Local-to-remote cortical connectivity in early- and adulthood-onset schizophrenia

Abstract

Schizophrenia is increasingly thought of as a brain network or connectome disorder and is associated with neurodevelopmental processes. Previous studies have suggested the important role of anatomical distance in developing a connectome with optimized performance regarding both the cost and efficiency of information processing. Distance-related disturbances during development have not been investigated in schizophrenia. To test the distance-related miswiring profiles of connectomes in schizophrenia, we acquired resting-state images from 20 adulthood-onset (AOS) and 26 early-onset schizophrenia (EOS) patients, as well as age-matched healthy controls. All patients were drug naive and had experienced their first psychotic episode. A novel threshold-free surface-based analytic framework was developed to examine local-to-remote functional connectivity profiles in both AOS and EOS patients. We observed consistent increases of local connectivity across both EOS and AOS patients in the right superior frontal gyrus, where the connectivity strength was correlated with a positive syndrome score in AOS patients. In contrast, EOS but not AOS patients exhibited reduced local connectivity within the right postcentral gyrus and the left middle occipital cortex. These regions' remote connectivity with their interhemispheric areas and brain network hubs was altered. Diagnosis-age interactions were detectable for both local and remote connectivity profiles. The functional covariance between local and remote homotopic connectivity was present in typically developing controls, but was absent in EOS patients. These findings suggest that a distance-dependent miswiring pattern may be one of the key neurodevelopmental features of the abnormal connectome organization in schizophrenia.

Figure 1

Mapping local functional homogeneity in schizophrenia patients and healthy controls. Group mean 2dReHo maps are depicted for early-onset schizophrenia (EOS; a), adulthood-onset schizophrenia (AOS; b), typically developing controls (TDCs; c) and healthy adult controls (HACs; d). Maps of group differences in 2dReHo are compared between EOS and TDC (e) as well as between AOS and HAC (f). The vertex-wise significance of group comparisons are measured with signed log10-transformed P-values and are rendered onto the cortical surfaces of the left hemisphere (LH) and the right hemisphere (RH). These inflated surfaces are defined by FreeSurfer as the fsaverage5 surface model and visualized from lateral and medial views. Light-gray colors indicate the position of a cortical gyrus, whereas dark-gray colors show the position of a cortical sulcus.

Figure 2

Mapping remote functional connectivity in early-onset schizophrenia (EOS) and typically developing controls (TDCs). Group mean correlation maps of two regions of interest as seeds (left column, left middle occipital cortex, MOC; right column, right postcentral gyrus, PosCG) are depicted for EOS patients (a, b) and TDC (c, d). Group differences in Fisher z-transformed correlations are compared between EOS and TDC (e, f). The vertex-wise significance of group comparisons is measured with signed log10-transformed P-values and is rendered onto the cortical surfaces of the left hemisphere (LH) and the right hemisphere (RH). These inflated surfaces are defined by FreeSurfer as the fsaverage5 surface model and visualized from lateral and medial views. Light-gray colors indicate the position of a cortical gyrus, whereas dark-gray colors show the position of a cortical sulcus.

Figure 3

Mapping age–diagnosis (early-onset schizophrenia (EOS) versus typically developing controls (TDCs)) interactions on functional connectivity. The vertex-wise significance (the signed log10-transformed P-values) of interactions are visualized on the cortical surface for the local connectivity (2dReHo) (a) and the remote functional connectivity (correlation) seeded by the right precuneus (c: PCU) and the left middle occipital cortex (e: MOC), in which the light-green balls indicate the location of the two seeds. The details of these interactions are further plotted as scatter graphs in (b) 2dReHo, (d) PCU seed connectivity and (f) MOC seed connectivity. Each dot represents the individual connectivity metrics and each line indicates the connectivity correlation with age (red for EOS patients and blue for TDC; solid for significant and dashed for insignificant correlations).