a dysfunction of the dopaminergic reward , or motivation , system has been postulated in patients with schizophrenia .
evidence of a dopamine hypothesis in schizophrenia has been primarily provided by studies of the effects of antipsychotics .
furthermore , positron emission tomography ( pet ) and single - photon emission computed tomography ( spect ) studies have revealed dysfunction of the striatal dopaminergic system , noting an increase in the presynaptic synthesis of dopamine in patients with schizophrenia .
a hyper dopaminergic state within the ventral striatum in patients with schizophrenia may be associated with enhanced ideas and thoughts in the context of delusions .
a hypodopaminergic state may be related to an amotivational syndrome characterized by apathy , anhedonia , and other negative symptoms . in the hypodopaminergic state ,
however , the administration of antipsychotics has to be taken into account , because antipsychotics may affect motivational salience .
the main problem in this regard is the blockade of dopamine d2 receptors , especially by typical neuroleptics , also known as first - generation antipsychotics ( fgas ) .
this results in clinical depression in 20% to 40% of patients taking fgas , which block d2 receptors . in terms of secondary negative symptomatology , such blockade results in loss of drive , energy , and motivation ; apathy , anhedonia , and patient noncompliance .
the advantage of the new atypical neuroleptics , also called second - generation antipsychotics ( sgas ) , is that they only partially block the d2 receptors in the ventral striatum ( especially clozapine . ) . particularly with regard to the heteroreceptor mechanism involving antagonism of the presynaptic serotonin 5-hydroxytryptamine ( 5-ht2 ) receptor , the administration of sgas results in a sufficient and permanent flow of dopamine within the ventral striatum , thus maintaining affectivity and drive .
the function of the reward system can be visualized with functional magnetic resonance imaging ( fmri ) ; for this purpose , knutson et al developed the monetary incentive delay ( mid ) task .
this is a simple monetary - gain game that requires subjects to respond to a sequence of geometric shapes that are projected onto the screen of the mri scanner during fmri measurement .
this game ( figure 1 ) consists of two runs of 72 trials each , at the beginning of which a geometric shape informs the volunteer about the following : that money can be gained ( indicated by a circle ) , that loss of money can be avoided ( square ) , or that it is a neutral trial ( triangle ) with no monetary consequence .
after these cues have been given , a delay phase follows during which the volunteer waits for the appearance of a target .
the task is to press a button with the thumb when the briefly presented target is visible . immediately after this
, success or failure is indicated , and the cumulative total of money won is shown .
the chance of winning is set to 66% by means of an adaption mechanism , so that the volunteer anticipates the receipt of monetary gain on appearance of a reward - indicating cue .
it is well - known that the occurrence of the dopaminergic signal is to be expected during the anticipation phase .
the game was administered while subjects underwent scanning with a 1.5-tesla scanner ( magnetom vision , siemens ) with an echo - planar imaging ( epi)-sequence ( repetition time [ tr]=1.9 s , echo time [ te]=40 ms , flip angle=90 , voxel size=4x4x3.3 mm ) .
data were analyzed with spm2 ( statistical parameter mapping software version 2 ; http://www.fil.ion.ucl.ac.uk/spm ) . using the normalized preprocessed data ( slice timing , motion correction , spatial normalization , and spatial smoothing with 8-mm full width at half maximum [ fwhm ] )
, we developed single models  according to the general linear model  for each volunteer , by defining the different gain , loss , and neutral cues as single conditions .
using random effects analysis , we examined the contrast between  anticipation of gain  and  neutral consequence  ( for detailed descriptions , see refs 5 and 6 ) .
a few years ago , we examined the influence of fgas and sgas on the reward system in patients with schizophrenia .
three groups were tested : a group of 10 schizophrenic patients who received an fga ( 4 received flupenthixol 124 mg ; 4 , haloperidol 105 mg ; and 2 , fluphenazine 12 + 4 mg ) , a group of 10 schizophrenic patients who were treated with an sga ( 4 received risperidone 51 mg ; 4 , olanzapine 196 mg ; 1 , aripiprazole 30 mg ; and 1 , amisulpride 300 mg ) and a group of 10 healthy control subjects . there were no significant differences between the three groups for age , gender , and total weight gain .
there were no significant differences in psychopathology in both patient groups ( total positive and negative syndrome scale [ panss ] score in patients taking an fga , 70.1120.37 ; those taking an sga , 64.44 + 22.59 ) . in the healthy control subjects ,
we observed activation for the contrast between gain anticipation versus neutral consequence at both sides of the ventral striatum ( left : [ x y z ] = [ -21 5 -3 ] , t=9.53 ; right : [ x y z ] = [ 12 2 -10 ] , t=4.25 ) . whereas no activation in response to reward - indicating stimuli was observed in the schizophrenic patients taking an fga ,
activation was seen in the patients taking an sga , in the right ventral striatum ( [ x y z ] = [ 12 12 -1 ] , t=3.58 ) ( figure 2 ) . in group comparisons
, there was a significant difference between the healthy subjects and the schizophrenic patients taking an fga ( [ x y z ] = [ -21 9 -3 ] , t=3.39 ) , but there was no difference between healthy subjects and patients taking an sga .
the reduction in activation in response to reward- indicating stimuli was inversely correlated with the severity of negative symptomatology ( spearman 's r = -0.67 , p<0.05 ) in the group of patients being treated with an fga , as well as in the group of nonmedicated schizophrenic patients .
as cross - sectional studies are not sufficient to evaluate the effects of antipsychotic medication on ventral striatum activation during the mid task , further studies using a longitudinal design have been carried out in which schizophrenic patients were treated with an fga ( such as haloperidol , flupenthixol , or fluphenazine ) for at least 2 weeks , and then with an sga ( such as risperidone , olanzapine , or aripiprazole ) for another 2 weeks . in such studies , after 2 weeks of the respective treatments , the patients were examined by fmri while carrying out the mid task .
they were then compared with healthy subjects , who were examined twice by fmri at similar time intervals . in a study of changes associated with a switch to olanzapine
, 10 schizophrenic patients treated with an fga ( 4 received haloperidol : 10.8 + 4.3 mg / d ; 5 , flupenthixol 7.0 + 5.1 mg / d ; 1 , fluphenazine 15 mg / d ) were first examined by fmri while performing the mid task and were afterwards switched to olanzapine ( 18.57.5 mg / d ) .
the mean treatment period was 17.8 days ( 15 .0 ) for fgas and 20.2 days ( 6.7 ) for olanzapine .
the repeat examination by fmri after olanzapine treatment was carried out 31.717.3 days after the first fmri examination ( which followed fga treatment ) .
ten healthy subjects were also examined twice , the repeat examination performed 32.715.5 days after the first fmri , in order to control for a potential time effect . in anticipation of monetary gain , healthy subjects showed a significant activation of the ventral striatum ( left : [ x y z ] = [ -18 6 -9 ] , t=3.87 ; right : [ x y z ] = [ 18 6 -3 ] , t=4.70 ) , whereas schizophrenic patients treated with an fga did not show any activity ( figure 3 ) . however , after switching to olanzapine treatment , activation of the ventral striatum was observed on the right side ( [ x y z ] = [ 15 6 -12 ] , t4.36 ) . in the healthy control subjects , activation of the ventral striatum , due to the anticipation of a reward , remained quite stable over time . presumably due to secondary negative symptomatology in the schizophrenic patients ,
there was a significant correlation between the activation of the ventral striatum and the panss negative score ( r=-0.721 , p=0.019 ) , though only after treatment with an fga . in a pilot study ( gj et al , unpublished data , 2015 ) investigating the change in activation associated with a switch from treatment with an fga to an sga , 8 male schizophrenic patients under treatment with either haloperidol or flupentixol ( fgas ) at baseline ,
the average age of these patients was 3513 years ; the healthy controls were aged 33.612.5 years . at baseline ,
fmri scans carried out during performance of the mid task in fga - treated schizophrenic patients showed a significantly lower activation of the ventral striatum than healthy controls ( t - values 2.5 to 3.0 , t=0.03 to 0.04 , corrected for ventral striatum region of interest false discovery rate [ roi fdr ] ) . after changing the medication to the sga risperidone , fmri scans  carried out nearly 2 months after the baseline scans in order to minimize any residual fga effects , known to be long - acting  showed a visible increase in activity over that seen under fga treatment on both sides of the ventral striatum for gain anticipation ( left : t=3.6 , p=0.04 corrected for roi ; right : t=3.6 , p=0.02 corrected for roi ) .
this implies a possible regeneration of the dopaminergic reward system in the ventral striatum after the change to an sga . in another study ,
switching from an fga to the sga aripiprazole , also resulted in increased activation of the ventral striatum ( t=2.17 , p<0.05 ) .
dysfunction within the dopaminergic reward system can be explored in schizophrenic patients , with or without treatment by fgas and sgas , by fmri during performance of the mid task .
schizophrenic patients have been shown to have less activation of the ventral striatum , a core region of the reward system , than healthy controls ; the severity of the ( primary ) negative symptomatology is associated with reduced activation of the ventral striatum .
the findings about the effects of fgas in the cross - sectional and switch - longitudinal studies can be interpreted as expressions of the secondary fga - induced negative symptoms caused by a flattening of ventral striatal dopaminergic tone , symptoms that were not present , or that disappeared , after switching to an sga .
the findings of the two study types about the influence of fgas and sgas on the reward system may be summarized as follows : ( i ) patients with schizophrenia treated with fgas , but not with sgas , had less activity in the ventral striatum than healthy controls and ( ii ) the severity of the negative symptomatology correlated with the reduction in activity in the ventral striatum in patients treated with fgas the better effectiveness of sgas on negative symptomatology , shown in clinical studies , potentially correlates with lower impairment of the reward system .
sgas , for example , risperidone or olanzapine , cause relatively low blockade of the striatal dopamine d2 receptors and are not bound so tightly to these receptors .
moreover , they interact with other transmitter systems , such as the serotonergic system ( through effects on the 5-ht2a receptor ) .
secondly , the exact mechanism of the dopaminergic reward dysfunction can not be clarified by fmri .
the application of multimodal methods with a combination of dopamine - pet and fmri could possibly explain which mechanisms cause the dysfunction of the reward system in patients with schizophrenia . in order to compare fgas and sgas ,
therefore , the results discussed here require replication in a better and longer longitudinal study in patients in which treatment with fgas is then switched to treatment with sgas .
alternatively , a controlled before - and - after study of patients receiving no treatment and then receiving a specific antipsychotic monotherapy would also help to elucidate the relationship between different antipsychotic treatments and the mesolimbic dopaminergic reward system in schizophrenia . to this end
, one study has compared 23 antipsychotic - naive patients before and after a 6-week treatment with amisulpride . similarly to our findings , patients without any medication showed clear attenuation of brain fmri activation during reward anticipation in the ventral striatum during the mid task , with activation normalized after a 6-week treatment with an sga .
 the mesolimbic dopaminergic reward system is responsible for the negative affective symptomatology of schizophrenia , which may be related to a low dopamine tonus within the ventral striatum . 
 the monetary incentive delay ( mid ) task can be used to study the response of the ventral striatum to incentive stimuli . 
 we show that activation of the ventral striatum is low in patients with schizophrenia , and that this low activation is related to primary and secondary negative symptoms induced by neuroleptics , also known as antipsychotics . switching from first-(typical ) to second - generation ( atypical ) 
 antipsychotics increased activation of the ventral striatum due to less blocking of dopamine d2 receptors . 
 this and similar studies show that functional magnetic resonance imaging ( fmri ) tasks are suitable to investigate important aspects of antipsychotic mechanisms . 
The mesolimbic dopaminergic reward system in schizophrenia
The monetary incentive delay task in functional magnetic resonance imaging
First-versus second-generation antipsychotics: a cross-sectional study
Switch from first- to second-generation antipsychotics: reactivation of the ventral striatum in patients with schizophrenia in longitudinal studies
Conclusions