Orbitofrontal-Striatal Structural Alterations Linked to Negative Symptoms at Different Stages of the Schizophrenia Spectrum

Abstract

Negative symptoms such as anhedonia and apathy are among the most debilitating manifestations of schizophrenia (SZ). Imaging studies have linked these symptoms to morphometric abnormalities in 2 brain regions implicated in reward and motivation: the orbitofrontal cortex (OFC) and striatum. Higher negative symptoms are generally associated with reduced OFC thickness, while higher apathy specifically maps to reduced striatal volume. However, it remains unclear whether these tissue losses are a consequence of chronic illness and its treatment or an underlying phenotypic trait. Here, we use multicentre magnetic resonance imaging data to investigate orbitofrontal-striatal abnormalities across the SZ spectrum from healthy populations with high schizotypy to unmedicated and medicated first-episode psychosis (FEP), and patients with chronic SZ. Putamen, caudate, accumbens volume, and OFC thickness were estimated from T1-weighted images acquired in all 3 diagnostic groups and controls from 4 sites (n = 337). Results were first established in 1 discovery dataset and replicated in 3 independent samples. There was a negative correlation between apathy and putamen/accumbens volume only in healthy individuals with schizotypy; however, medicated patients exhibited larger putamen volume, which appears to be a consequence of antipsychotic medications. The negative association between reduced OFC thickness and total negative symptoms also appeared to vary along the SZ spectrum, being significant only in FEP patients. In schizotypy, there was increased OFC thickness relative to controls. Our findings suggest that negative symptoms are associated with a temporal continuum of orbitofrontal-striatal abnormalities that may predate the occurrence of SZ. Thicker OFC in schizotypy may represent either compensatory or pathological mechanisms prior to the disease onset.

Keywords: apathy; cortical thickness; first-episode psychosis; negative symptoms; orbitofrontal cortex; schizophrenia spectrum; schizotypy; striatum; structural MRI.

Fig. 1.

Correlation analyses in schizotypal personality traits (SPT) and first-episode psychosis (FEP) groups of the discovery dataset. (A) Association between striatal volumes and subclinical apathy in schizotypy. SPT Zurich sample (n = 27). For visualization purpose, partial correlations between subcortical volume and Brief Negative Symptom Scale (BNSS) apathy are shown as regressions adjusted for age, sex, and intracranial volume using R. Error shadings correspond to standard errors. Significant associations are observed in right putamen (rs = −.58, P_FDR = .01), left putamen (rs = −.63, P_FDR = .009), and right accumbens (rs = −.54, P_FDR = .02). In contrast, correlation analysis between BNSS apathy and right caudate volume (rs = −.20, P_FDR = .80), left caudate volume (rs = −.16, P_FDR = .80), and left accumbens (rs = −.38, P_FDR = .19) was not significant. Bottom, visualization of the 6 striatal volumes. (B) Association between cortical thickness and total negative symptoms in FEP. FEP Zurich Sample (n = 26). For visualization purpose, partial correlations between orbitofrontal cortex (OFC) thickness and BNSS total scores as regressions adjusted for age and sex in R. Error shadings correspond to standard errors. Significant associations are observed in right lateral orbitofrontal cortex (LOFC; rs = −.624, P_FDR = .02) and left LOFC (rs = −.613, P_FDR = .02). Nonsignificant negative association are observed in right medial orbitofrontal cortex (MOFC; rs = −.374, P_FDR = .20) and left MOFC (rs = −.365, P_FDR = .20). Bottom, visualization of OFC parcellations in surface space.

Fig. 2.

Group comparison of putamen volume and orbitofrontal cortex (OFC) thickness across all sites (n = 337). Putamen volume and OFC thickness are presented as standardized residuals after regressing out age, sex, and site (and intracranial volume [ICV] for putamen volume). Significant larger bilateral putamen volume in schizophrenia (SZ) compared with healthy controls (HC; left: P = .008, right: P = .02) and SPT (left: P = .035, right: P = .037) (table 4). Significant greater left lateral orbitofrontal cortex (LOFC) thickness in schizotypal personality traits (SPT) compared with all other groups (all Ps < .001). Significant greater right medial orbitofrontal cortex (MOFC) thickness in SPT compared with all other groups (all Ps < .05) (table 4). All post hoc group tests Bonferroni corrected for multiple comparison (P < .05). *<.05, **<.01, and ***<.001.