Low-intensity focused ultrasound provides the means to noninvasively stimulate or release drugs in specified deep brain targets. However, successful clinical translations require hardware that maximizes acoustic transmission through the skull, enables flexible electronic steering, and provides accurate and reproducible targeting while minimizing the use of MRI. We have developed a device that addresses these practical requirements. The device delivers ultrasound through the temporal and parietal skull windows, which minimize the attenuation and distortions of the ultrasound by the skull. The device consists of 252 independently controlled elements, which provides the ability to modulate multiple deep brain targets at a high spatiotemporal resolution, without the need to move the device or the subject. And finally, the device uses a mechanical registration method that enables accurate deep brain targeting both inside and outside of the MRI. Using this method, a single MRI scan is necessary for accurate targeting; repeated subsequent treatments can be performed reproducibly in an MRI-free manner. We validated these functions by transiently modulating specific deep brain regions in two patients with treatment-resistant depression.