Non-invasive neuromodulation using low-intensity transcranial focused ultrasound in the human brain

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Low-intensity focused ultrasound (LIFUS) is an emerging but powerful method for non-invasive neuromodulation of the human brain. Compared to transcranial magnetic stimulation (TMS) and transcranial direct current stimulation, LIFUS is more focal and can reach greater depths. Only a few studies have tested LIFUS in animals and humans. How LIFUS affects the human brain remains unclear. Importantly, different LIFUS parameters and induction of brain plasticity have not been systematically investigated. We will systematically investigate the neuromodulatory effects of LIFUS in the human brain. Healthy subjects will be recruited. Aim 1 will investigate the effects of different parameters of LIFUS including pulse repetition frequency, intensity, duty cycle, sonication duration on the excitability, intracortical facilitatory and inhibitory circuits in the motor cortex (M1) using single and paired pulse TMS. Aim 2 will assess how LIFUS affects connections to the motor cortex from other brain areas. LIFUS will be applied to the cerebellum to modulate the cerebello-thalamocortical pathway while TMS is applied to the contralateral M1. Similarly, LIFUS to M1 and TMS to the contralateral M1 will test interhemispheric connections. Further studies will test the connections of the posterior parietal cortex and dorsal premotor cortex to M1. Aim 3 will assess the functional consequences of LIFUS. Subjects will perform a cued reaction time task during LIFUS of M1. Inhibitory functions will be tested by applying LIFUS to the right inferior frontal gyrus and the presupplementary motor area while subjects perform a stop signal task. Aim 4 will use induce brain plasticity to assess the after effects of LIFUS. LIFUS in regular trains and in theta burst pattern will be applied the M1. Changes in M1 will be assessed by TMS up to 80 min after LIFUS. Aim 5 will test how LIFUS changes functional brain connectivity. We will apply LIFUS to the M1, cerebellum, premotor cortex or posterior parietal cortex in the MRI and assess changes resting state functional magnetic resonance imaging (fMRI). Aim 6 will examine the neurotransmitters mediating the effects of LIFUS. Normal subjects will be administered a single dose of a drug with known mechanism of action including carbamazepine (Na+ channel blocker), nimodipine (L-type Ca2+ channel blocker), lorazepam (increases GABA transmission), dextromethorphan (NMDA receptor antagonist) or placebo. The effects of each drug will be compared to that of placebo. This will be the first study to comprehensively and systematically examine LIFUS for neuromodulation. The proposed studies will define the optimal parameters, and determine the effects and the underlying mechanisms of LIFUS for neuromodulation in the human brain. It will lead to the development and adoption of LIFUS as a valuable tool in neuroscience research to understand and non-invasively modulate brain functions and connectivity.