Interaction of language, auditory and memory brain networks in auditory verbal hallucinations

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Interaction of language, auditory and memory brain

networks in auditory verbal hallucinations

Branislava Ćurčić-Blake, Judith M. Ford, Daniela Hubl, Natasza D. Orlov,

Iris E. Sommer, Flavie Waters, Paul Allen, Renaud Jardri, Peter W.

Woodruff, Olivier David, et al.

To cite this version:

Branislava Ćurčić-Blake, Judith M. Ford, Daniela Hubl, Natasza D. Orlov, Iris E. Sommer, et al..

In-teraction of language, auditory and memory brain networks in auditory verbal hallucinations. Progress

in Neurobiology, Elsevier, 2017, 148, pp.1-20. �10.1016/j.pneurobio.2016.11.002�. �hal-02502901�

Review

article

Interaction

of

language,

auditory

and

memory

brain

networks

in

auditory

verbal

hallucinations

Branislava 

Cur

9cic-Blake

*

,

Judith

M.

Ford

,

Daniela

Hubl

,

Natasza

D.

Orlov

,

Iris

E.

Sommer

,

Flavie

Waters

,

Paul

Allen

,

Renaud

Jardri

,

Peter

W.

Woodruff

,

Olivier

David

_,

_Christoph

_Mulert

_,

_Todd

_S.

_Woodward

_,

_André

_Aleman

a

DepartmentofNeuroscience,UniversityofGroningen,UniversityMedicalCenterGroningen,Groningen,TheNetherlands

b

UniversityofCaliforniaandVeteransAffairsMedicalCenter,SanFrancisco,UnitedStates

c

TranslationalResearchCenter,UniversityHospitalofPsychiatry,UniversityofBern,Switzerland

d

InstituteofPsychiatry,PsychologyandNeuroscience,King’sCollegeLondon,UnitedKingdom

e_{BrainCenterRudolfMagnus,UniversityMedicalCenterUtrecht,TheNetherlands}

f_{GraylandsHospital,NorthMetroHealthServiceMentalHealth,TheUniversityofWesternAustralia,Australia} g

SchoolofPsychiatryandClinicalNeurosciences,TheUniversityofWesternAustraliaGraylandsHospital,Australia

h

DepartmentofPsychology,UniversityofRoehampton,London,UnitedKingdom

i

UniversityofLille,CNRSUMR9193,SCA-Lab&CHULille,FontanHospital(CURE),Lille,France

j

DepartmentofNeuroscience,TheUniversityofSheffield,UnitedKingdom

k_{UniversityofGrenobleAlpes,Inserm,U1216,GrenobleInstituteofNeuroscience,Grenoble,France}

l_{UniversityMedicalCenterHamburg-Eppendorf,DepartmentofPsychiatryandPsychotherapy,PsychiatryNeuroimagingBranch,Hamburg,Germany} m

DepartmentofPsychiatry,UniversityofBritishColumbia,Vancouver,Canada

n

BCMentalHealthandAddictionResearchInstitute,Vancouver,Canada

ARTICLE INFO Articlehistory: Received23July2016

Receivedinrevisedform4October2016 Accepted20November2016

Availableonline24November2016 Keywords:

Auditoryverbalhallucinations Functionalconnectivity Anatomicalconnectivity fMRI EEG DTI Language Memory Auditoryprocessing Psychosis Schizophrenia ABSTRACT

Auditory verbalhallucinations(AVH)occurinpsychoticdisorders,but alsoasasymptomofother conditionsandeveninhealthypeople.SeveralcurrenttheoriesontheoriginofAVHconverge,with neuroimaging studies suggestingthat the language, auditoryand memory/limbic networksare of particularrelevance.However,reconciliationofthesetheorieswithexperimentalevidenceismissing. Wereview50studiesinvestigatingfunctional(EEGandfMRI)andanatomic(diffusiontensorimaging) connectivityinthesenetworks,andexploretheevidencesupportingabnormalconnectivityinthese networks associated with AVH. We distinguish between functional connectivity during an actual hallucinationexperience(symptomcapture)andfunctionalconnectivityduringeithertherestingstate orataskcomparingindividualswhohallucinatewiththosewhodonot(symptomassociationstudies). Symptomcapturestudiesclearlyrevealapatternofincreasedcouplingamongtheauditory,languageand striatalregions.Anatomicalandsymptomassociationfunctionalstudiessuggestthatthe interhemi-sphericconnectivitybetweenposteriorauditoryregionsmay dependon thephaseofillness, with increasesinnon-psychoticindividualsand firstepisodepatientsanddecreasesinchronicpatients. Leadinghypothesesinvolvingconceptsasunstablememories,sourcemonitoring,top-downattention, andhybridmodelsofhallucinationsaresupportedinpartbythepublishedconnectivitydata,although several caveats and inconsistencies remain. Specifically, possible changes in fronto-temporal connectivityarestillunderdebate.Precisehypothesesconcerning thedirectionalityofconnections deducedfromcurrenttheoreticalapproachesshouldbetestedusingexperimentalapproachesthatallow fordiscriminationofcompetinghypotheses.

©2016TheAuthors.PublishedbyElsevierLtd.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Abbreviations:ACC,anteriorcingulatecortex;AF,arcuatefasciculus;AVH,auditoryverbalhallucinations;dACC,dorsalanterioscingulatecortex;DTI,diffusionweighted imaging;EC,effectiveconnectivity;EEG,electroencephalogram;FA,fractionalanisotropy;FC,functionalconnectivity;fMRIt,functionalmagneticresonanceimaging;IFG, inferiorfrontalgyrus;MD,meandiffusivity;MTG,middletemporalgyrus;No-AVH,patientswithouthallucinations;PFC,prefrontalcortex;RS,restingstate;SMA, supplementarymotorarea;STG,superiortemporalgyrus;WM,whitematter.

* Correspondingauthor.

E-mailaddress:b.curcic@umcg.nl(B. Cur9cic-Blake).

http://dx.doi.org/10.1016/j.pneurobio.2016.11.002

0301-0082/©2016TheAuthors.PublishedbyElsevierLtd.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

ContentslistsavailableatScienceDirect

Progress

in

Neurobiology

Contents

1. Introduction ... 2

2. Majorhypothesesinthecurrentliterature ... 2

2.1. Unstablememories ... 3

2.2. Sourcemonitoring ... 3

2.3. Interhemisphericmiscommunication ... 4

2.4. Top-downeffectandbottom-uppredictions ... 4

2.5. HybridmodelsofAVH ... 5

3. Functionalconnectivitystudies ... 5

3.1. Auditorynetwork ... 5

3.1.1. Symptomassociationstudies ... 5

3.1.2. Symptomcapturestudies ... 7

3.1.3. Conclusionforauditorynetworks ... 7

3.2. Languagenetworks ... 8

3.2.1. Symptomassociationstudies ... 8

3.2.2. Symptomcapturestudies ... 8

3.2.3. Conclusionforlanguagenetworks ... 9

3.3. Memoryandthelimbicnetworks ... 9

3.3.1. Symptomassociationstudies ... 9

3.3.2. Symptomcapturestudies ... 9

3.3.3. Conclusionformemory/limbicnetwork ... 10

4. Anatomicalconnectivity ... 10

4.1. Anatomicalconnectivityofauditoryregions ... 10

4.2. Memorylimbicregions ... 12

4.3. Languagenetwork ... 12

5. EEG-basedconnectivityanalyses ... 13

5.1. Self-monitoringofself-generatedsensations ... 13

5.2. Interhemisphericmiscommunication ... 13

6. Discussion ... 15

6.1. Generalsummary ... 15

6.2. EvidencefortheoreticalproposalsregardingAVH ... 15

Acknowledgments ... 17

References ... 17

1.Introduction

Recentfindingsfrombrainimaginghaverevealedthatauditory verbalhallucinations(AVH)inschizophreniaareassociatedwith alterations in brain connectivity (Brown and Thompson, 2010; Jardrietal.,2011)thatincorporatebothfunctionalandanatomical connections (Allen et al., 2008). These studies have pointed towards a prominent role for language, auditory and memory networks in AVH (Allenet al., 2012; Vercammen et al., 2010). Although many studies have been conducted, some are in discrepancywith each other.For example, somefindings point towardsincreasedconnectivitywithinthelanguageandmemory networks(Hubletal.,2004;Shergilletal.,2007),whereasothers demonstrateadecreaseinfractionalanisotropy(FA),implicating decreasedconnectivity(Catanietal.,2011;DeWeijeretal.,2013; Cur9cic-Blakeetal.,2015)inthesamepathwaywithinthenetwork (Geoffroy et al., 2014).In addition,memory regions havebeen implicatedinAVH(Allenetal.,2012)buttheirrelationshiptothe language and auditory networks is as yet unclear. Therefore, investigationsoftheinteractionofthelanguagenetworkwiththe auditoryandmemorynetworksappearstimelyandbeneficialto thefield.

AVHs arehypothesizedto beaccompanied byabnormalities both within and between these networks. The most recent comprehensive review related to the neural underpinnings of AVHs(Allenetal.,2012)concludedthatthere was“insufficient neuroimagingevidence to fullyunderstand theneurobiological substrateofAH.”Recentreviewsfocusedonanatomical connec-tivity of the arcuate fasciculus involved in language functions (Geoffroyet al.,2014)andfunctional connectivityRS studiesin relationtoAVH(Alderson-Dayetal.,2015,2016;Northoff,2014). However, there is no comprehensive review that covers both

functional and structural connectivity studies of language, auditoryperceptionandmemoryprocessing.Inaddition,togather informationspecifictoAVH,itisimportanttoobservechangesin connectivity not only in patients with AVH but also in other populationssuchasnon-psychoticindividualswithAVH,at-risk mental state and first-episode patients. Previous studies have shownthatAVHoccurinapproximately5–10%ofhealthypeople– theso-callednon-clinicalpopulation(vanOsetal.,2009;Aleman andLarøi,2008).Thesepeopledonotfulfillcriteriaforadiagnosis of schizophrenia, nor psychosis in general. Furthermore, non-clinical,at-riskmentalstateandfirst-episodepatientshaveusually notusedmedicationandexhibitnobrainchangesassociatedwith durationof illness.Therefore, wewillhereinclude connectivity studiesthatincorporatetheseAVHpopulations.In recentyears, around20 newstudieshavebeenpublishedonconnectivityin relationtoAVH,involvingfMRImeasurementsduringataskand duringtheRS,EEGstudiesandvariousanatomicalstudies.Many theoreticalmodelsweredevelopedbeforethesenew neuroscien-tific findings, and that it is timely to see how models can be reconciledwithconnectivityevidence.Thisimpliestheneedfora newreviewofneuroimagingstudiesthatmaycontributetoanovel neurobiologicalmodelofAVHs.Inordertoputthesenewstudies intoatheory,wefirstpresentthemajorhypothesisregardingthe mechanisms behind AVH and then investigate whether recent literaturesupportsthese.

2.Majorhypothesesinthecurrentliterature

Inthissection,wefirstoutlinethemostinfluentialhypotheses (or models) of AVH, specifically: Unstable memories and self-monitoring deficits, interhemispheric miscommunication, top-downandbottom-uppredictionsandHybridmodel.Second,we

willreviewevidenceforthesemodelsinviewofthefunctionaland structural connectivityfindings with regard tomajor networks subservingauditory,languageandmemoryprocessing.Finally,we willcomebacktothemodelsandevaluatethemintermsofthe reviewedfindings.

2.1.Unstablememories

Oneearly theoryproposedthatverbalhallucinationsmaybe ‘parasitic’ memories due to disrupted language production processeswhichspontaneouslyanderroneouslyactivatelanguage basedmemory(Hoffman,1986).Arecent variant ofthis model proposesthatAVHmightresultfromtheintrusionandunintended activation of memories and other mental representations (i.e. innerspeech,auditoryimages)(Watersetal.,2006).Insupport, people who hear voices experience these as intrusive and unwanted(Morrisonetal.,1995),asmightbeexpectedifmemory systems fail to suppress mental associations which are not currentlyrelevant.Problems mightarise becauseof incomplete encodingofmemories,increasingtheirvulnerabilitytobecoming incorrectly primed, or abnormal storage, leading to weak contextual harnessing. In support of this, tangentiality and looseningofassociations,typesofformalthoughtdisorderhave oftenbeenreportedinpatientsandhealthyindividualswithAVH (Sommeretal.,2010).Inhibitoryde_ficitswouldalsocontributeto thefailuretocontrolthecontentsofmemories(Jardrietal.,2016; Waters et al., 2006). If memory is indeed implicated in AVH, regionsengagedwouldincludethehippocampalcomplex(Fig.1), andtheputamentotranslatememoriesintolanguageexperience (Price, 2010) and bring the experience into consciousness (Mhuircheartaigh et al., 2010), as wellas speechand auditory network (Wernicke’s, Broca’s areas; Fig. 2). This theory could

provideaneurobiologicalexplanationforthestrongassociation betweenchildhoodtraumaandAVH,whichispresentinpatients withschizophrenia,withpost-traumaticstressdisorderandalsoin non-clinical populations (Daalman et al., 2012). In support, hippocampaldeactivationshavebeenobservedimmediatelyprior AVH, pointingtothe releaseof memory(Hoffmanet al.,2008; Diederenetal.,2010).

2.2.Sourcemonitoring

Source monitoring hypothesis proposes that AVH comprise de_ficitsinself-monitoringandrealitydiscrimination(Bentalland Slade,1985; McGuire et al.,1993; Allen et al., 2007), whereby internally events (thoughts, inner speech, actions) lack ‘self’ attributes,resultinginbroaddifficultiesinself-recognition.

Oneapproachhasbeentoexplaintheseimpairmentsinterms ofsensory-motorpredictionsfromone’sownactionsviaforward modellingandefferencecopymechanisms(Feinberg,1978;Frith etal.,1992).Ofthese,self-monitoringofinnerspeechmodelhas been the one most often studied using neuroimaging and neurophysiologicalmonitoringtechniques(suchasEEG). Neuro-scientistshaveaskedabouttheneuralmechanismsthattag self-generatedinnerexperiencesas“comingfromself”enablingthem to be distinguished from externally generated percepts. In nonhumanspecies, theexperiments ofteninvolve vocalizations andrecordinglocalfieldpotentialsfromauditorycorticalneurons (EliadesandWang,2008,2013).HumanstudiesusingEEG-based methodshavemimickedthisworkandthefindings(Fordetal., 2002).Regardless of thespecies, auditorycortexresponses are suppressed during vocalization. Connectivity between frontal (perhaps Broca’sarea)and temporalareas(auditorycortex)has been suggested to be responsible for the auditory cortical

suppression,asthedegreeof connectivitybetweentheseareas duringtalkingisrelatedtothedegreeofsuppression(Fordetal., 2007;Chenetal.,2011;Wangetal.,2014).Thiscommunication couldsignalthearrivalofself-generatedsensations.Alternatively itmaybethatperceptionofspeechitselfinhibitsauditorycortical activity according to the ‘saturation hypothesis’ (see later). Certainly patientswith stressful AVHs find relief by talking to themselves or to others (Nayani and David, 1996; Farhall and Gehrke,1997;Farhalletal.,2007).Onepossiblemechanismisthe reductionofendogenousauditorycorticalactivitydrivingAVHs, althoughother mechanisms (e.g.involving emotion regulation) cannot be excluded. The increased endogenous activity in the auditorycortexinpatientswithAVHhasbeenobservedearlier (Kompusetal.,2011)andtheactivationinthesecondaryauditory cortexhasbeenrelatedtoAVH(Jardrietal.,2011).Furthermore, theparadoxicaldeactivationoftheauditorycortexduringauditory stimuliwasreportedinameta-analysis(Kompusetal.,2011)and thiscouldpossiblyexplainthereliefthatAVHpatientsexperience whentheylistentoexternalstimuli.ChoandWuconsideredthis modelinsufficientasitdoesnotexplainwhatistobemonitored– i.e.aninternalsignalstillhastoarisefromsomewhere(Choand Wu,2013).

A second approach has viewed these ‘source-monitoring’ problemsasmemorydeficits,involvingfailuretocorrectlybind andretrievememoryfeaturestoformacohesiverepresentationof an experience (Mitchell and Johnson, 2009). Together, these deficitsspeaktotheroleofthemedialtemporallobes (hippocam-palcomplex,perirhinal),becauseofitsroleinrelationalencoding, andmoreposteriorregionsandparietalcortexintheretrievaland/ orflexibleuseofrelationalinformationduringlaterremembering (Lepageetal.,1998).Prefrontalareasarealsoinvolved,butmoreso forattributionandreasoning.Akeywhitematterstructureinthis theoryisthearcuatefasciculusconnectingtheseareas.

2.3.Interhemisphericmiscommunication

This hypothesis entails that increased synchrony between bilateralauditoryareasmaycontributetotheunderlying neural correlateofAVH(Steinmannetal.,2014b).Thetheoryoriginates fromresearchintotinnitus,whichisanauditorypreceptofatone withoutanycorrespondingexternalstimuli.Basedonfindingsof hyper-synchrony between the auditory cortices (Eggermont, 2007),Dieschandcolleaguessuggestedthatstronger interhemi-sphericauditory pathways mayfacilitate thedevelopment and persistence of a positive feedback loop between tinnitus gen-eratorslocatedinbothhemispheres(Dieschetal.,2012).Studies

usingseveralmodalities(fMRI,DTI,EEG)supporttheconceptthat altered connectivity between bilateral auditory areas via the corpuscallosum (Fig.1)isrelatedtotheemergenceofauditory AVH (Steinmann et al., 2014b). This idea is based on the observation that the abovementioned pathway is involved in healthy auditory processing and speech comprehension. For example, lesion studies demonstrated a crucial role of this pathwayintheintegrationofprosodicandsyntacticinformation (Friederici et al., 2007). In other words, disturbances in this pathway, crucial for auditory and language processing, may underlie the pathophysiology involved in auditory phantom perceptssuchasAVHortinnitus(Steinmannetal.,2014b). 2.4.Top-downeffectandbottom-uppredictions

Anotherapproachthatfocusesonperceptionandattentional processes is based on the idea that AVH may be caused by unbalancedmechanismsforbottom-upsensoryprocessingonone hand and top-downmechanismsonthe otherhand(Behrendt, 1998;Grossberg,2000;Alemanetal.,2003).Ithasbeenreported that patients withmore severe hallucinations showed a larger influenceofimageryonperceptioninpatientswithactiveAVH, suggesting disturbances in top-down influences on auditory perception (Aleman et al., 2003). They interpreted this as disturbances in top-down influences on auditory perception. The authors suggested that abnormalities in two cognitive mechanisms are simultaneouslyassociated with AVH: (a) de fi-ciencyinrealitymonitoringand(b)increasedtop-downinfluence overimagery(restrictedtohallucinationperiods). Metzaket al. foundthatthedefault modenetworkdeactivates duringreality monitoring,whilenetworksinvolvingthesupplementarymotor area(SMA),anteriorcingulatecortex(ACC)andoccipitalregions becomemoreactivated(Metzaketal.,2015).Ifthereisdeficiency in reality monitoring then it is expected that coordinated activationincreases(failuretodeactivate)inanetworkinvolving thedefaultmodenetworkandthesuperiortemporalgyrus(STG) and decreases in the SMA and ACC (Metzak et al., 2015) in associationwith AVH. Increased top-downinfluence should be reflectedinstatestudiesshowingeitherprefrontalcortex(PFC)or higherorderperceptualregionsincreasedconnectivitytoauditory perceptionregionssuchas theSTGand middletemporal gyrus (MTG)(Fig.1).

Later,intheframeworkofBayesianinferencesandAVH,Friston suggestedunbalancedmechanismsfor bottom-upsensory proc-essing onone hand and the formation of top-downpriors for encodingthebottom-upinformationontheotherhand(Friston,

Fig.2.Illustrationoflanguageandauditorynetwork.Thetwonetworksharesomeregions(suchasSTG)andaredifficulttodisentanglefromeachother.Wernickeareais drawninthemostglobalmanner.SomeauthorsincludeonlyTPJpartofthetemporallobe(BA22),butofteninarticlestheWernicke’sareaincludespartsofparietallobewith BA39and40(Mesulam,1990).

2005). If for example the bottom-up sensory processing is perception,andthetop-downpriorexpectationisattention,then one might see the cause of hallucinations as perception and attention deficit. This is conceived as a unitary deficit i.e. predictive coding. Hugdahlet al. also endorsed the idea of an imbalanceintop-down/bottom-upinfluencesandsuggestedthat whileAVHsoriginateinperisylvianregions(Hugdahl,2009),they areingeneralnotasconstrainedbythePFCinpatientsastheyare in non-psychotic voice-hearers. This would mainly involve abnormalitiesinthePFC-temporo-parietalconnectivity.

Nazimek et al. suggested that AVHs arise from attenuated prediction error processing (Nazimek et al., 2012). Similar to Hugdahl(2009),theysuggesttheauditorycorticesmightproduce anerrorsignal.Theypostulateinaccuratetop-downprocessingPFC viathalamustoperceptioninauditory cortexinvoicehearers.Thisin turn might prevent auditory cortex from generating an error predictionsignalwhentheinformationisplausible.Thusabnormal interactionof PFC,thalamus andauditorycortices coupledwith hypersensitivityofauditorycortexmightbeatthecoreofAVH.This theorywasbasedoninitialfindingofHunteretal.,whoshowed increasedactivityduringrestinauditorysensoryareasofpeople morepronetohallucinate(Hunteretal.,2006).

2.5.HybridmodelsofAVH

Fordand Hoffmanproposeda hybrid model of spontaneous activationsandself-monitoring(FordandHoffman,2013a).They suggestedtheneuralbasis ofAVHisahyper-connected cortico-striatal network whereby otherwise nascent activity can gain accesstoconsciousness.Thisnetworkisresponsiblefor registra-tionofsensoryaspectsoftheexperience,includingtheacoustic vocalcharacteristics.The non-self-perceptionofthis experience mayresultfromdysfunctionoftheself-monitoringmechanism.As yettherearenodatafromasingleanalysissupportingthishybrid model.However,wewillshowherethatthereisevidencefrom separate studiesthat both maycontributetotheexperienceof voices.Otherauthorshavealsoproposedcombinationsofseveral hypotheses mentioned above. For example, Aleman and Larøi (2011)combinedthetop-downaccountwiththeself-monitoring account into a single descriptive model of perception and hallucination. Similarly, Waters et al. (Waters et al., 2012) integratedaspectsofreducedinhibition,impairedself-monitoring andalteredtop-downfactorsintotheirmodelofAVH.

Inaddition,Northoffincorporatedseveralalterationsinresting statenetworksandinteractionsamongthem,includingauditory areasandareasinvolvedinspeechmonitoring belongingtothe defaultmodenetwork(ACC),intoarestingstatehypothesisofAVH (NorthoffandQin,2011;Northoff,2014;Alderson-Dayetal.,2016). Manyaspectsofthemodelssummarizedabovecanbetested usingconnectivitymeasures,asobtainedwithfMRIandEEG.We willnowreview_findingsofsuchstudiestocompareplausibilityof previouslymentionedhypothesis.

3.Functionalconnectivitystudies

Functionalconnectivity(FC)referstothecorrelationsofactivity betweendifferentbrainregions. Withtime-seriesderived from functionalMRI(fMRI)data,functionalconnectivityisassessedby calculating the temporal correlation between a blood-oxygen-ation-leveldependent(BOLD)activitiesin twoor moreregions (Friston,2011).Functionalconnectivitycanbecalculatedfromdata acquired during rest or tasks. The former method has the advantageofallowinginferencesaboutconnectivitytobemade without consideration of the cognitive impairment commonly observedinpatientswithschizophrenia.Thelattermethodhasthe advantageof, through careful task selection, focusing onbrain

networksthatunderliecognitiveoperationsthoughttobeinvolved in AVH. While FC refers to simultaneous activation (such as correlationsinfMRIorcoherenceinEEG),effectiveconnectivity (EC)referstocausalinfluencesofoneareaoveranotherarea.EC approaches allow inferences about the influence one neural systemexertsoveranother(Friston,2011),havebeenused,toa lesserextent.

TheapplicationofFCanalysestothestudyofAVHsismotivated byarangeofstudiesdemonstratingthatinter-regionfunctional coordination plays an important role in determining whether neuralactivity is experiencedconsciouslyas percepts(Cosmelli etal.,2004;SergentandDehaene,2004;Mellonietal.,2007;John, 2002). Here, we reviewed the evidence linking the following networks to AVH: auditory, memory/limbic and language net-works(Table1).

FunctionalMRIstudieshaveinvestigatedthefunctionalbrain networks during the experience of hallucinations but also compared thefunctional brainnetworksbetweenpatientswho hallucinate and those that do not,based onreports of hearing hallucinationduringthepast(Allenetal.,2012;Woodruff,2004). We will refer to brain imaging investigations of groups that hallucinate as symptom association studies (also called trait studies),andtheexperienceofhallucinationsassymptomcapture studies(alsocalledstatestudies).

3.1.Auditorynetwork

Soundsareperceivedandprocessedfirstinprimaryauditory cortex(PAC)whichislocatedinthesuperiorplaneofthesuperior temporal gyri (STG) calledHeschl’sgyrus(Zatorreet al., 2002) (Fig.2)andfromthere,soundsandvoices areprocessedinthe secondaryauditorycortexencompassingvariouspartsoftheSTG, MTGandthenalsoviathethalamus(Zatorreetal.,2002,2007; Belinetal.,2000;JavittandSweet,2015)senttohigherorderareas suchareGeschwind’sareaandotherlanguageareas.Ithasbeen knownforsometimethatimageryactivatesthebrainareasthat overlap with those that sub-serve perception (Kosslyn and Ochsner,1994;Zatorreetal.,2007).Auditoryhallucinationsthat formevenstrongersensoryexperiencesaccordingly,activatethe auditory cortex (including left STG; Fig. 1), which houses the linguistic auditoryperceptionregions of thebrain(Allenet al., 2012;Woodruffetal.,1995a,1997).

3.1.1.Symptomassociationstudies

Thehallucinatorystatecanbeconsideredatypeofchallenge state that recombines the naturally occurring resting state networks.AreviewoftheRSliteraturecomparingAVHtoNoAVH psychoticpatientssuggeststhatconnectionsbetweenaspectsof the dorsal anterior cingulate cortex/supplementary motor area (dorsal ACC/SMA (dACC/SMA);overlapping BAs 24/32/8 onthe midsagittalplane)andtheSTGareassociatedwiththeseverityof AVH (Alderson-Day et al., 2015), which is in line with the RS hypothesisproposedbyNorthoff(NorthoffandQin,2011; North-off, 2014). Speci_fically,two seed-based studies reported hyper-connectivityinnetworksinvolvingSTGandthedACC/SMAforAVH patientsrelativetoNoAVH(Alonso-Solisetal.,2015;Rollandetal., 2015). The dACC/SMA regions span the fronto-parietal, ventral attentionand sensorimotor networksonthemedial plane(Yeo et al., 2011), so all are candidates for resting-state-network combinations underlying AVH. These studies also reported hallucination-severity-specific hyperconnection between the STGandmanyotherregionsthatdidnotreplicateacrossstudies. AswiththeRSliterature,thetask-basedliteraturealsoprovides evidencefortheimportanceofconnectionsbetweentheSTGand dACC/SMA,withonesourcemonitoringstudydirectlytestingand reportingreducedconnectivityintheleftSTGanddACC/SMAfor

Table1

Articlesinvestigatingfunctionalconnectivity(FC)inoneormoreofthe3networksinrelationtohallucinations. Type Study Author HC/AVH/ NoAVH Type Network

Typestudy/Task/Analysis Questionaire Summaryofresults State

FC

Raijetal. (2009)

11AVHSz L/M/A Buttonpressingonthe onsetandoffsetifAVH, Joystickdeclinationtonote realityofAVH;PPI

Subjectiverealityof hallucinations(SRH)(Hunter, 2004)

SRH(+)FCbetweenIFG(B)and:theventral striatum,theauditorycortex,therightposterior temporallobe,andthecingulatecortex

Hoffman etal.(2011a)

23HC32AVH Sz24NoAVH Sz

M/L Baloonpressingduringthe AVH

IncreasedFCinAVH:WtoIFG;IFGtoputamen

Hoffman etal.(2011b)

11AVHSZ 10NoAVHSz

L Baloonpressingduringthe AVH

IncreasedFCinAVH:leftIFGtorightTemporal ROI(MTGandSTG)

Thomaetal. (2016)

11AVHSZ4 AVHSzAff

A/L Buttonpressingonthe onsetandoffsetofAVH; ICA

PANSS;PSYRATS;Semistructured interviewtogatherqualitative dataabouttheirAVHexperiences duringscanning

Outof4commonAVHrelatedICAnetworks (Insulanetwork;leftFTN;bilateralFTNand AuditorycortexandposteriorLanguage Network)onlyACPLN(+)withAVHoccurrence, whileOccipital-temporal( )andMedial prefrontal( )withAVHoccurence State and Trait FC Closetal. (2014) 49HC49AVH Psychotic patients

L/M RS CASHandPANSS PatientswhohadAVHduringscan:1.Reduced

FCbtheAGandthesurroundingleftIPL2. IncreasedFCbetweenthethalamusandtheleft fusiformgyrus/hippocampus;P3(+) leftIFG-VMPFC;P3( )thal-righPHG;P3( ) thal-rightPrecentralG

TraitFC Lawrieetal. (2002)

10HC3AVH Sz5NoAVHSz

L SeveralTasksandRS Krawieckascale ReducedFCinAVH:leftDLPFCtoMidd/STC

Vercammen etal.(2010)

27HC27AVH Sz

L RS AHRSandPANSS TotalAHRS( )conn:leftTPJ bilateralACC;left TPJ thebilateralamygdala

Gavrilescu etal.(2010)

16HC13AVH Sz13NoAVH Sz

A RS ReducedFCinAVH:interhemisphericPACs,

interhemisphericSACs Escartíetal. (2010) 31/27/14AVH chronic, NoAVHnever

M-emotion task-ICA:listeningto emotionallychargedwords

PANSS;PSYRARS;BPRS Reducedsync.InAVH:STG,IFGandtheinsula

Sommer etal.(2012) 49HC49AVH Sz L/M RS PANSS P3( )leftSTG-left_hippocampus Diederen etal.(2013) 25HC25AVH Non-psychotic

RS;Seedregression IncreasedFCinAVH:leftST-rightSTregions; leftST-rightIFregions;leftpHregion leftIFG; Nonegativecorrelationsasincontrolgroup:left ST-rightIF

Trait Mouetal. (2013)

13HC13AVH Sz13NoAVH Sz

Task:Voicerecognition SAPS-AH ReducedFCinAVH:tightSTGtorightSFG;voice recognitionaccuracy(+)FCrightSTG–rightSFG

Shinnetal. (2013)

28HC27AVH Sz14NoAVH Sz

A RS PSYRATS-AH IncreasedinAVH:leftHGFCwithleft

frontoparietalregions;ReducedinAVH:leftHG FCwithrighthippocampalformationand mediodorsalthalamus;AVHseverity(+)FCleft HGwith:leftIFG(Broca'sarea),leftlateralSTG, rightpre-andpostcentralgyri,cingulatecortex, andorbitofrontalcortex

Alonso-Solis etal.(2015)

20HC19AVH Sz14NoAVH Sz

A;DMN RS Historyofhallucinations;PANSS IncreasedinAVH:FCdMPFCROIandbilateral: centralopercularcortex,insularcortexand precentralgyrus;DecreasedinAVH:vMPFCROI andbilateralparacingulateanddorsalACC

Rollandetal. (2015) 16AVHSz14 NoAVHSz15 AH/VHSz A: mesolimbic pathway VTA-Nacc

RS IncreasedinAVH:FCNAccwiththeleftSTG,the

cingulategyri,andtheVTA

Lavigneetal. (2015)

27HC10AVH Sz13NoAVH Sz22Bipolar

A/L Tasks:Innerverbaltought andSpeechperception; constrainedPCA

SSPi IncreasedinAVHduringSpeechperception:FC spfronto-temporalnetworkincluding speech-relatedauditoryandmotorregions

Benettietal. (2015) 22HC28AVH ARMS+FEP 18NoAVH ARMS+FEP

L Task:HaylingSentence CompletionTask;DTI tractography

PANSS;PSYRATS IntermediateinAVHbetweenHCandNoAVH (butnotsugbuficant):FCLMTGandLIFG:AVH; NoAVHthelowest;

Mechelli etal.(2007) 10HC11AVH Sz10NoAVH Sz A:dACC/ SMA–STG

Task:Sourcemonitoring; DCM

Historyofhallucinations;SAPS Greater(condition)inAVH:ECleftSTGtoACC forself-initiatedthanexternal-initiatedspeech inpatientscomparedtoNoAVHandHC

Cur9cic-Blake etal.(2013)

31HC30AVH Sz17NoAVH Sz

L Task:Innerspeech;DCM PANSS ReducedinAVHECFromWernicke'stoBroca's areacomparedtoNoAVHandHC;trendreduced EFfromBroca'shomologuetoBroca'sarea

dela Iglesia-Vayaetal. (2014) 31HC27AVH Sz14NoAVH Sz

Task:Emotionalword listening;ICAandGC

PANSS;PSYRATS-AH;BPRS InthepatientswithAH,theprincipalcausal sourcewasanoccipital–cerebellarcomponent, versusatemporalcomponentinthepatients withoutAHandthehealthycontrols

AVHrelativetoNoAVHpatients(Mechellietal.,2007).However, using speech perception, and comparing AVH and NoAVHs patients, anotherstudy foundincreased coordinatedactivityin theSTGanddACC/SMA(Lavigneetal.,2015).Theimportanceofthe co-activationoftheSTGandthedACC/SMAparallelstheRSwork, andobservationofadisconnectionisapparentlymorefrequentin thetask-basedthanintheresting-statestudies.

Using RS fMRI,Gavrilescu and colleaguesinvestigated inter-hemisphericconnectivityintheprimaryandsecondaryauditory cortex in patientswith and without AVH and healthy controls (Gavrilescu et al., 2010). They used individual seed regions established onfunctional activationmask maps in response to passivelylisteningtowords.TheyreportedAVHpatientshaving reducedinterhemisphericFCinboththeprimaryandsecondary auditorycortex,ascomparedtobothNoAVHpatientsandhealthy controls.Thesefindingssuggestadisruptionofmultipleauditory functions, both at a basic auditory level and in higher-order languageprocessingabilities.

Iglesia-Vayaetal.presentedemotionalwordstopatientswith andwithoutAVHsandfounddifferencesinconnectivitypatterns that suggestmore cortico-corticalfunctional synchrony outside languageregions in those with AVHs (de la Iglesia-Vayaet al., 2014).Specifically,inthepatientswithAVHs,theprincipalcausal sourcewas anoccipital–cerebellarcomponent, asopposed toa temporalcomponentobservedinthepatientswithoutAVHsand thehealthycontrols.The authorsconcludedthatan anomalous process of neural connectivity involves the cerebellum when patientswithAVHsprocessemotionalauditorystimuli. Cerebel-lum is important for brain synchrony and action prediction (D'Angelo and Casali, 2013) by coordinating and modulating corticalactivity(Picardetal.,2008).

Inreviewingstudiesthatexaminedinter-hemispheric commu-nicationinAVHpatients,Steinmannetal.(2014b),notedthestrong evidenceofalinkbetweenAVHsandbothstructuralandfunctional disruptionofinter-hemisphericfibres,whilstacceptingthatsome studiesreport increasedand somedecreased connectivity. It is possible that such variability denotes the requirement for an optimallevelofconnectivitytogainhealthyfunction,andthatAVH arisewhenconnectivityiseitheraboveorbelowthisoptimallevel (Steinmannetal.,2014b).

3.1.2.Symptomcapturestudies

Theauditorysystem activatedduringtheexperience ofAVH includesprimary(Dierksetal.,1999)andsecondarycortices(STG; MTG)aswellas otherregionssuchas anteriorcingulate,SMA, insula,precentralgyrus,frontaloperculum,inferiorparietallobule, hippocampus,andparahippocampalregion(Shergilletal.,2000; Raijetal.,2009).TheSTG(leftandright)arealmostuniversally activeduringAVH(Jardrietal.,2011;KuhnandGallinat,2010).The questioniswhethersuchactivation(whichbydefinitionmustbe brain-derived)ariseswithinSTGorotherbrainregions,andifso,

howitsactivityrelatesfunctionallytootherregionsthatappearto beinvolvedintheexperienceofhallucinations.

Theobservationthatauditoryhallucinationsreduceresponsivity toexternalspeechwithinSTGandrelatedregionssuchasMTGhas ledtothe‘saturationtheory’wherebythesignaldriving hallucina-tions competes for common neurophysiological resources with thoseusedforperceiving externalspeech(Woodruffetal.,1997;Ford etal.,2009).Hence,wecangainusefulinferentialknowledgefrom studyingthebrain’salteredresponsivitytoexternalauditorysignals duringsuchexperiences.Thisinturnindicatestheimportanceof auditorycortexfortheexperienceofAVHs,asthesameapparatusis usedinperceptionofnormalspeech.

Upadhyay et al. (Upadhyayet al., 2008) found that passive listeningtofemalevoicesrevealedeffectiveconnectivitybetween primaryauditorycortexandanteriorandposteriorSTG,regions thathavealsobeendemonstratedtoberesponsibleforattributing externalitytoperceivedspeech(Hunteretal.,2003),externality being one main factor in how hallucinated voices sound real (Nayaniand David,1996).Interestingly, Jardriet al. found that primaryauditorycortexwasnotsystematicallyactiveduringAVH but when active, this was linked with increased vividness in hallucinatoryexperiences(Jardrietal.,2013).

Shinnetal.reportedapositivecorrelationbetweenAVHsand functionalconnectivitybetweenHeschl’sgyrusandBroca’sarea,left lateralSTG,anteriorcingulateandorbito-frontalgyrus(Shinnetal., 2013).Aswellasanincreasedconnectivitywithinauditoryregions, theirevidenceinvokesconnectivitytoregionsthatcouldrelateto attentional systems in the pathophysiology of AVHs. This is important, as we have known for some time that attention modulates auditorysensorycortex (Woodruff etal.,1995a) and thatattentionmodifiesthehallucinatoryexperience(Nayaniand David,1996).TheobservationthattheSTGandanteriorcingulate were functionallyconnected duringspontaneousSTGactivity in acoustic silence adds further weight to the idea proposed by Woodruff(Woodruff, 2004)andHunter andcolleagues(Hunter et al., 2006)thatsignalwithintheSTGareyokedtoattentionalsystems thatcouldbringtheexperienceofAVHstoconsciousawareness. However,thelatterwasnevertestedinpatientswithAVH. 3.1.3.Conclusionforauditorynetworks

Evidencederivedfromsymptomassociationstudies,involving both restingstateandtasks,suggeststhataberrantconnections betweentheSTGanddACC/SMAarecommontoindividualswith AVH.Ahealthyconnectionbetweentheseregionsmayplayarole inmonitoringverbalthoughtsandtaggingthemascomingfrom ‘self’;dysfunctionofthisconnectionmayreducetheabilitytotag theseexperiencesasinternal,resultinginAVH.Wenotethatno connectivity studies have directly tested self-monitoring in its physiologicalsense,althoughthemonitoringprocessofalerting that “something is wrong”, of the need to make behavioral corrections,clearlyinvolvesthedACC/SMA(Behrensetal.,2007;

Table1(Continued) Type Study Author HC/AVH/ NoAVH Type Network

Typestudy/Task/Analysis Questionaire Summaryofresults

Cuietal., (2016)

19HC17AVH FEPSz15 NoAVHFEPSz

M/L RS;ALF&regional homogeneity;FC

PANSS;AHRS IncreasedinAVHrightputamen-seededFCwith theleftDLPFC

andBroca'sarearelativetothosewithoutAVHs AVH–auditoryverbalhallucinations.NoAVH-patientswithoutAVH;L-LanguageNetwork;M–Memorynetwork;A–auditorynetwork;Sz–schizophreniapatients;(+) positivecorrelation;( ) negativecorrelation;PAC-primaryauditorycortex,SAC–secondaryauditorycortex;PANSS–positiveandnegativesyndromescale;SRH– subjectiverealityofhallucinations;PSYRATS–PsychoticSymptomRatingScale;SAPS-ScalefortheAssessmentofPositiveSymptoms;SANS–ScalefortheAssessmentof NegativeSymptoms;AHRS-Auditoryhallucinationsratingscale;BPRS–Briefpsychiatricratingscale;Cash–ComprehensiveAssessmentofSymptoms;STG–superior temporalgyrus;STC–superiortemporalcortex;AG–angulargyrus;PFCprefrontalcortex;DLPFC–dorsolateralPFC;VMPFC–ventromedialPFC;MTG–middletemporal gyrus;IFG–inferiorfrontalgyrus;B-Broca’sarea;ACC–anteriorcingulate;Nacc–nucleusaccumbens;VTA–ventraltagmentalarea;ICA-independentcomponentanalysis; RS–restingstate;PPI–psychophysicalinteractions;DCM–dynamiccausalmodelling;PCA–principalcomponentanalysis;ALFF–amplitudeoflow-frequencyfluctuation.

Egner,2011;Woodwardetal.,2008).Similarconceptshavebeen put forward as the breakaway speech and unbidden thoughts accountofAVH(David,1994;FordandHoffman,2013b;Hoffman, 2010).Inaddition,thealteredactivityindACC/SMAisconsistent withtherecentmorphologicalstudyshowingtheparacingulate sulcusisshorterinpatientswithAH–thisareaisthoughttobe involvedinrealitymonitoring(Garrisonetal.,2015).

It mayalsobepossible that spontaneoussignals withinthe auditoryapparatus(including STGand MTG)incertain circum-stancesexceedathresholdforconsciousawareness,whetherby enhancedintrinsicactivityormodulatedviaareductionin ‘top-down_’attentionalconstraint.

3.2.Languagenetworks

Themostprominentbrainareasinvolvedinlanguage process-ingareBroca’sandWernicke’sareas(Fig.2),intheinferiorfrontal gyrus and temporal-parietal junction of the left hemisphere, respectively.Lateralfrontaland temporalregionsofboth hemi-spheresareinvolvedinsyntacticprocessingofconnectedspeech withpredominanceinthelefthemisphere(Friedericietal.,2000), whiletherighthemispherehasmoreimportantroleinprocessing ofemotionalinformation(prosody)andtoneofspokenlanguage (Meyeretal.,2002;Mitchelletal.,2003).Neoclassicallanguage network includes frontal and temporal areas, as well as the supplementary motor area (SMA) (Fig. 2), ACC, and insula (Mesulam,1990).

Various mechanisms including misattribution or impaired monitoringofinner speech andperturbedinteractions between bottom-upand top-downprocessesin auditoryperception have beensuggestedascognitivemechanismsthatunderlieAVH.Such dysfunctionispotentiallyrelatedtodisruptedconnectivitybetween frontalandtemporo-parietalbrainregions(Allenetal.,2012). 3.2.1.Symptomassociationstudies

Vercammenand colleaguesusedaregionof interestanalysis comprisingneuronalnetworksinvolvedininnerspeechprocessing, based around a seed region in the tempo-parietal junction (Vercammenetal.,2010).TheyfoundreducedFCbetweentheleft temporal-parietaljunctionandtherighthomologueofBroca’sarea inpatientswithschizophrenia.Furthermore,moresevereAVHwere associated with reduced FCbetween theleft temporo-parietalregion andthebilateralanteriorcingulateandbilateralamygdala.

Task based fMRI studies commonly reportdisruption in the frontotemporalnetwork. Oneofthefirst studiesbyLawrie and colleagueshasshownthatFCisreducedbetweenleftdorsolateral PFCandtemporalregionsinpatientswithschizophreniaduringa sentencecompletiontask,comparedtohealthycontrols(Lawrie etal.,2002).Importantly,thisFCwasnegativelycorrelatedwith severityofAVH.

ECdifferenceshavealsobeenreportedbetweenschizophrenia patientswithandwithoutAVH.Mechelliandcolleaguesutiliseda sourcejudgment taskusing pre-recorded single words(self vs otherspeech)(Mechellietal.,2007)andestimatedtheeffective connectivitybetween thetemporal lobe and anterior cingulate using dynamic causal modelling (Friston et al., 2003). It was reportedthatleftsuperiortemporalgyrustoanteriorcingulateEC was greater for ‘self-spoken’ words compared to ‘other-person spoken’words in patientswith AVH. The opposite pattern, i.e. greater EC for ‘other-person’ spoken words compared to self-spokenwords,wasobservedinbothNoAVHpatientsandhealthy controls.Bothofthesestudies(Wangetal.,2011;Mechellietal., 2007),althoughemployingdifferentanalyticalapproaches,report altered connectivity between temporal and medial PFC areas duringsourcejudgments,withthelatterstudy(Mechelli etal., 2007)reportingthatthiseffectisspecifictopatientswithAVH.

Cur9cic-Blake and colleagues investigated EC using dynamic causalmodellinginthelanguagecircuitryduringaninnerspeech taskinpatientswithAVHandcomparedittohealthycontrolsand patientswho didnot have AVHfor at least 6 months prior to participation(Cur9cic-Blakeetal.,2013).Theyfoundthatpatients withAVHhaddecreasedconnectionstowardsBroca’sarea,mainly from Wernicke’s area, but also from the right homologues of Wernicke’sand Broca’s areas(interhemispheric connections)to Broca’sarea.PatientswithoutAVHhadintermediateconnection strengths. Based on a reduced input from temporal to fontal languageareas,theauthorssuggestedthatBroca’sactivitymaybe less constrained by perceptual information received from the temporal cortex in schizophrenia patients withAVH. This may subsequently affect self-monitoring and lead tothe erroneous interpretation of emotional speech activity from the right hemisphere as comingfrom an external source.Note that this interhemispheric EC is between frontal areas and might not necessarily involve the auditoryinterhemispheric pathway dis-cussed inSection 2.3 which isbetweenposteriorlanguageand auditoryregions.

Shinn and colleagues reported contradictory results (Shinn etal.,2013).Theyexaminedprimaryauditorycortexconnectivity inrelationtothewholebrainand foundincreasedconnectivity withtheleftsuperiorparietallobuleandleftmiddlefrontalgyrus, and reduced connectivity to right hippocampal and thalamic regionsinAVHpatientscomparedtoNoAVHpatients.

3.2.2.Symptomcapturestudies

Inasymptomcapturestudy,Raijandcolleaguesaskedpatients withschizophreniatoindicatewhenevertheyexperiencedAVH duringresting-statefMRIscans(Raijetal.,2009).Theirfindings confirmed the involvement of language related networks including the bilateral inferior frontal gyrus (Broca’s regions and its right hemisphere homologue), the right posterior temporallobe(Wernicke’sarea),theleftanteriortemporallobe, andtherightanteriorcingulatecortexandtheparahippocampal cortexduringhallucinations.Theyfoundthatthestrengthofthe connectivitybetweentheleftinferiorfrontalgyrus(IFG)andright ventralstriatum,themiddlerightanteriorcingulatecortex,the right posteriortemporallobe,theauditorycortex, andtheleft nucleus accumbens was positively correlated with subjective experience of the reality of AVH. Moreover, strength of connectivity between the left IFG and parts of the cingulate cortex negatively correlated with subjective experience of the reality of AVH. The stronger the subjective experience of the reality,theweakerthecouplingoftheIFGwiththeposteriorand rostral anterior cingulate cortex. Thus, this study directly demonstrates complex interactionbetween language, auditory andmemorynetworks.

Hoffman and colleagues used a bilateral Wernicke’s area (posteriorSTG)delineatedseedtoinvestigateFCinpatientswith schizophrenia with and without AVH, and healthy controls (Hoffmanetal.,2011a).TheyfoundgreaterFCbetweentheseed region and IFG in the AVH patients, as compared to NoAVH patients.However,theydidnotreportanydifferencebetweenAVH patientsandhealthycontrols.Furtherinvestigations,usingtheIFG asaseedregion,revealedhighersubcorticalFCintheputamenin AVH patients with relative to NoAVH patients. Furthermore, strongerFCinAVHpatientswasseeninalooplinkingWernicke’s area, the IFG and the putamen, as compared to both NoAVH patients and healthy controls. In another study, Hoffman investigated time courseof AVH and functionalconnectivity at thevariousstagesofhallucinations(Hoffmanetal.,2011b).They foundanincreasedcouplingjustpriortohallucinationsbetween leftIFG(closetoBroca’sarea)andtherighttemporalareas.Note thatallfindingsregardingbuttonandballoonpressingarepartially

confoundedbymotorplanningandimageryspecificallyforSMA/ ACCregion(Hanakawaetal.,2008).

3.2.3.Conclusionforlanguagenetworks

Insummary,anumberofstudieshavereportedalterationsin functional connectivity in patients with schizophrenia who experienceAVHascompared tothosewithoutthesesymptoms. While most studies report decreased connectivity between language areas and other brain regions, these studies show considerableheterogeneityintheirfindings.Inconsistencyismost likelyduetomethodologicaldifferencesbetweenthestudies,such us different seed regions and different types of analyses. Nonetheless, these studies also reveal consistencies that likely underlietheexperienceofAVH.Task-relatedparadigms demon-strate deficits in source monitoring associated with aberrant frontotemporalFC.Disruptionofthesemechanismsisconsistent withcognitivemodelswhichpostulateimpairedself-monitoring duringspeechgeneration.

Similarly, functional connectivity studies, during RS scans, demonstratedisrupted FCin several networks in patientswith AVH.The mostconsistent findings areaberrant connectivityin temporo-parietallanguageregionsandinFCintheprimaryand secondaryauditorycortexinpatientswith,ascomparedtopatient withoutAVHandhealthycontrols.Inaddition,evidencesuggests thatAVHareassociatedwithincreasedconnectivityina cortico-striatal brain network, linking Wernicke’s area, inferior frontal gyrusandtheputamen.

3.3.Memoryandthelimbicnetworks 3.3.1.Symptomassociationstudies

Themostimportantregionsformemoryandemotionsarethe medialtemporalloberegions(Fig.3).Thesecomprisetheamygdala and“thememoryregions”:thehippocampus,thepara-hippocampal gyrusinvolvedinemotionalmemory(PhelpsandLeDoux,2005; LeDoux,1996;McGaughetal.,1996)andtogetherwithstriatumin associativememory(Sperlingetal.,2001).

Sommeret al. investigated FCin patientswithchronicAVH during the RS (Sommer et al., 2012). They found a negative

correlationofconnectivitybetweenthelefthippocampusandthe leftIFGandtheseverityofhallucinations.However,Diederenand colleagues investigated para-hippocampal gyrus resting-state connectivity in non-psychotic individuals with AVH (Diederen et al., 2013) and found increased resting-state connectivity between the left para-hippocampal gyrus and the left IFG in individualswithAVHascomparedtocontrols.Theseapparently contradictoryfindingssuggestthatpresence,severityandstageof illnessmatter,giventhatthefirststudyincludedchronicpatients, whereasthelatterconcernednon-psychoticindividuals.

Escarti et al. investigated the limbic networks, defined by independent component analysis (ICA) during listening to emotional words in chronic patients. Patients with AVH had reducedsynchronyofthesenetworksintheSTG,IFGandtheinsula as compared with NoAVH patients. The AVH patients had no activationduringthetaskintheinsulathatwasobservedinHCand NoAVH patients. Interestingly, AVH patients had increased activationduringthistaskintheamygdalaandpara-hippocampal gyrus. Amad et al. (Amad et al., 2014) examined connectivity between the hippocampal complex and other regions that includedSTGinpatientswithauditory,andpatientswithauditory and visual, hallucinations. In patientswith auditoryand visual hallucinations, FC between the hippocampal complex and: bilateral medial prefrontal cortex and theleft caudate nucleus, wasincreased,andthisconnectivitywasdecreased,betweenthe hippocampalcomplexandSTG,leftlenticularnucleus,thalamus andrightpre-/post-centralgyri.Theseauthorsarguedthattheir findingsfit wellwiththeoriesofAVHsbeing‘underconstrained’ perceptionsthat arisewhentheimpactofsensoryinputonthe activation of thalamocortical circuits and synchronization of thalamocorticalgammaactivityisreduced(Behrendt,2003).They notethatthisrelationshipisreinforcedbythefactthatthefrontal and temporal regions, anatomicallyconnected to the thalamus through the lentiform nucleus, werestrongly functionally con-nectedwiththehippocampusinthepatientswithAVH.

3.3.2.Symptomcapturestudies

Fewstudieshaveassessedpotentialco-activationof memory-relatedstructuresduringtheexperienceofAVH.Ameta-analysis

Fig.3.Illustrationofmemory/limbicnetworkincludingstriatalregions(apossibleintermediatestepbetweenhippocampusandauditoryregions).PHG–para-hippocampal gyrus.

showedinvolvementofthehippocampusandpara-hippocampal gyrusduringtheexperienceofAVH(Jardrietal.,2011),suggesting that memory retrieval plays a role in these experiences. Interestingly, two studies that differentiated between signal changesduringAVHandsignalchangesprecedingtheAVHfound thatthehippocampalcomplexwas mainlyinvolvedinthetime perioddirectlybeforetheAVHandnotsomuchduringtheAVH itself (Diederen et al., 2010; Hoffman et al., 2011b). This may suggestthatamemoryoccursandsubsequentlyactivatestheareas thatwerealsoactiveduringtheinitialexperience,i.e.thelanguage relatedareas.Thus, itisconceivablethata decreasein memory inhibitionenablesthe_“escape”ofmemoryfragmentsthatleadtoa re-lived experience. Memory fragments are usually inhibited duringfocusedattention(Benoitetal.,2015),butmaybecomeless inhibitedduringtimesofdaydreamingandrelaxation,whenthe default mode network is more active. Indeed, patients often mentiontheirhallucinationsoccurringmostfrequentlyattimes whenfocusedattentionislow,atthebeginningandendoftheday (Krans et al., 2015; Nayani and David, 1996). Also, in healthy subjectsAVH can occurat the borders of sleep, when focused attentionisextremelylow.Inaddition,viewingAHasaresultof memory-intrusionsmayhelpunderstandthestrikingassociation betweenpsychologicaltraumaandthistypeofhallucination(Chou etal.,2014),observedinpatientsaswellasinnon-clinicalpeople withAVH(Daalmanetal.,2012).Thesemechanismsareconsistent with the general idea that top-down cortical inhibition over sensorycortexisreducedallowingspontaneoussensoryactivityto reachconsciousawareness(Hunteretal.,2006).

Regarding the striatal involvement, Hoffman and colleagues investigatedFCinpatientswithAVH,patientswithoutAVH,and healthy controls (Hoffman et al., 2011a). They found that FC summedalongaloopofWernicketoIFGtoputamenisrobustly greaterforAVHpatientswhencomparedwithhealthycontrolsand patientswithout AVH.Even though this study is based onthe languagearea,greaterconnectivitybetweenputamenandBrocais inlinewiththehypothesisofspontaneousgenerationofmemories becauseaccordingtothattheory,putamenistranslatingmemories intolanguageanddistributingthemtolanguageareas.

3.3.3.Conclusionformemory/limbicnetwork

Insummary,thereisclearevidencethatthememorynetwork interactswithlanguageareasinanaberrantwayinpatientswith AVH as well as in non-psychotic individuals. There is a clear differentiationofthe strengthof this interactionduringrestor during a task as compared to the experience of hallucination. Namely,mostsymptomassociationstudiespointtowardsreduced connectivitybetweenthememoryandlanguageareasinpatients withAVHcomparedtothose without.However,thereisaclear increaseintheconnectivityduringandpriortoexperienceofAVH (symptomcapturestudies).

4.Anatomicalconnectivity

Anatomical connectivity refers to physical connections be-tweenbrainregions–bundlesofmyelinatedaxonsknownaswhite matter (WM). In the past 20 years novel MRI sequences and analysistechniques have enabled non-invasiveinvestigation of brainanatomyincludingboththemorphologyandconnections. Themostimportantmethodsfor investigationofbrain connec-tions are based on the estimation of WMthe diffusion tensor imaging(DTI)(Jonesetal.,1999).

Inbrainregionswithahighdensityofalignedaxons(suchas WMpathways),waterwillhaveapreferreddirectioninwhichit candiffuse,whichcanbemeasuredbydiffusionweightedimaging. This directionality is called anisotropy. The most widely used outcomeisthefractionalanisotropy(FA)coefficient,estimatedper

voxel. FAhasbeenproventoreflect theintegrityof theaxonal membraneandmyelinsheet(Beaulieu,2002),aswellasthelocal coherenceofmyelinatedaxons(CercignaniandHorsfield,2001). However,decreasesinFAdonotalwaysimplyaberrantintegrity, butcanalsoindicatecrossingfibers(seeforexample(Hoeftetal., 2007; Soares et al., 2013)). OtherDTI-derived metrics (such as meandiffusivityandradialFA)mayalsobeofinterestinAVHsince theymayreflectdifferentpathophysiologicalprocessesoccurring inWMthaninFA,butarelesscommonlyreported.

Inthenextsectionwewillreviewthemostimportantfindings regardingWMqualityandAVHs(Table2).

4.1.Anatomicalconnectivityofauditoryregions

There is a large body of evidence implying faulty auditory processing in patients with AVHs (Javitt and Sweet, 2015; Steinmannetal.,2014b).Increasedactivationhasbeenobserved intheprimaryauditorycortexduringrest,whichdecreasesduring auditorytasks(Kompusetal.,2011).Furthermore,decreasesinthe primary(Modinosetal.,2013)andsecondaryauditorycortexGM volume(reviewedbyAllenetal.(Allenetal.,2012))suggestthat thereareabnormalitiesinthetop-downregulationoftheauditory cortices, which poses questions regarding the underlying WM integrityofpathwaysconnectingauditoryregions.

TheauditorycorticesconsistoftheposteriorpartofHeschl’s gyrus(knownastheprimaryauditorycortex)andthesecondary auditory cortex protruding to the planum temporale and the superiorbankoftheposteriorsuperiortemporalgyrus(Belinetal., 2000).TheWMpathways projectingfrom theauditoryregions that are involved in higher order auditory processing are the arcuate fasciculus and the interhemispheric pathways in the posterior partofthe corpuscallosum. Thearcuate fasciculusis involvedinbothauditoryandlanguageprocessing(Duffau,2008). Therefore, the association of abnormalities in the arcuate fasciculuswithAVHsisdescribedinmoredetailinSubsection4.3. Another important pathway connects the primary and secondary auditory cortices between hemispheres – the isthmusandspleniumofthecorpuscallosum.Previousfindings regarding the interhemispheric auditory pathway are contra-dictory at first glance. Hubl et al. (2004) found that acute patients with AVH had increased FA values in the posterior parts of the interhemispheric commissures of the corpus callosum. Similar findings were obtained by Mulert and colleagues (Mulert et al., 2011b), who found that within the first episode patient group, subjects who heard voices had significantly increased FA in the auditory tract compared to patientswhodidnothavethissymptom.Bothfindingssuggest increased connectivity along the interhemispheric auditory pathway in AVH patients. Meanwhile, Knöchel and colleagues investigated FA and mean diffusivity (Knochel et al., 2012), a measure of the compactness of axons and intercellular space (Beaulieu, 2002). In contrast to the abovementioned two studies, it was found that a decrease in the corpus callosum volume was associatedwith the severity of AVH andthat the mean diffusivityvalues in theisthmusof the corpus callosum correlated significantly with the severity of AVH in patients withparanoidschizophrenia.Thisisinprincipleoppositetothe finding of increased FA values in the same area. Wigand and colleagues reported decreased FA in AVH patients over the entire pathway compared to patients without AVH in chronic patients (Wigand et al., 2015). In addition, in the midsagittal section of the auditory tract – a similar part of the posterior corpus callosum tothatstudied in previous investigations the AVHgroupdisplayeddecreasedFAinthemidsagittalsection.It is worth noting that AVH occur in heterogeneous conditions, and that reduced corpus callous isthmus size (found in

schizophrenia in a meta-analysis(Woodruff etal.,1995b) may alsoberelatedtodelusionswhichoccurinthesamecondition (Woodruff et al.,1993).

In summary, several studies have reported abnormalities in auditory pathways, interhemispheric as well as within one hemisphere. However, their findings are contradictory with

respecttothedirectionofdifferentiation.Themaintrendseems tobethatinthefirstepisodepatientsoracutepatientsfractional anisotropyisincreased,whereasinchronicpatientsFAdecreases. Nevertheless,theresultsareinlinewithourprevioussuggestion thatanydeparturefromhealthyconnectivitycausesanimbalance infunctioningandisatthecoreofAVH.

Table2

Articlesinvestigatinganatomicalconnectivityusingdiffusiontensorimaging(DTI),diffusionspectralimaging(DSI),magnetictransferimaging(MTI)orstimulationofawhite mattertract.

Author HC/AVH/NoAVH Type Network

Typestudy ROItracts Questionaire Summaryofresults

Hubletal. (2004)

13HC13AVHSz 13NoAVHSz

A/L/M DTItractography;a specialline-scan technique

PANSS,CGI IncreasedinAVH:15clusters:alongAF(6clustersleft; 4clustersright);Cingulatebundle(limbic); InterhemisphericalcommissuralfibersoftheCC; ReducedinAVH;2clusters:ILF

Shergill etal. (2007)

40HC33Sz M/A DTIvoxelwise BPRS PropensitytoAVH(+)withFAinSLFandanterior cingulum

Seoketal. (2007)

22HC15AVHSz 15NoAVHSz

L DTIvoxelwise+ROI ROI'sfromANOVAof3groups:2 clusterscingulumbundle,3in SL,1themiddlecerebellar peduncle

PSYRATS-AH IncreasedinAVH:meanFAinmiddlepartofSLF; PSYRATS-AH(+)FAinleftfrontalSLF

Szeszko etal. (2008)

33HC33Sz L DTIwholebrain;FA SeverityofAVH(+)FAinIFOF;Actuallywithall modalitiiesofhallucinations(V,tactileetc)

Leeetal. (2009)

22HC21ChrSz L Linescandiffusion imaging

Left&RightSTG SAPS&SANS MD(+)inLSTG(WM)withSAPS-Auditory Hallucination;MD(+)inLSTG(WM)with“Voices Conversing” Mulert etal. (2011a, b) 10HC5AVHFEP (paranoid)5 NoAVHFEP (paranoid) A DTI;fibre tractography; averageFAoverthe wholetract

Homotopicauditoryareasvia theCC

PANSS IncreasedinAVH:FAintheinterhemisphericpathway HCintermediatebetweenNoAVHandAVH;FA valuestrendwise(+)andAVHsymptoms

DeWeijer etal. (2011)

42HC44AVHSz M//L DTI-FA;MTI-MTR; FibertrackingFACT

AF;corticalspinaltract, cingulumandUF

PANSSand PSYRATS

PANS_pos(+)withMTRinL&RAF

DeWeijer etal. (2011) 36HC35AVHSz 35AVH non-psychotic M/L DTI-FA;MTI-MTR; FibertrackingFACT

AF;corticalspinaltract, cingulumandUF

PANSS IncreasedAVHvsHC:MTRinAF;ReducedinAVHSz onlyvsHC:FAinallbundless

Knöchel etal. (2012) 15HC16Sz16 FD-relatives A DTI&VBM; automatized segmentationofCC

wholeandsegmentedCC PANSSand RHS

SeverityAVH( )FAinCC;SeverityAVH( )VBM volumeinCC; Whitford etal. (2014) 26HC24Sz M Cingulum;5subconecctionsof Cingulum

SAPS&SANS SAPS(4itemsubscale)&Hallucinationssubscale( ) FAintheI1sub-connection(cingulumtorostraland caudalACC) Bracht etal. (2014) 22HC24Sz M DTIProbabilistic tractographySPM8

NAccconnectionsto:VTA,NAcc, amygdala,mOFC,lOFCand dlPFC

PANSS P3+P1

P3+P1(+)PIBIFAvaluesNacc-Amygdala

Wu(2014) 18HC18SZ L DSI ventralstream-IFOFanddorsal stream-AF;semantictask

PANSS GFA( )withsymptomseverity(hallucination/ delusions)inAFandIFOFandlateralizationduring semantictask Wigand etal. (2015) 33HC24AVHSz 9NoAVHSz A DTI;streamline tractography interhemisphericAuditory Pathway(AP)

ReducedinAVH:FAoverentireAP;FAandModein MidsagitalsectionofAP;IncreasedinAVH:radial diffusitivyinMidsagitalsectionofAP.

Cur9cic-Blake etal. (2015) 14HC17AVHSz 14AVHSz

L/A DTITBSS left:IFOF,UF,SLF,AF,cingulum; BilateralACR

ReducedinAVH:FAinleft:anteriorIFOF,UF,ACR,AF (anteriorandlongpartsoftheAF frontalregions suchasBA44,andtemporalregions),CCmedialand posteriorpart—theforcepsmajor,thecingulum, corticospinaltractandtheATR

Benetti etal. (2015) 22HC28AVH ARMS+FEP18 NoAVH ARMS+FEPnoSz L DTItractography; fMRItaskHayling Sentence CompletionTask

LeftAF PANSS;

PSYRATS

IntermediateinAVHbetweenHCandNoAVH(butnot sugbuficant):FAinAF;NoAVHthelowest;

Oestreich etal. (2015)

40HC39AVHSz 74NoAVHSz

L DTItractography IFOFsegmentedin4regions: frontal,fronto-temporal; temporal;occipital

DIPitems51, 52and53

ReducedinAVH:FAfronto-temporalfibersoftheleft IFOF McCarthy-Jones etal. (2015) 40HC39AVHSz 74NoAVHSz

L leftlongdirectsegmentofAF IncreasedinAVH:RadialDiffusivityleftlongsegment AF;ReducedinAVH:FALeftlongsegmentofAF(less thanNoVAHandHC)

Koubeissi etal. (2016) 3epliepsy patient L Stimulationofleft AF

leftAF ComplexAVHoccuruponstimulationofAF

FA–fractionalanisotropy;GFA–generalizedfractionalanisotropy;MTR–magnetictransferratio;MD–meandiffusivity;AF–arcuatefasciculus;IFOF–inferior fronto-occipitalfasciculus;UF–uncinatefasciculus;ACR–anteriorcoronaradiata;ATR–anteriorthalamicradiation;CC–corpuscallosum;SLF–superiorlongitudinalfasciculus; AP–auditorypathway;ForotherabbreviationsseethelegendofTable1.NotethatMTRandMDareconsideredtobeinverselyproportionaltoFA,thusincreasesinFAare oftencorrelatedwithdecreasesinMTRandMD.

4.2.Memorylimbicregions

The phenomenologyof AVHstronglyimplicatesthe involve-mentofbrainregionssubservingbothretrievalofmemoriesand theexperienceofnegativeemotion.Memoryimpairmentiswell documented in schizophrenia but has not been investigated intensivelyinrelationtoAH(Alemanetal.,1999).Nevertheless, theories/empirical evidence of impairments in memory (Sec-tion2.1 of this paper)and emotional processing,added tothe negativeemotionalconnotationofAVHinpatientswith schizo-phrenia(HillandLinden,2013),demandsfurtherinvestigationof thememory/limbicnetwork.

Thememory/limbicnetworkisinvolvedinemotional process-ing and regulation, self-monitoring, memory and attention. It comprisesthefollowingareas:theanteriorcingulate,involvedin errormonitoring and emotional processing and learning (Bush et al., 2000); the hippocampus, generally involved in memory processes (Squire et al., 2004); the parahippocampal gyrus involved in contextual associations closely related to memory (Aminoff et al., 2013); the amygdala, involved in emotional processing and emotional learning (McGaughet al.,1996);the entorhinal cortex, which is closely associated with memory functionsofthehippocampus(Squireetal.,2004);theperirhinal cortex,whichhasafunctioninsensoryintegration,semanticand long-termmemory(MurrayandRichmond,2001;Murrayetal., 2005). The largest white matter pathways connecting these regionsaretheuncinatefasciculusandthecingulum.

Theuncinatefasciculusconnectslateralandmedialprefrontal corticestotheuncus,theentorhinalandperirhinalcortices,and thetemporalpole/anterior temporallobe(VonDerHeide etal., 2013).Arecentreviewsuggeststhatuncinatefasciculushasarole in valence-based biasing of decisions. Given this function, the uncinatefasciculusappearstobeagoodcandidatetoplayarolein theemotionalpartofAVH.

Thusfaronlyonestudy,usingtract-basedspatialstatistics,has foundevidenceof anassociationofwhitematterabnormalities withintheuncinatefasciculusandAVH(Cur9cic-Blakeetal.,2015). Specifically,patientswithhallucinationswithlowerFAvalueshad moresevereAVH.Asmentionedabove(Section4.1),Hubletal. (2004)foundnodifferenceinFAintheuncinatefasciculusinAVH compared to patients who had never experienced AVH. Both studies had relatively small samples., In a larger sample (42 patientswithAVH),DeWeijerandcolleaguesfoundnocorrelation between FA in uncinate fasciculus and symptom severity (De Weijeretal.,2011).

The cingulum is the long-range white matter tract placed underneaththecingulatecortex.ItconnectstheACC,theposterior cingulate cortex, the isthmus of the cingulate gyrus and the parahippocampal cortex. Decreased FA in various parts of the cingulumhasconsistentlybeenobservedinschizophreniapatients (Hubl et al., 2004; Shergill et al., 2007; Knöchel et al., 2012). However,therelationwithhallucinationsremainspuzzling.Even though a few studies have found no association of cingulum integritywithAH(Knöcheletal.,2012),severalotherstudieshave founddifferences betweenpatientswithandwithoutAH along thistract.

Inoneofthesestudies,Shergilletal.(2007)comparedhealthy controlsandpatientswithvariousseverityof AVH.Theauthors reportedthathigherFAinthesuperiorlongitudinalfasciculusand anteriorcingulumwasassociatedwithapropensitytoexperience auditoryhallucinations,althoughoverallFAwasloweroverallin patientscompared tohealthyvolunteers (Shergill et al.,2007). Similarly,Hubletal.(2004)demonstratedreducedanisotropyin thecingulatebundleinpatientswithoutAVHcomparedtopatients who had experienced AVH, but this was restricted to the left hemisphere.Incontrast,Whitfordetal.(2014)founda negative

correlationofFAvaluesinSubsection 4.1of therightcingulum withthehallucination subscale ofSAPS. Thissubsection of the cingulumprojectsintotherostralanteriorcingulategyrusandthe caudal anterior cingulate gyrus. These two regions assume differentroles,theformerbeinginvolvedinemotionalprocessing and thelatter incognitive processesformemoryandexecutive functioning.Theauthorsproposedthatthisnegativecorrelationis inlinewithsuggestionsthatAVHarisefromabnormalinteractions betweencognitionandemotion.Seoketal.foundincreasedvalues of FA in the left caudate cingulum in patients with AVH as compared topatientswithout(Seoketal., 2007).However,the correlation with symptom severity was diminished after a correction for antipsychotic use was made. Cur9cic-Blake et al. (2015)foundanegativecorrelationofthehallucinationseverity withFAintheleftcingulum.

InsupportoftherelationshipbetweenAVHandlimbicnetwork abnormalities,Brachtetal.(2014)reportedapositivecorrelation betweenseverityofbothhallucinationsanddelusion(summary score) and connectivity between amygdala and the nucleus accumbens using probabilistic tractography methods. However, thisstudydidnotaimtoinvestigateAVHperse(Brachtetal.,2014). In summary, most studies have found altered FA values in cingulumwithAVH,andcontradictoryresultscannotbeexplained bythedurationofillnessbecause increaseswereseenin both chronic andacutepatients.Thesediscrepanciesareprobablycausedbythe useofdifferentacquisitionmethodsoranalysismethods,butthe generalconsensusneverthelesspointstowardsabnormalanatomy ofthememory/limbicnetworkinrelationtoAVH.

4.3.Languagenetwork

Arecentmeta-analysisincludedDTIstudieshighlightingthe resultsonthemostimportantfronto-temporalfibertract,which integrity is essential for a functioning language network, the arcuatefasciculus(AF)(Geoffroyetal.,2014).AFplaysacentralrole in languageperceptionand production.Four outof fivepapers retainedinthemeta-analysisreporteddecreasedFAoftheleft(but notright)AFofpatientswithAVHascomparedtopatientswithout AVH(Seoketal.,2007;Catanietal.,2011;DeWeijeretal.,2011; Cur9cic-Blakeetal.,2015).Similarresultswererecentlyobtained when comparing ultra-high-risk and first-episode-psychosis individualsfollowingAVHepisodeswithNoAVHsubject(Benetti etal.,2015).

However, one study included (Hubl et al., 2004)as well as studies noteligible for beingincludedin the abovementioned meta-analysis demonstrated increased connectivity within the languagenetworkinthesepatients(Shergilletal.,2007; Rotarska-Jagielaetal.,2009;Knöcheletal.,2012).

Seoketal.alsofoundincreasedFAindifferentwhite-matter tracks,likee.g.inthecaudalpartoftheleftcingulategyrusandthe left inferior longitudinal fasciculus. These authors reported a positive correlationbetweenAVH severityand the leftsuperior longitudinal fasciculus FA – the region with the highest white matterdensityinAVHcomparedtoallothergroups(Seoketal., 2007).

Abdul-Rahman and colleagues specifically investigated WM abnormalitiesinparticularlocialongtheAFaswellasitsregional lateralization in schizophrenia (Abdul-Rahman et al., 2012) by examiningdifferentWMalongthewholeextentoftheAF.This studyrevealedthat schizophreniapatientshad lowerFAin the frontalaspectsoftheleftAFcomparedwithhealthycontrols.On thecontrary,patientsexhibitedgreaterleftFAandaxialdiffusivity lateralizationinthetemporalsegmentofAFfoundcorrelatedwith theseverityofdelusionsandhallucinations.

Themostrecentstudy,comprising74patientswithnohistory of AVH, and 39 patientswith lifetime AVH foundthat FAwas