Melanopsin and cone signals in human visual processing

 描述（由申请人提供）：许多眼科和神经系统疾病的症状是灯光恐惧症：闪烁和明亮的灯光引起的不适和疼痛。更具体地说， 头痛恐惧症是偏头痛患者的一个主要症状，在头痛期间和无头痛发作间期都是如此。系统行为研究证实了这一临床观察结果，表明此类患者的视觉刺激不适阈值较低。还有证据表明，某些形式的视觉不适可能与来自含有黑视素的固有光敏视网膜神经节细胞（ipRGC）的信号有关。该提案的三个目标将测试与偏头痛相关的恐惧症与黑视素刺激的反应改变有关的假设，以及表征介导在有先兆的偏头痛中观察到的记录升高的对光的神经反应的光感受器机制。所有这三个目标将采用数字光积分器来产生光谱调制，选择性和鲁棒性地刺激个别的色素类。我们将测量分别针对黑视蛋白和视锥光感受器的刺激的效果，以及黑视蛋白和视锥信号之间的相互作用。目的1将研究黑视素刺激对健康受试者的直接影响，使用三种不同但互补的反应措施：视觉不适和亮度感知的行为报告，fMRI和瞳孔光反应。我们将研究黑视素在行为评估的视觉不适和亮度感知中的具体作用，测量大脑对直接黑视素刺激的持续反应，并使用瞳孔光反应来评估黑视素反应的个体差异以及这些差异随时间的稳定性。目标2还将研究健康对照受试者，并表征黑视蛋白信号是否以及如何与来自视锥的信号相互作用，以调节对视锥介导的光闪烁的反应。我们将测量用于检测视锥细胞介导的闪烁的心理物理阈值，并评估这些阈值如何受到适应背景光的黑视成分变化的影响，使用fMRI测量心理物理效应的神经相关性，并采用一种新的范式，使我们能够使用缓慢的瞳孔光反应来测试黑视素信号调节对锥细胞反应的假设，介导的闪烁在早期网站沿着视觉途径。目的3将建立在目的1和2的结果上，以表征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是否表现出与对照组在黑视素的直接或交互作用方面的系统性差异，以及这些差异是否与该患者群体的光敏感性增强有关。

 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.