About 85% of people experiencing a migraine attack seek sanctuary in a dark environment in order to lessen headache intensification brought on by ambient light. The neural mechanism of this photophobic reaction remains a puzzle. Current views on the neural basis of migraine headache implicate trigeminal pain fibers in cranial dura mater, and central nociceptive neurons in the medullary dorsal horn, thalamus, and cortex. Our studies on dura-sensitive thalamic neurons as mediators of extracephalic allodynia led us, quite fortuitously, to evaluate if such neurons may play a role in migraine photophobia. In a clinical study leading up to this grant proposal, we learned that migraine photophobia occurs in blind persons (cone/rod degeneration) that perceive light (intact melanopsin photoreceptors), but not in migraineurs who are totally blind. We postulate that activity along migraine pain pathways may be modulated by converging signals transmitted from the retina to the brain through the optic nerve. In the rat thalamus, we identified dura-sensitive neurons whose ongoing activity was strongly modulated by light. Neural tract-tracing indicated that the cell bodies and dendrites of these thalamic neurons were apposed by many afferents of retinal origin, and that their own axons branched extensively into the primary somatosensory cortex. Here we will focus on this unique integration of meningeal nociception and retinal photoreception by thalamocortical neurons as a candidate mechanism for migraine photophobia. Study 1 will test the hypothesis that activity of dura/light-sensitive thalamic neurons is differentially modulated by classical photoreceptors (rods, cones) and melanopsinergic photoreceptors as it relates to qualitative and quantitative characteristics of migraine photophobia. Study 2 will test the hypothesis that photomodulation of dura-sensitive thalamic neurons is mediated by the optic nerve rather than by trigeminal innervation of the eye. Study 3 will test the hypothesis that cell bodies and dendrites of dura/light-sensitive neurons in the thalamus are apposed by axons of melanopsinergic retinal ganglion cells, providing a candidate neural substrate for incorporating retinal photoreception into a pathway of meningeal nociception in blind migraineurs with cone/rod degeneration. Study 4 will test the hypothesis that cell bodies and dendrites of dura/light-sensitive neurons in the thalamus are richly apposed by axons containing specific neuromodulating molecules as potential targets for pharmacological interception of migraine photophobia. Study 5 will test the hypothesis that thalamic neurons that integrate sensory information from the dura and retina project to cortical areas involved in the pain perception (e.g., somatosensory and insular cortices) or/and photoperception (visual cortices). Our working hypothesis that migraine headache can be exacerbated by non-image-forming retinal input converging upon dura-sensitive thalamocortical neurons represents a new concept in the field of migraine pathophysiology. As such, we submit this project as a new application that could potentially open a unique window into the biology of an adverse phenomenon described by millions of headache sufferers.
Almost every person undergoing a migraine attack seeks sanctuary in a dark environment in order to lessen the intensification of headache caused by exposure to light. This grant proposal will test a novel hypothesis that migraine headache is exacerbated by non-image-forming signals from the retina that are incorporated in the thalamus by nociceptive neurons that project to cortical areas involved in pain perception. This application could potentially open a unique window into the biology of an adverse phenomenon described by millions of headache sufferers.
|Schain, Aaron J; Melo-Carrillo, Agustin; Borsook, David et al. (2018) Activation of pial and dural macrophages and dendritic cells by cortical spreading depression. Ann Neurol 83:508-521|
|Nir, Rony-Reuven; Lee, Alice J; Huntington, Shaelah et al. (2018) Color-selective photophobia in ictal vs interictal migraineurs and in healthy controls. Pain 159:2030-2034|
|Burstein, Rami; Blake, Pamela; Schain, Aaron et al. (2017) Extracranial origin of headache. Curr Opin Neurol 30:263-271|
|Noseda, Rodrigo; Lee, Alice J; Nir, Rony-Reuven et al. (2017) Neural mechanism for hypothalamic-mediated autonomic responses to light during migraine. Proc Natl Acad Sci U S A 114:E5683-E5692|
|Melo-Carrillo, Agustin; Noseda, Rodrigo; Nir, Rony-Reuven et al. (2017) Selective Inhibition of Trigeminovascular Neurons by Fremanezumab: A Humanized Monoclonal Anti-CGRP Antibody. J Neurosci 37:7149-7163|
|Schain, Aaron J; Melo-Carrillo, Agustin; Strassman, Andrew M et al. (2017) Cortical Spreading Depression Closes Paravascular Space and Impairs Glymphatic Flow: Implications for Migraine Headache. J Neurosci 37:2904-2915|
|Noseda, Rodrigo; Borsook, David; Burstein, Rami (2017) Neuropeptides and Neurotransmitters That Modulate Thalamo-Cortical Pathways Relevant to Migraine Headache. Headache 57 Suppl 2:97-111|
|Becerra, Lino; Bishop, James; Barmettler, Gabi et al. (2017) Brain network alterations in the inflammatory soup animal model of migraine. Brain Res 1660:36-46|
|Burstein, Rami (2017) Reply: Pupil area and photopigment spectral sensitivity are relevant to study of migraine photophobia. Brain 140:e3|
|Perry, Carlton J; Blake, Pamela; Buettner, Catherine et al. (2016) Upregulation of inflammatory gene transcripts in periosteum of chronic migraineurs: Implications for extracranial origin of headache. Ann Neurol 79:1000-13|
Showing the most recent 10 out of 29 publications