Fig. 5: Real-time PCD modulation of PNP ensures the safety of sonicated brain tissue without compromising gadolinium delivery.
a, Applied PNP versus time during PCD feedback-controlled approach. Each line indicates the average applied PNP across two sonication targets for the same mouse during a single FUS sonication period. b, Representative T1-weighted contrast images before and after FUS-MB with PCD-modulated PNPs. c, T1 contrast enhancement as the fold change in greyscale intensity of sonicated CCMs in the post image over the pre image. n = 7. Data are means ± s.d. *P = 0.016; two-tailed Wilcoxon matched-pairs signed-rank test. d, T1 contrast enhancement as the fold change in greyscale intensity of sonicated CCMs in the post image over the pre image for CCM mice. Data are means ± s.d. n = 7, 8, 9 and 4 for PCD, 0.4 MPa, 0.5 MPa and 0.6 MPa groups, respectively. *P = 0.0293; one-way ANOVA with Dunnett’s multiple comparison’s test. e, Spectrogram of the frequency response for each burst during the FUS application averaged over CCM mice with PCD-modulated PNP (n = 4 mice and 2 sonication replicates per mouse). Dotted line indicates time of microbubble injection. f, Acoustic emissions for CCM mice. Data are means ± s.d. n = 8, 3, 3 and 3 for PCD, 0.4 MPa, 0.5 MPa and 0.6 MPa groups, respectively. **P = 0.003 for all comparisons; two-way ANOVA with Šidák’s multiple comparisons test. g, Representative T2-weighted spin echo images of CCM mice at 1, 7 and 30 days post sonication with PCD-modulated PNP. h, Line graphs of ipsilateral-to-contralateral greyscale intensities over the 1-month imaging period for CCM mice and all PNP regimens. n = 6, 6, 3 and 4 for 0.4 MPa, 0.5 MPa, 0.6 MPa and PCD-mod groups, respectively. Data are means ± s.d. i, Scatterplot of ipsilateral-to-contralateral greyscale intensity versus time-averaged PNP for CCM with single treatments and fixed PNP, repeat treatments and fixed PNP, or repeat treatments and PCD-modulated PNP mice on day 1 (left) or day 30 post FUS (right). For oedema, there is no correlation. *P = 0.0163 for haemosiderin; linear regression with F-test. j–m, BBB opening duration in CCM mice after FUS-MB treatment with PCD-modulated PNP. j, Representative high-resolution T2-weighted baseline (left; 24 h pre FUS), low-resolution T1 contrast (middle; immediately post FUS) and high-resolution T1 RARE (right; 5 h post FUS) MRIs. Yellow outline denotes FUS application region. k, Contrast enhancement immediately post FUS (left; **P = 0.0025) and 5 h post FUS (right; **P = 0.0092). n = 3 per group. Two-tailed paired t-tests. l, Representative high-resolution T2-weighted baseline (left; 24 h pre FUS), low-resolution T1 contrast (middle; immediately post FUS) and high-resolution T1 RARE (right; 24 h post FUS) MRIs. Yellow outline denotes FUS application region. m, Contrast enhancement immediately post FUS (left; **P = 0.0039) and 24 h post FUS (right; P = 0.4136). n = 3 per group. Two-tailed paired t-tests.
