Summary Neurological and psychiatric disorders absorb one-third of the total health care expenditures; more than cancer, cardiovascular diseases, and diabetes combined. On average, approximately one in three patients fails to respond to medication treatments or has intolerable side effects. Neuromodulation, which aims to treat brain disorders at their neural source, provides a new path to effective and personalized treatments. Unfortunately, existing invasive neuromodulation approaches are currently limited to specific patients and brain targets, and noninvasive approaches do not have the necessary spatial resolution. As a consequence, a large proportion of patients do not receive adequate treatment. To address this issue, we have developed a non-invasive approach and hardware that enable noninvasive and targeted neuromodulation. The tool modulates specific brain targets on command and at high spatial and temporal resolution. The approach has the precision of implanted electrodes but is applied remotely and entirely noninvasively. To achieve this, the approach combines two forms of noninvasive energies—focused ultrasonic and magnetic fields. The product of these fields generates localized electrical stimulation (“Lstim”). The ultrasound bestows Lstim with sharp focus and targeting flexibility. The stimulated regions can be as small as a grain of rice deep in the human brain. To realize the potential of the method, we have developed a programmable transducer array that can target specified brain regions rapidly on demand, enabling the stimulation of multiple brain targets in succession or concert. We have validated the neuromodulatory effects of Lstim in the peripheral nervous system of 18 human subjects. We now propose to develop effective and safe Lstim protocols for modulating deep circuits in the brain and thus harness the full power of the approach. We will perform the work in non-human primates to maximize clinical relevance and accelerate translation. Specifically, we will determine which Lstim parameters excite and inhibit neurons most effectively (Aim 1). We will target deep brain visual regions and assess the magnitude and polarity of the neuromodulatory effects using an established electrophysiological readout. We will validate the safety of Lstim using a sensitive behavioral task, contrast-enhanced MRI, and histological examination of brain slices (Aim 2). The completion of these two aims will maximize the effectiveness of a new, non-invasive and targeted neuromodulation technique and validate its safety. The approach has the potential to provide treatment options for a large number of medication-resistant patients. We will disseminate the developed hardware along with the effective protocols for the benefit of clinicians, patients, and researchers.

Narrative We will develop a noninvasive targeted neuromodulation tool. The tool will enable scientists to manipulate brain function in humans, and provide a treatment option for patients with treatment-resistant neurological and mental disorders. The development of this new technology and the intended use resonate with the mission of the NIH Brain Initiative.