UC San Diego

Abstract Background: In a recent prospective longitudinal neuroimaging study, clinical high-risk (CHR) individuals who later developed full-blown psychosis showed an accelerated rate of gray matter thinning in superior and medial prefrontal cortex (PFC) and expansion of the ventricular system after applying a stringent correction for multiple comparisons. Although cortical and subcortical volume loss and enlarged ventricles are well characterized structural brain abnormalities among patients with schizophrenia, no prior study has evaluated whether these progressive changes of neuroanatomical indicators are linked in time prior to onset of psychosis. Therefore, we investigated the relationship between the changes in cortical gray matter thickness and ventricular volume using the longitudinal neuroimaging data from the North American Prodrome Longitudinal Study (NAPLS) at the whole-brain level. Methods: MRI structural data were acquired at baseline and 12-month follow-up, and follow-up scans for those who developed fully psychotic symptoms were assessed at the point of conversion. In total, 37 CHR cases who converted to psychosis, 230 CHR cases who did not convert (nonconverters), and 132 healthy comparison subjects had usable baseline and second time point scans. Imaging measures were first transformed to annualized rates of percent change (ARCH) in each cortical vertex. Interval is the time between BL and FU scans in years. Relationships between ARCH of total ventricle volume and ARCH of cortical gray matter values were tested vertex-wise using the general linear model. Among the subjects with BL and 12-FU data available, 125 CHR cases and 66 controls were followed to an additional third time point for a 24-month MRI assessment. For the purpose of testing the replicability of our main hypotheses, neuroanatomical ARCH measures between the 12 and 24 month follow-ups were also computed with a parallel set of statistical tests as described earlier. Results: The results showed that ventricular expansion is linked in time to progressive reduction of gray matter, rather than to structural changes in proximal subcortical regions, in a broadly distributed set of cortical regions among CHR youth, including superior, medial, lateral, and inferior PFC, superior temporal gyrus, and parietal cortices. In contrast, the healthy controls did not show the same pattern of associations. The main findings were further replicated using a third assessment wave of MRI scans in a subset of study participants who were followed for an additional year. Conclusion: In summary, expansion of the ventricular spaces is linked in time with an accelerated rate of widespread cortical thinning prior to psychosis onset. The cortical regions experiencing altered maturation during the psychosis prodrome may be more widespread than the regionally specific clusters that have been identified in previous case–control studies