Model-based prediction of muscarinic receptor function from auditory mismatch negativity responses

Drugs affecting neuromodulation, for example by dopamine or acetylcholine, take centre stage among therapeutic strategies in psychiatry. These neuromodulators can change both neuronal gain and synaptic plasticity and therefore affect electrophysiological measures. An important goal for clinical diagnostics is to exploit this effect in the reverse direction, i.e., to infer the status of specific neuromodulatory systems from electrophysiological measures. In this study, we provide proof-of-concept that the functional status of cholinergic (specifically muscarinic) receptors can be inferred from electrophysiological data using generative (dynamic causal) models. To this end, we used epidural EEG recordings over two auditory cortical regions during a mismatch negativity (MMN) paradigm in rats. All animals were treated, across sessions, with muscarinic receptor agonists and antagonists at different doses. Together with a placebo condition, this resulted in five levels of muscarinic receptor status. Using a dynamic causal model - embodying a small network of coupled cortical microcircuits - we estimated synaptic parameters and their change across pharmacological conditions. The ensuing parameter estimates associated with (the neuromodulation of) synaptic efficacy showed both graded muscarinic effects and predictive validity between agonistic and antagonistic pharmacological conditions. This finding illustrates the potential utility of generative models of electrophysiological data as computational assays of muscarinic function. In application to EEG data of patients from heterogeneous spectrum diseases, e.g. schizophrenia, such models might help identify subgroups of patients that respond differentially to cholinergic treatments. SIGNIFICANCE STATEMENT: In psychiatry, the vast majority of pharmacological treatments affect actions of neuromodulatory transmitters, e.g. dopamine or acetylcholine. As treatment is largely trial-and-error based, one of the goals for computational psychiatry is to construct mathematical models that can serve as "computational assays" and infer the status of specific neuromodulatory systems in individual patients. This translational neuromodeling strategy has great promise for electrophysiological data in particular but requires careful validation. The present study demonstrates that the functional status of cholinergic (muscarinic) receptors can be inferred from electrophysiological data using dynamic causal models of neural circuits. While accuracy needs to be enhanced and our results must be replicated in larger samples, our current results provide proof-of-concept for computational assays of muscarinic function using EEG.