increase is related to antidromic activation of retinal ganglion cells which bifurcate and project to both SCN and IGL. We tested whether phase shifts induced by IGL stimulation are also dependent on intact retinal innervation. Electrical stimulation of the IGL for 60 min at circadian time (CT)9 (with CT12 defined as activity onset) induced phase advances in nine hamsters with electrodes in the IGL, while other placements did not evoke shifts. After optic enucleation, six of these hamsters received an identical second stimulation; none showed substantial phase shifts. These results are consistent with the hypothesis that phase shifts induced by IGL stimulation depend on antidromic activation of retinal ganglion cells.