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Overcoming the Brain Barrier
Figure 3. A: Large-animal FUS BBB opening system. DOF, degrees of freedom. B: BBB opening detection (blue) in the orthogonal MRI planes. C: Real-time cavitation monitoring. SCDh, harmonic stable cavitation dose; SCDu, ultraharmonic cavitation dose; ICD, inertial cavitation dose.
strated in previous studies that include imaging contrast agents (Hynynen et al., 2001; Choi et al., 2007; Samiotaki et al., 2016), antibodies (Kinoshita et al., 2006; Raymond et al., 2008), growth factor proteins (Baseri et al., 2012; Samio- taki et al., 2015; Figure 4), stem cells (Burgess et al., 2011), and gene delivery vectors (Wang et al., 2015, 2017; Figure 5). Molecular delivery studies (Choi et al., 2011; Chen and Konofagou, 2014) have indicated that the size of the BBB opening increases with the ultrasonic pressure, allowing larger molecules to diffuse of several orders of magnitude when the pressure is sufficiently high.
The permeability of the barrier increases with both the pres- sure and microbubble size (Vlachos et al., 2010), indicating that the BBB opening occurs at multiple sites within the capillary tree and that the BBB opening is larger with larger microbubbles, most likely due to the larger area of contact between the bubble and the capillary wall.
Safety and Reversibility of Blood-Brain Barrier Opening
The safe operating parameters of ultrasound exposure of brain cells have been identified (Konofagou, 2012). In sum- mary, BBB opening starts occurring at 0.3 MPa rarefactional
Figure 4. Neurotrophic protein delivery. A: Contrast-enhanced MRI of a Parkinsonian mouse model. B: Optical imaging showing protein uptake. C: Histological examination of protein uptake (brown tint) by neurons (arrows). D: Cell uptake in the striatum. RET, cell mem- brane receptor; ERK1/2, cytoplasm; CREB, neuronal nucleus. NTN, overall neurturin.
pressure amplitude and beyond (Figure 5). At pressures un- der 0.6 MPa, no extravasation of red blood cells (RBCs) or neuronal damage was observed in the regions of the hippo- campus exhibiting the most pronounced BBB opening. Be- yond 0.6 MPa, RBC extravasation was detected, and beyond 0.9 MPa, neuronal damage was observed. These preliminary findings suggest that there is overlap between the feasibil- ity and safety windows within the pressure range of 0.3-0.6 MPa, meaning that the BBB can be opened throughout the entire hippocampus without endothelial or neuronal dam- age at those pressures (Baseri et al., 2010). FUS-induced BBB opening was reported to close within 24 hours under specific parameters in rabbits (Hynynen et al., 2001), mice (Samio- taki et al., 2016), and monkeys (Marquet et al., 2014). Be- havioral studies in mice that survived over six months when BBB opening was performed every week for six months showed no evidence of behavioral or motor control damage (Olumolade et al., 2016). Similarly, repeated sonications in Rhesus macaques demonstrated no changes in behavioral or physiological health of the animals after monitoring for two years (Downs et al., 2015). A recent report indicated that highly overlapping FUS exposure regions could increase in- flammation, including ischemia immediately after exposure
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  A) B)
C) D)

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