1000 Section - Anatomically Informed Parameter Stratification of Transcranial Focused Ultrasound for the Aging Brain via a Simulation Guided Multi Modal Clinical Trial Targeting the Left Dorsolateral Prefrontal Cortex

To validate a simulation-to-clinic translational framework and determine the optimal acoustic parameters for modulating the left dorsolateral prefrontal cortex (DLPFC) to enhance executive function in older adults , thereby addressing the translational barrier posed by age-related cranial morphological variability and the lack of population-specific dosing protocols.

Design: A simulation-guided, prospective, randomized, double-blind, within-subject crossover study. High-fidelity computational simulations based on the "Chinese2020" standard brain template were first employed to screen the propagation characteristics and thermal safety of 2,400 parameter combinations (intensities 1–30 W/cm², frequencies 200–1000 kHz, duty cycles 5–50%). Guided by a safety threshold of < 1.0°C, four distinct protocols were selected for clinical validation in 30 healthy older adults (aged 58.47±7.88 years). Interventions targeted the left DLPFC using a 2×2 factorial arrangement of Frequency (500 kHz vs. 800 kHz) and Duty Cycle (20% vs. 33%). Outcomes were assessed via a multi-modal framework comprising 64-channel EEG, 106-channel fNIRS, and cognitive behavioral tasks.

Results: Acoustic simulations confirmed that peak tissue temperature rise remained < 0.31°C for all clinical protocols, ensuring safety. Clinical validation revealed a frequency-dependent dissociation of effects: Protocol 2 (500 kHz, 20% duty cycle) elicited the most robust neural response, characterized by significantly increased prefrontal Alpha/Theta power (p< 0.001) and enhanced functional connectivity between the left DLPFC and Broca’s area (p=0.024). Behaviorally, this protocol significantly improved strategy matching performance in high-load visuospatial tasks (p< 0.001). Conversely, 800 kHz stimulation modulated simple motor reaction times but failed to effectively activate the higher-order executive control network.
 

Conclusion: Low-frequency (500 kHz), low-duty-cycle tFUS is identified as the optimal protocol for activating the executive control network in the aging brain, likely due to optimized transcranial transmission modeled on population-specific anatomy. This work establishes a robust framework for precision tFUS dosing, bridging the chasm between physical modeling and functional clinical outcomes.