PhD Thesis Defense: Tomas Jordan

For info on how to attend this videoconference, please email tomas.jordan.TH@dartmouth.edu

"Ultrasound Neurostimulation Enhancement with Piezoelectric Nanotransducers"

Abstract

Minimally invasive stimulation of select neurons in the brain with high spatio-temporal precision is a long-term goal of neuroscience. Focused ultrasound (FUS) is a promising neurostimulation modality due to its ability to non-invasively penetrate through the skull and target a small volume in tissue. However, the sensitivity of neurons to ultrasound energy is low and the stimulation mechanisms are not clearly understood. The goal of this work was to develop neuron-bound piezoelectric nanotransducers that enhance the effects of ultrasound by converting acoustic energy into electric charges. We used barium titanate nanoparticles (BTNPs), which are biocompatible and exhibit strong piezoelectricity. To further enhance the piezoelectric properties of BTNPs, we permanently realigned their ferroelectric domains by electrical poling in a strong electric field at a high temperature. We then performed surface modifications to achieve a stable aqueous BTNP dispersion and to promote nanoparticle biocompatibility. The surface coating gave rise to conjugation of antibodies. We developed a new chemistry for covalent attachment of IgG antibodies to the nanoparticle surface, enabling efficient molecular targeting to cells of interest.

To demonstrate the feasibility of our proposed technology, we incubated the modified BTNPs with cultured rat hippocampal neurons and applied FUS stimulation. We found that 1.1 MHz FUS sonication in presence of neuron bound BTNPs led to calcium and glutamate signaling, indicating neuronal activity. Successful activation was achieved with single ultrasound pulses as short as 45.5 µs. Further, we observed no calcium or glutamate responses to stimulation when BTNPs were not present. The next steps in the development of this technology involve optimization of stimulation efficiency and demonstration of stimulation in a more advanced three-dimensional nervous system. To facilitate the transition to more complex models, we developed a system for FUS stimulation of ex vivo abdominal ganglia of the California sea hare (Aplysia californica). This system enables multi-frequency ultrasound stimulation and electrical recordings with possible single-cell resolution. Further, the neurons stay viable for several hours, allowing for long-lasting recordings. These characteristics make the system ideal for a comprehensive study of sonication parameters and investigating the interactions between FUS and neuronal circuits.

Thesis Committee

• Geoffrey Luke, PhD (Chair)
• Solomon Diamond, PhD
• Michael Hoppa, PhD
• Adam Cohen, PhD (External)

Contact

For more information, contact Daryl Laware at daryl.a.laware@dartmouth.edu.