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, 48 (1), 82-94

Prefrontal Cortical Thinning Links to Negative Symptoms in Schizophrenia via the ENIGMA Consortium


Prefrontal Cortical Thinning Links to Negative Symptoms in Schizophrenia via the ENIGMA Consortium

E Walton et al. Psychol Med.


Background: Our understanding of the complex relationship between schizophrenia symptomatology and etiological factors can be improved by studying brain-based correlates of schizophrenia. Research showed that impairments in value processing and executive functioning, which have been associated with prefrontal brain areas [particularly the medial orbitofrontal cortex (MOFC)], are linked to negative symptoms. Here we tested the hypothesis that MOFC thickness is associated with negative symptom severity.

Methods: This study included 1985 individuals with schizophrenia from 17 research groups around the world contributing to the ENIGMA Schizophrenia Working Group. Cortical thickness values were obtained from T1-weighted structural brain scans using FreeSurfer. A meta-analysis across sites was conducted over effect sizes from a model predicting cortical thickness by negative symptom score (harmonized Scale for the Assessment of Negative Symptoms or Positive and Negative Syndrome Scale scores).

Results: Meta-analytical results showed that left, but not right, MOFC thickness was significantly associated with negative symptom severity (β std = -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, age of onset, antipsychotic medication or handedness weakened the association of negative symptoms with left MOFC thickness. As part of a secondary analysis including 10 other prefrontal regions further associations in the left lateral orbitofrontal gyrus and pars opercularis emerged.

Conclusions: 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.

Keywords: Cortical thickness; ENIGMA; FreeSurfer; MRI; PANSS; SANS; medial orbitofrontal cortex; negative symptoms; schizophrenia.

Conflict of interest statement

Conflict of Interest

The authors of this manuscript have no conflicts of interest to disclose.


Figure 1
Figure 1
Forest plot of association between global SANS and cortical thickness in the left medial orbitofrontal cortex across all 17 study sites, controlling for age, gender and number of sites (if applicable; of note the global SANS-left MOFC thickness relationship did not differ between single vs multisite samples (p=0.422; see SI 2.1 section o)). Fisher’s transformed standardized regression coefficients are denoted by black boxes. Black lines indicate 95% confidence intervals. The combined estimate for all sites is represented by a black diamond with the outer edges of the diamond indicating the confidence interval limits.

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