Functional connectome organization predicts conversion to psychosis in clinical high-risk youth from the SHARP program

Abstract

The emergence of prodromal symptoms of schizophrenia and their evolution into overt psychosis may stem from an aberrant functional reorganization of the brain during adolescence. To examine whether abnormalities in connectome organization precede psychosis onset, we performed a functional connectome analysis in a large cohort of medication-naive youth at risk for psychosis from the Shanghai At Risk for Psychosis (SHARP) study. The SHARP program is a longitudinal study of adolescents and young adults at Clinical High Risk (CHR) for psychosis, conducted at the Shanghai Mental Health Center in collaboration with neuroimaging laboratories at Harvard and MIT. Our study involved a total of 251 subjects, including 158 CHRs and 93 age-, sex-, and education-matched healthy controls. During 1-year follow-up, 23 CHRs developed psychosis. CHRs who would go on to develop psychosis were found to show abnormal modular connectome organization at baseline, while CHR non-converters did not. In all CHRs, abnormal modular connectome organization at baseline was associated with a threefold conversion rate. A region-specific analysis showed that brain regions implicated in early-course schizophrenia, including superior temporal gyrus and anterior cingulate cortex, were most abnormal in terms of modular assignment. Our results show that functional changes in brain network organization precede the onset of psychosis and may drive psychosis development in at-risk youth.

Figure 1

Image preprocessing and connectome analysis steps Overview of image preprocessing (A), connectome reconstruction (B), and modular community detection analysis (C). Of note, the colors of the modules shown in the connectivity matrices in panel C correspond to the modules as shown in Figure 2A.

Figure 2

Modular organization of the functional connectome A) Modular partitions of group-networks, plotted on cortical surface from superior, lateral, medial, and inferior angle, and subcortical structures (top to bottom row respectively). Colors indicate separate modules, with the prefrontal central-executive (CE) module in dark blue, the central sensorimotor (SM) module in green, the posterior visual (VIS) module in red, the (para)limbic (LIM) module in orange, the medial default mode (DM) module in light blue, and the cingulo-opercular (CO) module in yellow. B) Degree of similarity to average healthy network (S_R) for individual subjects. Jittered data are plotted for each group, with mean (sd) values represented by the box behind the raw data. * indicates significant group-difference.

Figure 3

Regional findings of abnormal module assignment Surface plots showing exploratory regional findings (S_Rnode) at uncorrected p < .05 for surface-based (A) and MNI-based (B) processing methods respectively. * FDR-corrected significant effect for right superior temporal gyrus, anterior division.

Figure 4

Psychosis-free survival for typical vs. atypical baseline connectome organization Kaplan-Meier plot showing psychosis-free survival functions for CHRs with above-average (red) and below-average (blue) levels of S_R (reflecting typical and atypical connectome organization respectively) as a functional of time since baseline (days).