2026 ECNP Congress

PS03-3177

Computational modeling of magnetoencephalographic auditory oddball responses in adolescents at familial high-risk for psychosis

Oskar Jefsen — M. Gregersen, S.B. Roed, R. Nudel, D. Hauke, A.F. Bundgaard, A.F. Laursen, L. Veddum, K.S. Madsen, W. Baaré, K.M. Larsen, H.R. Siebner, T. Lund, L. Østergaard, N. Hemager, A.A.E. Thorup, M. Nordentoft, A.N. Greve, O. Mors, K. Friston, Y. Shtyrov, M. Dietz · Aarhus University Hospital, Psychosis Research Unit, Aarhus N, Denmark

2026 ECNP Congress

Background

Schizophrenia (SZ) and bipolar disorder (BP) are severe mental illnesses with a typical onset in early adulthood. Auditory oddball responses, including the mismatch negativity (MMN) are consistently found to be impaired in adult patients with schizophrenia and bipolar disorder [1]. However, data regarding these neurophysiological markers in high-risk adolescent populations remains sparse, leaving a critical gap in our understanding of early disease mechanisms. Recent advancements in computational modeling suggest that oddball response impairments in chronic SZ are driven by reduced synaptic gain of excitatory pyramidal cells, but whether similar alterations are present in adolescents with familial or genetic risk remains unknown.

Methods

We studied participants enrolled in The Danish High Risk and Resilience Study – VIA15 [2], a nationwide-representative, prospective cohort study. We measured auditory oddball responses in 59 adolescents at familial high risk of SZ (FHR-SZ), 38 adolescents at familial high risk of BP (FHR-BP), and 75 population-based controls (PBC) using magnetoencephalography (MEG) during a roving auditory oddball paradigm. We investigated sensor- and source-level evoked responses using Statistical Parametric Mapping (SPM) software, applying multiple sparse priors to for source localization. We modeled brain connectivity using convolution-based dynamic causal modelling (DCM) for event-related responses. The cortical network architecture consisted of 6 sources: of bilateral primary auditory cortices, bilateral (posterior) superior temporal gyri, and bilateral (ventral) precentral gyri. We examined the impact of familial and polygenic risk for SZ and BP, and associations with global level of functioning and auditory psychotic-like experiences on model parameters using parametric empirical Bayes (PEB).

Results

Sensor- and source-level analyses detected only trend-level differences in oddball responses between adolescent at familial high risk of SZ and PBCs, but no differences between FHR-BP and PBCs. Global level of functioning was associated with trend-level alterations in oddball-responses. DCM analyses revealed reduced oddball-dependent gain of frontal pyramidal cells in individuals at FHR-SZ vs. PBC, FHR-BP vs. PBC. Similar associations were found with lower level of functioning, also when adjusting for high risk-status. Sensitivity analyses using simulated data confirmed that a reduction in frontal pyramidal gain could replicate the trend-level effects observed in sensor-level MEG data. Auditory psychotic experiences were associated with oddball-dependent disinhibition of the left superior temporal gyrus and increased feed-forward connectivity from the right primary auditory cortex to the right superior temporal gyrus, suggesting a link between emerging psychotic symptoms and disinhibition of auditory circuits.

Conclusions

In this study, computational modelling of magnetoencephalographic auditory oddball responses identifies latent synaptic connectivity alterations in adolescents at familial risk of SZ and BP that traditional analyses may overlook. By mapping these circuit-level deficits to clinical symptoms and functional decline, this study highlights the utility of biophysical modeling in bridging the gap between genetic risk and the emergent pathophysiology of psychotic and mood disorders during the critical adolescent developmental period.

References

  1. Adams RA, Pinotsis D, Tsirlis K, Unruh L, Mahajan A, Horas AM, et al. Computational modeling of electroencephalography and functional magnetic resonance imaging paradigms indicates a consistent loss of pyramidal cell synaptic gain in schizophrenia. Biological psychiatry. 2022;91(2):202-15.
  2. Thorup, A.A.E., Hemager, N., Bliksted, V.F., Greve, A.N., Ohland, J., Wilms, M., Rohd, S.B., Birk, M., Bundgaard, A.F., Laursen, A.F. and Jefsen, O.H., 2022. The danish high-risk and resilience study—VIA 15–a study protocol for the third clinical assessment of a cohort of 522 children born to parents diagnosed with schizophrenia or bipolar disorder and population-based controls. Frontiers in psychiatry, 13, p.809807.