Epilepsy disease model treated in a laboratory dish

A research team led by Cortical Labs has used an epilepsy-like disease model in a laboratory dish to demonstrate that improved information processing and neural function can be achieved using a medication designed specifically to treat the disease. The research marks a significant breakthrough in the study and treatment of neurological disorders in real time, and was made possible thanks to collaborators at the University of Cambridge and bit.bio.

Assessment of pharmacological intervention on in vitro neural systems often emphasises 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.

Cortical Labs’ DishBrain, an in vitro synthetic biological intelligence (SBI) assay embodying a neural system in a simulated game world, enables the quantification of this information-processing capacity. However, the question remained as to whether such a system permits classical pharmacological interrogation and dose-response profiling.

Hyperactive glutamatergic dysregulation is linked to neurological disorders including epilepsy, and inducible overexpression of neurogenin 2 (NGN2) in human induced pluripotent stem cells (hiPSCs) generates glutamatergic cultures with dysregulated hyperactivity. The research, therefore, tested three anti-seizure medications (ASMs) — phenytoin, perampanel and carbamazepine — on NGN2 neurons from day 21 of differentiation in this system.

The key finding was that, while all compounds altered spontaneous firing, carbamazepine 200 µM significantly improved gameplay metrics. This marks the first known demonstration of altered SBI following exogenous drug treatment, with the results published in the journal Communications Biology.

“This breakthrough is a major step forward in … how we study and understand diseases and drugs that are designed to treat related neural processes impacted by these diseases,” said Brett Kagan, Chief Scientific Officer at Cortical Labs. “For the first time, alongside some of the world’s most eminent researchers in their field, we’ve been able to show that impaired information processes [in] a disease in a dish can be restored using a drug designed specifically to treat it.”

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.

“One of the most pressing challenges in neuroscience is improving the success rate of effective new treatments reaching patients,” said Brad Watmuff, Head of Biology at Cortical Labs. “Our work highlights a key obstacle to this goal — that the neural functional endpoints we typically rely on to define treatment efficacy may not be optimal. Importantly, we show these endpoints can be influenced and even improved with drug intervention, opening the door to more meaningful measures of therapeutic success.”

“While this is an incredibly significant milestone, and the realisation of years of focus at Cortical Labs, it’s only the start,” Kagan said. “The ability to observe how living neurons react to real-time stimulation and drug treatment opens up entirely new ways to develop, test and personalise therapies — all without relying on animal models. Based on our early findings, we’ll continue to refine the modelling with the aim of developing more effective, patient-specific therapies in the future.”

Image credit: iStock.com/koto_feja