Drug treatment alters performance in a neural microphysiological system of information processing

Assessment of pharmacological intervention on in vitro neural systems often emphasizes molecular and structural changes. However, neural systems fundamentally process and act on information. For preclinical assays to predict drug efficacy, they must model these physiological functions. DishBrain, an in vitro assay embodying a neural system in a simulated game-world, enables quantification of information-processing capacity and dose-response profiling. Hyperactive glutamatergic dysregulation is linked to many neurological disorders. Inducible overexpression of neurogenin 2 (NGN2) in hiPSCs generated glutamatergic cultures with dysregulated hyperactivity. Anti-seizure medications (ASMs) were trialed on this model within a game-world using closed-loop electrophysiological stimulation and recordings. MEA data from day 21 of differentiation revealed significant electrophysiological development. Treatments included dimethyl sulfoxide (DMSO), phenytoin, perampanel, or carbamazepine. Carbamazepine 200 μM significantly reduced firing rates and improved gameplay metrics, such as hit/miss ratio and rally length. This marks the first demonstration of altered synthetic biological intelligence (SBI) in a neural model after drug treatment. Notably, only inhibitory compounds enhanced goal-directed activity, linking glutamatergic attenuation to performance. Neurocomputational analysis revealed nuanced pharmacological responses during closed-loop stimulation, highlighting insights beyond spontaneous activity metrics.