Disturbances of emotional experience, and in particular

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1 Article Prefrontl Corticl Deficits nd Impired Cognition-Emotion Interctions in Schizophreni Stefn Ursu, M.D., Ph.D. Ann M. Kring, Ph.D. Mrj Germns Grd, Ph.D. Michel J. Minzenberg, M.D. Jong H. Yoon, M.D. J. Dniel Rglnd, Ph.D. Mrjorie Solomon, Ph.D. Cmeron S. Crter, M.D. Objective: Despite schizophreni ptients reports of diminished experience of emotion in interviews nd self-report mesures, their emotionl experience in the presence of emotionl stimuli nd in dily life ( in the moment ) ppers lrgely intct. To exmine emotion-cognition interctions, the uthors tested the hypothesis tht schizophreni ptients hve unimpired in-the-moment emotionl rectivity but hve deficit in prefrontl corticl mechnisms needed to mintin nd report on experience following exposure to emotionl stimuli. Method: Using slow event-relted functionl MRI prdigm, the uthors exmined the brin ctivity of 3 schizophreni ptients nd helthy comprison subjects during trils in which they viewed n ffective picture nd, fter dely, reported their emotionl experience while viewing it. Results: The ptients self-reports of emotionl experience differed from those of the helthy subjects when they rted their experience on dimensions inconsistent with the stimulus vlence but not when the dimension ws consistent with it. In the presence of emotionl stimuli, brin ctivity in the ptients ws similr to tht of the comprison subjects. During the dely, however, ptients showed decresed ctivtion in network of brin structures, including the dorsolterl prefrontl cortex nd other prefrontl, limbic, nd prlimbic res. In ptients, the dely-relted response of the dorsolterl prefrontl cortex to plesnt stimuli correlted negtively with n nhedoni mesure. Conclusions: These results suggest tht schizophreni is chrcterized by filure of prefrontl circuitry supporting the link between emotion nd gol-directed behvior nd tht the filure of this mechnism my contribute to deficits in processes relted to emotion-cognition interction. (Am J Psychitry ; :7 ) Disturbnces of emotionl experience, nd in prticulr decrese in cpcity to experience plesure (nhedoni), hve long been regrded s chrcteristic fetures of pthology in schizophreni (), nd they hve been ssocited with functionl impirment (). However, recent reserch on emotionl disturbnces in schizophreni hs rised fundmentl questions bout the nture of these deficits. Schizophreni ptients report experiencing lower levels of plesure in their dily lives thn nonptients on mesures of trit socil nd physicl nhedoni (3). In contrst, the ptients immedite (or in the moment ) rtings of experienced emotion re intct, in both lbortory experiments nd rel life, nd reflect the sme two-dimensionl structure (vlence nd rousl) s tht of helthy subjects (). A possible mechnism underlying the ptients deficits in trit reports of emotionl experience cn be formulted when one considers model of cognitive control () in which the dorsolterl prefrontl cortex provides top-down guided ctivtion tht bises representtions towrd context-pproprite responding nd wy from utomtic but inpproprite ones. Together with dt from ffective science (), this model points towrd integrtion of emotion nd cognitive control when people mke decisions bsed on ffective sttes. Cognitive control processes supported by the dorsolterl prefrontl cortex hve indeed been found to modulte the prediction, genertion, interprettion, or regultion of emotions (7) nd to trnslte ffectively vlenced motivtionl sttes into gol-oriented behvior (). Thus, reporting on one s experienced emotion outside the presence of n eliciting stimulus, s is often the cse with clinicl interviews or nhedoni mesures, likely relies on cognitive control processes tht depend on the dorsolterl prefrontl cortex, such s estblishing nd mintining representtions tht link nd integrte ffective sttes with tsk-relevnt responses. Consequently, the ptients deficits s reflected in clinicl interviews or nhedoni mesures my stem in prt from n impired cpcity to build nd mintin such representtions, which re necessry for genertion nd mintennce of emotionl responses in the fce of competing ones. This possibility is consistent with previous behviorl findings (e.g., s in references 9 nd ) nd functionl mgnetic resonnce This rticle is fetured in this month s AJP Audio nd is discussed in n editoril by Dr. Gold (p. 37) 7 jp.psychitryonline.org Am J Psychitry :3, Mrch

2 URSU, KRING, GARD, ET AL. imging (fmri) results (such s in references 3) indicting tht schizophreni ptients exhibit impirments of dorsolterl prefrontl cortex functioning necessry for mintining tsk-relevnt informtion needed to override prepotent responses. It lso ccords with findings tht better working memory performnce in ptients is ssocited with smller discrepncy between in-the-moment nd delyed reports of experienced emotion (). fmri studies exmining brin ctivtion during presenttion of emotion-eliciting stimuli in schizophreni ( 7) hve generted vrible findings, including limbic nd prefrontl increses nd decreses in ctivity in ptients reltive to helthy subjects. To our knowledge, no fmri study hs specificlly exmined the neurl correltes of cognitive control processes relted to mintining nd reporting on emotionl experience in schizophreni. We used event-relted fmri to explore brin ctivity during trils in which subjects viewed ffective imges nd, fter dely, rted how positive, negtive, nd energizing the emotion ws while they were viewing the imge. Performing this tsk required controlled processes depending on the dorsolterl prefrontl cortex, such s ctive mintennce of ffective representtions nd effective mnipultion of vlenced spects of the emotionl experience in order to ccurtely rte it on dimensions both consistent nd inconsistent with its overll vlence. This design llowed us to test the hypothesis tht schizophreni ptients in-the-moment emotionl rectivity is spred but tht they hve deficit in cognitive control processes needed to mintin nd report on emotionl experience fter the eliciting stimulus is removed. In support of this hypothesis, we sought evidence of ) robust brin ctivtion during the presence of emotionl stimuli, in prticulr in limbic nd prlimbic structures, consistent with n intct bility to generte n emotionl response in the presence of n emotionl stimulus, nd ) ltered delyed rtings of experienced emotion nd delyed brin ctivtion, in prticulr in res criticl for ctive implementtion of cognitive control (e.g., dorsolterl prefrontl cortex). In contrst, the lterntive hypothesis (tht schizophreni ptients re chrcterized by fundmentl impirment in emotion genertion) would be supported by impired brin ctivtion even during the presence of the emotionl stimuli in structures involved in ffective representtions. Method Subjects The prticipnts were 3 ptients nd helthy comprison subjects. Exclusion criteri for ptients included ) ge bove yers or below yers, ) dignosis of substnce buse or dependence (except one involving nicotine or cffeine) in the months before testing, 3) score less thn 7 on the Wechsler Abbrevited Scle of Intelligence, ) color blindness, ) dignosis of neurologicl disorder, nd ) pregnncy. Ptient dignoses of schizophre- ni (N=) nd schizoffective disorder (N=) were confirmed by using the Structured Clinicl Interview for DSM-IV-R, dministered by trined reserch personnel. The Brief Psychitric Rting Scle (BPRS), the Scle for the Assessment of Positive Symptoms (SAPS), nd the Scle for the Assessment of Negtive Symptoms (SANS) were used to mesure symptom severity. Six ptients were not medicted with neuroleptics t the time of testing. The other 7 were being treted with typicl ntipsychotics (risperidone, N=3; olnzpine, N=; ripiprzole, N=; quetipine, N=; ziprsidone, N=; clozpine, N=; perphenzine, N=) nd typicl gent (hloperidol, N=), with one ptient receiving two neuroleptics. The groups did not differ in ge, hndedness, or prentl eduction (Tble ). After dt from three ptients nd four comprison subjects were excluded becuse of excessive movement during the scnning (five subjects) nd visible rtifcts in the functionl imges (two subjects), dt from ptients (five women, medicted) nd helthy subjects (seven women) were included in subsequent imging nlyses. These subgroups lso did not differ in ge, hndedness, or prentl eduction (Tble ). Helthy comprison subjects were recruited from the community. Additionl exclusion criteri used for comprison subjects included ) history of xis I disorder, ) first-degree reltive with psychotic disorder, nd 3) hving been treted with ny psychotropic mediction within the pst months. All procedures, including written informed consent, were prt of protocol pproved by the institutionl review bord of the University of Cliforni, Dvis. Emotionl Experience Tsk The subjects viewed 7 picture stimuli ( plesnt, unplesnt, neutrl) selected from the Interntionl Affective Picture System () (see supplementl text in online dt supplement). The stimuli were pseudorndomly presented by projector, in three runs of trils ech, nd viewed in mirror ttched to the hed coil. Ech -second tril (Figure ) included picture, dely, nd three rting questions. The questions (presented in counterblnced order reltive to picture vlence) sked subjects to rte the vlence of the emotion experienced ( positive nd negtive ) nd their rousl level (how energized they felt) during the presenttion of the previous picture, on -point scle. Subjects responses were recorded online by mens of five-button MRI-comptible response unit ttched to the dominnt hnd. The rre rtings with ltency below 3 msec were considered the result of guessing or lte responses to the preceding scle, nd therefore they were not included in the behviorl nlyses. Functionl Imging Functionl T * mgnetic resonnce volumes were cquired by using.-t GE Sign scnner (spirl in-out sequence, 3 oblique coronl -mm-thick slices, mtrix, -mm field of view, TR=. sec, TE=3 msec, flip ngle=7 ). After slice time correction nd motion correction, dt were excluded if the men totl movement exceeded voxel or if the men scn-toscn movement exceeded mm. For subjects included in the imging nlyses, the motion prmeters were not different cross groups, ccording to multivrite nlysis of vrince (MANOVA) (group-by-prmeter interction: p>.3). For these subjects, the dt were filtered for low-frequency drift nd differences in men signl cross runs, resliced to -mm 3 voxels, sptilly normlized (with the Montrel Neurologicl Institute reference brin, 9-prmeter nonliner wrping lgorithm [9]), nd sptilly smoothed (-mm full width t hlf mximum threedimensionl Gussin filter). Am J Psychitry :3, Mrch jp.psychitryonline.org 77

3 COGNITION-EMOTION INTERACTIONS IN SCHIZOPHRENIA TABLE. Demogrphic nd Clinicl Chrcteristics of Ptients With Schizophreni nd Helthy Comprison Subjects in Study of Cognition-Emotion Interctions Full Group Imging Anlysis Subgroup Chrcteristic Ptients With Schizophreni (N=3) Comprison Subjects (N=) Ptients With Schizophreni (N=) b Comprison Subjects (N=) N % N % N % N % Demogrphic Mle gender White rce 9 39 Right-hnded Men SD Men SD Men SD Men SD Age (yers) Eduction (yers) Prentl eduction (yers) Clinicl Brief Psychitric Rting Scle (BPRS) score Scle for the Assessment of Negtive Symptoms score Scle for the Assessment of Positive Symptoms score Two ptients were dignosed with schizoffective disorder. b One ptient ws dignosed with schizoffective disorder. Sttisticl Anlyses The sttisticl tests were conducted in SPM ( ion.ucl.c.uk/spm) by using multiple regression model tht included regressors. Three were for picture onset (one per vlence), three were for delyed ctivity ( seconds fter the end of picture presenttion, cpturing ctivity during the lst 3 seconds of the dely []), nd three were for the rting scles ( positive, negtive, nd energized ). The other one mrked excluded events, either rtings with rection times less thn 3 msec or entire trils in which the rection time ws less thn 3 msec for the scle mtching the stimulus vlence, i.e., the positive scle for plesnt pictures, the negtive scle for unplesnt pictures, nd the energized scle for neutrl pictures. For most subjects, fewer thn % of the trils were excluded (dt from four ptients nd one helthy subject lost % % nd % of the trils, respectively). This did not result in sttisticlly significnt combined effect of stimulus vlence cross groups in the proportion of excluded trils (one-wy between-group MANOVA with plesnt, unplesnt, nd neutrl trils s dependent vribles: F=., df=3, 3, p=., Wilks s lmbd=.). The prmeter estimtes obtined from fitting this omnibus model were used to compute within-subjects contrsts (e.g., dely ctivity fter plesnt picture versus bseline ctivity), which were used in group-level rndom-effects nlyses. Given previous reports of ltered brin ctivity in response to neutrl pictures in ptients (), we explored the brin responses to the three types of stimuli individully, rther thn s plesnt versus neutrl nd unplesnt versus neutrl subtrctions, which cn obscure complex interctions driven by group differences in the subtrcted condition (i.e., neutrl). Consequently, the lph levels used for group-level multiple comprisons were Bonferroni corrected to ccount for seprte exmintions of the three types of stimuli (tht is, group-level contrst ws considered corrected only if it reched corrected lph level of. or less, i.e., pproximtely./3). Since testing our specific hypothesis required investigting network of regions specified by previous results, we used the set level lph of <. within volume of serch (creted by using the Wke Forest PickAtls toolbox of SPM) tht included the dorsolterl prefrontl cortex, medil prefrontl cortex, orbitofrontl cortex/bsl gngli, thlmus, hippocmpl formtion, mygdl (, ), nd fusiform fce re (s positive control for stimulus-relted nonspecific ctivity). For the schizophreni ptients, we computed correltions between individul differences in brin ctivity (s indexed by ech subject s bet weight of given regressor, verged cross ll the voxels of region of interest) nd clinicl rting of nhedoni, computed s the verge of the nhedoni items from the SANS nhedoni/socility subscle (i.e., recretionl interests nd sexul interest/ctivity) (3). Results Delyed Experience Rtings Three seprte 3 nlyses of vrince (ANOVAs) were conducted for the positive, negtive, nd energized rtings, with group s between-subjects fctor (ptient, comprison subject) nd stimulus vlence s withinsubjects fctor (plesnt, unplesnt, neutrl) (Figure ). For ech rting type, the only significnt min effect ws tht of the stimulus vlence, indicting tht ll subjects experience ws most positive in response to plesnt stimuli, most negtive in response to unplesnt ones, nd more energizing in response to plesnt nd unplesnt pictures thn to neutrl pictures. The interctions between group nd stimulus vlence were significnt for the positive nd energized rtings but did not rech significnce for negtive rtings. These interctions ppered to be driven by group differences in rtings of feelings tht were inconsistent with the stimulus (i.e., how positive subjects felt while viewing n unplesnt picture nd how negtive they felt when exposed to plesnt picture). To exmine this effect more closely, we grouped 7 jp.psychitryonline.org Am J Psychitry :3, Mrch

4 URSU, KRING, GARD, ET AL. FIGURE. Sequence of the Emotionl Experience Tsk Administered to Ptients With Schizophreni nd Helthy Comprison Subjects Stimulus seconds (two scns) Dely. seconds (five scns) Rting Scles seconds (two scns) ech Intertril Intervl. seconds (five scns) How energized did you feel while viewing the picture? How negtive did you feel while viewing 3 the picture? How positive did you feel not t ll while extremely viewing 3 the picture? not t ll extremely 3 not t ll extremely The picture shown is n exmple of neutrl stimulus. Ech picture ws presented for seconds, followed by.-second mintennce period, during which subjects viewed fixtion point. After the mintennce period, subjects were instructed to rte how positive, how negtive, nd how energized they felt during the previously viewed picture, on -point scle. The three scles ( positive, negtive, energized ) were present on the screen for seconds ech, nd their order ws counterblnced reltive to stimulus vlence (plesnt, unplesnt, or neutrl). Following the three rting scles, fixtion point ws presented s n intertril intervl of. seconds. Thus, the dely between two consecutive pictures ws seconds. The long dely between the stimulus nd rtings nd the long intertril intervl llowed for good estimte of the bseline ctivity without the need for seprte fixtion trils. On the grphicl timeline t the top of the figure, the rrows mrk the onset of the regressors used to model the events in the multiple regression nlysis of the fmri dt (in order: stimulus, dely, first scle, second scle, third scle). the stimuli in terms of their degree of mtch with the rting type. This resulted in two strightforwrd groupings of stimuli, nmely one for positive rtings (for which plesnt pictures were mtch nd for which unplesnt or neutrl pictures were mismtch) nd one for negtive rtings (for which unplesnt pictures were mtch nd plesnt or neutrl pictures were mismtch). The results of these ANOVAs (Figure B) confirmed tht the ptients differed from the helthy subjects in the experience of mismtch stimuli: the ptients reported more positive emotion in response to unplesnt or neutrl pictures nd more negtive emotion in response to plesnt or neutrl pictures thn did the comprison subjects. Note tht ll of the condition-relted nd betweengroup differences just described were present, lbeit less robustly, in the subgroup of subjects included in the fmri nlyses (see Figure S in the online dt supplement). fmri Results We explored the brin responses to ech type of stimulus (plesnt, unplesnt, neutrl) seprtely () (see Method section), but the plesnt versus neutrl nd the unplesnt versus neutrl subtrctions were lso exmined post hoc, nd these were consistent with the differences noted cross vlences (see Tbles S nd S3 in the online dt supplement). Stimulus-relted ctivity. The direct group contrsts of the ctivity during presenttion of plesnt, unplesnt, nd neutrl stimuli showed no evidence of differentil ctivity in ptients reltive to comprison subjects (the uncorrected sttisticl mps re provided s Figure S in the online dt supplement). Within-group nlyses conducted seprtely in the ptient nd comprison groups confirmed tht this lck of group differences ws likely due to robust, extensive ctivtion by both groups in response to ll types of stimuli (Figure 3). In both groups, these ctivtions were locted in severl regions predicted by our model, including dorsolterl prefrontl res (Brodmnn s res, 9, ), the orbitofrontl nd ventromedil prefrontl cortex, the bsl gngli, nd the mygdle. The complete list of ctivtions identified by these nlyses nd the coordintes of locl mxim re provided s Tble S in the online dt supplement. While the ptients ppered to show less extensive ctivtion in the presupplementry motor nd supplementry motor res on the medil frontl wll, these differences were not sttisticlly significnt in the between-group contrsts (see discussion nd Tble S nd Figure S in the supplementl mteril). Dely-relted ctivity. In notble contrst to the stimulusrelted nlysis, the direct group contrst of dely-relted ctivity reveled severl brin res with stronger ctivity in the comprison subjects thn in the ptients (Figure A), including severl prefrontl foci, both dorsolterl nd orbitofrontl/ventromedil. These group differences were confirmed by the two seprte within-group nlyses: these reveled robust ctivtion in comprison subjects in n extensive network of dorsl prefrontl, limbic, nd prlimbic regions (Figure B); the sme nlyses in the ptient group showed very little ctivity, which did not Am J Psychitry :3, Mrch jp.psychitryonline.org 79

5 COGNITION-EMOTION INTERACTIONS IN SCHIZOPHRENIA FIGURE. Delyed Experience Rtings by Ptients With Schizophreni nd Helthy Comprison Subjects After Viewing Pictures With Vrying Emotionl Vlence Prt A: Stimulus Vlence Prt B: Mtch Between Rting nd Stimulus Vlence b Positive Rting Positive Rting Men (±SD) Rting 3 Men (±SD) Rting 3 Plesnt Unplesnt Neutrl Mtch (Plesnt) Mismtch Negtive Rting Negtive Rting Men (±SD) Rting 3 Men (±SD) Rting 3 Plesnt Unplesnt Neutrl Mtch (Unplesnt) Mismtch Energized Rting Stimulus Vlence Mtch Men (±SD) Rting 3 Comprison subjects (N=) Ptients (N=3) Plesnt Unplesnt Stimulus Vlence Neutrl Dt re displyed ccording to the type of rting (how positive, negtive, or energized the subject felt while viewing the preceding picture) nd vlence of the stimulus (plesnt, unplesnt, or neutrl picture). The difference in men rtings cross stimulus vlence illustrtes higher positive rtings for plesnt stimuli thn for unplesnt or neutrl ones, higher negtive rtings for unplesnt stimuli thn for plesnt or neutrl ones, nd higher energized rtings for plesnt nd unplesnt stimuli thn for neutrl ones. The min effect of stimulus vlence ws significnt in the positive rtings (F=3.3, df=,, p<.), negtive rtings (F=3.3, df=,, p<.), nd energized rtings (F=7.9, df=,, p<.). The group-by-vlence interctions were significnt for the positive rtings (F=3., df=,, p=.) nd energized rtings (F=3., df=,, p=.3) but not for the negtive rtings (F=., df=,, p=.). b Dt for positive nd negtive rtings re displyed ccording to the degree of mtch between the type of rting nd stimulus vlence. For positive rtings, plesnt pictures were considered mtching stimuli while unplesnt or neutrl ones were mismtches; for negtive rtings, unplesnt pictures were mtching stimuli, while plesnt or neutrl ones were mismtches. Group differences were reflected in significnt group-by-mtch interctions for positive rtings (F=., df=,, p=.3) nd negtive rtings (F=3., df=,, p=.). Anlyses of simple min effects confirmed tht these interctions were driven by differences between the ptients nd comprison subjects in the rtings when the stimulus vlence ws mismtch reltive to the type of experience being rted (p=. nd p=. for positive nd negtive rtings, respectively) but not when the stimulus vlence mtched the rting (p>.39 in both cses). survive the correction for multiple comprisons. The online dt supplement includes the complete list of sttisticlly significnt ctivtions (Tble S3 in online dt supplement) nd figure of the uncorrected sttisticl mps generted by the within-group nlysis in the schizophreni ptients (supplementl Figure S3). Correltions with clinicl mesures nd tsk performnce. In order to explore the hypothesized inverse reltionship jp.psychitryonline.org Am J Psychitry :3, Mrch

6 URSU, KRING, GARD, ET AL. FIGURE 3. Brin Activity in Helthy Comprison Subjects nd Ptients With Schizophreni While Viewing Pictures With Vrying Emotionl Vlence A. Stimulus-Relted Activity in Comprison Subjects (N=) Plesnt Unplesnt Neutrl B. Stimulus-Relted Activity in Ptients (N=) Plesnt Unplesnt Neutrl Whole-brin sttisticl prmetric mps of brin ctivity during presenttion of plesnt, unplesnt, nd neutrl pictures, obtined from seprte nlyses of ech group. Significnt ctivtion ws noted in similr set of brin structures, mny of which were included in the predefined volume of the serch msk, which included the lterl, medil prefrontl, nd orbitofrontl cortices, bsl gngli, mygdle, nd fusiform fce res. Activtion in the medil prefrontl presupplementry motor/supplementry motor res during presenttion of plesnt nd neutrl stimuli ppered more extensive in the helthy subjects, but this difference ws not sttisticlly significnt (see Figure S in online dt supplement). between dorsolterl prefrontl functioning nd severity of negtive symptoms, we computed the correltion between the clinicl rting of nhedoni nd mesures of brin ctivity in the left nd right dorsolterl prefrontl cortex fter the dely in trils with plesnt stimuli (Figure ). The ctivity of the dorsolterl prefrontl cortex in the left hemisphere ws negtively correlted with the nhedoni rting (r=.7, df=, p=.), nd the correltion with ctivity on the right pproched sttisticl significnce (r=.33, df=, p=.). However, correltions between brin ctivity nd overll severity of symptoms (indexed by the totl BPRS score) were not sttisticlly significnt (p>.3 in both cses). We lso conducted post hoc nlyses nd found tht the correltion between ctivity in the right orbitofrontl cortex nd the nhedoni rting ws significnt for the ptients. Moreover, the correltion between dely-relted brin ctivity nd tsk performnce (indexed by the difference between mtched nd mismtched rtings of emotionl experience) ws positive nd stronger in the dorsolterl prefrontl cortex in helthy subjects thn in ptients, but it ws similr cross groups in the prhippocmpl gyrus nd orbitofrontl cortex (see dditionl text in the online dt supplement). Discussion The min findings of this study were ) in the presence of stimuli with ffective content, the brin ctivity of schizophreni ptients ws similr to tht of comprison subjects in network of prefrontl, limbic, nd prlimbic structures, ) during the dely between stimulus offset Am J Psychitry :3, Mrch jp.psychitryonline.org

7 COGNITION-EMOTION INTERACTIONS IN SCHIZOPHRENIA FIGURE. Dely-Relted Brin Activity in Helthy Comprison Subjects nd Ptients With Schizophreni After Viewing Pictures With Vrying Emotionl Vlence A. Group Differences (Comprison > Schizophreni) in Dely-Relted Activity b Plesnt Unplesnt Neutrl B. Dely-Relted Activity in Comprison Subjects (N=) c Plesnt Unplesnt Neutrl C. Dely-Relted Activity in Ptients (N=) d Plesnt Unplesnt Neutrl Whole-brin sttisticl prmetric mps of brin ctivity during the dely phse of n emotionl experience tsk feturing pictures with plesnt, unplesnt, nd neutrl vlence. b Severl of these regions fell within the predefined volume of serch nd survived the criterion of correction for multiple comprisons. These regions included the dorsolterl, medil, nd ventrolterl prefrontl cortices for plesnt stimuli, medil frontl (supplementry motor re) nd bsl gngli for unplesnt stimuli, nd dorsolterl, ventromedil, nd ventrolterl prefrontl cortices for neutrl stimuli. c For ech type of stimulus, significnt ctivtion ws generlly noted in suprset of the brin structures tht showed greter ctivity for the helthy subjects thn for the ptients in the direct group contrst for the corresponding stimulus type. d The few suprthreshold clusters identified (ll shown in the figure) did not survive the correction for multiple comprisons. Uncorrected mps (p<.) re presented in Figure S3 in the online dt supplement. jp.psychitryonline.org Am J Psychitry :3, Mrch

8 URSU, KRING, GARD, ET AL. FIGURE. Correltions Between Anhedoni Score nd Brin Activity in the Left nd Right Dorsolterl Prefrontl Cortex in Ptients With Schizophreni During the Dely Phse of Trils With Plesnt Pictures Left Dorsolterl Prefrontl Cortex Right Brin Activity (bet weight) Brin Activity (bet weight) Score on Anhedoni Index From Scle for the Assessment of Negtive Symptoms The regions of interest in the dorsolterl prefrontl cortex were obtined by isolting two clusters of voxels tht showed greter ctivity in comprison subjects thn in ptients during the dely phse of tsk trils with plesnt stimuli. The left region of interest ws cluster of voxels isolted from cluster with locl mximum pek t coordintes,, 3 in the Montrel Neurologicl Institute system, while the right region of interest included voxels with the pek t,, 3. Both correltion coefficients were negtive (.7 nd.33, respectively), lthough only the one for ctivity on the left reched sttisticl significnce (df=, p=. nd p=., respectively, two-tiled). nd emotion rtings (when mintennce nd evlution of pst emotions required significnt support from cognitive control), ptients showed less ctivtion in this network, which included the dorsolterl prefrontl cortex, nd furthermore, 3) the ptients rtings of emotionl experience showed evidence of impirment when the emotion ws rted on dimensions incongruent with the stimulus vlence, nd ) the dely-relted ctivity elicited in the ptients dorsolterl prefrontl cortex by plesnt stimuli correlted negtively with clinicl mesure of nhedoni. Tken together, these results suggest tht schizophreni my be chrcterized by filure of the prefrontl circuitry supporting the criticl link between ffect nd gol-directed behvior. These results help shed new light on the precise mechnism behind disturbnces of emotion-cognition interctions in schizophreni, nd they my provide prsimonious ccount of the vribility noted in previous studies. The experimentl design used here llowed for clerer seprtion thn in previous studies between the immedite emotionl experience nd the control processes necessry for rtings of tht experience. This hs llowed us to detect robust in-the-moment ffect-relted brin ctivity in ptients, s in nother recent study (), followed by prominent hypoctivity during the dely in much of the sme ffect-relted circuitry, s well s in control-relted structures (necessry for the mintennce nd reporting of ffective experience fter the stimulus offset). The significnt negtive correltion between dely-relted dorsolterl prefrontl cortex ctivity nd nhedoni supports the ide tht much of the disconnect between emotionl experience nd behvior observed in ptients, t lest in lbortory contexts, my be relted to dysfunctionl top-down support from cognitive control processes (, ). Furthermore, the vribility in previous results my be ccounted for, t lest in prt, by disturbnces in the ptients neurl substrtes of cognitive control. It is likely tht these deficits my hve contributed, by mens of dynmic interctions with ffect-relted systems (7, ), to mnifesttions of group differences in emotionrelted brin ctivity, especilly since the mjority of previous studies used designs tht led to significnt overlp between brin ctivity relted to experiencing emotion nd tht elicited by cognitive control (). The trnsltion of ffective-motivtionl sttes into gol-directed behvior is thought to depend criticlly on effective implementtion of top-down controlled processes (, 7). Therefore, deficits in cognitive control my lso contribute to impired representtions of the vlue of outcomes () nd my ccount for hypothesized decoupling of ffect from motivted behvior (9). In our study, the ptients dorsolterl prefrontl hypoctivity ws wekly correlted with rtings of volition, but the correltion did not rech sttisticl significnce. However, since deficits in stritl responses to primry reinforcers correlted with volition in other studies (3), the specific role of cognitive control dysfunction in schizophreni ptients volition symptoms needs further explortion. The precise nture of the dorsolterl prefrontl-dependent control processes supporting delyed reporting of emotionl experience cnnot be unequivoclly resolved by this experiment. For instnce, the timing of control processes my vry cross subjects, lthough it is unlikely tht the two groups differed in this respect. Notbly, post hoc nlyses of correltions between brin ctivtion nd tsk performnce (Tble S in the online dt supplement) provided indirect evidence consistent with criticl role of sustined dorsolterl prefrontl cortex ctivity in delyed rtings of emotionl experience, in prticulr for rtings tht did not mtch the vlence of the stimulus Am J Psychitry :3, Mrch jp.psychitryonline.org 3

9 COGNITION-EMOTION INTERACTIONS IN SCHIZOPHRENIA (i.e., mismtch rtings). Furthermore, the ptients bnormlities in the delyed mismtch rtings ppered relted primrily to dysfunction of the dorsolterl prefrontl cortex, rther thn other brin res previously proposed to be dysfunctionl in schizophreni, such s the hippocmpus, or other structures involved in ffective representtions, such s the orbitofrontl cortex (see Comprison of DLPFC nd Other Brin Ares... in online supplementl text file). Considering the numerous previous reports tht dysfunction of the sme prefrontl re (Brodmnn s re 9) correltes with filure of cognitive function in schizophreni, even when emotionl sttes re irrelevnt to tsk performnce, this dorsolterl prefrontl functionl deficit is probbly not vlence specific or even emotion relted. Insted, it is likely tht prefrontl representtions re the ctul contextul link between ffective sttes nd tsk-pproprite responses, nd these representtions pper to degrde fster in ptients, similr to previously described deficits in tsk context processing (). This my lso explin why the ptients performnce ws similr to tht of the helthy subjects when such representtions were more redily vilble (i.e., for rtings mtching the stimulus vlence). Nevertheless, these mechnisms remin to be definitively chrcterized by more studies involving systemtic mnipultions of the ffective spects nd the cognitive demnds of the tsk. Another potentil limittion is tht most ptients were chroniclly ill nd, consequently, medicted. It is unlikely tht mediction sttus cn fully ccount for our findings, s previous results hve shown emotionl responding not to be strongly ffected by mediction (3) nd deficits in prefrontl cognitive processes hve been documented in first-episode nd never-medicted schizophreni ptients (, ). Nevertheless, future studies of individuls t risk for developing schizophreni or of mediction-nive firstepisode ptients would be helpful in understnding wht, if ny, role mediction or illness durtion hs in this type of tsk. It is interesting tht in the within-group sttisticl mps of stimulus-relted ctivity, some ctivtions in the presupplementry motor nd supplementry motor res ppered to be more extensive in helthy subjects thn in ptients (Figure 3), nd these res hve been implicted in vrious spects of motor control (3). While this pprent difference ws not sttisticlly significnt, it could, theoreticlly, reflect rel but smll effect. Indeed, such n effect would be consistent with the hypothesized reduced cognitive control in schizophreni ptients. Another spect worth noting is tht the dely between stimulus offset nd experience rting ws evidently short enough so tht the ptients nd comprison subjects did not differ in their mtched rtings, finding tht hs been repetedly reported when rtings were not delyed (,, 33, 3). However, differences did emerge in rtings of experience tht did not mtch the stimulus. These findings extend previous reports of stronger version reported by ptients in response to positive nd neutrl stimuli (3), s well s stronger rousl in response to neutrl stimuli (), but their precise mechnisms remin elusive. Previous results suggest tht encoding of the vlence of emotionl stimuli, t lest negtive stimuli, depends on controlled processes supported by the dorsolterl prefrontl cortex (3). Thus, rting emotionl experiences on dimensions inconsistent with the stimulus vlence my require support from control processes in order to overcome prepotent responding to vlence tht is mtch between stimulus nd rting type. Our dditionl correltionl nlyses support this ide (see Tble S in the online dt supplement). Nevertheless, further reserch is necessry to confirm tht this mechnism contributes to the higher mismtch rtings in ptients (see lso reference 3). In conclusion, the results presented here suggest tht disturbnce of prefrontl cognitive control processes my ccount to greter degree thn previously thought for the hypothesized dysfunctionl interction of cognition nd emotion in schizophreni. As such, they provide bsis for formulting nd testing hypotheses in future reserch imed t investigting the nture of neurl deficits in this disorder, their clinicl correltes, nd even possible therpeutic pproches. Presented in prt t the th Interntionl Congress on Schizophreni Reserch, Colordo Springs, Colo., Mrch to April, 7, nd t the 7 nnul meeting of the Society for Neuroscience, Sn Diego, Nov. 3 7, 7. Received Aug., 9; revisions received Feb., June, nd Sept., ; ccepted Oct., (doi:.7/ ppi.jp..9). From the Deprtment of Psychitry nd Behviorl Sciences, School of Medicine, nd the Deprtment of Psychology, University of Cliforni, Dvis; nd the Deprtment of Psychology, University of Cliforni, Berkeley. Address correspondence nd reprint requests to Dr. Crter, Deprtment of Psychitry nd Behviorl Sciences, University of Cliforni Dvis School of Medicine, 3 Stockton Blvd., Scrmento, CA 97; cmeron.crter@ ucdmc.ucdvis.edu (e-mil). Dr. Crter reports receiving reserch funding from GlxoSmithKline nd serving s consultnt to Eli Lilly, Merck, Pfizer, Roche, nd Servier. Dr. Minzenberg holds shres in Eln Phrmceuticls. The other uthors report no finncil reltionships with commercil interests. Supported in prt by NARSAD Young Investigtor Awrd to Dr. Ursu nd NIMH grnts MH-93 to Dr. Crter nd MH-7 to Drs. Crter nd Ursu. The uthors thnk Ryn Wlter, Shun Gordon-McKeon, Andrew Wtrous, Aln Firl, nd Rent Ooms for ssistnce with dt collection nd nlysis. References. 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