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      Manipulation of Subcortical and Deep Cortical Activity in the Primate Brain Using Transcranial Focused Ultrasound Stimulation

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          Summary

          The causal role of an area within a neural network can be determined by interfering with its activity and measuring the impact. Many current reversible manipulation techniques have limitations preventing their application, particularly in deep areas of the primate brain. Here, we demonstrate that a focused transcranial ultrasound stimulation (TUS) protocol impacts activity even in deep brain areas: a subcortical brain structure, the amygdala (experiment 1), and a deep cortical region, the anterior cingulate cortex (ACC, experiment 2), in macaques. TUS neuromodulatory effects were measured by examining relationships between activity in each area and the rest of the brain using functional magnetic resonance imaging (fMRI). In control conditions without sonication, activity in a given area is related to activity in interconnected regions, but such relationships are reduced after sonication, specifically for the targeted areas. Dissociable and focal effects on neural activity could not be explained by auditory confounds.

          Highlights

          • Ultrasound stimulation exerts regionally specific neural effects in primates

          • It can be used to alter activity even in subcortical and deep cortical areas

          • After stimulation, activity in a brain area is less related to that of its network

          • The effect lasted for more than 1 h and was not mediated by auditory confounds

          Abstract

          Ultrasound can be used to modulate activity in deep brain areas. After stimulation, activity in the targeted brain area becomes less coupled to its network. Effects are specific to the stimulation site, long-lasting, and not due to auditory confounds.

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          Most cited references22

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          The anatomical basis of functional localization in the cortex.

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            Remote Excitation of Neuronal Circuits Using Low-Intensity, Low-Frequency Ultrasound

            Possessing the ability to noninvasively elicit brain circuit activity yields immense experimental and therapeutic power. Most currently employed neurostimulation methods rely on the somewhat invasive use of stimulating electrodes or photon-emitting devices. Due to its ability to noninvasively propagate through bone and other tissues in a focused manner, the implementation of ultrasound (US) represents a compelling alternative approach to current neuromodulation strategies. Here, we investigated the influence of low-intensity, low-frequency ultrasound (LILFU) on neuronal activity. By transmitting US waveforms through hippocampal slice cultures and ex vivo mouse brains, we determined LILFU is capable of remotely and noninvasively exciting neurons and network activity. Our results illustrate that LILFU can stimulate electrical activity in neurons by activating voltage-gated sodium channels, as well as voltage-gated calcium channels. The LILFU-induced changes in neuronal activity were sufficient to trigger SNARE-mediated exocytosis and synaptic transmission in hippocampal circuits. Because LILFU can stimulate electrical activity and calcium signaling in neurons as well as central synaptic transmission we conclude US provides a powerful tool for remotely modulating brain circuit activity.
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              Focused ultrasound modulates region-specific brain activity.

              We demonstrated the in vivo feasibility of using focused ultrasound (FUS) to transiently modulate (through either stimulation or suppression) the function of regional brain tissue in rabbits. FUS was delivered in a train of pulses at low acoustic energy, far below the cavitation threshold, to the animal's somatomotor and visual areas, as guided by anatomical and functional information from magnetic resonance imaging (MRI). The temporary alterations in the brain function affected by the sonication were characterized by both electrophysiological recordings and functional brain mapping achieved through the use of functional MRI (fMRI). The modulatory effects were bimodal, whereby the brain activity could either be stimulated or selectively suppressed. Histological analysis of the excised brain tissue after the sonication demonstrated that the FUS did not elicit any tissue damages. Unlike transcranial magnetic stimulation, FUS can be applied to deep structures in the brain with greater spatial precision. Transient modulation of brain function using image-guided and anatomically-targeted FUS would enable the investigation of functional connectivity between brain regions and will eventually lead to a better understanding of localized brain functions. It is anticipated that the use of this technology will have an impact on brain research and may offer novel therapeutic interventions in various neurological conditions and psychiatric disorders. Copyright © 2011 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Neuron
                Neuron
                Neuron
                Cell Press
                0896-6273
                1097-4199
                20 March 2019
                20 March 2019
                : 101
                : 6
                : 1109-1116.e5
                Affiliations
                [1 ]Wellcome Centre for Integrative Neuroimaging (WIN), Department of Experimental Psychology, University of Oxford, Oxford OX1 3SR, UK
                [2 ]Wellcome Centre for Integrative Neuroimaging (WIN), Centre for Functional MRI of the Brain (FMRIB), Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK
                [3 ]Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, 6525 HR Nijmegen, the Netherlands
                [4 ]School of Psychology, University of Plymouth, Plymouth PL4 8AA, UK
                [5 ]Physics for Medicine Paris, Inserm, ESPCI Paris, CNRS, PSL Research University, Univ Paris Diderot, Sorbonne Paris Cité, Paris 75012, France
                [6 ]Physics for Medicine Paris, Inserm, ESPCI Paris, CNRS, PSL Research University, Paris 75012, France
                Author notes
                []Corresponding author davide.folloni@ 123456psy.ox.ac.uk
                [∗∗ ]Corresponding author lennart.verhagen@ 123456psy.ox.ac.uk
                [∗∗∗ ]Corresponding author jerome.sallet@ 123456psy.ox.ac.uk
                [7]

                These authors contributed equally

                [8]

                Lead Contact

                Article
                S0896-6273(19)30046-7
                10.1016/j.neuron.2019.01.019
                6520498
                30765166
                1a0a160f-95e2-4d34-a58d-82223272f014
                © 2019 The Authors. Published by Elsevier Inc.

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 18 July 2018
                : 29 November 2018
                : 14 January 2019
                Categories
                Article

                Neurosciences
                ultrasound,amygdala,cingulate cortex,limbic,macaque monkey,neuromodulation,transcranial stimulation,functional connectivity,resting-state connectivity

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