John Pearson

Ganchao Wei, John Pearson

High-dimensional count data arise in applications such as single-cell RNA sequencing and neural spike trains, where mapping between distributions across successive batches or time points form critical components of data analysis. The recent success of diffusion- and flow-based deep generative models for images, video, and text motivates extending these ideas to count-valued settings, but many existing methods either treat each count as a categorical state or transform counts into a continuous space, neither of which is natural or efficient when the count range is large. We propose count-FM, a flow-matching framework for count data based on a continuous-time birth-death process with local unit jumps. Count-FM learns marginal transitions efficiently in count space through simulation-free training of conditional transition rates, allowing transport between arbitrary count-distributed source and target populations. In simulation, count-FM achieves better sample quality than representative baselines while using substantially fewer parameters. We further apply count-FM to scRNA-seq and neural spike-train data for unconditional generation, transport, and conditional generation. Across these tasks, count-FM yields improved sample quality, greater modeling efficiency, and interpretable transport paths.

Daniela de Albuquerque, John Pearson

Beyond estimating parameters of interest from data, one of the key goals of statistical inference is to properly quantify uncertainty in these estimates. In Bayesian inference, this uncertainty is provided by the posterior distribution, the computation of which typically involves an intractable high-dimensional integral. Among available approximation methods, sampling-based approaches come with strong theoretical guarantees but scale poorly to large problems, while variational approaches scale well but offer few theoretical guarantees. In particular, variational methods are known to produce overconfident estimates of posterior uncertainty and are typically non-identifiable, with many latent variable configurations generating equivalent predictions. Here, we address these challenges by showing how diffusion-based models (DBMs), which have recently produced state-of-the-art performance in generative modeling tasks, can be repurposed for performing calibrated, identifiable Bayesian inference. By exploiting a previously established connection between the stochastic and probability flow ordinary differential equations (pfODEs) underlying DBMs, we derive a class of models, inflationary flows, that uniquely and deterministically map high-dimensional data to a lower-dimensional Gaussian distribution via ODE integration. This map is both invertible and neighborhood-preserving, with controllable numerical error, with the result that uncertainties in the data are correctly propagated to the latent space. We demonstrate how such maps can be learned via standard DBM training using a novel noise schedule and are effective at both preserving and reducing intrinsic data dimensionality. The result is a class of highly expressive generative models, uniquely defined on a low-dimensional latent space, that afford principled Bayesian inference.

Anne Draelos, Pranjal Gupta, Na Young Jun et al.

While most classic studies of function in experimental neuroscience have focused on the coding properties of individual neurons, recent developments in recording technologies have resulted in an increasing emphasis on the dynamics of neural populations. This has given rise to a wide variety of models for analyzing population activity in relation to experimental variables, but direct testing of many neural population hypotheses requires intervening in the system based on current neural state, necessitating models capable of inferring neural state online. Existing approaches, primarily based on dynamical systems, require strong parametric assumptions that are easily violated in the noise-dominated regime and do not scale well to the thousands of data channels in modern experiments. To address this problem, we propose a method that combines fast, stable dimensionality reduction with a soft tiling of the resulting neural manifold, allowing dynamics to be approximated as a probability flow between tiles. This method can be fit efficiently using online expectation maximization, scales to tens of thousands of tiles, and outperforms existing methods when dynamics are noise-dominated or feature multi-modal transition probabilities. The resulting model can be trained at kiloHertz data rates, produces accurate approximations of neural dynamics within minutes, and generates predictions on submillisecond time scales. It retains predictive performance throughout many time steps into the future and is fast enough to serve as a component of closed-loop causal experiments.

Anne Draelos, Eva A. Naumann, John M. Pearson

One of the primary goals of systems neuroscience is to relate the structure of neural circuits to their function, yet patterns of connectivity are difficult to establish when recording from large populations in behaving organisms. Many previous approaches have attempted to estimate functional connectivity between neurons using statistical modeling of observational data, but these approaches rely heavily on parametric assumptions and are purely correlational. Recently, however, holographic photostimulation techniques have made it possible to precisely target selected ensembles of neurons, offering the possibility of establishing direct causal links. Here, we propose a method based on noisy group testing that drastically increases the efficiency of this process in sparse networks. By stimulating small ensembles of neurons, we show that it is possible to recover binarized network connectivity with a number of tests that grows only logarithmically with population size under minimal statistical assumptions. Moreover, we prove that our approach, which reduces to an efficiently solvable convex optimization problem, can be related to Variational Bayesian inference on the binary connection weights, and we derive rigorous bounds on the posterior marginals. This allows us to extend our method to the streaming setting, where continuously updated posteriors allow for optional stopping, and we demonstrate the feasibility of inferring connectivity for networks of up to tens of thousands of neurons online. Finally, we show how our work can be theoretically linked to compressed sensing approaches, and compare results for connectivity inference in different settings.

Shariq Iqbal, John Pearson

Despite increasing attention paid to the need for fast, scalable methods to analyze next-generation neuroscience data, comparatively little attention has been paid to the development of similar methods for behavioral analysis. Just as the volume and complexity of brain data have grown, behavioral paradigms in systems neuroscience have likewise become more naturalistic and less constrained, necessitating an increase in the flexibility and scalability of the models used to study them. In particular, key assumptions made in the analysis of typical decision paradigms --- optimality; analytic tractability; discrete, low-dimensional action spaces --- may be untenable in richer tasks. Here, using the case of a two-player, real-time, continuous strategic game as an example, we show how the use of modern machine learning methods allows us to relax each of these assumptions. Following an inverse reinforcement learning approach, we are able to succinctly characterize the joint distribution over players' actions via a generative model that allows us to simulate realistic game play. We compare simulated play from a number of generative time series models and show that ours successfully resists mode collapse while generating trajectories with the rich variability of real behavior. Together, these methods offer a rich class of models for the analysis of continuous action tasks at the single-trial level.

Xin, Chen, Jeffrey M Beck et al.

Experiments that study neural encoding of stimuli at the level of individual neurons typically choose a small set of features present in the world --- contrast and luminance for vision, pitch and intensity for sound --- and assemble a stimulus set that systematically varies along these dimensions. Subsequent analysis of neural responses to these stimuli typically focuses on regression models, with experimenter-controlled features as predictors and spike counts or firing rates as responses. Unfortunately, this approach requires knowledge in advance about the relevant features coded by a given population of neurons. For domains as complex as social interaction or natural movement, however, the relevant feature space is poorly understood, and an arbitrary \emph{a priori} choice of features may give rise to confirmation bias. Here, we present a Bayesian model for exploratory data analysis that is capable of automatically identifying the features present in unstructured stimuli based solely on neuronal responses. Our approach is unique within the class of latent state space models of neural activity in that it assumes that firing rates of neurons are sensitive to multiple discrete time-varying features tied to the \emph{stimulus}, each of which has Markov (or semi-Markov) dynamics. That is, we are modeling neural activity as driven by multiple simultaneous stimulus features rather than intrinsic neural dynamics. We derive a fast variational Bayesian inference algorithm and show that it correctly recovers hidden features in synthetic data, as well as ground-truth stimulus features in a prototypical neural dataset. To demonstrate the utility of the algorithm, we also apply it to cluster neural responses and demonstrate successful recovery of features corresponding to monkeys and faces in the image set.