Longitudinal Motor and Behavioral Assessment of Blood-Brain Barrier Opening with Transcranial Focused Ultrasound.

Focused ultrasound (FUS), in combination with microbubbles, has been found to open the blood-brain barrier (BBB) non-invasively. When this technique is used for drug delivery, repeated drug administration and BBB opening are likely required. Therefore, it is worth investigating the long-term effects of FUS-induced BBB opening. In this study, we focused on the assessment of potential behavior changes in mice that could be attributed to repeated BBB opening for up to 6 months. The striatum of animals was unilaterally sonicated either monthly or biweekly throughout the monitoring period. Behavioral assessments were conducted using open-field and rotarod performance tests. Upon completion of each sonication, mice underwent magnetic resonance imaging (MRI) to confirm and assess the volume of the BBB opening. No differences in locomotor activity between BBB-opened and control groups in both biweekly and monthly treated mice were evident up to 6 months. Similarly, there was no affinity for a particular turn angle in the sonicated mice compared with the control animals. However, the positive control group exhibited a significant decrease in locomotor activity, as well as rotation ipsilateral to the sonicated hemisphere. Our results based on the assessment using open-field and rotarod tests indicated that repeated opening of the BBB in the striatum using FUS in conjunction with microbubbles over a period of 6 mo and under the parameters used here did not cause motor impairment, behavioral changes or morphologic alterations. This reinforces the tolerability of repeated and long-term drug delivery using FUS-induced BBB opening.