Microstructural Cortical Gray Matter Changes Preceding Accelerated Volume Changes in Individuals at Clinical High Risk for Psychosis

Recent studies show that accelerated cortical gray matter (GM) volume reduction seen in anatomical MRI can help distinguish between individuals at clinical high risk (CHR) for psychosis who will develop psychosis and those who will not. This reduction is thought to result from an accumulation of microstructural changes, such as decreased spine density and dendritic arborization. Detecting the microstructural sources of these changes before they accumulate is crucial, as volume reduction likely indicates an underlying neurodegenerative process. Our study aimed to detect these microstructural GM alterations using diffusion MRI (dMRI). We tested for baseline and longitudinal group differences in anatomical and dMRI data from 160 individuals at CHR and 96 healthy controls (HC) acquired in a single imaging site. Eight cortical lobes were examined for GM volume and GM microstructure. A novel dMRI measure, interstitial free water (iFW), was used to quantify GM microstructure by eliminating cerebrospinal fluid contribution. Additionally, we assessed whether these measures differentiated the 33 individuals at CHR who developed psychosis (CHR-P) from the 127 individuals at CHR who did not (CHR-NP). At baseline the CHR group had significantly higher iFW than HC in the prefrontal, temporal, parietal, and occipital lobes, while volume was reduced only in the temporal lobe. Neither iFW nor volume differentiated between the CHR-P and CHR-NP groups at baseline. However, in most brain areas, the CHR-P group demonstrated significantly accelerated iFW increase and volume reduction with time than the CHR-NP group. Our results demonstrate that microstructural GM changes in individuals at CHR have a wider extent than volumetric changes and they predate the acceleration of brain changes that occur around psychosis onset. Microstructural GM changes are thus an early pathology at the prodromal stage of psychosis that may be useful for early detection and a better mechanistic understanding of psychosis development.