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Correlation of Increase in Phosphene Threshold With Reduction of Migraine Frequency: A Comment

I read with extreme interest the paper from Young and coworkers, showing increased phosphene thresholds after reduction in headache frequency following preventive treatment. Several studies have suggested that individuals with migraine have decreased phosphene threshold upon transcranial magnetic stimulation (TMS) of the visual cortex. The study of Young also reported that increasing age, nonwhite race, and diagnosis of tension-type headache were associated with a higher mean TMS threshold both at baseline and at follow up. Conversely, increasing body mass index was found to be associated with a lower mean TMS threshold (P =.005), which was unanticipated by the authors, and seems to me as being of extreme interest. Several studies suggest that obesity is a risk factor for migraine severity and frequency, and for progression from an episodic into a chronic form. As the evidence linking migraine and obesity is now very well demonstrated, putative mechanisms explaining the relationship are necessary. Indeed, obesity leads to alterations at both the peripheral (systemic) and neurological level, which may contribute to increased headache frequency in migraineurs. To mention just a few of these dysfunctions, inflammatory mediators (interleukins) and certain neuropeptides (eg, calcitonin gene-related peptide [CGRP]) are increased in obese individuals and are important in migraine pathophysiology. Furthermore, both migraine and obesity are prothrombotic states. Additionally, substances that are important in metabolic control (eg, adiponectin) are nociceptive at lower levels. However, to the best of my knowledge, none of these dysfunctions would justify the decreased threshold levels seen by the authors (and justified by them as possibly reflecting changes in cortical excitability induced by obesity), which point us to the central component of the link between both diseases. Several peptides are involved in the modulation of appetite and energy homeostasis, including the orexins (orexin A and B). Orexins are implicated in a variety of functions including feeding, sleep wake cycle, cardiovascular function, hormone secretion, and more recently the modulation of nociceptive processing. The orexins are of importance also on weight control. The orexins have a dual action on pain modulation. In an animal model of trigeminovascular activation, agonism of the orexin receptord 1 and 2 in the posterior hypothalamus differentially modulate nociceptive dural input; orexin A, but not orexin B, was able to inhibit neurogenic dural vasodilatation, resulting in inhibition of prejunctional release of CGRP from trigeminal neurons. This is of importance, as regulation of autonomic and neuroendocrine functions as well as nociceptive processing are closely coupled in the hypothalamus, possibly mediated by orexinergic mechanisms. Thus, it has been speculated that the orexinergic system could be a possible link between migraine pain and the possible hypothalamic dysfunction seen in migraineurs. Goadsby et al has recently pointed to the importance of the orexinergic system in migraine and other headaches. In a seminal paper, they highlight the importance of the hypothalamic orexinergic dysfunction as a gating or switching mechanism, emphasizing that through direct excitatory projection on to second order relay neurons, the orexinergic fibers also form excitatory synapses with inhibitory interneurons. Thus, a gated mechanism exists via which the hypothalamic orexinergic projections could facilitate or inhibit the activation of these ascending sensory neurons. Accordingly, dysfunction in orexinergic hypothalamic circuits would allow the destabilization of the proand anti-nociceptive inputs on the trigeminovascular system accompanied by autonomic and sensory disturbances. They speculate that the actions could “result of direct actions on the trigeminal-autonomic reflex or a combined action on the reflex and higher autonomic centers,” and emphasize the crucial role of the suprachiasmatic nucleus, which influences many other hypothalamic, thalamic, and cortical structures.