Neural mechanism for hypothalamic-mediated autonomic responses to light during migraine

Abstract

Migraineurs avoid light because it intensifies their headache. However, this is not the only reason for their aversion to light. Studying migraineurs and control subjects, we found that lights triggered more changes in autonomic functions and negative emotions during, rather than in the absence of, migraine or in control subjects, and that the association between light and positive emotions was stronger in control subjects than migraineurs. Seeking to define a neuroanatomical substrate for these findings, we showed that, in rats, axons of retinal ganglion cells converge on hypothalamic neurons that project directly to nuclei in the brainstem and spinal cord that regulate parasympathetic and sympathetic functions and contain dopamine, histamine, orexin, melanin-concentrating hormone, oxytocin, and vasopressin. Although the rat studies define frameworks for conceptualizing how light triggers the symptoms described by patients, the human studies suggest that the aversive nature of light is more complex than its association with headache intensification.

Keywords: colors; emotions; parasympathetic; photophobia; sympathetic.

Fig. 1.

Effects of light and color on autonomic responses, hypothalamic functions, and affect. (A and B) Proportion of migraine patients and control subjects experiencing autonomic responses to nonselective (A; all colors combined) and selective [B; white (w), blue (b), green (g), amber (a), red (r)] photic stimuli. Autonomic responses included the perception of chest tightness, throat tightness, shortness of breath, fast breathing, faster-than-usual heart rate, light-headedness, dizziness, nausea, vomiting, dry mouth, salivation, rhinorrhea, stuffy sinus, and/or lacrimation. (C and D) Proportion of migraine patients and control subjects experiencing alteration in hypothalamic functions related to regulation of sleep and food intake in response to nonselective (C) and selective (D) photic stimuli. Hypothalamic responses included feeling sleepy, drowsy, tired, hungry, and/or thirsty. (E and F) Proportion of migraine patients and control subjects experiencing negative emotions in response to nonselective (E) and selective (F) photic stimuli. Emotions were classified negative when defined by participants as intense, irritable, angry, nervous, hopeless, needy, agitated, sad, scared, cranky, upset, depressed, disappointed, jittery, worried, stressed, anxious, “panic and fear,” and/or actual crying. (G and H) Proportion of migraine patients and control subjects experiencing positive emotions in response to nonselective (G) and selective (H) photic stimuli. Emotions were classified positive when defined by participants as happy, relaxing, soothing, and/or calming. Migraine patients were tested twice: once during the ictal and once during the interictal phase. Asterisk shows statistically significant P values (P < 0.03) considering Bonferroni-corrected α for multiple comparisons. Note that autonomic responses to light occurred most frequently during migraine and least frequently in control subjects, whereas most reports of positive emotions were provided by control subjects and the least by migraine patients undergoing acute attack. Also note lack of color effect in all aspects of the study except the percentage of patients experiencing positive emotions to green light during migraine (H) (P< 0.001).

Fig. 2.

Retinal innervation of hypothalamic neurons that project to the SSN in the brainstem and IML of the spinal cord. (A) Iontophoretic injections of FG into the SSN (Left) were confirmed by staining sections containing the injection site with choline acetyltransferase (Middle), a marker of parasympathetic preganglionic neurons in the SSN. Location of SSN in the brainstem is represented on the right. (B) Anterogradely labeled retinal axons (green; GFP) shown in close apposition (arrowheads) with retrogradely labeled neurons in the hypothalamus, preoptic area, and PAG that project to the SSN. (C) Iontophoretic injections of FG into the IML (Left) and illustration of its location in the spinal cord (Right). (D) Anterogradely labeled retinal axons (green; GFP) shown in close apposition (arrowheads) with retrogradely labeled hypothalamic neurons that project to the IML. A11, dopaminergic hypothalamic nucleus; AAV, adenoassociated virus with reporter gene for GFP; AH, anterior hypothalamus; LSO, lateral superior olive; Pr5, principal sensory trigeminal nucleus; py, pyramidal tract; PVN, paraventricular hypothalamic nucleus; sp5, spinal trigeminal tract; T3/T5, thoracic spinal cord segments 3 and 5; VLPO, ventrolateral preoptic area; 7n, facial nerve; 4V, fourth ventricle. (Scale bars: A, 500 μm; C, 200 μm; B and D, 50 μm.)

Fig. 3.

Retinal innervation of hypothalamic neurons containing the neurotransmitters dopamine and histamine and the neuropeptides orexin, MCH, oxytocin, and vasopressin. (A) Immunopositive TH neurons (red) in close apposition to retinal axons and varicosities (green). (B) Immunopositive histaminergic neurons in close apposition to retinal axons and varicosities. (C) Immunopositive orexinergic neurons in close apposition to retinal axons and varicosities. (D) Immunopositive MCH neurons in close apposition to retinal axons and varicosities. (E) Immunopositive oxytocinergic and vasopressinergic neurons in close apposition to retinal axons and varicosities. Reconstructions in lower right panels show locations of neurons in the different hypothalamic areas and nuclei. Numbers in red indicate distance from bregma. Arrowheads point to close appositions. (Scale bars: 50 μm.) Arc, arcuate nucleus; cp, cerebral peduncle; DM, dorsomedial hypothalamic nucleus; DTM, dorsal tuberomammillary nucleus; f, fornix; HDB, horizontal limb of the diagonal band; ic, internal capsule; LPO, lateral preoptic area; MeA, medial amygdaloid nucleus; MPO, medial preoptic nucleus; mt, mammillothalamic tract; opt, optic tract; Pe, periventricular nucleus; PH, posterior hypothalamic nucleus; PLH, peduncular part of the LH; RCh, retrochiasmatic area; SO, supraoptic nucleus; sox, supraoptic decussation; VLH, ventrolateral hypothalamic nucleus; VMH, ventromedial hypothalamus; VTM, ventral tuberomammillary nucleus; ZI, zona incerta; 3V, third ventricle. Other abbreviations are defined in Fig. 2.

Fig. S1.

Close apposition between anterogradely labeled retinal axons and hypothalamic neurons. Examples of retinal axons (green; AAV-GFP) in close proximity (arrowheads) with hypothalamic neurons (red) that were (A) retrogradely labeled from the SSN in the brainstem, (B) retrogradely labeled from the IML in the spinal cord, and (C) chemically identified (Orexin A in this example) using immunofluorescence. A series of 2D (XY) images were obtained by scanning every 1 µm across the z plane. These images were used to create orthogonal views in the XZ and YZ planes to provide evidence that retinal fibers may contact neuronal somas and/or dendrites in the hypothalamus (as shown in Figs. 2 and 3). The XY image in (B) is a composite obtained by overlapping a small portion of two adjacent images. Definitive evidence for actual synapses, however, requires examination with EM. (Scale bars: 50 µm.)

Fig. 4.

Proposed pathways for modulation of autonomic responses, hypothalamic functions, and emotions by light. (A) Pathways for induction of symptoms associated with activation of the parasympathetic system. (B) Pathways for induction of symptoms associated with activation of the sympathetic system. (C) Pathways for inductions of symptoms mediated by dopamine, orexin, histamine, MCH, oxytocin, and vasopressin.