Cross-Frequency Coupling as a Neural Substrate for Prediction Error Evaluation: A Laminar Neural Mass Modeling...

Predictive coding frameworks suggest neural computations rely on hierarchical error minimization, yet the neural implementation of this inference remains unclear. We propose that cross-frequency coupling (CFC) furnishes fundamental mechanism for this process. Using our laminar neural mass model (LaNMM), we demonstrate that signal-envelope coupling (SEC) an envelope-envelope coupling (EEC) instantiate a hierarchical comparator mechanism. Specifically, SEC generates prediction-error signals by subtracting top-down predictions from bottom-up oscillatory envelopes, while EEC operates at slower timescales to implement gating-a critical mechanism for precision weighting. To establish the face validity and clinical implications of this proposal, we model perturbations of these CFC mechanisms to investigate their roles in pathophysiological and altered neuronal function. In Alzheimer's disease, interneuron dysfunction disrupts the comparator, causing aberrant prediction error amplification in early stages and drastic attenuation in late phases. Conversely, serotonergic psychedelics increase excitatory gain, diminishing the modulatory effect of predictions and causing a failure of sensory attenuation. Collectively, these findings implicate multiscale cross-frequency coupling as a key computational mechanism supporting predictive coding and its disruption in disease.