Blood‐Brain Barrier Closure Time After Controlled Ultrasound‐Induced Opening Is Independent of Opening Volume

Abstract

Objectives Microbubble-mediated focused ultrasound (US) opening of the blood-brain barrier (BBB) has shown promising results for the treatment of brain tumors and conditions such as Alzheimer disease. Practical clinical implementation of focused US treatments would aim to treat a substantial portion of the brain; thus, the safety of opening large volumes must be investigated. This study investigated whether the opened volume affects the time for the BBB to be restored after treatment. Methods Sprague Dawley rats (n = 5) received bilateral focused US treatments. One hemisphere received a single sonication, and the contralateral hemisphere was targeted with 4 overlapping foci. Contrast-enhanced T1-weighted magnetic resonance imaging was used to assess the integrity of the BBB at 0, 6, and 24 hours after focused US. Results At time 0, there was no significant difference in the mean enhancement between the single- and multi-point sonications (mean ± SD, 29.7% ± 18.4% versus 29.7% ± 24.1%; P = .9975). The mean cross-sectional area of the BBB opening resulting from the multi-point sonication was approximately 3.5-fold larger than that of the single-point case (14.2 ± 4.7 versus 4.1 ± 3.3 mm2; P < .0001). The opened volumes in 9 of 10 hemispheres were closed by 6 hours after focused US. The remaining treatment location had substantially reduced enhancement at 6 hours and was closed by 24 hours. Histologic analysis revealed small morphologic changes associated with this location. T2-weighted images at 6 and 24 hours showed no signs of edema. T2*-weighted images obtained at 6 hours also showed no signs hemorrhage in any animal. Conclusions The time for the BBB to close after focused US was independent of the opening volume on the time scale investigated. No differences in treatment effects were observable by magnetic resonance imaging follow-up between larger- and smaller-volume sonications, suggesting that larger-volume BBB opening can be performed safely.

Blood–brain barrier opening with focused ultrasound in experimental models of Parkinson's disease

“…The time necessary for the barrier to be fully restored has been found proportionally related to the opening volume assuming the induction of a single opening . The decoupling of this dependence has been achieved by substituting large openings with small multifoci openings decreasing the necessary time for the barrier to be restored . Longitudinal studies on rodents and primates have shown that repeated ultrasound‐induced BBB opening in the absence of vascular damage is a transient and reversible application .…”

“…24 The decoupling of this dependence has been achieved by substituting large openings with small multifoci openings decreasing the necessary time for the barrier to be restored. 25,26 Longitudinal studies on rodents and primates have shown that repeated ultrasound-induced BBB opening in the absence of vascular damage is a transient and reversible application. 27,28 Restoration of the barrier was not only macroscopically evaluated by magnetic resonance imaging but also neurologically by visual, cognitive, motivational, and motor function behavioral testing.…”

Nanotherapy for Early Dementia: Targeting Senile Dementia

“…Lastly, a completely separate and additional advantage of such LCM/ND lipid nanoemulsion(s), as a component of this combination therapeutic, stems from the characteristic lipid-coated microbubble subpopulation (D'Arrigo 2011) existing in this nanoemulsion type. Specifically, such preformed (lipidstabilized) microbubbles are well known to substantially reduce the acoustic power levels needed for accomplishing temporary noninvasive (transcranial) ultrasound treatment Alonso et al 2010;Alonso et al 2011;Aslund et al 2017;Bing et al 2014;D'Arrigo 2015;Delalande et al 2013;Goliaei et al 2015;Kotopoulis et al 2013;Kotopoulis et al 2014;Lammers et al 2015;Marquet et al 2011;Meairs 2015;Meng et al 2017;Miller and O'Callaghan 2017), or sonoporation (Aubry et al 2016;Bouakaz et al 2016;Burgess and Hynynen 2016;Castle and Feinstein 2016;Delalande et al 2015;Horodyckid et al 2016;O'Reilly et al 2017;Paefgen et al 2015;Qin et al 2016;Sennoga et al 2016), if additionally desired for the Alzheimer's patient.…”

Ultrasound-mediated microbubble destruction: a new method in cancer immunotherapy

“…O’Reilly et al investigated the time taken for the BBB to close and the opening volume on the time scale of closure after focused US exposure; no significant differences were detected on MRI between large- and small-volume sonications, suggesting that safe BBB opening can be achieved by US combined with microbubbles 79. Lin et al demonstrated that the BBB can be successfully opened by US-triggered microbubble destruction and thus the delivery of exogenous substances can be significantly improved, although the specific mechanisms are still unclear 80.…”