Focused ultrasound alters neural time irreversibility independently of response amplitude

Abstract Transcranial focused ultrasound (tFUS) can modulate activity in deep brain regions non-invasively, yet its effects remain variable and incompletely understood. Because sonication deposits mechanical energy into tissue, we asked whether responses could be clarified through the lens of stochastic thermodynamics, which links nonequilibrium dynamics to dissipation and time-irreversibility. Analyzing previously published fiber-photometry recordings from freely moving mice, we estimated the entropy production rate (EPR) before, during, and after thalamic sonication. GCaMP fluorescence rose monotonically with acoustic dose, but EPR followed a non-monotonic profile peaking at moderate intensity. Immediately after sonication, EPR was elevated yet uncorrelated with GCaMP, and retained a significant dose relationship even after accounting for response amplitude. Finally, trials with lower baseline EPR showed larger subsequent changes in both EPR and GCaMP during sonication. These findings indicate that tFUS reshapes neural dynamics beyond what signal amplitude captures, while highlighting the insights afforded by adopting stochastic thermodynamics in neuromodulation research. Competing Interest Statement The authors have declared no competing interest.