Non-invasive, Deep Brain, and Focal Neuromodulation in Nonhuman Primates

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The ability to non-invasively perturb specific regions deep in the human brain would enable researchers and clinicians to study the causal relationships between specific brain structures and behavior. Current non-invasive neuromodulatory techniques enable the perturbation of the human cortex but a method that is simultaneously non-invasive, focal, and capable of perturbing deep brain circuits remains elusive. The goal of this project is to develop a non-invasive and focal technique capable of perturbing individual deep brain nuclei in humans. Such a technique has the capacity to revolutionize neuroscience in both the clinic and the laboratory by enabling the systematic study of causal relationships between neural circuits and behavior in regions that are inaccessible with current technologies. Investigating these causal relationships requires the capacity to perturb individual deep brain nuclei while monitoring the resulting impact on a patient's symptoms or behaviors. Transcranial ultrasound can enable this technique by focusing acoustic waves to deep brain structure through the intact skull. The capacity of transcranial ultrasound to target deep brain structures while sparing intervening tissue has been thoroughly demonstrated by high intensity focused ultrasound treatments in which the thermal energy carried by ultrasound is used to ablate a 4-5 mm volume in the thalamus. These treatments are outpatient and require no incision. At much lower intensities, ultrasound has been shown to modulate neural activity without significant increases in temperature. The combination of these properties makes ultrasound an ideal technology for developing non-invasive, deep brain, and focal neuromodulation techniques. Ultrasound can modulate neural activity directly or through the use of nanoparticle carriers designed to release a neuromodulatory drug when exposed to sufficient ultrasound pressure. Clinical translation of ultrasonic neuromodu- lation requires characterizing the relative efficacy and safety of these techniques. Such a comparison would enable researchers to select ultrasound protocols that meet the constraints of a given trial or treatment. The goal of this project is to provide a systematic characterization of the efficacy and safety of both ultrasonic neuromodulation approaches in the most relevant pre-clinical model, nonhuman primates, while targeting a deep brain structure, the lateral genic- ulate nucleus (LGN). The investigation will measure how each ultrasound stimulus changes a macaque's behavior during a commonly used visual discrimination task. The task provides a single signed, quantitative metric of the neu- romodulatory effects. When no stimulus is applied, the task serves as a sensitive indicator of safety, a metric which is supplemented with MR imaging. The training goal of the project is to facilitate the applicant's transition to independent research that leverages ultrasound to better understand and treat neurological disorders. The proposal provides the applicant with training in systems neuroscience and the design and execution of ultrasonic neuromodulation experiments in awake, behaving subjects. This combination will enable the investigator to design and execute future ultrasonic neuromodulation experiments exploring the role of deep brain structures in human behavior and disease.