Neuromodulation, or the manipulation of the brain's circuitry, has proven to be a powerful tool in neuroscience and for the treatment of neurologic disease. Current methods for neuromodulation in the brain can be limited by the skull, invasive delivery to the deep structures or by inadequate spatial resolution. Recently, ultrasound technology has advanced such that acoustic energy can be precisely delivered through the intact human skull. Our group has used high intensity focused ultrasound (HIFU) to perform stereotactic thalamic ablations through the intact skull for the treatment of severe tremor in humans. During these transcranial HIFU procedures, we observed neuromodulation of the ventrolateral thalamus with temporary suppression of tremor and paresthesia, but the mechanism of effect was likely thermal. Low intensity focused ultrasound (LIFU) utilizes different properties where neural tissue is affected by mechanical properties and without heat or damage to the brain. Thus, we hypothesize that low intensity focused ultrasound can be used for reversible, safe, and precise neuromodulation of deep brain circuits making it an ideal modality for non-invasive brain mapping. To prove this hypothesis, we have designed experiments where LIFU neuromodulation will be tested and optimized in a large brain, swine model. Firstly, systematic adjustments of the amplitude of pulse pressure or duration of LIFU delivered to the sensory thalamus will be used to differentially inhibit or augment these somatosensory pathways measured by evoked potentials. Theoretically, LIFU can also be targeted to axonal pathways like the corticospinal tract in the internal capsule instead of to nuclear targets to similarly manipulate the motor system. The development of an animal model to systematically optimize subcortical neuromodulation is unique. Our initial results have suppressed a deep brain circuit as evidenced by transiently reduced somatosensory evoked potentials and LIFU is capable of mapping the receptive fields of the somatosensory thalamus. We will also be able to explore different parameters with shorter duration and more bursting, which presumably will activate neuronal tissue or augment SSEP. This project in swine will optimize the technique of subcortical LIFU neuromodulation and confirm its safety so that it can be immediately implemented during stereotactic focused ultrasound thalamotomy procedures in humans. The relevance of LIFU neuromodulation has tremendous implications for noninvasive brain mapping and treating the human neurologic and psychiatric disease.