The Phenomenology and Neurobiology of Visual Distortions ...

Syndromes of Visual Hallucinations ThisarticleispartoftheResearchTopic HallucinationsfromthePerspectiveofAlteredExperiencesofSelf:AMultidisciplinaryApproach Viewall 7 Articles Articles CheriseRosen UniversityofIllinoisatChicago,UnitedStates LisaWagels DepartmentofPsychiatry,PsychotherapyandPsychosomatics,UniversityHospitalAachen,Germany DanielCollerton NewcastleUniversity,UnitedKingdom Theeditorandreviewers'affiliationsarethelatestprovidedontheirLoopresearchprofilesandmaynotreflecttheirsituationatthetimeofreview. Abstract Introduction VHinSchizophrenia SyndromesofVisualHallucinations CorticalMechanismsofVHandVisualDistortionsinSchizophrenia PotentialRetinalContributionstoVHandVisualDistortionsinSchizophrenia AssociationsbetweenVisualProcessingImpairmentsWithVHandVisualDistortionsinSchizophrenia AnUpdatedModelofVHandVisualDistortionsinSchizophrenia AdditionalQuestionsandFutureDirections Summary AuthorContributions Funding ConflictofInterest Acknowledgments Footnotes References SuggestaResearchTopic> DownloadArticle DownloadPDF ReadCube EPUB XML(NLM) Supplementary Material Exportcitation EndNote ReferenceManager SimpleTEXTfile BibTex totalviews ViewArticleImpact SuggestaResearchTopic> SHAREON OpenSupplementalData REVIEWarticle Front.Psychiatry,11June2021 |https://doi.org/10.3389/fpsyt.2021.684720 ThePhenomenologyandNeurobiologyofVisualDistortionsandHallucinationsinSchizophrenia:AnUpdate StevenM.Silverstein1,2,3,4*andAdriannLai1 1DepartmentofPsychiatry,UniversityofRochesterMedicalCenter,Rochester,NY,UnitedStates 2DepartmentofNeuroscience,UniversityofRochesterMedicalCenter,Rochester,NY,UnitedStates 3DepartmentofOphthalmology,UniversityofRochesterMedicalCenter,Rochester,NY,UnitedStates 4CenterforVisualScience,UniversityofRochesterMedicalCenter,Rochester,NY,UnitedStates Schizophreniaischaracterizedbyvisualdistortionsin~60%ofcases,andvisualhallucinations(VH)in~25–50%ofcases,dependingonthesample.Thesesymptomshavereceivedrelativelylittleattentionintheliterature,perhapsduetothehigherrateofauditoryvs.visualhallucinationsinpsychoticdisorders,whichisthereverseofwhatisfoundinotherneuropsychiatricconditions.Giventheclinicalsignificanceoftheseperceptualdisturbances,ouraimistohelpaddressthisgapbyupdatingandexpandinguponpriorreviews.Specifically,we:(1)presentfindingsonthenatureandfrequencyofVHanddistortionsinschizophrenia;(2)reviewproposedsyndromesofVHinneuro-ophthalmologyandneuropsychiatry,anddiscusstheextenttowhichthesecharacterizeVHinschizophrenia;(3)reviewpotentialcorticalmechanismsofVHinschizophrenia;(4)reviewretinalchangesthatcouldcontributetoVHinschizophrenia;(5)discussrelationshipsbetweenfindingsfromlaboratorymeasuresofvisualprocessingandVHinschizophrenia;and(6)integratefindingsacrossbiologicalandpsychologicallevelstoproposeanupdatedmodelofVHmechanisms,includinghowtheircontentisdetermined,andhowtheymayreflectvulnerabilitiesinthemaintenanceofasenseofself.Inparticular,weemphasizethepotentialroleofalterationsatmultiplepointsinthevisualpathway,includingtheretina,therolesofmultipleneurotransmitters,andtheroleofacombinationofdisinhibiteddefaultmodenetworkactivityandenhancedstate-relatedapical/contextualdriveindeterminingtheonsetandcontentofVH.Inshort,ourgoalistocastafreshlightontheunder-studiedsymptomsofVHandvisualdistortionsinschizophreniaforthepurposesofinformingfutureworkonmechanismsandthedevelopmentoftargetedtherapeuticinterventions. Introduction Hallucinationsareoneofthecharacteristicsymptomsofschizophreniaandotherpsychoticdisorders,occurringatsomepointin~60-80%ofthoseaffected(1–3).Althoughhallucinationsinpsychoticdisordersoccurmostcommonlyintheauditorymodality,arecentreviewofvisualhallucinations(VH)inschizophreniareportedaweightedmeanprevalenceof27%,withanotablywiderangeacrossstudies(range:4–65%;SD=9)(4).Asubsequentlarge-scalestudyofnon-affectivepsychosis(N=1,119)indicatedthat37%ofpeoplewithschizophreniaand47.5%ofpeoplewithschizoaffectivedisorderhadexperiencedVHatsomepoint(5).FindingsfromotherindividualstudiessuggestthatthevariabilityinprevalenceacrossinvestigationsmaybeduetomethodologicaldifferencesinhowVHareassessed,aswellasclinicaldifferencesacrosssamples.Forexample,Brachaetal.(6)foundthatachartreviewofdischargedschizophreniapatientswithachroniccourseofillnessidentifiedahistoryofVHin32%ofthecases,whereastheirprospectiveevaluationwithanotherpatientsampleindicatedaVHprevalenceof56%;notably,in43%ofthecaseswithahistoryofVH,itwastheresearchinterviewthatfirstdocumentedthissymptom(6).TheseresultssuggestthatstudiesthatrelyonclinicianreportsmayyieldunderestimatesofVHprevalence.Severalotherstudiesofpeoplewithachroniccourseofschizophreniahavereportedsimilarrates,suchas40%(7),49%(8),57.2%(intheUnitedStatesvs.39%inIndia)(9),and63%(10)1.Thesedatasuggestthat,atleastinsomesubgroupsofindividualswithschizophrenia,therateofVHmaybehigherthantraditionallythought,andthatstandardassessmentsinclinicalsettingsmayoftenfailtoadequatelyprobethistypeofsymptom. Visualhallucinationsarenottheonlyformofvisualperceptualanomalyexperiencedinschizophrenia.Forexample,over60%ofpeoplewithschizophreniaexperiencevisualdistortionsinvolvingchangesinclarity,form,brightness,color,motion,orpersistenceofvisualstimuli(8,12–18)(seeTable1).Ithasalsobeenreportedthatvisualimageryisincreasedinpeoplewithschizophrenia(19).Inadditiontovisualanomalies,itiswell-establishedthatschizophreniaisassociatedwithvisualprocessingimpairmentsonlaboratorytasks,includingincontrastsensitivityandperceptualorganization(17)(seeTable2).Alterationsinsuchvisualfunctionshavealsobeenobservedamongthoseathighriskforpsychosis(20,21),andvisualperceptualdisturbancesinchildhood(22,23)andadulthood(24)predictthelaterdevelopmentofschizophrenia[andtoagreaterextentthanothersensoryanomalies(23)]. TABLE1 Table1.Examplesofvisualdistortionsexperiencedbypeoplewithschizophrenia. TABLE2 Table2.Definitionsandexamplesofdifferentlevelsofvisualprocessing,emphasizingthosethatareclearlyimpairedinmanypeoplewithschizophrenia. Thevisualsystemisthemostunderstoodpartofhumanbrain,andthemoststudiedareainneuroscience(29).Fortheseandotherreasons,itprovidesanexcellentmodelsystemforunderstandingneuralfunctionandcircuitry,includingforgeneratingandtestinghypothesesaboutwhatmaybeoccurringinothersystemsinthebrain(30).Therefore,thepotentialforstudiesofalterationsinvisualfunctionsinschizophreniaspectrumdisorderstoinformourunderstandingofthedevelopment,pathophysiology,andheterogeneityoftheseconditionsappearstobesignificant.Indeed,therearenumerousexamplesoffindingsfromsuchstudiesthathaveadvancedknowledgeintheseareas,including:(1)thepredictivevalidityofvisualdisturbancesforalaterdiagnosisofschizophrenia(22–24);(2)thedocumentationofvisualimpairmentsinhighriskindividuals(20,21);(3)linksbetweenhigh-levelvisualchanges(seeTable2)andpsychoticsymptoms(31)suggestingtheutilityofspecificvisualtasksforprobingpredictivecodingmechanisms(i.e.,thedegreetowhichperceptioncanbeconsideredoptimalfromaBayesianperspective,withanappropriatebalanceofemphasesonsensorydataandpriorexperience)(32–34);(4)linksbetweenmid-levelvisualprocessingalterationsanddisorganizedsymptomssuggestingsharedimpairmentsatthelevelofapicaldendrite-mediatedcontext-basedamplificationoffeedforwardinput(17,35–37)(5)linksbetweenlow-levelvisualdisturbancesandnegativesymptomssuggestingsharedmechanismsinvolvinggaincontrol(38–41);and(6)consistentfindingsofassociationsbetweenspecificvisualimpairmentsandcharacteristicssuchaspoorpremorbidsocialfunctioningandpoorprognosis(17).Itiscurious,however,thatdespiteconsistentaccumulationofinformationonvisualimpairmentsinschizophrenia,thesefindingshaverarelybeenappliedtoanunderstandingofvisualhallucinationsanddistortions.Onepurposeofthisreviewistoaddressthisgapintheliterature. VHinSchizophrenia VHinpsychosisaretypicallyexperiencedasbeingasrealandvividastypicalperceptsofstimuliinexternalspace,andaregenerallyoutofthecontroloftheindividualexperiencingthem,althoughsomepeoplehaveinsightastothehallucinatorynatureofthepercepts(4,42,43).Contentistypicallyincolor(butcanbeinblackandwhite),complexratherthansimple,andincludespeople(e.g.,strangers,supernaturalbeings,orlovedones),faces,animals,shadows,orotherfullyformedobjectsorbeings(4,42–45).VHinschizophreniaaretypicallythree-dimensionalandareincorporatedintovisualscenes(46).However,insomecases,theVHmaybeintheformofsimplegeometricpatterns(17,45).Incontrasttosomeofthefindingsreportedabove,Lindaletal.(47)foundalowerfrequencyofVHinvolvingpeopleandahigherfrequencyofunformedimages(e.g.,lights)inschizophreniacomparedtoVHinthegeneralpopulation.Thisisconsistentwiththefindingsofanearlierreview(48).ItispossiblethesediscrepantfindingsreflectdifferencesacrossstudiesintherelativecontributionsoffactorsrelatedtotheexpressionofVHwithwhichsamplesofpatientsareheterogeneous[e.g.,reducedretinalsignaling,hippocampalchanges,excessivestriataldopamine(DA);seeFigure2].Thesefactorswillbediscussedinlatersectionsofthepaper. Inastudyinvolvingpatientswithvariouspsychoticdisorders,includingschizophrenia(49),mostVHwerelocatedinthemidlineofthevisualfieldorlocatedacrossbothhemifieldsandappearedtobeclosetotheviewer,butnotcloseenoughtotouch.OnestudyreportedthatthemajorityofVHoccurredwhenpatientswerealone,inquietenvironments,orindimlightingconditions(49),whereasanolderpre-DSM-IIIstudyreportedthatonly6%ofpeoplewithschizophreniahadVHwhentheywerealone(43).VHmaybefleetingorpersistforhoursatatime(3,42,43).Thereactionstosuchvisionscanbenegativeorpositive,butVHinpeoplewithschizophreniamostcommonlycausedistress,whichoftenleadstofunctionalimpairment(4,42,49–52).PeoplewhohaveVHaswellashallucinationsinothermodalitiesaremorelikelytoreporttheirVHasreal,irritating,anddistressing.IfthecontentofVHisacceptedasreal,orpossiblyreal,theycancontributetotheformationofdelusions(e.g.,ofcontrol,thoughtinsertion,etc.),which,inturn,canleadtoevengreaterdistress(53)andfunctionalimpairment.Eventhemilderchangesthatcharacterizevisualdistortionscanbeclinicallysignificant.Forexample,astudyofvisualdistortionsinadolescentsataclinicalhighriskclinic(54)indicatedthattheyweresignificantlyassociatedwithsuicidalideation(OR=4.33,95%CI=1.28–14.64)evenaftercontrollingforage,gender,depression,thoughtdisorder,paranoia,andauditorydistortions. FewschizophreniapatientswhoexperienceVHdosowithoutalsoexperiencingauditoryhallucinations,eithersimultaneouslyoratothertimes.TherateofpatientswhoexperienceVHandauditoryhallucinationshasbeenestimatedat80–98%,whereasitisfarlesscommonforthosewhohaveauditoryhallucinationstoalsoexperienceVH(1,3,6,7).Ofnote,thepredominanceofauditoryhallucinationsrelativetoVHinpsychoticdisorderscontraststowhatisobservedinneurologicaldisorderssuchasParkinson'sdiseaseandvariousformsofdementia;intheselatterconditions,VHaremuchmorecommonthanauditoryhallucinations(4).ThecommonpresenceofauditoryhallucinationswithVHinschizophreniasuggeststhataspectsofVHpathophysiologyinpsychoticdisordersaresharedwiththatofauditoryhallucinations.Inthesectiononcorticalmechanismsbelowwediscussevidencethatallformsofhallucinationsmayshareaspecificbrainnetworkabnormality,whilehallucinationsinagivensensorymodalityinvolveadditionalimpairmentsspecifictothatmodality. TherearemixedresultsregardingapossiblerelationshipbetweenVHandillnessseverityinschizophrenia,althoughnumerousreportssuggestthatthepresenceofVHisassociatedwithamoreseverecourseofillness(1,7).FurtherevidenceforalinkbetweenillnessseverityandVHcomesfromstudiesindicatingthatVHareassociatedwithlowerIQandearlierageofonset(5,6).Ithasalsobeenobservedthatchildhood-onsetschizophrenia,whichisgenerallycharacterizedbypoorlong-termoutcomes(55–57),isassociatedwithhigherratesofVHthanisadult-onsetschizophrenia(58). Incontrasttothesefindings,however,aretheresultsfromseveralstudiessuggestingthatVHmaybeassociatedwithabetterprognosis.Forexample,Smalletal.(52)reportedthatpatientswithacuteschizophreniawhoexperiencedmultimodalauditory-visualhallucinationshadshorterandfewerprevioushospitalizationscomparedtopatientswithschizophreniawhodidnotexperienceVHSimilarly,McCabeetal.(59)foundthatparticipantswithschizophreniawhowereclassifiedashavinga“goodprognosis”weremorelikelytohaveahistoryofVHthanthosewitha“poorprognosis”profile.Relatedly,astudyofyoungpeopleatclinicalhighriskforpsychosisreportedthatthosewithvisualperceptualanomalieswereatlowerriskforconversiontofullpsychosisthanthosewithauditoryperceptualabnormalities(60). OnepotentialexplanationforthesediscrepantfindingsregardingVH/distortionsandillnessseverityinschizophreniaisthathallucinatoryexperiences,includingVH,areoftenassociatedwithahistoryofseveretraumaandpost-traumaticstressdisorder(61).TheclinicalpresentationofPTSDwithVHcanbedifficulttodiscriminatefromthatofschizophreniaintheshortterm,andthesedisorderscanalsoco-occur,complicatingthediagnosticassessment(61,62).AhistoryoftraumaalsoincreasesriskforbothPTSDandapsychoticdisorder(63,64).Mooddisorderswithpsychoticfeatures,especiallybipolardisorder,canalsobedifficulttodistinguishfromschizophrenia,especiallyearlyintheillness,andhallucinationsinbipolardisorderaremorelikelytobeinthevisualmodalitycomparedtothoseinschizophrenia(65).ThestudiesbySmalletal.andMcCabeetal.,whichsuggestedthatVHinschizophreniaareassociatedwithabetterprognosis,wereconductedbeforetheDSM-IIIera(i.e.,priortotheestablishmentofresearch-gradediagnosticcriteria);thus,thesesamplesmayhaveincludedpeoplewithpsychoticsymptomsbutwhowouldnotmeetcurrentdiagnosticcriteriaforschizophrenia(e.g.,peoplewithPTSDoramooddisorderwithpsychoticfeatures).ThisisconsistentwiththerecognitionthatpriortoDSM-III,atleastintheUnitedStates,thediagnosticcategoryofschizophreniahadbecomesobroadastoincludeconditionsthatarenolongerconsideredschizophreniaspectrumdisorders,andwasappliedtomanypeoplewhowouldnowbeconsideredtohavebipolardisorder(66).EvidenceforthisintheMcCabeetal.(59)studyisthatthegoodprognosisgroup(theonewithahigherrateofVH)wasmorelikelytohavediagnosablemajordepressionormania,andsoitispossiblethatmanyofthesepatientswould,currently,beconsideredtohaveamooddisorderwithpsychoticfeaturesratherthanschizophrenia.Withregardtothemorerecentstudyofindividualsatclinicalhighriskforpsychosis(60),althoughspeculative,itispossiblethatyoungpeoplepresentingatthehigh-riskclinicwithvisualperceptualdisturbancesweremorelikelytobecharacterizedbyPTSDorbywhatwouldeventuallyturnouttobeamooddisordercomparedtothosewithoutsuchsymptoms;ifthiswerethecase,itmayhavecontributedtothereducedriskofconversiontoapsychoticdisorderamongthosewithvisualperceptualsymptomsinthatsample.Inshort,whileVHisnot,ingeneral,agoodprognosticindicatorwhencomparedtonothavinganyhallucinations,whenVHoccurearlyinapsychiatricillnessitmaysometimesbeanaspectofseverePTSDoramooddisorderinpeoplewhoarenotlikelytodevelopaschizophreniaspectrumdisorder.Incontrast,inpeoplewithadefinitediagnosisofaschizophreniaspectrumdisorder,especiallythosewithahistoryofchronicillness,theoccurrenceofVHappearstobeanaspectofamoreseverepsychoticdisorder.Itisinterestingthatverypoorprognosisschizophreniapatientsarecharacterizedbygrayandwhitematterlossintheoccipitallobe(67,68),whereasthisismorerareinpatientswithbetteroutcomes.Itisunclear,however,ifsuchvolumelossinvisualcortexisrelatedtoVHorvisualdistortionsinthispatientgroup. SyndromesofVisualHallucinations ffytche(69)proposedthattherearethreeindependentvisualhallucinatorysyndromes,eachofwhichhavetheirownpatternsofpathophysiology,content,andotherassociatedphenomena.One,thedeafferentationsyndrome,involveslossofinputtothevisualcortexduetoretinaland/orsubcorticalimpairment.Itencompassesvisualanomaliesrelatedtoeyeconditionssuchasmaculardegeneration,Stargardt'sdisease,andglaucoma.TheVHassociatedwiththedeafferentationsyndromecanbesimple,geometricpatternsorfullyformedobjectsandpeople.ThelattercaseisknownasCharlesBonnetSyndrome.Withregardtomechanisms,itisthoughtthatthereductionin,orcompletelossof,visualinputassociatedwiththeseeyeconditionsdisinhibitsvisualcorticalneurons,whichresultsinareleaseofnormallydormantpatternsofactivationthataresubjectivelyexperiencedasVH(70).ThismodeloverlapswiththeActivation,InputandModulation(AIM)modelproposedbyHobsonetal.(71),whichwasappliedtoVHinParkinson'sdiseaseandLewybodydementiabyDiederichetal.(72).Ithasbeenshownthatsuchanincreaseinexcitabilityconsequenttolossofretinalinputinpartreflectsincreasedplasticityandcorticalreorganizationfollowingalesion.Forexample,animalandcomputationalstudiesindicatethatafteravisualcorticallesion,peri-lesionneuronsincreasetheirreceptivefieldsize,andtheiractivitylevelisincreasedduetoremovalofinhibitoryinputfromthelesionedneurons(73,74).Thisactivityhasbeendemonstratedincattoresultinillusionsandperceptualfilling-inphenomena(75).Hyper-excitabilityofvisualcircuitshasbeenassociatedwithstimulation-inducedVHinhealthyvolunteers(76),andwithspontaneousVHinCharlesBonnetsyndrome(77).Agoodsummaryofdataonhyper-excitabilityafterreducedinputtothevisualsystem,anditsrelationshiptoVHcanbefoundinBurke(78).Dataonvisualsystemhyper-excitabilityandVHinschizophrenia,Parkinson'sdisease,andLSDuseisreviewedinWatersetal.(4).Itmustbenoted,however,thatwhileretinal/LGNdeafferentationtypicallyleadstohyper-excitabilityinvisualcortex,lesionsinV1orV2canalsoleadtodisinhibitionofactivitywithintheoccipitallobethatcanbeassociatedwithVH(79).Hyper-excitability,intheformofseizure-likeactivity[“localparoxysmsinthesensorysystem”(78),p.537]can,ingeneral,bearesultofisolationofcorticalcircuitryduetobraintrauma,lesions,hypoxia,orothercauses.Whilethiscanbethoughtofasaformofdeafferentation,itisnotstrictlythetypeofsensorydeafferentationthatffytchediscussedinhis3-syndromemodel. Inthetypologyproposedbyffytche(69)[seealso(76)],schizophreniawasnotincludedinthegroupofconditionscharacterizedbythedeafferentationsyndrome.Thereandinalaterpaper(76),heconcludedthatsensorydeafferentation-inducedsimplehallucinationssuchasthosefoundinCharlesBonnetsyndromearenotagoodmodelforVHindisorderssuchasschizophreniawheretheearlyvisualsystemisthoughttobeintact,andVHarethoughttoinvolvereducedcholinergicinputsfromthebasalforebrainandsubsequenteffectsonventraltemporalregions(resultingincomplexVH;seeparagraphbelow).However,aswedescribeinalatersection,inthepastdecadeandespeciallywithinthepast5years,therehasbeenconsistentreportingofretinalfunctionalandstructuralimpairmentinschizophrenia,specificallyintheformofreducedstrengthofretinalneuralcelloutputandthinningofretinalneurallayers(28,46,80).Inaddition,someofthevisualdistortionsreportedbypeoplewithschizophreniaresemblethoseseenincasesofretinaldisease(18,24,25).Thereisalsoemergingevidencethatglaucomaisaneurodegenerativeconditionwhoseoccurrenceprecedesarangeofneurodegenerativedisorders[e.g.,Alzheimer'sdisease(81)andmildcognitiveimpairment(82),aswellasindirectevidenceforglaucoma-likechangesinschizophrenia,includinganenlargedcup-to-discratio(83)andabnormalitiesinfrequencydoublingperimetryreviewedinAlmonteetal.(84)].Recentfindingsalsoindicatethatglaucomaoftenprecedesadiagnosisofschizophrenia,bipolardisorder,ormajordepressionbyseveralyears(85).Theseobservationsconvergetosuggestthatsomeoftheabnormalvisualactivityinschizophreniamaybesecondarytoreducedretinalinputtothevisualcortex,ahypothesisthatreceivedpreliminarysupportinacomputationalmodel(86).Animportantdistinction,however,isthatwhilepeoplewithCharlesBonnetsyndromehaveinsightintothenon-realityoftheirVHinmostcases,inschizophreniatheVHarelikelytobeexperiencedasbeingpartofachangedreality. Thesecondsyndromedescribedbyffytche(69),thecholinergic(Ach)syndrome,iscausedbydysfunctioninthebrainstemandascendingbrainstemneurotransmitterpathways,particularlytheprojectionsofthecholinergicpathwaytothebasalforebrainandcerebralcortex(87).Thissyndromeisdefinedbyillusions,delusions,andfullyformed,hallucinationsinmultiplemodalities,andffytchesuggestedthatitmayunderliethepsychoticsymptomsassociatedwithneurodegenerativedisorderssuchasAlzheimer'sdisease,Parkinson'sdisease,andLewybodydementia.Intermsofthethreesyndromesdescribedbyffytche,Watersetal.(4)suggestedthattheAchsyndromeisthebestfitforschizophreniafromaphenomenologicalperspective,withthecaveatthatthereareimportantdifferencesbetweenschizophreniaandtheotherconditionslistedinthecategory(seebelow).EvidenceinsupportoftheviewthatAchisinvolvedinVHinschizophreniaisthatthedisorderhasbeencharacterizedbyreducedAchtransmission,andareductioninbothmuscarinicandnicotinicAchreceptors(88).Deficientcholinergictransmissionatthelevelofthebasalforebrainleadstoreducedsignal-to-noiseratios(89,90),andthereforetoanincreasedrelianceonstoredinformationindeterminingthenatureofincomingstimuli,whereasbasalforebrainAchactivitydecreaseseffectsoftop-downprojectionsandincreasesrelianceonsensorydata(91).Deficientcholinergictransmissionmay,therefore,beamechanisminvolvedinhallucinationformationinschizophreniaandotherconditions,asdescribedbythepredictivecodingmodelofpsychosis(92).FurtherevidencefortheAchhypothesisofVHinschizophreniacomesfromfindingsthathighdosesofanticholinergicmedicationscaninduceapsychoticstate[reviewedinTerry(88)],thatnormaldosesofthesemedicationscaninducerecurrenceofpsychosis(93),andthatacetylcholinesteraseinhibitors(whichincreasetheamountofacetylcholineavailableinthesynapticcleft),usedinconjunctionwithantipsychoticmedication,canreducethefrequencyofVH(94,95).Inaddition,arecentmodelofVHinsynucleinopathies(e.g.,Parkinson'sdisease,LewyBodydementia,andmultiplesystematrophy)positsthattheyresultfromlossofsuppressionofthedefaultmodenetwork(DMN)bytask-positivenetworksduringwakefulness,andthatthisisaconsequenceofcholinergicdysfunction(96–102).InadequatesuppressionofDMNactivityisthoughttoleadtothereleaseofunconsciousrepresentationsthatcanbeconsideredpriorsintheemergingalteredordissociativestate,whichthensupersedepriorsrelatedtocurrentexternalstimuli.Thisproposalisessentiallyapredictivecodingmodel.ThebiologicalbasisoftheproposeddisturbanceisthoughttoinvolvealterationsinDAsignaling,aswellasinserotoninandAchactivity,allofwhicharehighlyinteractive(103,104).Furtherconsiderationofthisnetworkmodel,asitmayapplytoschizophrenia,isfoundinalatersectionofthepaperoncorticalmechanisms.IncontrasttothehypothesisofAchinvolvementinVHinschizophrenia,Watersetal.(4)notedthattheclinicalpresentationofhallucinationsinschizophreniadiffersfromwhatisobservedintheotherdisordersinthiscategoryintermsofageofonset,emotionalcontent,attributionsoftheirorigins(i.e.,levelofinsightintotheirrealityinexternalspace),fMRIfindingsregardingpotentialmechanisms,andthepredominanceofauditoryovervisualhallucinations.Therefore,whilecholinergicdysfunctionmaycontributeinparttoVHinschizophrenia,additionalresearchisneededtoclarifyitsinteractionwithotherfactorsthatdeterminethatnatureofVHinpeoplewiththedisorder. Theserotonergic(5-HT)syndromeisthethirdsyndromeidentifiedbyffytche(69).ItistypicallycharacterizedbysimpleVHthatarethoughttobeduetoanoveractiveserotonergicsystem.ExamplesofthissyndromeincludeLSDflashbacks,migraineauras,andMDMA-inducedhallucinations.Althoughneitherffytche(69)norWatersetal.(4)includeschizophreniainthisgroup,andwhileschizophreniadoesnotseemtobeprimarilyadisorderofalteredserotonergictransmission,findingsfrommultiplelinesofresearchimplicateserotonergicdysfunctioninthiscondition(105,106).Forexample,basedonseveralobservations,includingserotonergiceffectsofhallucinatorydrugssuchasLSD,themodulatoryroleofserotoninonDAtransmission,andthesubstantialantagonisticactionoftheatypicalantipsychoticmedicationclozapineatserotonin2A(5-HT2A)receptorsrelativetoitsmodestaffinityforD2receptors,ithasbeensuggestedthatincreasedactivityatthe5-HT2Areceptormayberelatedtothepositivesymptomsinschizophrenia(103,105,107–110).Ontheotherhand,arecentreviewofemerging5-HT2Areceptorantagonistsforthetreatmentofschizophrenia(pimavanserin,roluperidone,lumateperone,ritanserin,andvolinanserin)suggestedthatthesedrugshavetheirstrongesteffectsonnegativeandcognitivesymptoms,andthattheirantipsychoticeffectsinvolvereducingthelikelihoodofDAreceptorstransitioningtoasupersensitivestateinresponsetoother(DAreceptorblocking)antipsychoticmedications(111).Inshort,despitesubstantialresearchinthisarea,thedirectandindirectrolesthatserotonergicalterationsplayinthepathophysiologyofSZarenotyetclear.WithregardtoVHinpsychoticdisordersspecifically,ithasbeennotedthatthedifferencesinthenatureofhallucinationsinschizophreniaandinalteredstatesinducedbyhallucinogenicdrugs[reviewedinLeptourgosetal.(112)]suggestthatVHinschizophreniaarenotprimarilytheresultofexcessiveserotonergictone. InadditiontothethreeVHsyndromesdiscussedabove,inasubsequentpaperffytche(76)consideredtheissueoftopological(i.e.,region-specific)vs.hodological(i.e.,networkconnectivity)changesrelatedtoVH.Anintegrationoftheseviewsledtothehodotopicframework,inwhichVHareseenasduetobothhyper-excitabilityinspecificcorticalregions,aswellashypo-connectivityand/orhyper-connectivitybetweenvisualcortexandotherbrainregions.BothBurke(78)andffytche(76)suggestedthatwhileVHcontentislargelydefinedbytheregionundergoingexcessactivation(e.g.,fusiformfaceareainthecaseoffaces,V1-V2forsimplefeaturesandgeometricpatterns),itisthedeficientnetworkactivitythatisnecessaryforVHtooccur(seesectiononcorticalmechanismsbelowformoreonthis).AnadditionalrelevantsetofdimensionswasproposedbyOerteletal.(113),whosuggestedthatexcesshippocampalactivationdeterminestheextentandnatureofmemory-relatedcontentsinVH,whereasactivationinsensoryregionsmaydeterminethevividnessoftheVH(seesectiononcorticalmechanisms,formoredetailonhippocampalinvolvementinVHinschizophrenia). Thehodotopicframework,alongsidethepreliminaryevidenceforinvolvementofthehippocampusinVHinschizophrenia(seenextsection),isconsistentwiththeviewweproposebelowinthesensethatchangesinnetworkfunctionoccuralongsideregionalchanges,andthatlifeexperienceandstoredrepresentationscanbeunderstoodasdrivingindividualdifferencesintheextentofmemoryfragment-relatedimageryinVH,andthereforeinthenatureofandemotionalreactionstoVH.However,aswediscussbelowinthesectionontheretina,evidencehasbeenaccumulatingthatsuggestsdirectandindirecteffectsofretinalimpairmentonVHinschizophrenia,andthereforethattheassumptionofalackofinvolvementoflow-levelsensoryimpairmentinVHinschizophreniawaspremature. CorticalMechanismsofVHandVisualDistortionsinSchizophrenia Asnotedabove,theoriesofVHimplicatereducedvisualinputandsubsequentcorticalcompensations;cholinergicdysfunctionleadingtolowsignal-noiseratioandthesubsequentexcessiveinfluenceoftop-downpriors(experience-basedhypotheses)duringthegenerationofperceptualrepresentations;and/orserotonergicdysfunction.RecentmodelsofVHhavefocusedmoreheavilyonnetworkdysfunction,althoughthiswasimpliedinsomeoftheoldertheories,andexplicitinmodelsinvolvingdisinhibitionoftheDMN.Evidenceforinvolvementofnetwork-leveldysfunctioninVHinschizophreniacomesfromaresting-statefMRIstudybyFordetal.(114),whichdemonstratedthatpatientswithVHshowhyperconnectivitybetweentheamygdalaandcorticalareasinvolvedinhigherordervisualprocessing.ThislinkmayexplaintheemotionallyintensecontentandoftendistressingreactionstoVHinpeoplewithschizophrenia.Asnotedabove,involvementofregionsofthehippocampusmaydeterminetheextentofmemoryfragmentinclusioninVHinschizophrenia.Aresting-statefMRIstudydemonstratedincreasedconnectivitybetweenthenucleusaccumbensandtheinsula,putamen,parahippocampalgyri,andventraltegmentalareainpatientswithVHcomparedtopatientswithonlyauditoryhallucinations(115).Furtherevidencesuggestingbothlocalandnetwork-relatedaspectsofhippocampaldysfunctionhasbeenfoundinmultiplestudies,includingfindingsthatbothhypertrophyofthehippocampus,andhyper-connectivityofthisregionwithfrontalandvisualregionsisfoundinschizophreniapatientswithVHcomparedtopatientswithauditoryhallucinationsalone(116).OtherevidenceofdysregulatedhippocampalactivityanditsroleinnetworkchangesassociatedwithVHwasobservedbyHareetal.(117)andAmadetal.(116).Theroleofhippocampalabnormalitiesleadingtoalteredrelationalmemorylinks,andtheirroleinVHwasdiscussedbyBehrendt(118).Finally,neurodevelopmentalevidenceconsistentwithhippocampalinvolvementinVHcomesfromfindingsofincompletehippocampalinversioninschizophreniapatientswithVHcomparedtothosewithonlyauditoryhallucinations(119).WhileJardrietal.(120)didnotfindevidenceofabnormalhippocampal/parahippocampalgyrusactivationinhallucinatingschizophreniapatients,theyneverthelesssuggestedthatinstabilityinfiringfromthisareacould“triggerdispersedstoragesiteswithinmodality-dependentassociationsensorycortices,therebycausinghallucinations”(p.1114).Ofnote,increasedinputofmemory-relatedmaterialintoconsciousnessisconsistentwithfindingsofdisinhibitionofDMNactivityduringwakingconsciousness,giventheroleofthehippocampusandparahippocampusinthemedialtemporalsubsystemoftheDMN. Arecentstudyexaminednetworkcomponentsthatarecommontohallucinationsingeneral,andcomponentsthatarespecifictothesensorymodalityofahallucination(121).Inthisstudyofpatientswithfocalbrainlesions,90%offocallesionsoccurringinpeoplewhosubsequentlydevelopedhallucinationshadpositiveconnectivitytothecerebellarvermislobuleVI,positiveconnectivitytobilateralcerebellarlobuleX,andnegativeconnectivitytotherightsuperiortemporalsulcus.InpatientswithVH,95%oflesionsdemonstratedconnectivitytotheLGN.Interestingly,95%ofsubcorticallesionsassociatedwithVHdemonstratednegativeconnectivitytoextrastriatevisualcortex(Brodmannareas18and19),while100%ofcorticallesionsassociatedwithVHdemonstratedpositiveconnectivitytothissameregion.Moreover,in60of61cases,thesubcorticalorcorticalregionassociatedwithVHdemonstratedsignificantconnectivitytothesameregioninextrastriatevisualcortex.Althoughpeoplewithpriorhistoriesofneurologicorpsychiatricdisorders(includingschizophrenia)werenotincludedintheKimetal.study,thedatasuggestthatinvolvementofcorticalandsubcorticalvisualregionsareanecessarycomponentfortheexperienceofVH,whereasawidernetworkmaybeinvolvedinenablingtheshiftawayfromastateinwhichexternalstimulideterminewhatisperceivedasexternal. Otherfindingsrelatedtotheissueofgeneralvs.modality-specificaspectsofhallucinationscomefromastudybyJardrietal.(120),inwhichhallucinationswereassociatedwithunstableDMNandtasknetworkdynamics,involvingtransientdisengagementoftheDMN—asoccurswithexternalstimulation,butinthiscaseintheabsenceofanythingexternalthatshouldleadtothe(hallucinated)percept.Thisabnormalandunexpectedtransitioningbetweenrestingandtask-positivestateswasfoundtobeageneralcorrelateofhallucinations,independentofsensorymodality.Thisstudyalsofoundthatincreasedactivityinprimarysensorycorticeswasnotnecessarilyassociatedwithhallucinations,butthatactivityinassociationsensorycorticeswasrelatedspecificallytothesensorymodalityoftheexperiencedhallucination.OfnoteisthatthefindingsofJardrietal.(120)ondisengagementoftheDMNdifferfromthosecitedearlierinwhichdisinhibitionofDMNactivitywasassociatedwithVH.ThisdifferencemaybeduetostudyingbrainactivityduringVH(120)incontrasttostudyingcharacteristicsassociatedwithhavingVHingeneral(i.e.,trait-levelsettingconditions).EvidenceconsistentwiththisviewcomesfromanfMRIstudyofauditoryhallucinationsinwhichchangesinnetworkconnectivityovertimewerenotassociatedwithseverityofhallucinationsonthedayofscanning,butpatientsmorelikelytohallucinateingeneralshowedaweakerinverserelationshipbetweentheDMNandtask-positivenetworksthanpatientswithalowergeneralfrequencyofhallucinations(122).Ontheotherhand,Jardrietal.studiedpeoplewithbriefpsychoticdisorder,whereasstudiesthathavefocusedonVHandDMNactivitywereconductedinneurologicalpopulations(althoughstudieslinkingincreasedhippocampalconnectivitywithVHinschizophreniaarerelevanttothedisinhibitionofDMNhypothesis(seeabove),asarefindingsofketamine-inducedreducedsuppressionofDMNactivity[e.g.,(123)]andauditoryandvisualhallucinationsanddistortions(124).Seebelow,thesectiononanupdatedmodelofVHinschizophrenia,forfurtherdiscussionoftheseissues. Inadditiontonetworkmechanisms,acellularmechanismthatmaybeimportantinunderstandingVHinschizophreniainvolvesdisturbancesintheinfluenceofapicaldendriticactivityonthesomaticcompartmentofpyramidalneurons.Ithasbeenproposedthatduringnormalwakingconsciousness,informationaboutexternaleventsisprocessedviafeedforwardmechanismsinvolvingthesomaticcompartmentsofpyramidalcellsincorticallayer5,whilethisactivityismodulatedbyactivityfromareasoutsidetheclassicalreceptivefield,andmoredistantregionsofthebrain(representingcontextual,mnemonic,andother“top-down”influences),viasynapsesontoapicaldendritesofpyramidalcellsinsuperficialcelllayers(e.g.,layer1)(35,36,125).Activityfromdifferentinputstotheapicaldendriteareintegratedintheapicalintegrationzone(AIZ),priortoAIZoutputaffectingthecell'sfiringrateortiming.Duringsleeporunderanesthesia,arousallevelanddegreeofexternalinputaregreatlyreduced,andsothereisproportionallygreateractivationatapicalrelativetosomadendrites(seeFigure1).ThisallowsthecombinedAIZactivitytodrive(asopposedtoonlymodulate)activityinpyramidalneurons(36).AresultofthiscanbeprocessingofAIZactivityasifitwereexternalstimulation,ratherthanactivitythatnormallyservesonlytoalterthestrengthortimingoffiring,asinthewakingstate(126).Thiseffect,calledapicaldrive,hasbeenproposedasamechanisminvolvedindreams,butalsoinmentalimagery(125,127–130),andalterationsinthismechanismcouldbeinvolvedintheformationofVHandalso(atamilderlevel)visualdistortions,aswedelineatefurtherbelow.AdetailedaccountofhowdisruptionsinapicalamplificationcouldaccountforarangeoffeaturesofschizophreniacanbefoundinPhillipsetal.(35).SimilartothepredictivecodingandexcessiveDMNactivityhypotheses,thisproposalsuggeststhatthereisanexcessiveinfluenceofstoredinformationrelativetoexternalinputindeterminingperceptualexperience.Thehypothesizedneurobiologyisdifferent,however,inthatitisseenasinvolvingmultipleneurotransmitters(e.g.,glutamate,DA,Ach),includingreducednoradrenergicactivity.AsdiscussedfurtherbelowinthesectiononanupdatedmodelofVHinschizophrenia,thematerialthatservesascontextmayvarygreatlydependingonwhetherapersonisengagedininstrumentalactivity(whentask-positivebrainnetworksareactive),orisfocusedoninternalstatesordaydreaming(whenDMNactivityisrelativelyincreased),orisdreamingduringsleep(whenDMNactivityisfurtherincreased,alongwithotherchangesinbrainfunction).Alongthiscontinuum,itcanbeexpectedthatthenatureofcontextualinputwillbecomemoreself-referential,moretiedtobasicissuesaroundsecurity/dangerandfulfillmentofbiologicalneeds,andmorebasedinsymbolismandvisual/auditoryimagerythanonlogicalrelationships(131).ThismayaccountforthefrequentappearanceofreligiousandotherarchetypalcontentintheVHofpeoplewithschizophrenia(132,133). FIGURE1 Figure1.Comparisonofpyramidalcellcomponentcontributionsduringwakinganddreamingconsciousness.Theimageontheleftdemonstratesthatduringwakingconsciousnesstheprimarydeterminantsofperceptionareexternalinputs(continuousredarrow),whichareprocessedasfeedforwardactivitythroughthesomaticintegrationzone(reddottedovals)oflayer5pyramidalneurons.Thisactivitycanbeamplifiedorsuppressedbasedoninternalcontextualinput(includingepisodicmemorytraces,expectations,andemotionalfactors;horizontalbluedottedarrow),whichisprocessedinlayer1ofthesameneurons,viaactivationofapicaldendritictufts.Thecombinedcontextualactivityisintegratedwithintheapicalintegrationzone(AIZ)ofpyramidalneurons(bluedottedovals),whoseactivationlevelaffectsthefiringrateoftheneuron(verticalbluedottedarrow),butdoesnotleadtheneurontofireintheabsenceofexternalinput.Duringdreaming,internalcontextualinput(continuoushorizontalbluearrow)canactivateanapicaldendriticmechanismthatenablesittodrivetheneuron'soutput(continuousverticalbluearrow),andthatoutputisinterpreted(bydownstreamcircuits)asconveyinginformationabouttheexternalworld(externalinput)eventhoughitdoesnot.Weproposethatinthecaseofvisualhallucinationsascenariomidwaybetweenthetwoextremesofwakingconsciousnessanddreamingisoperative,whereinAIZactivitycanexertbothmodulatoryanddrivinginfluences,resultingininternally-generatedvisualrepresentations,ofteninvolvingsignificantcontributionsfromtrauma-basedmemoriesandrelatedemotionalandsymbolicmaterial,beingexperiencedashavingbeenexternallygenerated.Intheviewproposedinthispaper,complexhallucinationsinvolvingthismechanismdifferinmanyrespectsfromsimplevisualhallucinationsandvisualdistortionsinthatthelattertwophenomenaprimarilyrepresentcompensationswithinthevisualsystemformissing,weakened,ordegradedinput,andwithrelativelyfewercontributionsfromepisodicmemoryandemotionalfactors.However,evensimpleVHcanberelatedtoasmeaningfulandcanreflectpsychologicalfactors(15).Theimageinthisfigure,andportionsofthefigurecaption,arereproducedfrom:Aruetal.(126).Apicaldrive-Acellularmechanismofdreaming?NeuroscienceandBiobehavioralReviews119,440–55,withpermissionfromElsevierviaaCCBYlicense. EvidenceinsupportofincreasedapicaldriveinVHinschizophreniacomesfromstudiesindicatingthatschizophreniapatientswithVHaremorelikelytomis-rememberitemsaspicturesthathadbeenpresentedtothemaswords(134–136).Thissuggeststhattheoriginalmemorytraceishavingareduceddrivingeffectontheconsciousrepresentation,whereasthemoredistantassociationstotheword(e.g.,pictorialrepresentations)thatwouldnormallyserveamodulatoryrolearedrivingwhatisremembered.Interestingly,intheAynsworthetal.(134)studythehighVHgroupalsoreportedmoreintensevisualimagery,andmorenegativevisualimagery,findingsthatareconsistentwithhyperconnectivitybetweenthehippocampusandotherregions(seeabove),andwithhistoriesoftraumaticexperience(137,138)(whichitselfhasbeenrelatedtohippocampalatrophysecondarytoneurotoxiceffectsofchronicallyelevatedcortisol). Finally,ithaslongbeenrecognizedthatexcessiveDAactivityisinvolvedinthegenesisofpositivesymptoms[e.g.,(139,140)].Forexample,increasesinDAturnoverintheassociativestriatumwereassociatedwithhallucinationseverity(alltypescombined,andsopresumablymostlyauditory),especiallyunderconditionsofuncertaintyinpeoplewithschizophrenia(141).OtherevidencehasalsolinkedDAactivitywithhallucinations(includingthecombinationofauditoryandvisualhallucinations)inschizophrenia(115,142).DatafromtheseandotherstudiesfitwellwiththeproposedroleofDAinthepredictivecodingdisturbancesinpsychosis(143),includingtheviewthathallucinatoryactivityrepresentsexcessiveinfluenceofpriors.Therefore,increasedstriatalDAmaybeanothermechanism,inadditiontoreducedcholinergicactivity,thattipsthebalanceofprocessingtowardanincreasedinfluenceofinternallygeneratedrepresentationsonconsciousperception. Thefindingsreviewedinthissectionhighlighttheincreasinglyappreciatedpotentialrolesofcellular,andlocalandlong-rangebrainnetworkactivityinthegenesisofVHinschizophrenia.Thisincludesthecontributionsofstoredinformation,expectations,andother“top-down”inputs,aswellaschangesintherelativestrengthofbottom-upsignals.Regardingthelatter,Bernardinetal.(46)notedthattherehasbeenalackofappreciationofpossibleretinalcontributionstoVHinschizophrenia,incontrasttothestudyofotherneuropsychiatricconditionssuchasParkinson'sdisease.Inthefollowingsection,weprovideanupdatedsummaryofthisliterature. PotentialRetinalContributionstoVHandVisualDistortionsinSchizophrenia AnimportantandlargelyunaddressedquestionintheVHandvisualdistortionsliteraturesinschizophreniaistheextenttowhichthesesymptomsmaybeduetoalteredretinalstructureorfunctioninthedisorder.Sincethepublicationofthetypologyproposedbyffytche(69),andevensincethemorerecentreviewsofWatersetal.(4)andBernardinetal.(46),therehasbeenrapidgrowthinthefieldofoculomics[i.e.,thestudyofretinalmarkersofbrainandsystemicdiseases(144)].Thisincludesmanystudiesdemonstratingretinalstructuralandfunctionalimpairmentinschizophrenia,andasmallnumberofpapersonalteredretinalmicrovasculature.Comprehensivereviewsofthisliteraturehavebeenrecentlypublished(28,80,144),andsoonlyabriefreviewoftherelevantfindingsareprovidedhere. Thereisnowconvincingdatafromanumberofstudies,publishedindifferentcountriesacrossmultiplelaboratories,demonstratingthatthereisthinningofmultipleretinallayersinpeoplewithschizophrenia(145–151).Theselayersincludetheinnermostlayer,theretinalnervefiberlayer(RNFL),comprisingtheaxonsoftheganglioncells,whichformtheopticnervethatleavestheretinaandsynapsesatthelateralgeniculatenucleus(LGN)ofthethalamus;theganglioncellbodyandinnerplexiformlayers;andthevascularlayers(e.g.,choroid)thatsupporttheoutermostneurallayers(28,80).Thereisalsoevidenceforotherstructuralretinalabnormalitiesinschizophrenia,suchasanincreaseinopticcupvolumeandcup-to-discratio(83),suggestingchangessimilartothoseobservedinglaucoma(83).ThesefindingsraisethepossibilitythatretinalsignalsreachingtheLGN,andeventuallyV1,aredegraded,andthatcompensatoryprocessescouldleadtovisualdistortionsandVH,asdescribedabove(46).EvidenceforsuchapathologicalcompensatoryprocesshasbeenobservedinCharlesBonnetsyndrome(152).InParkinson'sdisease,onestudydemonstratedarelationshipbetweenRNFLthinningandVH(153),butasecondstudyfoundnoevidenceforsuchalink(154).Arecentstudyinschizophrenia(155,156)indicatedthatfourseparatesamplesofpatientswithbothauditoryandvisualhallucinationsofatleastmoderateseveritywerecharacterizedbysignificantmaculaandRNFLthinningrelativetoacontrolgroup.Thelackofacontrolgroupofpatientswithauditoryhallucinationsonlyand/ornohallucinationsprecludesadefinitiveconclusionregardingspecificrelationshipswithVH,however.Therefore,theissueofretinalstructuralcontributionstoVHinschizophrenianeedsfurtherclarification. Alterationsinretinalfunctionhavealsobeenobservedinschizophreniausingflashelectroretinography(fERG)andpatternelectroretinography(pERG)[reviewedin(28,80)].Thesedataindicateweakenedanddelayedsignalingfromphotoreceptorandbipolar-Mullercells,andweakenedsignalingfromganglioncells.ThesestudieshavegenerallynotinvestigatedrelationshipsbetweenfunctionalretinalimpairmentandVH.However,arecentstudy(157)reportedthatschizophreniapatientswithlifetimeVHwerecharacterizedbyslowersignalinginbipolarcellsandretinalganglioncellscomparedtopatientswithoutahistoryofVH.ThisisconsistentwithfindingsofarelationshipbetweenERGlatencyincreases(andamplitudedecreases)andVHinParkinson'sdisease(158). Animplicationofthefindingsofimpairedretinalstructureandfunctioninschizophreniaisthatthevisualcortexcanbethoughtofascharacterizedbylow-levelsensorydeafferentation.Whilethisisnotassevereasincasesofadvancedretinaldisease,itmaybesufficientinmanypeopletocausephenomenasuchasvisualdistortions,andsimpleandcomplexhallucinations.Whencombinedwiththedisturbancesnotedabovethatarenotcharacteristicofconditionssuchasforexample,CharlesBonnetsyndrome,includingrelativelyincreasedapicaldrivewhichcanleadtoconfusionbetweenrealityandfantasy,heightenedinputfromlimbicregions,anddisinhibitionoftheDMN,thesereleasephenomenamaybeelaborateduponintomorecomplexandemotionallyintenseVH.AgoodexampleofhowasimpleVHinvolvedacomplexsetofmeaningsisdescribedinKaminskietal.(15). Amoresubtleconsequenceofalteredretinal,LGN,orearlyvisualcorticalactivityinschizophreniaisthatneuralrepresentationsofvisualinputmaybedegradedorotherwiseambiguous.Whilethiswouldnotnecessarilyleadtoreleasephenomenaastraditionallydefined,itwouldcreateaburdenonpredictivecodingmechanismsbyincreasingthenumberofrequiredcomparisonsbetweentop-downandbottom-upsignals(86,159).Thisincreasedcomputationalburdencouldpotentiallyleadtoerrorsininterpretingthenatureandsignificanceofvisualstimuli,suchasthegenerationofrepresentationsthatarebasedexcessivelyontop-downinformation(e.g.,hallucinations),orthatinvolvecombinationsofveridicalperceptionandaspectsofnon-veridicalrepresentations(e.g.,visualdistortions).ThisviewisconsistentwiththeproposalofCollertonetal.(160),whichemphasizesthemultipleproto-objectrepresentationsthatcanbeactivatedbyasinglestimulus,andtheroleofattentionalprocesses(oftenguidedbytop-downgoalsandotherschemata)inselectingamongthecompetinghypotheses/perceptsforallowingaccesstoconsciousawareness.Accordingtothisview,VHoccurwhenthetop-downprocessesleadtotheselectionofaperceptualrepresentationthatisunrelatedtotheexternalstimulus. Takentogether,thefewrelevantfindingssuggestthatitisreasonabletofurtherinvestigatethepotentialroleofretinaldysfunctiontoVHinschizophrenia.Cross-sectionaldataareneeded,asarelongitudinalstudiesthatrelatechangesinretinalstructureandfunctionovertimetotheemergenceofvisualperceptualsymptomsandstate-andstage-relatedchangesinthesesymptoms. AssociationsbetweenVisualProcessingImpairmentsWithVHandVisualDistortionsinSchizophrenia Asnoted,despitetheextensiveliteratureonvisualprocessingimpairmentsinschizophrenia,therehavebeenfewattemptstoinvestigatepotentiallinksbetweentheseimpairmentsandvisualdistortionsand/orVHinthiscondition.Weareawareofthreestudiesexploringlinksbetweenthewell-documentedvisualprocessingimpairmentsinschizophreniaandvisualdistortionsorVH.Kerietal.reportedthat,inasampleofpeoplewithahistoryofschizophrenia(meanage=34.1years),impairmentsonlow-andmid-levelvisualprocessingtaskswererelatedtoincreasedself-reportsofvisualdistortions(26).Kissetal.(27)reportedthat,inasampleoffirstepisodepatients,increasedmagnocellularactivity,asreflectedbyenhancedcontrastsensitivityforlowspatialfrequencyinformation,wasrelatedtoanincreaseinperceptualdistortionsinpeoplewithschizophrenia.Asnotedabove,arecentstudybyBernardinetal.(157)demonstratedalinkbetweenanomaliesintheERG,includingslowersignalingofbipolarandganglioncells,andvisualhallucinationsinpeoplewithschizophrenia.Thisevidencesuggeststhatlaboratorymeasuresoflow-andmid-levelvisionmaybeusefulinclarifyingmechanismsinvolvedinvisualdistortionsandpossiblyVH.Additionalstudiesareneededtoreplicatethesefindings,andtoclarifytheroleofhigh-levelvisualdisturbancestoVH,especiallyasthesehavebeenrelatedtopsychoticsymptomsinpeoplewithschizophrenia(31). AnUpdatedModelofVHandVisualDistortionsinSchizophrenia ThefindingsreviewedabovesuggestthatseveralfactorsmaybeinvolvedinVHinschizophrenia,including:alterationsinretinalstructureandactivity,suchasdelayed,weak,and/orambiguoussignaling,andcompensatory,predictiveandreleaseprocessesinitiatedwithinvisualcortex;impairmentsinfunctioninginvisualprocessingregions[e.g.,thosethatleadtothewell-documentedchangesincontrastsensitivity,perceptualorganization,motionprocessing,etc.(17)];changesinactivityinascendingcholinergicpathways;andabnormalnetworkconnectivity,includingexcessiveinfluenceofDMNactivityandincreasedapicaldrive. ArecentcomprehensiveviewofVHthatintegratesseveralofthesefactors,toaccountforVHinsynucleopathies(100),proposedthatcholinergicimbalanceleadstothalamocorticaldysrhythmia,whichresultsinreducedmodulationofactivityincortical-striatal-thalamo-corticalloops.OneconsequenceofthesealterationsisthatthereislessinhibitionoftheDMNfromtask-positivenetworkssuchasthedorsalandventralattentionnetworks.IthasbeenproposedthatdisinhibitionoftheDMNcausesittoenterinto“anunstable,entropic,statethatunleashestheproductionofoneiric,dissociative,oralteredstate(sic)ofconsciousness,andultimatelyVH”[(98),p.4](96,97,99,100).ThishypothesisregardingVHmechanismsisconsistentwiththeproposalthatdisinhibitionofDMNactivitycontributestopsychoticsymptomsinschizophrenia(123,161,162).BecausetheDMNisthoughttoplayacriticalroleinmaintenanceofthesenseofself(163),includingintegrationofautobiographicalmemories(164),disinhibitionanddysregulationofthisnetworkwouldbeexpectedtoleadtoVHthatareself-relevantandthatoftencontainfragmentsofmemoriesofemotionallyintenseexperiences(e.g.,thoserelatedtotrauma),andothercontentthatfrequentlyservesasbasisforrumination(165),includingimagesandideationassociatedwithreligiousthemes.Itispossiblethathallucinationsinschizophrenia,moresothaninsynucleopathies,involveanadditionalcontributionofexcessivestriataldopamine,whichcouldfurthershiftthebalanceofbottom-upandtop-downactivitytowardthelatter. AnimportantconsiderationinconsideringtheroleofapicaldriveinVHisthatthenatureofwhatservesascontextislikelytobedifferentacrossmentalstates,especiallybetweennormaltask-positivebehavioranddefaultmodeactivity.Forexample,duringastateofhighlyfocusedattentionandtaskactivity,thenatureofcontextualinputtoagivenneuronwillbedifferentthanitwouldbeduringdaydreamingordreamingwhileasleep.Duringfocusedactivity,contextualinputsshouldinvolvememoriesrelatedtopriorexperienceswiththecurrenttask,andideationandlinguisticassociationsassociatedwithstatisticalregularitiesintheworldrelatedtotaskperformance(i.e.,tooutcomesthatcanrealisticallyoccur).Duringdaydreamingorinternallyfocusedstatesassociatedwithanxiety,however,theseconstraintsarelikelytobeloosened,resultinginmorewide-ranging,illogical,andemotion-andfantasy-basedassociations(166–168).Duringdreamingwhileasleep,thereislikelytobethegreatestproportionofimageryandideationrelatedtosafetyandsecurityissues,andotherbasicbiologicalconcerns(e.g.,fear,rage,sexualarousal,isolation),withthelinksbetweenideasoftenexpressedusingnon-logicalconnectionsbasedonemotions,symbolism,sounds,colors,andotherbasicstimulusfeatures.Totheextentthatthecontentofhallucinationsreflectscomponentsofsensorymemoriesthatareinappropriatelyactivatedbyassociation[ashasbeenproposedwithauditoryhallucinations(169)],itwouldbeexpectedthatVHwillcontainimageryfrompriormemoriesorsymbolicallyrelatedtothoseevents.Inshort,VHmayinvolvetransientrelativeincreasesintheeffectsofnormallynon-consciousemotionalandideationalactivity,andaqualitativeshiftwhereinthismentalcontentisprocessedasfeedforward(i.e.,sensory)activityratherthanmodulatoryinfluences.Inaddition,thefrequentarchetypalcontentofVHinpeoplewithpsychoticdisorders,whichincludesimagerysuchasGod(orgods),Jesus,theVirginMary,thedevil,saints,andangels(132,133),suggeststhatinmanycasestheVHimageryispartofacomplexofmentalrepresentationsthatinvolvestrongemotionsrelatedtotheconceptoftheself[possiblysecondarytoincreasedconnectivitybetweentheamygdalaandcorticalregionsinvolvedinhighervisualprocessing,asnotedabove(114)],andfragmentsofvisualmemories,thataremostproductivelyrelatedtoinsymbolicform.Thiscombinationofinfluencesmayexplainthenuminousorhighlycompellingnatureofvisualhallucinations:theimagesarenotonlysurprising(aswouldbe,forexample,animageofarulerappearinginfrontofoneself),theyalsoreflectdeep-seatedemotional,self-maintenance,andsurvivalconcernsandarefelttobehighlyself-relevant.AnexcellentphenomenologicalanalysisofVH,presentedwithinthecontextofapredictivecodingaccount,wasprovidedbyKaminskietal.(15).Inthiscase,theVHofathinveilofrainthatfellinfrontofthepatientwasinterpretedasanaspectofaself-preservationtendencytopreventfusionbetweentheselfandtheouterworld. Inadditiontothefactorsreviewedintheaboveparagraph,wesuggestedthattheroleoftheretinalchangesinschizophreniareviewedaboveneedstobegivengreaterconsideration.Theco-occurrenceofVHandretinalchangesinschizophrenia(157)highlightstheneedtoclarifytheextenttowhichalteredvisualsysteminputcontributestothalamocorticaldysrhythmia,orotherwisecontributestoormodifiesthelevelofcortico-thalamicconnectivity,orthetypesofoutputsassociatedwithDMNdysregulation.Regardingthelatter,wesuggestthat,inschizophrenia,whenthequalityofrepresentationsinthevisualsystemismoredegradedand/orambiguousthannormalduetochangesinprecorticalpathways[e.g.,intheretina(80)oropticradiations(170,171)],aconditioniscreatedwhichincreasesthelikelihoodofdistortedvisualperceptions,activationofinappropriatevisualrepresentations,andVH.Thatis,consistentwiththepredictivecodingmodel,ambiguitieswithregardtothenatureofvisualinput—-duetopoor-qualitysignalsandcompensatoryresponsessuchasbroadeningofneuraltuningfunctions(86,159,172–175)—-willfurtherincreasetheinfluenceofpriorsinthegenerationofvisualrepresentations.Further,withinthecontextofDMNdysregulation,thesepriorsbecomemorelikelytoinvolvematerialrelatedtosecurityandsafetyconcernsandtoimageryandsymbolismaroundthese,thanduringtask-positivebrainstates.Incaseswheretherearehistoriesoftrauma,bullying,chronicsocialdefeatandothernegativeexperiences,whichoccuratanelevatedfrequencyinthehistoriesofpeoplewithschizophrenia,VHmaybecomeespeciallydisturbing(176,177).Thislinkwithmemoriesofthreatstotheself,andrelatedthoughtsandfeelings,mayaccountforwhyhallucinationsinschizophreniaaremorelikelytobeperceivedasreal,andtobemoredistressingthan,forexample,thoseinParkinson'sdiseaseorCharlesBonnetSyndrome. Iftheviewproposedhereisvalid,itbecomesnecessarytoexplainwhymanyschizophreniapatientsdonothaveanyVH,andwhyamongthosethatdoexperienceVH,thefrequencyandformtheytakecanvarytotheextentthattheydo.Theanswerstothesequestionsarenotclearatpresent.OnecluecomesfromdatareviewedabovethatVHareassociatedwithamoresevereformofillness[includingpoorerpre-diagnosisfunctioning(8)]andthat,inschizophreniatheyrarelyoccurintheabsenceofAH.Itmaybethecase,therefore,thatspecificgenetic,neurodevelopmental,and/orneurodegenerativefactorsthatincreasesymptomatologyanddisabilityovertimealsoleadtochangesinthevisualsystem.Thisisconsistentwithfindingsofoccipitallobeatrophyinthepoorestoutcomeschizophreniapatients(67,68),andwithpreliminaryevidenceofgreaterretinalatrophyinmorechronicallyillpatients(148,178)andthosewithmorepositivesymptoms(179),althoughthelatterfindinghasnotbeenconsistentlyreplicated[e.g.,(149)foundrelationshipsbetweenretinalatrophyandnegative,butnotpositive,symptoms].Animportanttaskforfutureresearch,therefore,involvesclarifyingthefactorsthatdeterminethedifferentialexpressionoftheproposedmechanismsacrosspatients.SpecificquestionsincludewhethertheVHofpatientswithretinalimpairmentsdifferfromthosewithnormalretinalfunction(andifso,inwhatways),andexplorationofthedifferences(e.g.,intraumahistory)betweenpatientswiththreateningorsurvival-relatedVHimageryandpatientswithVHwithoutsuchcontent[geometrichallucinationsorVHinvolvinglilliputianfigures(180)]. AdditionalQuestionsandFutureDirections AlthoughtherearenowseverallikelycandidatemechanismsforinvolvementinVH,thereisstillmuchtobelearnedaboutVHinschizophrenia.Twocriticalissuesinvolvecausality,andwhichmechanisms,ifany,canbeconsiderednecessaryandsufficientforVHtooccur.Thedatareviewedabovecomemainlyfromstudiescomparingschizophreniapatientswithvs.withoutVH,orfromcorrelationalstudies.Causalitycannotbedeterminedusingthesestudydesigns.Studiesthatdirectlyinfluencedeachofthemechanismsdiscussed,andcandidatemechanismsthatemergeinthefuture,arenecessary.Forexample,brainstimulation,neurofeedback,orpharmacologicalmanipulationsthatleadtoVH,andwhosecessationleadstoterminationofVH,wouldprovidemoreconvincingevidenceaboutcausality. Regardingnecessaryandsufficientfactors—-nosinglefactorhasbeenfoundtobenecessaryorsufficientinstudiesofVHinschizophrenia.Asnotedabove,anetworkcommontohallucinationscausedbybrainlesionshasbeenidentified(121),butitisnotclearwhetherthisnetworkisanecessarycomponentofVHinschizophrenia.ThatstudyalsodemonstratedthatVHspecificallywereassociatedwithalteredconnectivitywiththeLGNandextrastriatecortex.Importantly,however,VHincasesofbraininjurycandifferfromwhatisexperiencedbypeoplewithschizophrenia,andregionsoutsideofthenetworkidentifiedbyKimetal.(121)(e.g.,amygdala,hippocampus,visualassociationareas)havebeenlinkedtoVHinpeoplewithschizophrenia,asdiscussedabove.Inshort,itisnotpossibletodemonstrateatthispointthataspecificsetofbrainregionsoranetworkisnecessaryforVHtooccurinschizophrenia.TheextenttowhichpeoplewithschizophreniaandVHvaryinwhichfactorscontributetoVHisalsonotclear.Anadditionalquestioniswhethersomeoffactorsaretrait-related(e.g.,capacityformoreintenseimagery;predictivecodingimpairments),andthereforeserveasanecessarysettingconditionuponwhichstate-relatedmechanismsimposequalitativechanges.Themajorityofthedatareviewedabove,however,canbeconsideredtorepresenttraitcharacteristics,giventhefocusonpatientswithVHingeneral,asopposedtopatientsexperiencingVHduringthestudysession. Asnotedbyareviewerofthispaper,thebiologicalandpsychologicalmechanismsdiscussedabove(e.g.,disinhibitionofDMN,alteredpredictivecoding)arefoundinmanystudiesofschizophreniaandyetthemajorityofpatientsdonothaveVHandmany(1/3)donothavevisualdistortions.Thesameissueappliestoallworkthatattemptstoidentifyamechanisminvolvedinasymptomofschizophrenia,giventhelargedegreeofoverlapbetweenpatientandcontrolsamplesinstudiesofpotentialbiologicaldiseasemarkers.Forexample,withaneffectsizeofd=0.80,generallyconsideredalargeeffect,therewillbe68.9%ofoverlapbetweengroups,andeffectsizesinmostPETandMRIstudiesinschizophreniaarewell-belowthatlevel(181,182).Therefore,clarifyingwhichfactorsandtheirinteractionsareinvolvedinVH,inwhichpeoplewithschizophrenia,isacriticaltaskforfutureresearch.RecognizingthatpatientsmayvaryinthefactorscausingtheirVH,andclarifyingwhichfactorsandtheirinteractionsareinvolvedinVH,foranysinglepatient,maythereforebeanecessaryassessmenttaskrequiredfortheeffectivetreatmentofVH.Inourview,whilethestateoftheevidencedoesnotallowforconclusionstobedrawnforallpatientsatthistime,thedatadosuggestthatseveralcandidatemechanismswouldbeusefultoassesswithinthecontextofdifferentsymptompresentations.Forexample,incaseswheresimpleVHaredominant,assessmentofretinalstructureandfunction,visualevokedpotentials,low-levelvisualfunctionsandoccipitallobestructureandfunctioningmayyieldusefulinsightsregardingdegradedinputtoV1andsubsequentcompensatoryfilling-ineffortswithinvisualregions,thatleadtodistortionsandsimpleVH.IncasescharacterizedprimarilybycomplexVH,especiallyofathreateningorsaving(e.g.,angelic,salvific)nature,thereislikelytobegreaterinvolvementofDMN,hippocampusandamygdalaactivity,andgreatercontributionsofapicaldrive.Wehypothesizethatinsuchcases,reducedcholinergicactivityinthebasalforebrainand/orelevatedstriatalDAwillcausereducedsignal-noiseratiosinperceptionandcontributetoanover-relianceonstoredrepresentationsandemotionalfactorsindrivingperception,inamanneranalogoustohowretinalimpairmentsreducesignal-noiseratioandleadtofilling-inphenomenainvisualregionsincasesofsimpleVH(seeFigure2). FIGURE2 Figure2.Proposedrelativecontributionsofbiologicalfactors,andtheirpsychologicalconsequences,involvedindifferenttypesofalteredvisualphenomenainschizophrenia.Arrowattopdepictsacontinuumfromvisualdistortionstosimplevisualhallucinations(VH)tocomplexVH,movingfromlefttoright.Trianglesbelowthetoparrowdepicthypothesizedincreasinganddecreasinginfluencesacrossthecontinuum.Thegreentriangle,becominglargermovingfromlefttoright,representsanincreasedinfluenceofbasalforebrainacetylcholine(Ach)reduction,striataldopaminergic(DA)increases,defaultmodenetwork(DMN)disinhibition,andapicaldriveingeneratingmorecomplexhallucinatoryphenomenainwhichepisodicmemorytracesandassociatedemotionalfactorsarethoughttobeinvolved.Incontrast,therelativecontributionsofretinalandprimaryvisualcortexchangesarehypothesizedtobegreatestincasesofvisualdistortionsandsimpleVH,wheretheanomalousperceptsinvolvefilling-inandreleasephenomenawithinvisualcortexregions.Notethateachofthesefactorsinvolvesadditionalfactors(e.g.,increasedapicaldriveinvolveseffectsofmultipleneurotransmitters). Testingtheviewsproposedabovewillinvolve,first,carefulassessmentofthenatureoftheVHinindividualpatients,andthendeterminingwhetherthehypothesizedimpairmentscanbeobservedinpatientswithsimilarVHcharacteristics.UsingtypeofVHasthegrouping(independent)variableinstudiesofschizophreniaisnotroutine,butisprobablynecessarytoanswerthequestionsposedhere.Itshouldalsoberelativelysimpletodetermineif,forexample,patientswithsimpleVHdemonstrategreaterretinalandearlyvisualcortexdifferencescomparedtopatientswithoutVH,andcomparedtopatientswithonlycomplexVH.Thelattergroup,incontrast,shoulddemonstratemoreevidenceofDMNdisinhibition,cholinergicdysfunction,andapicaldrive,andlinksbetweenthesechangesandvisualsystemactivity(especiallyinvisualassociationareas),relativetopatientswithsimpleVH.ItmaybenecessarytocontrolforlevelofauditoryhallucinationsinstudiesfocusedoncomplexVHsincethesearelikelytosharesomecommonmechanisms.Itshouldalsobenotedthattherearenodirecttestsofapicaldrivethatcanbeusedinhumanexperimentalstudies;however,extentofapicaldrivecanbecomputationallymodeledfromphysiologicaldatausinginformationtheorymetrics(183),anditshouldbepossibletodothesamefromteststhatexamineperformanceasafunctionofinternalinfluencesonperception,suchasthoseshowingexcessinfluenceofvisualimageryontheperformanceofschizophreniapatientswithVH(134–136).StudiesexaminingcovariationbetweenaspectsofVHandlevelsofimpairmentsinthemechanismsdiscussedabovewouldalsobeuseful.And,asnoted,investigationsofeffectsofbrainstimulation,medications,andothermanipulationsthataffectbrainfunction(e.g.,neurofeedback)onaspectsofVHcouldbeinformative. TheissueofthedegreetowhichVHisariskfactorforschizophreniaalsoisneedofclarification.Clearly,theonsetofVHinelderlypeopleisapotentialsymptomofaconditionsuchasLewybodydementiaorParkinson'sdisease.ButthepredictivevalidityofVHforapsychoticdisorderinayoungerperson,wheneyediseaseandsubstanceabusecanberuledout,remainsinneedofclarification.Also,whilesomedatasuggestthatthepresenceofVHindicatesamoreseveremanifestationofschizophrenia,thereismuchabouttheclinicalsignificanceandcourseofillnessthatVHmayindicatethatisunknown. OtherthanknowingthatVH,likeallpsychoticsymptoms,canbereducedbydopamine-blockingmedicationsinpeoplewithschizophrenia,littleisknownabouttheirtreatment.However,giventhehighdistresslevelassociatedwithVH,wesuggestthatfurtherresearchintoeffectivetreatmentsiswarranted.Russoetal.(100)reviewedarangeofmedicationoptionsforVHthatarerelevantforpeoplewithschizophrenia,includinganti-serotonergicdrugs,acetylcholinesteraseinhibitors,typicalandatypical(includingnovel)antipsychotics,andopioidantagonists.Additionaltreatmentdirectionscouldinvolvetargetingsymptom-relateddistress(e.g.,viacognitivebehaviortherapy),orthesymptomitselfviaimagery-basedinterventions(e.g.,virtualrealitytoengagewiththecontentoftheVH),trauma-focusedtreatmenttoreducedissociation,andpotentiallyvisualremediationandbrainstimulationinterventionstoincreaseinputtocorticalregionsthatarereceivingdeficientinput.Regardingthelatter,repetitivetranscranialmagneticstimulation(rTMS)overtheoccipitalcortexofawomanwithschizophreniasuccessfullydecreasedtheseverityandcomplexityofherVH(184).RTMSalsosignificantlyreducedtheauditoryandVHinanothercasestudyofamanwithparanoidschizophrenia(185).Whetherthisorsimilarinterventionswouldproveefficaciousinrandomizedcontrolledtrials,however,stillneedstobedetermined. AnissuerelevanttobothmechanismandtreatmentistheextenttowhichevensimpleVHcanrepresentmeaningfulconceptsandconceptualrelationshipsinpeoplewithschizophrenia.Ithasbeennotedthatvisualimagescanbeviewedaspropositionalrepresentations,whereinbasicconcepts(e.g.,higher/lower,ahead/behind,complete/incomplete,growing/decaying,etc.)arerepresented,wheredeformationsofimagescanrepresentpastandfutureactions,andwhereimagesarestructuredinsuchawaythatotherbrainmodulescandecodethemeaningtheycontain—-inshort,thatvisualimagesareconcreterepresentationsthatcanexpresscomplexconceptsconsistentwithabasic“languageofthought”thatallowsforcommunicationbetweenbrainmodules(167,186–188).Totheextentthatthisisthecase,thenevensimpleVHcanbeinfusedwithmeaning,asdemonstratedinKaminskietal.(15).ThissuggeststhatbothcomplexandsimpleVHmaybeausefulwindowintotheself. Finally,thereremainstheimportantquestionofwhyVHoccurlessfrequentlythanauditoryhallucinationsinpeoplewithschizophrenia(albeitnotaslessfrequentlyasthoughtinthepast),whereasthesituationisreversedinotherneuropsychiatricconditions(e.g.,Parkinson'sdisease).Theanswer(s)tothisquestionwillsurelybeinformativeregardingthenatureofschizophrenia.Onepossibilityinvolvesfindingsthatsomeproportionofauditoryhallucinationsinschizophreniainvolveaweakenedcorollarydischargesignal,leadingtofailuretorecognizethatsubvocalspeechactivityisinternallygenerated(189–193).Itmaybethecasethatthereisnoparallelinthevisualdomaintothisself-generatedormotorprogram-linkedhallucinationmechanism(i.e.,oneisfarlesslikelytomotoricallygenerateavisualstimulusthananauditorystimulus),andthereforeaweakenedefferencecopymechanismwouldbeexpectedtoleadtoahigherrateofauditoryvs.visualhallucinations.Conversely,thevisualsystemmechanismswediscussedabovemaybemoreoperativeinneurodegenerativedisorders,andmoreprominentintheseconditionsrelativetothespeech-languagecenterdysconnectivitythathasbeenobservedinschizophrenia. Summary Visualhallucinationsinschizophreniaaremorecommonthanpreviouslythought.Theycanbeviewedasaseveremanifestationofvisualsystemchangesthatoccuronacontinuumofseverityfromvisualdistortionstohallucinations.Severalcandidatefactorsforinvolvementinthegenesisofthesechangeshavebeenproposedandstudied,includingretinalandvisualcortexvolumelossandfunctionalimpairments,disinhibitionoftheDMNduetocholinergicandthalamicfunctionalchanges,excessiveweightingofpriorsrelativetosensoryinputrelatedtoDA(butalsoAchandglutamatergic)alterations,excessiveapicaldrive,andhyperconnectivitybetweenlimbicandhippocampalregionsandvisualareas.Ingeneral,however,muchremainsunknownaboutthecausesofVHinschizophrenia,themappingbetweencontributionsoftheproposedmechanismsandVHinindividualpatients,andtheclinicalsignificanceofVHintermsoftreatmentandprognosis.Onebenefitoffurtherresearchintothesequestionswouldbeimprovedunderstandingofschizophreniaasaneuropsychiatricdisorder,includingitssimilaritiesanddifferenceswithotherconditionswithvisualmanifestations,suchasParkinson'sdiseaseandLewybodydementia.Anintriguingpossibilityis,totheextentthatthecontentofVHreflectscorevulnerabilitiesoftheself(e.g.,security/dangerconcerns),thecontentofVHcanbeusedtoexploreandmodifydysfunctionalcognitiveschemataand/ortogenerateinsightintointerpersonalandexistentialissuesintheserviceofbehaviorchange[e.g.,(15,194)]. AuthorContributions SSconceivedofthemanuscript.SSandALconductedtheliteraturereviewandwrotethesectionsofthemanuscript.Allauthorscontributedtothearticleandapprovedthesubmittedversion. Funding SupportforthisworkwasprovidedbyagrantfromtheNewYorkFundforInnovationinResearchandScientificTalent(NYFIRST)tofundtheCenterforRetinaandBrainattheUniversityofRochesterMedicalCenter(SS,Director). ConflictofInterest Theauthorsdeclarethattheresearchwasconductedintheabsenceofanycommercialorfinancialrelationshipsthatcouldbeconstruedasapotentialconflictofinterest. Acknowledgments TheauthorsthankDr.JudyThompsonandDr.PhilipCorlettfortheirhelpfulcriticalcommentsonanearlierdraftofthepaper. Footnotes 1.^ArateofVHof62%wasreportedinastudyofschizophreniapatientsinSaudiArabia(11).Asnotedbytheauthorsofthisstudy,culturalandreligiousfactorsmakeitdifficulttocomparethesedatatoratesofVHincountriessuchastheUSandUK. References 1.ClarkML,WatersF,VatskalisTM,JablenskyA.Ontheinterconnectednessandprognosticvalueofvisualandauditoryhallucinationsinfirst-episodepsychosis.EurPsychiatry.(2017)41:122–8.doi:10.1016/j.eurpsy.2016.10.011 PubMedAbstract|CrossRefFullText|GoogleScholar 2.LimA,HoekHW,DeenML,BlomJD,InvestigatorsG.Prevalenceandclassificationofhallucinationsinmultiplesensorymodalitiesinschizophreniaspectrumdisorders.SchizophrRes.(2016)176:493–9.doi:10.1016/j.schres.2016.06.010 PubMedAbstract|CrossRefFullText|GoogleScholar 3.McCarthy-JonesS,SmailesD,CorvinA,GillM,MorrisDW,DinanTG,etal.Occurrenceandco-occurrenceofhallucinationsbymodalityinschizophrenia-spectrumdisorders.PsychiatryRes.(2017)252:154–60.doi:10.1016/j.psychres.2017.01.102 PubMedAbstract|CrossRefFullText|GoogleScholar 4.WatersF,CollertonD,ffytcheDH,JardriR,PinsD,DudleyR,etal.Visualhallucinationsinthepsychosisspectrumandcomparativeinformationfromneurodegenerativedisordersandeyedisease.SchizophrBull.(2014)40(Suppl.4):S233–45.doi:10.1093/schbul/sbu036 PubMedAbstract|CrossRefFullText|GoogleScholar 5.vanOmmenMM,vanBeilenM,CornelissenFW,SmidHG,KnegteringH,AlemanA,etal.Theprevalenceofvisualhallucinationsinnon-affectivepsychosis,andtheroleofperceptionandattention.PsycholMed.(2016)46:1735–47.doi:10.1017/S0033291716000246 PubMedAbstract|CrossRefFullText|GoogleScholar 6.BrachaHS,WolkowitzOM,LohrJB,KarsonCN,BigelowLB.Highprevalenceofvisualhallucinationsinresearchsubjectswithchronicschizophrenia.AmJPsychiatry.(1989)146:526–8.doi:10.1176/ajp.146.4.526 PubMedAbstract|CrossRefFullText|GoogleScholar 7.MueserKT,BellackAS,BradyEU.Hallucinationsinschizophrenia.ActaPsychiatrScand.(1990)82:26–9.doi:10.1111/j.1600-0447.1990.tb01350.x CrossRefFullText|GoogleScholar 8.KeaneBP,CruzLN,PaternoD,SilversteinSM.Self-reportedvisualperceptualabnormalitiesarestronglyassociatedwithcoreclinicalfeaturesinpsychoticdisorders.FrontPsychiatry.(2018)9:69.doi:10.3389/fpsyt.2018.00069 PubMedAbstract|CrossRefFullText|GoogleScholar 9.ThomasP,MathurP,GottesmanII,NagpalR,NimgaonkarVL,DeshpandeSN.Correlatesofhallucinationsinschizophrenia:across-culturalevaluation.SchizophrRes.(2007)92:41–9.doi:10.1016/j.schres.2007.01.017 PubMedAbstract|CrossRefFullText|GoogleScholar 10.DelespaulP,VriesM,vanOsJ.Determinantsofoccurrenceandrecoveryfromhallucinationsindailylife.SocPsychiatryPsychiatrEpidemiol.(2002)37:97–104.doi:10.1007/s001270200000 PubMedAbstract|CrossRefFullText|GoogleScholar 11.ZarrougET.ThefrequencyofvisualhallucinationsinschizophrenicpatientsinSaudiArabia.BrJPsychiatry.(1975)127:553–5.doi:10.1192/bjp.127.6.553 PubMedAbstract|CrossRefFullText|GoogleScholar 12.BunneyWE,HetrickWP,BunneyBG,PattersonJV,JinY,PotkinSG,etal.StructuredInterviewforAssessingPerceptualAnomalies(SIAPA).SchizophrBull.(1999)25:577–92.doi:10.1093/oxfordjournals.schbul.a033402 PubMedAbstract|CrossRefFullText|GoogleScholar 13.CuttingJ,DunneF.Thenatureoftheabnormalperceptualexperiencesattheonsetofschizophrenia.Psychopathology.(1986)19:347–52.doi:10.1159/000284459 PubMedAbstract|CrossRefFullText|GoogleScholar 14.CuttingJ,DunneF.Subjectiveexperienceofschizophrenia.SchizophrBull.(1989)15:217–31.doi:10.1093/schbul/15.2.217 CrossRefFullText|GoogleScholar 15.KaminskiJA,SterzerP,MisharaAL.“SeeingRain”:integratingphenomenologicalandBayesianpredictivecodingapproachestovisualhallucinationsandself-disturbances(Ichstorungen)inschizophrenia.ConsciousCogn.(2019)73:102757.doi:10.1016/j.concog.2019.05.005 PubMedAbstract|CrossRefFullText|GoogleScholar 16.PhillipsonOT,HarrisJP.Perceptualchangesinschizophrenia:aquestionnairesurvey.PsycholMed.(1985)15:859–66.doi:10.1017/S0033291700005092 PubMedAbstract|CrossRefFullText|GoogleScholar 17.SilversteinSM.Visualperceptiondisturbancesinschizophrenia:aunifiedmodel.NebrSympMotiv.(2016)63:77–132.doi:10.1007/978-3-319-30596-7_4 PubMedAbstract|CrossRefFullText|GoogleScholar 18.SilversteinSM,DemminD,SkodlarB.Spaceandobjects:onthephenomenologyandcognitiveneuroscienceofanomalousperceptioninschizophrenia(AncillaryArticletoEAWEDomain1).Psychopathology.(2017)50:60–7.doi:10.1159/000452493 PubMedAbstract|CrossRefFullText|GoogleScholar 19.MatthewsNL,CollinsKP,ThakkarKN,ParkS.Visuospatialimageryandworkingmemoryinschizophrenia.CognNeuropsychiatry.(2014)19:17–35.doi:10.1080/13546805.2013.779577 PubMedAbstract|CrossRefFullText|GoogleScholar 20.HébertM,GagnéAM,ParadisME,JompheV,RoyMA,MéretteC,etal.Retinalresponsetolightinyoungnonaffectedoffspringathighgeneticriskofneuropsychiatricbraindisorders.BiolPsychiatry.(2010)67:270–4.doi:10.1016/j.biopsych.2009.08.016 PubMedAbstract|CrossRefFullText|GoogleScholar 21.MittalVA,GuptaT,KeaneBP,SilversteinSM.Visualcontextprocessingdysfunctionsinyouthathighriskforpsychosis:ResistancetotheEbbinghausillusionanditssymptomandsocialandrolefunctioningcorrelates.JAbnormPsychol.(2015)124:953–60.doi:10.1037/abn0000082 PubMedAbstract|CrossRefFullText|GoogleScholar 22.HayesJF,PicotS,OsbornDPJ,LewisG,DalmanC,LundinA.Visualacuityinlateadolescenceandfuturepsychosisriskinacohortof1millionmen.SchizophrBull.(2019)45:571–8.doi:10.1093/schbul/sby084 PubMedAbstract|CrossRefFullText|GoogleScholar 23.SchubertEW,HenrikssonKM,McNeilTF.Aprospectivestudyofoffspringofwomenwithpsychosis:visualdysfunctioninearlychildhoodpredictsschizophrenia-spectrumdisordersinadulthood.ActaPsychiatrScand.(2005)112:385–93.doi:10.1111/j.1600-0447.2005.00584.x PubMedAbstract|CrossRefFullText|GoogleScholar 24.KlosterkotterJ,HellmichM,SteinmeyerEM,Schultze-LutterF.Diagnosingschizophreniaintheinitialprodromalphase.ArchGenPsychiatry.(2001)58:158–64.doi:10.1001/archpsyc.58.2.158 PubMedAbstract|CrossRefFullText|GoogleScholar 25.NikitovaN,KeaneBP,DemminD,SilversteinSM,UhlhaasPJ.TheAudio-VisualAbnormalitiesQuestionnaire(AVAQ):Developmentandvalidationofanewinstrumentforassessinganomaliesinsensoryperceptioninschizophreniaspectrumdisorders.SchizophrRes.(2019)209:227–33.doi:10.1016/j.schres.2019.03.016 PubMedAbstract|CrossRefFullText|GoogleScholar 26.KeriS,KissI,KelemenO,BenedekG,JankaZ.Anomalousvisualexperiences,negativesymptoms,perceptualorganizationandthemagnocellularpathwayinschizophrenia:asharedconstruct?PsycholMed.(2005)35:1445–55.doi:10.1017/S0033291705005398 PubMedAbstract|CrossRefFullText|GoogleScholar 27.KissI,FabianA,BenedekG,KeriS.Whendoorsofperceptionopen:visualcontrastsensitivityinnever-medicated,first-episodeschizophrenia.JAbnormPsychol.(2010)119:586–93.doi:10.1037/a0019610 PubMedAbstract|CrossRefFullText|GoogleScholar 28.SilversteinSM,FradkinSI,DemminDL.Schizophreniaandtheretina:Towardsa2020perspective.SchizophrRes.(2020)219:84–94.doi:10.1016/j.schres.2019.09.016 PubMedAbstract|CrossRefFullText|GoogleScholar 29.KafaligonulH.Vision:asystemsneuroscienceperspective.JNeurobehavSci.(2014)2:1.doi:10.5455/JNBS.1395935766 CrossRefFullText|GoogleScholar 30.HeegerDJ,BehrmannM,DinsteinI.Visionasabeachhead.BiolPsychiatry.(2017)81:832–7.doi:10.1016/j.biopsych.2016.09.019 CrossRefFullText|GoogleScholar 31.KeaneBP,SilversteinSM,WangY,PapathomasTV.Reduceddepthinversionillusionsinschizophreniaarestate-specificandoccurformultipleobjecttypesandviewingconditions.JAbnormPsychol.(2013)122:506–12.doi:10.1037/a0032110 PubMedAbstract|CrossRefFullText|GoogleScholar 32.BornRT,BencomoGM.Illusions,delusions,andyourbackwardsbayesianbrain:abiasedvisualperspective.BrainBehavEvol.(2021)30:1–14.doi:10.1159/000514859 PubMedAbstract|CrossRefFullText|GoogleScholar 33.CorlettPR,FrithCD,FletcherPC.Fromdrugstodeprivation:aBayesianframeworkforunderstandingmodelsofpsychosis[researchsupport,non-U.S.Gov'treview].Psychopharmacology.(2009)206:515–30.doi:10.1007/s00213-009-1561-0 CrossRefFullText|GoogleScholar 34.CorlettPR,HorgaG,FletcherPC,Alderson-DayB,SchmackK,PowersAR.Hallucinationsandstrongpriors.TrendsCognSci.(2019)23:114–27.doi:10.1016/j.tics.2018.12.001 CrossRefFullText|GoogleScholar 35.PhillipsWA,ClarkA,SilversteinSM.Onthefunctions,mechanisms,andmalfunctionsofintracorticalcontextualmodulation.NeurosciBiobehavRev.(2015)52:1–20.doi:10.1016/j.neubiorev.2015.02.010 PubMedAbstract|CrossRefFullText|GoogleScholar 36.PhillipsWA,LarkumME,HarleyCW,SilversteinSM.Theeffectsofarousalonapicalamplificationandconsciousstate.NeurosciConscious.(2016)2016:niw015.doi:10.1093/nc/niw015 PubMedAbstract|CrossRefFullText|GoogleScholar 37.PhillipsWA,SilversteinSM.Convergenceofbiologicalandpsychologicalperspectivesoncognitivecoordinationinschizophrenia.BehavBrainSci.(2003)26:65–82.doi:10.1017/S0140525X03000025 PubMedAbstract|CrossRefFullText|GoogleScholar 38.DemminD,MoteJ,BeaudetteD,ThompsonJ,SilversteinS.Retinalfunctioningandrewardprocessinginschizophrenia.SchizophreniaRes.(2019)219:25–33.doi:10.1016/j.schres.2019.06.019 PubMedAbstract|CrossRefFullText|GoogleScholar 39.DemminDL,DavisQ,RocheM,SilversteinSM.Electroretinographicanomaliesinschizophrenia.JAbnormPsychol.(2018)127:417–28.doi:10.1037/abn0000347 CrossRefFullText|GoogleScholar 40.SlaghuisWL.Contrastsensitivityforstationaryanddriftingspatialfrequencygratingsinpositive-andnegative-symptomschizophrenia.JAbnormPsychol.(1998)107:49–62.doi:10.1037/0021-843X.107.1.49 PubMedAbstract|CrossRefFullText|GoogleScholar 41.SlaghuisWL,ThompsonAK.Theeffectofperipheralvisualmotiononfocalcontrastsensitivityinpositive-andnegative-symptomschizophrenia.Neuropsychologia.(2003)41:968–80.doi:10.1016/S0028-3932(02)00321-4 CrossRefFullText|GoogleScholar 42.DudleyR,CollertonD,Nicholson,MosimannU.Clinicalcharacteristicsofdisclosedvisualhallucinationsinusersofanearlyinterventioninpsychosisservice.Psychosis.(2013)5:127–33.doi:10.1080/17522439.2012.699543 CrossRefFullText|GoogleScholar 43.GoodwinDW,AldersonP,RosenthalR.Clinicalsignificanceofhallucinationsinpsychiatricdisorders.Astudyof116hallucinatorypatients.ArchGenPsychiatry.(1971)24:76–80.doi:10.1001/archpsyc.1971.01750070078011 PubMedAbstract|CrossRefFullText|GoogleScholar 44.DudleyR,AynsworthC,CheethamR,McCarthy-JonesS,CollertonD.Prevalenceandcharacteristicsofmulti-modalhallucinationsinpeoplewithpsychosiswhoexperiencevisualhallucinations.PsychiatryRes.(2018)269:25–30.doi:10.1016/j.psychres.2018.08.032 PubMedAbstract|CrossRefFullText|GoogleScholar 45.vanOmmenMM,vanLaarT,CornelissenFW,BruggemanR.Visualhallucinationsinpsychosis.PsychiatryRes.(2019)280:112517.doi:10.1016/j.psychres.2019.112517 CrossRefFullText|GoogleScholar 46.BernardinF,SchwanR,LalanneL,LigierF,Angioi-DuprezK,SchwitzerT,etal.Theroleoftheretinainvisualhallucinations:Areviewoftheliteratureandimplicationsforpsychosis.Neuropsychologia.(2017)99:128–38.doi:10.1016/j.neuropsychologia.2017.03.002 PubMedAbstract|CrossRefFullText|GoogleScholar 47.LindalE,StefanssonJG,StefanssonSB.Thequalitativedifferenceofvisionsandvisualhallucinations:acomparisonofageneral-populationandclinicalsample.ComprPsychiatry.(1994)35:405–8.doi:10.1016/0010-440X(94)90282-8 PubMedAbstract|CrossRefFullText|GoogleScholar 48.AsaadG,ShapiroB.Hallucinations:theoreticalandclinicaloverview.AmJPsychiatry.(1986)143:1088–97.doi:10.1176/ajp.143.9.1088 CrossRefFullText|GoogleScholar 49.Gauntlett-GilbertJ,KuipersE.Phenomenologyofvisualhallucinationsinpsychiatricconditions.JNervMentDis.(2003)191:203–5.doi:10.1097/01.NMD.0000055084.01402.02 PubMedAbstract|CrossRefFullText|GoogleScholar 50.Alderson-DayB,WoodsA,MoseleyP,CommonS,DeamerF,DodgsonG,etal.Voice-hearingandpersonification:characterizingsocialqualitiesofauditoryverbalhallucinationsinearlypsychosis.SchizophrBull.(2020)47:228–36.doi:10.1093/schbul/sbaa095 PubMedAbstract|CrossRefFullText|GoogleScholar 51.DudleyR,WoodM,SpencerH,BrabbanA,MosimannUP,CollertonD.identifyingspecificinterpretationsanduseofsafetybehavioursinpeoplewithdistressingvisualhallucinations:anexploratorystudy.BehavCognPsychother.(2012)40:367–75.doi:10.1017/S1352465811000750 PubMedAbstract|CrossRefFullText|GoogleScholar 52.SmallIF,SmallJG,AndersenJM.Clinicalcharacteristicsofhallucinationsofschizophrenia.DisNervSyst.(1966)27:349–53. PubMedAbstract|GoogleScholar 53.ChouinardVA,ShinnAK,ValeriL,ChouinardPA,GardnerME,AsanAE,etal.Visualhallucinationsassociatedwithmultimodalhallucinations,suicideattemptsandmorbidityofillnessinpsychoticdisorders.SchizophrRes.(2019)208:196–201.doi:10.1016/j.schres.2019.02.022 PubMedAbstract|CrossRefFullText|GoogleScholar 54.GranoN,SalmijarviL,KarjalainenM,KallionpaaS,RoineM,TaylorP.Earlysignsofworry:Psychosisrisksymptomvisualdistortionsareindependentlyassociatedwithsuicidalideation.PsychiatryRes.(2015)225:263–7.doi:10.1016/j.psychres.2014.12.031 PubMedAbstract|CrossRefFullText|GoogleScholar 55.ClemmensenL,VernalDL,SteinhausenHC.Asystematicreviewofthelong-termoutcomeofearlyonsetschizophrenia.BMCPsychiatry.(2012)12:150.doi:10.1186/1471-244X-12-150 PubMedAbstract|CrossRefFullText|GoogleScholar 56.DriverDI,ThomasS,GogtayN,RapoportJL.Childhood-onsetschizophreniaandearly-onsetschizophreniaspectrumdisorders:anupdate.ChildAdolescPsychiatrClinNAm.(2020)29:71–90.doi:10.1016/j.chc.2019.08.017 PubMedAbstract|CrossRefFullText|GoogleScholar 57.RemschmidtH,MartinM,FleischhakerC,TheisenFM,HennighausenK,GutenbrunnerC,etal.Forty-two-yearslater:theoutcomeofchildhood-onsetschizophrenia.JNeuralTransm.(2007)114:505–12.doi:10.1007/s00702-006-0553-z PubMedAbstract|CrossRefFullText|GoogleScholar 58.DavidCN,GreensteinD,ClasenL,GochmanP,MillerR,TossellJW,etal.Childhoodonsetschizophrenia:highrateofvisualhallucinations.JAmAcadChildAdolescPsychiatry.(2011)50:681–6.e683.doi:10.1016/j.jaac.2011.03.020 PubMedAbstract|CrossRefFullText|GoogleScholar 59.McCabeMS,FowlerRC,CadoretRJ,WinokurG.Symptomdifferencesinschizophreniawithgoodandpoorprognosis.AmJPsychiatry.(1972)128:1239–43.doi:10.1176/ajp.128.10.1239 PubMedAbstract|CrossRefFullText|GoogleScholar 60.Lehembre-ShiahE,LeongW,BrucatoG,Abi-DarghamA,LiebermanJA,HorgaG,etal.Distinctrelationshipsbetweenvisualandauditoryperceptualabnormalitiesandconversiontopsychosisinaclinicalhigh-riskpopulation.JAMAPsychiatry.(2017)74:104–6.doi:10.1001/jamapsychiatry.2016.3055 PubMedAbstract|CrossRefFullText|GoogleScholar 61.LindleySE,CarlsonE,SheikhJ.Psychoticsymptomsinposttraumaticstressdisorder.CNSSpectr.(2000)5:52–7.doi:10.1017/S1092852900021659 CrossRefFullText|GoogleScholar 62.ConghaileA,DeLisiLE.Distinguishingschizophreniafromposttraumaticstressdisorderwithpsychosis.CurrOpinPsychiatry.(2015)28:249–55.doi:10.1097/YCO.0000000000000158 PubMedAbstract|CrossRefFullText|GoogleScholar 63.BurnsJK,JhazbhayK,EsterhuizenT,EmsleyR.Exposuretotraumaandtheclinicalpresentationoffirst-episodepsychosisinSouthAfrica.JPsychiatrRes.(2011)45:179–84.doi:10.1016/j.jpsychires.2010.05.014 PubMedAbstract|CrossRefFullText|GoogleScholar 64.SolesvikM,JoaI,LarsenTK,LangeveldJ,JohannessenJO,BjornestadJ,etal.Visualhallucinationsinfirst-episodepsychosis:associationwithchildhoodtrauma.PLoSONE.(2016)11:e0153458.doi:10.1371/journal.pone.0153458 PubMedAbstract|CrossRefFullText|GoogleScholar 65.BaethgeC,BaldessariniRJ,FreudenthalK,StreeruwitzA,BauerM,BschorT.Hallucinationsinbipolardisorder:characteristicsandcomparisontounipolardepressionandschizophrenia.BipolarDisord.(2005)7:136–45.doi:10.1111/j.1399-5618.2004.00175.x PubMedAbstract|CrossRefFullText|GoogleScholar 66.WingJK.Internationalcomparisonsinthestudyofthefunctionalpsychoses.BrMedBull.(1971)27:77–81.doi:10.1093/oxfordjournals.bmb.a070819 PubMedAbstract|CrossRefFullText|GoogleScholar 67.MitelmanSA,BrickmanAM,ShihabuddinL,NewmarkRE,HazlettEA,HaznedarMM,etal.Acomprehensiveassessmentofgrayandwhitemattervolumesandtheirrelationshiptooutcomeandseverityinschizophrenia.Neuroimage.(2007)37:449–62.doi:10.1016/j.neuroimage.2007.04.070 PubMedAbstract|CrossRefFullText|GoogleScholar 68.MitelmanSA,BuchsbaumMS.Verypooroutcomeschizophrenia:clinicalandneuroimagingaspects.IntRevPsychiatry.(2007)19:345–57.doi:10.1080/09540260701486563 PubMedAbstract|CrossRefFullText|GoogleScholar 69.ffytcheDH.Visualhallucinatorysyndromes:past,present,andfuture.DialoguesClinNeurosci.(2007)9:173–89.doi:10.31887/DCNS.2007.9.2/dffytche PubMedAbstract|CrossRefFullText|GoogleScholar 70.CoganDG.Visualhallucinationsasreleasephenomena.AlbrechtVonGraefesArchKlinExpOphthalmol.(1973)188:139–50.doi:10.1007/BF00407835 CrossRefFullText|GoogleScholar 71.HobsonJA,LydicR,BaghdoyanHA.Evolvingconceptsofsleepcyclegeneration:Frombraincenterstoneuronalpopulations.BehavBrainSci.(1986)9:371–400.doi:10.1017/S0140525X00046215 CrossRefFullText|GoogleScholar 72.DiederichNJ,VaillantM,LeischenM,MancusoG,GolinvalS,NatiR,etal.SleepapneasyndromeinParkinson'sdisease.Acase-controlstudyin49patients.MovDisord.(2005)20:1413–8.doi:10.1002/mds.20624 PubMedAbstract|CrossRefFullText|GoogleScholar 73.Carreira-PerpinanMA,ListerRJ,GoodhillGJ.Acomputationalmodelforthedevelopmentofmultiplemapsinprimaryvisualcortex.CerebCortex.(2005)15:1222–33.doi:10.1093/cercor/bhi004 PubMedAbstract|CrossRefFullText|GoogleScholar 74.MerzenichMM,RecanzoneGH,JenkinsWM,GrajskiKA.Adaptivemechanismsincorticalnetworksunderlyingcorticalcontributionstolearningandnondeclarativememory.ColdSpringHarbSympQuantBiol.(1990)55:873–87.doi:10.1101/SQB.1990.055.01.082 PubMedAbstract|CrossRefFullText|GoogleScholar 75.PettetMW,GilbertCD.Dynamicchangesinreceptive-fieldsizeincatprimaryvisualcortex.ProcNatlAcadSciUSA.(1992)89:8366–70.doi:10.1073/pnas.89.17.8366 PubMedAbstract|CrossRefFullText|GoogleScholar 76.ffytcheDH.Thehodologyofhallucinations.Cortex.(2008)44:1067–83.doi:10.1016/j.cortex.2008.04.005 CrossRefFullText|GoogleScholar 77.ffytcheDH,HowardRJ,BrammerMJ,DavidA,WoodruffP,WilliamsS.Theanatomyofconsciousvision:anfMRIstudyofvisualhallucinations.NatNeurosci.(1998)1:738–42.doi:10.1038/3738 PubMedAbstract|CrossRefFullText|GoogleScholar 78.BurkeW.TheneuralbasisofCharlesBonnethallucinations:ahypothesis.JNeurolNeurosurgPsychiatry.(2002)73:535–41.doi:10.1136/jnnp.73.5.535 PubMedAbstract|CrossRefFullText|GoogleScholar 79.KazuiH,IshiiR,YoshidaT,IkezawaK,TakayaM,TokunagaH,etal.Neuroimagingstudiesinpatientswithcharlesbonnetsyndrome.Psychogeriatrics.(2009)9:77–84.doi:10.1111/j.1479-8301.2009.00288.x PubMedAbstract|CrossRefFullText|GoogleScholar 80.SilversteinSM,DemminDL,SchallekJB,FradkinSI.Measuresofretinalstructureandfunctionasbiomarkersinneurologyandpsychiatry.BiomarkNeuropsychiatry.(2020)2:100018.doi:10.1016/j.bionps.2020.100018 CrossRefFullText|GoogleScholar 81.MoonJY,KimHJ,ParkYH,ParkTK,ParkEC,KimCY,etal.AssociationbetweenOpen-AngleGlaucomaandtheRisksofAlzheimer'sandParkinson'sdiseasesinSouthKorea:A10-yearNationwideCohortStudy.SciRep.(2018)8:11161.doi:10.1038/s41598-018-29557-6 PubMedAbstract|CrossRefFullText|GoogleScholar 82.UmunakweO,GuptaD,TsengH.AssociationofOpen-AngleGlaucomawithNon-Alzheimer'sDementiaandCognitiveImpairment.OphthalmolGlaucoma.(2020)3:460–5.doi:10.1016/j.ogla.2020.06.008 PubMedAbstract|CrossRefFullText|GoogleScholar 83.SilversteinSM,PaternoD,CherneskiL,GreenS.Opticalcoherencetomographyindicesofstructuralretinalpathologyinschizophrenia.PsycholMed.(2018)48:2023–33.doi:10.1017/S0033291717003555 PubMedAbstract|CrossRefFullText|GoogleScholar 84.AlmonteMT,CapellanP,YapTE,CordeiroMF.Retinalcorrelatesofpsychiatricdisorders.TherAdvChronicDis.(2020)11:2040622320905215.doi:10.1177/2040622320905215 CrossRefFullText|GoogleScholar 85.LiuCH,KangEYC,LinYH,WuWC,LiuZH,KuoCF,etal.Associationofoculardiseaseswithschizophrenia,bipolardisorder,andmajordepressivedisorder:aretrospectivecase-control,population-basedstudy.BMCPsychiatry.(2020)20:486.doi:10.1186/s12888-020-02881-w PubMedAbstract|CrossRefFullText|GoogleScholar 86.SilversteinSM,DemminD,BednarJA.Computationalmodelingofcontrastsensitivityandorientationtuninginfirst-episodeandchronicschizophrenia.ComputationalPsychiatry.(2017)1:102–31.doi:10.1162/CPSY_a_00005 PubMedAbstract|CrossRefFullText|GoogleScholar 87.ffytcheDH.VisualhallucinationsandtheCharlesBonnetsyndrome.CurrPsychiatryRep.(2005)7:168–79.doi:10.1007/s11920-005-0050-3 CrossRefFullText|GoogleScholar 88.TerryAV.Roleofthecentralcholinergicsysteminthetherapeuticsofschizophrenia.CurrNeuropharmacol.(2008)6:286–92.doi:10.2174/157015908785777247 PubMedAbstract|CrossRefFullText|GoogleScholar 89.EverittBJ,RobbinsTW.Centralcholinergicsystemsandcognition.AnnuRevPsychol.(1997)48:649–84.doi:10.1146/annurev.psych.48.1.649 CrossRefFullText|GoogleScholar 90.PerryEK,PerryRH.Acetylcholineandhallucinations:disease-relatedcomparedtodrug-inducedalterationsinhumanconsciousness.BrainCogn.(1995)28:240–58.doi:10.1006/brcg.1995.1255 PubMedAbstract|CrossRefFullText|GoogleScholar 91.AveryMC,DuttN,KrichmarJL.Mechanismsunderlyingthebasalforebrainenhancementoftop-downandbottom-upattention.EurJNeurosci.(2014)39:852–65.doi:10.1111/ejn.12433 PubMedAbstract|CrossRefFullText|GoogleScholar 92.CorlettPR,PowersAR.Conditionedhallucinations:historicinsightsandfuturedirections.WorldPsychiatry.(2018)17:361–2.doi:10.1002/wps.20557 PubMedAbstract|CrossRefFullText|GoogleScholar 93.DasS,ChatterjeeSS,MalatheshBC.Anticholinergicmedicationsevenintherapeuticrangecancauserecurrenceofpsychosis.GeneralPsychiatry.(2020)33:e100235.doi:10.1136/gpsych-2020-100235 PubMedAbstract|CrossRefFullText|GoogleScholar 94.AbadNH,DoulatabadNS,MohammadiA,SraziHR.Treatmentofvisualhallucinationsinschizophreniabyacetylcholinesteraseinhibitors:acasereport.IranJPsychiatry.(2011)6:161–3. PubMedAbstract|GoogleScholar 95.PatelSS,AttardA,JacobsenP,ShergillS.AcetylcholinesteraseInhibitors(AChEI's)forthetreatmentofvisualhallucinationsinschizophrenia:acasereport.BMCPsychiatry.(2010)10:68.doi:10.1186/1471-244X-10-68 PubMedAbstract|CrossRefFullText|GoogleScholar 96.Carhart-HarrisRL,LeechR,HellyerPJ,ShanahanM,FeildingA,TagliazucchiE,etal.Theentropicbrain:atheoryofconsciousstatesinformedbyneuroimagingresearchwithpsychedelicdrugs.FrontHumNeurosci.(2014)8:20.doi:10.3389/fnhum.2014.00020 PubMedAbstract|CrossRefFullText|GoogleScholar 97.Carhart-HarrisRL,MuthukumaraswamyS,RosemanL,KaelenM,DroogW,MurphyK,etal.NeuralcorrelatesoftheLSDexperiencerevealedbymultimodalneuroimaging.ProcNatlAcadSciUSA.(2016)113:4853–8.doi:10.1073/pnas.1518377113 PubMedAbstract|CrossRefFullText|GoogleScholar 98.ClarkA.Whatevernext?Predictivebrains,situatedagents,andthefutureofcognitivescience.BehavBrainSci.(2013)36:181–204.doi:10.1017/S0140525X12000477 PubMedAbstract|CrossRefFullText|GoogleScholar 99.MuthukumaraswamySD,Carhart-HarrisRL,MoranRJ,BrookesMJ,WilliamsTM,ErrtizoeD,etal.Broadbandcorticaldesynchronizationunderliesthehumanpsychedelicstate.JNeurosci.(2013)33:15171–83.doi:10.1523/JNEUROSCI.2063-13.2013 PubMedAbstract|CrossRefFullText|GoogleScholar 100.RussoM,CarrariniC,DonoF,RispoliMG,DiPietroM,DiStefanoV,etal.Thepharmacologyofvisualhallucinationsinsynucleinopathies.FrontPharmacol.(2019)10:1379.doi:10.3389/fphar.2019.01379 PubMedAbstract|CrossRefFullText|GoogleScholar 101.ShineJM,HallidayGM,NaismithSL,LewisSJ.VisualmisperceptionsandhallucinationsinParkinson'sdisease:dysfunctionofattentionalcontrolnetworks?MovDisord.(2011)26:2154–9.doi:10.1002/mds.23896 PubMedAbstract|CrossRefFullText|GoogleScholar 102.ShineJM,KeoghR,O'CallaghanC,MullerAJ,LewisSJG,PearsonJ.Imaginethat:elevatedsensorystrengthofmentalimageryinindividualswithParkinson'sdiseaseandvisualhallucinations.ProcBiolSci.(2015)282:20142047.doi:10.1098/rspb.2014.2047 PubMedAbstract|CrossRefFullText|GoogleScholar 103.HaleemDJ.Serotonergicmodulationofdopamineneurotransmission:amechanismforenhancingtherapeuticsinschizophrenia.JCollPhysiciansSurgPak.(2006)16:556–62. PubMedAbstract|GoogleScholar 104.LesterDB,RogersTD,BlahaCD.Acetylcholine-dopamineinteractionsinthepathophysiologyandtreatmentofCNSdisorders.CNSNeurosciTher.(2010)16:137–62.doi:10.1111/j.1755-5949.2010.00142.x PubMedAbstract|CrossRefFullText|GoogleScholar 105.Abi-DarghamA.Alterationsofserotonintransmissioninschizophrenia.IntRevNeurobiol.(2007)78:133–64.doi:10.1016/S0074-7742(06)78005-9 CrossRefFullText|GoogleScholar 106.AghajanianGK,MarekGJ.Serotoninmodelofschizophrenia:emergingroleofglutamatemechanisms.BrainResBrainResRev.(2000)31:302–12.doi:10.1016/S0165-0173(99)00046-6 PubMedAbstract|CrossRefFullText|GoogleScholar 107.KusumiI,BokuS,TakahashiY.Psychopharmacologyofatypicalantipsychoticdrugs:Fromthereceptorbindingprofiletoneuroprotectionandneurogenesis.PsychiatryClinNeurosci.(2015)69:243–58.doi:10.1111/pcn.12242 PubMedAbstract|CrossRefFullText|GoogleScholar 108.MeltzerHY,HuangM.Invivoactionsofatypicalantipsychoticdrugonserotonergicanddopaminergicsystems.ProgBrainRes.(2008)172:177–97.doi:10.1016/S0079-6123(08)00909-6 PubMedAbstract|CrossRefFullText|GoogleScholar 109.RemingtonG.Alterationsofdopamineandserotonintransmissioninschizophrenia.ProgBrainRes.(2008)172:117–40.doi:10.1016/S0079-6123(08)00906-0 PubMedAbstract|CrossRefFullText|GoogleScholar 110.StepnickiP,KondejM,KaczorAA.Currentconceptsandtreatmentsofschizophrenia.Molecules.(2018)23:2087.doi:10.3390/molecules23082087 CrossRefFullText|GoogleScholar 111.JonesMT,StrassnigMT,HarveyPD.Emerging5-HTreceptorantagonistsforthetreatmentofSchizophrenia.ExpertOpinEmergDrugs.(2020)25:189–200.doi:10.1080/14728214.2020.1773792 PubMedAbstract|CrossRefFullText|GoogleScholar 112.LeptourgosP,Fortier-DavyM,Carhart-HarrisR,CorlettPR,DupuisD,HalberstadtAL,etal.Hallucinationsunderpsychedelicsandintheschizophreniaspectrum:aninterdisciplinaryandmultiscalecomparison.SchizophrBull.(2020)46:1396–408.doi:10.1093/schbul/sbaa117 PubMedAbstract|CrossRefFullText|GoogleScholar 113.OertelV,Rotarska-JagielaA,vandeVenVG,HaenschelC,MaurerK,LindenDE.Visualhallucinationsinschizophreniainvestigatedwithfunctionalmagneticresonanceimaging.PsychiatryRes.(2007)156:269–73.doi:10.1016/j.pscychresns.2007.09.004 PubMedAbstract|CrossRefFullText|GoogleScholar 114.FordJM,PalzesVA,RoachBJ,PotkinSG,vanErpTG,TurnerJA,etal.Visualhallucinationsareassociatedwithhyperconnectivitybetweentheamygdalaandvisualcortexinpeoplewithadiagnosisofschizophrenia.SchizophrBull.(2015)41:223–32.doi:10.1093/schbul/sbu031 PubMedAbstract|CrossRefFullText|GoogleScholar 115.RollandB,AmadA,PouletE,BordetR,VignaudA,BationR,etal.Resting-statefunctionalconnectivityofthenucleusaccumbensinauditoryandvisualhallucinationsinschizophrenia.SchizophrBull.(2015)41:291–9.doi:10.1093/schbul/sbu097 PubMedAbstract|CrossRefFullText|GoogleScholar 116.AmadA,CachiaA,GorwoodP,PinsD,DelmaireC,RollandB,etal.Themultimodalconnectivityofthehippocampalcomplexinauditoryandvisualhallucinations.MolPsychiatry.(2014)19:184–91.doi:10.1038/mp.2012.181 PubMedAbstract|CrossRefFullText|GoogleScholar 117.HareSM,LawAS,FordJM,MathalonDH,AhmadiA,DamarajuE,etal.Disruptednetworkcrosstalk,hippocampaldysfunctionandhallucinationsinschizophrenia.SchizophrRes.(2018)199:226–34.doi:10.1016/j.schres.2018.03.004 PubMedAbstract|CrossRefFullText|GoogleScholar 118.BehrendtRP.Hallucinatoryexperienceasaberranteventmemoryformation:Implicationsforthepathophysiologyofschizophrenia.ProgNeuropsychopharmacolBiolPsychiatry.(2016)71:203–9.doi:10.1016/j.pnpbp.2016.07.009 PubMedAbstract|CrossRefFullText|GoogleScholar 119.CachiaA,CuryC,BrunelinJ,PlazeM,DelmaireC,OppenheimC,etal.Deviationsinearlyhippocampusdevelopmentcontributetovisualhallucinationsinschizophrenia.TranslPsychiatry.(2020)10:102.doi:10.1038/s41398-020-0779-9 PubMedAbstract|CrossRefFullText|GoogleScholar 120.JardriR,ThomasP,DelmaireC,DelionP,PinsD.Theneurodynamicorganizationofmodality-dependenthallucinations.CerebCortex.(2013)23:1108–17.doi:10.1093/cercor/bhs082 PubMedAbstract|CrossRefFullText|GoogleScholar 121.KimNY,HsuJ,TalmasovD,JoutsaJ,SoussandL,WuO,etal.Lesionscausinghallucinationslocalizetoonecommonbrainnetwork.MolPsychiatry.(2021)26:1299–309.doi:10.1038/s41380-019-0565-3 PubMedAbstract|CrossRefFullText|GoogleScholar 122.WeberS,JohnsenE,KrokenRA,LobergEM,KandilarovaS,StoyanovD,etal.Dynamicfunctionalconnectivitypatternsinschizophreniaandtherelationshipwithhallucinations.FrontPsychiatry.(2020)11:227.doi:10.3389/fpsyt.2020.00227 PubMedAbstract|CrossRefFullText|GoogleScholar 123.AnticevicA,GancsosM,MurrayJD,RepovsG,DriesenNR,EnnisDJ,etal.NMDAreceptorfunctioninlarge-scaleanticorrelatedneuralsystemswithimplicationsforcognitionandschizophrenia.ProcNatlAcadSciUSA.(2012)109:16720–5.doi:10.1073/pnas.1208494109 PubMedAbstract|CrossRefFullText|GoogleScholar 124.PowersAR,GancsosMG,FinnES,MorganPT,CorlettPR.Ketamine-inducedhallucinations.Psychopathology.(2015)48:376–85.doi:10.1159/000438675 CrossRefFullText|GoogleScholar 125.AruJ,SuzukiM,LarkumME.Cellularmechanismsofconsciousprocessing.TrendsCognSci.(2020)24:814–25.doi:10.1016/j.tics.2020.07.006 CrossRefFullText|GoogleScholar 126.AruJ,SiclariF,PhillipsWA,StormJF.Apicaldrive-Acellularmechanismofdreaming?NeurosciBiobehavRev.(2020)119:440–55.doi:10.31234/osf.io/vwure PubMedAbstract|CrossRefFullText|GoogleScholar 127.LarkumM,WilliamP.Doesarousalenhanceapicalamplificationanddisamplification?BehavBrainSci.(2016)39:e215.doi:10.1017/S0140525X15001867 PubMedAbstract|CrossRefFullText|GoogleScholar 128.LarkumME,NevianT,SandlerM,PolskyA,SchillerJ.Synapticintegrationintuftdendritesoflayer5pyramidalneurons:anewunifyingprinciple.Science.(2009)325:756–60.doi:10.1126/science.1171958 PubMedAbstract|CrossRefFullText|GoogleScholar 129.PhillipsWA.Cognitivefunctionsofintracellularmechanismsforcontextualamplification.BrainCogn.(2017)112:39–53.doi:10.1016/j.bandc.2015.09.005 PubMedAbstract|CrossRefFullText|GoogleScholar 130.WilliamP,BachmannT,StormJ.Apicalfunctioninneocorticalpyramidalcells:acommonpathwaybywhichgeneralanestheticscanaffectmentalstate.FrontNeuralCircuits.(2018)12:50.doi:10.3389/fncir.2018.00050 PubMedAbstract|CrossRefFullText|GoogleScholar 131.AlcaroA,CartaS.The“Instinct”ofimagination.Aneuro-ethologicalapproachtotheevolutionofthereflectivemindanditsapplicationtopsychotherapy.FrontHumNeurosci.(2018)12:522.doi:10.3389/fnhum.2018.00522 PubMedAbstract|CrossRefFullText|GoogleScholar 132.FrieskeDA,WilsonWP.Formalqualitiesofhallucinations:acomparativestudyofthevisualhallucinationsinpatientswithschizophrenic,organic,affectivepsychoses.ProcAnnuMeetAmPsychopatholAssoc.(1966)54:49–62. PubMedAbstract|GoogleScholar 133.LoweGR.Thephenomenologyofhallucinationsasanaidtodifferentialdiagnosis.BrJPsychiatry.(1973)123:621–33.doi:10.1192/bjp.123.6.621 PubMedAbstract|CrossRefFullText|GoogleScholar 134.AynsworthC,NematN,CollertonD,SmailesD,DudleyR.Realitymonitoringperformanceandtheroleofvisualimageryinvisualhallucinations.BehavResTher.(2017)97:115–22.doi:10.1016/j.brat.2017.07.012 PubMedAbstract|CrossRefFullText|GoogleScholar 135.BrebionG,OhlsenRI,PilowskyLS,DavidAS.Visualhallucinationsinschizophrenia:confusionbetweenimaginationandperception.Neuropsychology.(2008)22:383–9.doi:10.1037/0894-4105.22.3.383 PubMedAbstract|CrossRefFullText|GoogleScholar 136.Stephan-OttoC,SiddiS,SeniorC,Cuevas-EstebanJ,Cambra-MartiMR,OchoaS,etal.Rememberingverbally-presenteditemsaspictures:Brainactivityunderlyingvisualmentalimagesinschizophreniapatientswithvisualhallucinations.Cortex.(2017)94:113–22.doi:10.1016/j.cortex.2017.06.009 PubMedAbstract|CrossRefFullText|GoogleScholar 137.Gonzalez-AcostaCA,Rojas-CeronCA,BuriticaE.Functionalalterationsandcerebralvariationsinhumansexposedtoearlylifestress.FrontPublicHealth.(2020)8:536188.doi:10.3389/fpubh.2020.536188 PubMedAbstract|CrossRefFullText|GoogleScholar 138.KunimatsuA,YasakaK,AkaiH,KunimatsuN,AbeO.MRIfindingsinposttraumaticstressdisorder.JMagnResonImaging.(2020)52:380–96.doi:10.1002/jmri.26929 PubMedAbstract|CrossRefFullText|GoogleScholar 139.GuillinO,Abi-DarghamA,LaruelleM.Neurobiologyofdopamineinschizophrenia.IntRevNeurobiol.(2007)78:1–39.doi:10.1016/S0074-7742(06)78001-1 CrossRefFullText|GoogleScholar 140.TodaM,Abi-DarghamA.Dopaminehypothesisofschizophrenia:makingsenseofitall.CurrPsychiatryRep.(2007)9:329–36.doi:10.1007/s11920-007-0041-7 PubMedAbstract|CrossRefFullText|GoogleScholar 141.CassidyCM,BalsamPD,WeinsteinJJ,RosengardRJ,SlifsteinM,DawND,etal.Aperceptualinferencemechanismforhallucinationslinkedtostriataldopamine.CurrBiol.(2018)28:503–14.e504.doi:10.1016/j.cub.2017.12.059 PubMedAbstract|CrossRefFullText|GoogleScholar 142.RollandB,JardriR,AmadA,ThomasP,CottencinO,BordetR.Pharmacologyofhallucinations:severalmechanismsforonesinglesymptom?BiomedResInt.(2014)2014:307106.doi:10.1155/2014/307106 PubMedAbstract|CrossRefFullText|GoogleScholar 143.SterzerP,AdamsRA,FletcherP,FrithC,LawrieSM,MuckliL,etal.Thepredictivecodingaccountofpsychosis.BiolPsychiatry.(2018)84:634–43.doi:10.1016/j.biopsych.2018.05.015 CrossRefFullText|GoogleScholar 144.WagnerSK,FuDJ,FaesL,LiuX,HuemerJ,KhalidH,etal.Insightsintosystemicdiseasethroughretinalimaging-basedoculomics.TranslVisionSciTechnol.(2020)9:6–6.doi:10.1167/tvst.9.2.6 PubMedAbstract|CrossRefFullText|GoogleScholar 145.AscasoFJ,Rodriguez-JimenezR,CabezonL,Lopez-AntonR,SantabarbaraJ,DelaCamaraC,etal.Retinalnervefiberlayerandmacularthicknessinpatientswithschizophrenia:Influenceofrecentillnessepisodes.PsychiatryRes.(2015)229:230–6.doi:10.1016/j.psychres.2015.07.028 PubMedAbstract|CrossRefFullText|GoogleScholar 146.CabezonL,AscasoF,RamiroP,QuintanillaM,GutierrezL,LoboA,etal.Opticalcoherencetomography:awindowintothebrainofschizophrenicpatients.ActaOphthalmol.(2012)90:s249.doi:10.1111/j.1755-3768.2012.T123.x CrossRefFullText|GoogleScholar 147.JeroticS,RisticI,PejovicS,MihaljevicM,PavlovicZ,BritvicD,etal.Retinalstructuralabnormalitiesinyoungadultswithpsychosisspectrumdisorders.ProgNeuropsychopharmacolBiolPsychiatry.(2020)98:109825.doi:10.1016/j.pnpbp.2019.109825 PubMedAbstract|CrossRefFullText|GoogleScholar 148.LeeWW,TajunisahI,SharmillaK,PeymanM,SubrayanV.Retinalnervefiberlayerstructureabnormalitiesinschizophreniaanditsrelationshiptodiseasestate:evidencefromopticalcoherencetomography.InvestOphthalmolVisSci.(2013)54:7785–92.doi:10.1167/iovs.13-12534 PubMedAbstract|CrossRefFullText|GoogleScholar 149.SamaniNN,ProudlockFA,SiramV,SuraweeraC,HutchinsonC,NelsonCP,etal.Retinallayerabnormalitiesasbiomarkersofschizophrenia.SchizophrBull.(2017)44:876–85.doi:10.1093/schbul/sbx130 PubMedAbstract|CrossRefFullText|GoogleScholar 150.Schönfeldt-LecuonaC,KregelT,SchmidtA,KassubekJ,DreyhauptJ,FreudenmannRW,etal.Retinalsingle-layeranalysiswithopticalcoherencetomography(OCT)inschizophreniaspectrumdisorder.SchizophrRes.(2020)219:5–12.doi:10.1016/j.schres.2019.03.022 PubMedAbstract|CrossRefFullText|GoogleScholar 151.Topcu-YilmazP,AydinM,CetinIlhanB.Evaluationofretinalnervefiberlayer,macular,andchoroidalthicknessinschizophrenia:spectralopticcoherencetomographyfindings.PsychiatryClinPsychopharmacol.(2019)29:28–33.doi:10.1080/24750573.2018.1426693 CrossRefFullText|GoogleScholar 152.SinghA,SorensenTL.TheprevalenceandclinicalcharacteristicsofCharlesBonnetSyndromeinDanishpatientswithneovascularage-relatedmaculardegeneration.ActaOphthalmol.(2012)90:476–80.doi:10.1111/j.1755-3768.2010.02051.x PubMedAbstract|CrossRefFullText|GoogleScholar 153.LeeJY,KimJM,AhnJ,KimHJ,JeonBS,KimTW.RetinalnervefiberlayerthicknessandvisualhallucinationsinParkinson'sDisease.MovDisord.(2014)29:61–7.doi:10.1002/mds.25543 PubMedAbstract|CrossRefFullText|GoogleScholar 154.KopalA,MejzlíkováE,PreiningerováJL,BreberaD,UlmanováO,EhlerE,etal.ChangesofretinaarenotinvolvedinthegenesisofvisualhallucinationsinParkinson'sdisease.ParkinsonDis.(2015)2015:709191.doi:10.1155/2015/709191 PubMedAbstract|CrossRefFullText|GoogleScholar 155.ZhuoC,XiaoB,ChenC,JiangD,LiG,MaX,etal.AbberantinvertedU-shapedbrainpatternandtrait-relatedretinalimpairmentinschizophreniapatientswithcombinedauditoryandvisualhallucinations:apilotstudy.BrainImagingBehav.(2020)15:738–47.doi:10.1007/s11682-020-00281-y PubMedAbstract|CrossRefFullText|GoogleScholar 156.ZhuoC,XiaoB,JiF,LinX,JiangD,TianH,etal.Patientswithfirst-episodeuntreatedschizophreniawhoexperienceconcomitantvisualdisturbancesandauditoryhallucinationsexhibitco-impairmentofthebrainandretinas-apilotstudy.BrainImagingBehav.(2020).doi:10.1007/s11682-020-00351-1 PubMedAbstract|CrossRefFullText|GoogleScholar 157.BernardinF,SchwitzerT,Angioi-DuprezK,GierschA,JansenC,SchwanR,etal.Retinalganglioncellsdysfunctionsinschizophreniapatientswithorwithoutvisualhallucinations.SchizophrRes.(2020)219:47–55.doi:10.1016/j.schres.2019.07.007 PubMedAbstract|CrossRefFullText|GoogleScholar 158.daSilvaMorganK,ElderGJ,ffytcheDH,CollertonD,TaylorJP.Theutilityandapplicationofelectrophysiologicalmethodsinthestudyofvisualhallucinations.ClinNeurophysiol.(2018)129:2361–71.doi:10.1016/j.clinph.2018.08.019 PubMedAbstract|CrossRefFullText|GoogleScholar 159.SilversteinSM,WibralM,PhillipsWA.Implicationsofinformationtheoryforcomputationalmodelingofschizophrenia.ComputPsychiatr.(2017)1:82–101.doi:10.1162/CPSY_a_00004 PubMedAbstract|CrossRefFullText|GoogleScholar 160.CollertonD,PerryE,McKeithI.Whypeopleseethingsthatarenotthere:anovelperceptionandattentiondeficitmodelforrecurrentcomplexvisualhallucinations.BehavBrainSci.(2005)28:737–57.doi:10.1017/S0140525X05000130 PubMedAbstract|CrossRefFullText|GoogleScholar 161.AnticevicA,ColeMW,MurrayJD,CorlettPR,WangXJ,KrystalJH.Theroleofdefaultnetworkdeactivationincognitionanddisease.TrendsCognSci.(2012)16:584–92.doi:10.1016/j.tics.2012.10.008 PubMedAbstract|CrossRefFullText|GoogleScholar 162.Whitfield-GabrieliS,ThermenosHW,MilanovicS,TsuangMT,FaraoneSV,McCarleyRW,etal.Hyperactivityandhyperconnectivityofthedefaultnetworkinschizophreniaandinfirst-degreerelativesofpersonswithschizophrenia.ProcNatlAcadSciUSA.(2009)106:1279–84.doi:10.1073/pnas.0809141106 PubMedAbstract|CrossRefFullText|GoogleScholar 163.DiPlinioS,PerrucciMG,AlemanA,EbischSJH.Iamme:brainsystemsintegrateandsegregatetoestablishamultidimensionalsenseofself.Neuroimage.(2020)205:116284.doi:10.1016/j.neuroimage.2019.116284 PubMedAbstract|CrossRefFullText|GoogleScholar 164.PaulER,FarmerM,KämpeR,CremersHR,HamiltonJP.Functionalconnectivitybetweenextrastriatebodyareaanddefaultmodenetworkpredictsdepersonalizationsymptomsinmajordepression:findingsfromanapriorispecifiedmultinetworkcomparison.BiolPsychiatry.(2019)4:627–35.doi:10.1016/j.biopsych.2019.03.389 PubMedAbstract|CrossRefFullText|GoogleScholar 165.WebbCA,IsraelES,BelleauE,ApplemanL,ForbesEE,PizzagalliDA.Mind-wanderinginadolescentspredictsworseaffectandislinkedtoaberrantdefaultmodenetwork-saliencenetworkconnectivity.JAmAcadChildAdolescPsychiatry.(2021)60:377–87.doi:10.1016/j.jaac.2020.03.010 PubMedAbstract|CrossRefFullText|GoogleScholar 166.AlcaroA,CartaS,PankseppJ.Theaffectivecoreoftheself:aneuro-archetypicalperspectiveonthefoundationsofhuman(andanimal)subjectivity.FrontPsychol.(2017)8:1424.doi:10.3389/fpsyg.2017.01424 PubMedAbstract|CrossRefFullText|GoogleScholar 167.GoodwynED.TheNeurobiologyoftheGods:HowBrainPhysiologyShapestheRecurrentImageryofMythandDreams.London:Routledge(2012).doi:10.4324/9780203141526 CrossRefFullText|GoogleScholar 168.PankseppJ.AffectiveneuroscienceoftheemotionalBrainMind:evolutionaryperspectivesandimplicationsforunderstandingdepression.DialoguesClinNeurosci.(2010)12:533–45.doi:10.31887/DCNS.2010.12.4/jpanksepp PubMedAbstract|CrossRefFullText|GoogleScholar 169.CopolovDL,SealML,MaruffP,UlusoyR,WongMT,Tochon-DanguyHJ,etal.Corticalactivationassociatedwiththeexperienceofauditoryhallucinationsandperceptionofhumanspeechinschizophrenia:aPETcorrelationstudy.PsychiatryRes.(2003)122:139–52.doi:10.1016/S0925-4927(02)00121-X PubMedAbstract|CrossRefFullText|GoogleScholar 170.ButlerPD,ZemonV,SchechterI,SapersteinAM,HoptmanMJ,LimKO,etal.Early-stagevisualprocessingandcorticalamplificationdeficitsinschizophrenia.ArchGenPsychiatry.(2005)62:495.doi:10.1001/archpsyc.62.5.495 PubMedAbstract|CrossRefFullText|GoogleScholar 171.ReavisEA,LeeJ,WynnJK,NarrKL,NjauSN,EngelSA,etal.Linkingopticradiationvolumetovisualperceptioninschizophreniaandbipolardisorder.SchizophrRes.(2017)190:102–6.doi:10.1016/j.schres.2017.03.027 PubMedAbstract|CrossRefFullText|GoogleScholar 172.LinskerR.Self-organizationinaperceptualnetwork.IEEEComputer.(1988)124:105–17.doi:10.1109/2.36 CrossRefFullText|GoogleScholar 173.RokemA,YoonJH,OomsRE,MaddockRJ,MinzenbergMJ,SilverMA.Broadervisualorientationtuninginpatientswithschizophrenia.FrontHumNeurosci.(2011)5:127.doi:10.3389/fnhum.2011.00127 PubMedAbstract|CrossRefFullText|GoogleScholar 174.SchallmoMP,SponheimSR,OlmanCA.Abnormalcontextualmodulationofvisualcontourdetectioninpatientswithschizophrenia.PLoSONE.(2013)8:e68090.doi:10.1371/annotation/f082ec4d-419c-43ce-ae50-e05107539bf3 PubMedAbstract|CrossRefFullText|GoogleScholar 175.YoonJH,RokemAS,SilverMA,MinzenbergMJ,UrsuS,RaglandJD,etal.Diminishedorientation-specificsurroundsuppressionofvisualprocessinginschizophrenia.SchizophrBull.(2009)35:1078–84.doi:10.1093/schbul/sbp064 PubMedAbstract|CrossRefFullText|GoogleScholar 176.HaciogluYildirimM,YildirimEA,KaserM,GudukM,FistikciN,CinarO,etal.Therelationshipbetweenadulthoodtraumaticexperiencesandpsychoticsymptomsinfemalepatientswithschizophrenia.ComprPsychiatry.(2014)55:1847–54.doi:10.1016/j.comppsych.2014.08.049 PubMedAbstract|CrossRefFullText|GoogleScholar 177.LeceiA,DecosterJ,DeHertM,DeromC,JacobsN,Menne-LothmannC,etal.Evidencethattheassociationofchildhoodtraumawithpsychosisandrelatedpsychopathologyisnotexplainedbygene-environmentcorrelation:Amonozygotictwindifferencesapproach.SchizophrRes.(2019)205:58–62.doi:10.1016/j.schres.2018.05.025 PubMedAbstract|CrossRefFullText|GoogleScholar 178.LaiA,CrostaC,LoftinM,SilversteinSM.Retinalstructuralalterationsinchronicversusfirstepisodeschizophreniaspectrumdisorders.BiomarkNeuropsychiatry.(2020)2:100013.doi:10.1016/j.bionps.2020.100013 CrossRefFullText|GoogleScholar 179.ChuEMY,KolappanM,BarnesTRE,JoyceEM,RonMA.Awindowintothebrain:Aninvivostudyoftheretinainschizophreniausingopticalcoherencetomography.PsychiatryResNeuroimag.(2012)203:89–94.doi:10.1016/j.pscychresns.2011.08.011 PubMedAbstract|CrossRefFullText|GoogleScholar 180.BlomJD.Leroy'selusivelittlepeople:asystematicreviewonlilliputianhallucinations.NeurosciBiobehavRev.(2021)125:627–36.doi:10.1016/j.neubiorev.2021.03.002 PubMedAbstract|CrossRefFullText|GoogleScholar 181.HeinrichsRW.InSearchofMadness.NewYork,NY:OxfordUniversityPress(2001).doi:10.1093/acprof:oso/9780195122190.001.0001 CrossRefFullText|GoogleScholar 182.HeinrichsRW.Theprimacyofcognitioninschizophrenia.AmPsychol.(2005)60:229–42.doi:10.1037/0003-066X.60.3.229 CrossRefFullText|GoogleScholar 183.KayJ,PhillipsW,AruJ,GrahamB,LarkumME.ABayesiandecompositionofBACfiringasamechanismsforapicalamplificationinneocorticalpyramidalneurons.bioRxiv.(2019).doi:10.1101/604066 CrossRefFullText|GoogleScholar 184.GhanbariJolfaeiA,NajiB,NasrEsfehaniM.Repetitivetranscranialmagneticstimulationinresistantvisualhallucinationsinawomanwithschizophrenia:acasereport.IranJPsychiatryBehavSci.(2016)10:e3561.doi:10.17795/ijpbs-3561 PubMedAbstract|CrossRefFullText|GoogleScholar 185.JardriR,PinsD,BubrovszkyM,LucasB,LethucV,DelmaireC,etal.Neuralfunctionalorganizationofhallucinationsinschizophrenia:multisensorydissolutionofpathologicalemergenceinconsciousness.ConsciousCogn.(2009)18:449–57.doi:10.1016/j.concog.2008.12.009 PubMedAbstract|CrossRefFullText|GoogleScholar 186.CavanaghP.Thelanguageofvision.Perception.(2021)50:195–215.doi:10.1177/0301006621991491 CrossRefFullText|GoogleScholar 187.GlezerVD.VisionandMind:ModelingMentalFunctions.Mahwah,NJ:LawrenceErlbaumAssociates,Inc.(1989) GoogleScholar 188.LoganGD,ZbrodoffNJ.Selectionforcognition:cognitiveconstraintsonvisualspatialattention.VisualCogn.(1999)6:51–81.doi:10.1080/713756797 CrossRefFullText|GoogleScholar 189.FordJM,MathalonDH.Corollarydischargedysfunctioninschizophrenia:canitexplainauditoryhallucinations?IntJPsychophysiol.(2005)58:179–89.doi:10.1016/j.ijpsycho.2005.01.014 PubMedAbstract|CrossRefFullText|GoogleScholar 190.GreenMF,KinsbourneM.Auditoryhallucinationsinschizophrenia:doeshumminghelp?BiolPsychiatry.(1989)25:633–5.doi:10.1016/0006-3223(89)90225-4 PubMedAbstract|CrossRefFullText|GoogleScholar 191.GreenMF,KinsbourneM.Subvocalactivityandauditoryhallucinations:cluesforbehavioraltreatments?SchizophrBull.(1990)16:617–25.doi:10.1093/schbul/16.4.617 PubMedAbstract|CrossRefFullText|GoogleScholar 192.MathalonDH,FordJM.Corollarydischargedysfunctioninschizophrenia:evidenceforanelementaldeficit.ClinEEGNeurosci.(2008)39:82–6.doi:10.1177/155005940803900212 PubMedAbstract|CrossRefFullText|GoogleScholar 193.ZhangW,LiS,WangX,GongY,YaoL,XiaoY,etal.Abnormaldynamicfunctionalconnectivitybetweenspeechandauditoryareasinschizophreniapatientswithauditoryhallucinations.NeuroimageClin.(2018)19:918–24.doi:10.1016/j.nicl.2018.06.018 PubMedAbstract|CrossRefFullText|GoogleScholar 194.SilversteinSM.IntegratingJungianandself-psychologicalperspectiveswithincognitive-behaviortherapyforayoungmanwithafixedreligiousdelusion.ClinCaseStud.(2007)6:263–76.doi:10.1177/1534650106287224 CrossRefFullText|GoogleScholar Keywords:visualhallucinations,visualdistortions,psychosis,schizophrenia,retina,mechanisms,self Citation:SilversteinSMandLaiA(2021)ThePhenomenologyandNeurobiologyofVisualDistortionsandHallucinationsinSchizophrenia:AnUpdate.Front.Psychiatry12:684720.doi:10.3389/fpsyt.2021.684720 Received:23March2021;Accepted:14May2021;Published:11June2021. Editedby:CheriseRosen,UniversityofIllinoisatChicago,UnitedStates Reviewedby:DanielCollerton,NewcastleUniversity,UnitedKingdomLisaWagels,Helmholtz-VerbandDeutscherForschungszentren(HZ),Germany Copyright©2021SilversteinandLai.Thisisanopen-accessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(CCBY).Theuse,distributionorreproductioninotherforumsispermitted,providedtheoriginalauthor(s)andthecopyrightowner(s)arecreditedandthattheoriginalpublicationinthisjournaliscited,inaccordancewithacceptedacademicpractice.Nouse,distributionorreproductionispermittedwhichdoesnotcomplywiththeseterms. *Correspondence:StevenM.Silverstein,[email protected] COMMENTARY ORIGINALARTICLE Peoplealsolookedat SuggestaResearchTopic>