Thepsychoticsyndromeofschizophrenia,comprisinghallucinationsanddelusions,remainsoneofthemost devastatingandcostlymedicalconditionsintheUSandworldwide.Despiteprogressintheunderstandingofits neurobiology,aunifyingmechanismremainselusive.Elucidatingsuchmechanismwouldbeamajoradvancein medicine,asitwouldprovideascientificexplanationtosymptomsthathavelongbeenconsideredsynonymouswith irrationality.Thiswouldcontributetode-stigmatizationofmentalillness.Itwouldalsopotentiallyleadtoimportant publichealthbenefitsbyidentifyingnoveltargetsthatcouldenablenewtreatmentsforasubstantialproportionof patients(~1/3)whodonotrespondtoortoleratecurrenttreatments.Previousworkhasseparatelystudiedthe substratesofhallucinations(falseperceptswithoutcorrespondingstimuli)andofdelusions(falseideasthatare maintainedwithhighconvictiondespitecontradictoryevidence).However,recenttheoriesofthebrainsuggestthat perceptionandideationarepartofaunitaryprocess,wherebythebraingeneratesandupdatesinternalpredictive modelsoftheexternalworld,thatcanexplainbothouridiosyncraticperceptualexperiencesandhowwereachcertain conclusionsorideasbasedontheseexperiences.Extensionsofthese?Bayesian?theorieshavebeenproposedto explainpathologicalabnormalitiesinperception(e.g.,hallucinations)andideation(e.g.,delusions)inpsychosisas derivingfromacommondeficit.Wesuggestthatthiscommondeficitisadopamine-relateddeficitinupdatingof beliefs(definedviacomputationalmodeling)givenexcessiverelianceofpriorbeliefsrelativetonewsensoryevidence. Wepositthatthisdeficitcanoccurattwodifferentlevelsofahierarchy:alowerlevel(insensorycortex)abnormalities inwhichwouldcausehallucinations,andahigherlevel(higher-orderprefrontalandparietalcorticessupporting inference)abnormalitiesinwhichwouldcausedelusions.Weproposeaconvergingapproachtodirectlytestthisnovel modelitbyleveragingcutting-edgetoolsincomputationalneuroscienceappliedtofunctionalneuroimaging(fMRI)and behavioraltoolsdesignedtodissecthierarchicalbeliefupdating.Specifically,wehypothesizeabehavioralandneural doubledissociationwherebydeficitsintheformerwillbespecificallyassociatedwithseverityofhallucinationswhile deficitsinthelatterwillbespecificallyassociatedwithseverityofdelusionsinunmedicatedpatientswith schizophrenia.Byanchoringourmodelonthewell-establisheddopaminedysfunctioninpsychosis,wewillexplain howincreaseddopamineinthemidbrain(specifically,inthenigrostriatalpathway,heremeasuredviaanovel,high- resolutionimagingtechniqueknownasneuromelanin-sensitiveMRI)alterscommonneuralcomputationsleadingto psychoticsymptoms(i.e.,howitresultsindeficientbeliefupdatingatlowandhighlevels,leadingtohallucinationsand delusions,respectively).Finally,wewilldefineneuraltargetstosetupfutureworkdevelopingnovelneuromodulation approachesaimedatnormalizingbeliefupdatingdeficitsdownstreamfromdopamineabnormalities.Thus,wewill establishnoveldownstreammechanismsofpsychosisthatcanbefurtherdissectedinpreclinicalworkandcanbe directlytargetedinhumansdependingonindividuals?symptomprofiles.
Thepsychoticsyndromeofschizophrenia(includinghallucinationsand delusions)remainsamongthemostincapacitatingandburdensomeconditionsworldwide,particularlyforasubstantialproportionofpatients(~1/3)whose symptomsdonotimprovesufficientlywithcurrentlyavailabletreatments,andisperhapsthemostpuzzlingstateinclinicalneuroscience.Byleveragingnew computational,statistical,imaging,andbehavioraltools,thisprojectaimsto establishanovelmodelthatintegratscurrentclinicalandneurobiological knowledgeintoaholisticmodelofpsychosisexplainingitscommoncognitivemechanismaswellassymptom-specificpathways.Thiswilladvanceour understandingofpsychosisbydelineatingcoreneuralprocessesdownstream fromdopamineabnormalitiesthataredirectlylinkedtospecificsymptomsand thatcanbetargetedvianovelpatient-tailoredfeedback-basedtreatments.
