Newhoff, Morgan2020-10-262020-10-262020-08https://hdl.handle.net/11299/216851University of Minnesota Ph.D. dissertation.August 2020. Major: Neuroscience. Advisor: Karen Mesce. 1 computer file (PDF); 225 pages.Focused ultrasound is an emerging neuromodulation technology with the unique potential to noninvasively modulate neuronal activity in deep brain structures with high spatial specificity, offering a potential alternative to invasive neural stimulators. Decades of research have confirmed that ultrasound induces profound effects on neuronal firing rates in a wide range of animal systems, yet the direction (increase or decrease) and primary effector of these effects remain a subject of debate. Here, we describe experiments designed to assess these core questions in a tractable invertebrate model, the medicinal leech (Hirudo verbana). We examined the effects of ultrasound (960 kHz) on an identified motoneuron, a class of cells believed to lack canonical mechanosensitive ion channels, and whose response to ultrasound we predict to be reflective of effects on most neuronal cell types. We observed both neuronal excitation and inhibition, with a bias towards inhibitory effects. These effects were direct, and persisted in the presence of synaptic blockers. Importantly, these effects were only observed when applying ultrasound of sufficient duration to generate heating in excess of 2 °C. Similar durations of ultrasound in a low-heat paradigm were insufficient to induce changes in neuronal firing rate. We thus concluded that heat is the primary effector of ultrasound neuromodulation in this system, which was reinforced by our ability to elicit comparable effects through the targeted application of heat alone. Additional experiments using non-thermal short pulses of ultrasound on sensory neurons failed to produce neuronal activation at and above intensities at which others have reported excitation, with the exception of effects we deemed artifactual due to electrode resonance, and which could be reliably mimicked with micromovements of the recording electrode. We conclude that the mechanical effects of ultrasound, which are frequently described in the literature, are less reliably achieved than thermal effects, and observations ascribed to mechanical effects may be confounded by activation of synaptically-coupled sensory structures or artifact associated with electrode resonance. Nonetheless, ultrasound can generate significant modulation at temperatures < 5 °C, which are believed to be safe for moderate durations. Ultrasound should therefore be investigated as a thermal neuromodulation technology for clinical use.enElectrophysiologyLeechNeuromodulationUltrasoundThesis or Dissertation