A Neural Pathway for Photophobia in Migraine
The neural mechanisms of many symptoms associated with migraine have yet to be elucidated. New research suggests that a non-image-forming retinal pathway and signals from the dura mater contribute to photophobia in patients with migraine. More research is needed to understand the mechanisms behind other migraine-associated symptoms such as nausea and osmophobia.
Introduction
Migraine has traditionally been viewed as too elusive for neuroscientific study. Over the past 25 years, however, migraine research has progressed faster than many fields within neurology, and important research and clinical advances have been made.[1] Internationally accepted, unambiguous diagnostic criteria and a hierarchical classification for migraine have been developed and widely implemented. Furthermore, cortical spreading depression has been accepted as the probable neural mechanism of migraine aura – the visual, sensory and other neurological symptoms that precede pain in many patients. Genes and mutations have been identified that explain the rare familial hemiplegic subtype of migraine, and the roles of the trigeminovascular system and the brainstem in migraine have been appreciated. Other studies have shown that several signaling molecules are involved in migraine, most notably nitric oxide and calcitonin gene-related peptide, which has led to mechanism-based development of new drugs that are now approaching the market.[2]
A further major advance in our understanding of the neurobiology of migraine has now been presented in Nature Neuroscience. Noseda and co-workers,[3] including group leader Rami Burstein from Harvard University, studied one of the key symptoms of migraine, hypersensitivity to light (photophobia). Photophobia is an important component of the diagnostic criteria for migraine, and is present in >80% of patients with this condition.[4] The mechanisms underlying photophobia in migraine, however, continue to elude many researchers in the field. For instance, why is migraine, in contrast to tension-type headache and cluster headache, so strongly associated with photophobia and other so-called associated symptoms?
The approach of Noseda et al.[3] to this scientific problem is a fine example of what one could call reverse translational research – going from human study to animal experimentation. Having noted the clinical phenomenon, the investigators first searched for an explanation by studying patients who lacked light perception because their optic nerves were damaged or their eyes had been surgically removed. They showed that migraine pain in these patients did not worsen during exposure to strong light. Another group of patients had a preserved sense of light but extremely low visual acuity, and their image-forming vision was totally destroyed. These patients nevertheless experienced worsening of their migraine pain by light. The logical inference from these findings is that hypersensitivity to light is transmitted via non-image-forming retinal projections. Noseda and colleagues[3] proceeded to map this pathway in animal models and successfully identified an area in the posterior thalamus that contained neurons that were sensitive to noxious stimulation of the dura mater. These cells were shown to respond to input from both retinal ganglion cells and the dura mater. The convergence of inputs onto these cells explains why light augments migraine pain, even in functionally blind individuals with preserved light perception. In a final series of studies, the researchers mapped projections from these neurons to the cerebral cortex – the first time that a putative migraine pathway has been traced above the thalamus.
This study raises a number of issues and possibilities. The researchers take for granted that migraine pain originates from the dura mater. This is a convenient view for basic scientists because the dura mater is easily accessible for study, but it is not necessarily shared by all or even the majority of migraine experts. In fact, a recent analysis of the origin of painful impulses (nociception) in migraine concluded that the available evidence provides an insufficient basis on which to decide whether migraine pain originates from extracranial tissues, from the dura mater, or from blood vessels in the pia mater, as was previously proposed.[5] One might argue, however, that Noseda et al.[3] provide support for a role for the dura mater, since neurons in the pain pathway that were responsive to light were also sensitive to stimulation of this meningeal layer.
The study also raises a broader question: is the convergence of inputs onto the trigeminal pain pathway an essential feature not only of photophobia but also of pain itself?[6] Previous experimental work has clearly demonstrated convergence of inputs from extracranial tissues and the dura mater onto trigeminal nucleus caudalis neurons. Less clear is whether input from the pia mater also converges on the same neurons. The difficulty in explaining the origin of migraine nociception could be rooted in widespread convergence of inputs. According to this view, migraine nociception arises not from extracranial, dural or pial input alone but from all three combined, perhaps with varying contribution in different patients.
In all likelihood, the symptoms of migraine will never all be explained by a simple mechanism. The paper by Noseda et al.[3] sheds light on one piece of the migraine puzzle and our hope is that future research will explain the many other pieces. A number of questions remain unanswered in migraine research, particularly with regard to the involvement of sensory systems other than the visual system in the symptoms of migraine. Patients with migraine are hypersensitive to smell (osmophobia) and sound (phonophobia), and the existence of special subsets of neurons, or vagal input projections to dura-sensitive neurons, might explain these phenomena. Other characteristic symptoms of migraine include nausea and vomiting, as well as sensitivity to movement and physical exercise, and the neural pathways that underlie these phenomena remain to be elucidated.
Jes Olesen
From Nature Reviews Neurology
References
1. Olesen, J., Goadsby, P. J., Ramadan, N. M., Tfelt-Hansen, P. & Welch, K. M. A (Eds) The Headaches 3rd edn (Lippincott Williams and Wilkins, Philadelphia, 2006).
2. Ho, T. W. et al. Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-treatment trial. Lancet 372, 2115–2123 (2008).
3. Noseda, R. et al. A neural mechanism for exacerbation of headache by light. Nat. Neurosci. 13, 239–245 (2010).
4. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 24 (Suppl. 1), 9–160 (2004).
5. Olesen, J., Burstein, R., Ashina, M. & Tfelt-Hansen, P. Origin of pain in migraine: evidence for peripheral sensitisation. Lancet Neurol. 8, 679–690 (2009).
6. Olesen, J. Clinical and pathophysiological observations in migraine and tension-type headache explained by integration of vascular, supraspinal and myofascial inputs. Pain 46, 125–132 (1991).