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BritishJournalofAnaesthesia111(1):64–72(2013) doi:10.1093/bja/aet174 Imaging pain: a potent means for investigating pain mechanisms in patients M.C.Lee*andI.Tracey NuffieldDivisionofAnaestheticsandCentreforFunctionalMRIoftheBrain(FMRIB), UniversityofOxford,Oxford,UK *Correspondingauthor.E-mail:[email protected] Summary. Chronic pain is a state of physical suffering Editor’skeypoints strongly associated with feelings of anxiety, depression and † Neuroimagingcanimproveourunderstandingofpain despair. Disease pathophysiology, psychological state, and mechanisms,analgesicactionandtheplaceboeffect. social milieu can influence chronic pain, but can be difficult to diagnose based solely on clinical presentation. Here, we † Newmodellingapproachescanexplorethedynamicprocesses review brain neuroimaging research that is shaping our influencingpainperception. understanding of pain mechanisms, and consider how such † Neuralmechanismsoftheeffectsofpersonalityandexpectancy knowledge might lead to useful diagnostic tools for the onpainperceptionandanalgesiahavebeenexplored. management of persistent pain in individual patients. † Futuredevelopmentswillcontinuetoexpandourknowledgeof Keywords: chronic pain; neuroimaging, magnetic resonance painmechanisms,allowingtranslationfromlaboratorytoclinic. imaging, functional Pain is an unpleasant sensation that is associated with, or much later (two decades ago) with the demonstration of described in terms of, a bodily injury.1 Clinicians have long increased and localized brain activation during pain in regarded pain as a symptom or warning of disease that humans.4Wenowacceptthatpainmaybecausedbybodily shouldbeinvestigatedtoexpeditetreatmentofpathology.Un- injury,butasaconsciousness,mustbegeneratedinthebrain. fortunately, medicine does not yet possess every cure, or Functional magnetic resonance imaging (fMRI), positron indeedknowledgeofeverypathophysiologythatcangenerate emissiontomography(PET),magnetoencephalography(MEG), pain. Pain can persist despite the best efforts of physicians. and scalp electroencephalography (EEG) are commonly used Chronic pain is currently defined by the duration of physical tostudytheneuralbasesofpain.Researchersarealsoincreas- symptomsbutis,inreality,sufferingstronglyassociatedwith ingly using other magnetic resonance-based measures (e.g. feelingsofanxiety,depression,anddespair.2 diffusion tensor imaging, spectroscopy, and volumetric In the individual, chronic pain is highly influenced by imaging)toassesspain-relatedchangesinthebrain’swiring, disease pathophysiology, psychological state, and social chemistry,andstructureinordertogainfurtherinsightsinto milieu.Thepathogenesisofchronicpainsyndromesisoften theneurobiologyofpain,particularlychronicpain.Thereareex- unclear.Researchcontinuestosuggestspecificpathophy- cellentreviewswritten recentlytosummarize the findings of siologies that may distinguish between different chronic neuroimagingstudiesinhealthyindividualsandinpatients.56 painsyndromes,forexample,fibromyalgia,complexregional Here, we focus on recent neuroimaging studiesthat continue painsyndrome.Whethertheseclinicalsyndromescanbedis- to shape our understanding of pain in health, disease, and tinguishedasdiseasesintheirownrightwithspecifictreat- illness.Wereviewtheprogressinneuroimagingresearchthat ments, orconsidered as acollection of symptoms that are is contributing to the development of clinically relevant tools drivenbysharedmechanisms,remainsunclear.Regardless, forthemanagementofpaininpatients. psychosocialfactorscansupervenetoinfluencehowpainis perceived or reported by patients, and these factors can Thepain‘neuromatrix’ operate unconsciously. Their contribution to the chronic pain state further determines appropriate and holistic Neuroimaging studies have now identified several cortical management of the patient. Hence, there is a desperate regions in humans that are considered to be important for needforadditionalmethodsthatcanquantifydiseaseload theperceptionofpain.Theprimaryandsecondarysomatosen- or psychosocial contributions to the chronic pain state in sorycortices(insularandanteriorcingulate)andtheprefrontal patients. cortices (PFCs) are commonly activated, often bilaterally, and InthefifthcenturyBC,Hippocratesdeclaredthatpain,like duringpainfulexperiences.Furthermore,alteredactivityinsub- all consciousness, must emerge from brain activity.3 Robust corticalareas(e.g.brainstemperiaqueductalgrey(PAG),hypo- scientific evidence for that philosophical intuition arrived thalamus, amygdala, hippocampus, and cerebellum) is also & TheAuthor[2013].PublishedbyOxfordUniversityPressonbehalfoftheBritishJournalofAnaesthesia. ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionNon-CommercialLicense (http://creativecommons.org/licenses/by-nc/3.0/),whichpermitsnon-commercialre-use,distribution,andreproductioninanymedium, providedtheoriginalworkisproperlycited.Forcommercialre-use,[email protected] BJA Imagingpain observedduringpain.Thus,activitywithinseveraldiverseregions understoodcomparedwithcentralneuronesontowhichthey ofthebrainseemtobenecessaryforthemultidimensionalex- projecttotransmitinformationtothebrain.26 perience that is pain.7–9 Some of these regions comprise the Investigatorshaveattemptedtotracetheflowofnocicep- so-called‘painneuromatrix’,10atermthatisoftenmisused,in tive information by examining the temporal sequence of whichmultipleinputsareprocessedtoproduceanoutput(neuro- brainactivationsevokedbynoxiousstimulation.Inhumans, signature)thatisbespokeforanindividualdependingoncontext, theearliestintra-corticalelectricalpotentialsthatareevoked moodandcognitivestate.8Hence,painistheproductofawidely bynoxiouslaserstimuliappliedtothehandoccursimultan- distributedandvariablyaccessibleneuralnetworkinthebrain, eously within theposterior insularregion and mid-cingulate ratherthananinevitableconsequenceofnoxiousstimulation. cortex.27 28 These regions receive nociceptive input via Current research suggests that parts of this network can be spino-thalamocortical pathways and are thought to provide accessedbynon-nociceptiveeventsorinputstoproduce‘pain- a primary interoceptive representation of the physiological like’experiences(e.g.duringempathyforothers,11romanticre- condition of the body.29 Activation of the posterior insula jection,12 and social exclusion).13 Hypnotically induced pain in duringnociceptioninhumanshasbeenshowntobesomatopi- susceptible individuals14 and central post-stroke pain are callyorganized.30 The importance of the posterior insulafor furtherexamplesthatillustratethelatentcapacityofthebrain nociceptive pain is further suggested by functional imaging toelicitpainwithoutconcomitantperipheralnociceptiveinputs. studies of pain empathy,11 hypnotically induced pain,14 and Remarkably, none of the brain regions identified above is recalledpainexperiences.3132Neuralactivationsduringsuch uniquelyassociated with pain; theyare also involved in many pains may be similar to that of physically induced pain but othersensory,motor,cognitive,andemotionalfunctions.Some there is often attenuation of activation within the posterior regions within the so-called pain neuromatrix exhibit signifi- insulawhenpainisreportedintheabsenceofnociceptivestimu- cantlycorrelatedactivitywithsensoryoremotionaldescriptions lation.14Researchersfromindependentgroupshaveshownthat ofthepainfulexperience,suggestingthattheyhaveasignifi- directelectricalstimulationoftheposteriorinsularregioncan cant role in pain generation but no brain region has been leadtopainfulsensationsbeingreported.3334Thesamedoes showntobeexclusivelyactivatedduringpainexperiences.15– notappeartobetrueofothercorticalregionsthatarealsocon- 18Disruptionofthespecificregionswithinthispainmatrixby sidered part of the pain neuromatrix.23 34 Additionally, the corticallesionsveryrarelyremoveor‘numb’paincompletely.19 insularcortexhasbeenidentifiedasthemostconsistentlyacti- 20Surgicalcingulotomies,performedforintractablepainsyn- vatedregionduringpainthatisinducedbynociceptivestimuli.9 dromes,mayreduceemotionalormotivationalaspectsofthe Theseconvergingdatasuggestthattheposteriorinsularregion clinicalpainstatebutleavesintactthecapacityfornociceptive mightrepresentacriticalneuralnodethroughwhichnocicep- pain.21Infact,priorfailuretoassociatecorticalactivityorcor- tive information must be processed. Hence, a ‘nociceptive tical lesions to the experience of pain had encouraged the cortex’ within the operculo-insula region may be postulated, view that pain had little true cortical representation.22 23 akintoothermajorsenses. These observations suggest that there is no critical or fixed brainregionforpain. Braindynamics Despite extensive research, an area of the brain that is analogous to the primary visual cortex (i.e. ‘primary pain As discussed above, the experience of pain requires activity cortex’) has not been identified. Todate, there is no pattern within various regions of the brain. Nevertheless, how pain ofbrainactivityindicatingpaininanindividualwithabsolute arises from the flow of information between these different certaintyforusebymedical,legal,orotherregulatorybodies. brainregionsislargelyunknown,asinvestigatingthisphenom- Forexample,‘pain-related’brainactivityfromnoxiousstimula- enonrequiresamultimodalapproach,ofwhichfewpublished tioncanoccurinpatientsinminimallyconsciousstates24but studiesexist.35MoststudiesinvolveEEGorMEGalone,which such activations do not necessarily prove pain perception in recordbrainactivitywithhightemporalresolutionbutrelative- theseindividuals.Nonetheless,theysuggestthattheneuro- lypoorspatialresolutionwhencomparedwithfMRI.Ahuman anatomical substrates for pain are functionally intact and scalpEEGstudyofcorticalpotentialsevokedbyhighlynoxious raisethepossibilityofpainintheseuncommunicativesubjects stimulihasrevealedthatlate,ratherthanearly,laser-evoked withobviousclinicalimplications. responsesareassociatedwithconsciousdetectionofnoxious stimuli.36 Hence, the consciousness of pain appears to emergeatlaterstagesofsuchprocessingwhenneuralinfor- Imagingnociception mationisbeingintegratedacrossmultiplecorticalregions. Nociception is defined as the ‘neural process of encoding Theprocessesbywhichthebrainprioritizesnociceptivein- noxious stimuli’. Although nociception is neither necessary formationovercompetingsensorystimuliforconsciousaware- norsufficientforpain,itisrequiredforprotectiveautonomic ness should also be examined.37 This may explain how the orreflexiveresponsesthatareessentialforoursurvival.Noci- perceptionofpainarisesfromnociceptiveinput.Synchronous ceptorsareperipheralsensoryneuroneswhichareevolvedto neuronal oscillations at gamma-band frequency (.40 Hz) respond specifically to high-intensity environmental stimuli are known to occur when the relevant sensory stimulus is that threaten the physical integrity of the organism.25 The selected for neural representation and perception.38 Using neurobiologyofthese first-orderafferents isarguably better MEG, Gross andcolleagues39 demonstrated that painfullaser 65 BJA LeeandTracey stimuliwereassociatedwithstrongergamma-bandoscillations descending control from supraspinal regions. This powerful (GBO)thanunperceivedstimuliofequalstimulusintensity,sug- modulatoryinput,emanatingfromthefrontal-limbicregions, gestingthattheperceptionofpainemergeswhennociceptive is integrated within the rostral ventromedial medulla (RVM) input is prioritized in the brain. A more recent EEG study andPAG;activitywithintheseregionsinthebrainstemdeter- furtherrevealedthat,unlikeevokedpotentials,GBOisnotsup- mineswhetherthenociceptiveinformationisprioritized.60De- pressed with repetitive noxious (laser) stimulation.40 In that pendingwhatthesituationdemands,thesebrainstemregions study, healthysubjectsperceivedand reported that repeated co-ordinatetheinhibitionorfacilitationofnociception.Classic- stimuliwerejustaspainfulastheoriginalstimulus.However, al ‘fight or flight’ responses engage immediate inhibitory the laser-evoked potentials tended to diminish in amplitude effects for survival in battlefield or success in competitive witheachstimulusrepetition.Hence,thesepotentialsappear sports.Afterretreat,thesamebrainstemnetworkcanfacilitate tosignalthenovelty,ratherthantheintensity,ofpainexperi- nociceptionifphysicalinjuriesaresustained.Heightenedsen- enced.41RepetitionsuppressiondoesnotoccurwithGBO;this sitivitytonoxiousstimuli(hyperalgesia)isprotectiveduringre- observationlendsfurthersupportfortheroleofGBOindeter- covery,promotingtissuehealing. miningtheemergenceofpainfromanoxiousstimulus. Dynamiccausalmodellingandstructuralequationmodel- Hyperalgesicstates lingareanalyticalmethodsthathavethepotentialtofurther We have demonstrated that, in healthy volunteers, the our understanding of pain. These techniques use data from mescencephalo-pontine reticular formation (MPRF), which EEG,MEG,fMRI,orPETstudiestoinvestigatebraindynamics projectstotheRVM,regulatestheexpressionofhyperalgesia andcorticalcoupling,42–44andarenowbeingappliedinthe indifferentcentralsensitizationstates.Forexample,cutane- fieldofpain.45Suchanalysestakeusbeyondasimplespatial ous capsaicin initiates central sensitization by activation of representationofpaintowardsanetwork-basedunderstand- peripheralnociceptors.Theresultishyperalgesiaanditsmain- ing of thiscondition thatbetter reflectsthedynamic nature tenanceinvolvesMPRFactivity.61Cessationofremifentanil,a ofthepainexperience. potenti.v.opioidcanalsoinduce62–64hyperalgesia.6566This opioid-inducedphenomenonwasinvestigatedinacombined Prefrontal-limbiccontrol psychophysical-fMRIstudy.64MPRFactivationwassignificantly NumerousimagingstudiesdemonstratethatthePFCcanregu- increasedonlyinhyperalgesicsubjectsandcorrelatednega- late the perception and behavioural expression of pain in tivelywiththedegreeofhyperalgesiasuggestingthatbrain- humans. The PFC is reciprocally connected to limbic regions stemactivityregulatesthebehaviouralexpressionofcentral and these connections form the neural substrates through sensitizationduringopioidwithdrawal. which the motivational-emotional aspects of pain can be regulated.Thebeliefthatpainfromnoxiousstimulationcan Personalityandpain becontrolledincreasestoleranceofsuchpainfulstimuli;this Thedegreetowhichlimbicandbrainstemregionsarefunction- analgesic effect involves the ventrolateral PFC.46 Individuals ally linked by neural activity can explain the influence of can be taught to reinterpret the significance of adverse personality on pain thresholds. Using fMRI, we found that events so that the negative emotional responses (e.g. fear) insular-brainstem functional connectivity67 was weaker in canbecontrolled.Duringsuccessfulreappraisal,thedorsolat- moreanxiousindividuals,whoalsohadlowerpainthresholds eral PFC engages the nucleus accumbens and suppresses when compared with less anxious individuals.68 Hence, the amygdalaactivation.47 48 Reducing the fearassociated with influence of personality traits on pain can be substantiated impending pain via extinction learning requires activation by mechanisms involving the descending control of pain; of the ventromedial PFC.49 50 However, anxiety levels can therefore, an anxious and pain-vigilant personality might increase if extinction learning fails to lower such fear,51 arisefromlesseffectiveintrinsicregulationofnociception.69 whichcanexacerbateapainexperienceviapara-hippocampal mechanisms.5253 Expectancyeffects Frontal-limbic regions are reciprocally connected to the Individualsoften‘getwhattheyexpect’fromanytreatmentfor brainstem.Thisneuroanatomicalconnectionpresentsanother pain. Expectancy is often used to explain the placebo effect routethroughwhichpaincanbecontrolled—viainhibitionof which is now substantiated by neuroimaging research as a neuroneswithinthespinalcordthattransmitnociceptiveinfor- genuinepsychobiologicalevent.Mechanismsforplaceboanal- mationtothebrain.Distractionfrompainhasbeenshownto gesia operate within the neural circuit for the descending involve activity within the cingulo-frontal cortex, thalamus, control of pain which include the ACC, PAG, and the spinal andPAG5455and,morerecently,suppressionofspinalcordac- dorsalhorn.59Morerecently,weinvestigatedwhethereffects tivity.56Likewise,placeboanalgesiainvokesandaltersactivity from positive and negative expectanciesof opioid analgesia insimilarregionswithinthecentralnervoussystem.57–59 engagedsimilarbrainregionsinhealthysubjects.70Theexperi- ment involved afixedand constantinfusion ofremifentanil. Thebrainstemintegrator Subjectsreportedslightlylowerpaincomparedwithbaseline Neuronesinthespinalcordthattransmitinformationregard- when the infusion commenced but knowledge of that was ingnoxiouseventstohighercentreswithinthebrainreceive hidden.Painreliefbecamesignificantlysuperiorwhensubjects 66 BJA Imagingpain weretoldthattheinfusionhadcommenced.Wheninformed becomeprominentonlyafterpeakbloodconcentrationswere that the infusion had ceased (though in reality the infusion achievedfromtheinfusion.Thesestudiesondrugandexpect- was continued), their ratings of pain returned to baseline. ancyeffectssuggest that expectancyeffects possess distinct ThefMRIdatarevealedthateffectsofpositiveandnegativeex- functional neuro-anatomies. Further research is needed to pectanciesonopioidanalgesiainvolvedistinctneuroanatom- explorethepossibilityofisolatingthecontributionofplacebo ical substrates. Expectation of poor analgesic effect was ornocebo effects on pain based on neuroimaging datafrom accompaniedbyactivationoftheentorhinalcortex,thehippo- clinicaldrugtrials.70 campalregionthatmediatestheexacerbationofpainthrough anxiety52andinhibition(negativeactivation)oftheperigenual Thebrainandchronicpain ACC (pgACC). Conversely, positive expectation of analgesic effect was associated with increased pgACCactivation, sug- Neuroimaging research in patients with chronic pain have gesting the descending mechanisms of pain inhibition were revealed altered structure, function, and neurochemistry in engaged. the frontal-limbic-brainstem regions compared with healthy Inourstudy,activationswithintheprimarysomatosensory, controls underscoring the importance of this descending insular,andmid-anteriorcingulatecorticesfollowedsubjective neuro-circuitfortheregulationofpaininhumans. reports of pain, with the intensity modulated by expectancy Convergingevidencesuggeststhatfrontal-limbicdysfunc- usingafixedremifentanildose.However,activationsinthese tion accompanies chronic pain (Fig. 1). Early fMRI studies same regions also correlate with pain modulated by varying have shown altered functional activation of PFC by noxious doses of remifentanil without psychological manipulations. stimuliinpatientswithchronicpain.Bothhypo-activity72–74 Thisraisesimportantquestionsaboutwhetherinnateplacebo and hyperactivity of the PFC75–77 have been observed. mechanisms in the brain might be altered fundamentally by Furtherevidenceoffrontal-limbicdysfunctioninchronicpain thepresenceoftheactiveopioid.Atlasandcolleagues71used statescomesfromPET-ligandstudieswhichsuggestsabnor- afullfactorialexperimentaldesignintheirrecentstudytoinves- mal opioidergic transmissionwithin frontal-limbic regions in tigate potential interaction effects between remifentanil and patients with chronic pain (e.g. complex regional pain syn- expectation on pain ratings and also brain activity. They did drome,78centralpost-strokepain,7980andfibromyalgia).81 notfindsignificantinteractioneffectsonpainratingsorbrain Numerousinvestigatorshaveusedvoxel-basedmorphometry activity.Painrelieffromremifentanilandexpectationwerein- (VBM) to demonstrate subtle but distinct alterations in distinguishablebasedonsubjectivepainratings.fMRIdidnot grey-matterdensitiesinthebrainsofpatientswithchronicpain reveal regions where interaction effects were significant. when compared with healthy controls. Distinct grey-matter Instead,expectancyandremifentanileffectsweredistinguish- changeshavebeenobservedintheprefrontal82–84andlimbic ablebecausetheyinfluenceddifferentbrainregions.Additional- regions85–88 in disparate chronic pain syndromes. However, ly, expectancy and remifentanil effects had different onsets. these MR-based changes do not necessarily imply neuronal Expectancy effects occurred soon after the subjects became loss. Furthermore as these MRI data are from cross-sectional aware the infusion had started, whereas remifentanil effects studiesinpatients,theycannotrevealwhetherthechronicpain Activation Opioidergic tone PFC hypo [72–74] Altered opioid receptor or hyper activity [75–77] Binding within limbic regions [78–81] Pain Depression PFC Anxiety limbic Fear Structural BrSt integrity Altered grey-matter Connectivity density [82–88] Altered frontal–striatal White matter tracts [84] functional connection [83, 84] Fig1 ThePFC-limbic-brainstem(BrSt)pathwaysisinvolvedinthedescendingmodulationofpain.Brainimagingstudies(referencesinbrackets) haverevealedalteredfunctionalactivation,structureandneurochemistryofprefrontalandlimbicregionsinassociationwithsymptomsreported bypatientswithchronicpain. 67 BJA LeeandTracey state is the cause or consequence of regional grey-matter symptoms.91–93Thesedatahavebeenextendedtochanges changes. Nonetheless, in rodent models of neuropathic pain, in cortical thickness which is a more quantitative measure neuronal remodelling,89 and altered MRI-based measures of that can be compared between studies, unlike grey-matter grey-matterstructures90occurinthefrontal-limbicregionsand densities.94 Seminowicz and colleagues demonstrated that correlate with ‘anxiety-like’ behaviours after the peripheral thedorsolateralPFCthickenedinpatientswithchroniclower nerve lesions. These animal data suggest that the brain can back pain who reported improved symptoms. Additionally, changeasaconsequenceofaberrantinputfromdamagednoci- thedegreeofthickeningcorrelatedwiththeextentofclinical ceptiveafferentsandpotentiallycontributetothestateofchronic improvement. Interestingly, when compared with controls, pain. patientswhosesymptomsimprovedstillhadthinnercortices LongitudinalVBMstudiesinpatientswithchronicpainnow intheDLPFC,thoughthedifferencedidnotreachstatisticalsig- suggest that abnormalities in grey-matter densities within nificance.Thisfindingmaywellreflectincompleterecoveryof specific brain regions can resolve with improvement in thepainstateinthatpatientcohort.However,itpromptsusto MRI-modality Physiological measure Neurovascular Activation maps Which brains regions show increased activity? FMRI-‐BOLD stimulus- evoked pain + Functional s n connectivity o Which brain regions show egi r closely correlated activity? n r ai ASL Br – Spontaneous, ongoing pain Brain regions Anatomical Grey matter White matter tracts Structural Where are grey matter densities Is anatomical connectivity Diffusion weighted or cortical thickness altered ? altered? Brain metabolites NAA Neurochemical MRS Cr/PCr Cho ml Glu/Gln Lac/Lip 4 3.5 3 2.5 2 1.5 1 0.5 Fig2 MRI-basedimagingmodalitiesthatmeasurethebrainfunction,structure,andneurochemistry.Bloodoxygenationleveldependent(BOLD) fMRIandASLtechniquescanmapthebrain’sneurovascularresponsesthatareassociatedwithpainsymptoms.Thesetechniquesrevealwhere activationorcerebralperfusionisalteredwithinthebrain.Moresophisticatedconnectivityanalysesprovideinformationregardingtheflowof neuralinformationwithinthebrain.AdvancedanalysesofanatomicalMRIscanscandemonstratesubtlechangesofgrey-matterdensitiesor alterationsintheconnectivityofwhite-mattertractsbetweenbrainregions.Magneticresonancespectroscopyquantifieschangesinbrainmeta- bolitestorevealpotentialareasofneuroinflammationorneurodegeneration. 68 BJA Imagingpain consider whether predisposition to chronic pain can be pre- integrate meditative practice and cognition-based therapy dictedbasedonprefrontalstructureorfunction. forthemanagementofchronicpain.106 The longitudinal fMRI study by Baliki and colleagues83 demonstrated the value of cortical-striatal connectivity in Thefuture predicting the 1-year outcome of patients with sub-acute MR-based brain imaging methods are developing rapidly back pain. Greater functional connectivity between the PFC (Fig.2).Usingquantitativearterialspinlabelling(ASL),weare andnucleusaccumbenspredictedpainpersistencesuggesting nowabletomeasureregionalchangesincerebralbloodflow thatthefrontal-striatalconnectionisinvolvedinthetransition thatcanbeassociatedwithtonic,ratherthanphasicneural from acute to chronic pain. Cortico-striatal connectivity is events.107–109Thisnon-invasivetechniqueprovidesanabso- knowntosub-serveanumberofneuropsychologicalfunctions lutemeasureofcerebralperfusionandprovidesuswiththeop- andisincreasedduringcognitivereappraisalofemotions,47a portunity to identify the neural correlates that underpin the skillthatmayberelevantforcopingwithchronicpain.Hence, unrelenting,spontaneousandongoingpainthatisthedomin- theincreasedfrontal-striatalFcobservedinpatients‘destined’ antcharacteristicofchronicpainsyndromes.SpinalcordfMRI forchronicpaincouldrepresentanadaptivemechanismthat isnowavailableandfurtherresearchisbeingundertakento waseventuallyoverwhelmed. enable simultaneous acquisition of neural activities (spinal dorsal horn, brainstem to the cortex) which, in combination withmicroneurography,102couldallowmappingoftheentire Braindynamics ‘pain-pathway’ (nociceptor to brain). Machine-learning algo- Inrecentyears,fMRIhasrevealedthatthebrainexhibitshighly rithmsimplementedin‘brain-reading’studiesprovidenewop- correlatedspontaneousandslow(,0.1Hz)oscillatoryactiv- portunities for dissecting the neural bases of pain ities,evenintheabsenceofanysensorystimulation.95Thebio- perception.110 Neuroimaging methods are also being devel- logical significance of these ‘resting’ state networks is still opedasclinicaltoolsthatrevealthemechanismsthatunderlie unclear.96Ithasbeensuggestedthatincomingsensorystimu- chronic pain in patients where disease pathophysiologyand lation sculpts the activity and temporal dynamics of these psychosocialinfluencesonpainareunclearbasedonclinical spontaneousnetworks,reducingthevariabilityoftheirfluctua- presentationalone.Thechallengenowistoimprovethesensi- tions,toallowstablepatternsofneuralfiringwithincortical tivityandspecificityofimagingtechniquestoallowtheirdevel- regions that are associated with stimulus perception.97 For opmentasdiagnostictoolsfortheindividualpatientinourpain example,baselinefluctuationsinfMRIactivitycaninfluence clinics. whetherpainarisesfromnoxiousstimulation.6898 Ourabilitytodetect,analyse,anddeterminechangesinthe Declarationofinterest brain’srestingstatenetworks(RSNs)hasimprovedconsider- Nonedeclared. ablyinrecentyears.Thedefault-modenetwork(DMN)isone such RSN and includes the medial PFC, medial temporal Funding lobes, posterior cingulate cortex, and retrosplenial cortex.99 Studies utilizing fMRI or PET have shown that patients with M.C.L.andI.T.aresupportedbyfundingfromtheNationalInsti- chronicpaincanhaveabnormalpatternsofintrinsicbrainac- tute of Health Research Oxford Biomedical Research Centre, tivityintheDMN.77100101Thesestudiesindicatethatresting WellcomeTrustandMedicalResearchCouncilofGreatBritain brain activity within various brain regions is associated in andNorthernIreland.OpenAccessisfundedbytheWellcome somewaywithspontaneouspaininthiscondition. 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Imaging pain: a potent means for investigating pain mechanisms in patients. PDF

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Preview Imaging pain: a potent means for investigating pain mechanisms in patients.

BritishJournalofAnaesthesia111(1):64–72(2013) doi:10.1093/bja/aet174 Imaging pain: a potent means for investigating pain mechanisms in patients M.C.Lee*andI.Tracey NuffieldDivisionofAnaestheticsandCentreforFunctionalMRIoftheBrain(FMRIB), UniversityofOxford,Oxford,UK *Correspondingauthor.E-mail:[email protected] Summary. Chronic pain is a state of physical suffering Editor’skeypoints strongly associated with feelings of anxiety, depression and † Neuroimagingcanimproveourunderstandingofpain despair. Disease pathophysiology, psychological state, and mechanisms,analgesicactionandtheplaceboeffect. social milieu can influence chronic pain, but can be difficult to diagnose based solely on clinical presentation. Here, we † Newmodellingapproachescanexplorethedynamicprocesses review brain neuroimaging research that is shaping our influencingpainperception. understanding of pain mechanisms, and consider how such † Neuralmechanismsoftheeffectsofpersonalityandexpectancy knowledge might lead to useful diagnostic tools for the onpainperceptionandanalgesiahavebeenexplored. management of persistent pain in individual patients. † Futuredevelopmentswillcontinuetoexpandourknowledgeof Keywords: chronic pain; neuroimaging, magnetic resonance painmechanisms,allowingtranslationfromlaboratorytoclinic. imaging, functional Pain is an unpleasant sensation that is associated with, or much later (two decades ago) with the demonstration of described in terms of, a bodily injury.1 Clinicians have long increased and localized brain activation during pain in regarded pain as a symptom or warning of disease that humans.4Wenowacceptthatpainmaybecausedbybodily shouldbeinvestigatedtoexpeditetreatmentofpathology.Un- injury,butasaconsciousness,mustbegeneratedinthebrain. fortunately, medicine does not yet possess every cure, or Functional magnetic resonance imaging (fMRI), positron indeedknowledgeofeverypathophysiologythatcangenerate emissiontomography(PET),magnetoencephalography(MEG), pain. Pain can persist despite the best efforts of physicians. and scalp electroencephalography (EEG) are commonly used Chronic pain is currently defined by the duration of physical tostudytheneuralbasesofpain.Researchersarealsoincreas- symptomsbutis,inreality,sufferingstronglyassociatedwith ingly using other magnetic resonance-based measures (e.g. feelingsofanxiety,depression,anddespair.2 diffusion tensor imaging, spectroscopy, and volumetric In the individual, chronic pain is highly influenced by imaging)toassesspain-relatedchangesinthebrain’swiring, disease pathophysiology, psychological state, and social chemistry,andstructureinordertogainfurtherinsightsinto milieu.Thepathogenesisofchronicpainsyndromesisoften theneurobiologyofpain,particularlychronicpain.Thereareex- unclear.Researchcontinuestosuggestspecificpathophy- cellentreviewswritten recentlytosummarize the findings of siologies that may distinguish between different chronic neuroimagingstudiesinhealthyindividualsandinpatients.56 painsyndromes,forexample,fibromyalgia,complexregional Here, we focus on recent neuroimaging studiesthat continue painsyndrome.Whethertheseclinicalsyndromescanbedis- to shape our understanding of pain in health, disease, and tinguishedasdiseasesintheirownrightwithspecifictreat- illness.Wereviewtheprogressinneuroimagingresearchthat ments, orconsidered as acollection of symptoms that are is contributing to the development of clinically relevant tools drivenbysharedmechanisms,remainsunclear.Regardless, forthemanagementofpaininpatients. psychosocialfactorscansupervenetoinfluencehowpainis perceived or reported by patients, and these factors can Thepain‘neuromatrix’ operate unconsciously. Their contribution to the chronic pain state further determines appropriate and holistic Neuroimaging studies have now identified several cortical management of the patient. Hence, there is a desperate regions in humans that are considered to be important for needforadditionalmethodsthatcanquantifydiseaseload theperceptionofpain.Theprimaryandsecondarysomatosen- or psychosocial contributions to the chronic pain state in sorycortices(insularandanteriorcingulate)andtheprefrontal patients. cortices (PFCs) are commonly activated, often bilaterally, and InthefifthcenturyBC,Hippocratesdeclaredthatpain,like duringpainfulexperiences.Furthermore,alteredactivityinsub- all consciousness, must emerge from brain activity.3 Robust corticalareas(e.g.brainstemperiaqueductalgrey(PAG),hypo- scientific evidence for that philosophical intuition arrived thalamus, amygdala, hippocampus, and cerebellum) is also & TheAuthor[2013].PublishedbyOxfordUniversityPressonbehalfoftheBritishJournalofAnaesthesia. ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionNon-CommercialLicense (http://creativecommons.org/licenses/by-nc/3.0/),whichpermitsnon-commercialre-use,distribution,andreproductioninanymedium, providedtheoriginalworkisproperlycited.Forcommercialre-use,[email protected] BJA Imagingpain observedduringpain.Thus,activitywithinseveraldiverseregions understoodcomparedwithcentralneuronesontowhichthey ofthebrainseemtobenecessaryforthemultidimensionalex- projecttotransmitinformationtothebrain.26 perience that is pain.7–9 Some of these regions comprise the Investigatorshaveattemptedtotracetheflowofnocicep- so-called‘painneuromatrix’,10atermthatisoftenmisused,in tive information by examining the temporal sequence of whichmultipleinputsareprocessedtoproduceanoutput(neuro- brainactivationsevokedbynoxiousstimulation.Inhumans, signature)thatisbespokeforanindividualdependingoncontext, theearliestintra-corticalelectricalpotentialsthatareevoked moodandcognitivestate.8Hence,painistheproductofawidely bynoxiouslaserstimuliappliedtothehandoccursimultan- distributedandvariablyaccessibleneuralnetworkinthebrain, eously within theposterior insularregion and mid-cingulate ratherthananinevitableconsequenceofnoxiousstimulation. cortex.27 28 These regions receive nociceptive input via Current research suggests that parts of this network can be spino-thalamocortical pathways and are thought to provide accessedbynon-nociceptiveeventsorinputstoproduce‘pain- a primary interoceptive representation of the physiological like’experiences(e.g.duringempathyforothers,11romanticre- condition of the body.29 Activation of the posterior insula jection,12 and social exclusion).13 Hypnotically induced pain in duringnociceptioninhumanshasbeenshowntobesomatopi- susceptible individuals14 and central post-stroke pain are callyorganized.30 The importance of the posterior insulafor furtherexamplesthatillustratethelatentcapacityofthebrain nociceptive pain is further suggested by functional imaging toelicitpainwithoutconcomitantperipheralnociceptiveinputs. studies of pain empathy,11 hypnotically induced pain,14 and Remarkably, none of the brain regions identified above is recalledpainexperiences.3132Neuralactivationsduringsuch uniquelyassociated with pain; theyare also involved in many pains may be similar to that of physically induced pain but othersensory,motor,cognitive,andemotionalfunctions.Some there is often attenuation of activation within the posterior regions within the so-called pain neuromatrix exhibit signifi- insulawhenpainisreportedintheabsenceofnociceptivestimu- cantlycorrelatedactivitywithsensoryoremotionaldescriptions lation.14Researchersfromindependentgroupshaveshownthat ofthepainfulexperience,suggestingthattheyhaveasignifi- directelectricalstimulationoftheposteriorinsularregioncan cant role in pain generation but no brain region has been leadtopainfulsensationsbeingreported.3334Thesamedoes showntobeexclusivelyactivatedduringpainexperiences.15– notappeartobetrueofothercorticalregionsthatarealsocon- 18Disruptionofthespecificregionswithinthispainmatrixby sidered part of the pain neuromatrix.23 34 Additionally, the corticallesionsveryrarelyremoveor‘numb’paincompletely.19 insularcortexhasbeenidentifiedasthemostconsistentlyacti- 20Surgicalcingulotomies,performedforintractablepainsyn- vatedregionduringpainthatisinducedbynociceptivestimuli.9 dromes,mayreduceemotionalormotivationalaspectsofthe Theseconvergingdatasuggestthattheposteriorinsularregion clinicalpainstatebutleavesintactthecapacityfornociceptive mightrepresentacriticalneuralnodethroughwhichnocicep- pain.21Infact,priorfailuretoassociatecorticalactivityorcor- tive information must be processed. Hence, a ‘nociceptive tical lesions to the experience of pain had encouraged the cortex’ within the operculo-insula region may be postulated, view that pain had little true cortical representation.22 23 akintoothermajorsenses. These observations suggest that there is no critical or fixed brainregionforpain. Braindynamics Despite extensive research, an area of the brain that is analogous to the primary visual cortex (i.e. ‘primary pain As discussed above, the experience of pain requires activity cortex’) has not been identified. Todate, there is no pattern within various regions of the brain. Nevertheless, how pain ofbrainactivityindicatingpaininanindividualwithabsolute arises from the flow of information between these different certaintyforusebymedical,legal,orotherregulatorybodies. brainregionsislargelyunknown,asinvestigatingthisphenom- Forexample,‘pain-related’brainactivityfromnoxiousstimula- enonrequiresamultimodalapproach,ofwhichfewpublished tioncanoccurinpatientsinminimallyconsciousstates24but studiesexist.35MoststudiesinvolveEEGorMEGalone,which such activations do not necessarily prove pain perception in recordbrainactivitywithhightemporalresolutionbutrelative- theseindividuals.Nonetheless,theysuggestthattheneuro- lypoorspatialresolutionwhencomparedwithfMRI.Ahuman anatomical substrates for pain are functionally intact and scalpEEGstudyofcorticalpotentialsevokedbyhighlynoxious raisethepossibilityofpainintheseuncommunicativesubjects stimulihasrevealedthatlate,ratherthanearly,laser-evoked withobviousclinicalimplications. responsesareassociatedwithconsciousdetectionofnoxious stimuli.36 Hence, the consciousness of pain appears to emergeatlaterstagesofsuchprocessingwhenneuralinfor- Imagingnociception mationisbeingintegratedacrossmultiplecorticalregions. Nociception is defined as the ‘neural process of encoding Theprocessesbywhichthebrainprioritizesnociceptivein- noxious stimuli’. Although nociception is neither necessary formationovercompetingsensorystimuliforconsciousaware- norsufficientforpain,itisrequiredforprotectiveautonomic ness should also be examined.37 This may explain how the orreflexiveresponsesthatareessentialforoursurvival.Noci- perceptionofpainarisesfromnociceptiveinput.Synchronous ceptorsareperipheralsensoryneuroneswhichareevolvedto neuronal oscillations at gamma-band frequency (.40 Hz) respond specifically to high-intensity environmental stimuli are known to occur when the relevant sensory stimulus is that threaten the physical integrity of the organism.25 The selected for neural representation and perception.38 Using neurobiologyofthese first-orderafferents isarguably better MEG, Gross andcolleagues39 demonstrated that painfullaser 65 BJA LeeandTracey stimuliwereassociatedwithstrongergamma-bandoscillations descending control from supraspinal regions. This powerful (GBO)thanunperceivedstimuliofequalstimulusintensity,sug- modulatoryinput,emanatingfromthefrontal-limbicregions, gestingthattheperceptionofpainemergeswhennociceptive is integrated within the rostral ventromedial medulla (RVM) input is prioritized in the brain. A more recent EEG study andPAG;activitywithintheseregionsinthebrainstemdeter- furtherrevealedthat,unlikeevokedpotentials,GBOisnotsup- mineswhetherthenociceptiveinformationisprioritized.60De- pressed with repetitive noxious (laser) stimulation.40 In that pendingwhatthesituationdemands,thesebrainstemregions study, healthysubjectsperceivedand reported that repeated co-ordinatetheinhibitionorfacilitationofnociception.Classic- stimuliwerejustaspainfulastheoriginalstimulus.However, al ‘fight or flight’ responses engage immediate inhibitory the laser-evoked potentials tended to diminish in amplitude effects for survival in battlefield or success in competitive witheachstimulusrepetition.Hence,thesepotentialsappear sports.Afterretreat,thesamebrainstemnetworkcanfacilitate tosignalthenovelty,ratherthantheintensity,ofpainexperi- nociceptionifphysicalinjuriesaresustained.Heightenedsen- enced.41RepetitionsuppressiondoesnotoccurwithGBO;this sitivitytonoxiousstimuli(hyperalgesia)isprotectiveduringre- observationlendsfurthersupportfortheroleofGBOindeter- covery,promotingtissuehealing. miningtheemergenceofpainfromanoxiousstimulus. Dynamiccausalmodellingandstructuralequationmodel- Hyperalgesicstates lingareanalyticalmethodsthathavethepotentialtofurther We have demonstrated that, in healthy volunteers, the our understanding of pain. These techniques use data from mescencephalo-pontine reticular formation (MPRF), which EEG,MEG,fMRI,orPETstudiestoinvestigatebraindynamics projectstotheRVM,regulatestheexpressionofhyperalgesia andcorticalcoupling,42–44andarenowbeingappliedinthe indifferentcentralsensitizationstates.Forexample,cutane- fieldofpain.45Suchanalysestakeusbeyondasimplespatial ous capsaicin initiates central sensitization by activation of representationofpaintowardsanetwork-basedunderstand- peripheralnociceptors.Theresultishyperalgesiaanditsmain- ing of thiscondition thatbetter reflectsthedynamic nature tenanceinvolvesMPRFactivity.61Cessationofremifentanil,a ofthepainexperience. potenti.v.opioidcanalsoinduce62–64hyperalgesia.6566This opioid-inducedphenomenonwasinvestigatedinacombined Prefrontal-limbiccontrol psychophysical-fMRIstudy.64MPRFactivationwassignificantly NumerousimagingstudiesdemonstratethatthePFCcanregu- increasedonlyinhyperalgesicsubjectsandcorrelatednega- late the perception and behavioural expression of pain in tivelywiththedegreeofhyperalgesiasuggestingthatbrain- humans. The PFC is reciprocally connected to limbic regions stemactivityregulatesthebehaviouralexpressionofcentral and these connections form the neural substrates through sensitizationduringopioidwithdrawal. which the motivational-emotional aspects of pain can be regulated.Thebeliefthatpainfromnoxiousstimulationcan Personalityandpain becontrolledincreasestoleranceofsuchpainfulstimuli;this Thedegreetowhichlimbicandbrainstemregionsarefunction- analgesic effect involves the ventrolateral PFC.46 Individuals ally linked by neural activity can explain the influence of can be taught to reinterpret the significance of adverse personality on pain thresholds. Using fMRI, we found that events so that the negative emotional responses (e.g. fear) insular-brainstem functional connectivity67 was weaker in canbecontrolled.Duringsuccessfulreappraisal,thedorsolat- moreanxiousindividuals,whoalsohadlowerpainthresholds eral PFC engages the nucleus accumbens and suppresses when compared with less anxious individuals.68 Hence, the amygdalaactivation.47 48 Reducing the fearassociated with influence of personality traits on pain can be substantiated impending pain via extinction learning requires activation by mechanisms involving the descending control of pain; of the ventromedial PFC.49 50 However, anxiety levels can therefore, an anxious and pain-vigilant personality might increase if extinction learning fails to lower such fear,51 arisefromlesseffectiveintrinsicregulationofnociception.69 whichcanexacerbateapainexperienceviapara-hippocampal mechanisms.5253 Expectancyeffects Frontal-limbic regions are reciprocally connected to the Individualsoften‘getwhattheyexpect’fromanytreatmentfor brainstem.Thisneuroanatomicalconnectionpresentsanother pain. Expectancy is often used to explain the placebo effect routethroughwhichpaincanbecontrolled—viainhibitionof which is now substantiated by neuroimaging research as a neuroneswithinthespinalcordthattransmitnociceptiveinfor- genuinepsychobiologicalevent.Mechanismsforplaceboanal- mationtothebrain.Distractionfrompainhasbeenshownto gesia operate within the neural circuit for the descending involve activity within the cingulo-frontal cortex, thalamus, control of pain which include the ACC, PAG, and the spinal andPAG5455and,morerecently,suppressionofspinalcordac- dorsalhorn.59Morerecently,weinvestigatedwhethereffects tivity.56Likewise,placeboanalgesiainvokesandaltersactivity from positive and negative expectanciesof opioid analgesia insimilarregionswithinthecentralnervoussystem.57–59 engagedsimilarbrainregionsinhealthysubjects.70Theexperi- ment involved afixedand constantinfusion ofremifentanil. Thebrainstemintegrator Subjectsreportedslightlylowerpaincomparedwithbaseline Neuronesinthespinalcordthattransmitinformationregard- when the infusion commenced but knowledge of that was ingnoxiouseventstohighercentreswithinthebrainreceive hidden.Painreliefbecamesignificantlysuperiorwhensubjects 66 BJA Imagingpain weretoldthattheinfusionhadcommenced.Wheninformed becomeprominentonlyafterpeakbloodconcentrationswere that the infusion had ceased (though in reality the infusion achievedfromtheinfusion.Thesestudiesondrugandexpect- was continued), their ratings of pain returned to baseline. ancyeffectssuggest that expectancyeffects possess distinct ThefMRIdatarevealedthateffectsofpositiveandnegativeex- functional neuro-anatomies. Further research is needed to pectanciesonopioidanalgesiainvolvedistinctneuroanatom- explorethepossibilityofisolatingthecontributionofplacebo ical substrates. Expectation of poor analgesic effect was ornocebo effects on pain based on neuroimaging datafrom accompaniedbyactivationoftheentorhinalcortex,thehippo- clinicaldrugtrials.70 campalregionthatmediatestheexacerbationofpainthrough anxiety52andinhibition(negativeactivation)oftheperigenual Thebrainandchronicpain ACC (pgACC). Conversely, positive expectation of analgesic effect was associated with increased pgACCactivation, sug- Neuroimaging research in patients with chronic pain have gesting the descending mechanisms of pain inhibition were revealed altered structure, function, and neurochemistry in engaged. the frontal-limbic-brainstem regions compared with healthy Inourstudy,activationswithintheprimarysomatosensory, controls underscoring the importance of this descending insular,andmid-anteriorcingulatecorticesfollowedsubjective neuro-circuitfortheregulationofpaininhumans. reports of pain, with the intensity modulated by expectancy Convergingevidencesuggeststhatfrontal-limbicdysfunc- usingafixedremifentanildose.However,activationsinthese tion accompanies chronic pain (Fig. 1). Early fMRI studies same regions also correlate with pain modulated by varying have shown altered functional activation of PFC by noxious doses of remifentanil without psychological manipulations. stimuliinpatientswithchronicpain.Bothhypo-activity72–74 Thisraisesimportantquestionsaboutwhetherinnateplacebo and hyperactivity of the PFC75–77 have been observed. mechanisms in the brain might be altered fundamentally by Furtherevidenceoffrontal-limbicdysfunctioninchronicpain thepresenceoftheactiveopioid.Atlasandcolleagues71used statescomesfromPET-ligandstudieswhichsuggestsabnor- afullfactorialexperimentaldesignintheirrecentstudytoinves- mal opioidergic transmissionwithin frontal-limbic regions in tigate potential interaction effects between remifentanil and patients with chronic pain (e.g. complex regional pain syn- expectation on pain ratings and also brain activity. They did drome,78centralpost-strokepain,7980andfibromyalgia).81 notfindsignificantinteractioneffectsonpainratingsorbrain Numerousinvestigatorshaveusedvoxel-basedmorphometry activity.Painrelieffromremifentanilandexpectationwerein- (VBM) to demonstrate subtle but distinct alterations in distinguishablebasedonsubjectivepainratings.fMRIdidnot grey-matterdensitiesinthebrainsofpatientswithchronicpain reveal regions where interaction effects were significant. when compared with healthy controls. Distinct grey-matter Instead,expectancyandremifentanileffectsweredistinguish- changeshavebeenobservedintheprefrontal82–84andlimbic ablebecausetheyinfluenceddifferentbrainregions.Additional- regions85–88 in disparate chronic pain syndromes. However, ly, expectancy and remifentanil effects had different onsets. these MR-based changes do not necessarily imply neuronal Expectancy effects occurred soon after the subjects became loss. Furthermore as these MRI data are from cross-sectional aware the infusion had started, whereas remifentanil effects studiesinpatients,theycannotrevealwhetherthechronicpain Activation Opioidergic tone PFC hypo [72–74] Altered opioid receptor or hyper activity [75–77] Binding within limbic regions [78–81] Pain Depression PFC Anxiety limbic Fear Structural BrSt integrity Altered grey-matter Connectivity density [82–88] Altered frontal–striatal White matter tracts [84] functional connection [83, 84] Fig1 ThePFC-limbic-brainstem(BrSt)pathwaysisinvolvedinthedescendingmodulationofpain.Brainimagingstudies(referencesinbrackets) haverevealedalteredfunctionalactivation,structureandneurochemistryofprefrontalandlimbicregionsinassociationwithsymptomsreported bypatientswithchronicpain. 67 BJA LeeandTracey state is the cause or consequence of regional grey-matter symptoms.91–93Thesedatahavebeenextendedtochanges changes. Nonetheless, in rodent models of neuropathic pain, in cortical thickness which is a more quantitative measure neuronal remodelling,89 and altered MRI-based measures of that can be compared between studies, unlike grey-matter grey-matterstructures90occurinthefrontal-limbicregionsand densities.94 Seminowicz and colleagues demonstrated that correlate with ‘anxiety-like’ behaviours after the peripheral thedorsolateralPFCthickenedinpatientswithchroniclower nerve lesions. These animal data suggest that the brain can back pain who reported improved symptoms. Additionally, changeasaconsequenceofaberrantinputfromdamagednoci- thedegreeofthickeningcorrelatedwiththeextentofclinical ceptiveafferentsandpotentiallycontributetothestateofchronic improvement. Interestingly, when compared with controls, pain. patientswhosesymptomsimprovedstillhadthinnercortices LongitudinalVBMstudiesinpatientswithchronicpainnow intheDLPFC,thoughthedifferencedidnotreachstatisticalsig- suggest that abnormalities in grey-matter densities within nificance.Thisfindingmaywellreflectincompleterecoveryof specific brain regions can resolve with improvement in thepainstateinthatpatientcohort.However,itpromptsusto MRI-modality Physiological measure Neurovascular Activation maps Which brains regions show increased activity? FMRI-‐BOLD stimulus- evoked pain + Functional s n connectivity o Which brain regions show egi r closely correlated activity? n r ai ASL Br – Spontaneous, ongoing pain Brain regions Anatomical Grey matter White matter tracts Structural Where are grey matter densities Is anatomical connectivity Diffusion weighted or cortical thickness altered ? altered? Brain metabolites NAA Neurochemical MRS Cr/PCr Cho ml Glu/Gln Lac/Lip 4 3.5 3 2.5 2 1.5 1 0.5 Fig2 MRI-basedimagingmodalitiesthatmeasurethebrainfunction,structure,andneurochemistry.Bloodoxygenationleveldependent(BOLD) fMRIandASLtechniquescanmapthebrain’sneurovascularresponsesthatareassociatedwithpainsymptoms.Thesetechniquesrevealwhere activationorcerebralperfusionisalteredwithinthebrain.Moresophisticatedconnectivityanalysesprovideinformationregardingtheflowof neuralinformationwithinthebrain.AdvancedanalysesofanatomicalMRIscanscandemonstratesubtlechangesofgrey-matterdensitiesor alterationsintheconnectivityofwhite-mattertractsbetweenbrainregions.Magneticresonancespectroscopyquantifieschangesinbrainmeta- bolitestorevealpotentialareasofneuroinflammationorneurodegeneration. 68 BJA Imagingpain consider whether predisposition to chronic pain can be pre- integrate meditative practice and cognition-based therapy dictedbasedonprefrontalstructureorfunction. forthemanagementofchronicpain.106 The longitudinal fMRI study by Baliki and colleagues83 demonstrated the value of cortical-striatal connectivity in Thefuture predicting the 1-year outcome of patients with sub-acute MR-based brain imaging methods are developing rapidly back pain. Greater functional connectivity between the PFC (Fig.2).Usingquantitativearterialspinlabelling(ASL),weare andnucleusaccumbenspredictedpainpersistencesuggesting nowabletomeasureregionalchangesincerebralbloodflow thatthefrontal-striatalconnectionisinvolvedinthetransition thatcanbeassociatedwithtonic,ratherthanphasicneural from acute to chronic pain. Cortico-striatal connectivity is events.107–109Thisnon-invasivetechniqueprovidesanabso- knowntosub-serveanumberofneuropsychologicalfunctions lutemeasureofcerebralperfusionandprovidesuswiththeop- andisincreasedduringcognitivereappraisalofemotions,47a portunity to identify the neural correlates that underpin the skillthatmayberelevantforcopingwithchronicpain.Hence, unrelenting,spontaneousandongoingpainthatisthedomin- theincreasedfrontal-striatalFcobservedinpatients‘destined’ antcharacteristicofchronicpainsyndromes.SpinalcordfMRI forchronicpaincouldrepresentanadaptivemechanismthat isnowavailableandfurtherresearchisbeingundertakento waseventuallyoverwhelmed. enable simultaneous acquisition of neural activities (spinal dorsal horn, brainstem to the cortex) which, in combination withmicroneurography,102couldallowmappingoftheentire Braindynamics ‘pain-pathway’ (nociceptor to brain). Machine-learning algo- Inrecentyears,fMRIhasrevealedthatthebrainexhibitshighly rithmsimplementedin‘brain-reading’studiesprovidenewop- correlatedspontaneousandslow(,0.1Hz)oscillatoryactiv- portunities for dissecting the neural bases of pain ities,evenintheabsenceofanysensorystimulation.95Thebio- perception.110 Neuroimaging methods are also being devel- logical significance of these ‘resting’ state networks is still opedasclinicaltoolsthatrevealthemechanismsthatunderlie unclear.96Ithasbeensuggestedthatincomingsensorystimu- chronic pain in patients where disease pathophysiologyand lation sculpts the activity and temporal dynamics of these psychosocialinfluencesonpainareunclearbasedonclinical spontaneousnetworks,reducingthevariabilityoftheirfluctua- presentationalone.Thechallengenowistoimprovethesensi- tions,toallowstablepatternsofneuralfiringwithincortical tivityandspecificityofimagingtechniquestoallowtheirdevel- regions that are associated with stimulus perception.97 For opmentasdiagnostictoolsfortheindividualpatientinourpain example,baselinefluctuationsinfMRIactivitycaninfluence clinics. whetherpainarisesfromnoxiousstimulation.6898 Ourabilitytodetect,analyse,anddeterminechangesinthe Declarationofinterest brain’srestingstatenetworks(RSNs)hasimprovedconsider- Nonedeclared. ablyinrecentyears.Thedefault-modenetwork(DMN)isone such RSN and includes the medial PFC, medial temporal Funding lobes, posterior cingulate cortex, and retrosplenial cortex.99 Studies utilizing fMRI or PET have shown that patients with M.C.L.andI.T.aresupportedbyfundingfromtheNationalInsti- chronicpaincanhaveabnormalpatternsofintrinsicbrainac- tute of Health Research Oxford Biomedical Research Centre, tivityintheDMN.77100101Thesestudiesindicatethatresting WellcomeTrustandMedicalResearchCouncilofGreatBritain brain activity within various brain regions is associated in andNorthernIreland.OpenAccessisfundedbytheWellcome somewaywithspontaneouspaininthiscondition. 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