| Transcranial ultrasound can alter brain function transiently and nondestructively, offering a new tool to study brain function now and to inform future therapies. Previous research on neuromodulation implemented pulsed low-frequency ultrasound with spatial peak temporal average intensities (ISPTA) of 0.1-10 W/cm2. That work used transducers that either insonified relatively large volumes of mouse brain (several mL) with relatively low-frequency ultrasound and produced bilateral motor responses, or relatively small volumes of brain (on the order of 0.06 mL) with relatively high-frequency ultrasound that produced unilateral motor responses. However, these previous studies have no modality for explaining how the ultrasound causes activation in the brain, and furthermore their ultrasound protocols do not allow for the precise activation that is required for the proper study of neuromodulation. This study seeks to increase anatomical specificity to neuromodulation with modulated focused ultrasound (mFU) as well as to provide an explanation for how the stimulation occurs biologically. We hypothesize that we can induce focal, central and associated peripheral activity in the motor cortex of primates using mFU in a manner comparable to electrical stimulation and capable of direct measurement by ECoG because we believe that neuromodulatory ultrasound stimulation of the brain excites neural circuits by depolarizing cells through the motor deformation of ion channels. Here, 'modulated' means modifying a focused 2-MHz carrier signal dynamically with a 500-kHz signal as in vibro-acoustography, thereby creating a low-frequency but small volume source of neuromodulation. We have shown that application of transcranial mFU to lightly anesthetized mice produces various motor movements with high spatial selectivity (on the order of 1 mm) that scales with the temporal average ultrasound intensity. Alone, mFU and focused ultrasound (FUS) each induce motor activity, including unilateral motions, though anatomical location and type of motion varied. We then moved to a primate model to determine the relative efficacy of mFU compared to electrical stimulation. Furthermore, our studies aimed to determine the biophysical processes through which they act. Currently, it is difficult to record neural activity after electric stimulation in the first few milliseconds after action potential onset due to various electrical problems. We have shown in vitro that with focused ultrasound, these problems can be bypassed. We explored the effects of this ultrasound applied to the brain by observing the resulting electrical activity induced through mechanical stimulation. We monitored neural excitation within our best approximation of the motor strip. Also of interest has been exploration of the potential research and clinical applications for targeted, transcranial neuromodulation created by modulated focused ultrasound, especially mFU's ability to produce compact sources of ultrasound at the very low frequencies (10-100s of Hertz) that correlate to the natural frequencies of the brain. |
