Safety of Clinical Ultrasound Neuromodulation
Abstract
:1. Introduction
2. Main Bioeffects
2.1. Cavitation Effects
2.2. Heating Effects
2.3. Comparing Physical Properties of FUS and TPS
3. Clinical Safety Data
3.1. Safety Assessments in Ovine, Porcine and Non-Human Primate Studies
3.2. Safety Assessments in Human Studies
3.3. TPS Treatment Center Data
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Darmani, G.; Bergmann, T.O.; Butts Pauly, K.; Caskey, C.F.; de Lecea, L.; Fomenko, A.; Fouragnan, E.; Legon, W.; Murphy, K.R.; Nandi, T.; et al. Non-Invasive Transcranial Ultrasound Stimulation for Neuromodulation. Clin. Neurophysiol. 2022, 135, 51–73. [Google Scholar] [CrossRef]
- Meng, Y.; Hynynen, K.; Lipsman, N. Applications of Focused Ultrasound in the Brain: From Thermoablation to Drug Delivery. Nat. Rev. Neurol. 2021, 17, 7–22. [Google Scholar] [CrossRef] [PubMed]
- Sarica, C.; Nankoo, J.-F.; Fomenko, A.; Grippe, T.C.; Yamamoto, K.; Samuel, N.; Milano, V.; Vetkas, A.; Darmani, G.; Cizmeci, M.N.; et al. Human Studies of Transcranial Ultrasound Neuromodulation: A Systematic Review of Effectiveness and Safety. Brain Stimulat. 2022, 15, 737–746. [Google Scholar] [CrossRef] [PubMed]
- Pereira, E.A.; Green, A.L.; Nandi, D.; Aziz, T.Z. Deep Brain Stimulation: Indications and Evidence. Expert Rev. Med. Devices 2007, 4, 591–603. [Google Scholar] [CrossRef]
- Alster, P.; Koziorowski, D.M.; Za̧bek, M.; Dzierzȩcki, S.; Ma̧dry, J.; Duszyńska-Wa̧s, K.; Grygarowicz, H.; Zielonko, J.; Królicki, L.; Friedman, A. Making a Difference—Positive Effect of Unilateral VIM Gamma Knife Thalamotomy in the Therapy of Tremor in Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS). Front. Neurol. 2018, 9, 512. [Google Scholar] [CrossRef] [PubMed]
- Hallett, M. Transcranial Magnetic Stimulation and the Human Brain. Nature 2000, 406, 147–150. [Google Scholar] [CrossRef] [PubMed]
- Medeiros, L.; Souza, I.; Vidor, L.; Souza, A.; Deitos, A.; Volz, M.; Fregni, F.; CAUMO, W.; Torres, I. Neurobiological Effects of Transcranial Direct Current Stimulation: A Review. Front. Psychiatry 2012, 3, 110. [Google Scholar] [CrossRef]
- Truong, D.Q.; Thomas, C.; Hampstead, B.M.; Datta, A. Comparison of Transcranial Focused Ultrasound and Transcranial Pulse Stimulation for Neuromodulation: A Computational Study. Neuromodul. Technol. Neural Interface 2022, 25, 606–613. [Google Scholar] [CrossRef]
- Cain, J.A.; Visagan, S.; Johnson, M.A.; Crone, J.; Blades, R.; Spivak, N.M.; Shattuck, D.W.; Monti, M.M. Real Time and Delayed Effects of Subcortical Low Intensity Focused Ultrasound. Sci. Rep. 2021, 11, 6100. [Google Scholar] [CrossRef]
- Spagnolo, P.A.; Wang, H.; Srivanitchapoom, P.; Schwandt, M.; Heilig, M.; Hallett, M. Lack of Target Engagement Following Low-Frequency Deep Transcranial Magnetic Stimulation of the Anterior Insula. Neuromodul. Technol. Neural Interface 2019, 22, 877–883. [Google Scholar] [CrossRef]
- Minjoli, S.; Saturnino, G.B.; Blicher, J.U.; Stagg, C.J.; Siebner, H.R.; Antunes, A.; Thielscher, A. The Impact of Large Structural Brain Changes in Chronic Stroke Patients on the Electric Field Caused by Transcranial Brain Stimulation. NeuroImage Clin. 2017, 15, 106–117. [Google Scholar] [CrossRef]
- Fomenko, A.; Neudorfer, C.; Dallapiazza, R.F.; Kalia, S.K.; Lozano, A.M. Low-Intensity Ultrasound Neuromodulation: An Overview of Mechanisms and Emerging Human Applications. Brain Stimulat. 2018, 11, 1209–1217. [Google Scholar] [CrossRef]
- Beisteiner, R.; Matt, E.; Fan, C.; Baldysiak, H.; Schönfeld, M.; Philippi Novak, T.; Amini, A.; Aslan, T.; Reinecke, R.; Lehrner, J.; et al. Transcranial Pulse Stimulation with Ultrasound in Alzheimer’s Disease—A New Navigated Focal Brain Therapy. Adv. Sci. 2019, 7, 1902583. [Google Scholar] [CrossRef]
- Collins, M.N.; Legon, W.; Mesce, K.A. The Inhibitory Thermal Effects of Focused Ultrasound on an Identified, Single Motoneuron. eNeuro 2021, 8, ENEURO.0514-20.2021. [Google Scholar] [CrossRef]
- Lohse-Busch, H.; Reime, U.; Falland, R. Symptomatic Treatment of Unresponsive Wakefulness Syndrome with Transcranially Focused Extracorporeal Shock Waves. NeuroRehabilitation 2014, 35, 235–244. [Google Scholar] [CrossRef]
- Monti, M.M.; Schnakers, C.; Korb, A.S.; Bystritsky, A.; Vespa, P.M. Non-Invasive Ultrasonic Thalamic Stimulation in Disorders of Consciousness after Severe Brain Injury: A First-in-Man Report. Brain Stimulat. 2016, 9, 940–941. [Google Scholar] [CrossRef]
- Dörl, G.; Matt, E.; Beisteiner, R. Functional Specificity of TPS Brain Stimulation Effects in Patients with Alzheimer’s Disease: A Follow-up FMRI Analysis. Neurol. Ther. 2022, 11, 1391–1398. [Google Scholar] [CrossRef]
- Matt, E.; Dörl, G.; Beisteiner, R. Transcranial Pulse Stimulation (TPS) Improves Depression in AD Patients on State-of-the-Art Treatment. Alzheimers Dement. Transl. Res. Clin. Interv. 2022, 8, e12245. [Google Scholar] [CrossRef]
- Cain, J.A.; Spivak, N.M.; Coetzee, J.P.; Crone, J.S.; Johnson, M.A.; Lutkenhoff, E.S.; Real, C.; Buitrago-Blanco, M.; Vespa, P.M.; Schnakers, C.; et al. Ultrasonic Deep Brain Neuromodulation in Acute Disorders of Consciousness: A Proof-of-Concept. Brain Sci. 2022, 12, 428. [Google Scholar] [CrossRef]
- Cain, J.A.; Spivak, N.M.; Coetzee, J.P.; Crone, J.S.; Johnson, M.A.; Lutkenhoff, E.S.; Real, C.; Buitrago-Blanco, M.; Vespa, P.M.; Schnakers, C.; et al. Ultrasonic Thalamic Stimulation in Chronic Disorders of Consciousness. Brain Stimulat. 2021, 14, 301–303. [Google Scholar] [CrossRef]
- Jeong, H.; Im, J.J.; Park, J.-S.; Na, S.-H.; Lee, W.; Yoo, S.-S.; Song, I.-U.; Chung, Y.-A. A Pilot Clinical Study of Low-Intensity Transcranial Focused Ultrasound in Alzheimer’s Disease. Ultrasonography 2021, 40, 512–519. [Google Scholar] [CrossRef]
- Lee, C.-C.; Chou, C.-C.; Hsiao, F.-J.; Chen, Y.-H.; Lin, C.-F.; Chen, C.-J.; Peng, S.-J.; Liu, H.-L.; Yu, H.-Y. Pilot Study of Focused Ultrasound for Drug-Resistant Epilepsy. Epilepsia 2022, 63, 162–175. [Google Scholar] [CrossRef]
- Szabo, T.L. Diagnostic Ultrasound Imaging: Inside Out, 2nd ed.; Academic Press: Cambridge, MA, USA, 2014; ISBN 978-0-12-680145-3. [Google Scholar]
- Hanson, M.A. Health Effects of Exposure to Ultrasound and Infrasound: Report of the Independent Advisory Group on Non-Ionising Radiation; Health Protection Agency: Chilton, UK, 2010; ISBN 978-0-85951-662-4. [Google Scholar]
- Iloreta, J.I.; Zhou, Y.; Sankin, G.N.; Zhong, P.; Szeri, A.J. Assessment of Shock Wave Lithotripters via Cavitation Potential. Phys. Fluids 2007, 19, 086103. [Google Scholar] [CrossRef]
- Kung, Y.; Lan, C.; Hsiao, M.-Y.; Sun, M.-K.; Hsu, Y.-H.; Huang, A.P.-H.; Liao, W.-H.; Liu, H.-L.; Inserra, C.; Chen, W.-S. Focused Shockwave Induced Blood-Brain Barrier Opening and Transfection. Sci. Rep. 2018, 8, 2218. [Google Scholar] [CrossRef]
- Tung, Y.-S.; Vlachos, F.; Choi, J.J.; Deffieux, T.; Selert, K.; Konofagou, E.E. In Vivo Transcranial Cavitation Threshold Detection during Ultrasound-Induced Blood–Brain Barrier Opening in Mice. Phys. Med. Biol. 2010, 55, 6141–6155. [Google Scholar] [CrossRef]
- Maxwell, A.D.; Cain, C.A.; Hall, T.L.; Fowlkes, J.B.; Xu, Z. Probability of Cavitation for Single Ultrasound Pulses Applied to Tissues and Tissue-Mimicking Materials. Ultrasound Med. Biol. 2013, 39, 449–465. [Google Scholar] [CrossRef]
- Haller, J.; Wilkens, V. Determination of Acoustic Cavitation Probabilities and Thresholds Using a Single Focusing Transducer to Induce and Detect Acoustic Cavitation Events: II. Systematic Investigation in an Agar Material. Ultrasound Med. Biol. 2018, 44, 397–415. [Google Scholar] [CrossRef]
- Haller, J.; Wilkens, V.; Shaw, A. Determination of Acoustic Cavitation Probabilities and Thresholds Using a Single Focusing Transducer to Induce and Detect Acoustic Cavitation Events: I. Method and Terminology. Ultrasound Med. Biol. 2018, 44, 377–396. [Google Scholar] [CrossRef]
- Vlaisavljevich, E.; Lin, K.-W.; Maxwell, A.; Warnez, M.T.; Mancia, L.; Singh, R.; Putnam, A.J.; Fowlkes, B.; Johnsen, E.; Cain, C.; et al. Effects of Ultrasound Frequency and Tissue Stiffness on the Histotripsy Intrinsic Threshold for Cavitation. Ultrasound Med. Biol. 2015, 41, 1651–1667. [Google Scholar] [CrossRef]
- Vlaisavljevich, E.; Maxwell, A.; Warnez, M.; Johnsen, E.; Cain, C.A.; Xu, Z. Histotripsy-Induced Cavitation Cloud Initiation Thresholds in Tissues of Different Mechanical Properties. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 2014, 61, 341–352. [Google Scholar] [CrossRef] [Green Version]
- Church, C.C.; Labuda, C.; Nightingale, K. A Theoretical Study of Inertial Cavitation from Acoustic Radiation Force Impulse Imaging and Implications for the Mechanical Index1. Ultrasound Med. Biol. 2015, 41, 472–485. [Google Scholar] [CrossRef] [PubMed]
- Dalecki, D.; Raeman, C.H.; Child, S.Z.; Penney, D.P.; Carstensen, E.L. Remnants of Albunex® Nucleate Acoustic Cavitation. Ultrasound Med. Biol. 1997, 23, 1405–1412. [Google Scholar] [CrossRef]
- Statement on Biological Effects of Ultrasound In Vivo. Available online: https://www.aium.org/officialStatements/82?__sw_csrfToken=48f282af (accessed on 1 August 2022).
- Huang, A.P.-H.; Lai, D.-M.; Hsu, Y.-H.; Kung, Y.; Lan, C.; Yeh, C.-S.; Tsai, H.-H.; Lin, C.-F.; Chen, W.-S. Cavitation-Induced Traumatic Cerebral Contusion and Intracerebral Hemorrhage in the Rat Brain by Using an off-the-Shelf Clinical Shockwave Device. Sci. Rep. 2019, 9, 15614. [Google Scholar] [CrossRef]
- Dalecki, D.; Raeman, C.H.; Child, S.Z.; Penney, D.P.; Mayer, R.; Carstensen, E.L. The Influence of Contrast Agents on Hemorrhage Produced by Lithotripter Fields. Ultrasound Med. Biol. 1997, 23, 1435–1439. [Google Scholar] [CrossRef]
- Fasano, A.; Sammartino, F.; Llinas, M.; Lozano, A.M. MRI-Guided Focused Ultrasound Thalamotomy in Fragile X–Associated Tremor/Ataxia Syndrome. Neurology 2016, 87, 736–738. [Google Scholar] [CrossRef] [PubMed]
- Dalecki, D. Mechanical Bioeffects of Ultrasound. Annu. Rev. Biomed. Eng. 2004, 6, 229–248. [Google Scholar] [CrossRef] [PubMed]
- Verhagen, L.; Gallea, C.; Folloni, D.; Constans, C.; Jensen, D.E.; Ahnine, H.; Roumazeilles, L.; Santin, M.; Ahmed, B.; Lehericy, S.; et al. Offline Impact of Transcranial Focused Ultrasound on Cortical Activation in Primates. eLife 2019, 8, e40541. [Google Scholar] [CrossRef]
- Kollmann, F.G.; Ter Haar, G.; Dolezal, G.; Hennerici, M.G.; Salvesen, K.A.; Valentin, L. Ultrasound Output: Thermal (TI) and Mechanical (MI) Indices. Ultraschall Med. 2013, 34, 422–434. [Google Scholar]
- Recommended Maximum Scanning Times for Displayed Thermal Index (TI) Values. Available online: https://www.aium.org/officialStatements/65?__sw_csrfToken=7cd109f3 (accessed on 1 August 2022).
- Lee, W.; Weisholtz, D.S.; Strangman, G.E.; Yoo, S.-S. Safety Review and Perspectives of Transcranial Focused Ultrasound Brain Stimulation. Brain Neurorehabil. 2021, 14, e4. [Google Scholar] [CrossRef]
- Daffertshofer, M.; Gass, A.; Ringleb, P.; Sitzer, M.; Sliwka, U.; Els, T.; Sedlaczek, O.; Koroshetz, W.J.; Hennerici, M.G. Transcranial Low-Frequency Ultrasound-Mediated Thrombolysis in Brain Ischemia. Stroke 2005, 36, 1441–1446. [Google Scholar] [CrossRef]
- Younan, Y.; Deffieux, T.; Larrat, B.; Fink, M.; Tanter, M.; Aubry, J.-F. Influence of the Pressure Field Distribution in Transcranial Ultrasonic Neurostimulation. Med. Phys. 2013, 40, 082902. [Google Scholar] [CrossRef] [PubMed]
- Kim, H.-C.; Lee, W.; Kunes, J.; Yoon, K.; Lee, J.E.; Foley, L.; Kowsari, K.; Yoo, S.-S. Transcranial Focused Ultrasound Modulates Cortical and Thalamic Motor Activity in Awake Sheep. Sci. Rep. 2021, 11, 19274. [Google Scholar] [CrossRef]
- Yoon, K.; Lee, W.; Lee, J.E.; Xu, L.; Croce, P.; Foley, L.; Yoo, S.-S. Effects of Sonication Parameters on Transcranial Focused Ultrasound Brain Stimulation in an Ovine Model. PLoS ONE 2019, 14, e0224311. [Google Scholar] [CrossRef]
- Yang, P.-F.; Phipps, M.A.; Newton, A.T.; Chaplin, V.; Gore, J.C.; Caskey, C.F.; Chen, L.M. Neuromodulation of Sensory Networks in Monkey Brain by Focused Ultrasound with MRI Guidance and Detection. Sci. Rep. 2018, 8, 7993. [Google Scholar] [CrossRef]
- Dallapiazza, R.F.; Timbie, K.F.; Holmberg, S.; Gatesman, J.; Lopes, M.B.; Price, R.J.; Miller, G.W.; Elias, W.J. Noninvasive Neuromodulation and Thalamic Mapping with Low-Intensity Focused Ultrasound. J. Neurosurg. 2018, 128, 875–884. [Google Scholar] [CrossRef]
- Lee, W.; Lee, S.D.; Park, M.Y.; Foley, L.; Purcell-Estabrook, E.; Kim, H.; Fischer, K.; Maeng, L.-S.; Yoo, S.-S. Image-Guided Focused Ultrasound-Mediated Regional Brain Stimulation in Sheep. Ultrasound Med. Biol. 2016, 42, 459–470. [Google Scholar] [CrossRef]
- Gaur, P.; Casey, K.M.; Kubanek, J.; Li, N.; Mohammadjavadi, M.; Saenz, Y.; Glover, G.H.; Bouley, D.M.; Pauly, K.B. Histologic Safety of Transcranial Focused Ultrasound Neuromodulation and Magnetic Resonance Acoustic Radiation Force Imaging in Rhesus Macaques and Sheep. Brain Stimulat. 2020, 13, 804–814. [Google Scholar] [CrossRef]
- Munoz, F.; Meaney, A.; Gross, A.; Liu, K.; Pouliopoulos, A.N.; Liu, D.; Konofagou, E.E.; Ferrera, V.P. Long Term Study of Motivational and Cognitive Effects of Low-Intensity Focused Ultrasound Neuromodulation in the Dorsal Striatum of Nonhuman Primates. Brain Stimulat. 2022, 15, 360–372. [Google Scholar] [CrossRef]
- Matt, E.; Kaindl, L.; Tenk, S.; Egger, A.; Kolarova, T.; Karahasanović, N.; Amini, A.; Arslan, A.; Sariçiçek, K.; Weber, A.; et al. First Evidence of Long-Term Effects of Transcranial Pulse Stimulation (TPS) on the Human Brain. J. Transl. Med. 2022, 20, 26. [Google Scholar] [CrossRef]
- Lee, W.; Kim, H.; Jung, Y.; Song, I.-U.; Chung, Y.A.; Yoo, S.-S. Image-Guided Transcranial Focused Ultrasound Stimulates Human Primary Somatosensory Cortex. Sci. Rep. 2015, 5, 8743. [Google Scholar] [CrossRef]
- Lee, W.; Kim, H.-C.; Jung, Y.; Chung, Y.A.; Song, I.-U.; Lee, J.-H.; Yoo, S.-S. Transcranial Focused Ultrasound Stimulation of Human Primary Visual Cortex. Sci. Rep. 2016, 6, 34026. [Google Scholar] [CrossRef] [Green Version]
- Stern, J.M.; Spivak, N.M.; Becerra, S.A.; Kuhn, T.P.; Korb, A.S.; Kronemyer, D.; Khanlou, N.; Reyes, S.D.; Monti, M.M.; Schnakers, C.; et al. Safety of Focused Ultrasound Neuromodulation in Humans with Temporal Lobe Epilepsy. Brain Stimulat. 2021, 14, 1022–1031. [Google Scholar] [CrossRef]
- Beisteiner, R.; Lozano, A.M. Transcranial Ultrasound Innovations Ready for Broad Clinical Application. Adv. Sci. 2020, 7, 2002026. [Google Scholar] [CrossRef]
- Legon, W.; Adams, S.; Bansal, P.; Patel, P.D.; Hobbs, L.; Ai, L.; Mueller, J.K.; Meekins, G.; Gillick, B.T. A Retrospective Qualitative Report of Symptoms and Safety from Transcranial Focused Ultrasound for Neuromodulation in Humans. Sci. Rep. 2020, 10, 5573. [Google Scholar] [CrossRef]
- Sanguinetti, J.L.; Hameroff, S.; Smith, E.E.; Sato, T.; Daft, C.M.W.; Tyler, W.J.; Allen, J.J.B. Transcranial Focused Ultrasound to the Right Prefrontal Cortex Improves Mood and Alters Functional Connectivity in Humans. Front. Hum. Neurosci. 2020, 14, 52. [Google Scholar] [CrossRef]
- Spivak, N.M.; Sanguinetti, J.L.; Monti, M.M. Focusing in on the Future of Focused Ultrasound as a Translational Tool. Brain Sci. 2022, 12, 158. [Google Scholar] [CrossRef]
Scale | Pressure Number (%) | Pain Number (%) |
---|---|---|
Sessions | 990 | 991 |
0 | 860 (86.67) | 932 (94.05) |
1–3 | 109 (11.01) | 49 (4.94) |
4–6 | 14 (1.41) | 9 (0.91) |
7–10 | 7 (0.71) | 1 (0.1) |
Patients | 101 | 101 |
0 | 86 | 93 |
1–3 | 10 | 6 |
4–6 | 3 | 2 |
7–10 | 1 | 1 |
Reported Adverse Events (during Treatment) | No. of Patients | No. of Sessions (%) |
No side-effects reported | 83 | 966 (97.28) |
Pressure | 6 | 8 (0.81) |
Pain | 4 | 6 (0.6) |
Uncomfortable | 4 | 5 (0.5) |
Other 1 | 4 | 8 (0.81) |
Reported Adverse Events (after Treatment) | No. of Patients | No. of Sessions (%) |
No side-effects reported | 70 | 917 (86.92) |
Tiredness | 31 | 51 (4.83) |
Dizziness | 19 | 30 (2.84) |
Pain | 16 | 23 (2.18) |
Pressure | 6 | 9 (0.85) |
Confusion | 3 | 4 (0.38) |
Disorientation | 2 | 2 (0.19) |
Nausea | 3 | 5 (0.47) |
Unsteady gait | 4 | 4 (0.38) |
Intensification of tremor | 4 | 6 (0.57) |
Sweating | 4 | 4 (0.38) |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Radjenovic, S.; Dörl, G.; Gaal, M.; Beisteiner, R. Safety of Clinical Ultrasound Neuromodulation. Brain Sci. 2022, 12, 1277. https://doi.org/10.3390/brainsci12101277
Radjenovic S, Dörl G, Gaal M, Beisteiner R. Safety of Clinical Ultrasound Neuromodulation. Brain Sciences. 2022; 12(10):1277. https://doi.org/10.3390/brainsci12101277
Chicago/Turabian StyleRadjenovic, Sonja, Gregor Dörl, Martin Gaal, and Roland Beisteiner. 2022. "Safety of Clinical Ultrasound Neuromodulation" Brain Sciences 12, no. 10: 1277. https://doi.org/10.3390/brainsci12101277
APA StyleRadjenovic, S., Dörl, G., Gaal, M., & Beisteiner, R. (2022). Safety of Clinical Ultrasound Neuromodulation. Brain Sciences, 12(10), 1277. https://doi.org/10.3390/brainsci12101277