Diffusion Tensor Imaging and Chemical Exchange Saturation Transfer MRI Evaluation on the Long-Term Effects of Pulsed Focused Ultrasound and Microbubbles Blood Brain Barrier Opening in the Rat

• Published in: Frontiers in neuroscience Vol. 14; p. 908
• Main Authors: Tu, Tsang-Wei, Kovacs, Zsofia I., Sundby, Maggie, Witko, Jaclyn A., Papadakis, Georgios Z., Reid, William C., Hammoud, Dima A., Frank, Joseph A.
• Format: Journal Article
• Language: English
• Published: Lausanne Frontiers Research Foundation 25.08.2020; Frontiers Media S.A
• Subjects: Blood-brain barrier; Brain; Cell adhesion & migration; Central nervous system; CEST; Clinical trials; Cortex; DTI; Experiments; FDG-PET; Gadolinium; Glucose metabolism; Glucose transporter; Hippocampus; Immunohistochemistry; Laboratory animals; Long-term effects; Magnetic resonance imaging; Neuroimaging; Neurological diseases; Neuroscience; Parenchyma; pFUS microbubble; Positron emission tomography; Rodents; Sonication; T2∗ abnormality; Ultrasonic imaging; Ultrasound
• ISSN: 1662-453X; 1662-4548; 1662-453X
• DOI: 10.3389/fnins.2020.00908

Blood-brain barrier opening (BBBO) with pulsed Focused Ultrasound (pFUS) and microbubbles (MB) has received increasing interest as a method for neurotherapeutics of the central nervous system. In general, conventional MRI (i.e., T2w, T2*w, gadolinium (Gd) enhanced T1w) is used to monitor the effects of pFUS+MB on BBBO and/or assess whether sonication results in parenchymal damage. This study employed multimodal MRI techniques and 18F-Fludeoxyglucose (FDG) PET to evaluate the effects of single and multiple weekly pFUS+MB sessions on morphology and glucose utilization levels in the rat cortex and hippocampus. pFUS was performed with 0.548MHz transducer with a slow infusion over 1 min of OptisonTM (5-8x107 MB) in 9 focal points in cortex and 4 in hippocampus. During pFUS+MB treatment, Gd-T1w was performed at 3.0T to confirm BBBO, along with subsequent T2w, T2*w, DTI and glucose CEST (glucoCEST)-weighted imaging by high field 9.4T and compared with FDG-PET and immunohistochemistry. Animals receiving a single pFUS+MB exhibited minimal hypointense voxels on T2*w. Brains receiving multiple pFUS+MB treatments demonstrated persistent T2w and T2* abnormalities associated with changes in DTI and glucoCEST when compared to contralateral parenchyma. Decreased glucoCEST contrast was substantiated by FDG-PET in cortex following multiple sonications. Immunohistochemistry showed significantly dilated vessels and decreased neuronal glucose transporter (GLUT3) expression in sonicated cortex and hippocampus without changes in neuronal counts. These results suggest the importance to standardize MRI protocols in concert with advanced imaging techniques when evaluating long term effects of pFUS+MB BBBO in clinical trials for neurological diseases.