A neural mechanism for exacerbation of headache by light

Journal name:
Nature Neuroscience
Year published:
Published online


The perception of migraine headache, which is mediated by nociceptive signals transmitted from the cranial dura mater to the brain, is uniquely exacerbated by exposure to light. We found that exacerbation of migraine headache by light is prevalent among blind individuals who maintain non–image-forming photoregulation in the face of massive rod/cone degeneration. Using single-unit recording and neural tract tracing in the rat, we identified dura-sensitive neurons in the posterior thalamus whose activity was distinctly modulated by light and whose axons projected extensively across layers I–V of somatosensory, visual and associative cortices. The cell bodies and dendrites of such dura/light-sensitive neurons were apposed by axons originating from retinal ganglion cells (RGCs), predominantly from intrinsically photosensitive RGCs, the principle conduit of non–image-forming photoregulation. We propose that photoregulation of migraine headache is exerted by a non–image-forming retinal pathway that modulates the activity of dura-sensitive thalamocortical neurons.

At a glance


  1. Projections of RGCs to the lateral posterior thalamic nuclei (LP) and posterior thalamic nuclear group (Po).
    Figure 1: Projections of RGCs to the lateral posterior thalamic nuclei (LP) and posterior thalamic nuclear group (Po).

    (a,b) Anterograde tracing of retinal afferents was performed using large (a) or small (b) injections of rAAV-GFP into the vitreous body of the eye. (a) Top, low-power images of coronal sections counterstained with thionin showing immunolabeled retinal afferents (brown) in the main visual pathway. Bottom, high-power detail of the boxed areas in the corresponding top panels showing retinal afferents in ventral lateral posterior thalamic nuclei and dorsal posterior thalamic nuclear group. These images show only the blue channel, which isolated the labeled fibers from the background Nissl staining. (b) Top, low-power images of coronal sections showing preferential labeling of retinal afferents in the IGL. Bottom, high-power detail of the boxed areas in the corresponding top panels showing immunolabeled retinal afferents in ventral lateral posterior thalamic nuclei and dorsal posterior thalamic nuclear group. Preferential labeling of non–image-forming pathways by the smaller rAAV-GFP injection (b) compared with the larger injection (a) reflected preferential labeling of ipRGCs. Note that the retinal afferents ran dorsoventrally from the main visual pathway through ventral aspect of lateral posterior thalamic nuclei and into dorsal aspect of posterior thalamic nuclear group (a,b). Note that the density of labeled axons in ventral lateral posterior thalamic nuclei and dorsal posterior thalamic nuclear group was similar between a and b, suggesting that most labeled axons in these areas were of ipRGC origin. Numbers indicate distance from bregma (mm). APT, anterior pretectal nucleus; bsc, brachium superior colliculus; DLG, dorsal part of lateral geniculate nucleus. Scale bars represent 500 μm.

  2. Photosensitivity of dura-sensitive thalamic neurons.
    Figure 2: Photosensitivity of dura-sensitive thalamic neurons.

    (a,b) Identifying neuronal responses to electrical (a), mechanical and chemical (b) stimulation of the dura. (c) Effects of ambient light (500 lx) and bright light (50,000 lx) on firing rate (mean ± s.e.m.) of dura-sensitive versus dura-insensitive thalamic neurons (* P < 0.05, Wilcoxon matched-pairs signed-ranks test). (d) Histological localization of the recorded neurons. Drawings and numbers indicating distance from Bregma (mm) are from ref. 46. LDVL, laterodorsal thalamic nucleus, ventrolateral; LPLC, lateral posterior thalamic nucleus, laterocaudal; LPLR, lateral posterior thalamic nucleus, laterorostral; LPMC, lateral posterior thalamic nucleus, mediocaudal; LPMR, lateral posterior thalamic nucleus, mediorostral; PLi, posterior limitans thalamic nucleus; PoT, posterior thalamic nuclear group, triangular; VPL, ventral posterolateral thalamic nucleus; VPM, ventral posteromedial thalamic nucleus. (e) Graphic representation of the dorso-ventral localization of the neurons shown in d. Color coding is as in d. (fj) Examples of delayed and immediate photoactivation of individual dura-sensitive thalamic neurons by 50,000 (f,g), 3,000 (h,i) and 500 lx (j) of white light (green line). Window discriminator spike output (top) and mean activity histogram (bottom) are shown in f and g. Mean activity histograms are shown in h and j. Window discriminator output (top) and oscillographic tracing (bottom) are shown in i. Each of the light intensities induced delayed activation in some neurons (f,h,j) and immediate activation in others (g,i). Each of the light intensities induced prolonged activation that outlasted the stimulus by several minutes. The numbers in parentheses indicate mean spikes per s for the corresponding interval. Black and red bars indicate, respectively, baseline and enhanced periods of activity in response to light. Bin widths are 0.5 (f,g,j) and 1 s (h).

  3. Close apposition between dura/light-sensitive neurons and retinal afferents in lateral posterior thalamic nuclei and posterior thalamic nuclear group.
    Figure 3: Close apposition between dura/light-sensitive neurons and retinal afferents in lateral posterior thalamic nuclei and posterior thalamic nuclear group.

    (a) Synchronization of neuronal activity (top) with the current (bottom) delivered by the TMR-dextran–filled recording micropipette. (b) Dura/light-sensitive units (U1–U4) filled with TMR-dextran (red) and retinal axons labeled anterogradely with CTB (green). Each image represents z stacking of approximately 30 1–1.5-μm-thick scans. Arrowheads point to potential axodendritic or axosomatic apposition. Localization of each cell body is marked by a yellow star in the low-power, darkfield inset. The numbers indicate distance from bregma. (c) Evidence for axodendritic and axosomatic apposition in a single 1–1.5-μm-thick scan taken from the units shown in b. (d) Neuronal firing in response to 50,000 lx of white light (green line and shaded area), corresponding to the individual neurons shown in b. Scale bars represent 50 μm (b,c).

  4. Cortical projections of three dura/light-sensitive thalamic neurons juxtacellularly filled with TMR-dextran.
    Figure 4: Cortical projections of three dura/light-sensitive thalamic neurons juxtacellularly filled with TMR-dextran.

    (a) Labeled cell bodies and their dendrites in the posterior thalamus. (b) Camera-lucida tracing of the cell bodies, dendrites and axonal trajectories coursing through thalamic reticular nucleus (Rt) en route the external capsule (ec). (c) Localization of cell bodies, Rt collaterals and entry point of the parent axon into the external capsule. (d) Tabulation of cortical areas and layers containing axons with synaptic boutons. PtA, parietal association cortex; RSA, retrosplenial agranular cortex; S1, primary somatosensory cortex; S1BF, primary somatosensory barrel field; S1Tr, primary somatosensory trunk region; S1DZ, primary somatosensory dysgranular region; V1B, binocular area of the primary visual cortex; V2L and V2M, lateral and mediolateral areas of the secondary visual cortex, respectively. (e) Camera-lucida tracing of axon terminal fields in different cortical areas. Au1, primary auditory cortex; AuD, secondary auditory cortex, dorsal; M1 and M2, primary and secondary motor cortices, respectively. (f) Photomicrographs of axons with synaptic boutons in several cortical areas. Drawings and numbers (b,c,e) indicating distance from bregma (mm) are based on ref. 46. Scale bars represent 100 μm (a,f). LDDM, laterodorsal thalamic nucleus, dorsomedial.


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Author information


  1. Department of Anesthesia, Boston, Massachusetts, USA.

    • Rodrigo Noseda,
    • Vanessa Kainz,
    • Moshe Jakubowski &
    • Rami Burstein
  2. Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

    • Joshua J Gooley &
    • Clifford B Saper
  3. Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, USA.

    • Clifford B Saper &
    • Rami Burstein
  4. Department of Neurology and Ophthalmology, Moran Eye Center, University of Utah, Salt Lake City, Utah, USA.

    • Kathleen Digre


R.B., M.J. and R.N. designed the study. R.N., V.K., J.J.G. and R.B. conducted the various experiments. M.J., R.N., C.B.S. and K.D. contributed to data analysis and presentation. R.B. and M.J. wrote the manuscript.

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