Durham Research Online
Deposited in DRO:
01 June 2015
Version of attached le:
Published Version
Peer-review status of attached le:
Peer-reviewed
Citation for published item:
Alderson-Day, B. and McCarthy-Jones, S. and Fernyhough, C. (2015) 'Hearing voices in the resting brain : a
review of intrinsic functional connectivity research on auditory verbal hallucinations.', Neuroscience and
biobehavioral reviews., 55 . pp. 78-87.
Further information on publisher's website:
http://dx.doi.org/10.1016/j.neubiorev.2015.04.016
Publisher's copyright statement:
c
2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
Additional information:
Use policy
The full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-prot purposes provided that:
• a full bibliographic reference is made to the original source • alinkis made to the metadata record in DRO
• the full-text is not changed in any way
The full-text must not be sold in any format or medium without the formal permission of the copyright holders. Please consult thefull DRO policyfor further details.
Durham University Library, Stockton Road, Durham DH1 3LY, United Kingdom Tel : +44 (0)191 334 3042 | Fax : +44 (0)191 334 2971
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
aaDepartmentofPsychology,DurhamUniversity,ScienceLaboratories,SouthRoad,DurhamDH13LE,UnitedKingdom bDepartmentofCognitiveScience,AustralianHearingHub,MacquarieUniversity,16UniversityAvenue,NSW2109,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.
©2015TheAuthors.PublishedbyElsevierLtd.ThisisanopenaccessarticleundertheCCBYlicense
(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
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
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
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
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
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
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,ICAandgroupcomparison
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.
aParticipantsinDiederenetal.(2013)andVanLutterveldetal.(2014)camefromthenon-clinicalpopulation.
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
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.
References
Allen,P.,Modinos,G.,Hubl,D.,Shields,G.,Cachia,A.,Jardri,R.,Thomas,P., Wood-ward,T.,Shotbolt,P.,Plaze,M.,Hoffman,R.,2012.Neuroimagingauditory hallucinationsinschizophrenia:fromneuroanatomytoneurochemistryand beyond. Schizophr.Bull. 38(4),695–703,http://dx.doi.org/10.1093/schbul/ sbs066
Baethge,C.,Baldessarini,R.J.,Freudenthal,K.,Streeruwitz,A.,Bauer,M.,Bschor, T.,2005.Hallucinationsinbipolardisorder:characteristicsandcomparisonto unipolardepressionandschizophrenia.BipolarDisord.7(2),136–145,http:// dx.doi.org/10.1111/j.1399-5618.2004.00175.x
Bauer,S.M.,Schanda,H.,Karakula,H.,Olajossy-Hilkesberger,L.,Rudaleviciene,P., Okribelashvili,N.,Chaudhry,H.R.,Idemudia,S.E.,Gscheider,S.,Ritter,K.,Stompe, T.,2011.Cultureandtheprevalenceofhallucinationsinschizophrenia.Compr. Psychiatry52(3),319–325,http://dx.doi.org/10.1016/j.comppsych.2010.06.008
Bluhm,R.L.,Miller,J.,Lanius,R.A.,Osuch,E.A.,Boksman,K.,Neufeld,R.W.J.,Théberge, J.,Schaefer,B.,Williamson,P.,2007.Spontaneouslow-frequencyfluctuationsin theboldsignalinschizophrenicpatients:anomaliesinthedefaultnetwork. Schizophr.Bull.33(4),1004–1012,http://dx.doi.org/10.1093/schbul/sbm052
Bolding,M.S.,White,D.M.,Hadley,J.A.,Weiler,M.,Holcomb,H.H.,Lahti,A.C.,2012. Antipsychoticdrugsalterfunctionalconnectivitybetweenthemedialfrontal
cortex,hippocampus,andnucleusaccumbensasmeasuredbyH215OPET.Front. Psychiatry3,105,http://dx.doi.org/10.3389/fpsyt.2012.00105
Bressler,S.L.,Menon,V.,2010.Large-scalebrainnetworksincognition:emerging methodsandprinciples.TrendsCogn.Sci.14(6),277–290,http://dx.doi.org/10. 1016/j.tics.2010.04.004
Brookes,M.J.,Hale,J.R.,Zumer,J.M.,Stevenson,C.M.,Francis,S.T.,Barnes,G.R.,Owen, J.P.,Morris,P.G.,Nagarajan,S.S.,2011.Measuringfunctionalconnectivityusing MEG:methodologyandcomparisonwithfcMRI.Neuroimage56(3),1082–1104,
http://dx.doi.org/10.1016/j.neuroimage.2011.02.054
Broyd,S.J.,Demanuele,C.,Debener,S.,Helps,S.K.,James,C.J.,Sonuga-Barke,E.J.S., 2009.Default-modebraindysfunctioninmentaldisorders:asystematicreview. Neurosci.Biobehav.Rev.33(3),279–296,http://dx.doi.org/10.1016/j.neubiorev. 2008.09.002
Buckner,R.L.,Andrews-Hanna,J.R.,Schacter,D.L.,2008.Thebrain’sdefaultnetwork: anatomy,function,andrelevancetodisease.Ann.N.Y.Acad.Sci.1124,1–38,
http://dx.doi.org/10.1196/annals.1440.011
Cho,R.,Wu,W.,2013.Mechanismsofauditoryverbalhallucinationinschizophrenia. Front.Schizophr.4,155,http://dx.doi.org/10.3389/fpsyt.2013.00155
Clos,M.,Diederen,K.M.J.,Meijering,A.L.,Sommer,I.E.,Eickhoff,S.B.,2014.Aberrant connectivityofareasfordecodingdegradedspeechinpatientswithauditory verbalhallucinations.BrainStruct.Funct.219(2),581–594,http://dx.doi.org/ 10.1007/s00429-013-0519-5
Coltheart,M.,2010.Theneuropsychologyofdelusions.Ann.N.Y.Acad.Sci.1191(1), 16–26,http://dx.doi.org/10.1111/j.1749-6632.2010.05496.x
Dennis,E.L.,Gotlib,I.H.,Thompson,P.M.,Thomason,M.E.,2011.Anxiety modu-latesinsularecruitmentinresting-statefunctionalmagneticresonanceimaging inyouthandadults.BrainConnect.1(3),245–254,http://dx.doi.org/10.1089/ brain.2011.0030
Diederen,K.M.J.,Neggers,S.F.W.,deWeijer,A.D.,vanLutterveld,R.,Daalman,K., Eickhoff,S.B.,Clos,M.,Kahn,R.S.,Sommer,I.E.C.,2013.Aberrantresting-state connectivityinnon-psychoticindividualswithauditoryhallucinations.Psychol. Med.43(8),1685–1696,http://dx.doi.org/10.1017/S0033291712002541
Dierks,T.,Linden,D.E.J.,Jandl,M.,Formisano,E.,Goebel,R.,Lanfermann,H.,Singer, W.,1999.ActivationofHeschl’sgyrusduringauditoryhallucinations.Neuron 22(3),615–621.
Feinberg,I.,1978.Efferencecopyandcorollarydischarge:implicationsforthinking anditsdisorders.Schizophr.Bull.4(4),636–640.
Ffytche,D.H.,Wible,C.G.,2014.Fromtonesintinnitustosensedsocialinteractionin schizophrenia:howunderstandingcorticalorganizationcaninformthestudy ofhallucinationsandpsychosis.Schizophr.Bull.40(Suppl.4),305–316,http:// dx.doi.org/10.1093/schbul/sbu041
Ford,J.,Mathalon,D.H.,Whitfield,S.,Faustman,W.O.,Roth,W.T.,2002.Reduced communication between frontal and temporal lobes during talking in schizophrenia.Biol.Psychiatry51(6),485–492.
Freeman,L.C.,1977.Asetofmeasuresofcentralitybasedonbetweenness. Sociom-etry40(1),35–41,http://dx.doi.org/10.2307/3033543
Frith,C.,1992.TheCognitiveNeuropsychologyofSchizophrenia.PsychologyPress, Hove.
Gavrilescu,M.,Rossell,S.,Stuart,G.W.,Shea,T.L.,Innes-Brown,H.,Henshall,K., McKay,C.,Sergejew,A.A.,Copolov,D.,Egan,G.F.,2010.Reducedconnectivity oftheauditorycortexinpatientswithauditoryhallucinations:arestingstate functionalmagneticresonanceimagingstudy.Psychol.Med.40(7),1149–1158,
http://dx.doi.org/10.1017/S0033291709991632
Geoffroy,P.A.,Houenou,J.,Duhamel,A.,Amad,A.,DeWeijer,A.D., ´Curˇci ´c-Blake,B., Linden,D.E.,Thomas,P.,Jardri,R.,2014.Thearcuatefasciculusinauditory-verbal hallucinations:ameta-analysisofdiffusion-tensor-imagingstudies.Schizophr. Res.159(1),234–237,http://dx.doi.org/10.1016/j.schres.2014.07.014
Greicius,M.D.,Supekar,K.,Menon,V.,Dougherty,R.F.,2009.Resting-statefunctional connectivityreflectsstructuralconnectivityinthedefaultmodenetwork.Cereb. Cortex19(1),72–78,http://dx.doi.org/10.1093/cercor/bhn059
Haddock,G.,McCarron,J.,Tarrier,N.,Faragher,E.,1999.Scalestomeasure dimen-sionsofhallucinationsanddelusions:thepsychoticsymptomratingscales (PSYRATS).Psychol.Med.29(4),879–889.
Hoffman,R.E.,Fernandez,T.,Pittman,B.,Hampson,M.,2011.Elevatedfunctional connectivityalongacorticostriatalloopandthemechanismofauditory/verbal hallucinationsinpatientswithschizophrenia.Biol.Psychiatry69(5),407–414,
http://dx.doi.org/10.1016/j.biopsych.2010.09.050
Hoffman,R.E.,Hawkins,K.A.,Gueorguieva,R.,Boutros,N.N.,Rachid,F.,Carroll,K., Krystal,J.H.,2003.Transcranialmagneticstimulationoflefttemporoparietal cortexandmedication-resistantauditoryhallucinations.Arch.Gen.Psychiatry 60(1),49–56.
Hubl,D.,Dougoud-Chauvin,V., Zeller,M.,Federspiel, A.,Boesch, C.,Strik,W., Dierks,T.,Koenig,T.,2010.StructuralanalysisofHeschl’sgyrusinschizophrenia patientswithauditoryhallucinations.Neuropsychobiology61(1),1–9,http:// dx.doi.org/10.1159/000258637
Hunter,M.D.,Eickhoff,S.B.,Miller,T.W.R.,Farrow,T.F.D.,Wilkinson,I.D.,Woodruff, P.W.R.,2006.Neuralactivityinspeech-sensitiveauditorycortexduringsilence. Proc.Natl.Acad.Sci.U.S.A.103(1),189–194,http://dx.doi.org/10.1073/pnas. 0506268103
Jardri,R.,Pouchet,A.,Pins,D.,Thomas,P.,2011.Corticalactivationsduringauditory verbalhallucinationsinschizophrenia:acoordinate-basedmeta-analysis.Am. J.Psychiatry168(1),73–81,http://dx.doi.org/10.1176/appi.ajp.2010.09101522
Jardri,R.,Thomas,P.,Delmaire,C.,Delion,P.,Pins,D.,2013.Theneurodynamic orga-nizationofmodality-dependenthallucinations.Cereb.Cortex23(5),1108–1117,
http://dx.doi.org/10.1093/cercor/bhs082
Johns,L.C.,Kompus,K.,Connell,M.,Humpston,C.,Lincoln,T.M.,Longden,E.,Preti, A.,Alderson-Day,B.,Badcock,J.C.,Cella,M.,Fernyhough,C.,McCarthy-Jones,S., Peters,E.,Raballo,A.,Scott,J.,Siddi,S.,Sommer,I.E.,Larøi,F.,2014.Auditory verbalhallucinationsinpersonswithandwithoutaneedforcare.Schizophr. Bull.40(Suppl.4),255–264,http://dx.doi.org/10.1093/schbul/sbu005
Kay,S.R.,Fiszbein,A.,Opfer,L.A.,1987.Thepositiveandnegativesyndromescale (PANSS)forschizophrenia.Schizophr.Bull.13(2),261.
Kim,D.I.,Manoach,D.S.,Mathalon,D.H.,Turner,J.A.,Mannell,M.,Brown,G.G.,Ford, J.M.,Gollub,R.L.,White,T.,Wible,C.,Belger,A.,Bockholt,H.J.,Clark,V.P., Lau-riello,J.,O’Leary,D.,Mueller,B.A.,Lim,K.O.,Andreasen,N.,Potkin,S.G.,Calhoun, V.D.,2009.Dysregulationofworkingmemoryanddefault-modenetworksin schizophreniausingindependentcomponentanalysis:anfBIRNandMCICstudy. Hum.BrainMapp.30(11),3795–3811,http://dx.doi.org/10.1002/hbm.20807
Kindler,J.,Hubl,D.,Strik,W.K.,Dierks,T.,Koenig,T.,2011.Resting-stateEEGin schizophrenia:auditoryverbalhallucinationsarerelatedtoshorteningof spe-cificmicrostates.Clin.Neurophysiol.122(6),1179–1182,http://dx.doi.org/10. 1016/j.clinph.2010.10.042
Kong,X.,Zhen,Z.,Li,X.,Lu,H.,Wang,R.,Liu,L.,He,Y.,Zang,Y.,Liu,J.,2014.Individual differencesinimpulsivitypredictheadmotionduringmagneticresonance imag-ing.PLOSONE9(8),e104989,http://dx.doi.org/10.1371/journal.pone.0104989
Kühn,S.,Gallinat,J.,2012.Quantitativemeta-analysisonstateandtraitaspectsof auditoryverbalhallucinationsinschizophrenia.Schizophr.Bull.38(4),779–786,
http://dx.doi.org/10.1093/schbul/sbq152
Lui,S.,Li,T.,Deng,W.,Jiang,L.,Wu,Q.,Tang,H.,Yue,Q.,Huang,X.,Chan,R.C., Col-lier,D.A.,Meda,S.A.,Pearlson,G.,Mechelli,A.,Sweeney,J.A.,Gong,Q.,2010. Short-termeffectsofantipsychotictreatmentoncerebralfunctionindrug-naive first-episodeschizophreniarevealedby“restingstate”functionalmagnetic reso-nanceimaging.Arch.Gen.Psychiatry67(8),783–792,http://dx.doi.org/10.1001/ archgenpsychiatry.2010.84
Manoliu,A.,Riedl,V.,Zherdin,A.,Mühlau,M.,Schwerthöffer,D.,Scherr,M.,Peters, H.,Zimmer,C.,Förstl,H.,Bäuml,J.,Wohlschläger,A.M.,Sorg,C.,2014.Aberrant dependenceofdefaultmode/centralexecutivenetworkinteractionson ante-riorinsularsaliencenetworkactivityinschizophrenia.Schizophr.Bull.40(2), 428–437,http://dx.doi.org/10.1093/schbul/sbt037
McCarthy-Jones,S.,Oesterich,L.,AustralianSchizophreniaResearchBank,Whitford, T.J.,2015.Reducedintegrityoftheleftarcuatefasciculusisspecificallyassociated withauditoryverbalhallucinationsinschizophrenia.Schizophr.Res.162(1–3), 1–6.
McCarthy-Jones,S.,Thomas,N.,Strauss,C.,Dodgson,G.,Jones,N.,Woods,A.,Brewin, C.R.,Hayward,M.,Stephane,M.,Barton,J.,Kingdon,D.,Sommer,I.E.,2014.Better thanmermaidsandstraydogs?Subtypingauditoryverbalhallucinationsandits implicationsforresearchandpractice.Schizophr.Bull.40(Suppl.4),275–284,
http://dx.doi.org/10.1093/schbul/sbu018
Mintz,S.,Alpert,M.,1972.Imageryvividness,realitytesting,andschizophrenic hallucinations.J.Abnorm.Psychol.79(3),310–316,http://dx.doi.org/10.1037/ h0033209
Modinos,G.,Costafreda,S.G.,vanTol,M.-J.,McGuire,P.K.,Aleman,A.,Allen,P.,2013. Neuroanatomyofauditoryverbalhallucinationsinschizophrenia:aquantitative meta-analysisofvoxel-basedmorphometrystudies.Cortex49(4),1046–1055,
http://dx.doi.org/10.1016/j.cortex.2012.01.009
Mowinckel,A.M.,Espeseth,T.,Westlye,L.T.,2012.Network-specificeffectsofage andin-scannersubjectmotion:aresting-statefMRIstudyof238healthyadults. Neuroimage63(3),1364–1373,http://dx.doi.org/10.1016/j.neuroimage.2012. 08.004
Northoff,G.,Qin,P.,2011.Howcanthebrain’srestingstateactivitygenerate hallucinations?A“restingstatehypothesis”ofauditoryverbalhallucinations. Schizophr.Res.127(1–3),202–214,http://dx.doi.org/10.1016/j.schres.2010.11. 009
Öngür,D.,Lundy,M.,Greenhouse,I.,Shinn,A.K.,Menon,V.,Cohen,B.M., Ren-shaw,P.F.,2010.Defaultmodenetworkabnormalitiesinbipolardisorderand schizophrenia.PsychiatryRes.:Neuroimaging183(1),59–68,http://dx.doi.org/ 10.1016/j.pscychresns.2010.04.008
Palaniyappan,L.,Balain,V.,Radua,J.,Liddle,P.F.,2012.Structuralcorrelatesof audi-toryhallucinationsinschizophrenia:ameta-analysis.Schizophr.Res.137(1–3), 169–173,http://dx.doi.org/10.1016/j.schres.2012.01.038
Pomarol-Clotet,E.,Salvador,R.,Sarró,S.,Gomar,J.,Vila,F.,Martínez,Á.,Guerrero,A., Ortiz-Gil,J.,Sans-Sansa,B.,Capdevila,A.,Cebamanos,J.M.,McKenna,P.J.,2008. Failuretodeactivateintheprefrontalcortexinschizophrenia:dysfunctionof thedefaultmodenetwork?Psychol.Med.38(8),1185–1193,http://dx.doi.org/ 10.1017/S0033291708003565
Power,J.D.,Barnes,K.A.,Snyder,A.Z.,Schlaggar,B.L.,Petersen,S.E.,2012. Spuri-ousbutsystematiccorrelationsinfunctionalconnectivityMRInetworksarise fromsubjectmotion.Neuroimage59(3),2142–2154,http://dx.doi.org/10.1016/ j.neuroimage.2011.10.018
Price,C.J.,2010.Theanatomyoflanguage:areviewof100fMRIstudiespublishedin 2009.Ann.N.Y.Acad.Sci.1191,62–88,http://dx.doi.org/10.1111/j.1749-6632. 2010.05444.x
Raichle,M.E.,MacLeod,A.M.,Snyder,A.Z.,Powers,W.J.,Gusnard,D.A.,Shulman, G.L.,2001.Adefaultmodeofbrainfunction.Proc.Natl.Acad.Sci.U.S.A.98(2), 676–682,http://dx.doi.org/10.1073/pnas.98.2.676
Rolls,E.T.,Loh,M.,Deco,G.,Winterer,G.,2008.Computationalmodelsof schizophre-niaanddopaminemodulationintheprefrontalcortex.Nat.Rev.Neurosci.9(9), 696–709,http://dx.doi.org/10.1038/nrn2462
Rotarska-Jagiela,A.,vandeVen,V.,Oertel-Knöchel,V.,Uhlhaas,P.J.,Vogeley,K., Linden,D.E.J.,2010.Resting-statefunctionalnetworkcorrelatesofpsychotic
symptomsinschizophrenia.Schizophr.Res.117(1),21–30,http://dx.doi.org/ 10.1016/j.schres.2010.01.001
Sambataro,F.,Blasi,G.,Fazio,L.,Caforio,G.,Taurisano,P.,Romano,R.,DiGiorgio,A., Gelao,B.,LoBianco,L.,Papazacharias,A.,Popolizio,T.,Nardini,M.,Bertolino,A., 2009.Treatmentwitholanzapineisassociatedwithmodulationofthedefault modenetworkinpatientswithschizophrenia.Neuropsychopharmacology35 (4),904–912,http://dx.doi.org/10.1038/npp.2009.192
Satterthwaite,T.D.,Wolf,D.H.,Loughead,J.,Ruparel,K.,Elliott,M.A.,Hakonarson,H., Gur,R.C.,Gur,R.E.,2012.Impactofin-scannerheadmotiononmultiplemeasures offunctionalconnectivity:relevanceforstudiesofneurodevelopmentinyouth. Neuroimage60(1),623–632,http://dx.doi.org/10.1016/j.neuroimage.2011.12. 063
Shinn,A.K.,Baker,J.T.,Cohen,B.M.,Öngür,D.,2013.Functionalconnectivityof leftHeschl’sgyrusinvulnerabilitytoauditoryhallucinationsinschizophrenia. Schizophr.Res.143(2–3),260–268,http://dx.doi.org/10.1016/j.schres.2012.11. 037
Sommer,I.E.,Clos,M.,Meijering,A.L.,Diederen,K.M.J.,Eickhoff,S.B.,2012.Resting statefunctionalconnectivityinpatientswithchronichallucinations.PLoSONE 7(9),e43516,http://dx.doi.org/10.1371/journal.pone.0043516
Sommer, I.E.,Daalman, K., Rietkerk,T., Diederen, K.M.J., Bakker, S., Wijkstra, J.,Boks,M.P.M.,2010.Healthy individualswithauditoryverbal hallucina-tions;whoare they?Psychiatricassessmentsofaselectedsampleof103 subjects.Schizophr.Bull.36(3),633–641,http://dx.doi.org/10.1093/schbul/ sbn130
Sommer,I.E.,Diederen,K.M.J.,Blom,J.-D.,Willems,A.,Kushan,L.,Slotema,K.,Boks, M.P.,Daalman,K.,Hoek,H.W.,Neggers,S.F.,Kahn,R.S.,2008.Auditoryverbal hallucinationspredominantlyactivatetherightinferiorfrontalarea.Brain131 (12),3169–3177,http://dx.doi.org/10.1093/brain/awn251
Sorg,C.,Manoliu,A.,Neufang,S.,Myers,N.,Peters,H.,Schwerthöffer,D.,Scherr,M., Mühlau,M.,Zimmer,C.,Drzezga,A.,Förstl,H.,Bäuml,J.,Eichele,T.,Wohlschläger, A.M.,Riedl,V.,2013.Increasedintrinsicbrainactivityinthestriatumreflects symptomdimensionsinschizophrenia.Schizophr.Bull.39(2),387–395,http:// dx.doi.org/10.1093/schbul/sbr184
Tyszka,J.M.,Kennedy,D.P.,Paul,L.K.,Adolphs,R.,2013.Largelytypicalpatterns ofresting-statefunctionalconnectivityinhigh-functioningadultswithautism. Cereb.Cortex,http://dx.doi.org/10.1093/cercor/bht040
VanDijk,K.R.A.,Sabuncu,M.R.,Buckner,R.L.,2012.Theinfluenceofheadmotion onintrinsicfunctionalconnectivityMRI.Neuroimage59(1),431–438,http:// dx.doi.org/10.1016/j.neuroimage.2011.07.044
VanLutterveld,R.,Diederen,K.M.J.,Otte,W.M.,Sommer,I.E.,2014.Networkanalysis ofauditoryhallucinationsinnonpsychoticindividuals.Hum.BrainMapp.35(4), 1436–1445,http://dx.doi.org/10.1002/hbm.22264
Vercammen,A.,Knegtering,H.,Boer,J.A.den,Liemburg,E.J.,Aleman,A.,2010. Audi-toryhallucinationsinschizophreniaareassociatedwithreducedfunctional connectivityofthetemporo-parietalarea.Biol.Psychiatry67(10),912–918,
http://dx.doi.org/10.1016/j.biopsych.2009.11.017
Wang, L., Metzak, P.D., Woodward, T.S., 2011. Aberrant connectivity during self–other source monitoringin schizophrenia.Schizophr. Res. 125(2–3), 136–142,http://dx.doi.org/10.1016/j.schres.2010.11.012
Waters,F.,Aleman,A.,Fernyhough,C.,Allen,P.,2012.Reportontheinaugural meet-ingoftheInternationalConsortiumonHallucinationResearch:aclinicaland researchupdate,and16consensus-setgoalsforfutureresearch.Schizophr.Bull. 38,258–262.
Waters,F.,Woods,A.,Fernyhough,C.,2014.Reportonthe2ndInternational Con-sortiumonHallucinationResearch(ICHR):evolvingdirectionsandtop-10‘hot spots’inhallucinationresearch.Schizophr.Bull.40,24–27.
Whitfield-Gabrieli,S.,Ford,J.M.,2012.Defaultmodenetworkactivityand connec-tivityinpsychopathology.Annu.Rev.Clin.Psychol.8(1),49–76,http://dx.doi. org/10.1146/annurev-clinpsy-032511-143049
Whitfield-Gabrieli,S.,Thermenos,H.W.,Milanovic,S.,Tsuang,M.T.,Faraone,S.V., McCarley,R.W.,Shenton,M.E.,Green,A.I.,Nieto-Castanon,A.,LaViolette,P., Woj-cik,J.,Gabrieli,J.D.,Seidman,L.J.,2009.Hyperactivityandhyperconnectivityof thedefaultnetworkinschizophreniaandinfirst-degreerelativesofpersons withschizophrenia.Proc.Natl.Acad.Sci.U.S.A.106(4),1279–1284,http://dx. doi.org/10.1073/pnas.0809141106
Whitford, T.J., Ford, J.M., Mathalon, D.H., Kubicki, M., Shenton, M.E., 2012. Schizophrenia,myelination,anddelayedcorollarydischarges:ahypothesis. Schizophr.Bull.38(3),486–494,http://dx.doi.org/10.1093/schbul/sbq105
Whitford, T.J.,Mathalon,D.H.,Shenton, M.E.,Roach, B.J.,Bammer, R.,Adcock, R.A.,Bouix,S.,Kubicki,M.,DeSiebenthal,J.,Rausch,A.C.,Schneiderman,J.S., Ford,J.M.,2011.Electrophysiologicalanddiffusiontensorimagingevidenceof delayedcorollarydischargesinpatientswithschizophrenia.Psychol.Med.41 (5),959–969,http://dx.doi.org/10.1017/S0033291710001376
Williamson, P., 2007. Are anticorrelated networks in the brain relevant to schizophrenia?Schizophr.Bull.33(4),994–1003,http://dx.doi.org/10.1093/ schbul/sbm043
Wolf,N.D.,Sambataro,F.,Vasic,N.,Frasch,K.,Schmid,M.,Schönfeldt-Lecuona, C.,Thomann,P.A.,Wolf,R.C.,2011.Dysconnectivityofmultipleresting-state networksinpatientswithschizophreniawhohavepersistentauditory ver-balhallucinations.J.PsychiatryNeurosci.36(6),366–374,http://dx.doi.org/10. 1503/jpn.110008
Zhou,Y.,Liang,M.,Tian,L.,Wang,K.,Hao,Y.,Liu,H.,Liu,Z.,Jiang,T.,2007.Functional disintegrationinparanoidschizophreniausingresting-statefMRI.Schizophr. Res.97(1–3),194–205,http://dx.doi.org/10.1016/j.schres.2007.05.029.