Info
Background:
Focused ultrasound (FUS) is a non-invasive technology that uses acoustic energy to induce bioeffects in targeted tissue. When combined with circulating microbubbles, FUS enables temporary blood-brain barrier opening (BBBO) with high spatial precision and depth in the brain. Microbubble oscillation, which is dictated by peak negative pressure, frequency, duty cycle, pulse length, and burst length, induces shear stress on vessel walls, transiently disrupting endothelial tight junctions and enhancing transcytosis to facilitate drug delivery across the BBB1. MR-guided FUS for transcranial BBBO is currently under clinical investigation for a range of neurological diseases2-4.
Current clinical feedback relies on (1) contrast-enhanced MRI, which provides high-resolution anatomical targeting and acute confirmation of BBBO and/or (2) acoustic emissions feedback, which lacks spatial information. MRI-based gadolinium enhancement is a limited proxy for small-molecule therapy delivery and does not directly quantify transport of pharmacological agents that can span a vast range of physicochemical properties such as molecular weight, charge, and lipophilicity5. Positron emission tomography (PET) offers high sensitivity and spatial resolution (<1 mm), enabling direct tracking and quantification of radiolabeled therapeutics for an ideal complementary technique to MRI for monitoring FUS-BBBO drug delivery. To date, the direct integration of PET with MRI-guided FUS for simultaneous validation of BBBO and drug transport remains unexplored.
Hypothesis/Objective:
To perform in-vivo validation of a novel preclinical trimodal PET/MRI/FUS system for confirming and optimizing FUS-mediated BBBO in mice.
Methods:
The trimodal system comprises a 1.15 MHz MRI-compatible FUS transducer and custom-built PET insert6 (<1 mm spatial resolution) integrated within a 9.4T Bruker MRI scanner. A single-channel transmit/receive surface RF coil was designed and fabricated in-house for integration into the trimodal system. Transcranial FUS-BBBO was performed in naïve mice at two distinct FUS pressures (PNP; 0.3 and 0.6 MPa) with co-administration of 64Cu-DOTA and gadolinium (Dotarem). Passive cavitation detection was performed with a 0.575 MHz hydrophone and acoustic emissions were quantified with an in-house algorithm for spectral analysis of harmonic, sub-/ultra-harmonic, and broadband emissions. Post-FUS PET and MRI were acquired and co-registered to assess tracer distribution and spatial localization of BBBO across modalities. Ex vivo biodistribution analysis was performed via automated gamma counting (HIDEX) for brains and peripheral organs.
Results:
The integrated RF coil enabled high-quality T1-weighted MRI for visualization of FUS-BBBO. 0.6 MPa FUS conferred significantly larger BBBO volumes versus 0.3 MPa (26.01 6.46 mm3 and 10.68 2.17 mm3, respectively; p=0.0005). Acoustic emissions spectra revealed sharp peaks at the fundamental frequency (f), second (2f), and third (3f) harmonics, with broader peaks at the sub- (0.5f) and ultra-harmonics (1.5f), which scaled with PNP. Harmonic and broadband cavitation signals were significantly elevated at 0.6 MPa and correlated with BBBO volume, affirming expected concordance between acoustic emissions and MRI contrast enhancement captured via trimodal. MRI and PET signals were spatially aligned, and MRI pixel intensity within BBBO regions significantly correlated with PET standardized uptake values (R2=0.29, p=0.03; Figure 1). Ex-vivo gamma counting confirmed significantly increased 64Cu-DOTA uptake in the targeted brain hemisphere for FUS-treated mice compared to controls, with ~2-fold and ~4-fold increases for 0.3 MPa and 0.6 MPa, respectively.
Conclusion:
This study provides the first in vivo demonstration of a first-in-class, integrated PET/MRI/FUS system for monitoring transcranial BBBO procedures. Harmonization of FUS-associated signal across MRI and PET images was observed, signifying successful integration of FUS, PET, and MRI instrumentation within a single-system framework. Together, these findings position this trimodal platform as a powerful tool for quantitative validation and optimization of FUS-mediated therapeutic delivery to the CNS.
Image/Figure:
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Image/Figure Caption:
Figure 1: (A) Axial (top) and coronal (bottom) views of MRI, PET, and co-registered images for 0.3 MPa (blue circles) and 0.6 MPa (orange circles) FUS conditions acquired with the trimodal system. (B) Quantification of MRI pixel intensity in the BBBO regions, showing significantly increased intensity for both FUS groups compared to sham (no FUS) (p=0.02, p=0.002 for 0.3 MPa and 0.6 MPa, respectively). (M) Quantification of PET standardized uptake values (SUV) (%ID/ml), showing significantly increased uptake of 64Cu-DOTA for both FUS groups compared to sham (p=0.039, p=0.001 for 0.3 MPa and 0.6 MPa, respectively). (N) Correlation between MRI average pixel intensity and average PET SUV, signifying agreement between MRI and PET images acquired with the trimodal system.
Author
Sarah Duclos
University of Virginia