Further evidence for aberrant prefrontal salience coding in schizophrenia

Abstract

The revised dopamine hypothesis of schizophrenia postulates that dopamine metabolism is impacted differently with increased dopamine in the subcortical mesolimbic system and decreased dopamine in prefrontal cortical regions. Recently, we described findings supporting this hypothesis using a financial reward task in patients with schizophrenia (Walter et al., 2009). In addition to analysing prediction and prediction error coding, we found in this study evidence for aberrant cortical representation of salience in the right ventrolateral prefrontal cortex (VLPFC) in patients. Here, we reanalysed data of four other published reward studies of our group in order to investigate (i) whether we could replicate this finding in an independent cohort of patients with schizophrenia and (ii) how dopaminergic modulation impacts on cortical salience representation. Our main result was that we could replicate the finding of aberrant salience coding in the right VLPFC in patients with schizophrenia. Furthermore, we found evidence that the degree of salience coding in this region was correlated inversely with negative symptoms (anhedonia). Results of dopaminergic modulation showed tentative evidence for an influence of dopaminergic stimulation, but were not conclusive. In summary, we conclude that the right VLPFC might play a crucial role in salience coding and is impaired in schizophrenia.

Keywords: dopamine; functional magnetic resonance imaging; reward; salience; schizophrenia.

Figure 1

Salience in outcome (reward magnitude). Brain activation and beta weights in the right VLPFC/anterior insula as found for the interaction of contrasts modelling salience in patients suffering from schizophrenia and controls scanned with the magnitude paradigm. The beta values were extracted from the maximum voxel of the demonstrated activation. The map was thresholded at p < 0.005 at the voxel-level and at an extent threshold of p < 0.05 at the cluster-level. The interaction contrast is masked by the contrast in the controls’ group alone thresholded at p < 0.005 at the voxel-level. The coefficient “a” taken as a measure of the shape of a U-shaped regression curve indicates a more shallow curve the lower the levels and an inverse U-shape with negative values. The values in control subjects were significantly higher than in the patients. r/high, r/low, no, o/low, o/high: receipt of high reward, receipt of low reward, receipt of no reward, omission of low reward, omission of high reward.

Figure 2

Salience and psychopathology (reward magnitude). In study 1 (index study) and study 2 (replication study) we found significant negative correlations with anhedonia scores (social anhedonia and physical anhedonia, respectively) and the coefficient “a” extracted from the VLPFC where group differences (controls > patients with schizophrenia) were found, that is, lower anhedonia scores predicted a pattern with steeper U-shaped curves as found in the controls. Correlations were significant for the social anhedonia scores (p = 0.04) in all subjects, patients and controls in the index study 1 and for the physical anhedonia scores in study 2 in all subjects (p = 0.03) driven by a significant effect in the patients (p = 0.02). Anhedonia scores were not obtained in three of 16 patients in study 1 and 4 of 12 patients in study 2.

Figure 3

Salience in outcome (reward probability). Brain activation and beta weights in the right VLPFC/anterior insula as found for the contrast modelling salience scanned during the probability paradigm. Study 3 was performed in healthy controls (HC), study 4 in patients with RLS off and on their regular medication. The beta values were extracted from the maximum voxel of the demonstrated activation. The map was thresholded at p < 0.005 FWE corrected for healthy controls and at p < 0.001 at the voxel-level and at an extent threshold of p < 0.05 at the cluster-level in patients. The coefficient “a” taken as a measure of the shape of a U-shaped regression curve indicates a more shallow curve the lower the levels in healthy controls. In RLS patients on regular medication, the coefficient “a” taken as a measure of the shape of a U-shaped regression curve indicates a trend (p = 0.06) towards a more shallow curve. r/25%, r/50%, r/75%, 0%, 100%, o/25%, o/50%, o75%: receipt (r) or omission (o) of reward expected at 0%, 25%, 50%, 75% or 100%.