migraine is a central nervous system disease traditionally characterized by acute painful attacks ( goadsby et al . , 2002 ) .
this definition , however , does not capture the effects of migraine that extend beyond episodic attack ( ictal ) periods ( goadsby et al .
, 2002 ; stewart et al , 1992 ) , including lasting alterations in brain structure and function ( lakhan et al . , 2013 ; noseda & burstein , 2013 ; sprenger & borsook , 2012 ) that closely mirror the effects of chronic pain conditions .
more broadly , migraine also appears to share physiological ( boyer et al . , 2014 ) and clinical profiles ( blumenfeld et al .
, 2004a ; mccracken & iverson , 2001 ) , migraine has been linked to impaired cognitive function .
pain demands and depletes cognitive resources , which is thought to contribute to cognitive impairments in chronic pain broadly defined ( eccleston & crombez , 1999 ; nes et al . , 2009 ) .
the behavioral effect of migraine on cognitive function , however , has been debated within the literature , largely due to mixed results ( calandre et al . , 2002 ; pearson et al . , 2006 ; suhr & seng , 2012 ; waldie et al . , 2002 ; zeitlin & oddy , 1984 ) .
a recent review noted that significant effects of migraine on cognitive function depended largely on study recruitment , such that patients recruited from neurology clinics show mild impairment across several cognitive domains , whereas migraine patients recruited from the community were less likely to show cognitive differences from healthy controls ( de arajo et al . , 2012 ) .
therefore , cognitive impairment in migraine may be dependent on disease severity ( e.g. disease duration , migraine frequency , migraine pain intensity ) . pain 
cognition interactions in neural response have been demonstrated among young healthy populations ( petrovic et al . , 2000 ;
seminowicz & davis , 2007a ) , such that cognitive engagement typically reduces pain - related activity .
cognitive - related activity , on the other hand , does not tend to be altered by simultaneous pain stimuli among healthy volunteers ( seminowicz & davis , 2007a ) . however , whether these patterns are preserved among people with migraine is not known .
chronic pain appears to alter the functional organization of brain networks involved in pain and cognitive processes ( farmer et al . , 2012 ) . initial evidence suggesting that cognitive modulation of pain processing may be altered or weakened in migraine patients indicated that , compared to healthy controls , patients with chronic and episodic migraine show deficient cognitive task - related suppression of evoked potential amplitude during acute pain stimulation ( de tommaso et al . , 2003 )
recently , the association between migraine and brain white matter lesion load ( kurth & tzourio , 2009 ; swartz & kern , 2004 ) has supported the hypothesis that prolonged suffering with migraine may lead to cognitive decline ( paemeleire , 2009 ) .
however , a longitudinal study did not find such a relationship ( rist & kurth , 2013 ) .
still , others have found correlations between structural differences between migraine patients and controls , and impairments on some cognitive tasks ( schmitz et al . , 2008 )
lending support to the hypothesis that cognitive decline in migraine may be due to structural brain changes over time .
while little is known about functional neural response to cognitive challenge among migraine patients , hypotheses can be drawn from evidence of abnormal brain activity in response to cognitive tasks within other chronic pain populations including chronic low back pain ( seminowicz et al . , 2011 ) and temporomandibular disorder ( weissman - fogel et al . ,
additionally , studies have reported abnormal functional resting state connectivity in migraine patients between brain regions associated with affective pain processing and cognitive networks ( schwedt et al . , 2013 ;
one recent study demonstrated that migraine patients also display greater evoked pain - related activity in areas thought to be associated with cognitive aspects of pain processing , including the contralateral premotor cortex ( pm ) , right dorsolateral prefrontal cortex ( dlpfc ) , and ipsilateral hippocampus ( schwedt et al . , 2014 ) . taken together , these findings suggest that changes in functional cognitive brain activity may be due to integration of pain and cognitive networks and pain  cognition interactions . in the current study
we examine neural response to cognitive challenge , and pain  cognition interactions during concurrent pain stimulation , among migraine patients and healthy volunteers .
we hypothesized that there would be group differences in task - related neural response , where migraine patients would have to recruit greater brain resources to perform the cognitive task equally well as healthy controls , and that task - related suppression of acute pain - related activity ( pain  cognition interactions ) would also be altered among migraine patients .
fourteen migraine patients ( 11 females , mean 40.8  years old ( sd  =  11.9 ) ) and 14 healthy controls ( 11 females , mean 38.9  years old ( sd  =  12.5 ) ) participated in this study and were compensated for their time .
migraine patients were recruited from the johns hopkins university ( jhu ) campuses and local headache clinics , and through community advertisements .
migraine patients also participated in a subsequent longitudinal study , but the procedures described here were all completed at baseline , before any intervention .
evaluation of prospective 3-month headache diaries revealed that ten patients met diagnosis criteria for chronic migraine ( range : 1428  headache  days per 28  days ) and four for episodic migraine ( range : 7.813.7  headache  days per 28  days ) .
diagnosis was determined by the study physician ( m.g . ) using the international classification of headache disorders - ii ( ichd - ii ) criteria ( headache classification subcommittee of the international headache society , 2004 ; olesen & steiner , 2004 ) .
we did not exclude any patients in our primary analysis for a number of reasons .
first , all patients were recruited based on reported chronic migraine . additionally , within our migraine group we examined migraine frequency as a continuous variable . though separable diagnostic criteria , chronic migraine and episodic migraine have a common underlying pathophysiology ( pietrobon & moskowitz , 2013 ) .
clinical and behavioral differences between chronic and episodic migraine patients have been demonstrated in factors that vary linearly with increasing frequency , and the demarcation created for diagnostic purposes is somewhat arbitrary ( borsook et al . , 2012 ; katsarava et al . , 2012 ; silberstein et al . ,
furthermore , others have examined chronic and episodic migraine patients together , which has led to a number of recent advances in the understanding of migraine ( e.g. anttila et al . , 2013 ; hamedani et al .
, 2013 ; hunter et al . , 2014 ) . nonetheless , to ensure that our findings were not dependent on the episodic migraine patients , we also report the main results excluding the four episodic migraine patients ( supplementary results ) .
patients had migraine for an average of 10.9  years ( se = 2.0 , range : 127  years ) and rated their average migraine pain intensity during the last month as a 5.4 on a 0 ( no pain ) to 10 ( worst pain imaginable ) scale ( se = 0.6 , range : 210 ) .
patients had an average of 20.1  headache  days per 28  day month according to prospective headache diaries ( se  =  2.0 , range : 7.828  days ) and retrospectively reported an average migraine frequency of 9.6 in the previous month ( se  =  2.1 , range : 230 migraines ) .
exclusion criteria included an unstable psychiatric disorder , pregnancy , illicit drug use and severe alcoholism .
this study was approved by the umb and jhu institutional review boards , and informed written consent was obtained from each participant prior to any study procedures .
the cognitive task and thermal stimuli were administered simultaneously according to a full 2 ( task difficulty )    3 ( thermal stimulus intensity ) factorial design , such that while participants completed either the difficult or easy cognitive task , they experienced a concurrent moderately painful , mildly painful , or non - painful thermal stimulus [ i.e. , ( difficult / moderate pain ( t1p2 ) , difficult / mild pain ( t1p1 ) , difficult / no pain ( t1p0 ) , easy / moderate pain ( t0p2 ) , easy / mild pain ( t0p1 ) , easy / no pain ( t0p0 ) ] . participants performed a modified attentional network test ( ant ) ( fan et al . , 2002 ) , which involved identifying the direction of a central arrow , while ignoring the direction of flanking arrows .
difficult tasks involved distracting , incongruent flankers , easy tasks involved congruent flankers . during both the pre - scan practice session and the mri scan sessions , participants indicated the direction of the arrow using a simple button press with their right hand .
an fmri - compatible thermal stimulator delivered thermal stimuli via a contact probe ( 30    30  mm medoc pathway ats peltier device ; medoc advanced medical systems ltd .
, ramat yishai , israel ) to the left volar surface of participants ' forearms .
the peak temperature ( moderate pain , p2 ) used throughout the study was determined at the beginning of the pre - scan session  using a simple ramp - and - hold procedure  as the temperature at which participant rated a 56 on a 0 ( no pain ) to10 ( most intense pain imaginable ) pain intensity scale . the mild pain ( p1 ) stimulus
stimuli were presented for a variable duration of 812  s with a ramp time of 1.6  s and variable ramp rate based on peak stimulus temperature .
stimuli were separated by intervals ( 48  s ) of baseline temperature ( 32  c ) .
the same temperature was used for each participant throughout the pre - scan and mri scan sessions with the exception of one patient who required the peak stimulus temperature to be lowered 1  c for the second functional run . prior to scanning ,
then , the individualized peak thermal stimulus ( p2 ) was determined , and participants were trained to a point where they performed with > 90% accuracy on the cognitive task .
participants then performed the full experimental paradigm , with concurrent task and thermal stimulation , identical to that experienced in the mri session .
pain intensity and unpleasantness ratings were obtained on a 010 numerical rating scale for each trial , and reaction time and accuracy were recorded .
participants also completed retrospective reports of migraine frequency and migraine pain intensity and the pain catastrophizing scale ( pcs ) ( sullivan et al .
pain catastrophizing is a cognitive coping strategy associated with increased rumination , magnification , and helplessness toward pain .
we included this measure because there is some evidence that migraine patients catastrophize more than healthy controls ( hassinger et al . , 1999 ) , and
pain catastrophizing increases preferential attention to pain ( sullivan et al . , 1995 ) .
high catastrophizers , therefore , may be less able to redirect their attention away from their pain , which may inhibit task - related suppression of pain .
the scan session included two functional runs ( run 1 : 9  min 20  s , run 2 : and 9  min 32.5  s ) containing 27 trials each .
there were six trial types consisting of all possible combinations of task difficulty and thermal stimulus intensity : difficult / moderate pain ( t1p2 ) , difficult / mild pain ( t1p1 ) , difficult / no pain ( t1p0 ) , easy / moderate pain ( t0p2 ) , easy / mild pain ( t0p1 ) , and easy / no pain ( t0p0 ) .
participants provided a real - time response to the cognitive task during each trial using a fiber optic mri - compatible button box in the scanner .
presentation of visual stimuli for the cognitive task was delivered via a desktop computer running e - prime 2.0 ( psychology software tools , http://www.pstnet.com ) .
visual stimuli were back - projected onto a translucent screen positioned behind the scanner bore and viewed from an angled mirror mounted on the head coil positioned at subject 's eye - level .
images were acquired using a siemens 3 t tim trio mri scanner equipped with a 12-channel head coil . participants completed a high - resolution t1-weighted mprage anatomical scan [ 144 slices , repetition time ( tr ) 2500  ms , echo time ( te ) 3.44  ms , flip angle 9.0 , fov 230  mm , resolution 0.9    0.9  mm , matrix size 256    256  mm , slice thickness 1  mm , no gap ] and two functional runs using multi - slice t2 * -weighted , echo planar imaging sequences [ spin - echo , 224 ( run 1)/229 ( run 2 ) volumes , 36 slices , tr 2500  ms ; te 30  ms ; flip angle 90 ; fov 230  mm , resolution 1.8    1.8 , matrix size 128    128  mm , slice thickness 4  mm , no gap , oblique slices ] .
the main effect of pain and group effects on pain processing are reported and discussed in a separate manuscript .
a 2 ( group : patients , controls )    2 ( task difficulty : easy , difficult )    3 ( thermal stimulus intensity : no pain , mild pain , moderate pain ) repeated - measures anova was used to analyze all behavioral data .
functional images were preprocessed and analyzed using spm8 software ( wellcome department of imaging neuroscience , london , uk ) implemented in matlab ( mathworks , cherborn , ma , usa ) .
. then , the high - resolution anatomical image was coregistered onto the mean functional image and segmented into csf , white matter , and gray matter .
all volumes were normalized to mni ( montreal neurological institute ) space and then spatially smoothed with an 8  mm gaussian kernel . after preprocessing , a general linear model was defined for each participant separately .
each model included six regressors of interest : difficult / moderate pain ( t1p2 ) , difficult / mild pain ( t1p1 ) , difficult / no pain ( t1p0 ) , easy / moderate pain ( t0p2 ) , easy / mild pain ( t0p1 ) , and easy / no pain ( t0p0 ) . in order to model only the period where cognitive load and thermal stimulation were stable and concurrent within each trial , the first and last portions ( 1.4  s off each end of the cognitive task trial , and corresponding , but variable tails of the thermal stimulus trial ) of each trial
resultant trial durations ( 5.711.8  s ) , reaction times ( parametric modulator ) , and six motion parameters ( covariates of no interest ) were modeled independently for each subject .
average task - related neural response was determined using contrast images [ difficult  >  easy , across thermal stimulus intensity levels , t1  >  t0 ] and [ difficult  >  easy in the absence of pain , t1p0  >  t0p0 ] for each participant .
to evaluate group differences in task - related activity , independent sample t - tests were also conducted on these contrasts .
the full task  pain interaction [ task ( difficult    easy )  +  pain ]    [ task ( difficult    easy )  +  no pain ] : [ ( t1p2    t0p2 )  +  ( t1p1    t0p1 ) ]    2[t1p0    t0p0 ] was examined across and within groups .
additionally , we further probed this interaction by examining task - related activations during pain [ pain ( mild  +  moderate )  +  difficult task ]  >  [ pain ( mild  +  moderate )  +  easy task ] : [ ( t1p1  +  t1p2 )    ( t0p1  +  t0p2 ) ] as well as task - related deactivations during pain [ pain ( mild  +  moderate )  +  easy task ]  >  [ pain ( mild  +  moderate )  +  difficult task ] : [ ( t0p1  +  t0p2 )    ( t1p1  +  t1p2 ) ] .
the latter was of particular interest as it may reflect task - related reductions in pain activity .
finally , we also examined pain - related activations during the difficult task [ difficult task  +  no pain ]  >  [ difficult task  +  pain ( mild  +  moderate ) ] : [ 2t1p0    ( t1p1  +  t1p2 ) ] to examine the effects of cognitive load on pain - related activity . across analyses ,
an initial extent threshold of p  <  .005 , cluster size k  >  25  voxels was used , corrected for multiple comparisons at the cluster level ( p  <  .05 ) , unless otherwise stated .
we used marsbar ( brett et al . , 2002 ) to extract beta values from regions of interest ( rois ) , defined as significant clusters identified by planned contrasts .
extracted values were used in 2 ( group : patients , controls )    2 ( task difficulty : easy , difficult )    3 ( thermal stimulus intensity : no pain , mild pain , moderate pain ) repeated - measures anovas to probe task  pain interactions and group differences in task - related activity .
migraine patients had marginally higher individualized peak stimulus ( p2 ) temperatures ( mean  =  47.5  c , se  =  .3 ) compared to healthy controls ( mean  =  46.4  c , se  =  .5 ) , t(26 )  =  2.0 , p  =  .06 . as expected ( seminowicz & davis , 2007a ) a main effect of task difficulty f(1,26 )  =  195.3 , p  <  .001 , and a marginal effect of pain f(2,52 )  =  2.7 , p  =  .08 , were found on reaction times . on average , participants were slower to respond during the difficult , relative to easy task t(27 )  =  14.2 , p  <  .001 , and during the mild ( p1 ) pain condition relative to the moderate ( p2 ; t(27 )  =  1.8 , p  =  .08 ) and no pain ( p0 ; t(27 )  =  2.0 , p  =  .06 ) conditions . a significant task  pain interaction f(2,52 )  =  4.7 ,
p  =  .01 was also seen in reaction time , such that the effect of pain on reaction time was larger during the easy task , and not significant during the difficult task ( fig . 
no other main effects or interactions were found . there was a main effect of task difficulty f(1,26 )  =  25.1 ,
p  <  .001 on accuracy , such that participants had lower accuracy in the difficult , relative to easy task , t(27 )  =  5.0 , p  <  .001 ( fig . 
notably , there were no main effects of group on reaction time or accuracy , suggesting that patients performed the task as well as controls .
when performance was examined within each of the six individual conditions , there were still no observable differences in performance between groups ( fig . 
patients ( mean  =  17.7 , se  =  2.3 ) had significantly higher pain catastrophizing scores than controls ( mean  =  6.9 , se  =  2.1 ) , t(26 )  =  3.5 , p  =  .002 .
an additional two patients and one control have partially missing reaction time and accuracy data .
for these participants , all available data were included . a main effect of task difficulty f(1,24 )  =  183.7 , p  <  .001 , and a main effect of pain f(2,48 )  =  3.6 , p  =  .04 were found on reaction time , such that participants were faster to respond during the easy , relative to difficult task t(25 )  =  13.8 , p  <  .001 , and during moderate ( p2 ) relative to the no pain ( p0 ; t(25 )  =  2.0 , p  =  .06 ) and mild pain ( p1 ; t(25 )  =  2.6 , p  =  .02 ) conditions .
a main effect of task difficulty f(1,24 )  =  23.4 , p  <  .001 was also found on task accuracy , such that participants had lower accuracy in the difficult , relative to easy conditions , t(25 )  =  4.7 , p  <  .001 .
no other effects were significant and there were no group differences in performance in any of the six individual conditions ( fig . 
task difficulty was associated with neural activity within regions known to be associated with cognitive processing ( table  1 , fig . 
all participants showed task - related activations in bilateral regions of the inferior occipital gyrus ( iog ) , superior parietal lobule ( spl ) and pm cortices , and task - related deactivations within midline regions , including the medial prefrontal cortex ( mpfc ) and posterior cingulate cortex ( pcc ) , and the r pins . in order to isolate smaller regions of interest ( task rois ) from large suprathreshold clusters , we increased the cluster forming threshold to p  <  .001 , k  >  25 for activations , and p  < 
when the effect of task was examined only within the no pain condition , similar patterns of activation were seen in bilateral regions of the iog , and pm cortices , as well as in the left inferior parietal lobule ( ipl ) , and similar task - related deactivations were seen within midline regions , including the mpfc and pcc , as well as the r pins ( table  1 , fig . 
, a more stringent threshold was used to isolate separable deactivation clusters ( p  <  .001 , k  >  25 ) .
controls displayed greater activity within a left ventral region of the pm ( vpm ) cortex compared with patients ( table  1 ) .
patients did not reveal any activity greater than controls that survived cluster - level correction ( see supplementary table  1 for suprathreshold clusters that did not survive correction ) . in the absence of the pain stimulus ,
migraine patients show less deactivation than controls within the l dlpfc as well as regions in the dorsal amcc and cerebellum during the difficult relative to easy task ( group difference task rois , table  1 , fig . 
patients who fell within the episodic migraine diagnostic criteria range were not outliers in this analysis ( supplementary fig .  1 ) , and the significant interaction between group and task - related deactivations remained when those with episodic migraine were excluded ( l dlpfc : f(1,22 )  =  14.6 , p  =  .001 ; amcc : f(1,22 )  =  26.0 , p  <  .001 ; r cerebellum : f(1,22 )  =  11.9 , p  =  .002 ) . to ensure that this group difference was not driven by structural abnormalities , we extracted gray matter volume ( gmv ) from one of these regions  the dlpfc  and found no difference in mean gmv between migraine patients ( m  =  .50 , se  =  .02 ) and controls ( m  =  .49 , se  =  .02 ; t(26 )  =  .55 , p  =  .6 ) .
we also found that the task - related group difference in dlpfc deactivation remained after controlling for individual gmv ( task difficulty    group interaction :
a significant task  group interaction was found in the r amcc group difference task roi ( defined as significant clusters from the patients  >  controls contrast in the absence of pain , fig . 
patients reveal a blunted pattern of responsiveness within the r amcc such that they have decreased activation during the easy task , and decreased deactivation during the difficult task , compared to controls . however , the simple effect of group within task condition was not significant .
no activation or deactivation clusters exceeded the cluster - level corrected threshold in the full task  pain interaction . in the full task  pain interaction , controls showed greater activity within the dorsal superior frontal gyrus ( sfg ) compared to patients ( table  2 , fig .  3 ) .
patients had no suprathreshold activity greater than controls . within sample analyses showed that patients had significant task 
pain interaction - related deactivations within the right dorsal medial sfg , which partially overlaps with the dorsal sfg identified by the two - sample analysis above . among patients ,
activity within the primary somatosensory cortex ( s1 ) was associated with the task  pain interactions , but this did not survive cluster - level correction ( supplementary table  1 ) . among controls ,
this suggests a different pattern of interaction - related activity between groups . across participants , task - related deactivations during pain [ pain ( mild  +  moderate )  +  easy task ] 
>  [ pain ( mild  +  moderate )  +  difficult task ] were seen across regions associated with the sensory ( e.g. r pins , amcc , s1 ) , cognitive ( e.g. mpfc , dorsal mpfc , l ventral lateral pfc ) , and affective ( e.g. l amygdala , l anterior insula ( ains ) , l orbitofrontal cortex ( ofc ) ) components of pain ( table  3 ) , suggesting that this may reflect task - related reduction of pain activity .
a more stringent threshold was used in this cross - participant analysis in order to isolate separable deactivation clusters ( p  <  .001 , k  >  25  for all but the two sample test ) .
patients revealed greater task - related deactivations during pain in the l posterior pm / primary motor ( m1 ) cortex compared to controls ( table  3 ) . within group
analyses suggest that this was largely due to greater activity among controls as seen in the reverse contrast within subjects ( task - related activity while in pain ) [ pain ( mild  +  moderate )  +  difficult task ]  >  [ pain ( mild  +  moderate )  +  easy task ] .
overall , more widespread reductions were observed among patients relative to controls ( fig . 
4 ) , whereas more robust task - related activity was seen among controls compared to patients .
there were no significant pain - related reductions in task activity [ difficult task  +  no pain ]  >  [ difficult task  +  pain ( mild  +  moderate ) ] .
effects of pain were seen across task rois ( defined as significant clusters from the difficult  >  easy contrast across participants and conditions , fig . 
a main effect of pain was found in all task - related activation rois as well as some of the task - related deactivation clusters ( r s1/pcc , r pins , r dlpfc , l m1 , l lateral pfc , l s1 , l ifg / ofc ) , such that pain was associated with more activity than no pain . a significant task 
a main effect of pain was also found in all of the group difference task rois ( defined as significant clusters from the patients  >  controls contrast in the absence of pain , fig . 
pain rois were defined as significant clusters from the pain ( p1  +  p2 )  >  no pain ( p0 ) contrast across participants and conditions ( supplementary fig . 
r pins was the only pain roi to show significant task - related modulation ( supplementary table  2 ) . a significant pain 
task interaction was found in the r pins , such that across participants there was deactivation during task ( difficult compared to easy ) in the no pain ( t(27 )  =  2.4 , p  =  .03 ) and moderate pain ( t(27 )  =  4.0 , p  <  .001 ) conditions , but no task difference in the mild pain condition ( p  > 
a main effect of task was found in the r pins such that the difficult task was related to less pain - related activity compared to the easy task . in the r thalamus ,
a three way interaction was seen in two of the group difference task rois ( i.e. , l dlpfc and r cerebellum ) .
controls show a greater decrease in activity within these regions in the difficult , relative to easy task compared to patients , particularly in the no pain condition ( fig . 
when we controlled for differences in pre - scan pain ratings , all of the task  pain  group interactions remained significant .
inferential statistics are reported in supplementary table  2 , and correlations are plotted in supplementary fig . 
pain catastrophizing was not correlated with activity in task rois across participants ( patients and controls ) . among patients ,
migraine pain intensity over the last month was positively correlated with activity in the r vpm task - roi ( supplementary fig . 
3b ) , indicating that migraine pain intensity was associated with enhanced task - related activation in this cluster .
migraine frequency over the last month was positively correlated with three task deactivation rois ( l middle temporal gyrus ( mtg ) , l amygdala , l posterior mtg , supplementary fig . 
3c ) , suggesting that increased migraine frequency was associated with abnormal task - related deactivations and may be associated with blunted deactivations observed among patients in task - related activity .
disease duration controlling for age was negatively correlated with the l s1 and l amygdala task deactivation rois , indicating that the longer patients have had migraines , the larger the magnitude of task - related deactivations in these regions ( supplementary fig . 
pain catastrophizing , migraine frequency , migraine pain intensity , and disease duration controlling for age , were not correlated with task - related activity in the group difference task rois . when we did not control for age , disease duration was negatively correlated with the l dlpfc , such that the longer patients have had migraines , the more they deactivate this area during the difficult task ( supplementary fig . 
patients show a similar relationship between l dlpfc activity and age as they do with disease duration .
3f ) , suggesting that age may not fully explain the relationship between disease duration and task - related activity in l dlpfc among migraine patients .
here , we characterize brain activity associated with cognitive task performance and pain  cognition interactions among patients with migraine .
overall differences in cognitive networks primarily demonstrated that acute pain - related modulation of task - related deactivations present in controls is absent in migraine patients , and that migraine patients show reduced task - related deactivations and altered task 
robust task - related activations in task - positive ( visual , sensorimotor , and executive ) networks and deactivations in regions of the default mode network were observed across migraine patients and healthy controls .
task difficulty increased activity within regions previously shown to increase as a function of cognitive load ( owen et al .
, 2005 ; seminowicz & davis , 2007a ) . also consistent with prior literature ,
greater task difficulty was associated with greater deactivation of midline regions of the default mode network , including the mpfc and pcc ( buckner et al . , 2008 ) .
this overall pattern of activations and deactivations was similar in the presence or absence of acute thermal pain . across participants , a significant pain 
task interaction was found in the r pins , such that task difficulty was associated with r pins deactivation , and pain intensity was associated with r pins activation .
this was true whether we defined the r pins region based on the pain contrast ( i.e. , task - related modulation of pain activity ) or based on the task contrast ( i.e. , pain - related modulation of cognitive activity ) .
this interaction pattern within the r pins has been demonstrated previously in healthy controls ( seminowicz & davis , 2007a ) , and suggests that the pins may be an important site of task  pain integrations . while no full interaction [ task ( difficult    easy )  +  pain ]    [ task ( difficult    easy )  +  no pain ] clusters survived in the whole - brain analysis , task - related reduction during pain [ pain ( mild + moderate ) + easy task ] > [ pain ( mild + moderate ) + difficult task ] was observed at the level of the whole - brain analysis across brain regions associated with the sensory , cognitive , and affective components of pain .
examination of task - related reduction in pain - related regions of interest revealed significant reduction in r pins , which is consistent with prior research ( bantick et al .
, 2000 ; peyron et al . , 1999 ; seminowicz & davis , 2007a ; shackman et al . , 2011 ;
2008 ) , and may reflect cognitive modulation of pain . however , pain intensity and unpleasantness ratings were not significantly attenuated by task - difficulty .
activity within a region of the thalamus identified in the pain contrast was increased during the difficult task , demonstrating an opposite pattern than was observed in the r pins and mcc .
the present findings are consistent with prior studies that have found posterior and mid - thalamic activity to be positively associated with pain modulation , displaying increased activation in response to concomitant pain stimulus and cognitive task ( peyron et al . , 1999 ; valet et al . , 2004 ) .
pain - related modulation of cognitive activity was not observed at the level of whole - brain analyses .
this is consistent with a previous study in healthy controls that reported no pain - related modulation of cognitive activity when univariate analyses were used ( seminowicz & davis , 2007a ) .
however , pain was associated with greater task - related activations and decreased task - related deactivations across most cognitive regions of interest , consistent with previous findings ( seminowicz & davis , 2007b ) .
as both pain and cognitive tasks engage cognitive processes ( eccleston & crombez , 1999 ) , it is possible that this increase is due to the increasing attentional demands when both the difficult task and pain are present .
this is supported by evidence that increased cognitive load is often associated with greater task - related deactivation ( mckiernan et al . , 2003 ) .
thus , the current findings generally support previous work on brain activity associated with pain  cognition interactions .
overall , aberrant task - related activity among migraine patients emerged as blunted task - related activations and deactivations . across conditions , patients revealed a blunted task - related response within cognitive regions of interest as well as at the whole brain level of analysis . during task performance in the absence of pain , migraine patients revealed blunted task - related deactivation in the l dlpfc , amcc , and cerebellum compared to controls .
analysis of activity within these clusters across conditions revealed that while controls show greater deactivation in these regions during the no pain condition , patients show no significant difference in activity within these regions across the pain and no pain conditions , suggesting that effects of acute pain on reducing task - related deactivation are absent among patients .
in other words , patients show a pattern of task - related activity within these regions during no pain that is similar to activity in the presence of an external pain stimulus .
these regions , therefore , may be important sites of alteration in cognitive processing in migraine . importantly , taken together with prior research , these results suggest that the dlpfc , in particular , may be an important site of alteration in chronic pain .
prior work also found decreased l dlpfc task - related deactivations among chronic low back patients , relative to healthy controls , in the absence of a pain stimulus ( seminowicz et al . , 2011 ) .
importantly , effective pain treatment was shown to normalize l dlpfc activity , such that deactivations became stronger and more like those seen among healthy controls ( seminowicz et al . , 2011 ) . furthermore , decreased dlpfc cortical thickness has been demonstrated within other pain populations ( apkarian et al . , 2004b ; seminowicz et al . ,
2011 ) , and is also partially reversible with cognitive interventions that reduce pain and pain catastrophizing ( seminowicz et al . , 2013 ) .
the blunted deactivation in l dlpfc task - related activity found here may reflect relatively constant engagement of the dlpfc across conditions  and perhaps chronically  among migraine patients .
dlpfc is involved in pain modulation ( lorenz et al . , 2003 ) , and among chronic pain populations may be chronically upregulated to increase descending modulation of pain ( seminowicz et al . , 2013 )
pcc activity was associated with the full task  pain interaction among controls , whereas deactivations in the dorsal sfg were associated with interactions among patients . to further probe this interaction , we examined whole - brain task - related activations and deactivations during pain , among patients and controls
. patients revealed greater and more widespread task - related deactivations within regions associated with pain processing , but less task - related activations in task - positive regions during pain , compared to controls . taken together , this suggests that cognitive effects may be more related to pain reduction in patients , and task performance in controls , and that the presence of pain appears to be disturbing cognitive processing to a greater extent in patients than it does in healthy controls . among healthy populations , attention to a task is associated with both cognitive task - specific and anti - nociceptive activations ( kucyi et al . , 2013 )
. however , among migraine patients , allocation of cognitive resources to pain suppression may be prioritized over task - specific processes .
disease duration was associated with greater l s1 and l amygdala task - related deactivation , even after controlling for patient age , such that the longer patients have had migraines , the more task - related deactivation is seen in the l s1 and l amygdala .
a plausible interpretation of this result is that patients have higher baseline levels of activity within these regions , resulting in greater task - related decreases , and this baseline activity increases with disease duration .
migraine frequency was associated with blunted deactivation in the l mtg , l amygdala , and l pmtg .
this suggests that increased migraine frequency may be leading to the abnormal task - related deactivations seen among migraine patients , and is consistent with a previous finding that cognitive impairment in migraine was related to migraine frequency ( calandre et al . , 2002 ) .
pain catastrophizing was not significantly associated with task - related activity or pain  task interactions .
the limitations of the current study include not strictly controlling the level of ongoing headache pain during scanning , the small sample size , and the inclusion of four patients with high frequency episodic migraine .
studies with larger samples powered to examine differences between clinical subtypes of migraine , including episodic migraine and chronic migraine , and the potential effects of medication overuse ( grazzi et al . , 2010 ) , will be informative .
future research should also examine the effects of migraine on cognitive networks over time , as symptom severity changes , as well as potential treatment effects on these alterations .
taken together , these findings suggest that migraine patients have blunted cognitive - related neural activity in brain regions associated with cognitive processing and altered patterns of activity related to pain  cognition interactions .
specifically , healthy controls have strong task - related deactivations in the dlpfc , amcc , and cerebellum that are decreased with acute pain , but patients have blunted task - related deactivations that are not modulated by acute pain .
while no behavioral cognitive decrements were observed , blunted neural response may be reflective of broader functional restructuring as has been shown in other chronic pain populations ( baliki et al . , 2008 ; seminowicz et al . ,
these changes may be related to migraine pain frequency , but were not associated with pain catastrophizing or migraine pain intensity in this sample .
furthermore , differential activity underlying pain  cognition interactions suggests that allocation of cognitive resources to pain suppression may be prioritized over task - specific processes in migraine .
 little is known about the effect of migraine on neural cognitive networks . 
 however , cognitive dysfunction is increasingly being recognized as a comorbidity of chronic pain . pain appears to affect cognitive ability and the function of cognitive networks over time , and decrements in cognitive function can exacerbate affective and sensory components of pain . 
 we investigated differences in cognitive processing and pain  cognition interactions between 14 migraine patients and 14 matched healthy controls using an fmri block - design with two levels of task difficulty and concurrent heat ( painful and not painful ) stimuli . across groups , 
 cognitive networks were recruited in response to a difficult cognitive task , and a pain  
 task interaction was found in the right ( contralateral to pain stimulus ) posterior insula ( pins ) , such that activity was modulated by decreasing the thermal pain stimulus or by engaging the difficult cognitive task . 
 migraine patients had less task - related deactivation within the left dorsolateral prefrontal cortex ( dlpfc ) and left dorsal anterior midcingulate cortex ( amcc ) compared to controls . 
 these regions have been reported to have decreased cortical thickness and cognitive - related deactivation within other pain populations , and are also associated with pain regulation , suggesting that the current findings may reflect altered cognitive function and top - down regulation of pain . during pain conditions , 
 patients had decreased task - related activity , but more widespread task - related reductions in pain - related activity , compared to controls , suggesting cognitive resources may be diverted from task - related to pain - reduction - related processes in migraine . 
 overall , these findings suggest that migraine is associated with altered cognitive - related neural activity , which may reflect altered pain regulatory processes as well as broader functional restructuring . 
Introduction
Methods
Results
Discussion