Hearing voices in the resting brain: A review of intrinsic functional connectivity research on auditory verbal hallucinations

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ContentslistsavailableatScienceDirect

Neuroscience

and

Biobehavioral

Reviews

j o u r n a l ho me p ag 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

Hearing

voices

in

the

resting

brain:

A

review

of

intrinsic

functional

connectivity

research

on

auditory

verbal

hallucinations

Ben

Alderson-Day

a,∗

_,

_Simon

_{McCarthy-Jones}

b

_,

_Charles

_Fernyhough

a

a_Department_of_Psychology,_Durham_University,_Science_{Laboratories,}_South_Road,_Durham_DH1_3LE,_United_Kingdom b_Department_of_Cognitive_Science,_Australian_Hearing_Hub,_Macquarie_University,₁₆_University_Avenue,_NSW_2109,_Australia

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received27November2014 Receivedinrevisedform16April2015 Accepted25April2015

Availableonline5May2015 Keywords:

Restingstate Defaultmodenetwork Voice-hearing Innerspeech Schizophrenia

a

b

s

t

r

a

c

t

Restingstatenetworks(RSNs)arethoughttoreﬂecttheintrinsicfunctionalconnectivityofbrainregions. AlterationstoRSNshavebeenproposedtounderpinvariouskindsofpsychopathology,includingthe occurrenceofauditoryverbalhallucinations(AVH).Thisreviewoutlinesthemainhypotheseslinking AVHandtherestingstate,andassessestheevidenceforalterationstointrinsicconnectivityprovided bystudiesofrestingfMRIinAVH.Theinﬂuenceofhallucinationsduringdataacquisition,medication confounds,andmovementarealsoconsidered.Despitealargevarietyofanalyticmethodsanddesigns beingdeployed,itispossibletoconcludethatrestingconnectivityinthelefttemporallobeingeneral andleftsuperiortemporalgyrusinparticulararedisruptedinAVH.Thereisalsopreliminaryevidenceof atypicalconnectivityinthedefaultmodenetworkanditsinteractionwithotherRSNs.Recommendations forfutureresearchincludetheadoptionofacommonanalysisprotocoltoallowformoreoverlapping datasetsandreplicationofintrinsicfunctionalconnectivityalterations.

(http://creativecommons.org/licenses/by/4.0/).

Contents

1. Restingstatenetworksandpsychopathology... 79

2. Restingstatehypothesesandauditoryverbalhallucinations... 79

3. Resting-stateﬁndingsinAVH-speciﬁcstudies... 80

3.1. Auditory/language-processingregions... 80

3.1.1. Primaryauditorycortex... 80

3.1.2. Superiorandmiddletemporalgyri... 80

3.1.3. Inferiorfrontalgyrus... 81

3.2. Defaultmoderegions... 82

3.2.1. Temporoparietaljunction... 82

3.2.2. Midlinestructures(cingulatecortexandprecuneus)... 82

3.2.3. Hippocampalformation(hippocampusandparahippocampalcortex)... 82

3.3. Othernetworksandbetween-networkinteractions... 82

3.3.1. Insulaandstriatum ... 82

3.3.2. InteractionsbetweentheDMNandothernetworks... 83

4. Confoundstotherestingstate:hallucinations,medication,andmovement ... 83

5. Discussion... 84

Acknowledgements... 85

References... 85

∗ Correspondingauthor.Tel.:+441913348147.

E-mailaddress:benjamin.alderson-day@durham.ac.uk(B.Alderson-Day).

Auditoryverbalhallucinations(AVH)refertohearingvoicesin theabsenceofanexternalstimulus.Theyareconsidereda core featureofschizophrenia,presentingin60–90%ofcases(Baethge etal.,2005;Baueretal.,2011).Theycanalsofeatureinarangeof otherpsychiatricdisorders(suchasbipolardisorderand depres-sion)andareexperiencedwithoutaneedforpsychiatriccarein http://dx.doi.org/10.1016/j.neubiorev.2015.04.016

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aminorityofthegeneralpopulation(Johnsetal.,2014).A num-berofstudieshaveexaminedbrainactivationeitherduringAVH orinrelationtohallucinationpredisposition,buttheneuralbasis ofthephenomenonisstillnotwellunderstood(Allenetal.,2012). Inthiscontext,therehasbeenagrowinginterestinthepotential forrestingstatenetworks—i.e.,theintrinsicorganizationand spon-taneousactivationofgroupsofbrainregions—toexplainhowand whyhallucinatoryexperiencesoccur(Jardrietal.,2013;Northoff andQin,2011).

1. Restingstatenetworksandpsychopathology

Restingstatenetworks(RSNs)denotegroupsofbrainregions thatcorrelateintheirspontaneousactivitywhenidleor‘atrest’.In fMRI,suchspontaneouscorrelationsoccurduetolow-frequency ﬂuctuationsinthehemodynamicresponse,andareinterpretedas evidenceofintrinsic,functionalconnectionsamongbrainregions. Intrinsicconnectivitycanbeassessedbyselectingaseedregionand examiningitscorrelationacrosstimewitheitherspeciﬁcregions ofinterestorthewholebrain.Alternatively,techniquessuchas independentcomponentsanalysis(ICA)canbeused toidentify networksofareasthattendtocovaryatrest,withouttheneedfor specifyingaseedregion.Partsofanetworkcanthenbeassessed fortheiraverageconnectivitywithotherregions(i.e.,connectivity strength)andtheextenttowhichtheymediateotherpathswithin thenetwork(sometimescalled‘betweennesscentrality’;Freeman, 1977).

Themost well-known restingnetwork isthe ‘default mode’ network(DMN;Raichleetal.,2001),acollectionofregions includ-ing the medial prefrontal cortex, medial temporal lobe, lateral parietalcortex,precuneus,andposteriorcingulate.TheDMNwas originallydeﬁnedbyitstendencytonegativelycorrelatewith task-positive activity,promptingthe conceptof a default state.It is nowrecognizedthattheDMN,whileoftenanti-correlatedwith externally-guidedactivity,isactiveinarangeofinternally-directed cognitiveprocesses,includingmind-wandering,autobiographical memory,andfuturethinking(Buckneretal.,2008).Othernotable networksshowingintrinsicconnectivityatrestincludethecentral executivenetwork(CEN),whichlinksposteriorparietalregionsto prefrontalcortex(sometimesalsoreferredtoasthefronto-parietal network,orFPN),andthesaliencenetwork(SN),whichincludes theinsula and its connectiontotheanterior cingulateand the supplementarymotorarea(Bresslerand Menon,2010).Speciﬁc networksunderpinningsensoryprocessingarealsoevidentatrest, althoughthesewillusuallybemoreapparentduringengagement inanexternally-driven,task-positiveprocess.

ThepotentialrelevanceofRSNstounderstanding psychopathol-ogyin general, and psychosis in particular, hasbeen noted by anumber ofauthors(Broydetal.,2009;Whitﬁeld-Gabrieliand Ford,2012;Williamson,2007).Studiesofpeoplewith schizophre-niahavereportedalteredconnectivitypatternsintheDMNand otherrestingnetworks,alongsideatypicalmodulationofinternally andexternallyfocusedattention(Kimetal.,2009;Öngüretal., 2010;Pomarol-Clotetetal.,2008).Itisunclear,however,howmuch schizophreniacase–controlstudiesalonecantellusaboutthe res-tingstateinrelationtoAVH,forthreereasons.

First,schizophreniaisahighlyheterogeneousdisorderinvolving widelyvaryingconfigurationsofpositiveandnegativesymptoms. Anyrestingdifferences observedbetweenpatientsand controls could relate to AVH, or a number of other symptoms or con-founds, including medication. Second, a significant minority of schizophreniapatientsdonotexperienceAVH(around1/3;e.g., Baueretal.,2011), againlimitinganyspecificconclusionsabout restingstatedifferencesandAVH.Third,moststudiesoftheresting stateinschizophreniahaveonlyexaminedrestingnetworksasif

theyreﬂectstable,trait-basedmarkersforpsychopathology.AVH, however,areintrinsicallytransientandunpredictablephenomena; understandinghowtheymightemergefromRSNsrequiresaclose examinationofthecurrenthallucinationstatusofparticipants,the presenceofhallucinationsduringscanning,andthetime-courseof neuralnetworkspriortohallucinationoccurring.

Thisproblemis nowbeginningtobeaddressedbya growth in the number of studies seekingdirectly to link resting-state characteristicstothepropensityforAVH.Insomecasesthishas involvedconstrainingschizophreniasamplestoonlyincludethose withAVH,andthencomparingthemeitherwithhealthycontrols (Sommeretal.,2012;Vercammenetal.,2010)orhealthycontrols plus a clinicalcontrol groupof participantswithschizophrenia but no hallucinations (Gavrilescu et al., 2010; Hoffman et al., 2011).Otherstudieshaveusedmixedschizophreniagroupsand speciﬁcallyreportedon correlationsbetween AVHseverityand resting-state characteristics (Rotarska-Jagiela et al., 2010; Sorg etal.,2013).Finally,twostudieshavereportedonintrinsic func-tional connectivityin a sample of peoplewho experience AVH withoutneedforpsychiatriccare,i.e.‘non-clinical’voice-hearers (Diederenetal.,2013;VanLutterveldetal.,2014).

Thefollowingreviewoutlineswhatcanbesaidsofaraboutthe restingstateanditsroleinunderstandingAVH.Section2outlines threemainhypothesesaboutrestingstatedysfunctionandAVH. InSection3,ﬁndingsfromAVH-speciﬁcresting-statestudiesare reviewed, organizedaccordingtothebrainareas andnetworks thathavebeentheprimaryfociofresearch.Section4considers aselectionofmethodologicalconfoundstostudyingintrinsic func-tionalconnectivityusingfMRI,andexamineshowtheyhavebeen addressedbyexistingstudies.

2. Restingstatehypothesesandauditoryverbal hallucinations

AsAVHbydeﬁnitionoccurintheabsenceofanexternal stim-ulus,thereisanimmediateplausibilitytotheideathatanatypical restingstatecouldgiverisetoahallucinatoryexperience.A start-ingassumptionmaybethatAVHresultfromabnormallyhighor atypicallymoderatedrestingactivityinprimaryauditorycortices, givingrisetospontaneousinternalsignalsthataremisattributed asexternal,oranover-sensitivityofauditorycorticestotop–down expectancyeffects(foraccountsofthiskind,seeChoandWu,2013; Hunteretal.,2006;MintzandAlpert,1972).

Such hypotheses are supported by evidence of structural changestoprimaryauditorycortexinschizophreniapatientswith AVH(Hubletal.,2010),andcomputationalmodelsofschizophrenia that posit shallow differences between resting and externally-generatedneuronalstates(Rollsetal.,2008).However,theyare notnecessarilysupportedbyneuroimagingevidenceofthe audi-torycortexduringAVH.Whilesomesymptom-capturestudieshave observedprimaryauditorycorticalactivityduringtheexperience ofAVH(Dierksetal.,1999),recentmetaanalyseshaveindicated thatsuchactivationisnotobviouslyapparentduringhallucinations (Jardrietal.,2011;KühnandGallinat,2012).Manystudieshave insteadreportedactivationofsecondaryandassociationauditory areasfurtheruptheauditoryprocessingstream.Accordingly,ithas beensuggestedthatevidenceofprimaryauditorycortexactivity duringAVH,whereithasbeenobserved,ismorelikelytoreﬂecta back-propagationofactivityfromassociationcortices(Jardrietal., 2013).

Amorecommonresultinsymptom-capturestudieshasbeen the observation of activation in areas associated with speech production, such as the left inferior frontal gyrus (IFG) (Kühn and Gallinat, 2012).Such ﬁndings supportmodels of AVHthat explaintheexperienceintermsofafailuretomonitorone’sown

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internalspeech,resultinginitsmistakenattributiontoanexternal source(Feinberg,1978;Fordetal.,2002;Frith,1992).Regarding therestingstate,suchmodelswouldpredictapatternofatypical functionalconnectivitybetweentypicalspeechprocessingareas, primarilywithinaleftfronto-temporalnetworkincludingtheIFG andsuperiorandmiddletemporalgyri,butpotentiallyextending torighthemispherelanguage‘homologue’areas(Sommeretal., 2008).Reducedstructuralconnectivityintheleftarcuate fascicu-lus,whichlinksfrontalandtemporallanguageregions,hasbeen foundin schizophreniapatientswithAVHcompared tohealthy controls(Geoffroyetal.,2014).Morerecentlythishasalsobeen observedforpatientswithAVHcomparedtobothschizophrenia patientswithouthallucinationsandschizophreniapatientswith hallucinationsinnon-auditoryverbalmodalities(McCarthy-Jones etal.,2015),supportingamodelofdisruptedfunctionalinteraction withinspeech-processingsystems.

AthirdhypothesisisthatAVHsomehowarisefromthe activ-ity and function of the DMN, which by deﬁnition will usually beprominent during rest.In suchan account AVHcould arise frommisattributedproductionsoftheDMN,eitherviaan atyp-ical interaction between the DMN and other networks at rest (NorthoffandQin,2011),orafailuretomaintaintheDMNin a stablestate(Jardrietal.,2013).Therangeoffunctionsassociated withtheDMN—includingintrospectivethought,autobiographical memoryandself–otherattributions—makeitamenableto explain-ingboththevariationinAVHsthatpeopleexperienceandtheir oftenpersonalandself-directednature(FfytcheandWible,2014; Vercammenetal.,2010).

Insupportofthelatterhypothesis,atypicalcharacteristicsof theDMNhavebeenfoundinschizophrenia.Comparedtohealthy controls,peoplewithschizophreniahaveshownreduced suppres-sionof theDMNduringtask-relatedperiods(Whitfield-Gabrieli etal.,2009),elevatedconnectivitywithintheDMNatrest(Zhou etal.,2007),atypicalconnectivitybetweenDMNhubs(Bluhmetal., 2007),andlessindependencebetweentheDMNandtask-positive networks(see Whitfield-Gabrieliand Ford,2012,for a review). WhilethesefindingspointtoatypicalDMNfunctionin schizophre-niaingeneral,theymayalsoplayaroleinthedevelopmentofAVH inparticular.

3. Resting-stateﬁndingsinAVH-speciﬁcstudies

FindingsonrestandAVHcanbegroupedintothreeclusters: (i)restingconnectivityoftheauditorycortexandlanguageregions (includingtheleftinferiorfrontalgyrusandleftsuperiorand mid-dletemporalgyri);(ii)areasassociatedwithdefaultmodefunction, includinglateraltemporoparietalregions,midlinestructures,and thehippocampalformation(Buckneretal.,2008),and(iii)other individualareasandnetworks,includinginteractionsbetween dif-ferentRSNs(seeTable1).

3.1. Auditory/language-processingregions 3.1.1. Primaryauditorycortex

Twostudies have speciﬁcally examinedconnectivity of pri-maryauditorycortex(PAC)inAVH.Usingaseed-basedapproach, Gavrilescuetal.(2010)comparedrestingconnectivitybetweenthe leftandrightPACinpatientswithschizophreniaandAVH(SzAVH+ henceforth),patientswithschizophrenia butnoAVH(SzAVH−), andasampleofhealthycontrols(HC).SzAVH+participantsshowed reduced connectivity between left and right hemispheres for both primary and secondary auditory areas compared to the two other groups, leading the authors to propose that inter-hemisphericconnectivityproblemsmaybespeciﬁctothosewith AVH.

Shinnetal. (2013)alsocomparedSzAVH+, SzAVH−, andHC groups,butexaminedPACconnectivityinrelationtotherestof thebrain.ForleftPAC,theyobservedincreasedconnectivitywith theleftsuperiorparietallobuleandleftmiddlefrontalgyrus,and reducedconnectivitytorighthippocampalandthalamicregionsin SzAVH+.Hallucinationseverityinthisgroupalsopositively corre-latedwiththeconnectivitybetweenleftPACandarangeofregions, includingleftIFG,left STG,theanteriorand posteriorcingulate cortex,andrightorbitofrontalcortex(noothersymptom correla-tionswerereported).Incontrast,noalteredconnectivitywasfound betweentherightPACandanyotherregion.

Thecontrastinﬁndingsbetweenthesetwostudiesislikelyto arisefromdifferencesinthekindofanalysisdeployed.Thefocus onleft–rightPACconnectivitybyGavrilescuetal.(2010)mayhave missedwiderconnectivityalterationswiththerestofthebrain. Incontrast,Shinnetal.’s(2013)whole-brainanalysiscouldhave highlightedspeciﬁcinterhemisphericproblems,butdidnot,even whenusingthesamevoxelthresholdasGavrilescuetal.(2010). ThelackofatypicalconnectivityforrightPACandwiderangeof connectivityalterationsforleftPACobservedbyShinnetal.(2013) suggestthatconnectivitydifferencesinAVHareunlikelyto pri-marilyresideinbilateralcommunicationoftheauditorycortices. Furthermore,thepresenceofsymptomcorrelationsinShinnetal. (2013)reinforcesthesuggestionthatintrinsicconnectivityofthe leftPACinparticularisrelatedtoAVH.

3.1.2. Superiorandmiddletemporalgyri

Fourstudieshavereportedonseedsplacedinsuperiorand mid-dletemporalgyri(Closetal.,2014;Diederenetal.,2013;Hoffman etal., 2011;Sommer etal., 2012),while two havereported on connectivityin these areasusing network-basedmethods (Van Lutterveldetal.,2014;Wolfetal.,2011).Hoffmanetal.(2011) examinedtheconnectivityofboththeleftandrightposterior supe-riortemporalgyri(STG)toleftinferiorfrontalgyrusinSzAVH+, SzAVH_−, and HC individuals. Although no altered connectivity betweenthesetworegionswasfoundspeciﬁctoSzAVH+,greater functionalconnectivitywasfoundinSzAVH+ comparedtoboth controlgroups,inacorticostriatalloopinvolvingtheIFG,the bilat-eralposteriorSTG,andtheputamen.Basedonevidenceofputamen involvement inlanguageinitiation(Price,2010), Hoffman etal. (2011)suggestedthatthismaygiverisetoan“overabundanceof languagerepresentationsthatcanbecomehallucinogenic”inthose withAVH(p.412).

Incontrast,Sommeretal.(2012)observedreducedconnectivity betweenleftSTGandleftIFGinasampleofparticipantswith psy-chosisandAVHcomparedtocontrols.Functionalconnectivitywas alsolowerbetweenleftSTGandlefthippocampus,aneffectthat wasparticularlyprominentinparticipantswhoreportedAVH dur-ingscanning,andcorrelatednegativelywithhallucinationseverity onthePANSS(Kayetal.,1987).Infurtheranalysisofthesame sam-ple,Closetal.(2014)alsoreportedreducedconnectivitybetweena seedinleftmiddletemporalgyrusandtherightSTG.However, neitherstudyincludeda comparison withindividuals who had psychosisbutnoAVH,meaningthattheobservedalterationsto connectivitymaynotbespeciﬁctothepresenceofhallucinations. Onewaytoavoidsuchaconcernistostudyintrinsic connec-tivityinthosewithAVHbutnopsychosis.Diederenetal.(2013) comparedconnectivityin25non-clinicalparticipantswithAVH and25controlsacrossaselectionofseedsthatincludedleftand rightSTG. Elevatedconnectivitywasobservedbetweenthetwo STGsitesandtherightIFG.Networkanalysisofanoverlapping groupofparticipantsbyVanLutterveldetal.(2014)indicatedthat theleftSTGinparticularshowedgreaterconnectivitystrengthand betweennesscentralityinparticipantswithAVHcomparedto con-trols.Thatis,theleftSTGappeared toactasa moreimportant restinghubforthosewithAVH,intermsofbeingmorelikelyto

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Table1

RestingfunctionalconnectivityMRIstudiesinindividualswithAVH.

Study Groups Method ConnectivityinAVH

participants

Symptomcorrelation

Gavrilescuetal.(2010) SzAVH+ SzAVH− HC

Seed

(leftandrightPAC)

↓LeftPAC-rightPAC – Shinnetal.(2013) SzAVH+

SzAVH− HC

Seed

(leftandrightPAC)

↑LeftPAC-leftSPL,left MFG

↓LeftPAC-rightPHC,right thalamus

↑LeftPAC-leftIFG, leftSTG,rightOFC, rightpre-andpost-central gyrus,ACCandPCC Hoffmanetal.(2011) SzAVH+

SzAVH− HC

Seed (bilateralSTG)

↑BilateralSTG-leftIFG -putamen

–

Sommeretal.(2012) Psychosis+AVH HC

Seed

(leftSTGandrightIFG)

↑RightIFG-rightPHC ↓RightIFG-rightDPLFC ↓LeftSTG-leftIFG,left hippocampus

↓LeftSTG-left hippocampus

Closetal.(2014) Psychosis+AVH HC

Seed

(leftIFG,MTG,AG, thalamus)

↑LeftIFG-leftinsula,SMA; Lefthippocampus-left thalamus

↓LeftIFG-leftIPL,left DLPFC,bilateralVLPFC ↓LeftMTG-rightSTG;left TPJ-leftAG;

Leftthalamus-right cerebellum

↑LeftIFG–leftVMPFC ↓Thalamus–rightPCG, rightPHC

Diederenetal.(2013) NC+AVH HC

Seed

(bilateralIFG,STG,PHC)

↑LeftSTG-rightSTG,right IFG;leftIFG-leftPHC VanLutterveldetal.(2014) NC+AVH

HC

Network/ICA ↑LeftSTG,rightMTG,PCC (strength)

↑LeftSTG(centrality) ↓LeftPCL,rightITG,right amygdala(centrality)

–

Wolfetal.(2011) SzAVH+ HC

Network/ICA ↑LeftSTG,rightSFG,right MFG,bilateralMTG ↓LeftACC,leftprecuneus, rightPCC

↑LeftSTG,rightMFG ↓LeftACC Vercammenetal.(2010) SzAVH+

HC

Seed

(leftandrightTPJ)

↓LeftTPJ-rightIFG ↓LeftTPJ-bilateralACC, amygdala

Rotarska-Jagielaetal.(2010) SZ HC

Network/ICA – ↓Lefthippocampus,left

STG Manoliuetal.(2014) SZ HC Network/ICA – ↓RightAI ↑DMN-CEN Sorgetal.(2013) SZ HC Network/ICA – ↓Putamen

Jardrietal.(2013) BriefPD HC

Network/ICA ↓GoFinDMN,DMN–ASC ↓DMNstability

AI=anteriorinsula,ACC=anteriorcingulatecortex,AG=angulargyrus,ASC=associationsensorycortex,AVH=auditoryverbalhallucination,CEN=centralexecutivenetwork, DLPFC=dorsolateralprefrontalcortex,DMN=defaultmodenetwork,GoF=goodnessofﬁt,HC=healthycontrol,ICA=independentcomponentsanalysis,IFG=inferiorfrontal gyrus,IPL=inferiorparietallobule,ITG=inferiortemporalgyrus,MFG=middlefrontalgyrus,MTG=middletemporalgyrus,NC=non-clinical,OFC=orbitofrontalcortex, PAC=primaryauditorycortex,PCC=posteriorcingulatecortex,PCG=precentralgyrus;PCL=paracentrallobule,PD=psychoticdisorder,PHC=parahippocampalcortex, SMA=supplementarymotorarea,SPL=superiorparietallobule,Sz=schizophrenia,SFG=superiorfrontalgyrus,STG=superiortemporalgyrus,TPJ=temporoparietaljunction, VLPFC=ventrolateralprefrontalcortex;VMPFC=ventromedialprefrontalcortex.

beconnectedtootherbrainareasingeneral.Inaddition,theright middletemporalgyrusalsoshowedgreaterlevelsofconnectivity tootherareasinAVHparticipants.Thesamplereportedoninthese twostudiesshowedsomeevidenceofsub-clinicalcharacteristics inotherdomainsofpsychosis(e.g.,unusualorgrandiosebeliefs), meaningthattheyshouldnotsimplybeseenastheequivalent ofhealthycontrolswithAVH(Sommeretal.,2010).However,it seemsunlikelythatsuchcharacteristicswouldexplainalterations toresting connectivitywhen the groupwas more prominently characterizedintermsofpronenesstoAVH.

TheﬁndingsofDiederen,vanLutterveld,and colleaguesalso correspondwithevidencefromanetworkanalysisinSzAVH+ indi-viduals.Wolfetal.(2011)foundthatSzAVH+participantsshowed increasedconnectivitystrength forleft STGand theMTG bilat-erallycomparedtoHC.Thisdidnot involvea non-hallucinating schizophrenia group, but did include some evidence of symp-tom correlation: a positive correlation was observed between symptom severity and left STG connectivity that was speciﬁc tohallucinations(asmeasuredonthePSYRATS;Haddock etal.,

1999)ratherthanpositivesymptomsingeneral(measuredonthe PANSS).

Insum,thereisevidenceofatypicalconnectivityoftheSTGand MTGfromresting-statestudies,butresultsareverymixed.Inboth clinicalandnon-clinicalparticipantsthereisevidencetosuggest thattheleftSTGinparticularislikelytoshowelevated connec-tivitytootherbrainregionsatrest.Thisisnotnecessarilythecase, however,forconnectivitybetweensuperiortemporalareasandleft IFG;insomecasesthishasbeenproposedtobeintactor possi-blyelevatedinthosewithAVH(Hoffmanetal.,2011),butthereis alsoevidenceofreducedSTG–IFGfunctionalconnectivity(Sommer etal.,2012).

3.1.3. Inferiorfrontalgyrus

Beyonditscouplingwithtemporalregions,threestudieshave speciﬁcallyreportedonconnectivityintheleftinferiorfrontalgyrus (IFG).Asnotedabove,Hoffmanetal.(2011)observedelevated con-nectivitybetweenleftIFGandtheputameninSzAVH+comparedto SzAVH−,whichformedpartofacorticostriatalloopencompassing

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languageregionsandthestriatum.InClosetal.(2014),decreased connectivityfor AVHparticipantswasevident betweenleftIFG, leftdorsolateralprefrontalcortex,ventrolateralprefrontalcortex, andinferiorparietalareas(bilaterally).Alongsidethis,increased connectivitywasobservedbetweenleftIFG,leftinsula,andthe supplementarymotorarea,althoughthelackofanSzAVH− con-trolgrouplimitsinferencesaboutthespeciﬁcityofthesechanges toAVH.Finally,innon-clinicalhallucinatingparticipants,Diederen etal.(2013)observedincreasedconnectivitybetweenleftIFGand leftparahippocampalcortex,suggestingelevatedcommunication betweenlanguage regions and areas responsible for mediating memoryretrieval.

Inaddition totheleft IFG,the rightIFGhasalso beenused asa seedregion.Sommer etal. (2012)foundthat SzAVH+ had increasedconnectivitywiththerightparahippocampalgyrus, com-pared to healthy controls, but reduced connectivity with the rightdorsolateralprefrontalcortex(DLPFC).However,thestrong associationof therightDLPFC withdelusions(Coltheart, 2010) highlightsthatthelackofaSzAVH−controlgroupcouldhaveled totheseresultsbeingconfoundedbyothersymptomsassociated withschizophrenia.Thisbringsintoquestiontheirspeciﬁcityto AVH.

Fortheinferiorfrontalgyri,then,thereissomeevidenceof atyp-icalconnectivitywiththestriatum,prefrontalcortex,andmedial temporalareas.Evidenceofreducedconnectivitywithdorsaland ventrallateralprefrontalcortexinSommeretal.(2012)andClos etal.(2014)islimited,though,bythelackofacomparisongroupof non-hallucinatingparticipantswithpsychosis.Twostudiespointto increasedcouplingbetweeninferiorfrontalandparahippocampal regions,butindifferenthemispheres.

3.2. Defaultmoderegions 3.2.1. Temporoparietaljunction

Vercammenetal.(2010)comparedrestingfunctional connec-tivityinSzAVH+andHCparticipantsamongseedsintheleftand righttemporoparietaljunction(TPJ)andavarietyofROIs,including theIFG,anteriorcingulate,insula,andamygdala.Whilereductions inconnectivitywereevidentgenerallyinAVHparticipants,theonly groupdifferencesurvivingcorrectionformultiplecomparisonswas areductioninconnectivitybetweentheleftTPJandrightIFG. Symp-tomcorrelationsforhallucinationseveritywerealsoobservedfor linksbetweentheleftTPJandbilateralROIsintheamygdalaand anteriorcingulate,suchthatgreaterseveritywasassociatedwith reducedconnectivity.Thisrelationshipwasobservedfortwo sepa-ratemeasuresofhallucinationseverity(P3onthePANSSandtotal scoreontheAuditoryHallucinationRatingScale;Hoffmanetal., 2003)butnotforpositive,negative,orgeneralsymptomscoreson thePANSS.Closetal.(2014)alsoreportedevidenceofalteredleft TPJconnectivityintheirsampleofparticipantswithAVHand psy-chosis.ComparedtoHCcontrols,participantswithAVHshowed reducedcouplingbetweenleftTPJandleftangulargyrus,andthis wasparticularlyevidentinthosewhohallucinatedduring scan-ning,suggestingbothtraitandstatealterationstoTPJconnectivity inAVH.

AsinClosetal.(2014),Vercammenetal.’s(2010)studydidnot includeaclinicalcontrolgroupofparticipantswithpsychosisbut notAVH.However,theirevidenceofsymptomcorrelationsspeciﬁc toAVH,andevidence ofstateeffects in Closetal. (2014), par-tiallyaddresstheconcernaboutotherpsychoticfactorsactingas confounds.Inaddition,thereisalsosomeevidenceofatypicalTPJ connectivityinnon-patientindividualswithAVH:Diederenetal. (2013)observedanegativecorrelationbetweenleftTPJandright IFGincontrolparticipants,butthiswasnotevidentinparticipants withAVH.

3.2.2. Midlinestructures(cingulatecortexandprecuneus)

Evidenceofconnectivitypatternsinmidlinestructures(anterior cingulate,posteriorcingulate,andprecuneus)hastendedtocome fromstudiesemployingnetworkanalysisratherthanseed-based methods.Wolfetal.(2011)observedreducedconnectivitystrength forSzAH+individualsintheleftanteriorcingulate,rightposterior cingulate,andleftprecuneus,alongsideincreasedconnectivityin rightsuperiorfrontalgyrusandmiddlefrontalgyrus(with connec-tivitybeingdeﬁnedasthevoxelweightingforthatregionwithin arestingnetwork).Connectivityintheleftanteriorcingulatewas alsonegativelyassociatedwithhallucinationseverity,i.e.greater connectivitystrengthinthatregionwasassociatedwithreduced hallucinationproneness.

ThissuggeststhatAVHmaybeassociatedwithreductionsinthe generalconnectivityofanteriorandposteriormidlinestructures. However,Wolfetal.(2011)didnotinclude anon-hallucinating patientgroup,whichlimitsinterpretationoftheirﬁndings. Con-trastingﬁndingswereevidentforposteriormedialcortexinVan Lutterveldetal.’s(2014)analysisofnon-clinicalAVHparticipants, whichfoundgreaterconnectivitystrengthfortherightposterior cingulateandprecuneus.CorrelationsbetweenACCconnectivity andhallucinationshavebeenobservedinotherstudies,butthey varywitharea: increasedhallucination severityhasbeen asso-ciatedwithreducedcouplingbetweenbilateralACCandleftTPJ (Vercammenetal.,2010),butelevatedconnectivitybetweenACC andleftPAC(Shinnetal.,2013).

3.2.3. Hippocampalformation(hippocampusand parahippocampalcortex)

Fourof theabove studies(Closet al.,2014; Diederen etal., 2013;Shinnetal.,2013;Sommeretal.,2012)andoneotherstudy (Rotarska-Jagiela etal.,2010)havereportedspeciﬁcresting dif-ferencesinthehippocampusandparahippocampalcortex(PHC). Rotarska-Jagielaetal.(2010)examinedrestingnetworksina sam-pleofpatientswithschizophreniaandahistoryofAVHcompared toanHCgroup.Whilegeneraldifferencesinconnectivitybetween Szand HCparticipantswerewidespread, hallucination severity wasrelated to decreased connectivity in thelower part ofthe hippocampusand theleft posterior STG.In both regions, how-ever,connectivityreductionswerealsoassociatedwithdelusion severity,suggestingarelationshipwithpositivesymptomatology ingeneral,ratherthanhallucinationsinparticular.

Elsewhere,increasedlevelsofconnectivityinAVHparticipants havebeenreported betweenleft hippocampustoleftthalamus (Closetal.,2014);leftPHCtoleftIFG(Diederenetal.,2013);and rightPHCtorightIFG(Sommeretal.,2012).Decreasedcoupling hasbeenobservedbetweenrightPHCandleftPAC(Shinnetal., 2013)andlefthippocampustoleftSTG(Sommeretal.,2012).The strongestoftheseﬁndingsis providedbySommer etal.(2012), whoalsoobserveddecreasedSTG-hippocampusconnectivityfor thosewhoreportedAVHduringscanningandscoredhigherfor AVHsymptomsingeneral.

Overall,then,ﬁndingsonhippocampalconnectivityin individ-ualswithAVHareverymixedandnon-replicating.Primarilythere isevidenceofalterationsinrestingconnectivityamongavarietyof hippocampalandlanguageregions,butthismayalsoreﬂectchoice of seeding regions. Onlyone study—Sommer et al. (2012)—has reportedcombinedevidenceofconnectivityalteration,symptom correlation,andstateeffects.

3.3. Othernetworksandbetween-networkinteractions 3.3.1. Insulaandstriatum

Onestudyhasspeciﬁcallystudiedconnectivityofthe insula-basedsaliencenetwork.Manoliuetal.(2014)usedICAtocompare connectivitylevelswithinthesaliencenetworkforindividualswith

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currentpsychosis,individualsinremission,andhealthycontrols. Hallucination(butnotdelusion)severitywasnegativelyassociated withconnectivitystrengthintherightanteriorinsulaspeciﬁcally. Increasedfunctionalconnectivitybetweentheleftinsulaandleft IFGwasalsoobservedinAVHparticipantsbyClosetal.(2014), whileVercammenetal. (2010)includedbilateralinsulaROIsin theiranalysisbutfoundnosigniﬁcantalterationsinconnectivity.

Sorgetal.(2013),usingthesamesampleasManoliuetal.(2014), reportedonrestingstateconnectivitywithinabasalganglia net-workthatincludedthestriatum,globuspallidus,andthethalamus. Hallucinationseveritywithinthenetworkwasspecifically associ-atedwithconnectivityintheputamen.However,thisrelationwas alsoobservedfordelusionscores.Thus,whilebothSorgetal.(2013) andManoliuetal.(2014)lackedaspecificcomparisonofclinical participantswithandwithoutAVH,onlythelattercould demon-stratehallucination-specificcorrelationswithrestingconnectivity. 3.3.2. InteractionsbetweentheDMNandothernetworks

Finally,two studies haveexaminedhow interactions among different networks may contribute toAVH (Jardri et al., 2013; Manoliuetal.,2014).Jardrietal.(2013)examinedneuralactivation duringhallucinatory episodesand at restin agroup of adoles-centswithbriefpsychoticdisorder,whoeitherexperiencedAVH, visualhallucinationsorboth.Hallucinationepisodeswere associ-atedwithgreateractivationinassociativesensoryareasspeciﬁcto themodalityofthehallucination(includingtheSTSand occipito-temporaljunction),andthiscorrelatedwithhallucinationseverity. Whenassociativesensorycorticalactivationincreased,this anti-correlated withactivityin theDMN, andhallucination severity predictedboththeDMNgoodnessofﬁt(ameasureofhowstable theDMNwasspatially)anditsvariabilityovertime.Furthermore, therewasnorelationshipobservedbetweenDMNinstabilityand positive symptomsin general.ThisledJardriand colleaguesto suggestthathallucinationperiodsmaybeprecededbyasudden disengagementofunstableDMNstates,leadingtointernal repre-sentations(suchasthoseactivatedbythememoryfunctionsofthe DMN)beingprocessedbyasiftheywereexternal,sensorystimuli. ThereisalsosomeevidencelinkingAVHwiththeinteraction betweentheDMNand thecentralexecutive network (CEN).In additiontoanalyzingthesaliencenetwork,Manoliuetal.(2014) examined properties of both the DMN and CEN in their sam-ple of participants with schizophrenia. A positive relationship wasobservedbetweenhallucinationseverityand interconnectiv-itybetweendorsalnodesoftheDMNandrightventralCEN,with nocorrespondingassociationfordelusionscores.Thus,while hal-lucinationonsetmaybeprompted byweakerormoreunstable interactionsbetweentheDMNandsensorynetworks,hallucination severitymaybeassociatedtotightercoupling(andbyextension, lessseparation)betweentheDMNandnetworksserving atten-tionalcontrol.

4. Confoundstotherestingstate:hallucinations, medication,andmovement

ObservingatypicalrestingstatesinthosepronetoAVHraises thequestionofwhethertheyshouldbeinterpretedastraitorstate effects:thatis,asmarkersofhallucination-pronenessoras charac-teristicsofthehallucinatorystateitself.Mostresting-statestudies focusontheformer,withseparatesymptom-capturedesignsbeing usedtostudythestudythestateofhallucination.Assuch,rulingout orcontrollingforthepresenceofAVHduringscanningisimportant forunderstandingtheircontributiontorestingdynamics.

Of the above studies, the majority have controlled for the state of AVH in various ways (see Table 2). Four studies only includedhallucination-freedata,eitherbyexcludingparticipants

whoexperiencedAVHduringscanning(Diederenetal.,2013;Van Lutterveldetal.,2014),analyzingAVHdataelsewhere(Hoffman etal.,2011),orcheckingthattheirparticipantsreportedno halluci-nations(Gavrilescuetal.,2010).Fourstudiesspeciﬁcallycompared datawithandwithoutAVH,eitherbetweenparticipants(Closetal., 2014;Shinnetal.,2013;Sommeretal.,2012)orwithin partici-pants(Jardrietal.,2013).Theremainingstudiesreportednospeciﬁc attemptstocontrolforthepresenceofhallucinations.

Useofantipsychoticmedicationisanotherfactorthatmaybe expected toaffectthe characteristicsof restingstatenetworks. Althoughthereareonlyalimitedofnumberofstudiesinthisarea, antipsychoticadministrationhasbeenfoundtoalterconnectivity strengthbetweenthevmPFCandtherestoftheDMN(Sambataro etal.,2009),betweenthemPFCandboththehippocampusand nucleusaccumbens(Boldingetal.,2012)andbetweentemporal and parietalregions, temporaland frontalregions andthe pre-cuneusandbasalganglia(Luietal.,2010).Antipsychoticshence havethepotentialtoactasanotableconfoundforexisting stud-iesoftherelationbetweenAVHandRSNs.Allofthestudiesthat includedclinicalparticipantgroupsreportedonmedicationuse, withtheexceptionofJardrietal.(2013),whospeciﬁcallyrecruited medication-freeparticipants.Attemptstocontrolformedication effects were mixed: two studies reportedno groupdifferences in medicationlevels betweenclinicalgroups with and without AVH(Gavrilescuetal.,2010;Shinnetal.,2013),whileﬁvestudies eithertestedforcorrelationswithmedicationlevelsorcorrected symptomcorrelationsaccordingtomedicationuse(seeTable2). Wolfetal.(2011)foundthatconnectivityabnormalitiesinright MTG in participantswith AVHalsocorrelated withmedication use,butnootherstudiesreportedsimilaroverlaps.Threestudies eitherreportednocorrectionformedicationuseorcouldnotdoso becauseofdiversityinthekindsofmedicationsused(Closetal., 2014;Sommeretal.,2012;Vercammenetal.,2010).

BeyondtheinfluenceofAVHandmedications,clinicalstatus is alsoassociated withother potentialconfounding factors.For instance,patientsoftenmoveinthescannermorethancontrols, andthiscangreatlyaffectconnectivityresultsforseed-based meth-odsinparticular(VanDijketal.,2012).Motionproblemsareknown toaffectimagingreliabilityinresearchwithchildren(Satterthwaite etal.,2012),olderadults(Mowinckeletal.,2012),andindividuals highinimpulsivity(Kongetal.,2014),anditishighlylikelythat studieswithpeoplecurrentlyexperiencingpsychosiswillbe sim-ilarlyaffected.Thisproblemcanbeaddressedtosomedegreeby regressingouthead-motionparametersandothernuisance vari-ables(suchascardiorespiratorymeasures)fromfMRItimeseries, buteventhishasbeenarguedtoleaveconsiderableartifactsinthe data,leadingtooverestimationoflocalconnectivityand underes-timationoflongdistanceconnectivity(Poweretal.,2012).Useof ICA-basedmethodsallowsfortheremovalofmovement-related components, but alsoinvolves a degree of subjective decision-makingintheidentificationofwhich componentstoignore.Of the above studies,six report useof standard regression meth-odstocorrectforheadmotion,whiletwo usedbothregression andICA(Rotarska-Jagielaetal.,2010;VanLutterveldetal.,2014). Theremainderreportednospecificmotioncorrectionbutmany ofthem diduseICA,which mayhave includedidentificationof motioneffects.Notably,onlytwostudiesreportedgroup compar-isonsforoveralllevelsofheadmovementduringscanning:Shinn etal.(2013)andVanLutterveldetal.(2014).

Finally,concurrentproblemswithagitationoranxietymaybe expectedtobemorecommoninpatientscomparedtocontrol par-ticipants,butoftheabovestudies,onlyone(Shinnetal.,2013) reportedspeciﬁcallyaskingparticipantsabouttheiranxietylevels andgeneralmoodduringscanning(theparticipantsstudiedbySorg andManoliuwereaskedaboutany“oddfeelings”duringscanning, butmorespeciﬁcdetailsarenotreported).Nostudieshaveused

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Table2

Controlforstateeffectsofhallucination,medication,andmovementinrestingstateAVHstudies.

Study AVHcontrol? Medicationcontrol? Motioncontrol?

Gavrilescuetal.(2010) Yes(noAVHdataincluded) Yes(nogroupdifference) Regression

Shinnetal.(2013) Yes(groupcontrast) Yes(nogroupdifference) Regressionandgroupcomparison Hoffmanetal.(2011) Yes(noAVHdataincluded) Yes(correlation) Regression

Sommeretal.(2012) Yes(groupcontrast) No Regression

Closetal.(2014) Yes(groupcontrast) No Regression

Diederenetal.(2013) Yes(noAVHdataincluded) N/Aa _Regression

VanLutterveldetal.(2014) Yes(noAVHdataincluded) N/Aa _Regression,_ICA_and_group_comparison

Wolfetal.(2011) No Yes(correlation) Nonereported(ICAused)

Vercammenetal.(2010) No No Nonereported

Rotarska-Jagielaetal.(2010) No Yes(correlation) RegressionandICA

Manoliuetal.(2014) No Yes(correlation) Nonereported(ICAused)

Sorgetal.(2013) No Yes(correlation) Nonereported(ICAused)

Jardrietal.(2013) Yes(within-subjectcontrast) Yes(unmedicated) Nonereported(ICAused) AVH=auditoryverbalhallucination,ICA=independentcomponentsanalysis.

a_Participants_in_Diederen_et_al.₍₂₀₁₃₎_and_Van_Lutterveld_et_al.₍₂₀₁₄₎_came_from_the_non-clinical_population.

standardizedstatemeasuresofanxiety,despitethefactthatitcan inﬂuenceresting-statecharacteristics(Dennisetal.,2011). 5. Discussion

Withinarelativelyshortspaceoftime(2010–2014),anumber ofstudieshavereportedonalterationsinintrinsicfunctional con-nectivityinindividualswithAVH.Thefirstkeyobservationtomake isthatfewifanyfindingshavedirectlyreplicatedacrossstudies. PerhapsmoststronglyimplicatedistheconnectivityoftheleftSTG, buteventhisshowsevidenceofbothelevatedandreduced func-tionalconnectivityacrossdifferentstudies.Thatsaid,fewstudies showdirectlyconflictingresults,withtheexceptionof IFG–STG connectivity(Hoffmanetal.,2011;Sommeretal.,2012)andthe resultsforprimaryauditoryareas(Gavrilescuetal.,2010;Shinn etal.,2013).

Thelackofreplicationacrossstudieslargelyreflects method-ologicalheterogeneity, ratherthan necessarily implying contra-dictoryfindings. Thestudies reviewed vary inseveral respects, including their use of seed-based or network methods, their selectionofseedplacements,theirchoiceofROIorwhole-brain connectivityanalyses, artifactcorrections, andthespecificity of participantgroups.Thisvariationacrossstudiesmakesita chal-lengetoclearlydistinguishreliablefindingsfromfalsepositives.

Nevertheless,thereviewedstudiesdohighlightsomeregions andnetworkswhoseintrinsicfunctionalconnectivityislikelyto beimplicatedinpronenesstoAVH.Inparticular,connectivityin lefttemporalcortexappearstobestronglyinvolvedinAVH, ran-gingfromPACtothesuperiortemporalgyrusandontotheleftTPJ area.LeftPACshowsmixedlevelsofconnectivityforitscoupling withfrontalcortexandhippocampalstructures,andmayalsohave reducedinterhemisphericconnectivitywithrightPAC,but resting-statedifferences arebynomeansconﬁnedtothis area(cf.Cho andWu,2013).LeftSTGshowsmostly elevatedfunctional con-nectivityacrossseed-andnetwork-basedstudies,butalsoreduced couplingwithhippocampalandthalamicareas.Thereisevidence oftheleftTPJshowingreducedcouplingwithimmediately sur-roundingstructures(angulargyrus),inferiorfrontalcortex,andthe anteriorcingulate.Inmanycasesrighttemporalseedregionshave alsobeenstudiedbuthavenotyieldedcomparablealterationsto connectivity,highlightingthespeciﬁcimportanceoflefttemporal cortextoAVH.

AlterationstorestingconnectivityinleftSTGareconsistentwith evidenceofassociationsbetweenhallucinationseverityandgray matterreductioninthisarea(Modinosetal.,2013;Palaniyappan etal.,2012),evidenceofitsactivationinsymptom-capturestudies (Jardri et al.,2011), and atypical connectivity withfrontal cor-texduring self-monitoring tasks(Wanget al., 2011).However,

evidenceofatypicalrestingconnectivitybetweenspeech produc-tionandcomprehensionareasismuchmoreequivocal,incontrast toevidenceofreducedstructuralconnectivitybetweenleftSTGand leftIFG(Geoffroyetal.,2014;McCarthy-Jonesetal.,2015).One studyhasindicated reduced IFG–STGsynchronization (Sommer etal., 2012),while anotherhasobservedelevatedconnectivity, albeitalonganextended loopthatalsocontainsstriatalregions (Hoffmanetal.,2011).Otherstudiesthatincludedthesameor simi-larseedregionsreportednoalterationstoleftIFG–STGconnectivity (Diederenetal.,2013;Vercammenetal.,2010).Takentogether, theresultsforleftPACandSTGsuggestthatbothbasicand higher-levelspeech-processingareasshowalteredintrinsicconnectivity, butnotnecessarilyintheircouplingwithspeechproductionareas. AlterationstorestingconnectivityinleftTPJand—toa more variedextent—hippocampalandmidlinestructuresimplicatesthe defaultmodenetworkinthedevelopmentofAVH.Thebest evi-denceof DMNinvolvementis provided byJardrietal.’s(2013) finding that DMN instability predicted hallucination severity. WeakercouplingwithintheDMN,asthecollectionoffindingsfor leftTPJandACCwouldappeartohighlight,couldconceivably con-tributetoanunstablerestingnetwork.Theexceptiontothisisthe findingofgreaterconnectivitystrengthinPCC/precuneusbyVan Lutterveldetal.(2014),althoughthismaybeduetotheuseof non-clinicalparticipantswithAVH.Basedonevidenceofgreater correlationbetweentheDMNandothernetworksinthosewith AVH(e.g.,Manoliuetal.,2014),itseemsplausiblethatatypical modulationof theDMNin eitherdirection(thatis, aweakand unstableDMNoranoverlystrongandactiveDMN)couldgiverise tointernalcognitionsbeingmistakenlyprocessedinsensory asso-ciationareas,andthatthismayvaryacrossclinicalandnon-clinical participantgroups. AtypicalDMNmodulationisalso evidentin generalschizophreniagroups(Whitfield-GabrieliandFord,2012), however,meaningthatmoreworkisneededtodelineatewhy hal-lucinations(andnototherpsychoticsymptoms)couldariseinthis way.

Methodologically,mostoftheabovestudieshavetakenclear stepstocontrolforthepotentialinfluenceofantipsychotic med-ication where appropriate, with only three studies making no correctionatall(Closetal.,2014;Sommeretal.,2012;Vercammen etal.,2010).ThosethatsoughttofocusspecificallyonAVH(rather than reporting on a general schizophrenia group with symp-tomcorrelations)alsocontrolledforthepresenceofAVHduring scanning,eitherviaexcludingAVHdataorincludingdirect com-parisonsbetweenparticipantsorepochsinwhichhallucinations werereported.Ofgreaterconcernisthegenerallackofspecific measurestocombatmotionartifacts,overandabovestandard nui-sance regression techniques.Headmotion—which is influenced bya rangeofindividualdifferences, includingclinicalstatus—is

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thoughttospecificallyreducelong-rangeconnectivityindicesand affectanterior–posteriornetworkssuchastheDMNorCEN(Van Dijketal.,2012).Assuch,evidenceofconnectivityreductionsfor thesenetworksinAVHparticipantscomparedtocontrolsmustbe interpretedwithcautionintheabsenceofmoreextensivemotion correctionmethods, suchas‘scrubbing’ of specificepochs with largeartifacts(Poweretal.,2012).Apparentdeficitsinlong-range functionalconnectivityhavebeenobservedtolargelydisappear whensuchtechniquesaredeployedinotherclinicalparticipant groups,suchasautism(Tyszkaetal.,2013);itmaybefruitfulto adoptsimilartechniquesinfutureresearchwithAVHsamples.

One of theclearest ways to minimizesuch confoundsis to includeanon-AVHclinicalcomparisongroupalongsideahealthy controlgroup.Medicationstatus,movementissues,andpresence ofother symptomsareall controlledfortoa greater degreein thethreestudiesthatincludedbothSzAVH+andSzAVH−groups (Gavrilescuetal.,2010;Hoffmanetal.,2011;Shinnetal.,2013)than theeightpatientstudiesthatdidnot.Theinclusionofaclinical com-parisongroup—ormultiplecomparisongroups,suchasparticipants withpost-traumaticstressdisorder,orbipolardisorder—is impor-tantforathoroughexaminationofwhatrestingstateabnormalities sayaboutthespecificmechanismsunderlyingAVH.Thelackof aclinicalcomparisongroupinanumberofthestudiesreviewed herelimitstheirevidentialvalue,althoughinmostcases signifi-cantsymptomcorrelations,specifictohallucinationseverity,were alsoreported.

Giventherangeofprocessingmethodsthatcanbedeployedfor measuringrestingconnectivity,someformofminimumanalysis protocolmayalsobenecessaryforfuturestudiesonthetopic,to allowfordirectcomparisonacrossdatasetsandconfidenceinthe reliabilityoffindings.Thismightincludeclearreportingpolicies ontheoverallstateofparticipantsduringscanning(includingbut notexclusivetothepresenceofAVH),specificmeasurestocounter motionproblems,anduseofcomprehensivesetsoftheory-driven ROIs(asinVercammenetal.,2010,andDiederenetal.,2013,for example).Thesecouldbereportedonforeachresting-statestudy ofAVHbeforethedeploymentofmore complexorexploratory analysis,suchas network or graph theoreticalapproaches. The specificationofseedregionswilldependonthedevelopmentof goodtheoreticalmodelsforthedevelopmentofAVH,althoughthis couldbeachievedinaniterativemanner,withrestingstate find-ingsandneurocognitivemodelsmutuallyinformingoneanother. The specification of prospective subtypes for AVH, including a distinction between voices relating to inner speech and mem-oryprocesses(McCarthy-Jonesetal.,2014),andthedevelopment ofcross-laboratory protocols, asadvocatedbytheInternational ConsortiumonHallucinationResearch(ICHR:Watersetal.,2012, 2014),couldprovideapreliminaryframeworkfornominating can-didateseedregions.

Otherfactors important to consider arehow resting neuro-physiologicaldifferencesmaycontributetoAVH,andtherelation between structural and functional connectivity alterations in those prone to hallucination. In particular, ﬂuctuation in EEG ‘microstates’—short-lastingbutstablecouplingsbetweenneuronal assembles—hasbeenlinkedtotheoccurrenceofAVH(Kindleretal., 2011).Howrestingdynamicsvaryonscaleofmilliseconds (com-paredtothe>1stemporalresolutionoffMRI),andhowtheyrelate totheRSNsdiscussedabove,requiresuseofcombinedEEG/MRI methodsorimprovedsourcelocalizationmethodsinMEG.Akey questioniswhethersuchﬂuctuationscouldunderpintheapparent instabilityintheDMNobservedbyJardrietal.(2013)for partici-pantswithhallucinations.

Resting functional connectivity also often (but not always) reﬂects underlying white-matter connections (Greicius et al., 2009). In the case of AVH, structural alterations may be expectedtoreﬂecttraitcharacteristicsofanetwork,whileresting

functionalconnectivityseemlikelytoreﬂectbothtraitandstate characteristics.Asnotedabove,evidenceofstructuralreductions in white-matter integrity in the left arcuate fasciculus do not clearly map ontoalterations in intrinsic functional connectivity betweenspeechproductionandcomprehensionregions(Hoffman et al., 2011).However, two issues are worthy of consideration here.First, thefailure of restingstatestudies toﬁndclear evi-dence for functional changes between leftIFG and left STG, in thecontextofdocumentedstructuralchangestotheleftarcuate fasciculus,maybedue tothelowtemporal resolution of fMRI-basedfunctionalconnectivitystudies.Evidencehasbeenfoundthat reducedstructuralintegrityintheleftarcuatefasciculusof peo-plewithschizophreniaisassociatedwithanapproximately50ms delayincorollarydischargesignalingbetweenfrontalandtemporal regions(Whitfordetal.,2011),potentiallyduetodysmyelination ordemyelinationofthistract(McCarthy-Jonesetal.,2015).Such subtletimingdifferencesmakeassessmentoffunctional connectiv-ityusingmixed-methods,includingEEG/MEG(e.g.,Brookesetal., 2011)apromisingwaytofurtherexplorehowunderlying differ-encesinphysicalconnectivitycontributetoRSNdynamicsinAVH. Second,theoreticalarguments(Whitfordetal.,2012)and empiri-calevidence(McCarthy-Jonesetal.,2015)thatstateAVHmaybe non-linearlyrelatedtostructuralchangesintheleftarcuate fas-ciculus,suggestthatexploringnon-linearrelationsbetweenAVH andIFG–STGfunctionalconnectivitymaybefruitful.

Inconclusion,initialresearchonintrinsicfunctional connectiv-ityinAVHhashighlightedavarietyofregionsthatshowaltered restingpropertiesinthosepronetohallucinations,includingareas implicated languageand default modenetworks.The strongest evidencesupportsalteredrestingconnectivityintheleftsuperior temporalgyrus,althoughthereisevidenceofconnectivity alter-ationsthroughoutthelefttemporalcortex.Theﬁeldofrestingstate researchhasgreatpotentialforunmaskingtheunderlying mech-anismsofAVHandindoingsoprovideacleartestinggroundfor differenttheoriesofvoice-hearing.However,comparisonsacross studies are limited by extensivemethodological heterogeneity, suggestingthatanagreedanalysispipeline,withmoreattemptsat directreplication,maybeimportantforfutureresearchtoprogress effectivelyandsystematically.

Acknowledgements

This work was supported by the Wellcome Trust (WT098455MA), and by an Australian Research Council Dis-covery EarlyCareer ResearcherAward(DE140101077)awarded toSimonMcCarthy-Jones.ChristianSorgandKellyDiederenare thankedforprovidinginformationonparticipantgroups.

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