Retracing Hodgkin and Huxley: State Recovery Does Not Certify Mechanism

Recent developments in brain recording are driving a demand for machine learning tools capable of decoding the latent structure of large populations of neurons. In this paper, we provide a comprehensive survey that outlines the trajectory of Latent Variable Models (LVMs) from early state-space models to more recent deep generative models. We organize the literature into three closely related domains: (1) Single-Region Latent Dynamics, which includes models such as linear dynamical systems to more complex dynamics represented by Recurrent Neural Networks (RNNs) and Neural Ordinary Differential Equations (ODEs); (2) Multi-Region Communication, which employs probabilistic as well as subspace methods to study how information is transferred across different brain areas considering synaptic propagation delays and network connectivity; and (3) Behavior-Aligned Modeling, which seeks to disentangle neural activity related to task performance from other internal states via supervised or contrastive learning. This survey also includes large-scale neural foundation models, such as Transformers and diffusion models, that rely on large-scale pre-training for optimal performance across subjects. Finally, we conclude and discuss benchmarks, evaluation criteria, and open challenges, such as the ability to identify causal links or directionality of communication, to facilitate future research for bridging interpretable brain dynamics with reliable neural decoding.

Biophysical neuron models link measurements of neural activity to underlying cellular mechanisms. Yet, a central challenge is that the kinetics of many ion channels are poorly characterized, and practical simplifications -- omitting channels or reducing morphological detail -- introduce systematic gaps between model and biology. Bridging these gaps requires approaches that can flexibly discover unmodeled dynamics while preserving mechanistic interpretability. Here, we introduce a hybrid modeling framework that embeds neural ordinary differential equations into conductance-based biophysical models to capture unknown currents or mis-specified channel kinetics. By parameterizing the neural ODE in terms of voltage-dependent steady-state and time-constant functions, we recover interpretable gating dynamics directly from voltage recordings without assuming a functional form. We show that the hybrid model fits the gating kinetics of 2400 ion channel models and recovers unknown gating dynamics from single current-clamp recordings, generalizing to out-of-distribution stimulus regimes under realistic inputs and parameter misspecification. We also use our method to reduce a multicompartment model of a cortical neuron into a single-compartment hybrid model with a learned axial current, yielding up to an order of magnitude lower computational cost. Together, our results establish a plug-and-play framework for selectively replacing unknown components of conductance-based models with neural ODEs while preserving their mechanistic structure.

Accurate reconstruction of long-duration neural recordings is challenging because local field potentials (LFPs) are high-resolution, multichannel, transient, and variable across subjects. We present PCA-DMD, a scalable operator-theoretic framework that segments LFP recordings into overlapping windows, projects them into a compact PCA space, learns linear Koopman evolution in the latent space, and reconstructs continuous signals through inverse projection and overlap-add aggregation. On 200,000-sample hippocampal recordings, PCA-DMD outperformed Classical DMD, SpDMD, MrDMD, and HODMD, achieving KLD=0.0761 and HD=0.0847. In all-pair cross-subject zero-shot generalization at 300,000 samples, correlations were 0.9504-0.9800, with HD=0.0010-0.0072 and KLD=0.0005-0.0022, without target-subject fine-tuning. The prediction showed close one-step agreement on temporally held-out LFP segments across the unseen interval and multiple channels. Scalability analysis from 400,000 to 900,000 samples showed stable zero-shot reconstruction, with mean correlation remaining about 0.965-0.968 while computational cost increased predictably. External validation on an independent 93-channel Allen Neuropixels recording yielded mean and median channel-wise correlations of 0.7427 and 0.7990, respectively. Koopman spectral and mode analyses revealed dominant eigenvalues concentrated near the unit circle. PCA-DMD therefore provides an interpretable, generalizable, and computationally scalable framework for reconstructing high-dimensional neural dynamics.