Understanding migraines: The blind leading the…err…rats

Chances are that you have either suffered from migraine yourself or have a family member or close friend who have, after all about 1 in 8 of us will suffer from migraine at some stage in our lifetime, and some sufferers experience repeated debilitating episodes over many years . While headache on one side of the brain is typical other symptoms such as nausea are very common, indeed in some migraine victims nausea is the primary symptom of the disorder.  Through a combination of studies in animals and clinical research using techniques such as fMRI and PET scans scientists have learned a lot in recent years about what happens before and during migraine episodes but we do not yet fully understand what ultimately causes the attacks, and debate rages over the relative importance of some mechanisms originating deep in brain regions such as the hypothalamus and others that start in membranes that surround the brain, (1,2).  Current treatments can help prevent migraine, reduce suffering and hasten recovery they do not work for all patients, and a better understanding of what exactly is happening before and during a migraine attack will aid the development of really effective treatments and preventative measures.  A study published in Nature Neuroscience combines clinical research with studies of rats to provide clues about a key characteristic of migraines that has until now remained unexplained, the exacerbation of the pain experienced by sufferers by light (3).

The team, lead by Rami Burnstein of Beth Israel Deaconess Medical Centre in Boston, decided to concentrate of the role of a particular subset of nerve cells in the retina known as intrinsically photosensitive retinal ganglion cells (ipRGCs) which they knew from previous mouse research to be involved in eye functions that are not image forming, such as setting the biological clock to the day night cycle.  The ipRGCs are stimulated by light both indirectly via the rods and cones and directly through a pigment called melanopsin that they themselves contain.  In order to discover if the ipRCGs are important to light sensitivity in migraine they performed a very neat clinical study involving 20 blind patients who also suffered from migraine. Six of these patients lacked any light perception due to removal of their eyes or damage to the optic nerve, while in the remaining 14 the damage to the eyes was less total, affecting the rods and cones but not ipRGCs, so that while they were unable to see images they could detect light. The results were clear, blue and grey light made the headaches of those who retained light sensitivity worse, while having no effect on the six blind individuals who lacked light perception.

Determining that the ipRGCs are involved in the exacerbation of migraine headaches by light is of course only part of the story, and Professor Burnstein’s team next turned to tracing the nerve pathways that are responsible for the increased pain, knowledge that might help to develop new treatments.  This they could not do in human subjects because the available imaging techniques do not have the precision to determine the connections between individual neurons.  In a series of studies they injected labels including Green Fluorescent Protein into particular areas of the eyes and brain, and in some cases even individual nerve cells, of anesthetized rats with and followed the path of the neurons.  They were also able to use tiny electrodes to record the effect of light on the firing of individual nerves in the brain, something that cannot yet be done in human subjects. An exciting observation was that the ipRCGs connected to cells in a region of the brain known as the posterior thalamus, itself part of the trigeminovascular pathway that is strongly implicated in migraine headache through transmission of nerve signals from the irritated outer brain membranes to the deep brain. When they examined the electrical activity of these cells they discovered that the majority of the cells within the posterior thalamus that are involved in mediating migraine pain are also light sensitive.  Finally they demonstrated that the light-sensitive pain-mediating neurons of the posterior hypothalamus connect to nerve cells in several regions of the somatosensory region of the cortex, an intriguing discovery since abnormalities in this region have previously been seen in migraine patients. This discovery is likely to encourage scientists to study the role of the somatosensory cortex in migraine in more detail.

So how important is this study? Well it’s unlikely that this discovery will lead to any treatment breakthrough in the immediate future, though the discovery that grey light can exacerbate migraine headache is new and may help patients to avoid it.  Despite a perhaps natural tendency for the news media to look for “breakthroughs” the majority of scientific papers published are like this one, providing valuable new insights into biology that contribute to our overall understanding of how biological systems work and happens when they go awry but not indicating an easy fix.  I’ve no doubt that this and many similar basic science studies will contribute to better treatments for migraine in the future, but perhaps not tomorrow!

Regards

Paul Browne

1)      Olesen J. et al “Origin of pain in migraine:evidence for peripheral sensitization” The Lancet Neurology Volume 8, Issue 7, Pages 679-690 (2009) doi:10.1016/S1474-4422(09)70090-0

2)      Alstadhaug K.B.  “Migraine and the hypothalamus” Cephalalgia Volume 29, Issue 8, Pages 809-817 doi: 10.1111/j.1468-2982.2008.01814.x

3)      Noseda R. et al. “A neural mechanism for exacerbation of headache by light” Nature neuroscience Advance Publication Online 10 January 2010 doi: 10.1038/nn.2475

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