Convergent and divergent gray matter volume abnormalities in unaffected first-degree relatives and ultra-high risk individuals of schizophrenia

Abstract High-risk populations of schizophrenia can be mainly identified as genetic high-risk based on putative endophenotypes or ultra-high-risk (UHR) based on clinically manifested symptoms. Previous studies have consistently shown brain structural abnormalities in both genetic high-risk and UHR individuals. In this study, we aimed to disentangle the convergent and divergent pattern of gray matter alterations between UHR and unaffected first-degree relatives from genetic high-risk individuals. We used structural MRI scans and voxel-based morphometry method to examine gray matter volume (GMV) differences among 23 UHR subjects meeting the Structured Interview for Prodromal Syndromes (SIPS) criteria, 18 unaffected first-degree relatives (UFDR), 26 first-episode schizophrenia patients (FES) and 54 healthy controls (CN). We found that a number of brain regions exhibited a monotonically decreasing trend of GMV from CN to UFDR to UHR to FES. Compared with CN, the UHR subjects showed significant decreases of GMV similar to the patients in the inferior temporal gyrus, fusiform gyrus, middle occipital gyrus, insula, and limbic regions. Moreover, the UHR transformed subgroup had significantly lower GMV than UHR non-transformed subgroup in the right inferior temporal/fusiform gyrus. On the other hand, the UFDR subjects only showed significant GMV decreases in the inferior temporal gyrus and fusiform. Moreover, we found GMV in the occipital lobe was negatively correlated with the UHR subjects’ composite positive symptom of SIPS, and GMV in the cerebellum was positively correlated with FES subjects’ symptom severity. Our results suggest that GMV deficits and regional dysfunction are evident prior to the onset of psychosis and are more prominent in the UHR than the UFDR individuals.