322 VOLUME 17 | NUMBER 2 | FEBRUARY 2014 NATURE NEUROSCIENCE TECHNICAL REPORTS Improved methods of noninvasively modulating human brain function are needed. Here we probed the influence of transcranial focused ultrasound (t FUS) targeted to the human primary somatosensory cortex (S1) on sensory-evoked brain activity and sensory discrimination abilities. The lateral and axial spatial resolution of the tFUS beam implemented were 4.9 mm and 18 mm, respectively. Electroencephalographic recordings showed that tFUS significantly attenuated the amplitudes of somatosensory evoked potentials elicited by median nerve stimulation. We also found that tFUS significantly modulated the spectral content of sensory-evoked brain oscillations. The changes produced by tFUS on sensory- evoked brain activity were abolished when the acoustic beam was focused 1 cm anterior or posterior to S1. Behavioral investigations showed that tFUS targeted to S1 enhanced performance on sensory discrimination tasks without affecting task attention or response bias. We conclude that tFUS can be used to focally modulate human cortical function. Current noninvasive neuromodulation methods, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimula- tion, offer low spatial resolutions. These methods typically produce electric fields having length scales on the order of several centimeters, which span anatomically and functionally distinct human brain cir- cuits 1,2 . As a result, current transcranial approaches often modulate activity not only in the intended target but also in surrounding brain circuits 1,3 . Therefore, improved approaches to the transcranial modu- lation of human brain circuit activity are sought to support global brain mapping efforts, as well as to advance diagnostics and therapies in neuroscience. In the present study, we investigated the potential use of pulsed ultrasound (US) for focally modulating cortical func- tion in humans. Studies examining the direct effects of US on neuronal activity date back to 1929, when US was first shown to excite nerve fibers in isolated turtle and frog muscle preparations 4 . Evidence accumulated since then has shown that US can directly modulate neuronal activity in peripheral nerves 5,6 , elicit action potentials in hippocampal slices 7,8 and stimulate retina 9 . Further, US can noninvasively stimu- late the hippocampus and motor cortex of intact mice 10,11 , modulate monosynaptic and polysynaptic spinal reflexes in cats 12 and disrupt seizure activity in cats 13 , rats 14 and mice 15 . Additional evidence from animal models has demonstrated that US can elicit functional mag- netic resonance imaging blood oxygen–level dependent contrast signals in the visual and motor cortices of rabbits 16 , reversibly sup- press the amplitudes of visual evoked potentials in both cats 17 and rabbits 16 , and functionally modulate neuronal activity in the frontal eye fields of awake, behaving monkeys 18 . At low intensities for short exposure times, tissue heating does not occur, so the mechanisms underlying the effects of US on neuronal activity are thought to par- tially stem from mechanical pressure effects of US on cellular mem- branes and ion channels 5,10,16,19,20 . These mechanical actions of US have not been reported to cause tissue damage when used to modulate neuronal activity 5,9–11,15,16,19 . Despite observations in different animal models, it has remained untested whether US can focally modulate the activity of intact human brain circuits. Therefore, we aimed to determine whether tFUS is capable of functionally modulating brain activity in the human pri- mary somatosensory cortex. Our findings indicate tFUS can focally modulate sensory evoked brain activity and cortical function in humans. These observations may help advance the development of enhanced noninvasive neuromodulation strategies. RESULTS Acoustic beam properties of tFUS The optimal acoustic frequencies for the transcranial transmission and brain absorption of US are known to be <0.65 MHz (refs. 21,22). We used 0.5-MHz US on the basis of previous observations that it can modulate mammalian brain activity 10,11 . First we quantified acoustic pressure fields emitted from a single-element focused ultra- sound (FUS) transducer having a center frequency of 0.5 MHz, a diameter of 30 mm and a focal length of 30 mm. Using a calibrated hydrophone mounted on a motorized, three-axis stage, we recorded acoustic pressure fields transmitted from the FUS transducer into the free space of an acoustic test tank, as well as through hydrated frag- ments of human cranium (Fig. 1; see Online Methods). Our measure- ments revealed that when FUS was transmitted through the skull the spatial-peak pulse-average intensity (I SPPA ) dropped by approximately fourfold (1/4.05), corresponding to a -6.07 dB insertion loss with 1 Virginia Tech Carilion Research Institute, Roanoke, Virginia, USA. 2 Department of Clinical Neurophysiology, Georg-August-University, Göttingen, Germany. 3 School of Biomedical Engineering and Sciences, Virginia Tech, Blacksburg, Virginia, USA. 4 Department of Psychiatry and Behavioral Medicine, Virginia Tech Carilion School of Medicine, Roanoke, Virginia, USA. Correspondence should be addressed to W.J.T. (wtyler@vt.edu). Received 10 September 2013; accepted 4 December 2013; published online 12 January 2014; doi:10.1038/nn.3620 Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans Wynn Legon 1 , Tomokazu F Sato 1 , Alexander Opitz 1,2 , Jerel Mueller 3 , Aaron Barbour 1 , Amanda Williams 1 & William J Tyler 1,3,4 npg © 2014 Nature America, Inc. All rights reserved.