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Symptoms and the body: Taking the inferential

leap

Article in Neuroscience & Biobehavioral Reviews · January 2017

DOI: 10.1016/j.neubiorev.2017.01.015

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Contents lists available atScienceDirect

Neuroscience and Biobehavioral Reviews

j o u r n a l h o m e p a g e :w w w . e l s e v i e r . c o m / l o c a t e / n e u b i o r e v

Review article

Symptoms and the body: Taking the inferential leap

Omer Van den Bergh

a,∗

, Michael Witthöft

b

, Sibylle Petersen

a,c

, Richard J. Brown

d,e

aHealthPsychology,UniversityofLeuven,Tiensestraat102,Belgium

bClinicalPsychology,Psychotherapy,andExperimentalPsychopathology,UniversityofMainz,Germany

cInstituteforHealthandBehaviour,UniversityofLuxembourg,LuxembourgandHealthPsychology,UniversityofLeuven,Belgium

dCentreforNewTreatmentsandUnderstandinginMentalHealth,DivisionofPsychologyandMentalHealth,SchoolofHealthSciences,FacultyofBiology, MedicineandHealth,UniversityofManchester,ManchesterAcademicHealthSciencesCentre,UK

ePsychologicalServices,GreaterManchesterMentalHealthNHSFoundationTrust,ManchesterAcademicHealthSciencesCentre,UK

a r t i c l e i n f o

Articlehistory:

Received12August2016

Receivedinrevisedform1December2016 Accepted11January2017

Availableonline17January2017

Keywords:

Symptomperception

Medicallyunexplainedsymptoms Predictivecoding

a b s t r a c t

Therelationshipbetweentheconsciousexperienceofphysicalsymptomsandindicatorsofobjective physiologicaldysfunctionishighlyvariableanddependsoncharacteristicsoftheperson,thecontext andtheirinteraction.Thisrelationshipoftenbreaksdownentirelyinthecaseof“medicallyunexplained”

orfunctionalsomaticsymptoms,violatingthebasicassumptioninmedicinethatphysicalsymptoms havephysiologicalcauses.Inthispaper,wedescribetheprevailingtheoreticalapproachtothisproblem andreviewtheevidencepertainingtoit.Wethenusetheframeworkofpredictivecodingtoproposea newandmorecomprehensivemodelofthebody-symptomrelationshipthatintegratesexistingconcepts withinaunifyingframeworkthataddressesmanyoftheshortcomingsofcurrenttheory.Wedescribe theconditionsunderwhichaclosecorrespondencebetweentheexperienceofsymptomsandobjective physiologymightbeexpected,andwhentheyarelikelytodiverge.Weconcludebyexploringsome theoreticalandclinicalimplicationsofthisnewaccount.

©2017ElsevierLtd.Allrightsreserved.

Contents

1. Thediseasemodelandmedicallyunexplainedsymptoms...186

1.1. ExtentandvarietiesofMUS...186

1.2. Somatosensoryamplificationandmisattribution...187

1.2.1. Peripheralarousalandstress-relatedphysiology...187

1.2.2. Interoceptivehypervigilance,thresholdsandawareness...189

1.2.3. Misattributionandinterpretationbias...189

1.2.4. Conclusion ... 189

1.3. Howdifferentare‘explained’and‘unexplained’symptoms?...190

1.4. Interimsummary...190

2. Anewperspective...190

2.1. Aimsandcentraltenets...190

2.2. Interoceptionasinference...191

2.2.1. Prediction,predictionerrorandprecision...191

2.2.2. Neurobiologicalconsiderations...193

2.2.3. Interoception,expectationsandthesenseofself...193

2.3. Interoceptiveinferenceandsymptomperception...194

2.4. Factorsinfluencingsymptomperception...195

2.4.1. Varietiesofafferentinput...195

2.4.2. Varietiesofattention...195

2.4.3. Gender...196

∗ Correspondingauthor.

E-mailaddress:omer.vandenbergh@kuleuven.be(O.VandenBergh).

http://dx.doi.org/10.1016/j.neubiorev.2017.01.015 0149-7634/©2017ElsevierLtd.Allrightsreserved.

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186 O.VandenBerghetal./NeuroscienceandBiobehavioralReviews74(2017)185–203

2.4.4. Threatandnegativeaffect(NA)...196

2.5. Summary...197

3. Implications...197

3.1. Theoreticalimplications...197

3.2. Clinicalimplications...198

3.2.1. Diagnosticimplications...198

3.2.2. Treatmentimplications...198

3.3. Translatingthemodelintotestablehypotheses...199

4. Summaryandconclusions...199

Conflictofinterest... 200

Authorscontribution...200

Acknowlegements...200

References...200

1. Thediseasemodelandmedicallyunexplainedsymptoms

Standard medical practice is premised on a disease model thattypicallycomprisestwophases.Thediagnosticphasebegins whensymptomsarereportedtoaphysician,wholookstodeter- minetheircausethroughhistorytaking,physicalexaminationand, whereappropriate,medicalinvestigations.Thisinformation,which mainlyconcernsthepatient’sbody,ismappedontoasetofpatho- physiologicalcriteriathatallowfordiagnosisandtreatment.Inthe therapeuticphase,theaimistoremedydysfunctionandthereby removethepatient’ssymptoms.

Thisapparentlylogicalprocessisoftensuccessful,butitsome- timesfailsdramatically.Aparticularlycompelling(andcommon) exampleofthisiswhenthepatientreportssymptomsdespitetests indicatingthattheirbodyishealthy,orwhere“successful”treat- mentfordiagnoseddiseasefailstoresolvesymptoms.Insuchcases, doctorsoftenmakerenewedattemptstoidentifydisease,reflect- ingoneofthefundamentalassumptionsofthismodel:thatphysical symptomshavephysiologicalcauses,andcanthereforebereduced tothem.Ifthesymptomspersistbutadiseasecauseremainselu- sive,thenthepatientmaybegivenadiagnosisthatsimplydescribes theircomplaint(e.g.,chronicfatigue)oranotherlabelthatidentifies themassufferingfrom“medicallyunexplainedsymptoms”(MUS).

Althoughthebiopsychosocialmodelhasensuredthatsymptoms arenolongerseenaspurelybiologicalphenomena,medicalprac- ticecontinuestobedominatedbytheviewthat“real”symptoms reflectbodilydysfunction,andthatthosesymptomsthatcannotbe validatedobjectivelyare“inthemind”orsimplymadeup.

Inthis paper,we drawonpreviousapproachestodevelop a novelmodel ofsymptom perceptionthat transcends theartifi- cialdistinction between“explained”and“unexplained”physical symptoms,whilst explaining the variablerelationship between symptoms and physiological dysfunction. The central principle underpinningthisaccountisthatphysicalsymptoms,asfeltand expressedbypatients,arenot adirectrecordofbodilyactivity, butaninferencebasedonimplicit predictionsaboutinterocep- tive information, derived from prior knowledge. An important implicationofthisaccountisthatsymptomsoftenresultfroman

“inferentialleap”,resultinginanexperiencethatisonlyloosely coupledwithdysfunctionalprocessesintheperipheralbody,and occasionallyhas norelationship at all. We usethis framework todescribetheconditions underwhich a closecorrespondence betweensubjectivesymptomsandobjectivephysiologymightbe expected,andwhenthetwoarelikelytodiverge.Weconcludeby exploringsomeclinicalandempiricalimplications.

1.1. ExtentandvarietiesofMUS

Physicalsymptomsthatoccurintheabsenceofdetectablephys- iologicaldysfunctionareubiquitous.Inapopulation-basedstudy

inGermany(N=2552),forexample,81.6%ofpeoplereportedat leastonemedicallyunexplainedsymptomcausing atleastmild impairment(Hilleretal.,2006).Inprimarycare,uptothreequar- tersofallsymptomsreportedarethoughtnottobeattributable toorganicdisease.About25%of generalpracticepatientshave clinicallyrelevantMUS(e.g.,Finketal.,2007;Körberetal.,2011) and 8–10%ofprimary carepatientshave a history of multiple, distressingMUS(e.g.,Kroenkeetal.,1997).Symptomburdenin individualswithMUSseemstobecontinuouslydistributed,rang- ingfromnon-consultingpeoplewithminimaldisability(Watson andPennebaker,1989)tothosewithnumerous,chronic,severely disablingsymptoms(e.g.,Jasperetal.,2012).

Theeconomicburdenisconsiderable.IntheUSA,theannual medical cost of MUS was previously estimated at $256 billion (Barsky et al., 2005), while in theUK theyare said toaccount for approximately 10% of the National Health Service Budget (Bermingham etal.,2010).Upto42 millionworkdaysarelost toMUSintheUKeachyear(Berminghametal.,2010),withthe associatedlossofproductivitybeingestimatedat$19,000(US)per patientover10yearsago(Hilleretal.,2003).

Thediseasemodel clearlystrugglestoaccommodateMUS.It is notclear whatthese conditionsshould becalled(e.g.,Creed etal.,2010)orhowtheyshouldbeclassified(e.g.,Kroenkeetal., 2007).VarioustermshavebeenusedapartfromMUS,including

“psychosomaticsymptoms”, “functional symptoms”, “subjective healthcomplaints”,“somatization”,“somaticsymptomdistress”, and“bodilydistress”.However,thereislittleagreementonwhich ismostappropriate(Creedetal.,2010;Kroenkeetal.,2007)oron thelevelofdescriptionandanalysisneeded(i.e.assymptoms,syn- drome,disorder,ordisease).Withingeneralmedicine,particular clustersofMUSareoftentermedfunctionalsomaticsyndromes,a categorythatincludesirritablebowelsyndrome,chronicfatigue syndrome, fibromyalgia and numerous other specialty-specific conditions(Brown,2007).Inpsychiatry,particularconstellations ofMUSareclassifiedassomatoformdisordersintheInternational ClassificationofDiseases(ICD-10;WHO,1992),apracticethatwas mirroredintheDiagnosticandStatisticalManual(DSM-IV-TR;APA, 2000)untilitsmostrecentrevisionwhentheterm“somaticsymp- tomdisorder”wascoined(DSM-5;APA,2013).Forthesomatoform disorders,theemphasisisonsymptoms,withdiagnoseslikesoma- tizationdisorder(whichpertainstoindividualswithmultipleMUS) implyingthatsufferershaveageneraltendencytoexperienceMUS thatencompassesallbodilysystems.Thisisalsotrueofothersys- tems for classifyingpatients withmultipleMUS (e.g., Fink and Schröder,2010;Kroenkeetal.,1997;RiefandHiller,1999),devel- opedinresponsetoconcernsaboutthesensitivityandspecificity oftheICD-10andDSM-IVcriteria.

Therehasbeenmuchdebateabouttheoverlapbetween(and within)thefunctionalsomaticsyndromesandsomatoformdisor- ders(e.g.,Henningsenetal.,2007;Wesselyetal.,1999;Wessely

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andWhite,2004;Witthöftetal.,2016),andaboutthenosological categorisationofthefunctionalsyndromesandsomatoformdisor- dersaseitherdiseasesor(mental)disorders(Geniats,2015;Jana etal.,2012).Inaddition,theblurreddistinctionbetweenMUSand non-MUShascontributedtotherecent removalofthesomato- formdisorders fromDSM 5(APA, 2013)and theirreplacement witha newSomatic Symptomand Related Disorders category.

Thecenterpieceofthisnewcategory,somaticsymptomdisorder, incorporatesallpatientswithchronic,distressingand/ordisabling somaticsymptomswhoare alsoexhibitingpositivepsychologi- calfeatures(e.g.,symptompreoccupation,excessivehealthworry, maladaptiveillnessbehavior),irrespectiveofwhetherorganicdis- easehasbeenfound.Assuch,somaticsymptomdisorderexcludes lessseverecasesofMUS/somatoformdisorderscomparedtoDSM- IV(Claassen-vanDesseletal.,2016),whistencompassingpatients withfunctionalsomaticsyndromesordocumentedorganicdisease wheretheassociatedpsychologicalfeaturesarealsopresent.

Byemphasizingthepositivepsychologicalfeaturesinresponse tobodilysymptoms,somaticsymptomdisorderresolvessomeof theissuesregardingtheclassificationofphysicalsymptomsbutnot others,leadingsometoproposeareturntoqualifyingdiagnosesby whetherthesomaticsymptomsinquestioncanbeexplainedbya biomedicalcondition(seeRiefandMartin,2014;foradiscussion).

Thisillustratesatensionthatislikelytoremainuntilthedisease modeliscomplementedbyaframeworkthatexplicitlyaddresses howconsciouslyperceivedsymptoms(medicallyunexplainedand otherwise)comeabout,andwhenandhowtheyrelate(ornot)to bodilydysfunction.

1.2. Somatosensoryamplificationandmisattribution

Probablythe mostinfluential account of MUS has beenthe somatosensoryamplificationmodel(BarskyandWyshak,1990).

The amplificationmodel assumes that MUS result fromstress- related physiological arousalin threat-sensitivepersons,whose illnessconcernsleadthemtomisattributenormalsensationsto diseasecauses(e.g.,BarskyandWyshak,1990;Kolketal.,2003).

Physiologicalarousalalsopromptstheindividualtofocusattention ontheirbody(attentionalbiasor‘interoceptivehypervigilance’), loweringthe thresholdfor perceiving somaticsensations while

primingdiseaseattributions(BarskyandWyshak,1990).Misinter- pretingthesensationsasthreateningthencausesafurtherincrease inarousal,creatingaviciouscycle.Thecoreprinciplesofphysiolog- icalarousal,hypervigilanceandmisattributionarguablyconstitute themodalmodelofMUS,whichissharedbyafamilyofclinical modelsexplaining MUS,hypochondriasis, hyperventilationsyn- dromeandpanicdisorder.TheseprinciplesaredisplayedinFig.1.

Variationsandelaborationsonthesethemesabound.Forexam- ple, there is some disagreement among the models as to the necessityof altered physiological arousal: in somemodelsit is assumed thatarousalis elevatedcomparedtothenormal state ofthebody,whileinothermodelsitisassumedthatarousalcan bewithinthenormal rangebutperceptionisincreasedbecause of hypervigilanceto it. Exemplars of this family of modelsare describedinTable1.

The assumptions shared by these models are central to cognitive-behavioraltreatmentsforthesecomplaints,becauseitis generallythoughtthatthereisgoodevidenceforthemodalmodel.

Wewillbrieflydiscussthisevidence.

1.2.1. Peripheralarousalandstress-relatedphysiology

Thepopularityoftheamplificationmodelreliesinpartonthe observationthatphysicalsymptomreportsarecommonlycomor- bidwithsymptomsofanxietyanddepression(Wesselyetal.,1999;

Kroenke, 2003) and consistently associated (r=0.40–0.50) with highertraitnegativeaffectivity(NA;i.e.,apervasivetendencyto experiencenegativeaffect;WatsonandPennebaker,1989)andele- vatedstresslevels(TakandRosmalen,2010).Increasedsymptom reportsinprimarycarehaveoftenbeeninterpretedasresulting fromelevatedautonomicarousal(Kolketal.,2003;Kirmayeretal., 2004).Itisnoteworthy,however,thatthemostextensivelabora- toryandambulatorystudieshavenotfoundsignificantdifferences betweenMUS reporters and healthy controlsacrossa range of peripheralphysiologicalstressorarousalindicators(e.g.,heartrate, cardiacautonomicactivity,respiration,salivarycortisol;Houtveen etal.,2010;HoutveenandvanDoornen,2007).

In functional somatic syndromes, where the clinical picture is generally more severe, there is ongoing debate about the importanceofphysiologicalabnormalities,withawiderangeof possiblecausesfor symptomsbeingcited,includingstress-and

Fig.1. Themodalmodelofsymptomperception.Accordingtothismodel,somaticsymptomperceptionstartswithperipheralsomaticafferentinput,followedbycognitive processingthatdeterminesthedegreeofcognitiverepresentationofthisinputandtherebythestrengthofconscioussymptomperception.

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188O.VandenBerghetal./NeuroscienceandBiobehavioralReviews74(2017)185–203 Table1

Familyofmodelsexplainingsymptomperception,MUSandclinicalmanifestationsbyrelyingonperipheralsomaticinputinteractingwithattentionalandattributionalmechanisms.

Authors Scopeofthemodel Peripheralsomaticinput Attention Attributionandinterpretation

Pennebaker(1982);

Watsonand Pennebaker(1989)

Aimstoexplainthevariabilityin somaticsymptomsindiseasestatesas wellastheoccurrenceofMUS.

Peripheralinputisnecessary;mayresultfrom illnessprocesses,from(stress-related)arousal orbepartofnormalbodilysensations.

Balancebetweenexternallyand internallydirectedattention,butalso beliefsandpersonality(e.g.negative affect)maydeterminethelikelihood ofperceivingbodilysensations, includingnormalbodilysensations.

Beliefs,attributionsandinterpretationsfurther determinehowthesensationswillbeexperienced.

Cioffi(1991) Aimstoexplainthevariabilityin somaticinterpretationsinrelationto symptomsandillnesses.

Peripheralinputisnecessary;mayresultfrom illnessprocesses,from(stress-related)arousal orbepartofnormalbodilysensations.

Attentionhasafocusanddirection, butalsoacontent:itcanbedirected toparticularpriorhypothesesand attributionspromotingtheuseofa specificlabelforthesensation

Theuseofalabelelicitsothermeaningsandbelief structurescontributingtocausalinferencesand anticipatedconsequences,affectingillnessbehavior

Leventhaland Leventhal(1993)

Aimstoexplainthevariabilityin somaticinterpretationsinrelationto symptomsandillnesses.

Peripheralinputisnecessary;mayresultfrom physiologicaldiseasesprocesses,from (stress-related)arousalandemotional distress,orbepartofnormalbodily sensations.

Laybeliefsandillnessrepresentations directattentiontophysicalsymptoms, increasingthechancesofthembeing perceived

Laybeliefsandillnessrepresentationsalsoshapethe attributionandinterpretationofthesensations.

BarskyandWyshak (1990)

Aimstoexplainsomatoformdisorders andmedicallyunexplainedsymptoms

Peripheralinputisnecessary;mayresultfrom illnessprocesses,from(stress-related)arousal orbepartofnormalbodilysensations.

Heightenedattentionalfocuson bodilysensationsintensifiesthe experienceandleadstotheperception ofrelativelyweaksensationsthat normallyremainoutsideofawareness (amplification)

Thesensationsareinterpretedasthreateningand noxious,increasingdistress,inducingheightened attentionandcreatingaviciouscircle.

KirmayerandTaillefer (1997)

Aimstoexplainsomatoformdisorders andmedicallyunexplainedsymptoms

Peripheralinputisnecessary;mayresultfrom illnessprocessesandfrom(stress-related) arousal.

Attentionalprocessesincrease chancesforthesesensationstobe perceived.

Attributionofsensationstoillness,illness-related worriesandconcernsinfluencedistress,illness behaviorandhelp-seeking,whichinteractwithsocial andculturalfactors.Thelatterfurtherinfluence copingwiththesymptoms.

Kolketal.(2003) Aimstoexplainthevariabilityin somaticsymptomsindiseasestatesas wellastheoccurrenceofMUS.

Peripheralinputisnecessary;mayresultfrom illnessprocesses,from(stress-related)arousal orbepartofnormalbodilysensations.

Externalcontext,selectiveattention andnegativeaffectivitymayinfluence hightenedattentionanddetection

Meaningsandattributionsguidedbyillnessbeliefs andschematadeterminetheinterpretationofthe sensationsasspecificsymptoms

Brown(2004) AimstoexplainMUSandsomatoform disorders

Peripheralinputisnotnecessary,chronically activatedsymptomschematainan

unconsciousprimaryattentionalsystem(PAS) mayundersomecircumstancesexceedthe awarenessthresholdandleadtoconscious symptomexperiences

Inasecondary,moreconscious attentionalsystem,concernsmay induceelevatedvigilanceforsomatic sensationscontributingtochronically activesymptomschemata

Cognitiveelaborationsguidedbyillnessbeliefsand schematamayfurtherdeterminetheinterpretationof thesymptomsandaffectillnessbehavior

RiefandBarsky(2005) Aimstoexplainsomatoformdisorders andmedicallyunexplainedsymptoms

Severalphysiologicalprocessesarethoughtto contributetophysicalsensations,butthey maybeoflowintensity

Afailingattentionalfiltersystem,to whichmultiplepsychologicaland biologicalfactorscontribute,cancause subthresholdphysicalsensationstobe felt

Cognitive,behavioralandemotionalprocesses becomeinvolvedinaviciouscirclewithbiological mechanisms

Dearyetal.(2007) AimstoexplainMUSingeneralwitha specificfocusalsoonCFSandIBS

Geneticvulnerability,personality-related distress,earlyadverseexperiences,lifeevents andHPA-relatedmechanismsareconsidered underlyingsourcesofsomaticsensations

Attentionalbiases,possiblyresulting from“cognitivesensitization”, increasetheprobabilityof subthresholdsensationsbeing perceived.

Illnessattributionsraisethethreatvalueofthe sensations,feedingbacktoattentionalprocesses, causingbehavioralavoidanceandleadingto escalatingcircles,oftenfurtherreinforcedby insufficientguidanceandreassurancebyhealthcare workers

Henningsenetal.

(2007)

Aimstoexplainalargevarietyof functionalsomaticdisorders(CFS,FM, IBS,IEI,nonspecificchestpain,and severalothers)

Experienceofbodilystress,resultingfrom specifiablebiological(disease),psychological, interpersonaland/orsocialfactors,isatthe core

Attentionalmechanismsarenot specified,butapparentlyimpliedina processofinterpretationofstress symptomsassymptomsofadisease

Attributionandinterpretationofbodilystress symptomsasdiseasemaycauseanxietyand depression,addingmorebodilystress,stimulating interpretationasseveredisease,andincreasing emotionaldistressandlossoffunctioning WitthöftandHiller

(2010)

AimstoexplainMUSingeneraland thecoreofsomatoformdisordersand functionalsomaticdisorders(CFS,FM, IBS,IEI).Focusesalsoonsimilarities anddifferenceswithhypochondriasis

Physiologicalprocesses,asrelatedto alterationsinHPA-activityandsustained physiologicalarousalmayunderliesomatic sensations,butalsomediareports, conditioningexperiencesandchronically activatedmemoryschematamaycontribute toMUSintheabsenceofdistinctphysiological input

Attentionalprocesses,expectancies andchronicallyactivatedsomatic memoriesincreasetheprobabilityof somaticsensationsentering awareness

Catastrophicinterpretationsandmisattributions, importantlydrivenbyneuroticism,amplifysomatic sensations,whichinturninspireavoidancebehaviors andillnessinterpretations.Inadequateresponseof healthcareworkersmayfurtherfueltheimpactof attentionalandcognitiveprocesses,includingworry, onsymptomperceptionandinterpretations.

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disease-relatedautonomic,endocrineandimmuneresponses.Itis importanttonoteinthiscontextthatasimplecausalmodelmay betoosimplistic,andthatadistinctionshouldbemadebetween predisposing, precipitating and perpetuating factors. A specific physiologicaldysfunctionelicitingsymptomsinaninitialstage(e.g.

inflammation,infection)maybefollowedbyprocessesthatserve tomaintainsymptoms,suchasstress-relatedphysiologyrelatedto, forexample,ongoingconcerns.Inthelattercase,however,reliable associationsshouldstillbefoundbetweensymptomsandphysio- logicalparametersifsymptomsreflectphysiologicaldysfunction.

Meta-analyticandsystematicreviewstudiestypicallyreveala mixedpicture.Ifrelationshipswithphysiologicalabnormalitiesare foundatall,theassociationsareinconsistent,generallysmall,and thedirectionofcausalitybetweenfunctionalsomaticsyndromes andthedysfunctionremainsunclear,mostlyleadingtothecon- clusionthatthereislittleconvincingevidenceforthecausalrole ofa particularphysiologicaldysfunction.Thispictureappliesto autonomicfunctionasindicatedbyheartratevariability:ameta- analysisbyTaketal.(2009)foundnosignificantdifferencebetween patientswithfunctional somaticdisorders andhealthy controls after controllingfor publication bias. Anotherreview found no differencesbetweenpatientswithfunctionalsomaticsyndromes and healthy controlsin halfof thestudies, and someevidence ofreducedcardiacvagalactivityinanotherhalf,dependingalso onthetypeoffunctionalsyndrome(TakandRosmalen,2010).A systematicreviewofVanCauwenberghetal.(2014)suggesteda reducedcardiacresponsetoahead-uptilttestinchronicfatigue patientsin7of8studies.Takingthecortisolresponsetoindicate hypothalamic-pituitary-adrenal(HPA)axisfunctioning,Taketal.

(2011)only foundevidence for lower cortisollevelsin chronic fatiguepatientsandinfemaleswithfibromyalgia,butnotinirri- tablebowelsyndrome.AreviewbyPowelletal.(2013)couldnot establishhypocortisolisminchronicfatiguepatients,butfoundevi- denceforanattenuationofthediurnalvariabilityofthecortisol response.Asimilarpicturearisesfromreviewstudiesontherole ofinflammatory,infectious,orautoimmunedysfunctioninfunc- tionalsomaticsyndromes:fewdifferencesarefound,andifso,they mostlypertaintodifferentparameters(seeBorchersandGershwin, 2015;Üc¸eyleret al.,2011; Blundelletal., 2015;Ishihara etal., 2013;Schwille-Kiuntkeetal.,2015).Importantly,wheneveradys- functionisobserved,fewstudiestestwhethertheabnormalities actuallycauseormediatethesymptomsinquestion.

1.2.2. Interoceptivehypervigilance,thresholdsandawareness Someversionsoftheamplificationmodelgiverelativelymore weighttohypervigilanceandloweredperceptualthresholdsfor normalphysiologicalarousal.Self-reportstudiesindeedshowthat individualswithMUSreportatendencytoscanthebodyforsignsof illness(e.g.,Gendollaetal.,2005;Riefetal.,1998).However,objec- tivemeasuresofattentiontohealth-relatedstimulihaveyielded lessconsistentfindings.Forsymbolicmaterial(e.g.,illnesswords), somestudieshavefoundincreasedinterferenceontheemotional StrooptaskinpatientswithMUS(e.g.,Afzaletal.,2006;Limand Kim,2005;Witthöftetal.,2006).Theseeffectsmaybeattributable toincreasedavoidanceofhealth-threatrather thanengagement withit(DeRuiterandBrosschot,1994),however,orstimulusneg- ativitymoregenerally(Posserudetal.,2009).Studiesusingthe dot-probeandexogenouscueingparadigmshavenotfoundevi- denceofattentionalbiasinMUSpatients(ChapmanandMartin, 2011;Houetal., 2008;Martinand Alexeeva,2010; Martinand Chapman,2010;vanderVeeketal.,2014;Witthöftetal.,2006).

Studiescomparingfibromyalgiapatientsandhealthycontrols foundnodifferenceintheirabilitytodetectinnocuoustactilestim- uli(Vandenbrouckeetal.,2014;VanDammeetal.,2014),and/or observedthatonlyNApredicteddailysymptomreports(Mussgay etal.,1999;Schaeferetal.,2012).Otherstudiesinvestigatingatten-

tionalprocessing ofbodilysensations themselvesprovidesome evidence for a relationship betweenattention tothe body and symptomreporting,althoughalsoimplicateavoidanceofbodily sensations(Brownetal.,2007;Brownetal.,2010).Interestingly, Katzeretal.(2012)foundthatlowertactileperceptualthresholds wereassociatedwithfewersymptomsinpatientswithsomato- formdisordersontheSomaticSignalDetectionTask(SSDT).Other studiesfoundthatbothsomatoformdisorders(Katzeretal.,2012) andsymptomreportingmoregenerally(Brownetal.,2010,2012;

Katzer et al., 2011) were associated witha tendency to report sensory experiences ontheSSDTregardlessof whetherstimuli wereactuallypresented(i.e.‘falsealarms’),seeminglycontradict- ingthepredictionofimprovedaccuracy.Similarly,VandenBergh andcolleaguesfoundsignificantlylowercorrespondencebetween inducedrespiratorychangesandself-reportedbreathlessnessina CO2inhalationparadigmfornon-clinicalMUSreporters(Bogaerts etal.,2008)andMUSpatients(Bogaertsetal.,2010b).

Insum,individualswithMUSconsistentlyreportatendencyto scantheirbodiesforsignsofillness,butstudiesmeasuringactual attentionaldeploymenttowardsbody-orillness-relatedstimuli failtoprovideconvincingevidenceforanattentionalbiastowards thesestimuli.Althoughtheavailableevidenceremainstoolimited forafirmconclusion,mostevidencepointstoalowercorrespon- dence between physiological changes and symptom reports in theseindividuals.

1.2.3. Misattributionandinterpretationbias

ThemodalmodelassumesthatpatientswithMUSandrelated conditionsshow:(i)atendencyto(mis)interpretbenignbodilysen- sationsinanegativemanner,thatis,asoverlyintense,noxious,and potentiallylife-threatening(NakaoandBarsky,2007);and(ii)a tendencytoattributesomaticsensationstosomaticdisease,rather thanpsychologicalorneutral/externalcauses(“somaticattribution bias”).Evidenceinlinewiththe(mis)interpretationassumption hasbeendocumentedformostMUS-relatedconditions,suchas chronicpain, somatoformdisorders, fatigue,health anxietyand hypochondriasis (Goedendorpet al.,2013; Marcus et al.,2007;

Riefetal.,1998;RiefandBroadbent2007;RiefandMartin,2014).

Thesebeliefs correlatewithvariousratingsindicating theaver- sivequalityofinducedorexistentbodilysensations,suchas(pain) thresholdand unpleasantness. Suchbeliefs arealsoreflected in behavioral evidenceof acorrelationbetweenMUS,health anxi- ety,hypochondriasisandtheautomaticnegativeevaluationofboth illness-relatedpictures(JasperandWitthöft,2013),illnesswords (Schreiberetal.,2014),andaversivetactilestimuli(Witthöftetal., 2012),althoughthis effectwasnotfoundinpatientswithnon- cardiacchestpain(Schroederetal.,2014).Itisnotclearwhether suchfindingspointtoacauseorconsequenceofMUS.Onerecent longitudinalpopulation-basedstudyfoundthatcatastrophicmis- interpretationsofbodilysensationsatbaselinewereasignificant predictorofhypochondriacalconcernsandfearofbodilysensations 18monthslater,butnotofphysicalsymptomreportsasassessed byasymptomchecklist(Woudetal.,2016).Apparently,inthis studycatastrophicmisinterpretationscontributedtolatercogni- tiveandemotionalresponsestoMUS,butnottotheoccurrence ofMUSthemselves.Obviously,replicationsareneededtoconfirm thisconclusion.

StudiesfocusingontheattributionstyleofpatientswithMUS suggestedadominanceofsomaticsymptomattributions(e.g.,Craig etal.,1993;RobbinsandKirmayer,1991),butrecentevidenceindi- catesthat theyaremorecomplex thanthis (Hilleret al.,2010) and thatsomaticattributionsdonot predictthecourseofMUS (DouzenisandSeretis,2013),implyingthattheyareunlikelytoplay acausalroleinthedevelopmentandmaintenanceofsymptoms.

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190 O.VandenBerghetal./NeuroscienceandBiobehavioralReviews74(2017)185–203

1.2.4. Conclusion

Althoughtheamplificationmodelisintuitivelyappealingand remainsclinicallypopular,theavailableevidencedoesnotprovide convincingsupportfor thenotionthatMUSresultfromdysreg- ulated peripheral (stress) physiology, hypervigilance for bodily sensations, heightened interoceptive accuracy, or misinterpre- tationsof bodily sensations. The notable lack of evidence that peripheralphysiologicalabnormalitiesplayaspecificandcausal roleinfunctionalsomaticsyndromeshascontributedtogrowing interestamongresearchersintheconceptofcentralsensitization asapotentialcommongroundforfunctionalsomaticsyndromes (seefurther;KimandChang,2012;Nijsetal.,2012;Bourkeetal., 2015).Moregenerally,theorizingseemstohaveevolvedtowards identifyingMUSasperceptual(orinteroceptive)conditions(e.g., Brown,2004;Edwardsetal.,2012).

1.3. Howdifferentare‘explained’and‘unexplained’symptoms?

IfstandardmedicalpracticeregardsMUSandfunctionalsomatic syndromes as unusual phenomena that should beexported to thepsychological/psychiatricdomain,itisgenerallyassumedthat thedisease modelfares betteras an account ofthe symptoms whendysfunctionisactuallypresent.Indeed,thecorrespondence betweensymptomsandobjectivephysiologicalparametersisgen- erallyhighforacuteandlocalizeddysfunctionorpain(Priceetal., 2001). This correspondence is both moderate and highly vari- ableinmanymulti-symptomaticandchronicdiseases,however.

For example, there is a poor correspondence between somatic symptomsandobjectivediseaseseverityinabout50%ofasthma patients depending on the measure (Janssens et al., 2009). In chronicobstructivepulmonarydisease(COPD),largescalestud- iesonseveralthousandsofpatientsshowedlargebetween-person variabilityintherelationshipbetweenobjectiveairflowlimitation (FEV1)andself-reportedbreathlessness,withamodestcorrelation overall(r=0.36,Agustietal.,2010;r=0.28,Müllerováetal.,2014).

Within cardiology, the observed correlation between self- reported symptoms and objective parameters of heart disease (24-hambulatorymonitoring,trans-telephonic ECGs,datafrom implanted pacemakers or defibrillators)ranges from near zero (Barsky,2001)to0.17(Searsetal.,2005).Similarly,thelikelihoodof reportedarrhythmiasymptomscoincidingwithanactualarrhyth- miarangesfrom17%to61.1%.Reportsofatrialfibrillationhave beenfoundintheabsenceoftachyarrhythmiasin25%to45%of cases(Atarashietal.,2008;Strickbergeretal.,2005).Furthermore, regardlessoftheireffectonobjectivephysiological functioning, traitnegativeaffect,negativeemotions,and/ordepression have oftenbeenfoundtopredictsymptomreportsbetterthanobjec- tivemeasuresofcardiacorrespiratorydisease(e.g.,Janssensetal., 2009;Searsetal.,2005;VanOudenhoveetal.,2008).Datahave alsoshownthatatransientincreaseinstresslevelscanalterthe perceptionofsymptomsinpatientswithgastro-esophagealreflux disease,resultinginincreasedsymptomreports(Fassetal.,2008;

Wrightetal.,2005).

Subjectivesymptomreportscorrelatingpoorlywithphysiolog- icalchangeshavealsobeenfoundindiabetes,forwhichaccurate detectionofhealthstatusisofcrucialimportance.Frankumand Ogden(2005),forexample,foundthat43.3%ofpatientsunderes- timatedtheirbloodglucoseand17.3%overestimatedit.Similarly, Ryanetal.(2002)foundthatestimationofbloodglucosewasonly 28%accurateforhypoglycemiaand38%foreuglycemiainasam- pleofadolescentsand youngadults. Althoughthere havebeen studiesshowinggreatercorrelations(0.70)betweenestimatedand actualbloodglucose(Schandryetal.,1996),symptomperception inthiscontextisgenerally consideredinaccurate.Evidencealso showsthatphysicians’assessmentofsymptomsismorehighlycor-

relatedwithobjectiveorganicparameters(0.52–0.92)thanthose ofpatients(0.34–0.70;Turneretal.,2010).

Insum,researchwithmedicalpopulationssuggeststhatcorre- lationsbetweensymptomreportsandobjectivediseaseindicators varysubstantially,areoftenlowtomoderate,andthatemotional factorsplayaparticularlysignificantroleinsymptomreporting.In otherwords,alargeproportionofthesymptomspresentedinthe contextofawell-defineddiseasecouldtechnicallybeconsidered

“MUS”.Thisismostlyoverlooked,however,asfewstudiesactually measurethewithin-personcorrespondencebetweenphysiological dysfunctionandsymptomreports.

1.4. Interimsummary

Thedivideofwesternmedicalsystemsintoeither‘physical’or

‘mental’healthdisciplinesisarguablyresponsibleformostcontro- versiesregardingMUS,withphysicalandmentalhealthspecialists favoringdistinctterms,diagnosticcriteriaandillnessnarrativesfor anoverlappingsetofcomplaints.Numerouscommentatorshave criticizedtheoversimplifying mind-bodydualismthat is inher- enttothisapproach(RiefandMartin,2014).Inaddition,abrief excursioninto“medicallyexplaineddiseases”castsdoubtonthe logic of a clear differentiation betweensymptoms that do and donothaveaphysiologicalexplanation.Evidently,thereissome continuityinthemechanismsunderlyingallsymptomreporting, whetheran‘organic’conditionispresentornot.Sincetheseminal monographofPennebakeronthepsychologyofphysicalsymptoms (Pennebaker, 1982), and extensive elaborationsin later models (seeCioffi,1991;LeventhalandLeventhal,1993;Leventhaletal., 1998),theroleofpsychologicalfactorsinsymptomreportingand healthcareusehasbeenclearlydocumented.Thesemodelstypi- callydescribehowfactorssuchasbeliefs,attributions,emotional statesandattentionmodulatetherelationshipbetweenphysio- logicaldysfunctionandsymptomreports,butrarelyquestionthe basicassumptionofthediseasemodel.Moreover,theyprovidelit- tleinsightintohowconsciouslyperceivedsymptomscomeabout, andwhenorhowtheyrelate(ornot)tobodilydysfunction.Thereis aclearneedforasymptomperceptionmodelthatcomplementsthe diseasemodelbyexplainingboth“explained”and“unexplained”

symptoms,withouthavingtorelyontheconceptof peripheral physiologicalchangeinallcases.Weattempttoprovidesucha frameworkbelow.

2. Anewperspective 2.1. Aimsandcentraltenets

Inthissectionwedescribeacomprehensivemodelofsymp- tomperceptionthatintegratesresearchandtheoryonMUSand functionaldisorderswiththatonsymptomandbodyperception moregenerally.Ourgoalistodescribethemechanismsunderly- ingtheconsciousexperienceofsomaticsymptoms,andthereby theconditionsthatgovernhowandwhenthosesymptomscorre- spondwithphysiologicaldysfunction.WearguethatMUSreflecta perceptualsystemthatiscontinuallygenerating,testingandrefin- inghypothesesaboutthecausesofsensoryinputs,andwhichis vulnerabletomistakeninferencesandfalseperceptsundercertain conditions.We suggestthatMUScanberegardedassomatovis- ceralillusions,comparabletovisualillusionsin castinglight on fundamentalaspectsofperception(alsoNormanetal.,2014).We claimthatthisprocessofautomaticandunconscioushypothesis testingappliesasmuchto“veridical”symptomperception(where symptomscorrespondcloselywithphysiologicaldysfunction),as tobiasedsymptomperception(wheresymptomreportsseemonly partlyconsistentwithphysiologicaldata),andMUS(wherenorela-

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tionshipwithphysiologicaldataisfoundatall).Thecentraltenets ofouraccountcanbesummarisedasfollows:

1.Somaticsymptomsareconsciousperceptsthatresultfromacon- structiveprocess,inwhichthebraininterpretsinformationfrom thebodyinthelightofpredictions(broadlyspeaking,expecta- tions)givenpastexperience;thisprocessismoderatedbythe relativeprecisionaffordedtothepredictionsandtheprediction errors;

2.Therelationshipbetweenparametersofbodilydysfunctionand self-reportedsymptoms is highlyvariable both betweenand withinindividualsovertime,dependingoninteractionsbetween characteristicsofthephysiologicalinput,the(historical)person andthecontext;keyfactorsinthisrespectarethosegoverning theindividual’sinteroceptivesensitivity/acuityandtheimplicit categorizationcriteriausedtodecidewhetherasensationisa symptom;

3.Therelationshipbetweenparametersofbodilydysfunctionand self-reportedsymptomsvariesdimensionally.AlthoughMUSare atoneendofthiscontinuum,theyarefunctionallycompara- blebothtobiasedsymptomreportsofidentifiablephysiological dysfunctionandsymptomsexperiencedinthecontextofwell- describeddiseases;

4.Theveryprocessofenquiringaboutthepresenceofsomaticper- ceptsinfluenceshowweexperienceourbodyandtherebythe symptomswereport.

Ourapproachisfundamentallydifferentfromtraditionalsymp- tomperceptionaccounts,whichassumethat“...theperceptionof physicalsymptomsisgenerallyprecededbyperipheral,physiological changes”(Kolketal.,2003,p.2344);seeTable1).Itbuildsonprevi- ousaccountsofMUS(theIntegrativeCognitiveModel,ICM;Brown, 2004,2006,2013;BrownandReuber,2016)andfunctionalneu- rologicalandmotorsymptoms(“conversionsymptoms”;Edwards etal.,2012),whichassumethatperipheralphysiologicalinputis neithernecessarynorsufficientforsymptomstobeexperienced.

Bythisview,top-downprocessesnotonlyinfluencehow,butalso whetherweexperiencesymptoms.AsintheICM,weregardMUS asdistortionsinawarenessbroughtaboutbytheover-activation ofsymptomrepresentationsinmemory,withvarioustop-down factorsservingtomaintainthis;wemovebeyondtheICMbyinte- gratingourapproachmoreexplicitlywithexistingworkonbody perceptionandinteroception,andwithaccountsoftheneurobio- logicalsubstratesoftheseprocesses.Wealsoplacemoreemphasis onaffectiveprocessing,andaddresscertainlimitationsoftheICMin relationtotheroleofattentioninsymptomdevelopmentandmain- tenance.OuraccountfollowsEdwardsetal.(2012)inadoptinga predictivecodingperspectivetohelpelucidatethemechanismsof MUS.However,Edwardsetal.(2012)focusesspecificallyonfunc- tionalmotorandsensorysymptoms(e.g.,anaesthesia,movement disorders,sensoryloss),andexcludesfunctionalsymptomsinvolv- ingautonomicdysfunctionand/orarousal,functionalsyndromes andothersomatizationproblems(Edwardsetal.,2012p.3496).

Thelatterarethemainfocusofourpaper,inthecontextofsymp- tomperceptionmoregenerally.Welimit ourselvestoprocesses thathelpexplainhowtheconsciousexperienceofbodilysymptoms comesabout,althoughweacknowledgethatsymptomperception occursinaninterpersonalandsocialcontextthatevidentlyshapes howsymptomsarelabelledandreported.Forthesakeofbrevity, thesesocialprocessesareonlyindirectlytakenintoaccountinour model.

Westartbydescribingthebasicprocessesunderlyingpercep- tionoftheinternalstateofthebody.

2.2. Interoceptionasinference

Althoughacontinuous,fluctuatingarrayofstimuliimpingeson receptorsinsideourbody,mostinteroceptiveinformationisused bylocalandsubcorticalregulationsystemsandisnotamenableto consciousperception.Fromthelimitedamountofsensoryinforma- tionthatafferentsystemscanprocess,thebraincouldtheoretically createaninfinitenumberofpatternsofexperiences.Thetaskof thebrainistogroupinputintothosepatternsthataremostuseful, reducingcomputationalloadbyignoringinputsthatareunlikely tohaveadaptivevalue.SinceHelmholtz(1860),numeroustheo- rists(e.g.,Gregory,1980;Friston,2005;Kveragaetal.,2007;Clark, 2013)havearguedthatthebrainachievesthisthroughaninferen- tialprocess,involvingthecreationofprobabilisticmodelsaboutthe causesofcurrentinputstothesystem,basedonpriorknowledge.

Theseassumptionshaverecentlybeenelaboratedforinterocep- tiveandaffectiveinformationprocessingandtheirinteractionwith externalperception(BarrettandBar,2009;Edwardsetal.,2012;

Seth,2013;BarrettandSimmons,2015).Chronicpainhasrecently beenconceptualizedusingapredictivecodingperspective,ashas themodulationofpainperceptionbyplaceboandnoceboexpec- tations(seeBücheletal.,2014;Hechleretal.,2016;Wiech,2016).

Ouraccountbuildsontheseapproaches.

2.2.1. Prediction,predictionerrorandprecision

Inpredictivecodingmodels,learnedknowledgeabouttheworld isconceptualizedasasetofneuralrepresentationsor‘priors’,which capturethestatisticalregularitiesofbrainactivity.Thesearerepre- sentedasprobabilitydistributionsthatdescribeanexpectedrange ofvaluesforagiveninputandtheirassociatedlikelihood(Fig.2).

Differentpriordistributionsmatchsensoryinputs(“observation”

inFig.2)tovaryingdegrees,resultinginpredictionerrors(i.e.,the portionofinputnotpredictedbytheprior,orthedifferenceinmean betweenpriorand“observed”distributions).

Everycombinationofpriorandobserveddistributionsconsti- tutesamodelofthecausesoftheactualstimulation,eachwitha differentrangeofprobabilities(posteriordistribution).

Thesegenerativemodelsinitiallycapturethegistofthestim- ulusarray(Kveragaetal.,2007),and predictionerrorsarethen usedtofurtherrefinethem. Afundamental“motivation”of the systemistominimizepredictionerror(Friston,2005).Thispro- cesscan beaccomplishedby updating theprior to accountfor unpredictedstimulation(perceptualinference;broadlyspeaking:

changing“expectations”),bygeneratinginformationthatfitsthe priorthroughaction(activeinference),orbychanginghowinput issampledbythebrain(BarrettandSimmons,2015).Thesystem thataccomplishesthisishierarchicallyorganized,suchthatlower levelsofthehierarchyrepresentthebasicpropertiesofthesen- soryinput,withcomplexity,abstractionandspatio-temporalscale increasingasoneproceedsthroughthehierarchy.Thereisacon- tinuous,bi-directionalflowofinformationthroughthishierarchy, suchthateachlevelreceivespredictionsfrom,andfeedsbackpre- dictionerrorsto,thelevelsabove.Inacontinuousinterplayofthese processes,bottom-upinformation(predictionerrors)isdependent ontop-downinfluences(predictions),whichthemselvesareinflu- encedbypreviouspredictionerrorsdependingontheirprecision.It alsomeansthatdysfunctionalpredictionswillhaveconsequences forpredictionserrors,andviceversa(seebelow).

Across a number of experiences, predictions and prediction errors mayacquireassociated “confidence”, representedby the variancearoundthemeanofthedistribution(i.e.,theyhavediffer- entprecisions).Aprecisepriorcorrespondstoastrongprediction, allowingforperceptualdecisionswithahighlevelofconfidence.

Weusethetermconfidenceinastatisticalsenseonly,sincethese perceptualdecisionsrarelyreachthelevelofawarenessforthem

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192 O.VandenBerghetal./NeuroscienceandBiobehavioralReviews74(2017)185–203

Fig.2.a-c:Therelationshipbetweenpriorandposteriordistributionsinthelightofnewobservations.Theupperpanelrepresentstheimpactofalowprecisionprior(blue) ontheposteriordistribution(red)inthelightofnewevidence(green).Inthiscaseofaweakprior,newinformationhassubstantialimpactontheformationofaposterior interpretation.Themiddlepanelrepresentstheimpactofahighprecisionpriordistributionontheposteriordistribution,givenevidencethatdisconfirmsthepriortosome extent.Thelowerpanelshowsapriorthatishighinprecisionandnewobservationsthatareinconsistentwiththepredictionbutareimpreciseandthereforehavelittle impactonthesubsequentposterior.Seethetextforanelaboratedexamplewithspecificreferencetosymptomperception.(Forinterpretationofthereferencestocolorin thisfigurelegend,thereaderisreferredtothewebversionofthisarticle.)

tomanifestasmeta-cognitivecertainty;instead,thesubjectsimply perceiveswhatthesystemhasconcludedis(orisnot)there.

Consider the case of a newly developed condition such as asthma,whena patientstartstoencounterinteroceptivesensa- tionsthatmayormaynotrepresentanasthmasymptom.InFig.2a, relativelyfewpriorobservationsareavailable,meaningthatthe perceptualsystemislesscertainwhetherasensation(e.g.,feelingof tightnessinthechest)isarelevantindicatoroftheperson’shealth status.ThisisrepresentedinFig.2aasarelativelybroad,flatprior distribution,thatis,onewithrelativelylowprecisionwithacen- traltendencythatislocatedatalowprobability(centraltendency onthelefthandsideofthexaxis),indicatingthatthediagnostic valueofthissensationforasthmaislow.Comparativelyprecise newobservations(greyline)haveaconsiderableimpactonsucha

vaguepriorandshifttheinitialhypothesistobeclosertothenew evidence(theposterior;blackline).Asmoreobservationsaremade (e.g.,overthecourseofayear),thesystemlearnsthatthesensation isindeedavalidindicatorofasthma,resultinginanarrower,denser (i.e.,moreprecise) priordistributionthatshiftedtotherightas theestimatedprobabilityofthesensationbeinganasthmasymp- tomincreased(dashedlineinFig.2b).Thelargeramountofpast evidencebythispointmeansthatthesameamountofnewinfor- mation(i.e.,newencounterswiththesensation;greylinein2b) haslessofanimpactontheinferenceprocessthanbefore,mean- ingthattheposteriordistribution(blacklinein2b)remainsclose totheprior.Fig.2cillustratesacasewhere,incontrasttothefirst twoexamples,theprobabilityofasensationindicatingasthmaon thebasisofpriorexperiencesishigh,whilethesomaticsensation

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(observation)islessprecise.Herethereisevenlessofanimpactof thenewobservation,resultinginminimalchangefromtheprior distributionandstrongereditingoftheincominginformation.The resultisanexperience(posterior)thatreflectsthepriorratherthan theobservation,withpre-existingexpectationsbeingmaintained.

Inprecise distributionsthere isa greaterlikelihood thatthe expected/actualvaluefallsclosetothemean,resultinginalarger influence on the generative model. Typically, the model with thelowestoverall predictionerroristhatwiththeoptimalbal- ancebetweenprecisionandaccuracy(i.e.,thesmallestdifference betweenthemeansofthepredictedandpredictionerrordistribu- tions).Animportantaspectoftheperceptualprocessishowthe systemdetermineswhetherthepredictionisanadequateaccount oftheinput.In ordertodothis,itmustbeabletoestimatethe likelihoodofanyresidualpredictionerrorbeingrandomnoise,or whetheritcouldbereducedfurtherbyupdatingtheprediction.

Thesystemdoessobydevelopingcontext-dependentexpectations aboutthelikelyprecisionofitsinputs,anditcompensatesforthese byadjustingtheweightplacedonthemintheperceptualprocess (Hohwy,2012).Visualpredictionerrorsarehigherinthedark,for example,andrelativelymorelikelytobeaproductofnoisethan signalthanwhenitislight.Incontrast,thesystemlearnsthaterrors arisinginthelightarelikelytobemeaningful(i.e.,anunexpected stimulus),andshouldhavemoreofaninfluenceonperception.

Theprocessofattributingweightstothepredictionerrorsto optimizeperception(precisionoptimization)isthoughttobean importantfactordeterminingthedominantgenerativemodeland thereforeconsciouspercepts(FeldmanandFriston,2010;Hohwy, 2012).Typically,priorshavelessinfluenceandaremoresubject torevisionwhenprocessinginvolvesunitsexpectingpreciseinfor- mationfromthesensorium(e.g.,inthelight).Conversely,priors havemoreofaninfluenceonperception,andaremoreresistantto updating,whennoisy,imprecisesensoryinputisexpected(e.g.,in thedark).Oneconsequenceofthisisthatmistakescanbemade whenunexpected-but-meaningfulsignalsarisewhen inputsare predictedtobeimprecise,biasingperceptiontowardsaprecisebut inaccurateprior.Thus,wemaymistakeJoeforFredinthedarkif thereisastrongexpectationthatFredwillarrivefirst.Intheaccount belowwedeveloptheideathatMUSinvolveasimilarperceptual error.

2.2.2. Neurobiologicalconsiderations

Vagusnerveafferentsareamajorsourceofinteroceptiveinfor- mation,relayingsensoryinformation fromnearlyeveryvisceral andsomaticsystemtothebrainthroughthenucleustractussoli- tarius(NTS)and ascendingprojectionstobrainstem,limbicand corticalstructures(BerthoudandNeuhuber,2000).Severalbrain structuresandcircuitsarecriticalinconstructingandrepresenting aconsciousstateofthebody(e.g.,Craig,2002,2009)formingan interoceptivenervoussystem(Harshaw,2015).Forexample,the anteriorinsularcortex isgenerally consideredtoplaya central roleinconstructingamultimodalrepresentationoftheinternal stateofthebody,integratinghormonal,immunological,metabolic, thermal,autonomic,visceromotor,proprioceptive,exteroceptive, motivationaland cognitivesources ofinformation (Craig, 2009;

CritchleyandHarrison,2013).Theanteriorinsularcortexisalso considered to play a critical role as a source of visceromotor predictionsand in matching prediction errors with predictions (Seth, 2013; Seth etal., 2011).Through closeconnections with theanteriorcingulatecortex,thesemulti-modalrepresentations also involve affective-motivational components and associated approach-avoidance tendencies, consistent withthe close con- nectionbetweeninteroceptiveinferenceaboutbodilystatesand feelingsandemotions(Seth,2013;Zakietal.,2012).Otherstruc- turesinvolved inprocessingtheaffectivevalueofinteroceptive stimuliaretheorbitofrontal(BarrettandBar,2009)andventrome-

dialprefrontalcortex,which,togetherwithpartsofthecingulate cortex, are thoughtto constitute a stimulusvaluation network (Harshaw,2015)that engagesbehavioral controlsystemswhen localphysiologicalregulationfails(e.g.,gaspingforairandopening thewindowwhenbreathless).

Apredictivecodingperspectiveassumesthatprecisionisrepre- sentedbytheactionofspecificcellsthattunethesynapticgain(i.e., post-synapticresponsiveness)of cells encoding predictionsand predictionerrors(Friston,2008;BarrettandSimmons,2015).As thereisaconstantinterplaybetweenpriorsandpredictionerrors atmultiplehierarchicallevels,apredictivecodingmodelsurpasses simpleandunidirectionalconceptionsof“top-down”and“bottom- up” processes, aswell asthe notionthat specificfunctionsare localizedtoparticularbrainregions.Consistentwiththis,recent neurobiologicalmodelshaveemphasizedcontinuousinteractions betweencounter-flowingstreamsofinformationatmultiplehier- archicallevels.BarrettandSimmons’(2015)EmbodiedPredictive InteroceptiveCodingmodeldescribesanintegratedneuralnetwork thatserves bothhomeostaticandallostaticcontrol functionsas wellasinteroception.Itemphasizesmorewidespreadcorticocor- ticalconnectivityacrosshierarchicallyorganizedlamina(cortical columns) forming granular, agranular and (intermediate) dys- granularcortices.Thesecorticesconsistofanatomicallydifferent cellsactingasprediction,predictionerrorandprecisionneurons.

Agranularvisceromotorcorticescomprisingmid-cingulate,ante- riorcingulatecortex,posteriorventromedialprefrontalcortexand parts of theanterior insula generate autonomic, hormonal and immunologicalpredictionstoadjustthebodytoanticipatedneeds.

Thisinformationisalsosenttogranularcorticescomprisingthe mid-to-posteriorinsula,wherepredictionerrorsarecalculatedand sentbacktoagranularvisceromotorregions;here,outputstothe bodyaremodulatedandnewinteroceptivepredictionsarise.Vis- ceromotorcorticescanalsomodulatethegainofcorticothamalic and thalamocorticalconnections (i.e.,attentiontointeroceptive sensations).

Importantly,agranularvisceromotorregionsareconsideredto berelativelyinsensitivetopredictionerrorsignalsduetoprecision- weighting factors and aspects of the cytoarchitecture. For this reason,interoceptivepredictionerrorsaretypicallysmall,mean- ingthatinteroceptiveperception(theposteriormodel)islargely dominatedbypriorexpectations.AsBarrettandSimmons(2015, p.424)putit:“interoceptiveperceptionislargelyaconstruction ofbeliefs thatarekeptincheckbytheactualstateofthebody (ratherthanviceversa)”.Anotherimportantfeatureisthatagranu- larvisceromotorcorticesareacentralhubsendingefferentcopies ofpredictionstomultiplesensorysystemsacrossthebrain,and thussubserve“amultisensoryrepresentationoftheworldfrom theperspectiveofsomeonewithabody”(BarrettandSimmons (2015, p.424)).Thisarchitecturecontributestoembodimentof perception, cognition and emotion, and tobi-directional pene- trance(i.e.,cross-fertilisation)ofinteroceptiveandexteroceptive information(Harshaw,2015;forexamples).Theseneurobiological findingsplaceimportantconstraintsontheoriesofsymptomper- ception,whichisevidentlyhighlysensitivetopriorexpectations andcontextualcues.

2.2.3. Interoception,expectationsandthesenseofself

Conceptualisinginteroception as inferenceblursthe distinc- tionbetweenperceptionsandbeliefsorexpectations.Consistent with this, neurobiological findings show that largely the same brain areas are activated regardless of whether symptoms are producedusingexpectancymanipulationsorelicitedbyperiph- eral stimulation. For example, an fMRI study of patients with disablingself-reportedelectrosensitivityexposedtoshammobile phoneradiationfoundactivationinthesamebrainregions(ante- riorcingulatecortex;leftandrightanteriorinsularcortex)asthat

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