The time has come," the Walrus said, "To talk of many things: Of shoes--and ships--and sealing-wax-- Of cabbages--and kings-- And why the sea is boiling hot-- And whether pigs have wings."
The Walrus and The Carpenter ----- Lewis Carroll
(from Through the Looking-Glass and What Alice Found There, 1872)
This question has remained unsettled and has unsettled migraine research for as long as the migraine-epilepsy link has survived. The entire edifice of the migraine research enterprise rests on this pigs-can-fly assumption.
Let us address this question to our collective intellect. Besides those who have a vested interest in the perpetuation of this befuddlement to eternity - relishing the nihilistic confusion that envelopes primary headache comprehension - there are dedicated researchers / scientists who should shed the role of fence-sitters.
I am sure that migrain is due to astrocytes being iin inflammation state.
The same for fibrobyalgia.
Jerzy
Jerzy, thank you for contributing.
This is a good beginning. Others must participate.
We can break this deadlock.
Astrocytic inflammation can be evolved. Please present evidences and references.
Let this thread run till we solve this Gordian knot.
Best,
Vinod
I would say hyperexcitability is meant to be a favourable trait from an evolutionary perspective, yet it becomes deleterious under certain circumstances where metabolic reserves are unable to cope with the enhanced needs that it entails.
Cheers
Marco
We need evidence to carry forward any thread of thought. More importantly, what is missing is the template.
The current template of cortical spreading depression / cortical hyperexcitability needs to be reevaluated. I will add for your benefit the limitations of the current template as are being under review for a Neurology periodical, as well as the first stirrings of a new template.
Box 2. Clinical migraine phenomena that cannot be explained by CSD
1. Spontaneous (“self-cycling”) genesis / onset of migraine attacks (both for SS and for headache).
2. Lateralized pain / headache of migraine.
3. Gender asymmetry – female preponderance.
4. Protean nature of migraine, including predictable (menstrual) as well as unpredictable occurrences.
5. Prodrome of migraine running into hours or even a few days with “skip” neurological symptoms.
6. Significantly delayed onset of headache after exposure to triggers, including “stress” or alcohol.
7. Spontaneous defervescence / cessation of migraine attacks (both for SS and for headache)
8. Self-limited duration of migraine headache attacks (4-72 hours).
9. Link to a large number of heterogeneous clinical conditions -- migraine triggering factors.
10. Link to migraine remitting factors, particularly sleep and latter trimesters of pregnancy.
11. Precipitation of delayed atypical headache attacks by GTN in the absence of aura / SS.
12. Relief of SS with GTN / isoproterenol.
13. Large cohort of MwoA patients.
14. Migraine-linked lateralizing photophobia and light sensitivity.
15. Postdrome of migraine.
16. Sparing of nasal visual field by SS and limited spread of SS in temporal half of visual field.
17. Markedly slow pattern of development of SS as well as of headache.
18. Loss of migraine aura and SS in sightless eyes.
19. Loss or attenuation of photophobia in sightless eyes.
20. Loss of SS, typical migraine headache, and photophobia in enucleated eyes.
21. Autonomic manifestations of migraine.
22. Early nausea / vomiting in migraine attacks that can frequently abort headache.
23. Cyclical vomiting syndrome of migraine.
24. Prevention of MwA and MwoA attacks by hydrophilic atenolol, nadolol, and verapamil.
Box 3. Potential Adaptive Mechanisms in Migraine (Gupta 2009b)
1. AVP-brain instrinsic noradrenergic-brain intrinsic serotonin “system”
2. Nausea and vomiting
3. Thirst
4. Frequency of micturition
5. Hypomagnesemia
6. Excessive daytime sleepiness (Peres et al. 2005).
To get a grasp of this thread, you should begin with my 1997 article in Cephalalgia.
Cheers
Dear Vinod Kumar Gupta ,
Thanks for your prompt reply. Please notice that neuronal hyperexcitability (as in your question) and cortical spreading depression (as in your answer) constitute two different phenomena and therefore these terms cannot be used interchangeably. For consistency purposes I think it would be better to continue this thread the way it was originally proposed (cortical excitability).
Best
The best known template and most vigorously pursued proposal for brain cortical neuronal excitability as pathophysiological basis of migraine is cortical spreading depression since 1944.
I am equally interested in any other form of proposed cortical excitability. We all would like to get rid of myths and assumptions, and, put science in the centerstage.
I am impressed with the clarity of your thoughts. Hope you carry this forward.
Perhaps we need to tease apart the different elements of headache pathophysiology.
Migraines may well be a networking problem associated with a significantly hereditary element causing an imbalance between the excitatory and inhibitory continuum. The limbic system may well be an important component which goes some way to explain the co-morbidity with depression
Of recent years inflammatory processes (including the importance of the biome) have become centre stage in their influence of many pathological processes. Perhaps astrocytes are important in 'chronic' migraine, but not necessarily so in intermittent episodic migraine where any chronic inflammatory process abates
Perhaps CGRP drugs such as Erenumab illustrate a route to a new way of thinking. I certainly don't see inflammatory processes in the meningeal vessels as THE cause of migraine any more than CSD is THE pathophysiology. However, if they help us create a better classification system based on cause, than the IHS system which applies arbitrary descriptive definitions such as the division between episodic and chronic migraines to shoe-horn headache diagnoses into neat but counterproductive units, then this can only be good.
The IHS system has its uses but let us remember (as we are here!) how important it is not allow it to define how we understand headache. It must remain our servant and not our master, and I feel a good way would be to have a different classification system to remind us that it has not been handed down on tablets of stone!!
Let us refocus on brain neuronal cortical excitability that garnered the Harold G. Wolff 1999 July-August Issue, Headache, Volume 39 (7): 469-476.
But understanding of the pathophysiology of headace has improved enormously in 20 years!
Some neurologists may be stuck in a time warp about cortical spreading depression as even more restrictive than cortical excitability, but this is only one element of the networking pathophysiology.
If we want to talk about the richness of a complex abstract colour painting it is valid to concentrate on the detail of the red components but this says little about how they interact with the green and blue parts!
Words sometimes become surrounded by an emptiness that simply refuses to be dissipated at any cost and from any quarter.
Let us AGAIN refocus on brain neuronal cortical excitability that garnered the Harold G. Wolff 1999 July-August Issue, Headache, Volume 39 (7): 469-476.
If there has been any meaningful progress in primary headache research at all over the last 100 years, it can be summarized in just two plain sentences in any language.
Science and scientific principles are not a personal take on each other or one another. It is a serious matter. Laboratory methods and RCTs and epidemiological studies and meta-analyses have made it appear simple and simplistic. Each of these processes is reductionist and creates fragmentation of the whole, and, then further fragments of the fragments that refuse to come together by the salience of an era.
"...although a modern jumbo jet comprises manifold per se sophisticated components...they remain a 'heap of junk' until assembled and trimmed to the perfect level of coordination that characterizes the flying wonder..."--- Bjorn Folklow, Physiologist (Gupta, 2010).
Not only is the jumbo jet of migraine / primary headache research not flying, its sophisticated components in the form of 'data' keep multiplying almost every day, exponentially. We have ignored "assembling" and "trimming" and expect myths and assumptions and dogma to fly -- a long shot, indeed.
Thirty years ago, Edmeads (1991), Blau (1992), and earlier Graham (1953) pleaded to unmoved audiences of neuroscientists for the need to look beyond the neuronal and vascular theories of migraine. What emerged in the 21st Century was a fiasco --*neurovascular theory of migraine*.
Migraine research is being systematically dredged and drowned by the power and surfeit of words and the unassailable truth-by-fire of statistical numbers.
New Delhi 26 December 2018
ORCID iD: 0000-0002-6770-5916
I agree with Marco Lisicki that there needs to be a new way of looking at headache that goes beyond the simplistic cortical excitability (CE) model and the even more simplistic CSD model (which is in my mind only a particular manifestation of CE).
Indeed I also agree with Vinod Kumar Gupta Vinod that the reductionist desire to explain disease as a single problem (eg CE or CSD) is far too simplistic and bound to fail. If only the brain were so simple!!
However this doesn't mean that CE is not part of the process. It can be one of many entry points in exploring the migraine process. Another big point that has been emerging over the last few years is the inflammatory process, including how this is triggered by neuronal stimulation (eg via single pain fibres with a common single nucleus in the trigeminal ganglion, which project to the fibrous aponeurotic attachments of eg the corrugators and the adjacent blood vessels, the meninges and the adjacent blood vessels, and the trigemino-cervical tract, via the same nuceus in the trigeminal ganglion.
It is established that stimulation of the pain ending causes a neurogenic dilation of the blood vessels and also a release of inflammatory pathway chemical messengers.
And then there's the astrocyte involvement mentioned by Jerzy Zbigniew Achimowicz - another element in the inflammatory part of migraine aetiology.
Then we must add the importance of the gut biome as one of the causes of "inflammatory hyperexcitability"!
And just as the trigeminocervical tract appears to be involved with the 'excitatory' element of the migraine process and the related inflammatory pathways, the vagus nerve appears to be involved with reducing the inflammatory stimulus
I had found sowhere that migranes are due to infamatory state of glia astrocyte cells
Especially in fibromyalgia syndrom
Any info on that ????
@jerzy I suspect you may be right but what is the experimental evidence for believing this?
"The difficulty lies not so much in developing new ideas as in escaping from old ones"-- John Maynard Keynes
Let us AGAIN refocus on brain neuronal cortical excitability that garnered the Harold G. Wolff 1999 July-August Issue, Headache, Volume 39 (7): 469-476.
Bad ideas abound in migraine research, are highly contagious as they do not require a research vision, and, are highly expedient too as dissembling is made too easy, and, lurch from laboratory study to laboratory study in search of the key to fit the lock.
There is a wealth of experimental evidence in migraine for almost every possible idea -- but no blueprint.
He who rides a tiger cannot dismount. Riding the tiger of CE/CSD, migraine research/researchers march off magnificently into the night of endless confusion unable to escape the stranglehold and the fetters of the past.
But Vinod, I do not understand your position on CE/CSD. Are you dismissing it outright, or like me, you do not want to find all thinking dominated by the idea that it must be THE way of looking at migraines!
If you want to concentrate on CE, how do you want to do this. I really don't understand
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