High-fidelity transcranial ultrasound multi-focal stimulation via physics-aware hologram technique

Abstract

Introduction: Transcranial ultrasound stimulation (TUS) is an emerging non-invasive neuromodulation modality that offers deep brain access with high spatial precision. However, its broader application is limited by the difficulty of reliably generating complex transcranial acoustic fields, particularly for multi-target stimulation through the skull. These limitations can lead to focal distortion, off-target exposure, and reduced reliability of neuromodulation outcomes. Materials and methods: Here, we introduce a physics-aware thickness-only acoustic hologram (TOAH) technique for precise transcranial ultrasound neuromodulation. Unlike conventional approaches that rely on simplified phase-based approximations, TOAH directly generates fabrication-ready holographic implementations while preserving consistency between numerical field synthesis and physical acoustic realization. This enables accurate formation of single-, dual-, and tri-focal stimulation patterns under transcranial conditions. We validated TOAH through in silico simulations, ex vivo acoustic measurements through skulls, and in vivo experiments. Results: Compared with state-of-the-art methods, TOAH improved focal reconstruction, energy confinement, and multi-focal balance while reducing off-target acoustic leakage. Human-skull simulations further supported robust multi-focal reconstruction under clinically relevant transcranial conditions. In a neuropathic pain mouse model, bilateral thalamic stimulation induced measurable changes in neuronal activity, reflected by reduced c-Fos expression, together with preliminary improvements in pain-related behavioral responses. These findings support the capability of the proposed technique to enable spatially localized and reproducible neuromodulation in vivo. Conclusion: Collectively, this work provides a practical proof-of-concept strategy for achieving high-precision, multi-target transcranial neuromodulation and supports further investigation for neuroscience research and future therapeutic applications.