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==Overview==
==Overview==
Migraines are believed to be a neurovascular disorder<ref name="pmid11807151">{{cite journal| author=Goadsby PJ, Lipton RB, Ferrari MD| title=Migraine--current understanding and treatment. | journal=N Engl J Med | year= 2002 | volume= 346 | issue= 4 | pages= 257-70 | pmid=11807151 | doi=10.1056/NEJMra010917 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11807151  }} </ref><ref name=Bart10>{{cite journal |author=Bartleson JD, Cutrer FM |title=Migraine update. Diagnosis and treatment |journal=Minn Med |volume=93 |issue=5 |pages=36–41 |date=May 2010 |pmid=20572569 }}</ref> with evidence supporting its mechanisms starting within the brain and then spreading to the blood vessels.<ref name=HA29>The Headaches Chp. 29, Pg. 276</ref> Migraine begins by neuronal changes leading to the activation of the brainstem and diencephalic nuclei and subsequent dilatation of the large cranial and proximal intracranial vessels.<ref name="pmid11807151">{{cite journal| author=Goadsby PJ, Lipton RB, Ferrari MD| title=Migraine--current understanding and treatment. | journal=N Engl J Med | year= 2002 | volume= 346 | issue= 4 | pages= 257-70 | pmid=11807151 | doi=10.1056/NEJMra010917 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11807151  }} </ref>  Some researchers feel [[neuron]]al mechanisms play a greater role,<ref>{{cite journal|last=Goadsby|first=PJ|title=The vascular theory of migraine – a great story wrecked by the facts|journal=Brain : a journal of neurology|date=January 2009|volume=132|issue=Pt 1|pages=6–7|pmid=19098031|doi=10.1093/brain/awn321}}</ref> while others feel blood vessels play the key role.<ref>{{cite journal|last=Brennan|first=KC|coauthors=Charles, A|title=An update on the blood vessel in migraine|journal=Current Opinion in Neurology|date=June 2010|volume=23|issue=3|pages=266–74|pmid=20216215|doi=10.1097/WCO.0b013e32833821c1}}</ref> Others feel both are likely important.<ref>{{cite journal|last=Dodick|first=DW|title=Examining the essence of migraine – is it the blood vessel or the brain? A debate|journal=Headache|date=April 2008|volume=48|issue=4|pages=661–7|pmid=18377395|doi=10.1111/j.1526-4610.2008.01079.x}}</ref> High levels of the neurotransmitter [[serotonin]], also known as 5-hydroxytryptamine, are believed to be involved.<ref name=HA29/>
==Pathophysiology==
==Pathophysiology==
Migraine was once thought to be initiated by problems with [[blood vessels]]. This theory is now largely discredited.<ref name="CohenNeuroimaging">{{cite journal | author=Cohen AS, Goadsby PJ| title=Functional neuroimaging of primary headache disorders | journal=Curr Pain Headache Rep | year=2005 | pages=141-146 | volume=45 | issue=9 }}</ref> Current thinking is that a phenomenon known as [[cortical spreading depression]] is responsible for the disorder.<ref name="LauritzenM">{{cite journal | author=Lauritzen M. | title=Pathophysiology of the migraine aura. The spreading depression theory. | journal=Brain | year=1994 | pages=199-210 | volume=117 | issue=1 | id=PMID 7908596}}</ref> In [[cortical spreading depression]], [[neuron|neurological activity]] is depressed over an area of the [[cerebral cortex|cortex]] of the brain. This situation results in the release of [[inflammation|inflammatory]] mediators leading to irritation of [[cranial nerve]] roots, most particularly the [[trigeminal nerve]], which conveys the sensory information for the face and much of the head.This view is supported by [[neuroimaging]] techniques, which appear to show that migraine is primarily a disorder of the brain (neurological), not of the blood vessels (vascular). A spreading depolarization (electrical change) may begin 24 hours before the attack, with onset of the headache occurring around the time when the largest area of the brain is depolarized. The effects of migraine may persist for some days after the main headache has ended.  Many sufferers report a sore feeling in the area where the migraine was, and some report impaired thinking for a few days after the headache has passed.In 2005, research<ref name="PFOSchwerzmann">{{cite journal | author=Schwerzmann M, Wiher S, Nedeltchev K, Mattle HP, Wahl A, Seiler C, Meier B, Windecker S | title=Percutaneous closure of patent foramen ovale reduces the frequency of migraine attacks | journal=Neurology | year=2004 | pages=1399-401 | volume=62 | issue=8 | id=PMID 15111681}}</ref> was published indicating that in some people with a [[patent foramen ovale]] (PFO), a hole between the upper chambers of the heart, suffer from migraines which may have been caused by the PFO. The migraines reduce in frequency if the hole is patched. Several clinical trials are currently under way in an effort to determine if a causal link between PFO and migraine can be found. Early speculation as to this relationship has centered on the idea that the lungs detoxify blood as it passes through. The PFO allows uncleaned blood to go directly from the right side of the heart to the left without passing through the lungs.Migraine headaches can be a symptom of [[Hypothyroidism]].
===Aura===
[[Cortical spreading depression]] or spreading depression of [[Aristides Leão|Leão]] is bursts of neuronal activity followed by a period of inactivity, which is seen in those with migraines with an aura.<ref name=HA28>The Headaches, Chp. 28, pp. 269–72</ref> There are a number of explanations for its occurrence including activation of [[NMDA receptor]]s leading to calcium entering the cell.<ref name=HA28/> After the burst of activity the blood flow to the [[cerebral cortex]] in the area affected is decreased for two to six hours.<ref name=HA28/> It is believed that when depolarization travels down the underside of the brain, nerves that sense pain in the head and neck are triggered.<ref name=HA28/>
 
Shown below is an image depicting cortical spreading depression which is the underlying pathophysiology of aura.
 
[[File:Cortical spreading depression.gif]]
 
===Pain===
The exact mechanism of the head pain which occurs during a migraine is unknown.<ref name=Olesen2009>{{cite journal|last=Olesen|first=J|coauthors=Burstein, R; Ashina, M; Tfelt-Hansen, P|title=Origin of pain in migraine: evidence for peripheral sensitization|journal=Lancet neurology|date=July 2009|volume=8|issue=7|pages=679–90|pmid=19539239|doi=10.1016/S1474-4422(09)70090-0}}</ref> Some evidence supports a primary role for [[central nervous system]] structures (such as the [[brainstem]] and [[diencephalon]])<ref>{{cite journal|last=Akerman|first=S|coauthors=Holland, PR; Goadsby, PJ|title=Diencephalic and brainstem mechanisms in migraine|journal=Nature Reviews Neuroscience|date=2011-09-20|volume=12|issue=10|pages=570–84|pmid=21931334|doi=10.1038/nrn3057}}</ref> while other data support the role peripheral activation (such as via the [[sensory nerve]]s that surround [[blood vessel]]s of the head and neck).<ref name=Olesen2009/> The potential candidate vessels include [[dura mater|dural arteries]], [[Pia mater|pial arteries]] and extracranial arteries such as those of the [[scalp]].<ref name=Olesen2009/> The role of vasodilatation of the extracranial arteries, in particular, is believed to be significant.<ref>{{cite journal|last=Shevel|first=E|title=The extracranial vascular theory of migraine – a great story confirmed by the facts|journal=Headache|date=March 2011|volume=51|issue=3|pages=409–17|pmid=21352215|doi=10.1111/j.1526-4610.2011.01844.x}}</ref>
 
==Genetics==
Studies of twins indicate a 34% to 51% genetic influence of likelihood to develop migraine headaches.<ref name=Lulli2007>{{cite journal|last=Piane|first=M|coauthors=Lulli, P; Farinelli, I; Simeoni, S; De Filippis, S; Patacchioli, FR; Martelletti, P|title=Genetics of migraine and pharmacogenomics: some considerations|journal=The journal of headache and pain|date=December 2007|volume=8|issue=6|pages=334–9|pmid=18058067|doi=10.1007/s10194-007-0427-2|pmc=2779399|type=Review}}</ref> This genetic relationship is stronger for migraines with aura than for migraines without aura. A number of specific variants of genes increase the risk by a small to moderate amount.<ref name=Schurk2012/>
 
[[Single gene disorder]]s that result in migraines are rare.<ref name=Schurk2012>{{cite journal|last=Schürks|first=M|title=Genetics of migraine in the age of genome-wide association studies|journal=The journal of headache and pain|date=January 2012|volume=13|issue=1|pages=1–9|pmid=22072275|doi=10.1007/s10194-011-0399-0|pmc=3253157|type=Review}}</ref> One of these is known as [[familial hemiplegic migraine]], a type of migraine with aura, which is inherited in an[[autosomal dominant]] fashion.<ref>{{cite journal|last=de Vries|first=B|coauthors=Frants, RR; Ferrari, MD; van den Maagdenberg, AM|title=Molecular genetics of migraine|journal=Human Genetics|date=July 2009|volume=126|issue=1|pages=115–32|pmid=19455354|doi=10.1007/s00439-009-0684-z|type=Review}}</ref><ref>{{cite journal|last=Montagna|first=P|title=Migraine genetics|journal=Expert Review of Neurotherapeutics|date=September 2008|volume=8|issue=9|pages=1321–30|pmid=18759544|doi=10.1586/14737175.8.9.1321|type=Review}}</ref> Four genes have been shown to be involved in familial hemiplegic migraine.<ref name=Ducros2013>{{cite journal|last=Ducros|first=A|title=[Genetics of migraine]|journal=Revue neurologique|date=Apr 22, 2013|pmid=23618705|volume=169|issue=5|pages=360–71|doi=10.1016/j.neurol.2012.11.010}}</ref> Three of these genes are involved in [[ion transport]].<ref name=Ducros2013/> The fourth is an [[axon]]al protein associated with the [[exocytosis]] complex.<ref name=Ducros2013/> Another genetic disorder associated with migraine is [[CADASIL syndrome]] or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.<ref name=Amin2009>{{cite book|last=Aminoff|first=Roger P. Simon, David A. Greenberg, Michael J.|title=Clinical neurology|year=2009|publisher=Lange Medical Books/McGraw-Hill|location=New York, N.Y|isbn=9780071664332|pages=85–88|edition=7}}</ref>
 
==Evolution==
 
===Defense mechanism===
The tendency to develop head pain when faced with a stressor or strong sensory stimuli can be explained in two ways. First, it may be a side effect of other CNS processes that provide important evolutionary advantages. One example is counteracting the dilation of cranial arteries to counteract dangerous vasoconstriction in the brain.<ref>{{MEDRS|date=December 2013}}{{cite journal|last=Edvinsson|first=L.|coauthors=Olesen, I. J.; Kingman, T.; McCulloch, J.; Uddman, R.|title=Modification of vasoconstrictor responses in cerebral blood vessels by lesioning of the trigeminal nerve: possible involvement of CGRP|journal=Cephalalgia|date=1 October 1995|volume=15|issue=5|pages=373–383|doi=10.1046/j.1468-2982.1995.1505373.x|pmid=8536296}}</ref> Second, migraine may be an example of how pain has evolved to encourage organisms to avoid potentially harmful situations. Olfactory-induced migraines (migraines stimulated by strong smells) have been explained as an attempt to interrupt the entry of toxins into the brain via the olfactory nerve.<ref>{{MEDRS|date=December 2013}}{{cite journal|last=Covelli|first=Vito|coauthors=Massari, Franco; Ďandrea, Lucia; Cervo, M. Augusta; Buscaino, Giuseppe Andrea; Jirillo, Emilio|title=Could migraine be a "protective factor" against tumors?|journal=International Journal of Neuroscience|date=1 January 1994|volume=75|issue=1-2|pages=139–143|doi=10.3109/00207459408986297|pmid=8050847}}</ref> Similarly, the low threshold for nausea and vomiting may be a mechanism to enhance elimination of ingested toxins in food. Migraineurs have a lower prevalence of malignant neoplasms in the brain than controls, suggesting that migraines are protective against tumors. However, the mechanism responsible for this difference is unknown.<ref>{{MEDRS|date=December 2013}}{{cite journal|last=Snyder|first=RD|coauthors=Drummond, PD|title=Olfaction in migraine|journal=Cephalalgia|date=1 November 1997|volume=17|issue=7|pages=729–732|doi=10.1046/j.1468-2982.1997.1707729.x|pmid=9399001 |type=Clinical trial}}</ref>
 
===Conflicts with other organisms===
A headache-prone CNS may have resulted from interactions with other organisms in two ways. The first possibility is that migraine offers an advantage to the organism in fighting infection by increasing blood flow to the brain.  The second possibility is that certain pathogens evolved to cause headache as a way of speeding their transmission to other organisms.<ref name=Loder2002/> Finally, migraine may benefit neither the host nor the pathogen, but may simply be the result of certain infections.<ref>{{cite journal|last=Cochran|first=Gregory M|coauthors=Ewald, Paul W; Cochran, Kyle D|title=Infectious causation of disease: an evolutionary perspective|journal=Perspectives in Biology and Medicine|date=1 January 2000|volume=43|issue=3|pages=406–448|doi=10.1353/pbm.2000.0016|pmid=10893730|type=Historical article}}</ref> This last explanation is concordant with the apparent negative impact of migraine on human fitness.
 
===Novel environmental factors===
Modern environmental factors, with an increased sensory overload, may be especially permissive of the expression of genes that predispose for the disorder. If so, natural selection may not have had a chance to eliminate these genes yet. The increasing prevalence of migraine is easily a result of increased known triggers, such as bright light, loud noise, altered sleep/wake patterns, and emotional stress. This is an example of [[mismatch theory]], which states that the current environment differs from the evolutionary environment of a particular trait.<ref name=Loder2002/>
 
===Genetic harms and benefits===
Migraine is influenced on a polygenetic level (controlled by multiple genes). Therefore, researchers have theorized that migraine is a tradeoff and that it exists as a spectrum of susceptibility, with the majority of the population falling in the "heterozygous" zone between the two extremes of experiencing no headache and experiencing frequent, incapacitating headache. While it is not known for certain how or whether mild forms of the disorder would enhance survival, there is evidence of enhanced visual sensitivity in family members of migraineurs.<ref>{{MEDRS|date=December 2013}}{{cite journal|last=Puca|first=F.|coauthors=de Tommaso, M.; Tota, T.; Sciruicchio, V.|title=Photic driving in migraine: correlations with clinical features|journal=Cephalalgia|date=1 June 1996|volume=16|issue=4|pages=246–250|doi=10.1046/j.1468-2982.1996.1604246.x|pmid=8792036}}</ref> Additionally, this compromise theory may explain the higher prevalence among women, especially pregnant women and women of reproductive age (25-40). The avoidance of threatening environments is historically more important to the reproductive success of women.<ref>{{MEDRS|date=December 2013}}{{cite journal|last=Stewart|first=Walter F.|title=Prevalence of migraine headache in the United States. Relation to age, income, race, and other sociodemographic factors|journal=JAMA: The Journal of the American Medical Association|date=1 January 1992|volume=267|issue=1|pages=64|doi=10.1001/jama.1992.03480010072027|pmid=1727198}}</ref> The compromise between genetic harms and benefits is commonly seen in other disorders, such as cystic fibrosis and sickle cell anemia.
 
===Headache as a design construct===
Finally, migraine may be a component of imperfect central nervous system design. Evidence has suggested a dysfunction of pain-inhibitory pathways in migraine and discordant interaction between the ancient brain stem design and the more evolved neocortex.<ref>{{MEDRS|date=December 2013}}{{cite journal|last=Weiller|first=C|coauthors=May, A; Limmroth, V; Jüptner, M; Kaube, H; Schayck, RV; Coenen, HH; Diener, HC|title=Brain stem activation in spontaneous human migraine attacks|journal=Nature medicine|date=July 1995|volume=1|issue=7|pages=658–60|pmid=7585147}}</ref> The brain stem may be unable to suppress excessive input from higher brain centers.


==References==
==References==
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{{WH}}
{{WH}}
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[[Category:Needs overview]]
[[Category:Migraine]]
[[Category:Neurology]]
[[Category:Emergency medicine]]
[[Category:Disease]]
[[Category:Headaches]]
[[Category:Head and neck]]

Latest revision as of 22:44, 29 July 2020

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Migraines are believed to be a neurovascular disorder[1][2] with evidence supporting its mechanisms starting within the brain and then spreading to the blood vessels.[3] Migraine begins by neuronal changes leading to the activation of the brainstem and diencephalic nuclei and subsequent dilatation of the large cranial and proximal intracranial vessels.[1] Some researchers feel neuronal mechanisms play a greater role,[4] while others feel blood vessels play the key role.[5] Others feel both are likely important.[6] High levels of the neurotransmitter serotonin, also known as 5-hydroxytryptamine, are believed to be involved.[3]

Pathophysiology

Aura

Cortical spreading depression or spreading depression of Leão is bursts of neuronal activity followed by a period of inactivity, which is seen in those with migraines with an aura.[7] There are a number of explanations for its occurrence including activation of NMDA receptors leading to calcium entering the cell.[7] After the burst of activity the blood flow to the cerebral cortex in the area affected is decreased for two to six hours.[7] It is believed that when depolarization travels down the underside of the brain, nerves that sense pain in the head and neck are triggered.[7]

Shown below is an image depicting cortical spreading depression which is the underlying pathophysiology of aura.

Pain

The exact mechanism of the head pain which occurs during a migraine is unknown.[8] Some evidence supports a primary role for central nervous system structures (such as the brainstem and diencephalon)[9] while other data support the role peripheral activation (such as via the sensory nerves that surround blood vessels of the head and neck).[8] The potential candidate vessels include dural arteries, pial arteries and extracranial arteries such as those of the scalp.[8] The role of vasodilatation of the extracranial arteries, in particular, is believed to be significant.[10]

Genetics

Studies of twins indicate a 34% to 51% genetic influence of likelihood to develop migraine headaches.[11] This genetic relationship is stronger for migraines with aura than for migraines without aura. A number of specific variants of genes increase the risk by a small to moderate amount.[12]

Single gene disorders that result in migraines are rare.[12] One of these is known as familial hemiplegic migraine, a type of migraine with aura, which is inherited in anautosomal dominant fashion.[13][14] Four genes have been shown to be involved in familial hemiplegic migraine.[15] Three of these genes are involved in ion transport.[15] The fourth is an axonal protein associated with the exocytosis complex.[15] Another genetic disorder associated with migraine is CADASIL syndrome or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.[16]

Evolution

Defense mechanism

The tendency to develop head pain when faced with a stressor or strong sensory stimuli can be explained in two ways. First, it may be a side effect of other CNS processes that provide important evolutionary advantages. One example is counteracting the dilation of cranial arteries to counteract dangerous vasoconstriction in the brain.[17] Second, migraine may be an example of how pain has evolved to encourage organisms to avoid potentially harmful situations. Olfactory-induced migraines (migraines stimulated by strong smells) have been explained as an attempt to interrupt the entry of toxins into the brain via the olfactory nerve.[18] Similarly, the low threshold for nausea and vomiting may be a mechanism to enhance elimination of ingested toxins in food. Migraineurs have a lower prevalence of malignant neoplasms in the brain than controls, suggesting that migraines are protective against tumors. However, the mechanism responsible for this difference is unknown.[19]

Conflicts with other organisms

A headache-prone CNS may have resulted from interactions with other organisms in two ways. The first possibility is that migraine offers an advantage to the organism in fighting infection by increasing blood flow to the brain. The second possibility is that certain pathogens evolved to cause headache as a way of speeding their transmission to other organisms.[20] Finally, migraine may benefit neither the host nor the pathogen, but may simply be the result of certain infections.[21] This last explanation is concordant with the apparent negative impact of migraine on human fitness.

Novel environmental factors

Modern environmental factors, with an increased sensory overload, may be especially permissive of the expression of genes that predispose for the disorder. If so, natural selection may not have had a chance to eliminate these genes yet. The increasing prevalence of migraine is easily a result of increased known triggers, such as bright light, loud noise, altered sleep/wake patterns, and emotional stress. This is an example of mismatch theory, which states that the current environment differs from the evolutionary environment of a particular trait.[20]

Genetic harms and benefits

Migraine is influenced on a polygenetic level (controlled by multiple genes). Therefore, researchers have theorized that migraine is a tradeoff and that it exists as a spectrum of susceptibility, with the majority of the population falling in the "heterozygous" zone between the two extremes of experiencing no headache and experiencing frequent, incapacitating headache. While it is not known for certain how or whether mild forms of the disorder would enhance survival, there is evidence of enhanced visual sensitivity in family members of migraineurs.[22] Additionally, this compromise theory may explain the higher prevalence among women, especially pregnant women and women of reproductive age (25-40). The avoidance of threatening environments is historically more important to the reproductive success of women.[23] The compromise between genetic harms and benefits is commonly seen in other disorders, such as cystic fibrosis and sickle cell anemia.

Headache as a design construct

Finally, migraine may be a component of imperfect central nervous system design. Evidence has suggested a dysfunction of pain-inhibitory pathways in migraine and discordant interaction between the ancient brain stem design and the more evolved neocortex.[24] The brain stem may be unable to suppress excessive input from higher brain centers.

References

  1. ↑ 1.0 1.1 Goadsby PJ, Lipton RB, Ferrari MD (2002). "Migraine--current understanding and treatment". N Engl J Med. 346 (4): 257–70. doi:10.1056/NEJMra010917. PMID 11807151.
  2. ↑ Bartleson JD, Cutrer FM (May 2010). "Migraine update. Diagnosis and treatment". Minn Med. 93 (5): 36–41. PMID 20572569.
  3. ↑ 3.0 3.1 The Headaches Chp. 29, Pg. 276
  4. ↑ Goadsby, PJ (January 2009). "The vascular theory of migraine – a great story wrecked by the facts". Brain : a journal of neurology. 132 (Pt 1): 6–7. doi:10.1093/brain/awn321. PMID 19098031.
  5. ↑ Brennan, KC (June 2010). "An update on the blood vessel in migraine". Current Opinion in Neurology. 23 (3): 266–74. doi:10.1097/WCO.0b013e32833821c1. PMID 20216215. Unknown parameter |coauthors= ignored (help)
  6. ↑ Dodick, DW (April 2008). "Examining the essence of migraine – is it the blood vessel or the brain? A debate". Headache. 48 (4): 661–7. doi:10.1111/j.1526-4610.2008.01079.x. PMID 18377395.
  7. ↑ 7.0 7.1 7.2 7.3 The Headaches, Chp. 28, pp. 269–72
  8. ↑ 8.0 8.1 8.2 Olesen, J (July 2009). "Origin of pain in migraine: evidence for peripheral sensitization". Lancet neurology. 8 (7): 679–90. doi:10.1016/S1474-4422(09)70090-0. PMID 19539239. Unknown parameter |coauthors= ignored (help)
  9. ↑ Akerman, S (2011-09-20). "Diencephalic and brainstem mechanisms in migraine". Nature Reviews Neuroscience. 12 (10): 570–84. doi:10.1038/nrn3057. PMID 21931334. Unknown parameter |coauthors= ignored (help)
  10. ↑ Shevel, E (March 2011). "The extracranial vascular theory of migraine – a great story confirmed by the facts". Headache. 51 (3): 409–17. doi:10.1111/j.1526-4610.2011.01844.x. PMID 21352215.
  11. ↑ Piane, M (December 2007). "Genetics of migraine and pharmacogenomics: some considerations". The journal of headache and pain (Review). 8 (6): 334–9. doi:10.1007/s10194-007-0427-2. PMC 2779399. PMID 18058067. Unknown parameter |coauthors= ignored (help)
  12. ↑ 12.0 12.1 Schürks, M (January 2012). "Genetics of migraine in the age of genome-wide association studies". The journal of headache and pain (Review). 13 (1): 1–9. doi:10.1007/s10194-011-0399-0. PMC 3253157. PMID 22072275.
  13. ↑ de Vries, B (July 2009). "Molecular genetics of migraine". Human Genetics (Review). 126 (1): 115–32. doi:10.1007/s00439-009-0684-z. PMID 19455354. Unknown parameter |coauthors= ignored (help)
  14. ↑ Montagna, P (September 2008). "Migraine genetics". Expert Review of Neurotherapeutics (Review). 8 (9): 1321–30. doi:10.1586/14737175.8.9.1321. PMID 18759544.
  15. ↑ 15.0 15.1 15.2 Ducros, A (Apr 22, 2013). "[Genetics of migraine]". Revue neurologique. 169 (5): 360–71. doi:10.1016/j.neurol.2012.11.010. PMID 23618705.
  16. ↑ Aminoff, Roger P. Simon, David A. Greenberg, Michael J. (2009). Clinical neurology (7 ed.). New York, N.Y: Lange Medical Books/McGraw-Hill. pp. 85–88. ISBN 9780071664332.
  17. ↑ [unreliable medical source?]Edvinsson, L. (1 October 1995). "Modification of vasoconstrictor responses in cerebral blood vessels by lesioning of the trigeminal nerve: possible involvement of CGRP". Cephalalgia. 15 (5): 373–383. doi:10.1046/j.1468-2982.1995.1505373.x. PMID 8536296. Unknown parameter |coauthors= ignored (help)
  18. ↑ [unreliable medical source?]Covelli, Vito (1 January 1994). "Could migraine be a "protective factor" against tumors?". International Journal of Neuroscience. 75 (1–2): 139–143. doi:10.3109/00207459408986297. PMID 8050847. Unknown parameter |coauthors= ignored (help)
  19. ↑ [unreliable medical source?]Snyder, RD (1 November 1997). "Olfaction in migraine". Cephalalgia (Clinical trial). 17 (7): 729–732. doi:10.1046/j.1468-2982.1997.1707729.x. PMID 9399001. Unknown parameter |coauthors= ignored (help)
  20. ↑ 20.0 20.1
  21. ↑ Cochran, Gregory M (1 January 2000). "Infectious causation of disease: an evolutionary perspective". Perspectives in Biology and Medicine (Historical article). 43 (3): 406–448. doi:10.1353/pbm.2000.0016. PMID 10893730. Unknown parameter |coauthors= ignored (help)
  22. ↑ [unreliable medical source?]Puca, F. (1 June 1996). "Photic driving in migraine: correlations with clinical features". Cephalalgia. 16 (4): 246–250. doi:10.1046/j.1468-2982.1996.1604246.x. PMID 8792036. Unknown parameter |coauthors= ignored (help)
  23. ↑ [unreliable medical source?]Stewart, Walter F. (1 January 1992). "Prevalence of migraine headache in the United States. Relation to age, income, race, and other sociodemographic factors". JAMA: The Journal of the American Medical Association. 267 (1): 64. doi:10.1001/jama.1992.03480010072027. PMID 1727198.
  24. ↑ [unreliable medical source?]Weiller, C (July 1995). "Brain stem activation in spontaneous human migraine attacks". Nature medicine. 1 (7): 658–60. PMID 7585147. Unknown parameter |coauthors= ignored (help)

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