motivational impairments are a cardinal feature of schizophrenia , are present in the earliest phases of the illness and are a significant predictor of impaired real - world functioning ( foussias and remington , 2010 ; schlosser et al . , 2014 ) .
current clinical and neuroimaging data indicate that these motivational impairments may be related to neural and behavioral deficits in anticipating future rewards ( juckel et al . , 2006 ; simon et al . , 2010 )
specifically , growing evidence indicates that schizophrenia patients may not be able to use anticipation of future rewards to modulate subsequent goal - directed behavior , suggesting impairments in frontal 
striatal interactions and dopaminergic transmission between these regions ( abi - dargham , 2003 ; barch and dowd , 2010 ; gold et al . , 2008 ; strauss et al . , 2015 )
thus , the question remains as to whether recruitment of impaired frontal  striatal systems may enhance motivation and goal - directed behavior in schizophrenia patients or whether recruitment of other intact networks may be more useful targets for potentiating goal - directed functions in the real - world .
the present fmri study investigates this question . the reward circuitry is well established in healthy participants ( hc ) .
abundant neuroimaging evidence indicate that , in healthy participants , the motivation to receive upcoming monetary rewards is associated with anticipatory activity in frontal 
striatal networks , including the medial prefrontal cortex ( extending to the anterior cingulate cortex , mpfc / acc ) , caudate , putamen , ventral striatum and nucleus accumbens ( barch and dowd , 2010 ; knutson et al . , 2001 ; murray et al . ,
specifically , data suggest that activity in the ventral striatum ( vs ) , particularly within the nucleus accumbens , during immediate reward anticipation on a monetary incentive delay ( mid ) task ( knutson et al . , 2000 ) predicts arousal , positive affect , and , most importantly , real - world goal oriented consummatory behavior ( e.g. products purchased and money spent at a shopping mall ) ( knutson et al . , 2001 , 2003 , 2007 ) . by contrast , when schizophrenia patients perform the mid task , several studies have consistently revealed reduced ventral striatum ( vs ) activity during reward anticipation ( juckel et al . , 2006 ; kirsch et al . , 2007
prior behavioral research indicate that while patients with schizophrenia reveal specific deficits in anticipating signals leading to future rewarding outcomes , they experience similar levels of consummatory ( in the moment ) pleasure to hc participants ( gard et al . , 2007 ; herbener et al . ,
however , it must also be noted that not all studies have found trait differences between schizophrenia and hc participants in self - reported anticipatory pleasure ratings ( assayed with the teps anticipatory scale ) ( strauss et al . , 2011 ) ;
indeed some behavioral studies have shown that deficits in schizophrenia patients ' ability to respond to future rewarding stimuli occur only when the stimuli are not presently available compared to when the rewarding cues are more immediately present ( heerey et al . , 2011 ) .
together , these findings suggest that additional studies are needed that use anticipatory pleasure ratings from the teps anticipatory scale with neuroimaging measures of immediate reward anticipation , to determine the precise neural underpinnings of amotivation in schizophrenia . to this end ,
the purpose of this study is to use fmri in schizophrenia to explicitly examine the relationship between neural activity during the anticipation of an immediate reward ( assayed when participants anticipate winning money in response to a win $ cue ) in relation to self - reports of real world motivated behavior ( both in - the - moment pleasure as represented by the teps consummatory scale , and future representations of pleasure , as measured by the teps anticipatory scale ) .
therefore , it is possible that neural activation patterns during current representation of rewarding cues in schizophrenia may not directly be associated with future representations of reward ( measured with the teps - anticipatory scale ) , but rather with more intact consummatory pleasure levels ( assayed here with the teps - consummatory scale ) , as is shown in healthy participants ( knutson et al . , 2007 ) .
it also must be noted that while the process of anticipating pleasure can enhance motivation and preparation for upcoming future rewarding events , high levels of consummatory ( in the moment ) pleasure can also increase neural reward motivational processes to repeat a rewarding activity ( trmeau et al . , 2010 ) .
in the present study , we therefore hypothesized that it was possible for neural signal during immediate reward anticipation on the mid task to be correlated with either the teps - anticipatory scale , the teps - consummatory scale or with both scales . since deficits in anticipatory pleasure are related to deficits in motivation and functional outcome ( gard et al . , 2007 ) , and since amotivation in schizophrenia has been shown to be a central predictor of poor functioning , these findings suggest that deficits in anticipating pleasure can contribute to functional disability in schizophrenia ( foussias and remington , 2010 ; gard et al . , 2009 ) .
however , thus far , no one has investigated the explicit link between deficits during anticipation of immediate rewards , real world motivated behavior ( both in - the - moment and the future ) , and real - world functioning , and whether and how additional intact neural networks ( rather than impaired frontal  striatal circuits ) may mediate motivated behavior in schizophrenia . to this end , we examined whole - brain activation in sz patients and hc participants during the anticipatory phase of presentation of stimuli that predicted immediate monetary gain ( reward ) and loss ( punishment ) , as well as during the outcome phase when participants were notified as to whether they had won money or lost money ( knutson et al . , 2000 ) .
previous research has shown that activation within the ventral striatum during anticipation of an immediate reward is negatively correlated with negative symptoms , such as apathy ( i.e. , lack of motivation ) , as well as with positive symptoms , while striatal activation during reward outcome is negatively correlated with depressive symptoms ( juckel et al . , 2006
these findings suggest that lower striatal activation during anticipation of an immediate reward may contribute to patients ' lack of motivation as well as to the development of psychotic symptoms while lower striatal activation during reward outcome may contribute to depressive symptoms ( simon et al . , 2010 ) .
in the present study , we examine whole - brain neural activation in relation to clinical symptoms ( assayed with the positive and negative symptom scale ) , motivation ( assayed with the behavioral activation scale ) ; both anticipatory pleasure ratings of future representations of reward and in the moment consummatory pleasure ratings ( assayed with the teps ) ( gard et al . , 2007 ) and with real - world functional capacity ( ucsd performance - based skills assessment ) ( patterson et al . ,
given that prior meta - analyses have indicated that sz patients do not reveal deficits during  in the moment  emotional experiences ( cohen and minor , 2010 ) , we predicted that we would not observe overall group differences in neural activation when sz patients were notified that they had won money .
however , in view of the previous studies mentioned above , we hypothesized that sz patients would reveal hypoactivation in vs specifically during immediate reward anticipation . to our knowledge , this is the first study to investigate whether frontal 
striatal dysregulation during immediate reward anticipation may require recruitment of additional intact networks such as those within parietal regions in schizophrenia , that may predict better motivation ( assayed with bas - drive scale ) , consummatory pleasure ( teps ) and real - world functioning ( assayed with the ucsd performance - based skills assessment ) .
this study represents the baseline imaging data from the imaging component of our nimh - funded ro1 of a double - blind randomized clinical trial of cognitive training in schizophrenia ( clinicaltrials.gov nct02105779 ) .
thirty - seven clinically stable volunteer schizophrenia patients ( sz : mean age  =  45.14 ; mean education  =  14.55  years ; mean iq  =  102.11 ; mean illness duration  =  25.40  years ) , who were willing to undergo two imaging sessions , were recruited from the parent study .
all patients were stratified by age , education , gender , and symptom severity and then randomly assigned to either social computerized cognitive training , or to a control computerized cognitive training condition without the social training , performed for 80  h. informed consent was obtained from all subjects .
schizophrenia patients were scanned using fmri while they performed the monetary incentive delay task ( used to assay reward / punishment processing ) at baseline and after 80  h of intervention .
we report here the results at baseline of our reward / punishment fmri experiment investigating frontal 
striatal cortical systems in schizophrenia patients when compared to 20 healthy comparison participants ( hc ) , matched at a group level on age , gender , and education ( table 1 ) .
fmri data from two sz participants were later excluded due to very poor signal to noise ratio , resulting from excessive motion during the scan .
eligibility diagnosis for schizophrenia was determined using the structured interview for the dsm ( scid ) ( first et al . , 2002 ) .
symptom severity in schizophrenia was assessed with the positive and negative syndrome scale ( panss ) ( kay et al . , 1987 ) .
neurocognition was assessed using the matrics consensus cognitive battery ( mccb , nuechterlein et al . , 2008 ) which assesses seven cognitive domains : attention / vigilance , speed of processing , working memory , verbal learning , visual learning , reasoning and problem solving , and social cognition , and provides a global cognition score across all measures .
associations were conducted between reward anticipation and the mccb measures of global cognition and reasoning and problem solving ( neuropsychological assessment battery  mazes test ) .
recent research indicate that neurocognitive function predicts real - world functional outcome in patients with schizophrenia but this is largely mediated by functional capacity ( e.g. the ability to perform functionally relevant , everyday living skills such as writing a check , following a bus schedule ) , as measured with the ucsd performance - based skills assessment ( upsa ) ( bowie et al . , 2006 ) .
therefore , we thought that the upsa would be the most valid and reliable measure to assess functional capacity in schizophrenia , related to the skills essential to the individual 's ability to function independently in the community ( patterson et al . , 2001 ) .
the behavioral inhibition and behavioral activation scales ( bis / bas ) , which are a self - report measure of reward sensitivity , were used to assess aversive and appetitive motivation in schizophrenia ( carver and white , 1994 ) .
i worry about making mistakes  and  when i want something , i usually go all - out to get it .  the temporal experience of pleasure scale ( teps ) was used to measure individual dispositions in reward responsivity during real - world experiences of future anticipatory pleasure and in - the - moment consummatory pleasure ( gard et al . , 2007 ) .
examples of anticipatory pleasure items include :  looking forward to a pleasurable experience is in itself pleasurable  and consummatory pleasure items include :  a hot cup of coffee or tea on a cold morning is very satisfying to me .  the scid , panss , upsa , and bis / bas were administered only to sz patients .
the teps was administered to both hc and sz participants on the day of scanning .
we used a standard monetary incentive delay ( mid ) task , as described by knutson et al .
( 2001 ) , to assay the neural patterns associated with immediate anticipation and outcome of monetary reward ( gain ) and punishment ( loss ) in sz and hc participants ( knutson et al . , 2001 ) .
the mid paradigm is a reaction time ( rt ) task in which each trial has a pre - established monetary value . at the beginning of each trial ,
a cue ( i.e. , marking the onset of an anticipatory period ) indicates the amount of money at stake on that trial : win cues indicate potential monetary gain , null cues indicate no monetary gain / no outcome , and lose cues indicate potential monetary loss ( fig .
when the cue is presented , participants anticipate making a speeded response to the target ( a white square ) , which is presented on the screen after a variable fixation interval ( i.e. , the anticipation period , duration from 2 , 4 , 6 or 8  s , randomized across all trials ) .
such variable delays were used to jitter the events and optimize deconvolution of the fmri signal from successive events .
after participants respond to the target , they receive feedback on how they performed on that trial in terms of receiving rewarding , punishing or neutral feedback .
specifically , on win trials , participants are informed as to whether or not they won money ; on null trials , participants receive neutral feedback that they did not win / lose money ; and on lose trials , participants are informed as to whether or not they lost money on that trial . after the feedback prompt , there is a variable inter - trial - interval ( iti ) , jittered between 2 , 4 , 6 , or 8  s randomized across all trials , after which the next cue is presented ( marking the onset of the next anticipatory period ) .
for example , for each participant , performance level was titrated at 68% accuracy , such that the response window determining success was based on the participant 's mean rt within one standard deviation of the mean averaged across performance based on the previous run .
responses to the first run were roughly titrated at 68% accuracy based on a previous practice run .
responses to the white square were captured for the total target presentation duration ( i.e. , 0.5  s ) ; however , participants were specifically instructed to respond as fast as possible as soon as the target appeared .
early responses prior to target onset were not considered and participants were instructed not to make multiple responses .
each run consisted of 60 trials : 20 win trials , 20 null trials and 20 loss trials , pseudorandomized .
participants completed 3 runs altogether , with each run lasting for a total time of 12  min and 24  s. participants were provided with money based on their maximum earnings on their best performance run .
overall accuracy for each participant was calculated by computing the total number of win trials and no - loss trials , averaged across the three runs . immediately after the fmri scan
, participants rated their affect and arousal retrospectively on how they had felt when they viewed each condition on the mid task ( i.e. , win , lose , null ) .
affect was rated on a likert scale of 17 , labeled on each end from  negative  to  positive  , and arousal was similarly rated on a likert scale of 17 , labeled on each end from  not aroused  to  very aroused  .
was defined as feeling  activated , charged or energized , physically or mentally . 
we first conducted between - group one - way anovas in spss to examine between - group differences for overall accuracy ( only correct trials ) and rt ( for both correct and incorrect trials ) ( fig .
we next conducted between - group 2    2 repeated - measures anova on accuracy to examine the main effects of condition ( win / no - lose accuracy ) , main effects of group ( hc / sz ) , and group by condition ( win / no - lose ) interaction effects .
we also conducted between - group 2    3 repeated - measures anova on overall rt to examine the main effects of condition ( win / no - lose / null rt ) , main effects of group ( hc / sz ) , and group by condition ( i.e. , win / no - lose / null ) interaction effects . visual stimuli were presented with matlab and back - projected onto an lcd projector .
participants viewed the screen using a mirror attached to the head coil and made finger - press responses on a fiber - optic response pad .
fmri was acquired on a 3  tesla tim trio siemens scanner and twelve channel head coil , using an echo - planar sequence ( tr  =  2.4  s , 35 slices , 306 volumes , te  =  30  ms , fov  =  230  mm ; matrix  =  64    64 ) .
slice timing was performed in interleaved order , where the first slice was used as the reference .
images were realigned to correct for motion artifacts using a 6-parameter affine transformation , normalized to a standard stereotaxic space ( montreal neurological institute template ) using a 12 parameter affine / non - linear transformation , and spatially smoothed with an 8  mm full - width half - maximum ( fwhm ) gaussian kernel .
data were submitted to a general linear model analysis . for each participant ( i.e. , first - level analysis ) , we fit a reference canonical hemodynamic response function ( hrf ) to each event within the trial ( i.e. , cue , the fixation period between cue and target , target , and feedback ) ( see fig .
we then computed the following contrasts of interest:(i)for immediate reward anticipation , we contrasted signal during the anticipation to win money with no outcome trials ( i.e. , win cue plus fixation vs. null cue plus fixation ) by modeling the entire anticipatory period of the cue and fixation - cross presentation duration;(ii)for immediate punishment anticipation , we contrasted signal during the anticipation to lose money with no outcome trials ( i.e. , lose cue plus fixation vs. null cue plus fixation ) , by modeling the anticipatory period of the cue and fixation - cross presentation duration(iii)for reward outcome , we contrasted signal when participants were notified that they won money ( monetary gain ) compared to when they did not win money on win trials , by modeling the duration of the feedback prompt(iv)for punishment outcome , we contrasted fmri signal when participants were notified that they lost money ( monetary loss ) compared to not losing money on lose trials by modeling the duration of the feedback prompt . for immediate reward anticipation , we contrasted signal during the anticipation to win money with no outcome trials ( i.e. , win cue plus fixation vs. null cue plus fixation ) by modeling the entire anticipatory period of the cue and fixation - cross presentation duration ; for immediate punishment anticipation , we contrasted signal during the anticipation to lose money with no outcome trials ( i.e. , lose cue plus fixation vs. null cue plus fixation ) , by modeling the anticipatory period of the cue and fixation - cross presentation duration for reward outcome , we contrasted signal when participants were notified that they won money ( monetary gain ) compared to when they did not win money on win trials , by modeling the duration of the feedback prompt for punishment outcome , we contrasted fmri signal when participants were notified that they lost money ( monetary loss ) compared to not losing money on lose trials by modeling the duration of the feedback prompt .
we isolated activation during immediate reward / punishment anticipation by comparing brain activation for each participant during the win / lose cue with the null cue . during both null cue and win cue ,
participants anticipate making a response ( i.e. , pressing a button to a target ) . therefore , the only cognitive process that is different ( and , consequently , results in brain activation differences ) during the win cue versus null cue has to be specifically due to anticipation of a reward , rather than due to a preparatory motor response ( pressing a button to a target ) .
our general linear model ( glm ) analysis allowed us to extract signal to each trial - type , and to factor out signal due to temporally adjacent events ( e.g. to the feedback response ) , to ensure that signal could be isolated to the event of interest ( e.g. reward anticipation ) .
for example , when extracting signal related to anticipation events , we included in the analysis : the target and the feedback responses to factor out signal tied to those outcome events than to the anticipation event .
next , we conducted one sample t - tests to investigate random - effects whole - brain voxelwise analyses for each group for each contrast using a significance threshold of p  <  0.001 . in order to run conjunction analyses at the group level , we used imcalc in spm8 to determine the overlap between groups with the equation i1 
the resulting images that had a value of 3 ( i.e. , illustrated by the yellow voxels as shown in fig 3 , for example ) indicated activated voxels that were common to both hc and sz groups , revealing that the two groups activated the same network for all four contrasts .
we also conducted one - way anovas to examine whole - brain voxel - wise between - group differences for each contrast .
we did not find any regions that survived multiple comparison correction ( at fdr , p 
we now present regions showing voxel - wise group differences at an uncorrected threshold of p  <  .001 in the supplement as these regions have a small cluster extent which limit the reliability of these effects , but may be useful as exploratory analyses for future studies ( see supplementary table 1 ) .
we also conducted a whole - brain voxel - wise t - test in the sz group in which we included chlorpromazine ( cpz ) medication dosage equivalents as a covariate in order to find whether there were regions in the brain where cpz medication dosage predicted reward anticipatory / outcome activation .
finally , we conducted a whole - brain voxel - wise one - sample t - test in our combined cohort of hc and sz participants for each contrast .
table 3 shows all the areas that survived multiple comparison correction ( fwe , p 
we used our whole - brain voxel - wise one - sample t - test in our combined cohort for subsequent region - of - interest ( roi ) analyses that tested whether there were quantitative differences in the level of activation between the two groups during reward and punishment processing .
the rois were centered on the peaks of the whole - brain analyses in our combined sample of hc and sz participants for each of the contrasts , in order to minimize any bias from selecting clusters that may have been activated predominantly in one group versus the other ( poldrack , 2007 ) .
additionally , in order to minimize multiple comparisons , we only defined rois based on regions that showed activation overlap between the two groups . since the rois were selected based on a data - driven functional whole - brain analyses approach from the combined cohort without any knowledge of the results , there is no potential for bias .
we calculated mean beta values within a 5  mm radius spherical volume around each of the centroids for each contrast for each participant in the 2 groups ( hc and sz ) , in which the coordinates of the centroids are shown in table 4 .
the mean beta values extracted for each of the contrasts for each roi were then entered into one - way anovas in spss to compare between - group quantitative differences in signal for each contrast .
behavior associations for each group by comparing mean beta signal within the rois with our behavioral / clinical variables of interest .
behavioral variables of interest included : teps - anticipatory scores , teps consummatory scores , bas - drive , panss and upsa scores ( see supplementary table 2 ) .
whole - brain regression analyses were also conducted in order to study whether any of the behavioral / clinical variables predicted neural activation , thus providing additional confirmatory analyses to the brain 
finally , fisher r - to - z transformations were conducted to assess the significance of group differences between the two correlation coefficients .
a one - way anova revealed a group difference in overall accuracy ( f  =  4.05 , df  =  1,55 , p  <  .05 ) . the effect size ( cohen 's d ) of the overall accuracy difference between hc and sz subjects was 0.59 .
a 2    2 repeated - measures anova revealed a main effect of win / no - lose accuracy ( f  =  4.98 , df  =  1,55 , p  =  .03 ) and a main effect of group ( f  =  36.51 , df  =  1,55 , p  < 
.001 ) , but no group    win / no - lose accuracy interaction ( f  =  1.21 , df  =  1,55 , p  =  .28 ) .
subsequent between - group one - way anovas revealed that hc participants had better accuracy on both win ( f  =  38.91 , df  =  1,55 , p  <  .001 ) and lose conditions ( f  =  29.76 , df  =  1,55 , p  <  .001 ) when compared to sz participants ( fig .
2 ) . however , interestingly , within - group repeated - measures anovas indicated that both hc and sz groups revealed the same accuracy pattern with higher accuracy scores on the win versus lose condition ( hc : f  =  4.79 , df  =  1,19 , p  =  .041 ; sz : f  =  5.37 , df  =  1,36 , p  =  .026 ) .
a one - way anova revealed a group difference in overall rt ( f  =  10.39 , df  =  1,55 , p  <  .002 ) . a 2    3 repeated - measures anova revealed a main effect of condition ( f  =  20.88 , df  =  2,54 , p  < 
.001 ) , and a main effect of group ( f  =  10.39 , df  =  2,54 , p  < 
.002 ) but no group    condition interaction ( f  =  1.83 , df  =  2,54 , p 
subsequent between - group one - way anovas revealed that sz participants were slower than hc participants across all conditions ( win : f  =  11.18 , df  =  1,55 , p  =  .001 ; lose : f  =  8.53 , df  =  1,55 , p  =  .005 ; null : f  =  9.28 , df  =  1,55 , p  =  .004 ) . within - group repeated - measures anovas indicated that both hc and sz groups revealed the same rt pattern , with both groups being slowest in the null condition when compared to the win condition ( hc : f  =  20.77 , df  =  1,19 , p  =  .001 ; sz : f  =  13.05 , df  =  1,36 , p  =  .001 ) , and when the null was compared to the lose condition ( hc : f  =  5.95 , df  =  1,19 , p  =  .025 ; sz : f  =  5.84 , df  =  1,36 , p  =  .02 ) .
both groups were also fastest on the win condition when compared to the lose condition ( hc : f  =  13.37 , df  =  1,19 , p  =  .002 ; sz : f  =  10.04 , df  =  1,36 , p  =  .003 ) .
as confirmed by our whole - brain conjunction analyses , sz patients revealed a similar qualitative pattern of cortical  subcortical activation ( extending from frontal to striatal regions ) to that of hc participants ( fig .
however , as predicted , our roi analyses indicated quantitative between - group activation differences within the ventral striatum ( vs ) in sz participants ( table 4 ) .
specifically , one - way anovas revealed that sz participants showed hypoactivation in only one region , the ventral striatum ( vs ) , when compared to hc participants ( f  =  4.18 , df  =  1,53 , p  =  .046 ) .
sz patients exhibited marginally reduced levels of future representations of anticipatory pleasure ( i.e. , teps anticipatory pleasure ) compared to healthy participants ( p  =  .08 ) , although they exhibited similar arousal levels when viewing the win cue , as well as similar levels of consummatory pleasure ( i.e. , teps consummatory pleasure ) as hc participants ( all p values  >  .20 ) .
however , interestingly , we found distinct differences between the hc and sz groups in terms of their neural signal association with the teps consummatory pleasure scale .
specifically , the hc group revealed neural activity in four regions during reward anticipation that predicted higher self - ratings of teps consummatory pleasure ; this association was found in : left putamen ( r  =  .53 , df  =  18 , p  =  .02 ) , vs ( r  =  .48 , df  =  18 , p  =  .03 ) , mpfc ( r  =  .45 , df  =  18 , p  =  .04 ) , and right putamen ( r  =  .44 , df  =  18 , p  =  .05 ) .
in contrast , the sz group revealed signal increase in only one region , the right ipl , that predicted higher self - ratings in teps consummatory pleasure ( r  =  .35 , df  =  33 , p  =  .04 ) ( fig .
4 ) . signal in right ipl was also associated with higher self - ratings on bas - drive ( r  =  .39 , df  =  33 , p  =  .02 ) while signal in the left ipl predicted better real - world functional capacity , as measured by the upsa ( r  =  .34 , df  =  33 , p  =  .05 ) .
finally , whole - brain regression analyses provide additional confirmatory evidence that teps anticipatory pleasure , teps consummatory pleasure and bas - drive predicted r. ipl signal during immediate reward anticipation in schizophrenia patients ( see supplementary fig .
although , fisher r - to - z transformations did not reveal any significant between - group difference in the strength of the association between r. ipl and teps consummatory pleasure ( z  =  .58 , p  =  .28 ) , we did find a significant between - group difference in the relation between teps consummatory pleasure and ventral striatum ( z  =  1.91 , p  =  .03 ) , left putamen ( z  =  2.57 , p  =  .005 ) , as well as mpfc ( z  =  2.57 , p  =  .005 ) .
together , these findings suggest that sz and hc participants show significantly different associations between frontal  striatal activation during anticipation of immediate rewards , and self - ratings of real - world reward responsivity .
overall , symptom ratings were low in this clinically stable group of sz participants ( average rating slightly over 2 , mild ) .
however , we did find a positive correlation between positive symptom severity with mean beta signal in mpfc ( r  =  .33 , df  =  33 , p  =  .05 ) and mid - cingulate ( r  =  .37 , df  =  33 , p  =  .03 ) during immediate reward anticipation .
this positive relationship between mid - cingulate signal with positive symptoms was also confirmed by our whole - brain voxel - wise regression analyses in which positive symptom severity predicted activation in the mid - cingulate region during reward anticipation ( see supplementary fig .
2 ) . there was no association between mean beta signal in any of the rois during reward anticipation with either problem - solving or global cognition ( all p values  >  0.10 ) .
whole - brain conjunction analyses revealed that the two groups activated the same network , with activation overlap observed within bilateral putamen and l.ipl ( fig .
5 ) . additionally , further roi analyses revealed that signal in none of the three rois correlated with any clinical / neuropsychological measures ( all ps  >  .10 ) .
whole - brain conjunction analyses revealed similar qualitative activation patterns between hc and sz participants during anticipation of immediate punishments versus the null condition . specifically , schizophrenia patients recruited the same regions that healthy participants activated ( i.e. , mid - cingulate , bilateral putamen and occipital regions ) , although functional overlap was only observed within the left occipital region ( fig . 6 ) .
further roi analyses indicated that the left occipital region did not correlate with any clinical / neuropsychological measures ( all ps  >  .20 ) .
whole - brain 1-sample t - tests in the combined cohort revealed that only one region , the medial superior frontal gyrus ( extending to the anterior cingulate cortex , msfg / acc ) , showed increased activation during the outcome phase when participants were notified that they had lost money compared to no monetary loss ( fig .
interestingly , roi analyses indicated that the msfg / acc was also the only region in which between - group quantitative differences in signal were found .
specifically , sz participants revealed significantly reduced activation during monetary loss versus no loss when compared to hc participants ( f  =  4.69 , df  =  1,53 p  =  .035 ) ( table 4 ) .
we conducted an fmri study investigating neural activation patterns in schizophrenia during immediate prediction and outcome of rewards and punishments on the mid task , and investigated how neural signal related to measures of real - world reward sensitivity , responsivity , and functional outcome .
we found that:1)sz patients showed impaired accuracy on both win ( reward ) and lose ( punishment ) conditions when compared to hc participants .
although accuracy was titrated for each participant at roughly 68% based on the previous run , we still observed group differences in accuracy .
these findings suggest that hc participants performed better than sz participants with each subsequent run .
additionally , although sz participants were slower than hc participants on each condition , they showed the same accuracy and rt patterns as the hc group in that both groups had higher accuracy scores on the win compared to lose conditions , and both groups also had the slowest rt on the null condition and fastest rt on the win condition .
further , one - way between - group anovas did not yield any brain regions in which sz patients showed increased activation to neutral stimuli when compared to hc participants , confirming that the current findings can not be explained by aberrant salience to neutral stimuli compared to motivationally salient information ( esslinger et al . , 2012).2)during immediate reward anticipation , both hc and sz participants showed increased activation in several regions , including : vs , bilateral putamen , bilateral ipl , mpfc , mid - cingulate and occipital areas .
hc participants showed a significant relationship between reward - mediating regions ( i.e. , vs , mpfc , bilateral putamen ) and self - ratings of teps consummatory pleasure , whereas sz participants showed a significant association between right ipl and self - ratings of teps consummatory pleasure.3)during punishment outcome , sz patients revealed hypoactivation in the msfg when compared with hc participants .
sz patients showed impaired accuracy on both win ( reward ) and lose ( punishment ) conditions when compared to hc participants .
although accuracy was titrated for each participant at roughly 68% based on the previous run , we still observed group differences in accuracy .
these findings suggest that hc participants performed better than sz participants with each subsequent run .
additionally , although sz participants were slower than hc participants on each condition , they showed the same accuracy and rt patterns as the hc group in that both groups had higher accuracy scores on the win compared to lose conditions , and both groups also had the slowest rt on the null condition and fastest rt on the win condition .
further , one - way between - group anovas did not yield any brain regions in which sz patients showed increased activation to neutral stimuli when compared to hc participants , confirming that the current findings can not be explained by aberrant salience to neutral stimuli compared to motivationally salient information ( esslinger et al . , 2012 ) .
during immediate reward anticipation , both hc and sz participants showed increased activation in several regions , including : vs , bilateral putamen , bilateral ipl , mpfc , mid - cingulate and occipital areas .
hc participants showed a significant relationship between reward - mediating regions ( i.e. , vs , mpfc , bilateral putamen ) and self - ratings of teps consummatory pleasure , whereas sz participants showed a significant association between right ipl and self - ratings of teps consummatory pleasure . during punishment outcome , sz patients revealed hypoactivation in the msfg when compared with hc participants .
our whole - brain analyses indicate that as subjects anticipated immediate monetary rewards , several regions revealed increased activation , including vs , bilateral putamen , bilateral ipl , mpfc and mid - cingulate , in our combined cohort of hc and sz participants .
further , whole - brain conjunction analyses revealed all regions that showed activated voxels that were common to both hc and sz groups , suggesting similar whole - brain qualitative patterns of neural activity in the 2 groups .
interestingly , whole - brain regression analyses revealed that anticipatory representations of future reward ( assayed with teps anticipatory pleasure scale ) as well as consummatory pleasure ratings ( assayed with the teps consummatory pleasure scale ) predicted signal in only one region , the right ipl , in sz patients during immediate reward anticipation ( i.e. , during the win cue ) .
it has also been previously shown that remembered consummatory pleasure is a critical predictor of motivation in schizophrenia ( trmeau et al . , 2010 ) , which seem to be supported with the findings in our current neuroimaging study .
our roi analyses indicated that in sz patients , compared with hc participants , the vs showed reduced activation during immediate reward anticipation , and the medial sfg showed reduced activation during punishment outcome .
the medial sfg / acc region has been implicated in conflict monitoring and error detection ( alain et al .
, 2002 ; garavan et al . , 2003 ; gehring and knight , 2000 ) .
thus , it may be possible that hc participants recruit the msfg to a greater extent during error - monitoring , which , in turn , likely contributes to better subsequent performance during punishment trials and , consequently , may help them perform better at avoiding monetary loss in the future , when compared to sz participants . given past
research showing that striatal activation is associated with reward anticipation and that sz patients reveal lower striatum signal during anticipation of immediate upcoming rewards ( juckel et al . , 2006 ) , the present findings corroborate prior research confirming that although sz patients do show similar whole - brain neural activation patterns to hc participants , they do exhibit reduced striatal activation during anticipation of immediate rewards .
our findings also revealed that during immediate reward anticipation , sz patients showed a positive association between mpfc and mid - cingulate signal with positive symptom severity . while some prior studies have shown an inverse relationship between reward - related activation with positive symptoms ( schlagenhauf et al . , 2009 ) , other studies have shown positive associations between frontal and striatal signals with positive symptom severity ( rotarska - jagiela et al .
temporal connectivity positively correlated with positive symptom severity in schizophrenia , which suggests that psychopathology may be associated with intrinsic frontal aberrations .
temporal regions with positive symptoms ( such as hallucinations ) is that there is impaired connectivity between frontal areas ( involved in anticipatory processing for an upcoming action ) and temporal areas ( involved in auditory perception ) in which hallucinations are thought to result from misinterpreted speech intentions ( rotarska - jagiela et al . ,
in other words , frontal regions ( such as the mid - cingulate ) may be activated during prediction errors between anticipatory speech intentions and outcome .
similarly , in our study , one speculation is that the mid - cingulate may also be activated during prediction errors between immediate reward anticipation and outcome , in which mid - cingulate signal correlates with positive symptom severity . in our clinically stable sample of patients , since most of our patients were on atypical antipsychotic medications , we do not believe that these findings are due to effects of dopaminergic - blocking typical versus atypical medications ( juckel et al .
furthermore , we did not find any regions in the brain where cpz medication dosage predicted reward anticipatory / outcome activation in our whole - brain regression analyses .
striatal circuitry during immediate reward anticipation are inherent to the illness even in our low - symptom clinically stable sample of schizophrenia patients .
the present paper also extends prior research in that sz and hc participants showed different responses in their brain  behavior associations with self - ratings of reward responsivity ( i.e. , teps consummatory pleasure ratings ) .
hc participants revealed associations in bilateral putamen , mpfc and vs with hedonic consummatory pleasure ratings while sz participants revealed correlations with consummatory pleasure ratings within the right ipl .
it must also be noted that we did not find significant activation group differences within the ipl or a significant between - group difference in the strength of the association between r. ipl and reward responsivity .
however , we did find a significant between - group difference in the strength of the relation between reward responsivity , and left putamen , vs and mpfc .
we think that we did not observe a significant between - group difference in r. ipl because the slopes are in the same direction for both groups ( unlike the slopes within mpfc , vs and left putamen in which we do find a significant between group difference ) .
these findings hint at the possibility that both hc and sz groups may benefit from enhanced ipl signal during immediate reward anticipation ( although the association with reward responsivity seems to be stronger in the sz than that in the hc group ) . together , these findings suggest that sz and hc participants show significantly distinct associations between frontal 
striatal activation during anticipation of reward , and self - ratings of real - world reward responsivity .
consistent with prior studies , our findings indicate that sz patients did not differ from hc participants in the level of their consummatory pleasure ratings ( gard et al . , 2007 ) but only in terms of the brain regions that predicted consummatory pleasure .
furthermore , sz patients did not differ from hc participants in their positive affect and arousal ratings to the rewarding cue .
these findings suggest that patients ' experience of positive affect and arousal in response to immediate rewarding stimuli is intact , in agreement with previous literature ( cohen and minor , 2010 ; llerena et al . , 2012 ) , but point towards distinct differences between reward - related anticipatory neural activity and the reported subjective experience of pleasure . specifically , while healthy participants recruited regions known to mediate reward - anticipatory activity such as the basal ganglia ( bilateral putamen ) and vs ( barch and dowd , 2010 ; knutson et al . , 2001 ;
nielsen et al . , 2012 ) that predicted trait hedonic pleasure , sz patients revealed right ipl activation  a region that is not considered central to reward processing ( singh - curry and husain , 2009 ) .
during anticipation of immediate rewards , the right ipl was also correlated with overall motivational drive ( i.e. , bas - drive ) to move towards a desired goal in sz participants , while the left ipl predicted better functional capacity ( as measured by the upsa ) .
together , these findings indicate that the signal in the ipl ( rather than reward - mediating regions ) predicts enhanced functional capacity in individuals with schizophrenia .
finally , our findings suggest that activating impaired frontal circuits during the reward anticipatory phase may not be beneficial for clinical symptoms in our sample of chronically - ill albeit clinically stable sample of sz participants , but point towards recruitment of more intact systems within the ipl that are likely to predict enhanced motivation and functional capacity .
although the ipl is involved in multiple cognitive and emotional processes , it is particularly important for attention during saliency processing and consequently , facilitates goal - directed activities .
salient information activates both the right and left ipl ; however , the right ipl is thought to be more involved in directing attention to salient relevant information , while the left ipl is activated particularly during suppression of irrelevant information ( mevorach et al . , 2006 ) .
thus , both right and left ipl support attention to salient information that is needed for goal - directed functional capacity .
this is consistent with findings from other studies that indicate that the parietal cortex is modulated when participants engage in increased attentional effort across a broad range of cognitive tasks ( kanwisher and wojciulik , 2000 ; shuman and kanwisher , 2004 ) .
furthermore , damage to the ipl has been reliably associated with hemi - spatial attentional neglect ( mesulam , 1999 ) , in which patients fail to attend to information in their left visual field , indicating that ipl is necessary for attention processes .
2005 ) have specifically shown that ipl is modulated by changes in attentional cues that mediate motivational salience on their monetary incentive task , and ipl signal is enhanced when motivationally salient information ( i.e. , rewarding cues ) is combined with transcranial magnetic stimulation ( tms ) on the mid task ( stanford et al . , 2013 ) .
together , these findings suggest that in sz participants , enhanced ipl activity during immediate reward anticipation and its association with bas - drive supports enhanced attention to incoming salient information , which then increases patients ' motivation to move towards a desired goal , thus , contributing to enhanced functional capacity ( as shown by ipl signal association with the upsa scale ) . indeed , gard et al .
( 2009 ) also conducted path analyses to find that motivation plays a mediating role between neurocognition and functional outcome .
these findings corroborate prior research , suggesting that the ipl may have a functional attention - mediating compensatory role during reward motivation in psychiatric disorders such as schizophrenia ( stanford et al . , 2013 ) .
the present findings indicate that sz patients showed reduced accuracy on reward and punishment trials when compared to hc participants .
however , both hc and sz participants showed a similar accuracy and rt pattern , being most accurate and fastest on the win condition and slowest on the null condition .
therefore , we do not believe that the current findings can be explained by sz participants showing reduced willingness to expend effort in order to achieve monetary rewards .
the results point to common whole - brain qualitative activation patterns during immediate reward and punishment anticipation and outcome in the two groups , as well as quantitative between - group differences ( with sz patients showing hypoactivation in ventral striatum ) during immediate reward anticipation .
finally , whereas hc participants activated reward - related circuits in vs , bilateral putamen and mpfc during immediate reward anticipation , which predicted hedonic pleasure , sz participants activated regions such as the ipl ( mediating attention rather than reward mechanisms ) that predicted hedonic pleasure and functional capacity . together , these findings suggest that the study and treatment of motivation deficits in patients with schizophrenia may require a more detailed investigation of the role of the ipl as a circuit modulator during immediate reward anticipation that may contribute to real - world functioning capacity .
 amotivation in schizophrenia is a central predictor of poor functioning , and is thought to occur due to deficits in anticipating future rewards , suggesting that impairments in anticipating pleasure can contribute to functional disability in schizophrenia . in healthy comparison ( hc ) 
 participants , reward anticipation is associated with activity in frontal  striatal networks . by contrast , 
 schizophrenia ( sz ) participants show hypoactivation within these frontal  
 striatal networks during this motivated anticipatory brain state . here , we examined neural activation in sz and hc participants during the anticipatory phase of stimuli that predicted immediate upcoming reward and punishment , and during the feedback / outcome phase , in relation to trait measures of hedonic pleasure and real - world functional capacity . 
 sz patients showed hypoactivation in ventral striatum during reward anticipation . 
 additionally , we found distinct differences between hc and sz groups in their association between reward - related immediate anticipatory neural activity and their reported experience of pleasure . 
 hc participants recruited reward - related regions in striatum that significantly correlated with subjective consummatory pleasure , while sz patients revealed activation in attention - related regions , such as the ipl , which correlated with consummatory pleasure and functional capacity . 
 these findings may suggest that sz patients activate compensatory attention processes during anticipation of immediate upcoming rewards , which likely contribute to their functional capacity in daily life . 
Introduction
Materials and methods
Results
Discussion
Conclusions