Trimodal brain-wide ultrasound imaging of brain-tumor interaction

Patients with brain tumors often suffer debilitating neurological dysfunction as their tumors disrupt brain tissue, affecting both local and global neural activity and blood flow. However, studying tumor-brain interactions in animal models is challenging due to a lack of methods that simultaneously capture dynamics of tumor growth, neural activity and vascular alterations over time. Here, we overcome this limitation using a multimodal ultrasound imaging platform, an imaging technique that offers brain-wide coverage in living animals at 10-100 µm resolution. To monitor the co-evolution of tumor growth, neural activity and vascular remodeling, we integrated (1) nonlinear imaging of acoustic reporter gene expressing-tumors, (2) hemodynamic functional imaging of brain activity, and (3) super-resolution microscopy of the vasculature. Integrating these modalities for the first time and applying them to a common model of glioblastoma, we followed tumor-brain interactions in individual animals over their disease lifetimes. Our approach allowed us to precisely map the spatial displacement of functional brain regions, the local and global disruption of functional connectivity, and the remodeling of the blood supply to support tumor growth. This integrated method bridges a critical gap in brain cancer research and therapy development by providing a unified dynamic view of what happens to the brain as tumors grow within it.