This study revealed a mechanism for the exacerbation of migraine headache by light, whereby neuronal activity of a nociceptive pathway that underlies migraine pain (Supplementary Fig. 7
, green) is modulated at the level of the thalamus by retinal photoactivation. We propose that this photomodulation is exerted by novel axonal projections of retinal ganglion cells that converge upon dura-sensitive neurons in a discrete area in the posterior thalamus (Supplementary Fig. 7
, red). To a large extent, the retinal projections to the posterior region of the thalamus consisted of axons of ipRGC (; Supplementary Fig. 4
), which have been shown to play critical roles in a growing number of non-image-forming functions17,19–25
. The implication of ipRGC in migraine photophobia gains support from our finding that exacerbation of migraine headache by light was preserved in blind patients who could sense light in the face of severe degeneration of rod and cone photoreceptors. The mapping of the axonal projections of dura-sensitive thalamic neurons unraveled for the first time the cortical terminal fields of the trigeminovascular pathway.
In migraine patients with normal eyesight, exacerbation of headache by light is likely to involve both extrinsic photoactivation of ipRGC by rods and cones, as well as intrinsic photoactivation of melanopsin34,35
. The presence of migraine photophobia in blind patients with outer retinal degeneration was associated with the preservation of PLR and circadian photoentrainment, suggesting that non-image-forming pathways remained intact in these patients. Indeed, histological examination of eyes from retinitis pigmentosa patients with total loss of outer photoreceptor layer demonstrated preservation of the melanopsin-expressing ipRGC inner layer36
. In the case of our photosensitive blind patients, we cannot rule out the possibility that certain aspects of non-visual functions are mediated by functioning rods and cones that survived the retinal disease.
The novel retinal projection to lateral posterior thalamic nuclei and the posterior thalamic nuclear group is distinct from the main visual pathway. This novel projection appeared similar in cases in which a large intravitreal injection of rAAV-GFP produced dense labeling along all known visual pathways and cases in which a small injection produced preferential labeling in the SCN, IGL and OPT – structures that subserve non-image forming functions22–25
. Since 80% of retinal ganglion cells labeled by the small injection of the tracer expressed melanopsin22
, we conclude that the retinal projections we observed in the posterior thalamus originated to a large extent in ipRGC, and to a lesser extent in non-melanopsinergic RGC.
The photosensitivity of dura-sensitive units in the rat thalamus consisted of short (<1 s) or long (>1 s) response latencies, prolonged discharges, and slow decay of activity. To a limited degree, an instantaneous surge of firing in response to light may be attributed to activation of RGC and ipRGC by rods and cones, whereas subsequent long-lasting activity which subsides slowly in the dark may be attributed to ipRGC signals that are driven intrinsically by melanopsin photoactivation28,35,37,38
. Photoactivation of dura-sensitive thalamic neurons within hundreds of ms may be consistent with monosynaptic input from retinal ganglion cells triggered by rods and cones. This possibility may be further supported by the close apposition between dura/light-sensitive neurons and boutons of retinal axons in LP and Po observed within 1–1.5-μm-thick scans (). The number and nature of such close appositions at the level of a distal dendrite, proximal dendrite, or cell body () may influence the probability of firing in response to light by individual LP/Po neurons, including response latency, magnitude and duration (). It should be emphasized, however, that the intrinsic ongoing activity of dura-sensitive thalamic neurons, and the input they continue to receive from the meninges, may mask the onset of their activation by light, and confound the relative contribution of RGC or ipRGC to their response duration and response decay.
The instantaneous induction of neuronal firing in response to light and its slow decay in the dark may be consistent with the exacerbation of migraine headache by light and its slow relief in the dark. Most photosensitive blind migraineurs and those with normal eyesight testify that headache severity increases within few seconds of light exposure and decreases over 10-20 min after return to a dark environment (Supplementary Table 1
). Photoactivation of dura-sensitive thalamic units that was delayed by several minutes might be consistent with delayed exacerbation of migraine headache by light reported by some patients (Supplementary Table 1
), but cannot be explained at this juncture vis-à-vis the response properties of retinal ganglion cells.
This is the first study to map out the cortical terminal fields of the trigeminovascular pathway. Anterograde transport of tritiated amino acids from the Po to axons in S1 has been traced only to layers I and V39
. Here we identified singularly-labeled dura-sensitive thalamic neurons that form widespread axonal terminal fields spanning layers I–V of the barrel field and trunk region of the primary somatosensory cortex. While it is generally accepted that the primary somatosensory cortex is involved in certain aspects of the experience of pain40
, the role it plays in processing migraine headache remains to be determined. Additional projections to cortical areas involved in cognitive, motor and visual functions may mediate a number of transient symptoms associated with migraine, such as loss of short-term memory (retrosplenial cortex41
), muscle weakness and impaired motor coordination (motor cortex42
), attention deficits (parietal association cortex43
), and visual disturbances (visual cortex44,45