Frontal white matter abnormalities reveal the pathological basis underlying negative symptoms in antipsychotic-naïve,...

A major challenge in schizophrenia is to uncover the pathophysiological basis of its negative symptoms. Recent neuroimaging studies revealed that disrupted structural properties of frontal white matter (FWM) are associated with the negative symptoms of schizophrenia. However, there is little direct functional evidence of FWM for negative symptoms in schizophrenia. To address this issue, we combined resting-state connectome-wide functional connectivity (FC) and diffusion tensor imaging tractography to investigate the alteration of FWM underlying the negative symptoms in 39 drug-naive patients with adolescent-onset schizophrenia (AOS) and 31 age- and sex- matched healthy controls (HCs). Results revealed that the intrinsic FC and structural properties (fraction anisotropy and fibers) of the left FWM correspond to individual negative symptoms in AOS. Moreover, the serotonin network (raphe nuclei, anterior and posterior cingulate cortices, and prefrontal and inferior parietal cortices) and FWM-cingulum network were found to contributed to the negative symptom severity in AOS. Furthermore, the patients showed abnormal functional and structural connectivities between the interhemispheric FWM compared with HCs. Importantly, the decreased fiber counts between the interhemispheric FWM were inversely correlated with the negative symptoms in AOS. Our findings demonstrated the association between FWM and negative symptoms, and offered initial evidence by using WM connectome to uncover WM functional information in schizophrenia.