Intrinsically photosensitive melanopsin retinal ganglion cell contributions to the pupillary light reflex and circadian rhythm

Recently discovered intrinsically photosensitive melanopsin retinal ganglion cells contribute to the maintenance of pupil diameter, recovery and post-illumination components of the pupillary light reflex and provide the primary environmental light input to the suprachiasmatic nucleus for photoentrainment of the circadian rhythm. This review summarises recent progress in understanding intrinsically photosensitive ganglion cell histology and physiological properties in the context of their contribution to the pupillary and circadian functions and introduces a clinical framework for using the pupillary light reflex to evaluate inner retinal (intrinsically photosensitive melanopsin ganglion cell) and outer retinal (rod and cone photoreceptor) function in the detection of retinal eye disease.

A high-resolution binocular video-oculography system: assessment of pupillary light reflex and detection of an early incomplete blink and an upward eye movement

Background: The pupillary light reflex characterizes the direct and consensual response of the eye to the perceived brightness of a stimulus. It has been used as indicator of both neurological and optic nerve pathologies. As with other eye reflexes, this reflex constitutes an almost instantaneous movement and is linked to activation of the same midbrain area. The latency of the pupillary light reflex is around 200 ms, although the literature also indicates that the fastest eye reflexes last 20 ms. Therefore, a system with sufficiently high spatial and temporal resolutions is required for accurate assessment. In this study, we analyzed the pupillary light reflex to determine whether any small discrepancy exists between the direct and consensual responses, and to ascertain whether any other eye reflex occurs before the pupillary light reflex. Methods: We constructed a binocular video-oculography system two high-speed cameras that simultaneously focused on both eyes. This was then employed to assess the direct and consensual responses of each eye using our own algorithm based on Circular Hough Transform to detect and track the pupil. Time parameters describing the pupillary light reflex were obtained from the radius time-variation. Eight healthy subjects (4 women, 4 men, aged 24–45) participated in this experiment. Results: Our system, which has a resolution of 15 microns and 4 ms, obtained time parameters describing the pupillary light reflex that were similar to those reported in previous studies, with no significant differences between direct and consensual reflexes. Moreover, it revealed an incomplete reflex blink and an upward eye movement at around 100 ms that may correspond to Bell’s phenomenon. Conclusions: Direct and consensual pupillary responses do not any significant temporal differences. The system and method described here could prove useful for further assessment of pupillary and blink reflexes. The resolution obtained revealed the existence reported here of an early incomplete blink and an upward eye movement.

The pupillary light reflex in migraine

The literature suggests that there may be pupil size and response abnormalities in migraine headache sufferers. We used an infra-red pupillometer to measure dynamic pupil responses to light in 20 migraine sufferers (during non-headache periods) and 16 non-migraine age and gender matched controls. There was a significant increase in the absolute inter-ocular difference of the latency of the pupil light response in the migraine group compared with the controls (0.062 s vs 0.025 s, p = 0.014). There was also a significant correlation between anisocoria and lateralisation of headache such that migraine sufferers with a habitual head pain side have more anisocoria (r= 0.59, p < 0.01), but this was not related to headache laterally. The pupil changes were not correlated with the interval since the last migraine headache, the severity of migraine headache or the number of migraine headaches per annum. We conclude that subtle sympathetic and parasympathetic pupil abnormalities persist in the inter-ictal phase of migraine. © 2005 The College of Optometrists.

High-speed video-oculography applied to assess pupil light reflex

Póster presentado en el VII European/ I World Meeting in Visual and Physiological Optics

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.

阿片类药物成瘾者瞳孔光反射的检测和特征提取

建立了一种基于图像处理的快速瞳孔直径检测算法,运用此算法提取了反映阿片类药物成瘾人员与正常人对瞳孔光反射变化差异的3个特征值:绝对收缩幅度(absolute amplitude of contraction,AAC)、相对收缩幅度(relative amplitude of contraction,RAC)和收缩斜率(SCV,slope of contraction velocity);分别研究了成瘾、性别、近视、年龄、睡眠剥夺等因素对于这3个特征值的影响。不同性别、近视人员、睡眠剥夺人员与正常人之间的3个特征值均无显著差异,成瘾人员与之对比均显著减小。老年人相对于正常青年人,3个特征值都明显减小;与成瘾人员相比,仅在RAC值上有显著差异。结果表明,阿片类药物成瘾人员除了与正常人外,也与其他具有潜在影响瞳孔变化因素的非阿片成瘾人员在瞳孔对光反射的特征值上具有显著差异。该研究的实验数据为进一步建立基于检测瞳孔对光反射其直径发生变化的方法来快速、非接触地鉴别出阿片类药物成瘾人员提供了可靠的依据。

1. 快速扫视系统对瞳孔对光反射系统的调制作用2. 麻醉状态下纳洛酮对吗啡依赖大鼠的岛叶神经元的自发放的影响

一. 快速扫视系统对瞳孔对光反射系统的调制作用快速扫视系统是研究运动神经控制的一个很好的模型。瞳孔对光反射是由进入视网膜的光亮度的增加而引起的瞳孔的收缩。之前的实验研究表明这两个系统都是开放的系统。但是对快速扫视系统是否对瞳孔对光反射系统有调制作用并没有研究过。本实验研究了注视状态和快速扫视状态下的瞳孔对光反射的潜伏期和瞳孔直径的变化。结果显示在注视状态下的和出现快速扫视时瞳孔对光反射的潜伏期表现出显著不同。外展和内收会引起瞳孔对光反射的潜伏期和瞳孔相对收缩率不同变化。在出现外展运动时，瞳孔对光反射的潜伏期显著下降，而出现内收运动时，瞳孔对光反射的潜伏期表现出显著增加。而瞳孔相对收缩率在出现两种运动时与注视状态下相比也发生不同的变化：外展运动引起瞳孔对光反射的瞳孔相对收缩率的增加，而内收运动引起瞳孔相对收缩率的减少。尽管快速扫视本身会引起瞳孔的收缩，但是引起的瞳孔收缩的变化不等于在出现快速扫视时的瞳孔对光反射的瞳孔直径的变化，这个结果说明在出现快速扫视时的瞳孔对光反射的变化并不是来源于光效应和快速扫视效应的简单叠加。基于快速扫视出现时间的进一步分析说明在瞳孔对光反射周期内不同时间出现两种快速扫视引起的瞳孔对光反射的潜伏期和瞳孔相对收缩率的变化不同。这些结果说明两个系统是有相互作用的，快速扫视系统可以调节瞳孔对光反射系统。关键词：快速扫视 瞳孔对光反射 调制二. 麻醉状态下纳洛酮对吗啡依赖大鼠的岛叶神经元的自发放的影响药物成瘾是药物长期作用于脑而产生的一种慢性复吸性脑疾病。之前有研究表明岛叶参与成瘾的过程。本实验以CPP为检测手段，检测实验大鼠是否产生吗啡依赖(吗啡给药方式为隔天给药，腹腔注射(10mg/kg)，共三次。然后采用四合一电极对纳洛酮诱发戒断的麻醉大鼠的岛叶和体感皮层进行细胞外电生理记录。与对照组相比，在记录的神经元中，被激活的神经元的所占比例（71.43%）远远大于对照组。将对照组和实验组的发放显著增加的神经元在给药前后的相对平均发放进行比较，两组神经元发放增加并没有显著差异。采用卡方检验比较了对照组和实验组的发放模式，结果显示两组发放模式存在显著差异。说明岛叶参与的方式可能是有更多数目的神经元参与，而不是通过改变单个神经元的发放参与。这也在神经元水平上为岛叶参与成瘾过程提供了一个证据。

Comparison of anesthetic efficacy and adverse effects associated with peribulbar injection of ropivacaine performed with and without ultrasound guidance in dogs

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Toward a Clinical Protocol for Assessing Rod, Cone, and Melanopsin Contributions to the Human Pupil Response

PURPOSE. To better understand the relative contributions of rod, cone, and melanopsin to the human pupillary light reflex (PLR) and to determine the optimal conditions for assessing the health of the rod, cone, and melanopsin pathways with a relatively brief clinical protocol. METHODS. PLR was measured with an eye tracker, and stimuli were controlled with a Ganzfeld system. In experiment 1, 2.5 log cd/m(2) red (640 +/- 10 nm) and blue (467 +/- 17 nm) stimuli of various durations were presented after dark adaptation. In experiments 2 and 3, 1-second red and blue stimuli were presented at different intensity levels in the dark (experiment 2) or on a 0.78 log cd/m(2) blue background (experiment 3). Based on the results of experiments 1 to 3, a clinical protocol was designed and tested on healthy control subjects and patients with retinitis pigmentosa and Leber`s congenital amaurosis. RESULTS. The duration for producing the optimal melanopsin-driven sustained pupil response after termination of an intense blue stimulus was 1 second. PLR rod-and melanopsin-driven components are best studied with low-and high-intensity flashes, respectively, presented in the dark (experiment 2). A blue background suppressed rod and melanopsin responses, making it easy to assess the cone contribution with a red flash (experiment 3). With the clinical protocol, robust melanopsin responses could be seen in patients with few or no contributions from the rods and cones. CONCLUSIONS. It is possible to assess the rod, cone, and melanopsin contributions to the PLR with blue flashes at two or three intensity levels in the dark and one red flash on a blue background. (Invest Ophthalmol Vis Sci. 2011; 52: 6624-6635) DOI: 10.1167/iovs.11-7586

Melanopsin Retinal Ganglion Cells: relevance to circadian rhythms and sleep in neurodegeneration

In this PhD thesis 3 projects were addressed focusing on the melanopsin retinal ganglion cells (mRGCs) system and its relevance for circadian rhythms and sleep in neurodegeneration. The first project was aimed at completing the characterization of mRGCs system in hereditary optic neuropathies (LHON and DOA). We confirmed that mRGCs are relatively spared also in post-mortem retinal specimens of a DOA case and pupillometric evaluation of LHON patients showed preservation of the pupillary light reflex, with attenuated responses compared to controls. Cell studies failed to indicate a protective role exerted by melanopsin itself. The second project was aimed at characterizing the possible occurrence of optic neuropathy and rest-activity circadian rhythm dysfunction in Alzheimer (AD) and Parkinson disease (PD), as well as, at histological level, the possible involvement of mRGCs in AD. OCT studies demonstrated a subclinical optic neuropathy in both AD and PD patients, with a different pattern involving the superior and nasal quadrants in AD and the temporal quadrant in PD. Actigraphic studies demonstrated a tendency towards an increased intradaily variability (IV) and reduced relative amplitude (RA) of rest-activity circadian rhythm in AD and a significant increased IV a reduced RA in PD. Immunohistochemical analysis of post-mortem retinal specimens and optic nerve cross-sections of neuropathologically confirmed AD cases demonstrated a significant loss of mRGCs and a nearly significant loss of axons in AD compared to controls. The mRGCs were affected in AD independently from age and magnitude of axonal loss. Overall these results suggest a role of the mRGCs system in the pathogenesis of circadian dysfunction in AD. The third project was aimed at evaluating the possible association between a single nucleotide polymorphism of the OPN4 gene and chronotype or SAD, failing to find any significant association with chronotype, but showing a non-significant increment of TT genotype in SAD.

Reading on LCD vs e-Ink displays: effects on fatigue and visual strain

Purpose:  Most recently light and mobile reading devices with high display resolutions have become popular and they may open new possibilities for reading applications in education, business and the private sector. The ability to adapt font size may also open new reading opportunities for people with impaired or low vision. Based on their display technology two major groups of reading devices can be distinguished. One type, predominantly found in dedicated e-book readers, uses electronic paper also known as e-Ink. Other devices, mostly multifunction tablet-PCs, are equipped with backlit LCD displays. While it has long been accepted that reading on electronic displays is slow and associated with visual fatigue, this new generation is explicitly promoted for reading. Since research has shown that, compared to reading on electronic displays, reading on paper is faster and requires fewer fixations per line, one would expect differential effects when comparing reading behaviour on e-Ink and LCD. In the present study we therefore compared experimentally how these two display types are suited for reading over an extended period of time. Methods:  Participants read for several hours on either e-Ink or LCD, and different measures of reading behaviour and visual strain were regularly recorded. These dependent measures included subjective (visual) fatigue, a letter search task, reading speed, oculomotor behaviour and the pupillary light reflex. Results:  Results suggested that reading on the two display types is very similar in terms of both subjective and objective measures. Conclusions:  It is not the technology itself, but rather the image quality that seems crucial for reading. Compared to the visual display units used in the previous few decades, these more recent electronic displays allow for good and comfortable reading, even for extended periods of time.

Is pupil diameter influenced by refractive error?

Purpose: To investigate the relationship between pupil diameter and refractive error and how refractive correction, target luminance, and accommodation modulate this relationship. Methods: Sixty emmetropic, myopic, and hyperopic subjects (age range, 18 to 35 years) viewed an illuminated target (luminance: 10, 100, 200, 400, 1000, 2000, and 4100 cd/m2) within a Badal optical system, at 0 diopters (D) and −3 D vergence, with and without refractive correction. Refractive error was corrected using daily disposable contact lenses. Pupil diameter and accommodation were recorded continuously using a commercially available photorefractor. Results: No significant difference in pupil diameter was found between the refractive groups at 0 D or −3 D target vergence, in the corrected or uncorrected conditions. As expected, pupil diameter decreased with increasing luminance. Target vergence had no significant influence on pupil diameter. In the corrected condition, at 0 D target vergence, the accommodation response was similar in all refractive groups. At −3 D target vergence, the emmetropic and myopic groups accommodated significantly more than the hyperopic group at all luminance levels. There was no correlation between accommodation response and pupil diameter or refractive error in any refractive group. In the uncorrected condition, the accommodation response was significantly greater in the hyperopic group than in the myopic group at all luminance levels, particularly for near viewing. In the hyperopic group, the accommodation response was significantly correlated with refractive error but not pupil diameter. In the myopic group, accommodation response level was not correlated with refractive error or pupil diameter. Conclusions: Refractive error has no influence on pupil diameter, irrespective of refractive correction or accommodative demand. This suggests that the pupil is controlled by the pupillary light reflex and is not driven by retinal blur.

A digital signal processing approach for affective sensing of a computer user through pupil diameter monitoring

Recent research has indicated that the pupil diameter (PD) in humans varies with their affective states. However, this signal has not been fully investigated for affective sensing purposes in human-computer interaction systems. This may be due to the dominant separate effect of the pupillary light reflex (PLR), which shrinks the pupil when light intensity increases. In this dissertation, an adaptive interference canceller (AIC) system using the H∞ time-varying (HITV) adaptive algorithm was developed to minimize the impact of the PLR on the measured pupil diameter signal. The modified pupil diameter (MPD) signal, obtained from the AIC was expected to reflect primarily the pupillary affective responses (PAR) of the subject. Additional manipulations of the AIC output resulted in a processed MPD (PMPD) signal, from which a classification feature, PMPDmean, was extracted. This feature was used to train and test a support vector machine (SVM), for the identification of stress states in the subject from whom the pupil diameter signal was recorded, achieving an accuracy rate of 77.78%. The advantages of affective recognition through the PD signal were verified by comparatively investigating the classification of stress and relaxation states through features derived from the simultaneously recorded galvanic skin response (GSR) and blood volume pulse (BVP) signals, with and without the PD feature. The discriminating potential of each individual feature extracted from GSR, BVP and PD was studied by analysis of its receiver operating characteristic (ROC) curve. The ROC curve found for the PMPDmean feature encompassed the largest area (0.8546) of all the single-feature ROCs investigated. The encouraging results seen in affective sensing based on pupil diameter monitoring were obtained in spite of intermittent illumination increases purposely introduced during the experiments. Therefore, these results confirmed the benefits of using the AIC implementation with the HITV adaptive algorithm to isolate the PAR and the potential of using PD monitoring to sense the evolving affective states of a computer user.

A Digital Signal Processing Approach for Affective Sensing of a Computer User through Pupil Diameter Monitoring

Recent research has indicated that the pupil diameter (PD) in humans varies with their affective states. However, this signal has not been fully investigated for affective sensing purposes in human-computer interaction systems. This may be due to the dominant separate effect of the pupillary light reflex (PLR), which shrinks the pupil when light intensity increases. In this dissertation, an adaptive interference canceller (AIC) system using the H∞ time-varying (HITV) adaptive algorithm was developed to minimize the impact of the PLR on the measured pupil diameter signal. The modified pupil diameter (MPD) signal, obtained from the AIC was expected to reflect primarily the pupillary affective responses (PAR) of the subject. Additional manipulations of the AIC output resulted in a processed MPD (PMPD) signal, from which a classification feature, PMPDmean, was extracted. This feature was used to train and test a support vector machine (SVM), for the identification of stress states in the subject from whom the pupil diameter signal was recorded, achieving an accuracy rate of 77.78%. The advantages of affective recognition through the PD signal were verified by comparatively investigating the classification of stress and relaxation states through features derived from the simultaneously recorded galvanic skin response (GSR) and blood volume pulse (BVP) signals, with and without the PD feature. The discriminating potential of each individual feature extracted from GSR, BVP and PD was studied by analysis of its receiver operating characteristic (ROC) curve. The ROC curve found for the PMPDmean feature encompassed the largest area (0.8546) of all the single-feature ROCs investigated. The encouraging results seen in affective sensing based on pupil diameter monitoring were obtained in spite of intermittent illumination increases purposely introduced during the experiments. Therefore, these results confirmed the benefits of using the AIC implementation with the HITV adaptive algorithm to isolate the PAR and the potential of using PD monitoring to sense the evolving affective states of a computer user.

Mapeamento das projeções retinianas para o sistema óptico acessório, colículo superior e complexo pré-tectal do sagui (callithrix jacchus)

The accessory optical system, the pretectal complex, and superior colliculus are important control centers in a variety of eye movement, being extremely necessary for image formation, consequently to visual perception. The accessory optical system is constituted by the nuclei: dorsal terminal nucleus, lateral terminal nucleus, medial terminal nucleus and interstitial nucleus of the posterior superior fasciculus. From a functional point of view they contribute to the image stabilization, participating in the visuomotor activity where all system cells respond to slow eye movements and visual stimuli, which is important for the proper functioning of other visual systems. The pretectal complex comprises a group of nuclei situated in mesodiencephalic transition, they are: anterior pretectal nucleus, posterior pretectal nucleus, medial pretectal nucleus, olivary pretectal nucleus and the nucleus of the optic tract, all retinal projection recipients and functionally are related to the route of the pupillary light reflex and the optokinetic nystagmus. The superior colliculus is an important subcortical visual station formed by layers and has an important functional role in the control of eye movements and head in response to multisensory stimuli. Our aim was to make a mapping of retinal projections that focus on accessory optical system, the nuclei of pretectal complex and the superior colliculus, searching mainly for pretectal complex, better delineation of these structures through the anterograde tracing with the B subunit of cholera toxin (CTb) followed by immunohistochemistry and characterized (measured diameter) synaptic buttons present on the fibers / terminals of the nucleus complex pré-tectal. In our results accessory optical system, including a region which appears to be medial terminal nucleus and superior colliculus, were strongly marked by fibers / terminals immunoreactive CTb as well as pretectal complex in the nucleus: optic tract, olivary pretectal nucleus, anterior pretectal nucleus and posterior pretectal nucleus. According to the characterization of the buttons it was possible to make a better definition of these nucleus.