Neurogastroenterology & Molity 2016; 1–5 wileyonlinelibrary.com/journal/nmo | 1 © 2016 John Wiley & Sons Ltd Received: 29 July 2016 | Accepted: 7 November 2016 DOI: 10.1111/nmo.13004 HOT TOPIC Cyclic Voming Syndrome is characterized by altered funconal brain connecvity of the insular cortex: a cross-comparison with migraine and healthy adults D.-M. Ellingsen 1, 2 | R. G. Garcia 1, 3, 4 | J. Lee 1 | R. L. Lin 1 | J. Kim 1, 5 | A. H. Thurler 6 | S. Castel 6 | L. Dimisko 6 | B. R. Rosen 1 | N. Hadjikhani 1 | B. Kuo 6 * | V. Napadow 1 * *Contributed equally to this work. 1 Marnos Center for Biomedical Imaging, Department of Radiology, Massachuses General Hospital, Harvard Medical School, Boston, MA, USA 2 Department of Psychology, University of Oslo, Oslo, Norway 3 Neuroscience Group, School of Medicine, Universidad de Santander (UDES), Bucaramanga, Colombia 4 Connors Center for Women’s Health and Gender Biology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA 5 Korean Instute for Oriental Medicine, Daejeon, Korea 6 Department of Gastroenterology, Massachuses General Hospital, Harvard Medical School, Boston, MA, USA Correspondence Dan-Mikael Ellingsen Marnos Center for Biomedical Imaging Charlestown, MA, USA. Email: [email protected] Funding informaon Naonal Instutes of Health, Grant/Award Number: P01-AT006663, R01-AT007550, R01-AR064367, K23-DK069614 and R21-AR057920; Naonal Center for Research Resources, Grant/Award Number: P41RR14075 and CRC 1 UL1 RR025758; Norwegian Research Council/Marie Sklodowska-Curie Acons, Grant/Award Number: FRICON/COFUND-240553/F20; Marnos Compung, Grant/Award Number: S10RR023401, S10RR019307, S10RR019254 and S10RR023043; Internaonal Foundaon of Funconal Gastrointesnal Disorders. Abstract Cyclic Voming Syndrome (CVS) has been linked to episodic migraine, yet lile is known about the precise brain-based mechanisms underpinning CVS, and whether these associated condions share similar pathophysiology. We invesgated the func- onal integrity of salience (SLN) and sensorimotor (SMN) intrinsic connecvity net- works in CVS, migraine and healthy controls using brain funconal Magnec Resonance Imaging. CVS, relave to both migraine and controls, showed increased SLN connec- vity to middle/posterior insula, a key brain region for nausea and viscerosensory pro- cessing. In contrast, this same region showed diminished SMN connecvity in both CVS and migraine. These results highlight both unique and potenally shared patho- physiology between these condions, and suggest a potenal target for therapeucs in future studies. KEYWORDS brain imaging, CyclicVoming Syndrome, funconal Magnec Resonance, imaging, migraine
Cyclic Vomiting Syndrome is characterized by altered functional brain connectivity of the insular cortex: a cross-comparison with migraine and healthy adults
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Cyclic Vomiting Syndrome is characterized by altered functional brain connectivity of the insular cortex: a crosscomparison with migraine and healthy adultsReceived:29July2016 | Accepted:7November2016 DOI: 10.1111/nmo.13004
H O T T O P I C
Cyclic Vomiting Syndrome is characterized by altered functional brain connectivity of the insular cortex: a cross- comparison with migraine and healthy adults
D.-M. Ellingsen1, 2 | R. G. Garcia1, 3, 4 | J. Lee1 | R. L. Lin1 | J. Kim1, 5 | A. H. Thurler6 | S. Castel6 | L. Dimisko6 | B. R. Rosen1 | N. Hadjikhani1 | B. Kuo6 * | V. Napadow1 *
*Contributedequallytothiswork.
1MartinosCenterforBiomedical Imaging,Departmentof Radiology,MassachusettsGeneral Hospital,HarvardMedicalSchool,Boston, MA,USA 2DepartmentofPsychology,Universityof Oslo,Oslo,Norway 3NeuroscienceGroup,Schoolof Medicine,UniversidaddeSantander(UDES), Bucaramanga,Colombia 4ConnorsCenterforWomen’sHealthand GenderBiology,BrighamandWomen’s Hospital,HarvardMedicalSchool,Boston, MA,USA 5KoreanInstituteforOrientalMedicine, Daejeon, Korea 6DepartmentofGastroenterology, MassachusettsGeneralHospital,Harvard MedicalSchool,Boston,MA,USA
Correspondence Dan-MikaelEllingsen MartinosCenterforBiomedicalImaging Charlestown,MA,USA. Email:[email protected]
Funding information NationalInstitutesofHealth,Grant/Award Number:P01-AT006663,R01-AT007550, R01-AR064367,K23-DK069614and R21-AR057920;NationalCenterfor ResearchResources,Grant/AwardNumber: P41RR14075andCRC1UL1RR025758; NorwegianResearchCouncil/Marie Sklodowska-CurieActions,Grant/Award Number:FRICON/COFUND-240553/F20; MartinosComputing,Grant/AwardNumber: S10RR023401,S10RR019307,S10RR019254 andS10RR023043;InternationalFoundation ofFunctionalGastrointestinalDisorders.
Abstract Cyclic Vomiting Syndrome (CVS) has been linked to episodicmigraine, yet little is knownabout theprecisebrain-basedmechanismsunderpinningCVS, andwhether theseassociatedconditionssharesimilarpathophysiology.Weinvestigatedthefunc- tional integrityofsalience (SLN)andsensorimotor (SMN) intrinsicconnectivitynet- worksinCVS,migraineandhealthycontrolsusingbrainfunctionalMagneticResonance Imaging.CVS,relativetobothmigraineandcontrols,showedincreasedSLNconnec- tivitytomiddle/posteriorinsula,akeybrainregionfornauseaandviscerosensorypro- cessing. Incontrast, thissameregionshoweddiminishedSMNconnectivity inboth CVSandmigraine.Theseresultshighlightbothuniqueandpotentiallysharedpatho- physiologybetweentheseconditions,andsuggestapotentialtargetfortherapeutics infuturestudies.
K E Y W O R D S
brainimaging,CyclicVomitingSyndrome,functionalMagneticResonance,imaging,migraine
1 | INTRODUCTION
CyclicVomitingSyndrome(CVS)hasbeencomparedtoepisodicmi- grainebecauseofsimilarityintheirdynamicprogressionofsymptoms during ictal eventsor “attacks”.1Whilemigraine is characterizedby neuropathic/visceralsymptoms,2CVSsymptomsaremorepurelyvis- ceral and localized to the gut.Ultimately, little is known about the brainmechanismsunderpinningCVSorwhetherthesetwoanecdo- tallylinkeddisordersactuallyshareanysimilarityinpathophysiology.3
CVSisanepisodicdisordercharacterizedbyrecurrentepisodesof nauseaandvomitingwithinterictalsymptom-freeperiods.4Whilesev- eraltheorieshavelinkedthedisordertopredisposingfactorssuchas migraine,psychologicalorinfectiousstress,gastricdysrhythmias,food allergies,andmitochondrialdysfunction,5aberrantneuralphysiology forvisceroceptivebraincircuitrymaysupportacommonpathophys- iologicalpathwayforallthesefactors.Ourpreviousresearch,6using functionalMagneticResonanceImaging(fMRI)haslinkedtheanterior andmiddleinsulacortexwithnauseaperception.Infact,themiddle and/orposterior insula,7whichhasbeen referred to as theprimary viscerosensory cortex,8maybe a key region forviscerosensory and nausea-associated autonomic9 processing in CVS. Functional brain connectivity, a tool that has revealeddisruptions invarious chronic gastroenterological, neurological, and psychiatric disorders,10, 11 has highlightedaltered intrinsic informationflowatthenetwork level in migraine,12andcross-comparisontoCVSpatientsmayhelpdifferen- tiatethesetwolinkeddisordersintermsofneuralpathophysiology.
Theaimofourstudywastoinvestigatethefunctionalintegrityof twobrainnetworks thatencompass insula cortex, i.e. Sensorimotor (SMN)andSalience(SLN)Networks, inCVS.Whileprimary(S1)and secondary(S2)somatosensoryregionsincludedintheSMNplayakey role inbottom-upsomatosensoryprocessing, theSLN is thought to appraisetherelativeimportance(i.e.salience)ofinternalandsensory stimuli,13bothvisceralandsomatic.Moreover,bothofthesenetworks arecentraltopainprocessinginthebrain.14Forinstance,aprevious studyfoundthatevokeddeep-tissuesomaticpain involvedreduced functionalconnectivityofthesomatotopy-targetedS1areatoSMN, butincreasedconnectivitytoSLN.15Wehypothesizedthat(i)CVSis characterizedbyalteredconnectivitybetweenthesebrainnetworks andviscerosensoryprocessingbrainareas,and(ii)similaritiesanddif- ferencesinbrainconnectivitybetweenCVSandmigrainepatientswill highlightboththesharedanduniquepathophysiologyunderlyingCVS.
2 | MATERIALS AND METHODS
We enrolled 13 patients diagnosed with CVS (12 women; age 29.7±12.0,mean±SD),14patientsdiagnosedwithepisodicmigraine (13women;age35.8±13.4),and12healthycontrols(HC,11women, age25.8±3.6).Allparticipantswereright-handed.Written informed consentwasobtainedfromallparticipants,andtheprotocolwasap- proved by theHumanResearchCommittee of PartnersHealthcare andMassachusettsGeneralHospital.
Importantly,CVSpatientswereenrolledpriortosignificantneu- romodulatory pharmacotherapy (e.g. benzodiazepines, anticonvul- sants, andopioids).While this affected enrollment and sample size, maintainingthisstrictcriterionwasimportanttolimitpotentialfalse positivegroupdifferencesrelatedtodrug-inducedalterationsinneu- rovascularcoupling.InclusioncriteriaforCVSwereage18–80,diag- nosis ofCVS byRome III criteria, and English proficiency. Inclusion criterion forHCwas age18–64.Exclusion criteria forCVSandHC werepregnancy(orplannedpregnancy),acute illness,chronic illness suchaskidneyfailure,congestiveheartfailure,diabetes,thoseawait- ingorgantransplantation,useofprescriptionbenzodiazepineswithin theprevious7days,useofprescriptionopioids,useofcannabinoids withintheprevious7days,andanynausea/vomitingepisodewithin 48hours prior to experimental session. CVS patientswere also re- quiredtoavoidalcoholforatleast24hourspriortotesting,andnot to drink coffee (or caffeinated beverages) or smoke in themorning ofthedayoftesting.Inclusioncriteriaforepisodicmigrainepatients wereage18–60,diagnosisofmigrainebasedonclassificationbythe InternationalHeadacheSociety (HeadacheClassificationCommittee of the International Headache Society, 2004), and 2–15 uncompli- catedmigraineepisodespermonth.Exclusioncriteriaincludedother neurological ormajor psychiatric disorders. Similar to CVS andHC, noneoftheenrolledmigrainepatientswereusingprescriptionbenzo- diazepines,opioids,orcannabinoids.
AllCVS(140.5±189.6dayssincepreviousepisode,mean±SD)and migraine (6.1±5.8days since previous episode) patientswere in an interictalstateatthetimeofMRIscanning.AShapiro–Wilktestfor normalitydidnotindicatethatinterictalindexdatawasnon-normally distributedforeitherpatientgroup(CVS:0.94,P=.58;Migraine:0.93, P=.29).
Functional integrity of SLN and SMNwas assessed using in- trinsicnetworkanalysisofrestingstatefMRIdata.Heartrateand respirationweremonitored and used for physiological noise cor- rectionof the fMRIdata.Thedatawere corrected formotionar- tifacts, spatially smoothed (FWHM=5mm), and high-pass filtered
Key Points • CyclicVomitingSyndrome (CVS) andEpisodicMigraine have been suggested to share pathophysiology, but no studieshaveyetcomparedtheseconditions.
• CVS, compared to migraine and healthy controls, dis- playedincreasedconnectivitybetweenthesaliencebrain networkandthemid/posteriorinsula,abrainregionim- portantforviscerosensoryprocessing.BothCVSandmi- grainedisplayeddiminishedinsularconnectivitywiththe sensorimotornetwork.
• We identify both CVS-unique and potentially shared pathophysiology between CVS and episodic migraine, highlightingthemiddle/posteriorinsulaasapotentialtar- getfortherapeuticsinfuturestudies.
| 3ELLINGSEN Et aL.
(f>0.008).AdualregressionIndependentComponentsAnalysiswas performed to identify SLN (Fig. S2) and SMN (Fig. S3) networks, basedoncanonicaltemplatematching.ToinvestigatewhetherSLN connectivitydifferedbetweenCVSandHC,weperformedawhole- brainmixedeffectsanalysis(FSL-FLAME1+2,clustercorrectedfor multiple comparisons at FWE corrected P<.05), followed up by crossgroupregion-of-interest (ROI)analyses (seeDataS1forad- ditionaldetails).
3 | RESULTS
Thewhole-brainanalysisrevealedthat,comparedtoHC,CVSdem- onstratedincreasedSLNconnectivitytoaclusterencompassingpos- terior/middle insula(p/mINS),secondarysomatosensorycortex,and superior temporal sulcus (Fig.1A). A follow-up ROI analysis of this clusterevaluatedconnectivityrelativetomigraine,andfoundasignifi- cantAnalysisofVariance(ANOVA)groupeffectforSLNconnectivity (F(2,36)=12.7,P<.001),withadirectcontrastshowingincreasedSLN connectivityforCVScomparedtomigraine(95%confidenceinterval (CI)0.55–1.18,P=.012)(Fig.1B).Next,anROIanalysiswasperformed toevaluateifthisregion(p/mINS)alsoshowedalteredSMNconnec- tivity.TherewasagainasignificantANOVAgroupeffect(F(2,36)=5.3, P=.01),withgroup-wisecontrastsdisplayingreducedSMNconnectiv- itytothisp/mINSclusterforCVSrelativetoHC(CI−0.94to−0.191, P=.004),butnotmigraine(CI−0.46to0.26,P=.57)(Fig.1C).Infact, similartoCVS,migraineshowedreducedSMNconnectivityrelative toHC(CI−0.83to−0.097,P=.015).
Interestingly, fiveCVSpatients reportedmigrainediagnoses, re- flecting the noted comorbidity of these disorders.1 To investigate whether such comorbidity influenced the results, we performed
theaboveROIanalysescontrolling formigrainediagnosis. Including thisconfound regressor in themodeldidnot influenceANOVAsig- nificance (SLN:F(3,35)=8.28,P=.001;SMN:F(3,35)=3.46,P=.027). Similarly,as8ofthemigrainepatientsalsoreportedsomerecurring nauseaduringepisodes,weperformedtheaboveROIanalysescon- trollingfornauseareport. Includingthisconfoundregressoralsodid notinfluenceANOVAsignificance(SLN:F(3,35)=8.52,P<.001;SMN: F(3,35)=3.44,P=.027)(seeDataS1methodsformoredetail).These findings strengthen the conclusion that increased SLN connectivity with p/mINS is unique toCVS,while reducedSMNconnectivity to this region may characterize pathophysiology underlying both CVS and migraine.
4 | DISCUSSION
Theresults fromthisstudyelucidatealterations inbrainphysiology thatmayunderpinCVS,andidentifiesfeaturesthataredifferentfrom, andsharedwith,episodicmigraine.WhileCVSwascharacterizedby increased connectivity between a salience processing network and p/mINS, this viscerosensory region demonstrated diminished con- nectivity to a somatosensory processing network. Previous studies of episodic migraine have shown disruption of somatosensory and viscerosensorycortexmorphometry16,17andintrinsicconnectivity,16,
18anddisruptedposteriorinsularhabituationresponsestorepeated sensorystimuli.19Furthermore,a recentmeta-analysisof functional neuroimagingstudiesofIrritableBowelSyndrome(IBS)foundm/pINS tobeconsistentlyhyper-activatedinresponsetovisceralstimulation using rectal distension in IBS patients.20 Other idiopathic chronic disorders such as fibromyalgia have also been characterized by al- teredintrinsicsomatosensoryconnectivity,21suggestingthatchronic
F IGURE 1 Alteredfunctionalconnectivityofmiddle/posteriorinsula(m/pINS)withsalience(SLN)andsomatosensory(SMN)processing brainnetworksinCyclicVomitingSyndrome(CVS),episodicmigraine(MIG),andhealthycontrols(HC).(A)Awhole-brainvoxelwiseanalysis foundthatCVS,relativetoHC,showedincreasedrestingSLNfunctionalconnectivitytom/pINS.(B)Afollow-upregionofinterest(ROI)analysis foundthatCVSalsoshowedincreasedm/pINSconnectivitywithSLNcomparedtointerictalMIG.(C)AROIanalysisalsoindicatedsimilarity betweenCVSandMIG,inthatbothshoweddiminishedm/pINSconnectivitytoSMN,relativetoHC.Errorbarsrepresentstandarderrorsofthe mean. *P<.05; **P<.01
4 | ELLINGSEN Et aL.
suffering from somato-visceral symptomatology can alter intrinsic brainphysiology.
InCVS,butnotmigrainepatients,reductionsinm/pINSconnec- tivity to SMN was accompanied by increased m/pINS connectivity toSLN, compared tohealthy individuals.Thismay signify increased vigilanceofviscerosensorysignalsinCVSpatients,whichbearssimi- laritywiththerecentfindingthatsustaineddeep-tissuepainstimula- tionischaracterizedbyaSMN-to-SLNshiftinconnectivityinhealthy individuals.15
The mid/posterior insula has also been proposed as a primary viscerosensory-processing region, supported by neuroimaging stud- ies of experimentally induced nausea,6, 9 and the observation that direct electrocortical stimulation of central and posterior portions of the insulaelicitsvisceroceptivesensationssuchasnausea, stom- ach“buzzing”,etc.7.Thus,thisbrainregionmaybeapotentialtarget fortherapeutics.For instance,pregabalinhasbeenshowntomodu- lateposterior insularglutamate levelsandfunctionalconnectivity in chronicpainpatients.22
Severallimitationsshouldbenoted.Firstly,ascross-sectionalfMRI studieslimitinferencesaboutcausality,futurestudiesshouldaddress thedegreetowhichdisruptedm/pINSconnectivityisaconsequence oracauseofthesedisorders.Secondly,asallpatientswereinterictal at thetimeof testing, the resultscannot informusofbrainmecha- nisms involved during CVS attacks. However, fMRI during ongoing CVSepisodeswouldbepractically andethically challenging, due to patient discomfort and the risk ofvomitingwhile scanning in a su- pineposition.Itisneverthelessstrikingthatconsistentdisruptionsof theSLNandSMNnetworkscanbeobservedevenbetweenepisodes, consistentwithfindingsof altered intrinsic connectivity in interictal episodicmigraine.18Althoughwedidnotfindevidenceforlimbic(e.g. amygdala,hypothalamus)orbrainstemcircuitryashavingdifferential connectivitytoSLNorSMN, it ispossiblethat limbic/brainstemcir- cuitrymaybemoreinvolvedduringactualepisodesratherthanduring aninterictalstate.
In sum,whileCVShasbeen linked to episodicmigraine, little is knownabouttheprecisebrain-basedmechanismsunderpinningCVS, and whether these associated conditions share similar pathophysi- ology. Inourstudy,adirectcomparisonbetweenCVSandmigraine identifiedbothsimilaritiesanddifferencesinfunctionalnetworkinteg- rity,indicatingthatwhiledisruptionofsomatosensoryprocessing(i.e. SMNconnectivity)inthemid/posteriorinsulaissharedbetweenCVS andmigraine,increasedSLNconnectivitytothisviscerosensoryregion maybeuniquetoCVS,proposingatargetforfuturetherapeutics.
DISCLOSURES
AUTHOR CONTRIBUTIONS
VN,BKstudyconceptanddesign;RGG,JL,RLL,JK,AHT,SC,LDac- quisitionofdata;DME,VN,BKanalysis and interpretationofdata;
DME,VNdraftingofthemanuscript;DME,RGG,JL,NH,BK,VNcriti- calrevisionofthemanuscriptforimportantintellectualcontent;DME, VNstatisticalanalysis;BK,VNobtainedfunding;BK,VNtechnical,or materialsupport;BK,VNstudysupervision.
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SUPPORTING INFORMATION
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H O T T O P I C
Cyclic Vomiting Syndrome is characterized by altered functional brain connectivity of the insular cortex: a cross- comparison with migraine and healthy adults
D.-M. Ellingsen1, 2 | R. G. Garcia1, 3, 4 | J. Lee1 | R. L. Lin1 | J. Kim1, 5 | A. H. Thurler6 | S. Castel6 | L. Dimisko6 | B. R. Rosen1 | N. Hadjikhani1 | B. Kuo6 * | V. Napadow1 *
*Contributedequallytothiswork.
1MartinosCenterforBiomedical Imaging,Departmentof Radiology,MassachusettsGeneral Hospital,HarvardMedicalSchool,Boston, MA,USA 2DepartmentofPsychology,Universityof Oslo,Oslo,Norway 3NeuroscienceGroup,Schoolof Medicine,UniversidaddeSantander(UDES), Bucaramanga,Colombia 4ConnorsCenterforWomen’sHealthand GenderBiology,BrighamandWomen’s Hospital,HarvardMedicalSchool,Boston, MA,USA 5KoreanInstituteforOrientalMedicine, Daejeon, Korea 6DepartmentofGastroenterology, MassachusettsGeneralHospital,Harvard MedicalSchool,Boston,MA,USA
Correspondence Dan-MikaelEllingsen MartinosCenterforBiomedicalImaging Charlestown,MA,USA. Email:[email protected]
Funding information NationalInstitutesofHealth,Grant/Award Number:P01-AT006663,R01-AT007550, R01-AR064367,K23-DK069614and R21-AR057920;NationalCenterfor ResearchResources,Grant/AwardNumber: P41RR14075andCRC1UL1RR025758; NorwegianResearchCouncil/Marie Sklodowska-CurieActions,Grant/Award Number:FRICON/COFUND-240553/F20; MartinosComputing,Grant/AwardNumber: S10RR023401,S10RR019307,S10RR019254 andS10RR023043;InternationalFoundation ofFunctionalGastrointestinalDisorders.
Abstract Cyclic Vomiting Syndrome (CVS) has been linked to episodicmigraine, yet little is knownabout theprecisebrain-basedmechanismsunderpinningCVS, andwhether theseassociatedconditionssharesimilarpathophysiology.Weinvestigatedthefunc- tional integrityofsalience (SLN)andsensorimotor (SMN) intrinsicconnectivitynet- worksinCVS,migraineandhealthycontrolsusingbrainfunctionalMagneticResonance Imaging.CVS,relativetobothmigraineandcontrols,showedincreasedSLNconnec- tivitytomiddle/posteriorinsula,akeybrainregionfornauseaandviscerosensorypro- cessing. Incontrast, thissameregionshoweddiminishedSMNconnectivity inboth CVSandmigraine.Theseresultshighlightbothuniqueandpotentiallysharedpatho- physiologybetweentheseconditions,andsuggestapotentialtargetfortherapeutics infuturestudies.
K E Y W O R D S
brainimaging,CyclicVomitingSyndrome,functionalMagneticResonance,imaging,migraine
1 | INTRODUCTION
CyclicVomitingSyndrome(CVS)hasbeencomparedtoepisodicmi- grainebecauseofsimilarityintheirdynamicprogressionofsymptoms during ictal eventsor “attacks”.1Whilemigraine is characterizedby neuropathic/visceralsymptoms,2CVSsymptomsaremorepurelyvis- ceral and localized to the gut.Ultimately, little is known about the brainmechanismsunderpinningCVSorwhetherthesetwoanecdo- tallylinkeddisordersactuallyshareanysimilarityinpathophysiology.3
CVSisanepisodicdisordercharacterizedbyrecurrentepisodesof nauseaandvomitingwithinterictalsymptom-freeperiods.4Whilesev- eraltheorieshavelinkedthedisordertopredisposingfactorssuchas migraine,psychologicalorinfectiousstress,gastricdysrhythmias,food allergies,andmitochondrialdysfunction,5aberrantneuralphysiology forvisceroceptivebraincircuitrymaysupportacommonpathophys- iologicalpathwayforallthesefactors.Ourpreviousresearch,6using functionalMagneticResonanceImaging(fMRI)haslinkedtheanterior andmiddleinsulacortexwithnauseaperception.Infact,themiddle and/orposterior insula,7whichhasbeen referred to as theprimary viscerosensory cortex,8maybe a key region forviscerosensory and nausea-associated autonomic9 processing in CVS. Functional brain connectivity, a tool that has revealeddisruptions invarious chronic gastroenterological, neurological, and psychiatric disorders,10, 11 has highlightedaltered intrinsic informationflowatthenetwork level in migraine,12andcross-comparisontoCVSpatientsmayhelpdifferen- tiatethesetwolinkeddisordersintermsofneuralpathophysiology.
Theaimofourstudywastoinvestigatethefunctionalintegrityof twobrainnetworks thatencompass insula cortex, i.e. Sensorimotor (SMN)andSalience(SLN)Networks, inCVS.Whileprimary(S1)and secondary(S2)somatosensoryregionsincludedintheSMNplayakey role inbottom-upsomatosensoryprocessing, theSLN is thought to appraisetherelativeimportance(i.e.salience)ofinternalandsensory stimuli,13bothvisceralandsomatic.Moreover,bothofthesenetworks arecentraltopainprocessinginthebrain.14Forinstance,aprevious studyfoundthatevokeddeep-tissuesomaticpain involvedreduced functionalconnectivityofthesomatotopy-targetedS1areatoSMN, butincreasedconnectivitytoSLN.15Wehypothesizedthat(i)CVSis characterizedbyalteredconnectivitybetweenthesebrainnetworks andviscerosensoryprocessingbrainareas,and(ii)similaritiesanddif- ferencesinbrainconnectivitybetweenCVSandmigrainepatientswill highlightboththesharedanduniquepathophysiologyunderlyingCVS.
2 | MATERIALS AND METHODS
We enrolled 13 patients diagnosed with CVS (12 women; age 29.7±12.0,mean±SD),14patientsdiagnosedwithepisodicmigraine (13women;age35.8±13.4),and12healthycontrols(HC,11women, age25.8±3.6).Allparticipantswereright-handed.Written informed consentwasobtainedfromallparticipants,andtheprotocolwasap- proved by theHumanResearchCommittee of PartnersHealthcare andMassachusettsGeneralHospital.
Importantly,CVSpatientswereenrolledpriortosignificantneu- romodulatory pharmacotherapy (e.g. benzodiazepines, anticonvul- sants, andopioids).While this affected enrollment and sample size, maintainingthisstrictcriterionwasimportanttolimitpotentialfalse positivegroupdifferencesrelatedtodrug-inducedalterationsinneu- rovascularcoupling.InclusioncriteriaforCVSwereage18–80,diag- nosis ofCVS byRome III criteria, and English proficiency. Inclusion criterion forHCwas age18–64.Exclusion criteria forCVSandHC werepregnancy(orplannedpregnancy),acute illness,chronic illness suchaskidneyfailure,congestiveheartfailure,diabetes,thoseawait- ingorgantransplantation,useofprescriptionbenzodiazepineswithin theprevious7days,useofprescriptionopioids,useofcannabinoids withintheprevious7days,andanynausea/vomitingepisodewithin 48hours prior to experimental session. CVS patientswere also re- quiredtoavoidalcoholforatleast24hourspriortotesting,andnot to drink coffee (or caffeinated beverages) or smoke in themorning ofthedayoftesting.Inclusioncriteriaforepisodicmigrainepatients wereage18–60,diagnosisofmigrainebasedonclassificationbythe InternationalHeadacheSociety (HeadacheClassificationCommittee of the International Headache Society, 2004), and 2–15 uncompli- catedmigraineepisodespermonth.Exclusioncriteriaincludedother neurological ormajor psychiatric disorders. Similar to CVS andHC, noneoftheenrolledmigrainepatientswereusingprescriptionbenzo- diazepines,opioids,orcannabinoids.
AllCVS(140.5±189.6dayssincepreviousepisode,mean±SD)and migraine (6.1±5.8days since previous episode) patientswere in an interictalstateatthetimeofMRIscanning.AShapiro–Wilktestfor normalitydidnotindicatethatinterictalindexdatawasnon-normally distributedforeitherpatientgroup(CVS:0.94,P=.58;Migraine:0.93, P=.29).
Functional integrity of SLN and SMNwas assessed using in- trinsicnetworkanalysisofrestingstatefMRIdata.Heartrateand respirationweremonitored and used for physiological noise cor- rectionof the fMRIdata.Thedatawere corrected formotionar- tifacts, spatially smoothed (FWHM=5mm), and high-pass filtered
Key Points • CyclicVomitingSyndrome (CVS) andEpisodicMigraine have been suggested to share pathophysiology, but no studieshaveyetcomparedtheseconditions.
• CVS, compared to migraine and healthy controls, dis- playedincreasedconnectivitybetweenthesaliencebrain networkandthemid/posteriorinsula,abrainregionim- portantforviscerosensoryprocessing.BothCVSandmi- grainedisplayeddiminishedinsularconnectivitywiththe sensorimotornetwork.
• We identify both CVS-unique and potentially shared pathophysiology between CVS and episodic migraine, highlightingthemiddle/posteriorinsulaasapotentialtar- getfortherapeuticsinfuturestudies.
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(f>0.008).AdualregressionIndependentComponentsAnalysiswas performed to identify SLN (Fig. S2) and SMN (Fig. S3) networks, basedoncanonicaltemplatematching.ToinvestigatewhetherSLN connectivitydifferedbetweenCVSandHC,weperformedawhole- brainmixedeffectsanalysis(FSL-FLAME1+2,clustercorrectedfor multiple comparisons at FWE corrected P<.05), followed up by crossgroupregion-of-interest (ROI)analyses (seeDataS1forad- ditionaldetails).
3 | RESULTS
Thewhole-brainanalysisrevealedthat,comparedtoHC,CVSdem- onstratedincreasedSLNconnectivitytoaclusterencompassingpos- terior/middle insula(p/mINS),secondarysomatosensorycortex,and superior temporal sulcus (Fig.1A). A follow-up ROI analysis of this clusterevaluatedconnectivityrelativetomigraine,andfoundasignifi- cantAnalysisofVariance(ANOVA)groupeffectforSLNconnectivity (F(2,36)=12.7,P<.001),withadirectcontrastshowingincreasedSLN connectivityforCVScomparedtomigraine(95%confidenceinterval (CI)0.55–1.18,P=.012)(Fig.1B).Next,anROIanalysiswasperformed toevaluateifthisregion(p/mINS)alsoshowedalteredSMNconnec- tivity.TherewasagainasignificantANOVAgroupeffect(F(2,36)=5.3, P=.01),withgroup-wisecontrastsdisplayingreducedSMNconnectiv- itytothisp/mINSclusterforCVSrelativetoHC(CI−0.94to−0.191, P=.004),butnotmigraine(CI−0.46to0.26,P=.57)(Fig.1C).Infact, similartoCVS,migraineshowedreducedSMNconnectivityrelative toHC(CI−0.83to−0.097,P=.015).
Interestingly, fiveCVSpatients reportedmigrainediagnoses, re- flecting the noted comorbidity of these disorders.1 To investigate whether such comorbidity influenced the results, we performed
theaboveROIanalysescontrolling formigrainediagnosis. Including thisconfound regressor in themodeldidnot influenceANOVAsig- nificance (SLN:F(3,35)=8.28,P=.001;SMN:F(3,35)=3.46,P=.027). Similarly,as8ofthemigrainepatientsalsoreportedsomerecurring nauseaduringepisodes,weperformedtheaboveROIanalysescon- trollingfornauseareport. Includingthisconfoundregressoralsodid notinfluenceANOVAsignificance(SLN:F(3,35)=8.52,P<.001;SMN: F(3,35)=3.44,P=.027)(seeDataS1methodsformoredetail).These findings strengthen the conclusion that increased SLN connectivity with p/mINS is unique toCVS,while reducedSMNconnectivity to this region may characterize pathophysiology underlying both CVS and migraine.
4 | DISCUSSION
Theresults fromthisstudyelucidatealterations inbrainphysiology thatmayunderpinCVS,andidentifiesfeaturesthataredifferentfrom, andsharedwith,episodicmigraine.WhileCVSwascharacterizedby increased connectivity between a salience processing network and p/mINS, this viscerosensory region demonstrated diminished con- nectivity to a somatosensory processing network. Previous studies of episodic migraine have shown disruption of somatosensory and viscerosensorycortexmorphometry16,17andintrinsicconnectivity,16,
18anddisruptedposteriorinsularhabituationresponsestorepeated sensorystimuli.19Furthermore,a recentmeta-analysisof functional neuroimagingstudiesofIrritableBowelSyndrome(IBS)foundm/pINS tobeconsistentlyhyper-activatedinresponsetovisceralstimulation using rectal distension in IBS patients.20 Other idiopathic chronic disorders such as fibromyalgia have also been characterized by al- teredintrinsicsomatosensoryconnectivity,21suggestingthatchronic
F IGURE 1 Alteredfunctionalconnectivityofmiddle/posteriorinsula(m/pINS)withsalience(SLN)andsomatosensory(SMN)processing brainnetworksinCyclicVomitingSyndrome(CVS),episodicmigraine(MIG),andhealthycontrols(HC).(A)Awhole-brainvoxelwiseanalysis foundthatCVS,relativetoHC,showedincreasedrestingSLNfunctionalconnectivitytom/pINS.(B)Afollow-upregionofinterest(ROI)analysis foundthatCVSalsoshowedincreasedm/pINSconnectivitywithSLNcomparedtointerictalMIG.(C)AROIanalysisalsoindicatedsimilarity betweenCVSandMIG,inthatbothshoweddiminishedm/pINSconnectivitytoSMN,relativetoHC.Errorbarsrepresentstandarderrorsofthe mean. *P<.05; **P<.01
4 | ELLINGSEN Et aL.
suffering from somato-visceral symptomatology can alter intrinsic brainphysiology.
InCVS,butnotmigrainepatients,reductionsinm/pINSconnec- tivity to SMN was accompanied by increased m/pINS connectivity toSLN, compared tohealthy individuals.Thismay signify increased vigilanceofviscerosensorysignalsinCVSpatients,whichbearssimi- laritywiththerecentfindingthatsustaineddeep-tissuepainstimula- tionischaracterizedbyaSMN-to-SLNshiftinconnectivityinhealthy individuals.15
The mid/posterior insula has also been proposed as a primary viscerosensory-processing region, supported by neuroimaging stud- ies of experimentally induced nausea,6, 9 and the observation that direct electrocortical stimulation of central and posterior portions of the insulaelicitsvisceroceptivesensationssuchasnausea, stom- ach“buzzing”,etc.7.Thus,thisbrainregionmaybeapotentialtarget fortherapeutics.For instance,pregabalinhasbeenshowntomodu- lateposterior insularglutamate levelsandfunctionalconnectivity in chronicpainpatients.22
Severallimitationsshouldbenoted.Firstly,ascross-sectionalfMRI studieslimitinferencesaboutcausality,futurestudiesshouldaddress thedegreetowhichdisruptedm/pINSconnectivityisaconsequence oracauseofthesedisorders.Secondly,asallpatientswereinterictal at thetimeof testing, the resultscannot informusofbrainmecha- nisms involved during CVS attacks. However, fMRI during ongoing CVSepisodeswouldbepractically andethically challenging, due to patient discomfort and the risk ofvomitingwhile scanning in a su- pineposition.Itisneverthelessstrikingthatconsistentdisruptionsof theSLNandSMNnetworkscanbeobservedevenbetweenepisodes, consistentwithfindingsof altered intrinsic connectivity in interictal episodicmigraine.18Althoughwedidnotfindevidenceforlimbic(e.g. amygdala,hypothalamus)orbrainstemcircuitryashavingdifferential connectivitytoSLNorSMN, it ispossiblethat limbic/brainstemcir- cuitrymaybemoreinvolvedduringactualepisodesratherthanduring aninterictalstate.
In sum,whileCVShasbeen linked to episodicmigraine, little is knownabouttheprecisebrain-basedmechanismsunderpinningCVS, and whether these associated conditions share similar pathophysi- ology. Inourstudy,adirectcomparisonbetweenCVSandmigraine identifiedbothsimilaritiesanddifferencesinfunctionalnetworkinteg- rity,indicatingthatwhiledisruptionofsomatosensoryprocessing(i.e. SMNconnectivity)inthemid/posteriorinsulaissharedbetweenCVS andmigraine,increasedSLNconnectivitytothisviscerosensoryregion maybeuniquetoCVS,proposingatargetforfuturetherapeutics.
DISCLOSURES
AUTHOR CONTRIBUTIONS
VN,BKstudyconceptanddesign;RGG,JL,RLL,JK,AHT,SC,LDac- quisitionofdata;DME,VN,BKanalysis and interpretationofdata;
DME,VNdraftingofthemanuscript;DME,RGG,JL,NH,BK,VNcriti- calrevisionofthemanuscriptforimportantintellectualcontent;DME, VNstatisticalanalysis;BK,VNobtainedfunding;BK,VNtechnical,or materialsupport;BK,VNstudysupervision.
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