Non‐invasive photoacoustic tomography (PAT) of mouse brains with intact skulls has been a challenge due to the skull's strong acoustic attenuation, aberration, and reverberation, especially in the high‐frequency range (>15 MHz). In this paper, we systematically investigated the impacts of the murine skull on the photoacoustic wave propagation and on the PAT image reconstruction. We studied the photoacoustic acoustic wave aberration due to the acoustic impedance mismatch at the skull boundaries and the mode conversion between the longitudinal wave and shear wave. The wave's reverberation within the skull was investigated for both longitudinal and shear modes. In the inverse process, we reconstructed the transcranial photoacoustic computed tomography (PACT) and photoacoustic microscopy (PAM) images of a point target enclosed by the mouse skull, showing the skull's different impacts on both modalities. Finally, we experimentally validated the simulations by imaging an in vitro mouse skull phantom using representative transcranial PAM and PACT systems. The experimental results agreed well with the simulations and confirmed the accuracy of our forward and inverse models. We expect that our results will provide better understanding of the impacts of the murine skull on transcranial photoacoustic brain imaging and pave the ways for future technical improvements.

With balanced spatial resolution, imaging depth, and functional sensitivity, photoacoustic tomography (PAT) hold great promise for human brain imaging. However, the strong acoustic attenuation and aberration of the human skull (∼8 mm thick) are longstanding technical challenges for PAT of the human brain. In this work, we numerically investigated the impacts of the stratified human skull on photoacoustic wave propagation (i.e., the forward model) and PAT image formation (i.e., the inverse model). We simulated two representative transcranial PAT implementations: photoacoustic computed tomography (PACT) and photoacoustic macroscopy (PAMac). In the forward model, we simulated the detailed photoacoustic wave propagation from a point or line source through a digital human skull. The wave attenuation, refraction, mode conversation, and reverberation were thoroughly investigated. In the inverse model, we reconstructed the transcranial PACT and PAMac images of a point or line target enclosed by the human skull. Our results demonstrate that transcranial PAMac suffers mainly from wave reverberation within the skull, leading to prolonged signal duration and reduced axial resolution. Transcranial PACT is more susceptible to the skull’s acoustic distortion, mode conversion, and reverberation, which collectively lead to strong image artifacts and deteriorated spatial resolutions. We also found that PACT with a ring-shaped transducer array shows more tolerance of the skull’s adverse impacts and can provide more accurate image reconstruction. Our results suggest that incorporating the skull’s geometry and acoustic properties can improve transcranial PAT image reconstruction. We expect that our results have provided a more comprehensive understanding of the acoustic impact of the human skull on transcranial PAT.

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