Melanopsin and cone signals in human visual processing

 描述(申请人提供)：许多眼科和神经系统疾病的症状是畏光：由于闪烁和明亮的光线而引起的不适和疼痛。更确切地说， 畏光是偏头痛患者的主要症状，无论是在头痛期间还是在非头痛发作间歇期都是如此。这一临床观察已被系统的行为研究证实，表明此类患者对视觉刺激的不适阈值较低。也有证据表明，某些形式的视觉不适可能与含有光色素黑素的固有光敏视网膜神经节细胞(IpRGC)发出的信号有关。这项提议的三个目的将检验与偏头痛相关的畏光与对黑素刺激的反应改变有关的假设，以及表征光感受器机制，该机制介导了在有先兆的偏头痛中观察到的对光的神经反应升高。所有三个AIMS都将使用数字光积分器来产生光谱调制，以选择性和强有力地刺激个别光色素类别。我们将测量分别针对黑色素和视锥感光细胞的刺激的效果，以及黑素和视锥信号之间的相互作用。目的1将使用三种不同但互补的反应指标：视觉不适和亮度感知的行为报告、功能磁共振成像和瞳孔光反应，研究黑素刺激对健康受试者的直接影响。我们将研究黑素在行为评估的视觉不适和亮度感知中的具体作用，测量大脑对直接黑素刺激的持续反应，并使用瞳孔光反应来评估黑素反应的个体差异以及这些差异随时间的稳定性。目的2还将研究健康对照受试者，研究黑素信号是否以及如何与视锥细胞的信号相互作用，以调节对视锥细胞介导的光闪烁的反应。我们将测量检测视锥细胞介导的闪烁的心理物理阈值，并评估这些阈值是如何受到适应背景光的黑视成分变化的影响，使用功能磁共振成像来测量心理物理效应的神经相关性，并采用一种新的范式，允许我们使用迟缓的瞳孔光反应来测试这一假设，即黑色素蛋白信号调节视觉路径上早期位置对视锥细胞介导的闪烁的反应。目标3将以目标1和目标2的结果为基础，描述在有先兆的偏头痛中观察到的对光的增强神经反应的光感受器机制。我们还将测量偏头痛患者与对照组在黑素的直接或交互作用方面是否表现出系统性差异，以及这种差异是否与这一患者群体增强的光敏感度有关。

 DESCRIPTION (provided by applicant): A symptom of many ophthalmologic and neurologic disorders is photophobia: discomfort and pain from flickering and bright lights. More specifically, photophobia is a key symptom in patients with migraine, both during headache and also in the headache-free inter-ictal period. This clinical observation has been confirmed by systematic behavioral studies demonstrating lower discomfort thresholds for visual stimulation in such patients. There is also evidence that some forms of visual discomfort may be related to signals from intrinsically photosensitive retinal ganglion cells (ipRGCs) that contain the photopigment melanopsin. The three aims of this proposal will test the hypothesis that photophobia associated with migraine headache is related to altered responses to stimulation of melanopsin, as well as characterize the photoreceptor mechanisms that mediate the documented elevated neural response to light observed in migraine with aura. All three aims will employ a digital light integrator to produce spectral modulations that selectively and robustly stimulate individual photopigment classes. We will measure the effect of stimulation directed separately at melanopsin and the cone photoreceptors, as well as interactions between melanopsin and cone signals. Aim 1 will examine direct effects of melanopsin stimulation in healthy human subjects, using three distinct but complementary response measures: behavioral reports of visual discomfort and perception of brightness, fMRI and the pupillary light response. We will examine the specific role of melanopsin in behaviorally-assessed visual discomfort and brightness perception, measure sustained brain responses to direct melanopsin stimulation, and use the pupillary light response to assess individual differences in melanopsin responsivity as well as the stability of these differences over time. Aim 2 will also study healthy control subjects and characterize whether and how melanopsin signals interact with signals from cones, to regulate the response to cone-mediated light flicker. We will measure psychophysical thresholds for detection of cone-mediated flicker and assess how these are affected by changes in the melanopic component of an adapting background light, use fMRI to measure neural correlates of the psychophysical effects, and employ a novel paradigm that allows us to use the sluggish pupillary light response to test the hypothesis that melanopsin signals regulate the response to cone-mediated flicker at an early site along the visual pathways. Aim 3 will build on the results of Aims 1 and 2 to characterize the photoreceptor mechanism of the enhanced neural response to light observed in migraine with aura. We will also measure whether the migraineurs demonstrate systematic differences with controls in either the direct or interactive effects of melanopsin, and whether such differences are related to the enhanced light sensitivity of this patient population.