ALT Focused ultrasound (FUS) offers a promising, non-invasive method for modulating neural activity and delivering therapies deep within the brain with immense clinical potential. However, progress in developing transcranial ultrasound (TUS) for clinical applications has been hindered by several factors. The complexity of the human skull causes focal aberrations and attenuation, thereby presenting a major obstacle to the precise targeting of ultrasound waves. Although phased arrays can correct for these aberrations, their high cost and continuous reliance on magnetic resonance imaging (MRI) pose significant obstacles for widespread academic research and clinical translation. To address these challenges, this thesis proposes an innovative framework for the design, registration, and clinical application of acoustic holograms. First, we introduce a novel frequency-domain topology optimization method that overcomes the breakdown of traditional phase-only designs in the megahertz regime by acco

ALT Accurate acoustic modelling of the skull is essential for simulation-guided transcranial focused ultrasound (tFUS), but commonly used skull parameterisation strategies differ in complexity and reported accuracy. This study experimentally compared five k-Wave skull models: two voxel-wise linear mapping models, two three-layer models, and one single-layer fixed-parameter model. Nineteen regions of interest from five historical and two Thiel-embalmed human skulls were tested at 220 kHz, 680 kHz, and 1000 kHz. Bowl-surface source fields were reconstructed using acoustic holography, and simulated intracranial pressure fields were benchmarked against needle-hydrophone measurements. Across frequencies, mean peak-pressure errors ranged from 20% to 31%, whereas intensity errors reached 41% to 77%. Errors in -6 dB focal volume ranged from 11% to 67%, and focal-position discrepancies were typically several millimetres. Simulations generally predicted smaller insertion losses than measured, indica