Effective Ultrasound Neuromodulation in the Awake Primate Brain

Ultrasound neuromodulation promises to revolutionize treatment for neurological and mental disorders by providing pre- cise, non-invasive treatment of the neural circuits involved in disease. Ultrasound’s strength lies in its capacity to focus energy through the intact skull to grain of rice size regions deep in the brain. At these target regions, the ultrasound interacts with the neural tissue resulting in modulation of the neural activity. Transcranial ultrasound neuromodula- tion treatments are emerging in both pre-clinical and clinical studies as a promising approach to treat diseases from depression to Alzheimer’s and epilepsy. The effect of ultrasound on the target tissue depends on the sonication parameters—the amplitude, duration, duty cy- cle, and pulse repetition frequency of the ultrasound pulse. Studies show that, depending on the selected parameters, ultrasound can both excite and inhibit the target tissue. However, this flexibility is not yet utilized clinically because the relationship between the acoustic parameters and the neural response remains elusive. This study will develop a nonhuman primate (NHP) model capable of measuring real-time changes in neural activity after ultrasound neuro- modulation. Thus, the study aims to deliver clinic-ready protocols capable of optimally exciting or inhibiting the target region. To achieve this goal we will combine two existing technologies. Remus is a remote ultrasound system capable of flexibly delivering arbitrary ultrasound pulses to deep brain regions in an awake, behaving NHP. In.Tra is a cranial implant that is transparent to ultrasound and thus enables functional ultrasound imaging. Combined, the two technologies enable real-time monitoring of the awake brain’s response to ultrasound neuromodulation. Our two aims will validate this approach by measuring the response of the awake visual system to ultrasound neuro- modulation of the lateral geniculate nucleus (LGN). In Aim 1 we will measure the neural response of the targeted LGN and the ipsilateral primary visual cortex. In Aim 2 we will measure changes in the correlation coefficient (a marker of functional connectivity) between the same two regions. Both experiments will include systematic variation of the am- plitude, duration, duty cycle, and pulse repetition frequency of the neuromodulatory sonication, including parameters expected to excite and inhibit the targeted anatomy. Thus, validation of our platform will produce clinic-ready protocols to suppress or excite neural activity in the targeted circuit.