Photobiomodulation of the Visual System and Human Health.

Humans express an expansive and detailed response to wavelength differences within the electromagnetic (EM) spectrum. This is most clearly manifest, and most studied, with respect to a relatively small range of electromagnetic radiation that includes the visible wavelengths with abutting ultraviolet and infrared, and mostly with respect to the visual system. Many aspects of our biology, however, respond to wavelength differences over a wide range of the EM spectrum. Further, humans are now exposed to a variety of modern lighting situations that has, effectively, increased our exposure to wavelengths that were once likely minimal (e.g., "blue" light from devices at night). This paper reviews some of those biological effects with a focus on visual function and to a lesser extent, other body systems.

A circadian rhythm-gated subcortical pathway for nighttime-light-induced depressive-like behaviors in mice.

Besides generating vision, light modulates various physiological functions, including mood. While light therapy applied in the daytime is known to have anti-depressive properties, excessive light exposure at night has been reportedly associated with depressive symptoms. The neural mechanisms underlying this day-night difference in the effects of light are unknown. Using a light-at-night (LAN) paradigm in mice, we showed that LAN induced depressive-like behaviors without disturbing the circadian rhythm. This effect was mediated by a neural pathway from retinal melanopsin-expressing ganglion cells to the dorsal perihabenular nucleus (dpHb) to the nucleus accumbens (NAc). Importantly, the dpHb was gated by the circadian rhythm, being more excitable at night than during the day. This indicates that the ipRGC→dpHb→NAc pathway preferentially conducts light signals at night, thereby mediating LAN-induced depressive-like behaviors. These findings may be relevant when considering the mental health effects of the prevalent nighttime illumination in the industrial world.

The Antidepressant Effect of Light Therapy from Retinal Projections.

Observations from clinical trials have frequently demonstrated that light therapy can be an effective therapy for seasonal and non-seasonal major depression. Despite the fact that light therapy is known to have several advantages over antidepressant drugs like a low cost, minimal side-effects, and fast onset of therapeutic effect, the mechanism underlying light therapy remains unclear. So far, it is known that light therapy modulates mood states and cognitive functions, involving circadian and non-circadian pathways from retinas into brain. In this review, we discuss the therapeutic effect of light on major depression and its relationship to direct retinal projections in the brain. We finally emphasize the function of the retino-raphe projection in modulating serotonin activity, which probably underlies the antidepressant effect of light therapy for depression.

Detection and selective avoidance of near ultraviolet radiation by an aquatic annelid: the medicinal leech.

Medicinal leeches are aquatic predators that inhabit surface waters during daylight and also leave the water where they might be exposed to less screened light. Whereas the leech visual system has been shown to respond to visible light, leeches in the genus Hirudo do not appear to be as negatively phototactic as one might expect in order to avoid potential ultraviolet radiation (UVR)-induced damage. I used high intensity light emitting diodes to test the hypothesis that leeches could detect and specifically avoid near UVR (395-405 nm). Groups of unfed juvenile leeches exhibited a robust negative phototaxis to UVR, but had no behavioral response to blue or red and only a slight negative phototaxis to green and white light. Individual leeches also exhibited a vigorous negative phototaxis to UVR; responding in 100% of trials compared with modest negative responses to visible light (responding in ~8% of the trials). The responses in fed and unfed leeches were comparable for UVR stimuli. The responses depended upon the stimulus site: leeches shortened away from UV light to the head, and extended away from UV light to the tail. Electrophysiological nerve recordings showed that the cephalic eyes responded vigorously to UVR. Additionally, individual leech photoreceptors also showed strong responses to UVR, and a higher-order neuron associated with shortening and rapid behavioral responses, the S-cell, was activated by UVR, on both the head and tail. These results demonstrate that the leech can detect UVR and is able to discriminate behaviorally between UVR and visible light.

Paired-pulse depression at photoreceptor synapses.

Synaptic depression produced by repetitive stimulation is likely to be particularly important in shaping responses of second-order retinal neurons at the tonically active photoreceptor synapse. We analyzed the time course and mechanisms of synaptic depression at rod and cone synapses using paired-pulse protocols involving two complementary measurements of exocytosis: (1) paired whole-cell recordings of the postsynaptic current (PSC) in second-order retinal neurons and (2) capacitance measurements of vesicular membrane fusion in rods and cones. PSCs in ON bipolar, OFF bipolar, and horizontal cells evoked by stimulation of either rods or cones recovered from paired-pulse depression (PPD) at rates similar to the recovery of exocytotic capacitance changes in rods and cones. Correlation between presynaptic and postsynaptic measures of recovery from PPD suggests that 80-90% of the depression at these synapses is presynaptic in origin. Consistent with a predominantly presynaptic mechanism, inhibiting desensitization of postsynaptic glutamate receptors had little effect on PPD. The depression of exocytotic capacitance changes exceeded depression of the presynaptic calcium current, suggesting that it is primarily caused by a depletion of synaptic vesicles. In support of this idea, limiting Ca2+ influx by using weaker depolarizing stimuli promoted faster recovery from PPD. Although cones exhibit much faster exocytotic kinetics than rods, exocytotic capacitance changes recovered from PPD at similar rates in both cell types. Thus, depression of release is not likely to contribute to differences in the kinetics of transmission from rods and cones.

Differential modulation of thalamic neurons by optokinetic nuclei in the pigeon.

The visual system in the pigeon is composed of the tectofugal, thalamofugal and accessory optic pathways. Though their anatomy and physiology have been extensively studied, the functional interactions between these pathways are largely unknown. The present study shows by using multiple electrophysiological techniques that firing activity in the nucleus opticus principalis thalami (OPT) of the thalamofugal pathway is differentially modulated by the pretectal nucleus lentiformis mesencephali (nLM) and the nucleus of the basal optic root (nBOR) of the accessory optic system, two optokinetic nuclei responsible for generating eye movements to stabilize the image on the retina. Reversible inactivation, electrical stimulation, microiontophoresis and receptive field mapping experiments all consistently indicate that the nBOR-OPT pathway is inhibitory and mediated by GABA as a transmitter and its GABAA receptors, whereas the nLM-OPT pathway is excitatory and mediated by glutamate as a transmitter and its NMDA receptors. They also differentially modulate the size and/or responsiveness of receptive fields in OPT cells as well. Numerous electrode tip sites were histologically confirmed in the neural structures under study. The results suggest that these optokinetic nuclei may dually modulate the transfer of visual information from the retina to the telencephalon at the thalamic level during eye movements.

Corticosterone treatment of the chick embryo affects light-stimulated development of the thalamofugal visual pathway.

By injecting a single 60 microg dose of corticosterone into the eggs of domestic chicks on day 18 of incubation, we have shown that elevated levels of this hormone affect the development of asymmetry in the visual projections from the thalamus to the Wulst regions in the left and right hemispheres of the forebrain. In vehicle-treated (control) embryos this visual pathway develops asymmetry in response to light stimulation during the final stages of incubation, when the embryo is oriented so that its left eye is occluded by its body and its right eye can be stimulated by light entering through the egg shell. Pre-hatching exposure to light leads to more projections from the left side of the thalamus to the right Wulst than from the right side of the thalamus to the left Wulst, as confirmed here by injection of the tracers Fluorogold and Rhodamine into the left and right Wulst followed by counting the number of labelled cell bodies in the thalamus (asymmetry greater in males than females). The chicks injected with corticosterone pre-hatching did not develop any group bias for asymmetry in response to light exposure before hatching. They were random with respect to presence/absence of lateralization and, when present, the lateralization was not as strong as in the controls and its direction was random. The corticosterone-treated group had fewer projections from the left side of the thalamus to the right Wulst than did the controls. The results are considered with respect to maternal deposits of the hormone in the yolk and pre-hatching stress of the embryo.

Light-dependent development of asymmetry in the ipsilateral and contralateral thalamofugal visual projections of the chick.

Light-exposure of the chick embryo induces development of asymmetry in the thalamofugal visual projections to the Wulst regions of the forebrain since the embryo is turned so that it occludes its left and not its right eye. This asymmetry can be reversed by occluding the embryo's right eye and exposing its left eye to light. Here we show that three sub-regions of the thalamus (two in the dorsolateral anterior thalami (DLA) and one more caudal) have differing asymmetries of contralateral and/or ipsilateral projections. Hence the effect of asymmetrical light stimulation is regionally specific within the thalamus. Lateralised light stimulation appears to promote the development of ipsilateral projections from DLA pars dorsolateralis pars anterioris and contralateral projections from the caudal regions (the nucleus superficialis parvocellularis especially) but it may suppress the development of contralateral projections from the nucleus dorsolateralis anterior thalami pars lateralis rostralis. We also show that the light stimulation causes lateralised expression of c-fos and receptors for neurotransmitters.

Time course of the effects of prenatal gamma irradiation on the dorsal lateral geniculate nucleus of Swiss mice.

A previous study reported that adult mice irradiated at the 16th embryonic day present a severe neuronal number reduction in the dorsal lateral geniculate thalamic nucleus. In the present study, we investigated the time course of the effects of prenatal irradiation on this thalamic nucleus. One day after irradiation, a great number of pyknotic figures were seen mainly in the cerebral proliferative zones. In the geniculate nucleus, only scattered pyknotic figures were identified. On the first week after birth, the geniculate nucleus presented frequent pyknotic figures. From five days after birth onwards, a severe shrinkage of the occipital cortex and a great reduction in the geniculate nucleus neuronal number were found. On the second week after birth this neuronal number reduction reached as high as 75%. At each postnatal analyzed age, severe volumetric geniculate nucleus shrinkage was combined to non-significant neuronal density variations. The presence of few pyknotic figures in the geniculate nucleus one day after irradiation and its delayed neuronal loss indicate an indirect effect of irradiation. We suggest that the effect upon the geniculate nucleus is secondary to the damage of the occipital cortex. A possible interpretation for thalamic neuronal loss is that geniculate neurons fail to establish cortical arbors after major target loss. In this case, the loss of trophic support should also be considered.

Light-dependent induction of cFos during subjective day and night in PACAP-containing ganglion cells of the retinohypothalamic tract.

Environmental light stimulation via the retinohypothalamic tract (RHT) is necessary for stable entrainment of circadian rhythms generated in the suprachiasmatic nucleus (SCN). In the current report, the authors characterized the functional activity and phenotype of retinal ganglion cells that give rise to the RHT of the rat. Retinal ganglion cells that give rise to the RHT were identified by transsynaptic passage of an attenuated alpha herpesvirus known to have selective affinity for this pathway. Dual labeling immunocytochemistry demonstrated co-localization of viral antigen and pituitary adenylate cyclase activating polypeptide (PACAP) in retinal ganglion cells. This was confirmed using the anterograde tracer cholera toxin subunit B (ChB). In normal and retinally degenerated monosodium glutamate (MSG)-treated rats, ChB co-localized with PACAP in axons of the retinorecipient zone of the SCN. Light-induced Fos-immunoreactivity (Fos-IR) was apparent in all PACAP-containing retinal ganglion cells and a population of non-PACAP-containing retinal ganglion cells at dawn of normal and MSG-treated animals. Within the next 3 h, Fos disappeared in all non-PACAP-immunoreactive cells but persisted in all PACAP-containing retinal ganglion cells until dusk. When animals were exposed to constant light, Fos-IR was sustained only in the PACAP-immunoreactive (PACAP-IR) retinal ganglion cells. Darkness eliminated Fos-IR in all PACAP-IR retinal ganglion cells, demonstrating that the induction of Fos gene expression was light dependent. When animals were maintained in constant darkness and exposed to light pulses at ZT 14, ZT 19, or ZT 6, Fos-IR was induced in PACAP-IR retinal ganglion cells in a pattern similar to that seen at dawn. Collectively, these data indicate that PACAP is present in ganglion cells that give rise to the RHT and suggest a role for this peptide in the light entrainment of the clock.

Late effects of therapy of thalamic and hypothalamic tumors in childhood: vascular, neurobehavioral and neoplastic.

The late effects in children with hypothalamic and thalamic tumors relate to the effects of the tumor on the surrounding brain, the effects of surgery, radiotherapy (RT) and, to a lesser extent, chemotherapy. The clinical manifestations of late effects include endocrinologic dysfunction, neurocognitive sequelae, behavioral problems and second neoplasia. The prevention of late effects is an integral part of current treatment strategies. Early diagnosis, a rational use of surgery, and deferral of RT are the mainstays of the modern treatment in these patients. The improvement of RT techniques and the use of radioprotective compounds may further help spare normal brain tissue. A better understanding of chemotherapy use and the development of newer agents may increase efficacy, reduce side effects and allow deferral of RT in a greater percentage of patients. Finally, an aggressive management of endocrinological problems, physical and cognitive rehabilitation as well as psychological and school support help provide these children with maximal function within their potential.

Exposure to different wavelengths of light and the development of structural and functional asymmetries in the chicken.

The thalamofugal visual projections of the chick are known to develop in response to stimulation by light prior to hatching, and asymmetry in the number of projections develops as a consequence of the embryo being oriented in the egg so that it occuludes its left eye. The right eye only is stimulated by light and this causes the visual projections connected to the right eye to develop in advance of those connected to the left. We have now found that exposure of embryos, from day 19 of incubation to hatching, to red (peak transmission at 670 nm) or green (peak at 500 nm) light is as effective as broad-spectrum (white) light in establishing asymmetry in these projections. The intensities of the light to which the embryos were exposed in each case were equivalent, achieved in part by removing the air sac end of the egg shell. The thalamofugal visual projections, therefore, develop in response to light stimulation but appear to have no wavelength specificity. This result is consistent with the apparent lack of involvement of the thalamofugal visual pathway in colour vision. However, functional asymmetry, tested as left-right eye differences in categorising grain from pebbles, was found to be less marked in the chicks that had been exposed to green light compared to those that had been exposed to 'while' light, and it was absent in those exposed to red light or incubated in the dark. Thus, there is wavelength specificity for the development of the behavioural asymmetry, which suggests involvement of colour-coded neurons outside the thalamofugal visual pathway, probably in the tectofugal pathway. Exposure of the embryos to red and green light alternating at 30 min intervals is as effective as "white' light for establishing both the structural and functional asymmetry.

[Necrosis of the optic tract, hypothalamus and brain stem after irradiation of a pituitary adenoma with conventional doses]. / Nécrose des voies optiques, de l'hypothalamus et du tronc cérébral après irradiation d'un adénome hypophysaire a doses conventionnelles.

A 56-year-old man had radiation necrosis of the optic pathways, hypothalamus and brainstem following irradiation of a pituitary adenoma at a conventional dose. Factors which predispose to this complication are discussed. Vascular risk factors appear to facilitate radiation induced necrosis, and a reduction of doses is suggested in these cases.