Editors' ChoiceMigraine

Shining new light on migraine

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Science Translational Medicine  12 Jul 2017:
Vol. 9, Issue 398, eaan8206
DOI: 10.1126/scitranslmed.aan8206

Abstract

Migraine-related photophobia is multifaceted and may be mediated by numerous pathways.

Although light is notorious for worsening the pain associated with migraine, it can also evoke other symptoms, ranging from emotional states (sadness, anxiety) to unpleasant sensations (shortness of breath, chest tightness). To date, most studies investigated light-induced hyperexcitability in the visual cortex and resulting changes in headache sensitivity. Taking a different approach, Noseda et al. evaluated behavioral responses to light in patients with migraine. Then, they paired this study with axon tracing analysis in rats that highlighted multiple retino-hypothalamic pathways as potential neuroanatomical substrates for the range of unpleasant sensations associated with migraine.

The team first collected self-assessments of responses to light during and between migraine attacks in migraineurs and healthy controls and grouped responses into four distinct categories: (i) hypothalamic-mediated autonomic (changes in heart rate and breathing, dizziness, nausea); (ii) hypothalamic non-autonomic (regulation of feeding and sleep); (iii) affective negative (irritability, anger, sadness); and (iv) affective positive (happiness, relaxation, calmness). Indeed, light exacerbated hypothalamic-mediated autonomic responses in patients with migraine compared with controls both during and between migraine attacks. Additional analyses assessed the effects of delivering light of five different colors. The only color-specific effect was found for green light, which could trigger more positive emotions than other colors in migraine patients during attacks.

In this study, the authors hypothesized that several two-synapse pathways from retina to various brainstem nuclei via the hypothalamus may regulate light-induced autonomic responses in migraineurs. Therefore, they performed pathway tracing studies in rats, pairing anterograde viral labeling of retinal afferents with retrograde tracing from sympathetic and parasympathetic nuclei in the brainstem, to chart the convergence of retinal axons onto brainstem-projecting hypothalamic neurons. Immunolabeling studies with antibodies selective for neuropeptides and/or neurotransmitters then revealed that retinal axons likely converge on a range of hypothalamic neurons, including those expressing dopamine/noradrenaline, histamine, orexin, oxytocin, and vasopressin, suggesting the tantalizing possibility that activation of different subsets of these neurons may trigger different affective and autonomic symptoms associated with light exposure during migraine. The functional activation of these pathways during migraine was not assessed, and the functional connectivity between retina and hypothalamus in humans may be more complex than in rodents. Nevertheless, these analyses provide an interesting first step toward delineating the pathways regulating autonomic changes during migraine and suggest that photosensitivity associated with migraine involves several pathways through hypothalamus and brainstem. Emerging genetic tools should allow for future functional dissection of the specific circuits involved.

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