Advances in Photoacoustic Imaging for Brain Diseases: Principles, Applications, and Clinical Translation Challenges

The growing prevalence of brain diseases and the limitations of existing imaging techniques highlight the urgent demand for advanced, biocompatible, and high-resolution brain imaging approaches. Photoacoustic imaging (PAI) uniquely integrates scalable spatial resolution, deep penetration, and non-ionizing excitation, which enables multi-scale visualization from subcellular structures to the whole brain. This review systematically summarizes the fundamental principles of PAI, commonly used contrast agents, and key system components, and provides a comparative analysis of the major imaging modalities-optical-resolution and acoustic-resolution photoacoustic microscopy (OR-/AR-PAM), photoacoustic computed tomography (PACT), and photoacoustic endoscopy (PAE). PACT offers superior penetration depth and field of view, whereas OR-/AR-PAM provides higher spatial resolution at molecular scales. By aligning disease-specific imaging requirements with the functional strengths of each modality, PAI has enabled integrated structural and functional imaging in glioblastoma, neurodegenerative disorders, traumatic brain injury, and cerebrovascular diseases, highlighting its integrated advantages for multiscale brain imaging. Finally, the review discusses key challenges for clinical translation of PAI, including motion artifacts, blood-brain barrier constraints, contrast agent approval, limitations of single-modality approaches, and technical limitations, and proposes corresponding strategies to address these obstacles. This review provides forward-looking guidance for the clinical translation of multiscale brain imaging technologies.