Pulsed focused ultrasound (pFUS) with systemic microbubble (MB) infusion is a noninvasive technique that opens the blood–brain barrier (BBB) and is currently advocated for increasing drug or gene delivery in neurological diseases. The opening of the BBB by pFUS+MB resulted in immediate damage-associated molecular patterns that led to a sterile inflammation response within the parenchyma that lasted 24 h. Currently, pFUS+MB exposure is under consideration as an adjuvant in the treatment in malignancy or neurodegenerative disease. These results demonstrate that pFUS+MB induces a sterile inflammatory response compatible with ischemia or mild traumatic brain injury. Further investigation will be required before translation to clinical trials.
MRI-guided pulsed focused ultrasound (pFUS) combined with systemic infusion of ultrasound contrast agent microbubbles (MB) causes localized blood–brain barrier (BBB) disruption that is currently being advocated for increasing drug or gene delivery in neurological diseases. The mechanical acoustic cavitation effects of opening the BBB by low-intensity pFUS+MB, as evidenced by contrast-enhanced MRI, resulted in an immediate damage-associated molecular pattern (DAMP) response including elevations in heat-shock protein 70, IL-1, IL-18, and TNFα indicative of a sterile inflammatory response (SIR) in the parenchyma. Concurrent with DAMP presentation, significant elevations in proinflammatory, antiinflammatory, and trophic factors along with neurotrophic and neurogenesis factors were detected; these elevations lasted 24 h. Transcriptomic analysis of sonicated brain supported the proteomic findings and indicated that the SIR was facilitated through the induction of the NFκB pathway. Histological evaluation demonstrated increased albumin in the parenchyma that cleared by 24 h along with TUNEL + neurons, activated astrocytes, microglia, and increased cell adhesion molecules in the vasculature. Infusion of fluorescent beads 3 d before pFUS+MB revealed the infiltration of CD68 + macrophages at 6 d postsonication, as is consistent with an innate immune response. pFUS+MB is being considered as part of a noninvasive adjuvant treatment for malignancy or neurodegenerative diseases. These results demonstrate that pFUS+MB induces an SIR compatible with ischemia or mild traumatic brain injury. Further investigation will be required before this approach can be widely implemented in clinical trials.