| dc.description.abstract | Therapeutic ultrasound has the potential to non-invasively treat a host of brain-related disorders with millimeter precision. Non-destructive applications including neuromodulation, in which ultrasound alters the behavior of neural circuits, and blood-brain barrier opening (BBBO), where ultrasound temporarily increases the permeability of brain vasculature, have immediate applications in glioblastoma, depression, Alzheimer's disease, chronic pain and others. However, the robustness and precision of ultrasound neuromodulation and BBBO must be improved to reach clinical standards and improve patient outcomes. To this point, this dissertation makes strides towards understanding the mechanisms underlying ultrasound neuromodulation and increasing the spatial specificity of BBBO. We developed a model to study neural activity in the presence of ultrasound and used it to evaluate the effectiveness of a range of ultrasound parameters for modulating calcium influx in neurons. The model revealed a pulse repetition frequency dependence on neural activity and an ion channel dependence on the cellular mechanisms linking ultrasound and calcium influx. These findings strengthen the understanding of ultrasound neuromodulation and may increase the consistency of outcomes. We also designed and tested the first system for ultrasound BBBO at Vanderbilt. We used transcranial acoustic simulations to guide the design process towards an ultrasound array which limited the BBBO volume to match the frontal-eye field region in macaques. We also developed an acoustic feedback system to monitor cavitation during therapies, informing in situ pressure levels at the target and improving the consistency and safety of BBBO procedures. We tested the transducer and monitoring system in vivo in macaques using MRI and optical tracking for guidance and evaluation. The BBBO system achieved smaller opening volumes than comparable systems and enables targeted therapy to brain regions. The BBBO system will be used to facilitate non-invasive gene therapy at the frontal eye field in macaques. Combined, these efforts constitute a push in two non-destructive therapeutic ultrasound techniques with applications in brain related disorders. | |
