We used a focused ultrasound device consisting of 1024 individual transducers with a frequency of 220 kHz (ExAblate Neuro; InSightec Haifa). The device integrates intraoperative imaging, which was used for interim evaluations of the patient, and real-time acoustic monitoring to support decision-making on sonication parameters. On the day of the procedure, a Cosman-Roberts-Wells (CRW) stereotactic frame was fixed to the patient’s head under local anesthetic. The frame was then coupled to the helmet transducer array, with the patient entering the MRI supine and awake. A safety switch was given to the patient to abort the procedure in case of discomfort or pain. The patient was examined and questioned for adverse events after each sonication.
A 3-Tesla MRI (Signa MR750; GE Healthcare, Milwaukee, Wis.) was used to obtain T1, T2 (fast spin echo), and T2* (gradient echo) weighted images for surgical planning. A region in the right frontal lobe was then selected for BBB opening. To minimize the risk, we avoided areas containing sulci and vessels within two contiguous MRI slices in each of the axial, sagittal, and coronal planes. Once the target region was identified, patients received a weight-based intravenous injection of microbubble contrast (Definity®) (4 μl/kg), followed shortly by the application of low-frequency focused ultrasound to the target. MR thermometry was used to monitor tissue temperature at the sonicated region in real time. The sonication parameters were limited by the clinical device hardware and software, and corresponded to those previously tested in large animal models36 (link).
At each new target, a power ramp test was performed with the first microbubble injection. This test involves applying short sonications with increasing power in 5% increments until the device hydrophones detect a sub-harmonic acoustic feedback from the target, indicating a cavitation. Subsequent sonications are then performed at 50% of this ‘cavitation threshold’ power. The ramp test was developed from preclinical studies to determine the optimal power required for safe opening of the BBB36 (link),37 (link). Sonication volumes covered a rectangular spot approximately 9 mm by 9 mm, comprised of 3-by-3 grid of spots, each 3 mm in diameter. For the last three patients, given the extent of atrophy on their MRI, a 2-by-2 grid was utilized, yielding a spot approximately 5 mm by 5 mm. The device electronically steered the ultrasound through each grid for 50 s total, sonicating each spot with 2 ms on and 28 ms off bursts for 300 ms, with a repetition interval of 2.7 s (duty cycle 0.74%). For stage 2, performed approximately 1 month following stage 1, the procedure was repeated, opening the BBB at the original location as well as at an adjacent area, following the same protocol, but doubling the volume of tissue opened.
After completion of the sonication protocol, a gadolinium-enhanced T1 sequence was performed to verify definitive evidence of BBB opening. Contrast enhancement at the targeted region signified the end of the procedure. The patient was then taken out of the scanner, the stereotactic frame removed, and additional high-resolution MRI sequences obtained. Patients were admitted to the surgical short stay unit for overnight observation.
A 3-Tesla MRI (Signa MR750; GE Healthcare, Milwaukee, Wis.) was used to obtain T1, T2 (fast spin echo), and T2* (gradient echo) weighted images for surgical planning. A region in the right frontal lobe was then selected for BBB opening. To minimize the risk, we avoided areas containing sulci and vessels within two contiguous MRI slices in each of the axial, sagittal, and coronal planes. Once the target region was identified, patients received a weight-based intravenous injection of microbubble contrast (Definity®) (4 μl/kg), followed shortly by the application of low-frequency focused ultrasound to the target. MR thermometry was used to monitor tissue temperature at the sonicated region in real time. The sonication parameters were limited by the clinical device hardware and software, and corresponded to those previously tested in large animal models36 (link).
At each new target, a power ramp test was performed with the first microbubble injection. This test involves applying short sonications with increasing power in 5% increments until the device hydrophones detect a sub-harmonic acoustic feedback from the target, indicating a cavitation. Subsequent sonications are then performed at 50% of this ‘cavitation threshold’ power. The ramp test was developed from preclinical studies to determine the optimal power required for safe opening of the BBB36 (link),37 (link). Sonication volumes covered a rectangular spot approximately 9 mm by 9 mm, comprised of 3-by-3 grid of spots, each 3 mm in diameter. For the last three patients, given the extent of atrophy on their MRI, a 2-by-2 grid was utilized, yielding a spot approximately 5 mm by 5 mm. The device electronically steered the ultrasound through each grid for 50 s total, sonicating each spot with 2 ms on and 28 ms off bursts for 300 ms, with a repetition interval of 2.7 s (duty cycle 0.74%). For stage 2, performed approximately 1 month following stage 1, the procedure was repeated, opening the BBB at the original location as well as at an adjacent area, following the same protocol, but doubling the volume of tissue opened.
After completion of the sonication protocol, a gadolinium-enhanced T1 sequence was performed to verify definitive evidence of BBB opening. Contrast enhancement at the targeted region signified the end of the procedure. The patient was then taken out of the scanner, the stereotactic frame removed, and additional high-resolution MRI sequences obtained. Patients were admitted to the surgical short stay unit for overnight observation.
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