TMS-Induced Controlled BBB Opening: Preclinical Characterization and Implications for Treatment of Brain Cancer
Udi Vazana,
Lior Schori,
Uri Monsonego,
Evyatar Swissa,
Gabriel S. Pell,
Yiftach Roth,
Pnina Brodt,
Alon Friedman,
Ofer Prager
Affiliations
Udi Vazana
Departments of Physiology and Cell Biology, Cognitive and Brain Sciences, The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, no.1 Ben-Gurion Blvd., Beer-Sheva 8410501, Israel
Lior Schori
Departments of Physiology and Cell Biology, Cognitive and Brain Sciences, The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, no.1 Ben-Gurion Blvd., Beer-Sheva 8410501, Israel
Uri Monsonego
Departments of Physiology and Cell Biology, Cognitive and Brain Sciences, The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, no.1 Ben-Gurion Blvd., Beer-Sheva 8410501, Israel
Evyatar Swissa
Departments of Physiology and Cell Biology, Cognitive and Brain Sciences, The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, no.1 Ben-Gurion Blvd., Beer-Sheva 8410501, Israel
Gabriel S. Pell
Department of Life Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, no.1 Ben-Gurion Blvd., Beer-Sheva 8410501, Israel
Yiftach Roth
Department of Life Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, no.1 Ben-Gurion Blvd., Beer-Sheva 8410501, Israel
Pnina Brodt
Department of Surgery, Oncology and Medicine, McGill University and the Research Institute-McGill University Health Center, 2155 Rue Guy, Montreal, QC H3H 2L9, Canada
Alon Friedman
Departments of Physiology and Cell Biology, Cognitive and Brain Sciences, The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, no.1 Ben-Gurion Blvd., Beer-Sheva 8410501, Israel
Ofer Prager
Departments of Physiology and Cell Biology, Cognitive and Brain Sciences, The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, no.1 Ben-Gurion Blvd., Beer-Sheva 8410501, Israel
Proper neuronal function requires strict maintenance of the brain’s extracellular environment. Therefore, passage of molecules between the circulation and brain neuropil is tightly regulated by the blood–brain barrier (BBB). While the BBB is vital for normal brain function, it also restricts the passage of drugs, potentially effective in treating brain diseases, into the brain. Despite previous attempts, there is still an unmet need to develop novel approaches that will allow safe opening of the BBB for drug delivery. We have recently shown in experimental rodents and in a pilot human trial that low-frequency, high-amplitude repetitive transcranial magnetic stimulation (rTMS) allows the delivery of peripherally injected fluorescent and Gd-based tracers into the brain. The goals of this study were to characterize the duration and safety level of rTMS-induced BBB opening and test its capacity to enhance the delivery of the antitumor growth agent, insulin-like growth factor trap, across the BBB. We employed direct vascular and magnetic resonance imaging, as well as electrocorticography recordings, to assess the impact of rTMS on brain vascular permeability and electrical activity, respectively. Our findings indicate that rTMS induces a transient and safe BBB opening with a potential to facilitate drug delivery into the brain.
