migraine patients are hypersensitive to various stimuli even outside the headache attacks [ 16 ] . the underlying cause for such symptoms is still unknown . although positron emission tomography ( pet ) , magnetic resonance imaging ( mri ) and blink reflex studies support the presence of a  migraine generator  located in the brainstem [ 79 ] , the presence of visual evoked potentials ( vep ) habituation dysfunction , transcranial magnetic stimulation threshold changes and somatosensory evoked potential abnormality this notion of a cortical dysfunction in migraine is also supported by blinded electroencephalography ( eeg ) studies and controlled quantitative eeg ( qeeg ) studies showing that eeg abnormality rates are higher in migraineurs compared to headache - free controls [ 1215 ] . however , the results from qeeg studies in migraine are not consistent and partly contradictory [ 1619 ] . the cause for this disagreement has not been clarified , but many qeeg studies did apparently not take into account that some patients were in a pre - attack phase during recording [ 2028 ] . pre - ictal neurophysiological changes have indeed been found with qeeg   as well as with other methods [ 3038 ] . for this reason , it is important to re - evaluate eeg findings in migraineurs during a time period when neither the last attack nor the next attack may interact with the results . subclinical , possible ischemic , white matter lesions [ 3943 ] and grey matter changes [ 44 , 45 ] have also been described in migraine patients . these findings correlate with attack frequency [ 40 , 44 ] and disease duration . because cerebral ischaemia causes increased theta and delta and decreased alpha activity [ 4648 ] , it may be interesting to study whether interictal cortical function also correlates with migraine symptoms and severity . our aim was accordingly to estimate delta , theta and alpha eeg band power in controls and in migraineurs in a true interictal period , where both the time from the previous attack and the time to the following attack are controlled . we also evaluated interictal eeg findings in the symptomatic hemisphere , and the associations between interictal eeg band power and measures of headache duration , frequency , intensity , phono- and photophobia in migraineurs . migraine patients were recruited by a newspaper advertisement . after telephone screening by nurses trained in headache research , the eligible participant was aged 1865 with 26 migraine attacks per month during the previous 3  months . the diagnosis of migraine was made according to the international headache society s classification of headache disorders 2nd edition , using ichd - ii codes 1.1 ( migraine without aura ) and 1.2.1 ( typical aura with migraine headache ) . exclusion criteria ( migraineurs and controls ) were : coexisting frequent episodic or chronic tension - type headache , acute or chronic neurological disease , connective tissue disorder or other painful conditions , malignancy , previous craniotomy or cervical spine surgery , cardiopulmonary or cerebrovascular disease , hypertension , pregnancy , medication for acute or chronic pain , neuroleptics , alcohol or drug abuse , ferromagnetic implants , and use of neuroactive substances such as anti - depressive , anti - epileptic , or migraine prophylactic drugs within 4  weeks before the test . forty - one migraine patients ( 33 without aura , 8 with aura ) and 31 controls were considered for this eeg study . three eeg recordings were performed in each subject except for two patients who were not willing to undergo all three eeg recordings because headache worsened after the tests . patients completed a questionnaire about their headache asking about , e.g. , disease duration , attack duration , attack frequency ( 13 ) , headache intensity ( 13 ) , and phono / photophobia ( 03 ) . they kept a headache diary for minimum 2  weeks before and after the test , including entries on pain characteristics , accompanying symptoms , consequences for work and leisure , and time of start and end of headache . this enabled a correct retrospective classification of the headache attack and its relationship to the time of the eeg recordings . patients without at least one interictal recording ( no attack 36  h before and 36  h after the recording ) were excluded from the analysis . thirty - six hours cut - off was chosen because it has been shown that extending the time to 72  h did not influence power values . one of the three eeg recordings was selected from each control subject ( day 1 , 2 , or 3 ) according to the recording day of a corresponding age - matched patient . twenty - seven of the 33 patients reported laterality of the attack following the interictal eeg recording . the cranial side reported as most symptomatic during the following attack was selected as the symptomatic side ( s ) . s and  non - symptomatic  ( ns ) sides were selected by random ( either right or left ) in controls . definitions and calculations are described in details previously . in brief , we calculated band power values ( v ) by summing power across all bins in this frequency spectrum for 0.53.5  hz ( delta ) , 3.757.5  hz ( theta ) and 7.7512.5  hz ( alpha ) . relative power values were defined as r  =  band power / total power . occipitoparietal ( o1 , o2 , p3 , p4 ) , temporal ( t3 , t4 , t4 , t6 ) and fronto - central ( f3 , f4 , c3 , c4 ) regional average values were computed . absolute asymmetry was calculated as the sign - free difference between the left - sided and the right - sided regional power . in the subgroup of patients with unilateral symptom predominance ( hemicrania ) , we did also calculate the s    ns difference ( ln - transformed power ) . alpha peak changes and pre - attack eeg band power have been reported previously in paired studies [ 29 , 50 ] . other examinations in the 2.5-h long neurophysiological battery were vep , brainstem auditory evoked potentials , thermal pain thresholds   and pupillary reflex ( to be reported in another paper ) . the technicians , neurophysiologist , and other staff involved in data reduction and analysis were blinded regarding the diagnostic status . they received an amount equivalent to 150 usd after completing the three sessions to cover expenses ( not mentioned in the newspaper advertisement ) . the analysis was performed with spss ( version 15.0 ) and systat ( version 11 ) . as the distribution of qeeg data was often skewed and some group sizes were small , non - parametric tests were used . the combined ( mwoa  +  ma ) migraine group was compared to the control group with mann , we performed a post hoc comparison between ma and mwoa subgroups for the variable in question ( mann  whitney test ) . the associations between qeeg ( delta , theta , alpha absolute and relative power ) and headache history duration , headache attack duration , headache intensity , headache days in the last 3  months , phonophobia , and photophobia were explored with spearman s rho . significant associations were then controlled for age with an additional post hoc partial correlation analysis . with intention to avoid type ii errors , we considered two - sided p values < 0.05 to be significant . the analysis was performed with spss ( version 15.0 ) and systat ( version 11 ) . was often skewed and some group sizes were small , non - parametric tests were used . the combined ( mwoa  +  ma ) migraine group was compared to the control group with mann  whitney u tests . in case of significance , we performed a post hoc comparison between ma and mwoa subgroups for the variable in question ( mann  whitney test ) . the associations between qeeg ( delta , theta , alpha absolute and relative power ) and headache history duration , headache attack duration , headache intensity , headache days in the last 3  months , phonophobia , and photophobia were explored with spearman s rho . significant associations were then controlled for age with an additional post hoc partial correlation analysis . with intention to avoid type ii errors , we considered two - sided p values < 0.05 to be significant . groups were also comparable regarding coffee and alcohol use ( p  >  0.29 , z  >  11 , mann whitney u test ) as well as tobacco smoking ( p  =  0.18 , fisher exact test ) . eight of the controls and 12 of the migraine patients used hormonal active medication ( birth prevention or replacement therapy , p  =  0.43 , fisher exact test ) . three subjects in each group used histamine antagonists ( p  =  1.0 , fisher exact test).table  1demographic and clinical datamigraine ( n  =  33)migraine with attack asymmetry ( n  =  27)controls ( n  =  31)women / men30/325/228/3mwoa / ma27/621/6age ( years)36.5 ( 12.7)37.7 ( 12.9)40.0 ( 11.4)days from last menstruation11.0 ( 9.3)11.4 ( 9.3)10.2 ( 9.7)headache history ( years)19.3 ( 11.0)20.6 ( 10.3)headache days last 3  months6.2 ( 4.0)5.9 ( 4.2)headache intensity ( 04)2.4 ( 0.7)2.5 ( 0.6)headache duration ( h)17.8 ( 22.0)18.5 ( 22.9)photophobia ( 02)1.4 ( 0.7)1.4 ( 0.7)phonophobia ( 02)1.1 ( 0.8)1.3 ( 0.7)eeg epochs16.6 ( 2.2)16.8 ( 2.2)15.7 ( 1.6)percent drowsiness7 ( 13)7 ( 13)5 ( 12)eye blinks2.2 ( 3.9)2.2 ( 4.3)2.0 ( 2.8)alfa persistence ( 05)3.8 ( 1.6)4.0 ( 1.5)3.8 ( 1.4)ma migraine with aura , mwoa migraine without aura . eye blinks per minute . alfa persistence regularity of typical occipital alpha rhythm scored on a six - level scale . epochs number of 4-s artefact - free eeg epochs included in the spectral analysis demographic and clinical data ma migraine with aura , mwoa migraine without aura . alfa persistence regularity of typical occipital alpha rhythm scored on a six - level scale . epochs number of 4-s artefact - free eeg epochs included in the spectral analysis relative theta power was increased in migraine in the parieto - occipital ( p  =  0.045 ) , fronto - central ( p  =  0.06 ) and temporal region ( p  =  0.037 ; table  2 ; fig .  1 ) . migraineurs without aura had slightly more relative theta activity than controls in post hoc analysis [ mean ( sd ) in fronto - central area : 0.16 ( 0.04 ) vs. 0.13 ( 0.04 ) , p  =  0.03 ; parieto - occipital area : 0.12 ( 0.04 ) vs. 0.10 ( 0.04 ) , p  =  0.02 ; temporal area : 0.15 ( 0.05 ) vs. 0.12 ( 0.04 ) , p  =  0.02 ; mann  whitney u tests ] . the other relative power bands as well as absolute power and asymmetry ( not tabulated ) were similar between groups ( table  2).table  2absolute and relative spectral powermean absolute powermean relative powermigraine ( n  =  33)controls ( n  =  31)pmigraine ( n  =  33)controls ( n  =  31)pfronto - central  delta power ( v)7.4 ( 3.5)6.7 ( 2.8)0.390.30 ( 0.12)0.29 ( 0.14)0.64  theta power ( v)4.6 ( 4.2)3.3 ( 1.8)0.280.15 ( 0.04)0.13 ( 0.04)0.06  alpha power ( v)12.2 ( 12.3)10.9 ( 9.9)0.830.35 ( 0.15)0.35 ( 0.16)0.97parieto - occipital  delta power ( v)11.7 ( 10.3)8.5 ( 3.0)0.290.22 ( 0.13)0.20 ( 0.13)0.46  theta power ( v)8.3 ( 11.8)5.2 ( 3.5)0.180.12 ( 0.04)0.10 ( 0.04)0.045  alpha power ( v)45.8 ( 52.3)38.6 ( 35.3)1.000.50 ( 0.21)0.51 ( 0.21)0.73temporal  delta power ( v)8.9 ( 6.3)7.8 ( 3.2)0.800.24 ( 0.10)0.23 ( 0.13)0.42  theta power ( v)6.4 ( 7.0)4.6 ( 3.0)0.260.14 ( 0.05)0.12 ( 0.04)0.037  alpha power ( v)22.0 ( 21.1)21.2 ( 18.6)0.950.43 ( 0.16)0.43 ( 0.18)0.84bold values represent significant p values ( < 0.05)p value from non - parametric mann  whitney u testsfig . 1interictal relative theta power was increased in migraine in the fronto - central ( left box , p  =  0.06 ) , parieto - occipital ( middle box , p  =  0.045 ) and temporal region ( right box , p  =  0.037 ) ( mann  whitney u test ) absolute and relative spectral power bold values represent significant p values ( < 0.05 ) p value from non - parametric mann whitney u tests interictal relative theta power was increased in migraine in the fronto - central ( left box , p  =  0.06 ) , parieto - occipital ( middle box , p  =  0.045 ) and temporal region ( right box , p  =  0.037 ) ( mann  whitney u test ) fronto - central delta power was slightly increased on the symptomatic side ( mann  whitney u test , p  =  0.005 ; fig .  2 ) . non - symptomatic delta activity difference was also mainly present in mwoa patients ( 0.53  v ) compared to 0.03  v in ma ( mann  whitney u test , p  =  0.29 ) and 0.62  v in controls ( mann  whitney u test , p  =  0.003).fig . 2larger fronto - central delta power in migraineurs than in controls is observed on the symptomatic side compared to the pain - free side ( s    ns difference ; mann  whitney u test , p  =  0.005 ) . two outliers are not shown ( but included in the statistical analysis ) larger fronto - central delta power in migraineurs than in controls is observed on the symptomatic side compared to the pain - free side ( s    ns difference ; mann  whitney u test , p  =  0.005 ) . two outliers are not shown ( but included in the statistical analysis ) we observed a positive association between headache intensity and delta power ( table  3 ; fig . 3 ) as well as delta asymmetry ( fronto - central : rho  =  0.38 , p  =  0.03 ; parieto - occipital : rho  =  0.34 , p  =  0.05 ; temporal delta asymmetry : rho  =  0.52 , p  =  0.001 ) . the correlations between fronto - central and temporal delta power and headache intensity were also present after adjustment for age.table  3correlation between eeg and clinical data in migraine : spearman rho ( p values)age ( years)headache history ( years)headache intensityfronto - central  delta power ( v)0.51 ( 0.002)0.42 ( 0.02)0.55 ( 0.001 ) *  theta power ( v)0.13 ( 0.48)0.13 ( 0.46)0.12 ( 0.52 )  alpha power ( v)0.16 ( 0.38)0.11 ( 0.53)0.16 ( 0.38)parieto - occipital  delta power ( v)0.54 ( 0.001)0.48 ( 0.004)0.46 ( 0.01 )  theta power ( v)0.07 ( 0.71)0.08 ( 0.68)0.07 ( 0.69 )  alpha power ( v)0.11 ( 0.53)0.07 ( 0.71)0.14 ( 0.43)temporal  delta power ( v)0.52 ( 0.002)0.54 ( 0.001)0.50 ( 0.003 ) *  theta power ( v)0.07 ( 0.68)0.10 ( 0.58)0.16 ( 0.37 )  alpha power ( v)0.04 ( 0.85)0.01 ( 0.97)0.17 ( 0.35 )  age0.75 ( 0.000)0.55 ( 0.001)headache intensity0.51 ( 0.001)0.40 ( 0.01)bold values represent significant p values ( < 0.05 ) *  partial correlation ( adjusting for age ) was significant ( r  >  0.36 , p  <  0.05 ) . significant correlations were not found between eeg and headache attack duration , headache days last 3  months , phonophobia or photophobiafig . 3linear regression lines are shown for fronto - central ( open circles , solid line ) , parieto - occipital ( triangles , broken line ) and temporal ( inverted triangles , dotted line ) delta power ( log - transformed y - axis ) correlation between eeg and clinical data in migraine : spearman rho ( p values ) bold values represent significant p values ( < 0.05 ) *  partial correlation ( adjusting for age ) was significant ( r  >  0.36 , p  <  0.05 ) . significant correlations were not found between eeg and headache attack duration , headache days last 3  months , phonophobia or photophobia linear regression lines are shown for fronto - central ( open circles , solid line ) , parieto - occipital ( triangles , broken line ) and temporal ( inverted triangles , dotted line ) delta power ( log - transformed y - axis ) headache history and age were both negatively associated with delta power in migraine patients ( table  3 ) . no negative association between age and delta was found among controls ( rho  >  0.28 , p  >  0.12 ) , suggesting that headache history duration was a more important predictor for delta power than age . however , the relationship between delta power and headache history duration disappeared when age was controlled in partial correlation analysis ( r  >  0.24 , p  >  0.17 ) . headache history correlated negatively with delta asymmetry ( parieto - occipital : rho  =  0.40 , p  =  0.02 ; temporal : rho  =  0.49 , p  =  0.004 ; fronto - central : rho  =  0.33 , p  =  0.06 ) . age also correlated negatively with parieto - occipital ( rho  =  0.36 , p  =  0.04 ) and temporal ( rho  =  0.49 , p  =  0.004 ) delta asymmetry in migraineurs , but not in controls ( r  >  0.30 , p  >  0.10 ) . after correcting for age , headache history still correlated with parieto - occipital delta asymmetry ( log data : partial correlation r  =  0.36 , p  =  0.04 ) . photophobia correlated positively with fronto - central absolute theta asymmetry ( rho  =  0.35 , p  =  0.04 ) , but not after correcting for age . the main finding in this blinded controlled study was globally increased relative theta activity in migraineurs . this is in accordance with all of the earlier three studies we have come across analyzing interictal relative power in migraineurs . lia et al .   found increased relative theta activity in the parieto - occipital region in adults with and without aura . farkas et al .   found increased central relative theta power in children with and without aura . genco et al .   reported increased theta , all regions in children with and without aura while only delta was increased in adults . generally , older studies have shown slight and inconsistent interictal abnormalities in the alpha and theta bands as reviewed by sand . we did not find any interictal difference in absolute power values among controls and migraineurs in the present study . however , an increase of absolute theta activity has previously been found in migraineurs with aura . in a previous paper , we compared eeg power in the interictal period to power in the period before the attack within patients . interestingly , absolute theta power tended to increase even more just before the following headache attack in the same patients . taken together , these findings support a relative excess of slow activity in migraineurs between attacks that possibly increases even more when an attack approaches . we mainly found increased theta activity in migraineurs without aura , but it is plausible that increased theta is also present in migraineurs with aura since our aura subgroup was small and earlier studies have found increased theta in subjects both with and without aura [ 20 , 22 , 24 ] . theta activity in healthy subjects is linked to hippocampal memory networks during activated behavioural states and thalamic networks during stage 1 nrem sleep [ 53 , 54 ] . neuronal firing in several other subcortical nuclei including the dorsal raphe nucleus ( drn ) and anterior thalamus is phase locked to theta oscillations [ 55 , 56 ] . decreased serotonergic neurotransmission may cause increased theta activities , as serotonergic tone from the drn normally desynchronizes ( suppresses ) hippocampal theta . under experimental conditions , either electrically or chemically lesions or pharmacological depression of drn have been shown to elicit theta waves . cholinergic input is important in generating theta activity from the limbic system in awake states . however , during sleep , reduction of either cholinergic , monoaminergic or histaminergic tone from brainstem nuclei to thalamic and cortical neurons is responsible for the transition from faster rhythms towards theta and delta [ 54 , 57 ] . pathological theta waves may , on one hand , represent a slowing down of the alpha rhythm due to reduced cerebral blood flow and oxygen uptake in cortical grey matter [ 54 , 58 ] . such slowing is seen in mild to moderate hypoxia , cerebrovascular disease , dementias and mild degrees of metabolic encephalopathies . intermittent , frontotemporal theta , on the other hand , is often attributed to disturbances in deep midline structures . some believe that theta waves during wakefulness indicate one of several possible pathophysiological conditions , including migraine , collectively termed thalamic dysrhythmias . t- and r - type calcium channels and calcium spikes may be involved in the generation of theta waves [ 60 , 61 ] . it can be hypothesized that unstable or hyperactive calcium - channel function is involved in migraine patients , possibly explaining slight cognitive symptoms   or dysfunctions in some patients , although genetic studies for some calcium - channel genes have been negative in migraine so far [ 63 , 64 ] . another interesting finding was frontal slow delta activity at the side of the head becoming painful during the next headache attack . asymmetry due to reduction of alpha power with increased or decreased theta power   and frequency slowing   has been found earlier at the side of the hemicrania during attacks . as power reduction has also been seen 2448  h after the attack , we can not exclude an after - effect imposed by the previous attack on the same side . however , we did not find post - ictal qeeg after - effects in our previous study , so this seems less likely . non - linear sleep eeg analysis has found pre - ictal changes in cortical dynamics at the site of pain maxima of later pain perception . frontal slow delta may thus reflect unilateral prodromal cortical change in the side that is to be painful , possibly a marker of a latent cortical spreading depression . delta activities normally prevail during deep stages of sleep and are most likely generated by cortical , pyramidal neurons between layers ii , iii and v . it appears when the cholinergic tone from cortically projecting basal forebrain neurons decreases ( cortical deafferentation ) . t - type calcium channels in thalamocortical networks are also involved in the generation of delta activity during of stage 3 and 4 nrem sleep . pathological polymorphic delta activity may occur localized as well as unilateral , and can arise from both metabolic and structural pathologies . localized delta waves may appear over a subcortical white matter lesion or on the side of thalamic , midbrain reticular formation or hypothalamic lesions [ 54 , 68 ] . reduced frontal grey matter density and diffusion abnormalities have been found by several authors in migraineurs [ 45 , 62 , 69 ] ; however , localized lesions of the cortical grey matter do not produce delta activity , only depression of the eeg background activity . in conclusion , slight changes in activity in subcortical structures were not performed , we may not conclude whether cerebral lesions contributed to the findings in this study . our main finding in the correlation analysis was an association between headache intensity and increased delta power . in other words , migraineurs with high - intensity attacks have slower activity in their eeg in all cortical areas . whether our findings are linked to the cause of headache or if it is a consequence of more intense headaches over time remains to be answered . however , a slight cortical dysfunction due to heavy pain may be suspected , as white matter lesions and grey matter changes in migraine patients correlate with severity of migraine [ 40 , 44 , 45 , 69 , 70 ] . cognitive impairments have been found in migraineurs [ 62 , 71 ] correlating with mri findings . it has been hypothesized that repetitive activation of trigeminovascular neurons and consequently repetitive activation of modulatory pain pathways may lead to impairment of function or partial neuronal cell damage in these areas through the liberation of free radicals . asymmetry reduction in older subjects is a well - known phenomenon in functional mri and pet literature . a compensation theory ( age - related asymmetry reductions might counteract cognitive decline ) or a dedifferentiation view ( changes reflect a difficulty in recruiting specialized neural mechanisms ) is debated . it is , therefore , possible that our results can be explained by a more pronounced cortical  ageing  process in migraineurs compared to controls . it seems like the increased symmetrical activity depends on the disease duration , as headache history also correlated with parieto - occipital symmetry after correcting for age . some authors have found a higher degree of abnormalities in older migraine patients than in younger [ 28 , 52 ] , whereas others found no correlation to clinical severity . in another study ( on the same patients ) we did not find correlations with attack frequency , as seen in studies of mri alterations , but all patients were high frequency migraineurs ( between 2 and 6 attacks per month ) . some migraine prophylactics , such as anti - epileptic medication , may influence eeg [ 73 , 74 ] . therefore , all neuroactive drugs were ceased at least 4  weeks before eeg recording and did not contribute to the results . subjects were allowed to use rescue medication , including triptans . however , as all eegs recorded during attack or within 36  h before and after migraine attack were excluded , it seems unlikely that these substances could have influenced the results . the half - life of the relevant triptans is between 2 and 6  h. strengths of the present study are the prospective , paired , blinded and controlled design , and the detailed headache diaries completed before and after the tests . we reduced the amount of data and number of comparisons by restricting our computations to three frequency bands and three cortical regions . however , our data must be interpreted with caution , and they need to be replicated before firm conclusions are drawn . our results are mostly representative for migraineurs without aura and for women , as rather few aura patients and men were recruited . we have chosen not to do this because bonferroni - type corrections test the universal null hypotheses ( i.e. that all hypotheses are simultaneously non - significant ) . corrections aimed at preventing type i errors are also associated with increased type ii errors [ 7577 ] . in conclusion , in this blinded controlled study , migraineurs had increased relative theta power in a time period free from pre - ictal activity interference . delta activity was increased even before pain onset in the cranial side to become painful . patients with high pain intensities had more delta activity than those with less intense pain . these results suggest that migraine is associated with a slight brain dysfunction between attacks , possibly caused by activity changes in subcortical or limbic structures .
abnormal electroencephalography ( eeg ) in migraineurs has been reported in several studies . 
 however , few have evaluated eeg findings in migraineurs during a time period when neither the last attack nor the next attack may interact with the results . we , therefore , compared interictal eeg in migraineurs and headache - free subjects with a design controlled for interference by pre - ictal changes . pre 
 - ictal eeg findings in the painful cranial side during the next attack after registration were also investigated . 
 correlations between clinical variables and eeg are reported as well . 
 interictal eegs from 33 migraineurs ( 6 with and 27 without aura ) and 31 controls were compared . 
 absolute power , asymmetry and relative power were studied for delta , theta and alpha frequency bands in parieto - occipital , temporal and fronto - central areas . 
 eeg variables were correlated to attack frequency , headache duration , attack duration , pain intensity , photo- and phonophobia . compared with controls , 
 migraineurs had increased relative theta power in all cortical regions and increased delta activity in the painful fronto - central region . 
 absolute power and asymmetry were similar among groups . in age - adjusted analyses , headache intensity correlated with increased delta activity . 
 in this blinded controlled study , we found globally increased relative theta activity in migraineurs . 
 a slight interictal brain dysfunction is probably present between attacks .