Clearance of intracranial debris by ultrasound reduces inflammation and improves outcomes in hemorrhagic stroke models
Impaired clearance of the byproducts of neurologic injury exacerbates disease progression and severity. We have developed a noninvasive, low intensity transcranial focused ultrasound protocol that facilitates removal of pathogenic substances from the cerebrospinal fluid (CSF) and brain interstitium. This protocol clears blood products from the central nervous system in two mouse models of hemorrhagic brain injury. Cleared blood products accumulate in the cervical lymph nodes from both the CSF and interstitial compartments, indicating clearance through meningeal lymphatics. Treatment with this ultrasound protocol reduced neuroinflammation and neurocytotoxicity, improved behavioral outcomes, decreased morbidity and, importantly, increased survival. Clearance efficacy was independent of thermal effects, given the lack of significant heating noted by simulation and experimental verification. Instead, protocol application was associated with a shift of microglial polarization to a homeostatic state and an increase of astrocytic endfeet aquaporin-4 polarization. As these processes are thought to be downstream of mechanosensitive channels, we confirmed that blockade of mechanosensitive channels blocks clearance and that the protocol was effective when applied in anesthetized subjects. This indicates that ultrasound acts as a non-pharmacologic agonist of mechanosensitive channels to induce these homeostatic immune and glymphatic effects, in a way that does not depend on sensory stimulation or a specific neural activity pattern. Notably, the low intensity of this protocol is within FDA guidelines for safe ultrasound application, making it readily clinically translatable. Overall, our results demonstrate that this low-intensity transcranial focused ultrasound protocol induces cellular processes that clear hemorrhagic products from the brain via the meningeal lymphatic system, offering a novel therapeutic tool for the clearance of other neurotoxic byproducts in varied neurologic disorders. Overall design: Spatial transcriptomics using STOmics stereo-seq of 4 samples, Control, Control+UCC, ICH, ICH+UCC.