Blood-Brain Barrier Opening in Behaving Non-Human Primates via Focused Ultrasound with Systemically Administered Microbubbles

Downs, Matthew; Buch, Amanda; Karakatsani, Maria Eleni; Konofagou, Elisa E.; Ferrera, Vincent P.

doi:10.1038/srep15076

Cited by 93 publications

(67 citation statements)

References 48 publications

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“…The closure time of the BBB after opening is not the only safety consideration for clinical translation, but our results complement existing behavioral and cognitive studies that have considered the safety of this approach in mice and primates . The time for the BBB to close after focused US is independent of the opening volume when multiple overlapping foci are used.…”

Section: Discussionsupporting

confidence: 67%

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

O’Reilly

Hough

Hynynen

2017

J of Ultrasound Medicine

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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.

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Section: Discussionsupporting

confidence: 67%

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

O’Reilly

Hough

Hynynen

2017

J of Ultrasound Medicine

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“…Early attempts in rats suggested that high‐intensity FUS can be adjusted to induce transient thermal BBB disruption without producing a lesion . Soon after this, transient BBB opening was safely achieved by low‐intensity FUS combined with an ultrasound contrast agent (microbubbles) in rabbits, rodents, and primates . The potential of FUS BBB opening for targeted delivery of therapeutic agents, chemotherapy, immunotherapy, gene therapy, viral vectors, neural stem cells, and others is being tested extensively in animal models …”

Section: Bbb Opening To Halt Nigrostriatal Neurodegenerationmentioning

confidence: 99%

Focused ultrasound in Parkinson's disease: A twofold path toward disease modification

et al. 2019

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A major unmet need in Parkinson's disease (PD) is to slow the inexorable progression of neurodegeneration. Clinical trials that evaluated promising pharmacological strategies have repeatedly failed. Nonetheless, the advent of focused ultrasound provides new opportunities toward the goal of developing a safe and effective disease‐modifying therapy for PD. Here we discuss the rationale, possible avenues, and challenges along this path, exploiting the potential of focused ultrasound for (1) performing focal thermal lesions to restore the basic basal ganglia abnormalities associated with dopamine depletion, and (2) transiently opening the blood–brain barrier for targeted delivery of therapeutic agents. First, the classic idea of excitotoxicity mediated by hyperactivity of the subthalamic nucleus suggests that focused ultrasound subthalamotomy may offer a clinically viable disease‐modifying therapy in very‐early PD. Second, the concept of retrograde nigrostriatal neurodegeneration, supported by our recent cortical pathogenic theory of PD, points toward the putamen as a principal site for focused ultrasound blood–brain barrier opening and targeted drug delivery. In principle, both therapeutic strategies—subthalamotomy and putaminal blood–brain barrier opening—could eventually be applied in the same patient. Clinical application is still a long road ahead; nevertheless, focused ultrasound may open a twofold path toward disease modification in PD. © 2019 International Parkinson and Movement Disorder Society

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“…For example, Min et al (2011) and Yang et al (2012) applied low intensity single element ultrasound to the thalamus in rat and reported changes in frontal lobe neurotransmitter concentrations though did not report data from thalamus (Min et al, 2011;Yang et al, 2012). Downs, Buch, Karakatsani, Konofagou, and Ferrera (2015) directed single element focused ultrasound at thalamus in awake behaving primate and showed ultrasound (with the addition of microbubble contrast) to safely disrupt the blood-brain barrier (Downs et al, 2015). These studies provide initial evidence of the ability of single element ultrasound to target the thalamus though these studies did not expressly study the use of ultrasound for thalamic neuromodulation.…”

Section: Introductionmentioning

confidence: 99%

Neuromodulation with single‐element transcranial focused ultrasound in human thalamus

Legon

Bansal

et al. 2018

Human Brain Mapping

260

224

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Transcranial focused ultrasound (tFUS) has proven capable of stimulating cortical tissue in humans. tFUS confers high spatial resolutions with deep focal lengths and as such, has the potential to noninvasively modulate neural targets deep to the cortex in humans. We test the ability of single-element tFUS to noninvasively modulate unilateral thalamus in humans. Participants (N = 40) underwent either tFUS or sham neuromodulation targeted at the unilateral sensory thalamus that contains the ventro-posterior lateral (VPL) nucleus of thalamus. Somatosensory evoked potentials (SEPs) were recorded from scalp electrodes contralateral to median nerve stimulation. Activity of the unilateral sensory thalamus was indexed by the P14 SEP generated in the VPL nucleus and cortical somatosensory activity by subsequent inflexions of the SEP and through time/frequency analysis. Participants also under went tactile behavioral assessment during either the tFUS or sham condition in a separate experiment. A detailed acoustic model using computed tomography (CT) and magnetic resonance imaging (MRI) is also presented to assess the effect of individual skull morphology for single-element deep brain neuromodulation in humans. tFUS targeted at unilateral sensory thalamus inhibited the amplitude of the P14 SEP as compared to sham. There is evidence of translation of this effect to time windows of the EEG commensurate with SI and SII activities. These results were accompanied by alpha and beta power attenuation as well as time-locked gamma power inhibition. Furthermore, participants performed significantly worse than chance on a discrimination task during tFUS stimulation.

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Blood-Brain Barrier Opening in Behaving Non-Human Primates via Focused Ultrasound with Systemically Administered Microbubbles

Cited by 93 publications

References 48 publications

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

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

Focused ultrasound in Parkinson's disease: A twofold path toward disease modification

Neuromodulation with single‐element transcranial focused ultrasound in human thalamus

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