Thalamocortical Structural Covariation Networks Are Related to Familial Risk for Schizophrenia in the Context of Lower Nuclei Volume Estimates in Patients: An ENIGMA Study

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BACKGROUND Structural brain differences in the thalamus and the cortex have been widely reported in schizophrenia (SCZ) relative to neurotypical controls (NC). Most prior studies examined the thalamus as a whole, single region-of-interest. Additionally, findings in individuals at familial high-risk for schizophrenia (FHR) remain inconclusive. Here, we investigated whether local and network-wide thalamic-related structural alterations vary as a function of familial risk for schizophrenia. METHODS Structural MRI scans were obtained from 5,197 participants (3,409 NC, 257 FHR, 1,531 SCZ) across 32 cross-sectional samples within the ENIGMA Consortium. Random-effects meta-analyses, and network analyses were conducted on (i) local thalamic alterations (volume estimates of seven thalamic subdivisions), and (ii) network-wide thalamic alterations (thickness and surface-related thalamo-cortical/cortico-cortical co-variation patterns) across groups (NC, FHR, SCZ). RESULTS Individuals with SCZ showed significantly lower gray matter volume estimates in the anterior, pulvinar, medial, posterior, and ventral thalamic subdivisions compared to NC (q FDR <0.05). FHR did not differ from NC. At the network-wide level, thalamo-cortical co-variations discriminated FHR from NC (q FDR <0.05), with FHR showing intermediate co-variation between SCZ and NC. Cortico-cortical co-variation patterns revealed that SCZ and FHR shared similarly disconnected clustering configurations, distinct from NC (q FDR <0.05). CONCLUSIONS Results revealed lower thalamic volume estimates in SCZ but not in FHR, hence yielding no evidence of a familial risk trait, whereas thalamo-cortical and cortico-cortical co-variation estimates were associated with familial risk for SCZ These findings suggest that, once the thalamus is parsed into subdivisions, network-wide thalamo-cortical features may identify trait-dependent, neurobiological correlates of genetic risk for SCZ.

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