Nonparametric Causal Inference for Optogenetics: Sequential Excursion Effects for Dynamic Regimes

Gabriel Loewinger, Alexander W. Levis, Francisco Pereira

Journal of the American Statistical Association · Mon

DOI: 10.1080/01621459.2026.2635071

Abstract

Optogenetics is a powerful neuroscience technique for studying how neural circuit manipulation affects behavior. Standard analysis conventions discard information and severely limit the scope of the causal questions that can be probed. To address this gap, we 1) draw connections to the causal inference literature on sequentially randomized experiments, 2) propose nonparametric estimators for analyzing “open-loop” (static regime) optogenetics behavioral experiments, 3) derive extensions of history-restricted marginal structural models for dynamic treatment regimes with positivity violations for “closed-loop” designs, and 4) propose a taxonomy of identifiable causal effects that encompass a far richer collection of scientific questions compared to standard methods. From another view, our work builds upon “excursion effect” methods—popularized recently in the mobile health literature—to estimate causal contrasts for general treatment sequences in the presence of positivity violations. We describe sufficient conditions for identifiability of the proposed causal estimands, and provide asymptotic statistical guarantees for a proposed inverse probability-weighted estimator, a multiply-robust estimator (for two intervention timepoints), a hypothesis testing procedure, and a computationally scalable implementation. Finally, we apply our methodology to data from a recent neuroscience study and show how it provides insight into causal effects of optogenetics on behavior that are obscured by standard analyses.

Keywords

marginal structural models, optogenetics, excursion effects, dynamic treatment regimes, micro-randomized trials, sequentially randomized experiments, neuroscience

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