Reclassifying Transcranial Pulse Stimulation as TNUS: Nonlinear Mechanics Necessitate Departure from the ITRUSST Framework

AbstractBackground Transcranial ultrasound has emerged as a promising non-invasive neuromodulation modality for Alzheimer's disease (AD). However, its clinical translation is hindered by inconsistent biophysical classification between quasi-linear low-intensity focused ultrasound (LIFU) and nonlinear pulse-based approaches. Objective To propose a Transcranial Nonlinear Ultrasound Stimulation (TNUS) framework for the formal reclassification of Transcranial Pulse Stimulation (TPS), enabling clear differentiation of nonlinear wave mechanics from quasi-linear acoustics. Methods This perspective review integrates biophysical modeling within the nonlinear Westervelt regime, critically appraises recent clinical trial data, and conducts a comparative analysis of acoustic dosimetry by contrasting the periodic waves characteristic of linear LIFU with the shock-front dynamics of TPS. Results TPS is characterized by an extreme pressure gradient (), representing a five-order-of-magnitude divergence from LIFU. This regime facilitates a Volume Force model and Ballistic Gating of ion channels via displacement currents, a mechanism distinct from the steady-state pathways of intramembrane cavitation. In the atrophied AD brain, pathological expansion of the cerebrospinal fluid (CSF) compartment induces focal displacements and compromises wavefront integrity through refractive aberrations at the CSF–parenchyma interface. While the Glassy Regime of tissue provides a biomechanical safety buffer, the compromised compliance in Cerebral Amyloid Angiography (CAA) requires TPS protocols to remain below the vascular ultimate tensile strength (UTS). Conclusions Future clinical optimization of TPS necessitates a transition toward structure-aware dosimetry. The implementation of adaptive beamforming (e.g., TUSNet) and individualized impulse titration is essential to mitigate refractive aberrations and vascular failure risks in the pathologically heterogeneous aging brain.