Low intensity transcranial focused ultrasound stimulation (TUS) is a novel non-invasive brain stimulation (NIBS) technique. Compared to commonly used NIBS techniques such as transcranial magnetic stimulation and transcranial direct current stimulation, TUS is much more focal and can reach deeper brain structures. The talk will focus on induction of plasticity or after-effects by TUS, since lasting effects are likely required for non-invasive treatment for neurological and psychiatric disorders. In human subjects, a theta burst TUS (tbTUS) protocol with TUS repeated at bursts at 5 Hz (theta frequency) for 80 s can increase motor cortical (M1) excitability for 30 min to 1 hour. Pharmacological studies showed that tbTUS plasticity is blocked by calcium channel and NMDA receptor blockers, and by benzodiazepine which enhances GABAergic transmission, consistent with a long-term potentiation-like mechanism. A magnetoencephalography study showed that TUS to the M1 led to widespread changes in connectivity between brain regions. tbTUS to the dorsal anterior cingulate cortex and posterior cingulate cortex increased functional connectivity of the target regions, and decreased GABA level in the posterior cingulate cortex. These findings are consistent with an excitatory effect of tbTUS in deep cortical structures. In Parkinson’s disease (PD) patients off-medication, tbTUS induced plasticity in the M1 was diminished but was restored to levels similar to normal subjects in the on-medication state. In a pilot study, PD patients in the off-medication state received 3 sessions of bilateral M1 TUS in one day. The study was well tolerated and led to increased M1 excitability and non-significant improvement in PD motor signs. These findings suggest that multiple sessions of TUS can be further studied as novel non-invasive treatment for PD. TUS targeting of deep brain structures requires accurate modeling based on individual MRI/CT scan because ultrasound is absorbed and deflected by the skull. In normal subjects, a TUS study targeting the internal globus pallidus (GPi) showed widespread reduction in blood flow measured by MRI. TUS of the subthalamic nucleus (STN) and the anterior putamen but not the posterior putamen interfered with a stop-signal reaction time task. There are few TUS studies in patients and they are small, open-labeled studies. TUS of the central thalamus was associated with improvement in patient with acute or chronic disorders of consciousness. TUS of mesial temporal lobe in patients with intractable epilepsy was safe and the subsequently resected brain tissues did not show histological changes. Current studies in our laboratory includes targeting the GPi and STN in PD patients implanted with deep brain stimulation (DBS) device capable of chronic local field potential recordings to provide target validation of our ability to accurately target deep brain structures and to find stimulation parameters that can reduce beta oscillations, a reliable biomarker of PD motor symptoms. Other oning studies include TUS of the cerebellum to treat freezing of gait in PD, cervical dystonia and orthostatic tremor. TUS has the potential to be developed into a novel non-invasive DBS treatment for neurological and psychiatric disorders.