Central Nervous System diseases affect several millions of patients in the U.S. Current drug treatments are often associated with side-effects such as dyskinesia, confusion, dizziness, insomnia, depression, and pathological gambling among others. Neuromodulation can be achieved either with noninvasive techniques that are depth limited or invasive procedures that can go to large depths. Over the past few years, transcranial focused ultrasound (FUS) has been shown capable of both stimulating and suppressing brain activity in vivo. Ultrasound has several advantages over the aforementioned technologies for deep brain stimulation as it can penetrate the brain over several centimeters through the intact scalp and skull. Given its entirely noninvasive and nonionizing nature, the technique has been shown to be translatable to human brain studies with deep penetration (of several centimeters) without requiring introduction of electrodes or optic fibers inside the brain. In the proposed study, we will aim to harness from the technical expertise available by the group of investigators so as to develop monitoring of the underlying physical and physiological mechanisms in vivo and in real time and simultaneously sync technologies that will allow translation to humans. The three physical mechanisms to be investigated are radiation force, cavitation and perfusion, all of which can be monitored in conjunction with FUS modulation by the PI’s group. Therefore, the underlying hypothesis of the proposed studies is that if these underlying mechanisms, or the combination thereof, can be monitored during application, FUS can be more targeted and better monitored to improve on its reproducibility and optimization. To this end, we have assembled a highly complementary, multi-disciplinary team from ultrasound engineering, anatomical and functional imaging, neuroscience, neurology, neuroengineering and neurosurgery. The methodologies proposed require breakthroughs in current FUS methodologies used in order to selectively focus (on the order of a few millimeters) and steer across both shallow and deep-seated regions (on the order of several centimeters in depth) as well as informing on the physical (i.e., radiation force or cavitation - mechanical tissue effects exerted by ultrasound on the brain) and physiological (i.e., neuronal effects as a result of the aforementioned mechanical tissue effects) mechanism in real time. This study is thus aimed to optimize targeting and efficacy of FUS neuromodulation by mapping the physical mechanism so as to better explore noninvasive modulation of motor and motivation responses in humans for the first time for the ultimate treatment of conditions ranging from movement to psychiatric disorders.