A visual circuit related to the parabrachial nucleus for the antipruritic effects of bright light treatment.

In addition to its role in vision, light also serves non-image-forming visual functions. Despite clinical evidence suggesting the antipruritic effects of bright light treatment, the circuit mechanisms underlying the effects of light on itch-related behaviors remain poorly understood. In this study, we demonstrate that bright light treatment reduces itch-related behaviors in mice through a visual circuit related to the lateral parabrachial nucleus (LPBN). Specifically, a subset of retinal ganglion cells (RGCs) innervates GABAergic neurons in the ventral lateral geniculate nucleus and intergeniculate leaflet (vLGN/IGL), which subsequently inhibit CaMKIIα+ neurons in the LPBN. Activation of both the vLGN/IGL-projecting RGCs and the vLGN/IGL-to-LPBN projections is sufficient to reduce itch-related behaviors induced by various pruritogens. Importantly, we demonstrate that the antipruritic effects of bright light treatment rely on the activation of the retina-vLGN/IGL-LPBN pathway. Collectively, our findings elucidate a visual circuit related to the LPBN that underlies the antipruritic effects of bright light treatment.

Divergent outputs of the ventral lateral geniculate nucleus mediate visually evoked defensive behaviors.

Rapid alternations between exploration and defensive reactions require ongoing risk assessment. How visual cues and internal states flexibly modulate the selection of behaviors remains incompletely understood. Here, we show that the ventral lateral geniculate nucleus (vLGN)-a major retinorecipient structure-is a critical node in the network controlling defensive behaviors to visual threats. We find that vLGNGABA neuron activity scales with the intensity of environmental illumination and is modulated by behavioral state. Chemogenetic activation of vLGNGABA neurons reduces freezing, whereas inactivation dramatically extends the duration of freezing to visual threats. Perturbations of vLGN activity disrupt exploration in brightly illuminated environments. We describe both a vLGN→nucleus reuniens (Re) circuit and a vLGN→superior colliculus (SC) circuit, which exert opposite influences on defensive responses. These findings reveal roles for genetic- and projection-defined vLGN subpopulations in modulating the expression of behavioral threat responses according to internal state.

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.

Temporal information loss in the macaque early visual system.

Stimuli that modulate neuronal activity are not always detectable, indicating a loss of information between the modulated neurons and perception. To identify where in the macaque visual system information about periodic light modulations is lost, signal-to-noise ratios were compared across simulated cone photoreceptors, lateral geniculate nucleus (LGN) neurons, and perceptual judgements. Stimuli were drifting, threshold-contrast Gabor patterns on a photopic background. The sensitivity of LGN neurons, extrapolated to populations, was similar to the monkeys' at low temporal frequencies. At high temporal frequencies, LGN sensitivity exceeded the monkeys' and approached the upper bound set by cone photocurrents. These results confirm a loss of high-frequency information downstream of the LGN. However, this loss accounted for only about 5% of the total. Phototransduction accounted for essentially all of the rest. Together, these results show that low temporal frequency information is lost primarily between the cones and the LGN, whereas high-frequency information is lost primarily within the cones, with a small additional loss downstream of the LGN.

Functional Specialization of ON and OFF Cortical Pathways for Global-Slow and Local-Fast Vision.

Visual information is processed in the cortex by ON and OFF pathways that respond to light and dark stimuli. Responses to darks are stronger, faster, and driven by a larger number of cortical neurons than responses to lights. Here, we demonstrate that these light-dark cortical asymmetries reflect a functional specialization of ON and OFF pathways for different stimulus properties. We show that large long-lasting stimuli drive stronger cortical responses when they are light, whereas small fast stimuli drive stronger cortical responses when they are dark. Moreover, we show that these light-dark asymmetries are preserved under a wide variety of luminance conditions that range from photopic to low mesopic light. Our results suggest that ON and OFF pathways extract different spatiotemporal information from visual scenes, making OFF local-fast signals better suited to maximize visual acuity and ON global-slow signals better suited to guide the eye movements needed for retinal image stabilization.

Radiation-induced optic neuropathy after stereotactic and image guided intensity-modulated radiation therapy (IMRT).

BACKGROUND/PURPOSE: To quantify the risk of radiation-induced optic neuropathy (RION) after stereotactic/image-guided positioning and intensity-modulated radiotherapy (IMRT) with ≥50 Gy to the anterior visual pathway (AVP). METHODS: Patients irradiated with ≥50 Gy to the AVP using stereotactic/image-guided positioning between 2002 and 2011 in Mannheim were identified. Detailed dosimetric data were collected and patients or family members were retrospectively asked to rate visual acuity and visual disorders. RESULTS: 125 patients fulfilled the eligibility criteria. Average maximum equivalent point dose (Dmax-EQD-2[α/ß=1.6]) to the AVP was 53.1 ±â€¯3.9 Gy. 99 patients received ≥50 Gy bilaterally (chiasm or both optic nerves), resulting in 224 (99x2 bilateral plus 26 unilateral) visual-fields-at-risk (VFAR) for RION. Eighty-two patients provided pre/post-IMRT visual status information (n = 151 VFARs). Permanent visual deterioration occurred in 18 (22%) patients. In seven, visual deterioration was possibly related to radiotherapy (two-sided deterioration in one patient) for a crude incidence of 8.5% (7/82 patients) and 5.3% (8/151 VFARs). Two cases were caused by chronic keratitis/conjunctivitis; in five patients RION could not be excluded (one two-sided). In one of 13 patients with Dmax-EQD-2 > 58 Gy, RION could not be excluded. In all affected patients, visual acuity post-IMRT had decreased only mildly (1-2 points on the 5-point-scale). One patient with relevant baseline visual impairment (3/5) developed unilateral blindness (crude incidence of blindness on patient-/VFAR-level: 1.2% and 0.66%; competing risk-adjusted/actuarial 24-month incidence: patient/VFAR-level: 1.8% and 0.95%). CONCLUSION: Risk of RION was low in this cohort with accurate positioning and precise dosimetric information. Less conservative tolerance doses may be considered in patients with high risk of recurrence.

Recording Neural Activity in Unrestrained Animals with Three-Dimensional Tracking Two-Photon Microscopy.

Optical recordings of neural activity in behaving animals can reveal the neural correlates of decision making, but brain motion, which often accompanies behavior, compromises these measurements. Two-photon point-scanning microscopy is especially sensitive to motion artifacts, and two-photon recording of activity has required rigid coupling between the brain and microscope. We developed a two-photon tracking microscope with extremely low-latency (360 µs) feedback implemented in hardware. This microscope can maintain continuous focus on neurons moving with velocities of 3 mm/s and accelerations of 1 m/s2 both in-plane and axially. We recorded calcium dynamics of motor neurons and inter-neurons in unrestrained freely behaving fruit fly larvae, correlating neural activity with stimulus presentations and behavioral outputs, and we measured light-induced depolarization of a visual interneuron in a moving animal using a genetically encoded voltage indicator. Our technique can be extended to stabilize recordings in a variety of moving substrates.

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.

Homeostatic plasticity shapes the visual system's first synapse.

Vision in dim light depends on synapses between rods and rod bipolar cells (RBCs). Here, we find that these synapses exist in multiple configurations, in which single release sites of rods are apposed by one to three postsynaptic densities (PSDs). Single RBCs often form multiple PSDs with one rod; and neighboring RBCs share ~13% of their inputs. Rod-RBC synapses develop while ~7% of RBCs undergo programmed cell death (PCD). Although PCD is common throughout the nervous system, its influences on circuit development and function are not well understood. We generate mice in which ~53 and ~93% of RBCs, respectively, are removed during development. In these mice, dendrites of the remaining RBCs expand in graded fashion independent of light-evoked input. As RBC dendrites expand, they form fewer multi-PSD contacts with rods. Electrophysiological recordings indicate that this homeostatic co-regulation of neurite and synapse development preserves retinal function in dim light.

Optogenetic Neuronal Silencing in Drosophila during Visual Processing.

Optogenetic channels and ion pumps have become indispensable tools in neuroscience to manipulate neuronal activity and thus to establish synaptic connectivity and behavioral causality. Inhibitory channels are particularly advantageous to explore signal processing in neural circuits since they permit the functional removal of selected neurons on a trial-by-trial basis. However, applying these tools to study the visual system poses a considerable challenge because the illumination required for their activation usually also stimulates photoreceptors substantially, precluding the simultaneous probing of visual responses. Here, we explore the utility of the recently discovered anion channelrhodopsins GtACR1 and GtACR2 for application in the visual system of Drosophila. We first characterized their properties using a larval crawling assay. We further obtained whole-cell recordings from cells expressing GtACR1, which mediated strong and light-sensitive photocurrents. Finally, using physiological recordings and a behavioral readout, we demonstrate that GtACR1 enables the fast and reversible silencing of genetically targeted neurons within circuits engaged in visual processing.

Inhibition decorrelates visual feature representations in the inner retina.

The retina extracts visual features for transmission to the brain. Different types of bipolar cell split the photoreceptor input into parallel channels and provide the excitatory drive for downstream visual circuits. Mouse bipolar cell types have been described at great anatomical and genetic detail, but a similarly deep understanding of their functional diversity is lacking. Here, by imaging light-driven glutamate release from more than 13,000 bipolar cell axon terminals in the intact retina, we show that bipolar cell functional diversity is generated by the interplay of dendritic excitatory inputs and axonal inhibitory inputs. The resulting centre and surround components of bipolar cell receptive fields interact to decorrelate bipolar cell output in the spatial and temporal domains. Our findings highlight the importance of inhibitory circuits in generating functionally diverse excitatory pathways and suggest that decorrelation of parallel visual pathways begins as early as the second synapse of the mouse visual system.

The influence of the dose calculation resolution of VMAT plans on the calculated dose for eye lens and optic pathway.

To investigate the effect of dose calculation grid on calculated dose-volumetric parameters for eye lenses and optic pathways. A total of 30 patients treated using the volumetric modulated arc therapy (VMAT) technique, were retrospectively selected. For each patient, dose distributions were calculated with calculation grids ranging from 1 to 5 mm at 1 mm intervals. Identical structures were used for VMAT planning. The changes in dose-volumetric parameters according to the size of the calculation grid were investigated. Compared to dose calculation with 1 mm grid, the maximum doses to the eye lens with calculation grids of 2, 3, 4 and 5 mm increased by 0.2 ± 0.2 Gy, 0.5 ± 0.5 Gy, 0.9 ± 0.8 Gy and 1.7 ± 1.5 Gy on average, respectively. The Spearman's correlation coefficient between dose gradients near structures vs. the differences between the calculated doses with 1 mm grid and those with 5 mm grid, were 0.380 (p < 0.001). For the accurate calculation of dose distributions, as well as efficiency, using a grid size of 2 mm appears to be the most appropriate choice.

The effect of unilateral disruption of the centrifugal visual system on normal eye development in chicks raised under constant light conditions.

The centrifugal visual system (CVS) comprises a visually driven isthmic feedback projection to the retina. While its function has remained elusive, we have previously shown that, under otherwise normal conditions, unilateral disconnection of centrifugal neurons in the chick affected eye development, inducing a reduced rate of axial elongation that resulted in a unilateral hyperopia in the eye contralateral to the lesion. Here, we further investigate the role of centrifugal neurons in ocular development in chicks reared in an abnormal visual environment, namely constant light. The baseline ocular phenotype of constant light-reared chicks (n = 8) with intact centrifugal neurons was assessed over a 3-week post-hatch time period and, subsequently, compared to chicks raised in normal diurnal lighting (n = 8). Lesions of the isthmo-optic tract or sham surgeries were performed in another seventeen chicks, all raised under constant light. Ocular phenotyping was performed over a 21-day postoperative period to assess changes in refractive state (streak retinoscopy) and ocular component dimensions (A-scan ultrasonography). A pathway-tracing paradigm was employed to quantify lesion success. Chicks raised in constant light conditions with an intact CVS developed shallower anterior chambers combined with elongated vitreous chambers relative to chicks raised in normal diurnal lighting. Seven days following surgery to disrupt centrifugal neurons, a significant positive correlation between refractive error asymmetry between the eyes and lesion success was evident, characterized by hyperopia in the eye contralateral to the lesion. By 21 days post-surgery, these contralateral eyes had become emmetropic, while ipsilateral eyes had developed relative axial hyperopia. Our results provide further support for the hypothesis that the centrifugal visual system can modulate eye development.

Dose-Response Modeling of the Visual Pathway Tolerance to Single-Fraction and Hypofractionated Stereotactic Radiosurgery.

Patients with tumors adjacent to the optic nerves and chiasm are frequently not candidates for single-fraction stereotactic radiosurgery (SRS) due to concern for radiation-induced optic neuropathy. However, these patients have been successfully treated with hypofractionated SRS over 2-5 days, though dose constraints have not yet been well defined. We reviewed the literature on optic tolerance to radiation and constructed a dose-response model for visual pathway tolerance to SRS delivered in 1-5 fractions. We analyzed optic nerve and chiasm dose-volume histogram (DVH) data from perioptic tumors, defined as those within 3mm of the optic nerves or chiasm, treated with SRS from 2000-2013 at our institution. Tumors with subsequent local progression were excluded from the primary analysis of vision outcome. A total of 262 evaluable cases (26 with malignant and 236 with benign tumors) with visual field and clinical outcomes were analyzed. Median patient follow-up was 37 months (range: 2-142 months). The median number of fractions was 3 (1 fraction n = 47, 2 fraction n = 28, 3 fraction n = 111, 4 fraction n = 10, and 5 fraction n = 66); doses were converted to 3-fraction equivalent doses with the linear quadratic model using α/ß = 2Gy prior to modeling. Optic structure dose parameters analyzed included Dmin, Dmedian, Dmean, Dmax, V30Gy, V25Gy, V20Gy, V15Gy, V10Gy, V5Gy, D50%, D10%, D5%, D1%, D1cc, D0.50cc, D0.25cc, D0.20cc, D0.10cc, D0.05cc, D0.03cc. From the plan DVHs, a maximum-likelihood parameter fitting of the probit dose-response model was performed using DVH Evaluator software. The 68% CIs, corresponding to one standard deviation, were calculated using the profile likelihood method. Of the 262 analyzed, 2 (0.8%) patients experienced common terminology criteria for adverse events grade 4 vision loss in one eye, defined as vision of 20/200 or worse in the affected eye. One of these patients had received 2 previous courses of radiotherapy to the optic structures. Both cases were meningiomas treated with 25Gy in 5 fractions, with a 3-fraction equivalent optic nerve Dmax of 19.2 and 22.2Gy. Fitting these data to a probit dose-response model enabled risk estimates to be made for these previously unvalidated optic pathway constraints: the Dmax limits of 12Gy in 1 fraction from QUANTEC, 19.5Gy in 3 fractions from Timmerman 2008, and 25Gy in 5 fractions from AAPM Task Group 101 all had less than 1% risk. In 262 patients with perioptic tumors treated with SRS, we found a risk of optic complications of less than 1%. These data support previously unvalidated estimates as safe guidelines, which may in fact underestimate the tolerance of the optic structures, particularly in patients without prior radiation. Further investigation would refine the estimated normal tissue complication probability for SRS near the optic apparatus.

Extraretinal induced visual sensations during IMRT of the brain.

BACKGROUND: We observed visual sensations (VSs) in patients undergoing intensity modulated radiotherapy (IMRT) of the brain without the beam passing through ocular structures. We analyzed this phenomenon especially with regards to reproducibility, and origin. METHODS AND FINDINGS: Analyzed were ten consecutive patients (aged 41-71 years) with glioblastoma multiforme who received pulsed IMRT (total dose 60Gy) with helical tomotherapy (TT). A megavolt-CT (MVCT) was performed daily before treatment. VSs were reported and recorded using a triggered event recorder. The frequency of VSs was calculated and VSs were correlated with beam direction and couch position. Subjective patient perception was plotted on an 8x8 visual field (VF) matrix. Distance to the orbital roof (OR) from the first beam causing a VS was calculated from the Dicom radiation therapy data and MVCT data. During 175 treatment sessions (average 17.5 per patient) 5959 VSs were recorded and analyzed. VSs occurred only during the treatment session not during the MVCTs. Plotting events over time revealed patient-specific patterns. The average cranio-caudad extension of VS-inducing area was 63.4mm (range 43.24-92.1mm). The maximum distance between the first VS and the OR was 56.1mm so that direct interaction with the retina is unlikely. Data on subjective visual perception showed that VSs occurred mainly in the upper right and left quadrants of the VF. Within the visual pathways the highest probability for origin of VSs was seen in the optic chiasm and the optic tract (22%). CONCLUSIONS: There is clear evidence that interaction of photon irradiation with neuronal structures distant from the eye can lead to VSs.

Stereotactic radiosurgery for arteriovenous malformations of the postgeniculate visual pathway.

OBJECT: A visual field deficit resulting from the management of an arteriovenous malformation (AVM) significantly impacts a patient's quality of life. The present study was designed to investigate the clinical and radiological outcomes of stereotactic radiosurgery (SRS) performed for AVMs involving the postgeniculate visual pathway. METHODS: In this retrospective single-institution analysis, the authors reviewed their experience with Gamma Knife surgery for postgeniculate visual pathway AVMs performed during the period between 1987 and 2009. RESULTS: During the study interval, 171 patients underwent SRS for AVMs in this region. Forty-one patients (24%) had a visual deficit prior to SRS. The median target volume was 6.0 cm3 (range 0.4-22 cm3), and 19 Gy (range 14-25 Gy) was the median margin dose. Obliteration of the AVM was confirmed in 80 patients after a single SRS procedure at a median follow-up of 74 months (range 5-297 months). The actuarial rate of total obliteration was 67% at 4 years. Arteriovenous malformations with a volume<5 cm3 had obliteration rates of 60% at 3 years and 79% at 4 years. The delivered margin dose proved significant given that 82% of patients receiving ≥22 Gy had complete obliteration. The AVM was completely obliterated in an additional 18 patients after they underwent repeat SRS. At a median of 25 months (range 11-107 months) after SRS, 9 patients developed new or worsened visual field deficits. One patient developed a complete homonymous hemianopia, and 8 patients developed quadrantanopias. The actuarial risk of sustaining a new visual deficit was 3% at 3 years, 5% at 5 years, and 8% at 10 years. Fifteen patients had hemorrhage during the latency period, resulting in death in 9 of the patients. The annual hemorrhage rate during the latency interval was 2%, and no hemorrhages occurred after confirmed obliteration. CONCLUSIONS: Despite an overall treatment mortality of 5%, related to latency interval hemorrhage, SRS was associated with only a 5.6% risk of new visual deficit and a final obliteration rate close to 80% in patients with AVMs of the postgeniculate visual pathway.

Cerebral microinfarcts in primary open-angle glaucoma correlated with DTI-derived integrity of optic radiation.

PURPOSE: To evaluate the correlation between the extent of cerebral white matter lesions (WMLs) and the integrity of the visual pathway represented by fractional anisotropy (FA) in patients with primary open-angle glaucoma (POAG). METHODS: This case-control study included a total of 61 German patients (39 POAG patients, 22 controls) matched for age and sex. Fractional anisotropy of the optic radiation was determined by 3-Tesla diffusion tensor imaging. White matter lesions and brain volumes were manually measured by using a T2-weighted, 3-D fluid-attenuated inversion recovery sequence. RESULTS: In POAG patients WML volumes were significantly (P = 0.04) increased in the subcortical area. This applied for both absolute and relative units to the specific patient's brain volume, compared to controls. The WML volumes were significantly (P = 0.003) greater in middle-aged (40-59 years) POAG patients than control patients. In controls there was a significant age correlation of WML volumes in the total brain, subcortical, and optic radiation regions of interest. There was a significant correlation between FA and WML in POAG regarding the total brain, the periventricular region, and the optic radiation in both hemispheres. In POAG, FA left and right optic radiation correlated significantly with age (P = 0.002). CONCLUSIONS: We were able to demonstrate that (1) POAG patients aged 40 to 60 years had higher volumes of cerebral microinfarcts and (2) POAG patients showed a significant correlation between cerebral microinfarcts and degeneration of the optic radiation. This indicates that cerebral microinfarcts might be an intracerebral risk factor for glaucomatous optic nerve atrophy.

A hard-wired glutamatergic circuit pools and relays UV signals to mediate spectral preference in Drosophila.

Many visual animals have innate preferences for particular wavelengths of light, which can be modified by learning. Drosophila's preference for UV over visible light requires UV-sensing R7 photoreceptors and specific wide-field amacrine neurons called Dm8. Here we identify three types of medulla projection neurons downstream of R7 and Dm8 and show that selectively inactivating one of them (Tm5c) abolishes UV preference. Using a modified GRASP method to probe synaptic connections at the single-cell level, we reveal that each Dm8 neuron forms multiple synaptic contacts with Tm5c in the center of Dm8's dendritic field but sparse connections in the periphery. By single-cell transcript profiling and RNAi-mediated knockdown, we determine that Tm5c uses the kainate receptor Clumsy to receive excitatory glutamate input from Dm8. We conclude that R7s→Dm8→Tm5c form a hard-wired glutamatergic circuit that mediates UV preference by pooling ∼16 R7 signals for transfer to the lobula, a higher visual center.