An open-source framework for predicting ultrasound neuromodulation: bridging tissue elastomechanics and neuron firing dynamics

Transcranial focused ultrasound is a non-invasive neuromodulation modality with millimetre-scale resolution, but its biophysical mechanism of action remains unresolved. Exposure is conventionally specified by transducer surface or derated focal pressure, quantities only indirectly related to what matters for therapy: which neurons fire and through which pathway. We address this gap with an end-to-end computational framework that maps a transcranial acoustic field to per-voxel neural firing maps registered to anatomy. The pipeline couples heterogeneous nonlinear full-wave acoustic propagation, viscoelastic shear-wave propagation, Pennes bioheat diffusion, a bilayer-mechanics conversion from tissue strain to membrane tension, and a multi-compartment Hodgkin-Huxley neuron carrying mechanosensitive, cavitation-coupled, calcium-coupled, thermosensitive, astrocytic-gliotransmitter, and mechanosensitive-synaptic pathways. Six candidate mechanisms are implemented as interchangeable components on a shared neuron model, so their firing predictions can be compared directly on the same field, and every numerical parameter is classified by source and bracketed by sensitivity analysis. We demonstrate the framework on a theta-burst sonication delivered through a micro-CT human-skull specimen targeting the left dorsal anterior cingulate cortex, predicting a focal firing zone of approximately 8,500 mm^3 at a focal thermal rise well within ITRUSST consensus safety envelopes. The principal output is a per-voxel firing-volume map resolved jointly with the acoustic, elastic, and thermal field histories that drive it, giving spatially resolved, falsifiable predictions that are testable against high-density extracellular recordings and support parameter estimation, cell-type-resolved mechanism identification, and quantitative safety assessment for ultrasound neuromodulation.