SomaFocus

High-density extracellular recordings from the interior of intact brain organoids enable automated high-throughput functional assay

Fan Wu , Cuthbert Steadman, Liam Argent, Brian Jamieson, Shamsudheen Karuthedath Vellarikkal, Alex M. Tamburino, Iya Khalil, Vanessa M. Peterson, Matthew E. Kennedy, Rebecca Mathew, Eran Stark, Bilal Cakir

Abstract

Bridging the gap between preclinical screening and clinical outcomes remains a major challenge in drug development for neurological disorders. Brain organoids, derived from human induced pluripotent stem cells, offer a scalable and physiologically relevant platform to model human neural circuits. We develop a fully automated system to record neural activity from the interior of intact human cortical organoids using a highdensity microfabricated probe. The robotic system completes insertion within minutes while preserving organoid integrity and enables immediate recording of spontaneous spikes. We extract physiologically grounded and deterministic spike features, and train a long short-term memory classifier to distinguish between organoids derived from healthy individuals and those harboring familial Alzheimer’s disease (AD) mutations in the amyloid precursor protein. Despite intra-class variability, the classifier differentiates between organoid classes with 100% accuracy. The model classifies AD organoids treated with a drug candidate that reduces amyloid-β levels as retaining an AD-like electrophysiological phenotype, demonstrating that functional readout can contradict molecular markers. The findings establish a high-throughput functional framework that may complement and extend existing drug screening assays.