The Neural Impact Score benchmarks drugs in Multi-Region Brain Organoids

Only about 10% of drugs that clear animal testing succeeds in humans, and central nervous system (CNS) programs carry an even steeper translational gap. Human-relevant NAMs are gaining global regulatory and funding support, creating an urgent need for interpretable preclinical systems that can generate comparable, decision-ready evidence across assays, models, and species. Yet the multimodal treatment-response data such systems produce are still evaluated assay by assay, with no unified metric showing whether a compound moves neural tissue toward a desirable or undesirable state. Here we present a framework called the Neural Impact Score (NIS), which translates multimodal CNS drug-response data into a bidirectional score across four pre-defined biological categories: neurodevelopment, neuroinflammation, neurodegeneration, and longevity. A positive score indicates a desirable shift, and a negative score indicates the opposite, placing compounds on a single scale across assays, model systems, and species. To demonstrate NIS, we analyzed a vascularized human day-200 multi-region brain organoid (MRBO) composed of cortical, endothelial, and brainstem lineages and mimicking a mid-gestational cortical window (GW18–GW22). We tested five compounds with distinct mechanisms of action: glucagon-like peptide-1 receptor agonist (GLP-1RA); norepinephrine-dopamine reuptake inhibitor (NDRI); selective serotonin reuptake inhibitor (SSRI); sphingosine-1-phosphate receptor modulator; and Akt activator, using single-nucleus RNA sequencing, bulk RNA sequencing, proteomics, and multi-electrode array electrophysiology. NIS integrated these readouts into category and composite scores, separating beneficial from adverse effects for each compound and sorting them into interpretation tiers. Applying the same framework to independent human and rodent datasets without retraining, we recovered conserved human antidepressant responses despite near-chance gene-level agreement between human MRBO and rat brain and identified an endothelial-dependent human-specific GLP-1 response absent from murine dorsal vagal complex. NIS therefore provides a human-relevant framework for drug evaluation and cross-species benchmarking, with a design extensible to other neural systems.