What ails migraine / primary headache research (see: Ed. Gupta VK. Adaptive Mechanisms in Migraine. A Comprehensive Synthesis in Evolution. Breaking the Migraine Code. New York, Nova Science, 2009, Preface IX-XV, Chapter 1, 2, pages 3-9)

Under the compulsion of till (my) breath becomes air (Paul Kalanithi, When Breath Becomes Air, Copyright © 2016 by Corcovado, Inc.

Foreword copyright © 2016 by Abraham Verghese, PDF available as free download as a testament to our individual and collective frailty and fragility), I am in the throes of a overpowering peculiar rush propelling me to put in print the method in the exponentially and unendingly increasing pell-mell madness of the mess of published data and analyses related to migraine / primary headache research, which rush-to-print has crystallized into a continuously evolving robust, logical, generalizable, predictable, overarching, gestaltic, futuristic, and biologically-significant and -secure understanding unlinked to mathematical statistics but firmly anchored to the bio-physical and bio-physiologic natural sciences.

I have placed on ResearchGate, either as published articles or as pre-prints, the core of migraine pathophysiology for all to read and assimilate, criticize and tear-down, improve or decimate or eliminate the concepts and the data I have published -- put-up or shut-up. It took the innovation of the era of pre-print publication that made this advance possible. I would be remiss not to thank ResearchGate for assistance with pre-print publication. Pre-prints converted my tortoise-like crawl in science to giant saltatory steps / leaps to make sense of the one of the most baffling puzzles in Medicine / Ophthalmology / Neurology.

Several aspects of migraine / primary headache research and its researchers have contributed directly and indirectly, covertly or overtly, sentiently or insentiently, through narcissism or nihilism, marriage-without-possibility-of-divorce to a concept or concepts, incorrigible persistence and refusal to ever acknowledge error or limitation or reversal of approach, fear to challenge canonical posturing or flow-from-eminence, and to think critically while swimming against the current.

Migraine is the biggest graveyard of medical myths and assumptions, empirical and bizarre therapies advocated by the think-leaders of the time without pathophysiologic basis, including trephanation, pneumoencephalography, invasive lumbar puncture, physical therapies, surgical measures, Deep Brain Stimulation, cranial apparatuses circulating hot-and-cold water, magnesium supplementation, PFO-closure, Botulinum Toxin poisoning, and now use of suppression of Cortical Spreading Depression, the life-line adaptive inbuilt protective physiologic process for neurons and their vasculature.

In Medicine, the largest number of hedge terms are used in published migraine / pimary headache literature, each time pushing back or away the only thing that really matters, certitude. Hedge terms cover pitfalls and biases, providing the fig-leaf for a vicarious bridge over ignorance. When the author(s) were already aware of the deficiencies, this is not an efficient use of time (Lancet. Editorial. Flaws, hype, and critical assessment. 1993 (8864);342: 127; Lancet . Editorial: Trimming hedges. 1992;340:275-276). Problems that persist in a published study may not be apparent to most of its readers because of this pudendal-free fig-leaf of hiding ignorance or incomplete knowledge or justification for the study. Nobody controls use/abuse/overuse of hedge terms like 'although' 'indicate' 'despite' 'it seems' 'it suggests' 'may' 'might' 'should' 'possibly' 'likely' 'can' ' and many more abstruse terms that convert medical literature into a complex legalese, so difficult to understand that Palin English Abstracts are being added -- with no respite, as the harm is already done with the study having become an indelible part of medical scientific folklore that will strike a chord in many if not all generations to come -- the genie released. The miserable record of post-publication critiques in the form of critical (not supportive) Letters-to-the-Editor, commonly placed at the bottom of the index of an issue will be a later discussion. These are the 2 components of the opioid-like publishing behavior at the Editorial desk. Another component of Editorial Don Quixote-like quirk might be mentioned just en passant: 'keep egg of author's faces', and, preserving or protecting canonical eminence, the past and the present at the cost of the future. I am today not seized with loss or lack of ethics in science, with dis-informed consent and the RCCT and its accoutrements and will discuss it later (Gupta, 2010, Exp. Rev. Neurother. 10(9):1409-1422).

While eminence becomes a looming, enlarging danger, science takes a quiet backseat, giving homo sapiens the kick they deserve, just like all forms of Governance--including dance and pageantry of democracy.

The total scientific time is 1, over the millennia. How time flows down the drain, carrying with it enormous research funds and further misery for those suffering cannot be better illuminated than by the fiscal cost of migraine.

08-MAY-2024

New Delhi

ORCID iD: 0000-0002-6770-5916

I intend this discussion, even if one sided, to be part of the many intellectual diamonds I have collected from the rough over 50 years, as a absolutely free-spirited mentor for the future, to be marked in history of science and literature for my ground-breaking innovative transdisciplinary core legacy in Medicine across the specialties of Ophthalmology, Neurology, Neuro-Endocrinology, Pain Mechanisms, Autonomic Nervous System, and most importantly, the Ophthalmic division of the Fifth (trigeminal) cranial nerve, with a complete decoding of stress-related physiologic mechanisms, lateralizing headache, and scintillating scotoma.

Migraine is a magnificent teacher. Your senses and intellectual portals merely have to be attuned to its vibrancy, and it reveals itself, eagerly tumbling out of the darkness of ~8 millennia, fervently wishing not to be feared but understood as a stress-related adaptive evolution-promoting mechanism long lost in the piecemeal and exponentially expanding analyses of data and statistics, and, with the compounding of the Yin-Yang requirement to comprehend the absolute and create the abstract. Abstracts, even if structured, as published today are hardly abstracts. True abstracts allow a reading between and beyond the lines, and, to propel the essence of the study to waft forward several centuries or a few millennia, even with the minimal possible slice of truth. As the veil of ignorance is lifted, the 23rd Century marks the history and purpose of science as truly remarkable approach to one of the major unknown sectors of Medicine.

Sense and sensibility in migraine research has been kidnapped by Neurologists/ Neuroscience in the long run, serendipity beginning almost a 100 years ago, mathematical statistics since around 50 years, and the RCCT-placebo combine since few decades, straddling the 20th and 21st Century. In a short, eminence and ignorance have captured and stymied the science of migraine, at least as we as long as we can look back, with rare exceptions.

"migraine is an oculo-cephalic autonomic storm."

I can agree that migraine is an 'autonomic storm', or at least the sentiment behind it. I would make the analogy that the brain has a fire alarm panel that is too sensitive. Speaking more scientifically, the autonomic storm results from a generalised neuronal hyper-excitability, and treatment is directed at reducing this hyperexcitability, whether it is Botox reducing the free nerve afferent information, propranolol/amitriptyline/topiramate etc, vagus nerve stimulation (including daith piercing), hormonal treatments. The list goes on

The one thing I disagree with is 'oculo-cephalic'. Not everyone has aura symptoms, so why include it

There are hidden pearls in the scientific literature that shape and guide the perspective and approach of the researcher, converting the pseudo- or quasi-pretense of the all-knowing post-modern researcher in the Third Millennium and further in the future into the doomed quest for becoming a true scientist with a hyper-focused razor-sharp mind that slowly-but-surely prepares itself to receive insight lying between and beyond the lines, myths, assumptions, RCCT, and meta-analyses, losing the arrogance of ego, narcissism, nihilism, and partial-incomplete-false mathematical statistics supported biologic knowledge, with a perpetual supplication to the muses (5 Is), thereby being allowed to enter the realm of pure unadulterated magic beyond belief -- canonical or personal, prejudice, and bias with the Grace of Nature even if for just a moment -- the sine qua non for an exalted comprehension beyond mere printed words. The requirement for such Grace is both breadth and depth, which eludes the Board-certified specialist with tunnel-vision of a very small part of the human psyche and/or soma unless s/he prepares for a far broader vista and is primed to receive the vibrations of insight.

During their studies, researchers observe, with or without experiments in animals or humans. Researchers clothe and flesh their observations in data, statistics, words, flow-charts, sketches and elaborate diagrams to achieve publication of their idea/imagination generated data. All observation is selective; there is nothing like a purely objective [Lancet Editorial (1993); Medawar (1979)]. As Claude Bernard and Peter Medawar have emphasized, every systematic inquiry must start with a clearly preconceived idea and a careful phrasing of the research question. The scientist working on the core of migraine would remain continuously fascinated by the physiologic processes involved in the power or influence of stress / post-stress phase to generate migraine attacks, the self-limited nature of migraine attacks (4-72 hours), female predominance in adults, the capability of nausea/vomiting to terminate some migraine attacks, lateralizing headache (unilateral, bilateral, side-shifting, or side-locked), non-homonymous scintillating scotoma in approximately one-third of migraineurs, almost equal incidence in childhood / pubertal children, decline in incidence and severity with advancing age including menopause, variations in incidence with trimesters of pregnancy, pharmacologic absolute value of propranolol or atenolol to prevent migraine attacks in ~80% of patients, and much more...The scientist would constantly remind herself/himself or their larger groups in single-center or multi-center Institutional colleagues across one or several countries of the limitations of their own data and the crippling effect of data in expansion of critical thinking and advancing questions that have been swept under the carpet and long forgotten -- a classical form of irrational skepticism. Who remembers the role of serendipity in discovery of cortical spreading depression or the discovery of the well-established prophylactic role of propranolol or the shameful and fictitious role of both magnesium supplementation and the interventional closure of patent-foramen ovale in preventing migraine with tragic RCCTs triggered by a single personal letter to a researcher?

Migraine is like a chariot with a thousand horses yoked to it, with the skillful charioteer (scientist) managing all the reins simultaneously to progress to certitude. At this level, other researchers too can deign to agree or disagree, certainly, and not hold any submission in awe.

No personal or favored theory or therapy for migraine can hold sway at this level of undiluted pure science; nor can other substitutes like serendipity or the bias / fig-leaf of methodology or mind-blowing technology or blinding (single or double or triple) statistics / p-value. Or the Industry-Institution-Insurance-FDA-European Agencies sponsored RCCT with use/misuse of the placebo that toss ethics to the winds or the constricting and throttling Guidelines or the arbitrary purely symptomatic hyper-split nosology. Science cannot be supplanted by substitutes or props. Translational bench-to-bedside advances are retrogressive in every dimension of the word. As is machine learning. Or artificial intelligence. Or computational models. Or evidence from animal experimentations. Or the laboratory --both pathological and neuroimaging-radiology -- that creates artificial individuality and diverticula that let researchers get lost in the forests and woods of data. These are the genie(s) let loose frighteningly in the science of migraine / primary headache that have corralled the magnificent power of the human mind to solve gigantic Gordian knots in series and in parallel.

25 Centuries ago, Hippocrates, by offering uncluttered inference, did the science of migraine of today a big favor. All the present has done is to 'look a gift horse in the mouth!!'

MUST READ

Editorial. (1993) Does research make for better doctors? Lancet, 342. 1063-1064.

Medawar PB. (1979) Advice to a young scientist. New York: Harper and Row.

[HTML] Bimatoprost ophthalmic solution (BOS) 0.3 mg w/v for 1 open trial of long-term preventive therapy of migraine in 3 patients with pathophysiologic shift from …(OPEN ACCESS)

VK Gupta - Journal of Neuroscience and Neurological …, 2023 - neuroscijournal.com

11-MAY-2024

New Delhi

ORCID iD: 0000-0002-6770-5916

Nature is a jealous mistress, guarding its secrets with persistence and with an overpowering devastating diligence till the Time is ripe for butterfly wings to cause a hurricane. That time is upon science of migraine / primary headaches, straddling the 20th/21st Centuries, with the floodgates of intuition and insight and imagination, an immersive insurrective release from ~8 millennia of ignornance, myths, mysticism, serendipity, assumptions, technology, and of course, an explosive exponential amassing of data that have no central framework.

Migraine / primary headaches showcase, as nothing else in medicine, the limitations of a madding collection of diverse disparate contrary controversial data that do not promote critical or abstract thinking. Mathematical statistics and the specialty of Neurology, has for all purposes, kidnapped migraine / primary headache pathophysiology and management with an opioid crisis and extreme empiricism, lending wings to speculation in science of a kind that prove horribly incorrect gor generations of migraineurs, current and future. The butterfly wings will raise the insurrection, the hurricane, the nihilism, and the despondency that surrounds migraine / primary headache research, with the clarity, the certitude of a thousand Suns in the Solar system. In fact, such insurrection has progressed silently in last 5 decades, leaving the contemporary cohort breathless and trying their best to stymie the tide of absolute progress. The butterfly wings will, of course, prevail despite the dog-in-manger opposition.

Insurrection is an art to demolish the old with the new, and it has its own laws, and it always comes from an unexpected source free from the vanity of applause, grants, awards, patients, Institutional support, and general comprehension and acceptance. Medicine is not democratic. We all want to change the world, everyone has won, and all must get prizes with mental satisfaction and vacuous gloating ot the worst kind. Nature abhors vacuum, and the science of migraine / primary headache abhors pretense and contrived knowledge. In golf parlance, you have to be at par to put in an opinion, and then, there is alway data-linked opinion without references or solid robust defensible grounds. But butterfly wings can do magic, creating the hurricane to welcome the new.

Ideally, a successful education enhances the motivation, experiences, and learning of all medical students, not just a select few -- Dodo, in Alice's Adventures in Wonderland (Patel and David, 1996). Ability, like ethics, however, lies far ahead of successful education or experience.

Nature hunts for the specially prepared mind free from hubris and a mechanistically confined approach having fallen in love with her/his own words (the verbophilia that ruins contemplation and comprehension), not clinging to the wreckage of their own or favored so-called original principles, free from withholding of information, free from the deceit of veiling autonomy advocacy and the occult (not declared) conflict of interest, lost in sematic somersaults and mathematical statistics, divested from commonsense and compassion, but enveloped in caring and sensitive pragmatism, ready to receive the bestowed magnificence of the extraordinary. Genius has electricity, that no power on Earth can control -- Einstein.

MUST READ

Patel L, David TJ. Everybody has won, and all must win prizes. Lancet 1996; 348 (November 30): 1497.

Brewin TB. How much ethics is needed to make a good doctor? Lancet 1993; 341 (January 16): 161-163.