Dissertations and Theses
Date of Award
neuromodulation, low-intensity ultrasound, hippocampus, local field potentials, multi-unit activities
Techniques to non-invasively modulate brain activity are important for mapping human brain circuits, and also for the treatment of a host of neurological and psychiatric disorders marked by aberrant brain activity. Though a wide range of techniques for non-invasive neuromodulation have been proposed, the conventional approaches suffer from significant limitations. Most notably, focal stimulation of deep brain regions is presently only possible with invasive optogenetic and chemogenetic approaches that require craniotomies and genetic access to the brain.
Transcranial focused ultrasound stimulation (tFUS) possesses many of the characteristics desirable from a neuromodulation approach: non-invasiveness, a spatial resolution in the order of millimeters, the ability to penetrate deep brain regions even through a large cranium, and compatibility with MRI. Although it is known that ultrasonic pressure waves may be focused through the skull and mechanically stimulate neurons in targeted brain areas, there is considerable uncertainty about the mechanism of action, and importantly, how to tailor tFUS to produce a desired electrophysiological change (e.g. excite or inhibit activity in a targeted brain region).
In particular, the influence of baseline brain state on the sensitivity to tFUS is unknown. Another important gap in knowledge is the effect of the stimulation parameters, for example the acoustic intensity and waveform shape, on stimulation outcome. Addressing these gaps is critical to advancing tFUS as a non-invasive neuromodulation technique.
The aims of this dissertation are two-fold: (1) to identify the influence of pre-stimulation brain state on the neuronal response to tFUS, and (2) to identify the effect of waveform and intensity (collectively termed “the dose”) on the neuronal response to tFUS. Our working hypothesis in Aim 1 is that the level of synaptic input into the neuron leading up to stimulation, as captured by the power spectrum of the local field potential (LFP), predicts sensitivity to tFUS. Our working hypothesis in Aim 2 is that amplitude-modulated stimulation will produce qualitatively different outcomes compared to the conventionally tested pulsed and continuous wave stimulation. To test these hypotheses, we conducted electrophysiological recordings from the hippocampus during tFUS in n>100 anesthetized rats.
Our main findings are that: (1) high levels of gamma band (30-200 Hz) and theta band (3-10Hz) and low levels of delta band (1-3 Hz) LFP power leading up to tFUS promote successful neuromodulation (Chapter 3), (2) novel low-intensity amplitude modulated tFUS is capable of bimodal modulation of theta band powers (chapter 4), and (3) mechanical displacement of the probe caused by tFUS leads to an unexpected dominant electrophysiological artifact in the LFP: consisting of a slow time-locked response to sonication onset that is largely preserved across amplitude modulated, continuous wave, and pulsed wave stimulation (Chapter 5). These findings emphasize the importance of considering ongoing brain state when performing tFUS, while shedding light on the neurophysiological substrate of low-intensity ultrasonic neuromodulation.
Nguyen, Duc, "Low-Intensity Ultrasonic Neuromodulation of the Rat Hippocampus" (2022). CUNY Academic Works.
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