by Tiziano Balzano

Low-intensity focused ultrasound, combined with circulating microbubbles, opens new doors for delivering targeted therapies into the brain. Credit: Tiziano Balzano, created using Canva’s AI image generator

Neurological disorders such as Alzheimer’s and Parkinson’s disease are among the most debilitating and life-altering conditions that we face today. Despite years of research and advancements in medical treatments, these diseases continue to elude effective solutions—largely due to the protective barrier that surrounds our brain: the blood-brain barrier (BBB).

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Once thought of simply as a physical obstacle, the BBB is now understood as a crucial part of a larger system known as the neurovascular unit (NVU). This complex network includes endothelial cells, glial cells, neurons, and the extracellular matrix, all working together to control the passage of substances between the blood and the brain.

The BBB serves as the brain’s gatekeeper, ensuring that only essential nutrients enter while harmful substances are kept out. But while this is vital for the brain’s protection, it also creates a significant challenge: Many potential treatments—whether drugs or therapies—cannot cross the BBB and reach their intended targets.

A breakthrough in BBB research: Low-intensity focused ultrasound (LIFU)

Imagine being able to temporarily unlock this barrier, opening a direct path for therapeutic agents to reach the brain. That’s the promise of low-intensity focused ultrasound (LIFU). This innovative technology uses targeted sound waves, combined with microbubbles circulating in the bloodstream, to create brief, controlled openings in the BBB. This allows essential drugs or molecules to pass through the barrier, providing a new avenue for treating diseases such as Alzheimer’s, Parkinson’s and glioblastoma.

Early clinical and preclinical trials have shown that LIFU holds promise. However, what we still need to understand is how exactly LIFU affects the neurovascular unit and what happens after the BBB is opened. Our recent study, published in Journal of Controlled Release, sheds light on these critical questions. We focused on the putamen of adult macaques and tracked the response of the neurovascular unit at three key time points.

What we found: The dynamic response of the neurovascular unit

In our research, we observed significant changes over time. Three hours after the treatment, a mild inflammation was triggered in the brain, activating key immune cells such as microglia, astrocytes, and lymphocytes. This inflammatory response was accompanied by early signs of vascular disruption, marked by alterations in endothelial and pericyte markers.

By the seventh day, the brain began to repair itself. Angiogenic factors like PDGFR-β and VEGF-A played a crucial role in promoting the growth of new blood vessels, which helped restore vascular integrity. While some inflammation persisted, it was localized and did not spread.

By the 30th day, the neurovascular unit had fully recovered, with no signs of lasting damage—such as swelling, hemorrhaging, or structural abnormalities—demonstrating the brain’s remarkable ability to heal itself after the temporary disruption of the BBB.

The role of angiogenesis in repair

A key finding from our research is the central role of angiogenesis—the formation of new blood vessels—in the repair of the neurovascular unit. When the BBB is temporarily disrupted, the brain activates certain repair mechanisms.

The upregulation of PDGFR-β (a protein important for tissue repair) and VEGF-A (a potent factor that promotes the growth of new blood vessels) stimulates angiogenesis. This process helps restore the blood-brain barrier’s integrity, ensuring the brain remains protected and functional.

Implications for treating neurological disorders

Our study confirms that LIFU provides a safe and effective method for temporarily opening the BBB, with the potential to improve drug delivery for neurological conditions. This breakthrough offers hope for treating diseases that have long been resistant to current therapies. We’ve mapped out the timeline of how the neurovascular unit responds to LIFU, offering crucial insights into how to balance the therapeutic benefits with safety, especially if this approach is used repeatedly or long-term.

That said, our findings also highlight the importance of fine-tuning ultrasound energy levels and microbubble protocols to minimize potential risks, such as inertial cavitation or chronic inflammation, during clinical applications.

Looking ahead: A new frontier in brain treatment

LIFU is not just a breakthrough in our understanding of the BBB—it represents a transformative step in how we approach brain treatment as a whole. The research demonstrates that, with careful control, the neurovascular unit can repair itself and restore its function after disruption, opening up new possibilities for treating previously untreatable neurological disorders.

With this technology, the boundaries of brain treatment aren’t just being pushed—they’re being safely and temporarily opened, paving the way for new therapies and, hopefully, new hope for patients worldwide.

This story is part of Science X Dialog, where researchers can report findings from their published research articles. Visit this page for information about Science X Dialog and how to participate.

More information: Tiziano Balzano et al, Temporal dynamics of neurovascular unit changes following blood-brain barrier opening in the putamen of non-human primates, Journal of Controlled Release (2024). DOI: 10.1016/j.jconrel.2024.11.019

Journal information:Journal of Controlled Release

Tiziano Balzano is a postdoctoral researcher at HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain.

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