COMPUTATIONAL MODELLING OF MAGNETOENCEPHALOGRAPHIC ODDBALL RESPONSES IN ADOLESCENTS AT FAMILIAL HIGH-RISK FOR SCHIZOPHRENIA OR BIPOLAR DISORDER

Auditory responses, including the mismatch negativity (MMN), are impaired in patients with schizophrenia (SZ) and bipolar disorder (BP). However, prodromal data from adolescents at risk for a mental disorder are sparse. Computational modelling of the MMN implicates reduced excitability (cortical gain) of pyramidal cells in patients with SZ, but whether similar alterations are present in adolescents at familial or genetic risk remains unknown. We recruited participants enrolled in The Danish High Risk and Resilience Study – VIA15, a nationwide-representative, prospective cohort study. Using magnetoencephalography (MEG), we measured auditory oddball responses in 59 adolescents at familial high-risk for SZ (FHR-SZ), 38 adolescents at familial high-risk for BP (FHR-BP), and 75 population-based controls (PBC). We investigated evoked responses and modelled brain connectivity using dynamic causal modelling (DCM) - a biophysical model of excitatory and inhibitory synaptic connections. Sensor analyses did not detect any differences in oddball responses between adolescents at FHR compared to PBC. However, DCM revealed reduced excitability of superficial pyramidal cells in the left inferior frontal gyrus in individuals at FHR-SZ and FHR-BD compared to PBC. While there was no effect of polygenic risk for SZ, polygenic risk for BP was associated with stronger feedforward connectivity from right auditory cortex to superior temporal gyrus. Auditory psychotic experiences were associated with disinhibition (increased excitability) of the left superior temporal gyrus (Wernicke’s area). In conclusion, computational modelling of auditory responses reveals an association between genetic risk for SZ and BD and altered synaptic connectivity, otherwise undetected in classical analyses.