Prefrontal cortical thinning links to negative symptoms in schizophrenia via the ENIGMA consortium

Our understanding of the complex relationship between schizophrenia symptomatology and etiological factors can be improved by studying brain-based correlates of schizophrenia. Previous research has shown that impairments in executive functioning, which have been associated with prefrontal brain areas (particularly in the medial orbitofrontal cortex (MOFC)), give rise to negative symptoms. Here we tested the hypothesis that MOFC thickness is associated with negative symptom severity. This study included 1 985 individuals with schizophrenia from seventeen research groups around the world contributing to the ENIGMA Schizophrenia Working Group. MOFC thickness values were obtained from T1-weighted structural brain scans using FreeSurfer. A meta-analysis was conducted over effect sizes from a model predicting mean left or right MOFC thickness by negative symptom score (harmonized SANS or PANSS scores). Secondary models were run to investigate the effects of antipsychotic medication, duration of illness, overall illness severity, and handedness. Meta-analytical results showed that left MOFC thickness was significantly associated with negative symptom severity (βstd=−0.075; p=0.019) after accounting for age, gender and site. This effect remained significant (p=0.036) in a model including overall illness severity. Covarying for duration of illness, antipsychotic medication or handedness weakened the association of negative symptoms with left MOFC thickness. Using an unusually large cohort and a meta-analytical approach, our findings point towards a link between prefrontal thinning and negative symptom severity in schizophrenia. This finding provides further insight into the relationship between structural brain abnormalities and negative symptoms in schizophrenia. This article has been accepted and published by Cambridge University Press © 201