Editorial

© Future Drugs Ltd. All rights reserved. ISSN 1473-7175 333

Peter Kropp, PhDInstitute of Medical PsychologyUniversity of Kiel, GermanyTel.: +49 431 597 2646Fax: +49 431 597 2711kropp@med-psych.uni-kiel.de

Learning from headaches?Old problems and new insightsin migraine‘The impact of the acute attack in migraine is severe, and according to the World Health Organization, comparable with paraplegia ’.Expert Rev. Neurotherapeutics 4(3), 333–336 (2004)

Headache, especially migraine, is a commondisorder as old as mankind. Migraine attacksare described in the Bible and the symptomsreported from Saint John describe a migraineattack [1]. Caused by this predominance ofhead pain which is a highly prevalent disorder,one may question whether headaches mayinfluence the course of history or the progressin scientific research [2,3].

Migraine attacks lead to pulsating and throb-bing often unilateral head pain with featurefulaccompanying symptoms. In the case of anacute migraine attack, patients are usually notable to continue working due to the disablingpain intensity and accompanying symptoms,such as photo- and phonophobia, nausea orvomiting. Theyhave to interrupttheir daily workand social activi-ties and by with-drawing fromsociety, reduce theamount of sensory input for up to 72 h whentreatment is not available or fails. The impactof the acute attack in migraine is severe and,according to the World Health Organization,comparable with paraplegia. Often the attacksfrequently recur and worry the patient.

Over the last 25 years, migraine has beensubject to an increasing amount of scientificstudy into the pathophysiology of this painfulcondition. Recently, many new aspects of cor-tical sensory processing have been published[4,5]. A growing variety of effective therapeuticoptions has been developed. As a conclusion,

one may say that although head pain is a verynegative experience, its incentive for under-standing the pathophysiology of cortical painprocessing and of information processing ofthe brain in general, is enormous. This pointwill be illustrated on the basis of the fivefollowing subjective statements.

Headaches have triggersIt is a common observation that manymigraine attacks may follow a physical or psy-chological stressor or internal biological eventsuch as hormonal changes. There must be adiathesis, largely explained by inheritance, butin addition a stimulus to trigger the attack isneeded [6]. Therefore, keeping a migraine diary

is a good methodto elucidate tem-poral relation-ships between pre-ceding triggersand migraineattacks. The diary

provides patients and therapists with impor-tant information about the severity and fre-quency of the attacks and may help in theidentification of stressors. Even when there is aclear genetic vulnerability in migraine patho-genenesis, triggering the attack may be causedby environmental stressors. In children, thestressor can be the apprehensive anticipation ofperformance [7].

Since many headaches are triggered, patientscan learn to avoid migraine attacks by avoidingspecific trigger situations. These situations areindividual and often unknown but can be

‘Population-based studies suggest that approximately 1.2% of the general

population experience chronic migraine not caused by headache

medication overuse.’

For reprint orders, please contact reprints@future-drugs.com

Kropp

334 Expert Rev. Neurotherapeutics 4(3), (2004)

identified in behaviorally oriented therapeutical interventions byprecise evaluation of the diary. Patients can learn to modify theirreactions and reduce the stress which leads to the next attack.

Medication suppresses headache: often there is no causative treatmentBoth the acute and prophylactic medical treatment of migrainemay prevent or suppress the next attack but strictly speaking med-ication does not cure migraine. In the case of prophylactic treat-ment, medication prevents some attacks and with acute treatment,pain relief is usually obtainable. After initially successful pain relief,often the pain returns after some hours. It is well known that toofrequently, overuse analgetics designed for acute treatment canaccompany the development of almost daily, chronic migraineheadaches. Therefore, the overuse of acute migraine drugs (includ-ing the new class of the triptans),may promote migraine attacksand pain [8]. The best predictorfor medication misuse inmigraine was the regular intakeof preventive (not acute) medica-tion [9]. This fact has been takeninto acount by the revision of the International Headache Society(IHS) criteria and creating a category called ‘medication overuseheadache’ [10]. In spite of these possible negative courses, medicaltreatment coached by a migraine specialist, is the best way tomanage an acute attack or prevent attacks by use of a prophylac-tic. To prevent medication overuse headache, interdisciplinaryaction with neurologists and psychologists is the gold standardand should be employed in all pain centers.

Migraine attack is the end of a long lastingneurological disturbanceThe migraine attack begins before the pain starts. Over the lastfew years in migraine research, especially in migraine patho-physiology, the focus is on the days before the next attack.Often migraineurs are able to predict their attack by perceiving

certain sensory and emotional states during the 2 days beforethe attack. They report feelings of tiredness and weariness,have difficulty with concentration and they have to yawnmore frequently [11]. When recording visual evoked potentials(VEP/P300) during the pain-free interval and in the the acuteattack, the most pronounced disturbances can be observedjust before the migraine attack, while these functionsnormalize during the attack [12,13].

By recording the contingent negative variation (CNV), aslow event – related cortical potential between two contingentstimuli, migraine patients show a more pronounced negativityand reduced habituation during the recording session com-pared with healthy controls when recorded during the pain-freeinterval between two attacks (FIGURE 1) [14]. After prophylactictreatment with β-blockers, the pronounced negativity normal-

izes and habituation occurs,correlated with an reducedattack frequency [15].

However, in the last few daysbefore the next attack, CNVamplitudes in migraine patientsbecome more negative and

habituation diminishes, indicating the occurrence of the nextattack [16]. This may lead to an altered view in migraineresearch: we have to focus on the days before the attack and wehave to identify psychological/behavioral and neurologicalabnormalities which indicate the beginning of the migraineattack. These abnormalities can be described in terms of analtered electrophysiological cortical preactivation level whichmay result from an impaired sensory and cognitive thresholdand gain regulation in migraine patients [17].

If we have a chance to identify these abnormalities earlyenough we may possibly employ therapeutic measures to stopthe attack at a time when the migraine pain has not yet beendeveloped. This could be realized by specific medication, whichnormalizes the disturbed cortical processing level. This medica-tion intake would be no acute treatment (since there is no acutepain) but it is also not prophylaxis. The medication could betaken selectively only during the ‘susceptible’ days when there isa reliable method to assess this situation.

Frequent migraine attacks cause chronificationAnother new feature of the IHS revision is the inclusion ofchronic daily migraine (without medication overuse) as anew category. Migraine as a disease is called chronic, whenthere are more than 14 days with migraine per month. Thisformerly called ‘transformed migraine’ is the most commontype of chronic daily headache. Population-based studiessuggest that approximately 1.2% of the general populationexperience chronic migraine not caused by headache medi-cation overuse [18]. The reason why patients with episodicmigraine with few attacks develop chronic migraine withoutany medication overuse remains unclear and has to be exam-ined in future years. It could be speculated that specific psy-chological ‘habits’ which produce a higher amount of phasic

‘...although head pain is a very negative experience, its incentive for understanding

the pathophysiology of cortical pain processing and of information processing

of the brain in general, is enormous.’

Figure 1. Grand averaged CNV with an interstimulus-interval of t = 3 seconds, based on 32 trials. Starting with an acoustical warning stimulus (S1) the recording period begins, ending with an imperative stimulus (S2), where the subjects had to push a key immediately after presentation of S2. Records were made from vertex position with linked mastoids. Migraine patients during the pain-free interval exhibit higher CNV amplitudes (top line) compared with healthy controls (bottom line).CNV: Contingent negative variation.

S1 S2

1 2 3 4 5

U(µ

V)

-30

-20

-10

0

10

Problems and insights in migraine

www.future-drugs.com 335

cortical activation may cause this transformation. We alsohave to take into account that higher cortical activationenhances memory mechanisms which may generally beresponsible for chronification of disease. In the case oflower back pain, the above mentioned habits are ‘milddepression’ without any psychiatric relevance, ‘avoidancestrategies’ and a specific ‘hyperattentive action’ [19]. Preven-tion of chronification in lower back pain aims to preventdepression and anxiety. The development of chronicmigraine is linked to the disease duration of episodicmigraine [20]. There is a higher possibility of producingmore negative amplitudes in CNV when the lifetime his-tory of migraine is longer. This association remainssignificant when controlling for age [21].

Is a migraineurs brain immature?Examination of CNVs across various age ranges and popu-lations provides some insights into migraine pathogenesis.The CNV was used to record the influence of age in 162migraine patients and 320 healthy controls aged between 8and 59 years. Six age groups were created and the mean val-ues of a specific CNV component were analyzed [22]. Up tothe age group of 15–19 years, migraine patients andhealthy controls had similarly high CNV amplitudes andhabituation slopes. In the age group of 20–29 years,migraine patients and older healthy controls showed pro-nounced habituation and a decline in CNV amplitudes(FIGURE 2). Adult migraine patients revealed the same pro-nounced cortical excitability observed both in normal andin migraine-prone children.

The higher CNV amplitudes indicate that adultmigraineurs show a stronger attentional effort without habit-uation, over the trials within a CNV session. This deficiencyin habituation correspondsto the state necessary in anearly ontogenetic state,where increased facilitationof information processing isneeded. The observedassumption of a maturation effect in CNV parameters sug-gests two developmental stages. The first stage, up to the agegroup of 15–19 years, is characterized by high CNV ampli-tudes both in healthy controls and migraine patients. Thesecond stage is observed only in healthy adults. This stagecan be explained as development of the basis for habituationabilities and selective information processing, where a ‘jump’in amplitude and habituation of CNV can be observed.These findings are similar to observations in electroencepha-logram complexity, which shows maximum gain duringpuberty as an indicator of development of the frontal cortexand its cortio–cortical connections [23]. A recent study onpattern-reversal visual-evoked potentials in migraine chil-dren also supports the assumption that there is a maturationdisturbance in migraineurs [24].

What can be the causes of this maturation disorder? Studiessuggest that adult migraine brains behave as a child’s – suffer-ing from migraine or healthy. This is not necessarily a disad-vantage since the only evidence is that adult migraineursexhibit a greater sensory openness which is primarily neededduring sensory development. One can speculate that this sen-sory openness is the same as found during the sensitive periodwhile sensory imprinting takes place. It may be that inmigraine patients, this sensitive period is prolonged and

extends into adult age. Thisgreat sensory openness causessensory overload and, byreaching a threshold, themigraine attack. If thisassumption is true, high

CNV amplitudes would indicate the phasic status of the abilityto imprint. An impact for future research could be to elucidatethe mechanisms of human imprinting, especially themechanisms to stop the sensitive periods.

ConclusionMigraine is a serious disorder which affects 10–15% of theworlds population. The costs of effective prevention and acutetherapy are very high, patients have to adapt and change theirlife to a large extent. The need for help is great and this causesan important impact on the directions of scientific research.Therefore, not only do the patients have to learn from theirheadache to prevent the next migraine attack but also the scien-tific researcher has to grab the opportunity to gain new insightsand develop new aspects in the treatment of these pains.

‘An impact for future research could be to elucidate the mechanisms of human

imprinting, especially the mechanisms to stop the sensitive periods.’

iCN

V (

µV)

Age (years)

-14

-12

-10

-8

-6

-4

-2

08–14 15–19 20–29 30–39 40–49 50–590

NS

§§

§§ § § §

Figure 2. CNV amplitudes of migraineurs and healthy controls for different age groups. There is a pronounced decline in amplitude of healthy controls after the age group of 15–19 years.§p < 0.01§§p < 0.001. CNV: Contingent negative variation; NS: Not significant.

Kropp

336 Expert Rev. Neurotherapeutics 4(3), (2004)

References

1 Gobel H, Isler H, Hasenfratz HP. Headache classification and the Bible: was St Paul´s thorn in the flesh migraine? Cehalalgia 15(3), 180–181 (1995).

2 Bigal ME, Lipton RB, Stewart WF. The epidemiology and impact of migraine. Curr. Neurol. Neurosci. Rep. 4(2), 98–104 (2004).

3 Jones JM. Great pains: famous people with headaches. Cephalalgia 19(7), 627–630 (1999).

4 Aurora SK, Welch KMA. Brain excitability in migraine: evidence from transcranial magnetic stimulation studies. Curr. Opin. Neurol. 11, 205–209 (1998).

5 Ambrosini A, Schoenen J. The electrophysiology of migraine. Curr. Opin. Neurol. 16, 327–313 (2003).

6 Gerber WD, Schoenen J. Biobehavioral correlates in migraine: the role of hypersensitivity and information-processing dysfunction. Cephalalgia 18, 5–11 (1996).

7 Gerber WD, Stephani U, Kirsch E, Kropp P, Siniatchkin M. Slow cortical potentials in migraine families are associated with psychosocial factors. J. Psychosom. Res. 52(4), 215–222 (2002).

8 Limmroth V, Katsarava Z, Fritsche G, Przywara S, Diener HC. Features of medication overuse headache following overuse of different acute headache drugs. Neurology 59, 1011–1014 (2002).

9 Katsarava Z, Schneeweiss S, Kurth T et al. Incidence and predictors for chronicity of

headache in patients with episodic migraine. Neurology 62, 788–790 (2004).

10 International Headache Society. The international classification of headache disorders. Cephalalgia 24(Suppl. 1), 9–160 (2004).

11 Giffin NJ, Ruggiero L, Lipton RB et al. Premonitory symptoms in migraine. Neurology 60, 935–940 (2003).

12 Evers S, Quibeldey F, Grotemeyer KH, Suhr B, Husstedt IW. Dynamic changes of cognitive habituation and serotonin metabolism during the migraine interval. Cephalalgia 19(5), 485–491 (1999).

13 Schoenen J, Ambrosini A, Sandor PS, Maertens de Noordhout A. Evoked potentials and transcranial magnetic stimulation in migraine: published data and viewpoint on their pathophysiologic significance. Clin. Neurophysiol. 114(6), 955–972 (2003).

14 Kropp P, Siniatchkin M, Gerber WD. On the pathophysiology of migraine – links for empirically based treatment with neurofeedback. App. Psychophysiol. Biofeedback 27(3), 203–213 (2002).

15 Ahmed I. Contingent negative variation in migraine: effect of β blocker therapy. Clin. Electroencephal. 30(1), 21–23 (1999).

16 Kropp P, Gerber WD. Prediction of migraine attacks using a slow cortical potential, the contingent negative variation. Neurosci. Letters 275, 73–76 (1998).

17 Schoenen J. The pathophysiology of migraine: a review based on the literature and on personal contributions. Functional Neurol. 1, 7–16 (1998).

18 Lu SR, Fuh JL, Chen WT, Juang KD, Wang SJ. Chronic daily headache in Taipei, Taiwan: prevalence, follow-up and outcome predictors. Cephalalgia 21, 980–986 (2001).

19 Hasenbring M. Attentional control of pain and the process of chronification. Prog. Brain Res. 129, 525–534 (2000).

20 Wang SJ, Fuh JL, Lu SR et al. Chronic daily headache in Chinese elderly. Neurology 54, 314–319 (2000).

21 Kropp P, Siniatchkin M, Gerber WD. Contingent negative variation as indicator of duration of migraine disease. Functional Neurol. 15, 78–81 (2000).

22 Kropp, P, Sinatchkin M, Stephani U, Gerber WD. Migraine – evidence for a disturbance of cerebral maturation in man? Neurosci. Letters 276, 181–184 (1999).

23 Anokhin AP, Birbaumer N, Lutzenberger W, Nikolaev A, Vogel F. Age increases brain complexity. Electroencephal. Clin. Neurophysiol. 99, 63–68 (1996).

24 Oelkers-Ax R, Bender S, Just U et al. Pattern-reversal visual-evoked potentials in children with migraine and other primary headach: evidence for maturation disorder? Pain 108, 267–275 (2004).

Affiliations• Peter Kropp, PhD

Institute of Medical Psychology, University of Kiel, GermanyTel.: +49 431 597 2646Fax: +49 431 597 2711kropp@med-psych.uni-kiel.de