Migraine is a brainstem dysfunctional disorder: how far can we possibly get from the truth? Vinod Gupta, Migraine-Headache Institute, S-407, Greater Kailash-II, New Delhi-110 048, India. E-mail: firstname.lastname@example.org 18 January 2010 Goadsby et al. believe that migraine is consequent to a subtle brainstem dysfunction related to the locus coeruleus . In uncertainly discrediting cortical spreading depression (CSD), Goadsby et al  correctly underscore the long pre-CSD, pre-aura, and pre-headache phase of migraine. Conversely, these researchers accept dorsolateral (including locus coereleus) brainstem activation during migraine attacks – that is invariably recorded after several hours of onset of neurological aura or headache – as the strongest evidence in favour of their own brainstem pathogenetic hypothesis. To record a neuroimaging phenomenon during migraine attacks, and, then to extrapolate the same to the pre-attack pathogenetic phase does not seem to be a logically or scientifically secure assumption or an attractive investigative strategy. The distractability and anxiety of some migraineurs quoted by these authors as evidence in favour of brainstem origin of migraine  is a very weak circumstantial link. Most patients with anxiety neurosis or panic disorder or somatoform disorder do not suffer migraine. Moreover, no anxiolytic drug has proven to be of prophylactic value in migraine. Finally, how might a generalized systemic influence such as anxiety-related stress transform to a lateralizing cranial disorder such as migraine? Rather than remaining focused on the limited spatial resolution of PET , further progress in migraine depends on a revolutionary shift away from both the neuronal and the vascular theories [2-5]. This concern has been around for almost two decades. The creation of a scientific hypothesis imposes an onerous burden on its creators – to remain logically sound and generalizable. Implication of the locus coeruleus does not appear to explain the lateralization of headache, the unpredictable onset or offset of migraine attacks, the increased predisposition to attacks during menstruation, the susceptibility of migraine patients to a legion of precipitants many of which have nothing to do with neuronal brain/brainsten dysfunction, or the ability of drugs like atenolol, nadolol, verapamil, or nitroglycerin – that do significantly affect brain neuronal function – to prevent migraine headache attacks or abort aura [3,4,5]. A large number of carefully structured assumptions, extrapolations, and omissions support the neuronal theories of migraine . The review of Goadsby et al  does not mention atenolol, a pharmacologic agent as effective as propranolol for preventing migraine. Paradoxically, atenolol does not cross the blood-brain barrier significantly to critically influence any brain neuronal function [4,5]. A cranial (pupillary level) and cardiac autonomic dysfunction characteristically prevails in migraine patients – this feature does not appear to have any link to CSD or to activation of the locus ceruleus . The brainstem hypothesis for migraine , if correct, should incrementally be able to explain all major physiological, pharmacological, and clinical phenomena of migraine. Goadsby et al  could strengthen their hypothesis by offering an overarching theory that links these key facets of migraine pathophysiology. It has become nearly impossible to question – or be willing to question -- whether we are seeing the trees for the wood in migraine research . The role of the randomized controlled trial (RCT) has also become skewed in migraine research . Goadsby et al  project Botulinum Toxin as a new, potential therapy whereas there are serious limitations in the fundamental scientific basis for such an approach . The RCT is being misused in migraine to circumvent the need to advance background knowledge to an acceptable level, that in turn, (at least ideally, both ethically and scientifically) permits trials . Trials of patent foramen ovale closure are another example of systematic misuse of a powerful research tool [5,6]. While occipital nerve stimulation might be termed exciting and futuristic , neither does occipital nerve stimulation have any direct "stabilizing" effect on the locus coeruleus nor does the prolonged course of migraine over decades offer support for such therapies. Ignoring the “futility” principle by advancing statistical significance, such trials draw clinicians away from biological and clinical reality [5,6]. In migraine research and therapy, the RCT has become much more important than the migraine patient, a trend that must reversed [4,5,6]. To do so, theories that implicate brain / brainstem neuronal dysfunction in migraine must be dispassionately re-examined. While the positive (scintillating) scotoma of migraine is widely regarded as being of visual cortical origin, there is not even one documented case of such scotoma having been recorded in a homonymous (bilateral) distribution. The link between the locus coeruleus and migrainous scintillating scotoma is, furthermore, purely speculative. While belief (as well as statistics) gives wings to theoretical and investigative notions, it is Popperian logic that prepares us for the hard landing . The KISS (Keep It Simple…) principle applies to migraine research as it did to the bath-tub buoyancy, to the falling apple, to the immunity of milk-maids to small pox, to the forgotten broth in the laboratory (H. pylori), to the discovery of the importance of fibre in Africa… We have divided migraine into innumerable parts and are simply unable or unwilling to reconstruct the “whole” . Science is a process of simplification or de-mystification of observed phenomena . Current migraine research efforts, however, appear designed to increase the mystery of migraine. REFERENCES 1. Sprenger T, Goadsby PJ. Migraine pathogenesis and state of pharmacological treatment options. BMC Medicine 2009, 7:71 doi:10.1186/1741-7015-7-71 2. Gupta VK. Migraine: a disease in-waiting. BMJ Online response. Available at: http://bmj.bmjjournals.com/cgi/eletters/330/7482/54 3. Gupta VK. Migraine: searching for pathophysiology in semantics and nosology. J Neurol Neurosurg Psychiatry (17 January 2005). Available at: http://jnnp.bmjjournals.com/cgi/eletters/76/1/1-a 4. Gupta VK. Adaptive Mechanisms in Migraine: Breaking the Migraine Code. Nova Science Publishers, New York, 2009. 5. Gupta VK. CSD, BBB and MMP-9 elevations: animal experiments versus clinical phenomena in migraine. Expert Rev. Neurother. 2009;11:1595-1614. 6. Gupta VK. Patent foramen ovale closure: science, quasi-science, and empiricism. Cardiology 2009;113:108-110. 7. Carrel A. Man, The Unknown. Wilco Books, Hamish Hamilton Limited, London, 1959. Competing interests I have no competing interests.