Systematic examination of low-intensity ultrasound parameters on human motor cortex excitability and behavior
Anton Fomenko, Kai-Hsiang Stanley Chen, Jean-François Nankoo, James Saravanamuttu, Yanqiu Wang, Mazen El-Baba, Xue Xia, Shakthi Sanjana Seerala, Kullervo Hynynen, Andres M Lozano, Robert Chen, Anton Fomenko, Kai-Hsiang Stanley Chen, Jean-François Nankoo, James Saravanamuttu, Yanqiu Wang, Mazen El-Baba, Xue Xia, Shakthi Sanjana Seerala, Kullervo Hynynen, Andres M Lozano, Robert Chen
Abstract
Low-intensity transcranial ultrasound (TUS) can non-invasively modulate human neural activity. We investigated how different fundamental sonication parameters influence the effects of TUS on the motor cortex (M1) of 16 healthy subjects by probing cortico-cortical excitability and behavior. A low-intensity 500 kHz TUS transducer was coupled to a transcranial magnetic stimulation (TMS) coil. TMS was delivered 10 ms before the end of TUS to the left M1 hotspot of the first dorsal interosseous muscle. Varying acoustic parameters (pulse repetition frequency, duty cycle, and sonication duration) on motor-evoked potential amplitude were examined. Paired-pulse measures of cortical inhibition and facilitation, and performance on a visuomotor task was also assessed. TUS safely suppressed TMS-elicited motor cortical activity, with longer sonication durations and shorter duty cycles when delivered in a blocked paradigm. TUS increased GABAA-mediated short-interval intracortical inhibition and decreased reaction time on visuomotor task but not when controlled with TUS at near-somatosensory threshold intensity.
Keywords: brain stimulation; focused ultrasound; human; neuromodulation; neuroscience; noninvasive brain stimulation; transcranial magnetic stimulation; transcranial ultrasound.
Conflict of interest statement
AF, KC, JN, JS, YW, ME, XX, SS, KH, AL, RC No competing interests declared
© 2020, Fomenko et al.
Figures
References
- Ai L, Mueller JK, Grant A, Eryaman Y, Legon W. Transcranial focused ultrasound for BOLD fMRI signal modulation in humans. Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS; 2016.
- Ai L, Bansal P, Mueller JK, Legon W. Effects of transcranial focused ultrasound on human primary motor cortex using 7T fMRI: a pilot study. BMC Neuroscience. 2018;19:56. doi: 10.1186/s12868-018-0456-6.
- Andersen P, Hagan PJ, Phillips CG, Powell TP. Mapping by microstimulation of overlapping projections from area 4 to motor units of the baboon’s hand. Proceedings of the Royal Society of London. Series B, Biological Sciences. 1975;188:31–36. doi: 10.1098/rspb.1975.0002.
- Bashir S, Perez JM, Horvath JC, Pascual-Leone A. Differentiation of motor cortical representation of hand muscles by navigated mapping of optimal TMS current directions in healthy subjects. Journal of Clinical Neurophysiology. 2013;30:390–395. doi: 10.1097/WNP.0b013e31829dda6b.
- Beck S, Hallett M. Surround inhibition in the motor system. Experimental Brain Research. 2011;210:165–172. doi: 10.1007/s00221-011-2610-6.
- Brainard DH. The psychophysics toolbox. Spatial Vision. 1997;10:433–436. doi: 10.1163/156856897X00357.
- Braun V, Blackmore J, Cleveland RO, Butler CR. Transcranial ultrasound stimulation in humans is associated with an auditory confound that can be effectively masked. Brain Stimulation. 2020;13:1527–1534. doi: 10.1016/j.brs.2020.08.014.
- Bystritsky A, Korb A, Stern J, Cohen M. Safety and feasibility of focused ultrasound neurmodulation in temporal lobe epilepsy. Brain Stimulation. 2015;8:412. doi: 10.1016/j.brs.2015.01.314.
- de Almeida Marcelino AL, Horn A, Krause P, Kühn AA, Neumann WJ. Subthalamic neuromodulation improves short-term motor learning in Parkinson's disease. Brain. 2019;142:2198–2206. doi: 10.1093/brain/awz152.
- Deffieux T, Konofagou EE. Numerical study of a simple transcranial focused ultrasound system applied to blood-brain barrier opening. IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control. 2010;57:2637–2653. doi: 10.1109/TUFFC.2010.1738.
- Diederich A, Colonius H. Intersensory facilitation in the motor component? Psychological Research. 1987;49:23–29. doi: 10.1007/BF00309199.
- Duck FA. Medical and non-medical protection standards for ultrasound and infrasound. Progress in Biophysics and Molecular Biology. 2007;93:176–191. doi: 10.1016/j.pbiomolbio.2006.07.008.
- Ellaway PH, Davey NJ, Maskill DW, Rawlinson SR, Lewis HS, Anissimova NP. Variability in the amplitude of skeletal muscle responses to magnetic stimulation of the motor cortex in man. Electroencephalography and Clinical Neurophysiology/Electromyography and Motor Control. 1998;109:104–113. doi: 10.1016/S0924-980X(98)00007-1.
- Fadiga L, Craighero L, Buccino G, Rizzolatti G. Speech listening specifically modulates the excitability of tongue muscles: a TMS study. European Journal of Neuroscience. 2002;15:399–402. doi: 10.1046/j.0953-816x.2001.01874.x.
- Farzan F, Barr MS, Hoppenbrouwers SS, Fitzgerald PB, Chen R, Pascual-Leone A, Daskalakis ZJ. The EEG correlates of the TMS-induced EMG silent period in humans. NeuroImage. 2013;83:120–134. doi: 10.1016/j.neuroimage.2013.06.059.
- Flöel A, Ellger T, Breitenstein C, Knecht S. Language perception activates the hand motor cortex: implications for motor theories of speech perception. European Journal of Neuroscience. 2003;18:704–708. doi: 10.1046/j.1460-9568.2003.02774.x.
- Fomenko A, Neudorfer C, Dallapiazza RF, Kalia SK, Lozano AM. Low-intensity ultrasound neuromodulation: an overview of mechanisms and emerging human applications. Brain Stimulation. 2018;11:1209–1217. doi: 10.1016/j.brs.2018.08.013.
- Fomenko A. Ultrasound transducer holders for 70mm TMS coil and for TUS transducer alone - STL files for 3D printing. 9e494e2GitHub. 2019a
- Fomenko A. MATAB codes used to deliver TUS stimulation and analyze behaviour. fe4df0aGitHub. 2019b
- Fomenko A, Lozano AM. Neuromodulation and ablation with focused ultrasound - Toward the future of noninvasive brain therapy. Neural Regeneration Research. 2019;14:1509–1510. doi: 10.4103/1673-5374.255961.
- Forster B, Cavina-Pratesi C, Aglioti SM, Berlucchi G. Redundant target effect and intersensory facilitation from visual-tactile interactions in simple reaction time. Experimental Brain Research. 2002;143:480–487. doi: 10.1007/s00221-002-1017-9.
- Fox PT, Narayana S, Tandon N, Sandoval H, Fox SP, Kochunov P, Lancaster JL. Column-based model of electric field excitation of cerebral cortex. Human Brain Mapping. 2004;22:1–14. doi: 10.1002/hbm.20006.
- Gaur P, Casey KM, Kubanek J, Li N, Mohammadjavadi M, Saenz Y, Glover GH, Bouley DM, Pauly KB. Histologic safety of transcranial focused ultrasound neuromodulation and magnetic resonance acoustic radiation force imaging in rhesus macaques and sheep. Brain Stimulation. 2020;13:804–814. doi: 10.1016/j.brs.2020.02.017.
- Gibson BC, Sanguinetti JL, Badran BW, Yu AB, Klein EP, Abbott CC, Hansberger JT, Clark VP. Increased excitability induced in the primary motor cortex by transcranial ultrasound stimulation. Frontiers in Neurology. 2018;9:1007. doi: 10.3389/fneur.2018.01007.
- Gulick DW, Li T, Kleim JA, Towe BC. Comparison of electrical and ultrasound neurostimulation in rat motor cortex. Ultrasound in Medicine & Biology. 2017;43:2824–2833. doi: 10.1016/j.ultrasmedbio.2017.08.937.
- Guo H, Hamilton Ii M, Offutt SJ, Gloeckner CD, Li T, Kim Y, Legon W, Alford JK, Lim HH. Ultrasound produces extensive brain activation via a cochlear pathway. Neuron. 2018;99:866. doi: 10.1016/j.neuron.2018.07.049.
- Hamada M, Terao Y, Hanajima R, Shirota Y, Nakatani-Enomoto S, Furubayashi T, Matsumoto H, Ugawa Y. Bidirectional long-term motor cortical plasticity and metaplasticity induced by quadripulse transcranial magnetic stimulation. The Journal of Physiology. 2008;586:3927–3947. doi: 10.1113/jphysiol.2008.152793.
- Hameroff S, Trakas M, Duffield C, Annabi E, Gerace MB, Boyle P, Lucas A, Amos Q, Buadu A, Badal JJ. Transcranial ultrasound (TUS) effects on mental states: a pilot study. Brain Stimulation. 2013;6:409–415. doi: 10.1016/j.brs.2012.05.002.
- Holm S. A simple sequentially rejective multiple test procedure. Scandinavian Journal of Statistics. 1979;6:65–70. doi: 10.2307/4615733.
- Huber R, Mäki H, Rosanova M, Casarotto S, Canali P, Casali AG, Tononi G, Massimini M. Human cortical excitability increases with time awake. Cerebral Cortex. 2013;23:1–7. doi: 10.1093/cercor/bhs014.
- Hynynen K, Sun J. Trans-skull ultrasound therapy: the feasibility of using image-derived skull thickness information to correct the phase distortion. IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control. 1999;46:752–755. doi: 10.1109/58.764862.
- Kamimura HA, Wang S, Chen H, Wang Q, Aurup C, Acosta C, Carneiro AA, Konofagou EE. Focused ultrasound neuromodulation of cortical and subcortical brain structures using 1.9 MHz. Medical Physics. 2016;43:5730–5735. doi: 10.1118/1.4963208.
- Kim H, Chiu A, Lee SD, Fischer K, Yoo SS. Focused ultrasound-mediated non-invasive brain stimulation: examination of sonication parameters. Brain Stimulation. 2014;7:748–756. doi: 10.1016/j.brs.2014.06.011.
- King RL, Brown JR, Newsome WT, Pauly KB. Effective parameters for ultrasound-induced in vivo neurostimulation. Ultrasound in Medicine & Biology. 2013;39:312–331. doi: 10.1016/j.ultrasmedbio.2012.09.009.
- Kubanek J, Shi J, Marsh J, Chen D, Deng C, Cui J. Ultrasound modulates ion channel currents. Scientific Reports. 2016;6:24170. doi: 10.1038/srep24170.
- Lee W, Kim H, Jung Y, Song IU, Chung YA, Yoo SS. Image-guided transcranial focused ultrasound stimulates human primary somatosensory cortex. Scientific Reports. 2015;5:8743. doi: 10.1038/srep08743.
- Lee W, Chung YA, Jung Y, Song IU, Yoo SS. Simultaneous acoustic stimulation of human primary and secondary somatosensory cortices using transcranial focused ultrasound. BMC Neuroscience. 2016a;17:68. doi: 10.1186/s12868-016-0303-6.
- Lee W, Kim HC, Jung Y, Chung YA, Song IU, Lee JH, Yoo SS. Transcranial focused ultrasound stimulation of human primary visual cortex. Scientific Reports. 2016b;6:34026. doi: 10.1038/srep34026.
- Lee W, Lee SD, Park MY, Foley L, Purcell-Estabrook E, Kim H, Fischer K, Maeng LS, Yoo SS. Image-Guided focused Ultrasound-Mediated regional brain stimulation in sheep. Ultrasound in Medicine & Biology. 2016c;42:459–470. doi: 10.1016/j.ultrasmedbio.2015.10.001.
- Lee W, Croce P, Margolin RW, Cammalleri A, Yoon K, Yoo SS. Transcranial focused ultrasound stimulation of motor cortical areas in freely-moving awake rats. BMC Neuroscience. 2018;19:57. doi: 10.1186/s12868-018-0459-3.
- Legon W, Sato TF, Opitz A, Mueller J, Barbour A, Williams A, Tyler WJ. Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans. Nature Neuroscience. 2014;17:322–329. doi: 10.1038/nn.3620.
- Legon W, Ai L, Bansal P, Mueller JK. Neuromodulation with single-element transcranial focused ultrasound in human thalamus. Human Brain Mapping. 2018a;39:1995–2006. doi: 10.1002/hbm.23981.
- Legon W, Bansal P, Tyshynsky R, Ai L, Mueller JK. Transcranial focused ultrasound neuromodulation of the human primary motor cortex. Scientific Reports. 2018b;8:10007. doi: 10.1038/s41598-018-28320-1.
- Legon W, Adams S, Bansal P, Patel PD, Hobbs L, Ai L, Mueller JK, Meekins G, Gillick BT. A retrospective qualitative report of symptoms and safety from transcranial focused ultrasound for neuromodulation in humans. Scientific Reports. 2020;10:5573. doi: 10.1038/s41598-020-62265-8.
- Liuzzi G, Ellger T, Flöel A, Breitenstein C, Jansen A, Knecht S. Walking the talk--speech activates the leg motor cortex. Neuropsychologia. 2008;46:2824–2830. doi: 10.1016/j.neuropsychologia.2008.05.015.
- Manuel TJ, Kusunose J, Zhan X, Lv X, Kang E, Yang A, Xiang Z, Caskey CF. Ultrasound neuromodulation depends on pulse repetition frequency and can modulate inhibitory effects of TTX. Scientific Reports. 2020;10:15347. doi: 10.1038/s41598-020-72189-y.
- McDannold N, King RL, Hynynen K. MRI monitoring of heating produced by ultrasound absorption in the skull: in vivo study in pigs. Magnetic Resonance in Medicine. 2004;51:1061–1065. doi: 10.1002/mrm.20043.
- Mehić E, Xu JM, Caler CJ, Coulson NK, Moritz CT, Mourad PD. Increased anatomical specificity of neuromodulation via modulated focused ultrasound. PLOS ONE. 2014;9:e86939. doi: 10.1371/journal.pone.0086939.
- Meng Y, Volpini M, Black S, Lozano AM, Hynynen K, Lipsman N. Focused ultrasound as a novel strategy for Alzheimer disease therapeutics. Annals of Neurology. 2017;81:611–617. doi: 10.1002/ana.24933.
- Monti MM, Schnakers C, Korb AS, Bystritsky A, Vespa PM. Non-Invasive ultrasonic thalamic stimulation in disorders of consciousness after severe brain injury: a First-in-Man report. Brain Stimulation. 2016;9:940–941. doi: 10.1016/j.brs.2016.07.008.
- Mueller J, Legon W, Opitz A, Sato TF, Tyler WJ. Transcranial focused ultrasound modulates intrinsic and evoked EEG dynamics. Brain Stimulation. 2014;7:900–908. doi: 10.1016/j.brs.2014.08.008.
- Mueller JK, Ai L, Bansal P, Legon W. Computational exploration of wave propagation and heating from transcranial focused ultrasound for neuromodulation. Journal of Neural Engineering. 2016;13:056002. doi: 10.1088/1741-2560/13/5/056002.
- Mueller JK, Ai L, Bansal P, Legon W. Numerical evaluation of the skull for human neuromodulation with transcranial focused ultrasound. Journal of Neural Engineering. 2017;14:066012. doi: 10.1088/1741-2552/aa843e.
- Naor O, Krupa S, Shoham S. Ultrasonic neuromodulation. Journal of Neural Engineering. 2016;13:031003. doi: 10.1088/1741-2560/13/3/031003.
- Niu X, Yu K, He B. On the neuromodulatory pathways of the In vivo brain by means of transcranial focused ultrasound. Current Opinion in Biomedical Engineering. 2018;8:61–69. doi: 10.1016/j.cobme.2018.10.004.
- Opitz A, Legon W, Mueller J, Barbour A, Paulus W, Tyler WJ. Is sham cTBS real cTBS? the effect on EEG dynamics. Frontiers in Human Neuroscience. 2014;8:1043. doi: 10.3389/fnhum.2014.01043.
- Pasquinelli C, Hanson LG, Siebner HR, Lee HJ, Thielscher A. Safety of transcranial focused ultrasound stimulation: a systematic review of the state of knowledge from both human and animal studies. Brain Stimulation. 2019;12:1367–1380. doi: 10.1016/j.brs.2019.07.024.
- Plaksin M, Shoham S, Kimmel E. Intramembrane cavitation as a predictive Bio-Piezoelectric mechanism for ultrasonic brain stimulation. Physical Review X. 2014;4:011004. doi: 10.1103/PhysRevX.4.011004.
- Plaksin M, Kimmel E, Shoham S. Cell-Type-Selective effects of intramembrane cavitation as a unifying theoretical framework for ultrasonic neuromodulation. Eneuro. 2016;3:ENEURO.0136-15.2016. doi: 10.1523/ENEURO.0136-15.2016.
- Premoli I, Rivolta D, Espenhahn S, Castellanos N, Belardinelli P, Ziemann U, Müller-Dahlhaus F. Characterization of GABAB-receptor mediated neurotransmission in the human cortex by paired-pulse TMS-EEG. NeuroImage. 2014;103:152–162. doi: 10.1016/j.neuroimage.2014.09.028.
- Robertson J, Martin E, Cox B, Treeby BE. Sensitivity of simulated transcranial ultrasound fields to acoustic medium property maps. Physics in Medicine and Biology. 2017;62:2559–2580. doi: 10.1088/1361-6560/aa5e98.
- Robertson J, Urban J, Stitzel J, Treeby BE. The effects of image homogenisation on simulated transcranial ultrasound propagation. Physics in Medicine & Biology. 2018;63:145014. doi: 10.1088/1361-6560/aacc33.
- Rosnitskiy PB, Yuldashev PV, Sapozhnikov OA, Gavrilov LR, Khokhlova VA. Simulation of nonlinear trans-skull focusing and formation of shocks in brain using a fully populated ultrasound array with aberration correction. The Journal of the Acoustical Society of America. 2019;146:1786–1798. doi: 10.1121/1.5126685.
- Sanguinetti JL, Smith E, Allen JJB, Hameroff S. Human Brain Stimulation with Transcranial Ultrasound. In: Rosch P. J, editor. Bioelectromagnetic and Subtle Energy Medicine. Tylor and Francis; 2014. pp. 355–363.
- Sato T, Shapiro MG, Tsao DY. Ultrasonic neuromodulation causes widespread cortical activation via an indirect auditory mechanism. Neuron. 2018;98:1031–1041. doi: 10.1016/j.neuron.2018.05.009.
- Schimek N, Burke-Conte Z, Abernethy J, Schimek M, Burke-Conte C, Bobola M, Stocco A, Mourad PD. Repeated application of transcranial diagnostic ultrasound towards the visual cortex induced illusory visual percepts in healthy participants. Frontiers in Human Neuroscience. 2020;14:66. doi: 10.3389/fnhum.2020.00066.
- Schneider C, Devanne H, Lavoie BA, Capaday C. Neural mechanisms involved in the functional linking of motor cortical points. Experimental Brain Research. 2002;146:86–94. doi: 10.1007/s00221-002-1137-2.
- Stagg CJ, Bestmann S, Constantinescu AO, Moreno LM, Allman C, Mekle R, Woolrich M, Near J, Johansen-Berg H, Rothwell JC. Relationship between physiological measures of excitability and levels of glutamate and GABA in the human motor cortex. The Journal of Physiology. 2011;589:5845–5855. doi: 10.1113/jphysiol.2011.216978.
- Stern J. Low-intensity focused ultrasound pulsation (LIFUP) for treatment of temporal lobe epilepsy. [November 20, 2019]; ID: NCT02151175. 2014
- Stokes MG, Chambers CD, Gould IC, Henderson TR, Janko NE, Allen NB, Mattingley JB. Simple metric for scaling motor threshold based on scalp-cortex distance: application to studies using transcranial magnetic stimulation. Journal of Neurophysiology. 2005;94:4520–4527. doi: 10.1152/jn.00067.2005.
- Thielscher A, Antunes A, Saturnino GB. Field modeling for transcranial magnetic stimulation: a useful tool to understand the physiological effects of TMS?. Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS; 2015.
- Treeby BE, Cox BT. k-Wave: MATLAB toolbox for the simulation and reconstruction of photoacoustic wave fields. Journal of Biomedical Optics. 2010;15:021314. doi: 10.1117/1.3360308.
- Tremblay S, Beaulé V, Proulx S, de Beaumont L, Marjanska M, Doyon J, Pascual-Leone A, Lassonde M, Théoret H. Relationship between transcranial magnetic stimulation measures of intracortical inhibition and spectroscopy measures of GABA and glutamate+glutamine. Journal of Neurophysiology. 2013;109:1343–1349. doi: 10.1152/jn.00704.2012.
- Tsivgoulis G, Alexandrov AV. Ultrasound-enhanced thrombolysis in acute ischemic stroke: potential, failures, and safety. Neurotherapeutics. 2007;4:420–427. doi: 10.1016/j.nurt.2007.05.012.
- Tyler WJ, Tufail Y, Finsterwald M, Tauchmann ML, Olson EJ, Majestic C. Remote excitation of neuronal circuits using low-intensity, low-frequency ultrasound. PLOS ONE. 2008;3:e3511. doi: 10.1371/journal.pone.0003511.
- Udupa K, Ni Z, Gunraj C, Chen R. Effect of long interval interhemispheric inhibition on intracortical inhibitory and facilitatory circuits. The Journal of Physiology. 2010;588:2633–2641. doi: 10.1113/jphysiol.2010.189548.
- Udupa K, Bahl N, Ni Z, Gunraj C, Mazzella F, Moro E, Hodaie M, Lozano AM, Lang AE, Chen R. Cortical plasticity induction by pairing subthalamic nucleus Deep-Brain stimulation and primary motor cortical transcranial magnetic stimulation in Parkinson's Disease. The Journal of Neuroscience. 2016;36:396–404. doi: 10.1523/JNEUROSCI.2499-15.2016.
- United States Food and Drug Administration . Marketing Clearance of Diagnostic Ultrasound Systems and Transducers. Draft Guidance for Industry and Food and Drug Administration Staff; 2017.
- Wagner T, Fregni F. Non-invasive neurostimulation in Parkinson’s Disease. [November 20, 2019]; ID: NCT01615718. 2012
- Watanabe T, Hanajima R, Shirota Y, Ohminami S, Tsutsumi R, Terao Y, Ugawa Y, Hirose S, Miyashita Y, Konishi S, Kunimatsu A, Ohtomo K. Bidirectional effects on interhemispheric resting-state functional connectivity induced by excitatory and inhibitory repetitive transcranial magnetic stimulation. Human Brain Mapping. 2014;35:1896–1905. doi: 10.1002/hbm.22300.
- Yoo SS, Kim H, Filandrianos E, Taghados SJ, Park S. Non-invasive brain-to-brain interface (BBI): establishing functional links between two brains. PLOS ONE. 2013;8:e60410. doi: 10.1371/journal.pone.0060410.
- Yoon K, Lee W, Lee JE, Xu L, Croce P, Foley L, Yoo SS. Effects of sonication parameters on transcranial focused ultrasound brain stimulation in an ovine model. PLOS ONE. 2019;14:e0224311. doi: 10.1371/journal.pone.0224311.
- Yu K, Niu X, Krook-Magnuson E, He B. Intrinsic Cell-type selectivity and Inter-neuronal connectivity alteration by transcranial focused ultrasound. bioRxiv. 2019 doi: 10.1101/576066.
- Ziemann U, Reis J, Schwenkreis P, Rosanova M, Strafella A, Badawy R, Müller-Dahlhaus F. TMS and drugs revisited 2014. Clinical Neurophysiology. 2015;126:1847–1868. doi: 10.1016/j.clinph.2014.08.028.
Source: PubMed