Progressive reduction in cortical thickness as psychosis develops: a multisite longitudinal neuroimaging study of youth at elevated clinical risk

Abstract

Background: Individuals at clinical high risk (CHR) who progress to fully psychotic symptoms have been observed to show a steeper rate of cortical gray matter reduction compared with individuals without symptomatic progression and with healthy control subjects. Whether such changes reflect processes associated with the pathophysiology of schizophrenia or exposure to antipsychotic drugs is unknown.

Methods: In this multisite study, 274 CHR cases, including 35 individuals who converted to psychosis, and 135 healthy comparison subjects were scanned with magnetic resonance imaging at baseline, 12-month follow-up, or the point of conversion for the subjects who developed fully psychotic symptoms.

Results: In a traveling subjects substudy, excellent reliability was observed for measures of cortical thickness and subcortical volumes. Controlling for multiple comparisons throughout the brain, CHR subjects who converted to psychosis showed a steeper rate of gray matter loss in the right superior frontal, middle frontal, and medial orbitofrontal cortical regions as well as a greater rate of expansion of the third ventricle compared with CHR subjects who did not convert to psychosis and healthy control subjects. Differential tissue loss was present in subjects who had not received antipsychotic medications during the interscan interval and was predicted by baseline levels of an aggregate measure of proinflammatory cytokines in plasma.

Conclusions: These findings demonstrate that the brain changes are not explained by exposure to antipsychotic drugs but likely play a role in psychosis pathophysiology. Given that the cortical changes were more pronounced in subjects with briefer durations of prodromal symptoms, contributing factors may predominantly play a role in acute-onset forms of psychosis.

Keywords: Inflammation; MRI; Prefrontal cortex; Prodromal; Psychosis; Schizophrenia.

Figure 1

Statistical brain atlases plotting differences in the mean annualized rates of change in cortical thickness among converting CHR subjects (n=35), non-converting CHR subjects (n=239), and healthy controls (n=135). Panels on the left show differences between converters and controls and panels on the right show differences between converters and non-converters. In the uncorrected maps (upper panels), compared with both non-converters and controls, converters showed greater thinning (warmer colors) in left and right superior frontal, middle frontal, and medial orbitofrontal gyri and in the right superior and inferior parietal cortex, superior temporal gyrus and parahippocampal gyrus. After applying an FDR correction (p ≤ 0.01; lower panels), only the differences in right superior frontal, middle frontal, and medial orbitofrontal regions remained significant for both contrasts. The small clusters showing greater expansion (cooler colors) in the converters compared with controls in the uncorrected maps did not survive correction for multiple comparisons. There were no differences between non-converters and controls before or after FDR correction.

Figure 2

Mean annualized rates of change in right prefrontal cortex thickness and third ventricle volume by anti-psychotic (AP) drug exposure during the inter-scan interval. Group differences were significant for both variables (F=7.46, p=0.000008 for right prefrontal cortex; F=3.74, p=0.005 for third ventricle). Converters with and without AP medications showed significantly steeper reduction in right prefrontal thickness and significantly greater expansion of the third ventricle compared with non-converters with and without AP medications and controls.

Figure 3

Mean annualized rates of change in right prefrontal cortex thickness and third ventricle volume by duration of prodromal symptoms. Group differences were significant for both variables (F=9.68, p=0.0000002 for right prefrontal cortex; F=3.87, p=0.004 for third ventricle). Converters with short durations showed significantly steeper reduction in right prefrontal thickness compared with long-duration converters, short- and long-duration non-converters, and controls; they also showed significantly greater third ventricle expansion compared with all of the groups except for long-duration converters. Converters with long durations showed significantly steeper reduction in right prefrontal thickness and significantly greater expansion of the third ventricle compared with long-duration non-converters and controls.