Cross-species representation learning aligns mouse and human neural dynamics and tracks clinical drug efficacy

Integrating transcriptomic and electrophysiological data is essential for building multimodal foundation models for neuroscience. Patch-seq provides paired measurements of gene expression and intrinsic electrophysiology from the same neuron, establishing a basis for training cross-modal models. Here we introduce LangPatch, a foundation-model-based contrastive learning framework that uses paired Patch-seq data to align pretrained GenePT representations with electrophysiological phenotypes through a language-based interface. Gene descriptions and verbalized electrophysiological profiles are embedded by the same frozen text encoder. A context adapter and projection modules connect the modalities through paired contrastive learning. Across mouse visual, mouse motor, and human cortical cohorts, LangPatch achieves the highest mean transcriptome-to-electrophysiology prediction correlation among the evaluated foundation-model and representation-learning methods. It also improves held-out cross-modal alignment in the two mouse cohorts (FOSCTTM 0.107/0.135 vs. 0.208/0.222 for JAMIE, an existing cross-modal Patch-seq imputation method). It predicts transcriptomic family, type, cortical layer, and marker-gene expression from electrophysiology, exceeding other baselines on most endpoints. More importantly, the method transfers across brain areas and species: a model trained on mouse visual cortex predicts electrophysiology in motor cortex with approximately 70% correlation retention and in human cortex with 47% (58% on acute-slice recordings). Together, these results demonstrate alignment between molecular and functional representations of neurons, providing a building block for multimodal foundation models in neuroscience.

As AI models move toward clinical decision-making and personalized treatment, understanding \emph{what} a model learns is important beyond predictive accuracy alone. We investigate whether personalized latent dynamics reveal clinically associated differences even when predictive fit is similar. A lightweight CNN--Transformer EEG foundation model pretrained on the Temple University EEG Corpus (TUEG) extracts segment-level representations. Using the Temple University Epilepsy Corpus (TUEP), representations are mapped to a shared latent-state space, and sparse multinomial logistic transition distributions (mLTD) are fit independently to each subject to obtain personalized transition-dependency graphs $W_n$. Analyses include $n{=}198$ subjects (99 epilepsy / 99 non-epilepsy). At $k{=}4$, epilepsy subjects exhibit substantially denser learned dependency structure ($p{=}1.1\times10^{-7}$), with the same pattern at $k{=}6$ (19.90 vs. 13.46; $p{=}5.2\times10^{-5}$). Graph-derived features provide moderate group discrimination under 5-fold subject-wise cross-validation (AUROC 0.68 at $k{=}4$; 0.65 at $k{=}6$). In contrast, held-out log-likelihood is nearly identical between groups at $k{=}4$ ($-0.992$ vs. $-0.991$; $p{=}0.95$), with similarly matched next-state prediction (AUROC 0.855 vs. 0.861; $p{=}0.54$). Thus, similar predictive fit does not imply similar learned dynamics: groups can be comparably predictable while differing substantially in the internal dynamical structure learned by personalized models. This distinction motivates evaluating learned structure alongside predictive performance in personalized clinical models.

Does the relationship between learning rules and brain alignment generalize across species? We extend our prior finding that untrained CNNs match backpropagation at human V1 by testing the same five learning rules against macaque electrophysiology. The rules are backpropagation (BP), feedback alignment (FA), predictive coding (PC), spike-timing-dependent plasticity (STDP), and an untrained random-weights baseline. The macaque data come from two datasets: MajajHong2015 (V4/IT, 3,200 stimulus presentations, 88/168 neurons) and FreemanZiemba2013 (V1/V2, 135 stimuli, 102/103 neurons). Using RSA with identical model weights from our human study, we find: (1) all models achieve higher alignment with macaque early visual cortex (rho = 0.15-0.30 at V1/V2) than with human fMRI (rho = 0.01-0.08), consistent with the higher signal-to-noise ratio of electrophysiology; (2) STDP and PC produce the highest macaque V1/V2 alignment (rho ~ 0.30 and 0.28), consistent with their leading position among trained rules in human V1; (3) at IT, learning rule rankings show no detectable correlation across species (Kendall's tau = 0.00, p = 1.00), though this null result is expected given that n = 5 provides power only at tau = +/-1.0, and is further confounded by stimulus set differences; (4) a pretrained ResNet-50 (ImageNet) achieves rho = 0.25 at macaque IT, substantially above all custom CNN conditions (rho = 0.07-0.14), suggesting IT alignment is limited by model capacity and training data rather than by the learning rule. Noise ceilings, multi-seed variability (5 seeds), and a stimulus-control analysis are reported. These results demonstrate that early visual alignment is robust across species, while higher-area alignment is modulated by model capacity and stimulus domain.