Brain Activation and Aberrant Effective Connectivity in the Mentalizing Network of Preadolescent Children at Familial High Risk of Schizophrenia or Bipolar Disorder

Schizophrenia and bipolar disorder are characterized by social cognitive impairments and recent research has identified alterations of the social brain. However, it is unknown whether familial high-risk of these disorders is associated with neurobiological alterations already present in childhood.As part of The Danish High Risk and Resilience Study - VIA 11, we examined children at familial high-risk of schizophrenia (FHR-SZ, n = 121, 50% females) or bipolar disorder (FHR-BP, n = 75, 47% females) and population-based controls (PBC, n = 128, 48% females). Using functional magnetic resonance imaging and dynamic causal modeling, we investigated brain activation and effective connectivity during the social cognition paradigm from the Human Connectome Project.We found similar activation of the mentalizing network across groups, including visual area V5, dorsomedial prefrontal cortex (dmPFC), and posterior superior temporal sulcus (pSTS). Nonetheless, both familial high-risk groups showed aberrant brain connectivity in the form of increased feedforward connectivity from left V5 to pSTS compared with PBC. Children at FHR-SZ had reduced intrinsic connectivity in bilateral V5 relative to PBC, whereas children at FHR-BP showed increased reciprocal connectivity between left dmPFC and pSTS, increased intrinsic connectivity in right pSTS, and reduced feedforward connectivity from right pSTS to dmPFC compared with PBC.Our results provide first-time evidence of aberrant brain connectivity in the mentalizing network of children at FHR-SZ or FHR-BP. Longitudinal research is warranted to clarify whether aberrant brain connectivity during mentalizing constitutes an endophenotype associated with the development of a mental disorder later in life.