LOS ANGELES—While it has been known that light can exacerbate headache in patients with migraine, researchers have recently found that the same phenomenon occurs in some blind patients with migraine. This and other findings indicate that, in all patients, the exacerbation occurs through retinal projections containing the photopigment melanopsin, said Rami Burstein, PhD, at the 52nd Annual Scientific Meeting of the American Headache Society.
“We have evidence that retinal ganglion cells [RGCs] that contain melanopsin project directly to vascular trigeminal neurons in the posterior group of the thalamus,” he said. “These thalamic neurons are activated in response to stimulation of the meninges, as well as by light. They project to multiple cortical areas that can play a role in many of the associated symptoms of migraine.”
Dr. Burstein, Professor of Anesthesia and Neuroscience at the Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, and colleagues came to these conclusions through research involving both blind patients and animals.
Switching on Neural Activity
The group began their research after noticing, as they studied central sensitization in allodynia, that the activity of dura-sensitive neurons increased when room lights were turned on. “This is the first time we started to think about neurons that not only responded to stimulation of the dura but also changed activity in response to light,” said Dr. Burstein. “We figured out that we may have the tools to try to understand photophobia.”
Their first step toward such an understanding was asking patients with migraine whether they experienced photophobia as difficulty adjusting to bright sunshine after leaving a dark room or as exacerbation of headache with exposure to light. “If photophobia is a visual intolerance to light, one would think that it is a convergence of pain signals on the visual pathway that ends in the visual cortex,” Dr. Burstein explained. “However, if it is exacerbation of headache by light, it would be a convergence of light signals on the pain pathway that ends in the cortical areas involved in the perception of pain.”
Because most patients said they experienced the problem as exacerbation of headache by light, the researchers began to investigate the convergence of light signals and the pain pathway.
Looking to the Blind
Their next step was to study responses to light in six totally blind patients with migraine, to determine whether photophobia is mediated by the trigeminal nerve or by the optic nerve. None of the patients experienced a change in headache intensity with light exposure.
“This told us that we need to follow the optic nerve,” Dr. Burstein said.
Next, the researchers looked at findings from a 2003 study that traced RGCs to the CNS, and they noticed a group of axons that traveled to the posterior thalamus nucleus. “It was there; it was just never paid attention to,” said Dr. Burstein.
The researchers also studied responses to light in a second group of blind patients with migraine, who were able to detect light through the optic nerve, and these patients reported increases in headache intensity with light exposure. “Their sensitivity to light was worse on cloudy and snowy days—when the light tends to be a bit on the blue side,” Dr. Burstein added. “That certainly gave us a clue.”
The clue pointed toward intrinsically photosensitive RGCs (ipRGCs), which contain melanopsin and transmit blue light signals through the optic nerve to the brain. Discovered in 2000, ipRGCs play no visual role but help to set the biological clock to the dark-light cycle, adjust the size of the pupils to light, and suppress melatonin release by light.
“So at that point, our research started to focus more on the pathway that came from the RGCs that contained melanopsin, rather than on all the RGCs,” said Dr. Burstein.
Dural and Light Sensitivity in Rats
The researchers began to investigate the relationship between dural sensitivity and light sensitivity in heavily sedated rats. When they injected tracers into the rats’ vitreous bodies, the investigators found heavy axonal labeling in the optic tract and the main visual thalamic nuclei. And when they injected tracers into the thalamic nuclear group, they found labeling in RGCs, including ipRGCs, and the spinal trigeminal nucleus. Within the posterior thalamus, they found 14 neurons that were both dura-sensitive and light-sensitive.
“For a neuron to respond to light in that area, two conditions had to be met,” said Dr. Burstein. “It had to process information from the dura, and it had to be located in the most dorsal part of the posterior thalamus or in the lateral posterior nucleus. If the neurons were dura-sensitive but deeper in the thalamus, they did not respond to light. And if they were in the right area but they were not dural sensitive, they also did not respond to light.”