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<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Neurol.</journal-id>
<journal-title>Frontiers in Neurology</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Neurol.</abbrev-journal-title>
<issn pub-type="epub">1664-2295</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fneur.2023.1281684</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Neurology</subject>
<subj-group>
<subject>Opinion</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Opinion: Application of extracorporeal shock wave therapy in nervous system diseases</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name><surname>Jokinen</surname> <given-names>Leon L. J.</given-names></name>
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</contrib>
<contrib contrib-type="author">
<name><surname>Wuerfel</surname> <given-names>Tobias</given-names></name>
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</contrib>
<contrib contrib-type="author" corresp="yes">
<name><surname>Schmitz</surname> <given-names>Christoph</given-names></name>
<xref ref-type="corresp" rid="c001"><sup>&#x0002A;</sup></xref>
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<aff><institution>Department of Neuroanatomy, Faculty of Medicine, Ludwig-Maximilians University of Munich</institution>, <addr-line>Munich</addr-line>, <country>Germany</country></aff>
<author-notes>
<fn fn-type="edited-by"><p>Edited by: Noureddin Nakhostin Ansari, Tehran University of Medical Sciences, Iran</p></fn>
<fn fn-type="edited-by"><p>Reviewed by: Cyrill Slezak, Utah Valley University, United States</p></fn>
<corresp id="c001">&#x0002A;Correspondence: Christoph Schmitz <email>christoph_schmitz&#x00040;med.uni-muenchen.de</email></corresp>
</author-notes>
<pub-date pub-type="epub">
<day>19</day>
<month>12</month>
<year>2023</year>
</pub-date>
<pub-date pub-type="collection">
<year>2023</year>
</pub-date>
<volume>14</volume>
<elocation-id>1281684</elocation-id>
<history>
<date date-type="received">
<day>22</day>
<month>08</month>
<year>2023</year>
</date>
<date date-type="accepted">
<day>05</day>
<month>12</month>
<year>2023</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#x000A9; 2023 Jokinen, Wuerfel and Schmitz.</copyright-statement>
<copyright-year>2023</copyright-year>
<copyright-holder>Jokinen, Wuerfel and Schmitz</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/"><p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p></license></permissions>
<kwd-group>
<kwd>extracorporeal shock wave therapy</kwd>
<kwd>focused extracorporeal shock waves</kwd>
<kwd>radial extracorporeal shock waves</kwd>
<kwd>ESWT</kwd>
<kwd>rESWT</kwd>
<kwd>fESWT</kwd>
</kwd-group>
<counts>
<fig-count count="1"/>
<table-count count="0"/>
<equation-count count="0"/>
<ref-count count="13"/>
<page-count count="4"/>
<word-count count="2404"/>
</counts>
<custom-meta-wrap>
<custom-meta>
<meta-name>section-at-acceptance</meta-name>
<meta-value>Neurorehabilitation</meta-value>
</custom-meta>
</custom-meta-wrap>
</article-meta>
</front>
<body>
<sec id="s1">
<title>1 Introduction</title>
<p>We became aware of the article &#x0201C;Application of extracorporeal shock wave therapy (ESWT) in nervous system diseases: A review&#x0201D; by Guo et al. (<xref ref-type="bibr" rid="B1">1</xref>) published in Frontiers in Neurology. Unfortunately the information provided in the Section &#x0201C;Principles of ESWT&#x0201D; is partly incorrect and misleading. The first author of this commentary (LJ) suffers from an extreme disability (tetraplegia from C4), is regularly treated with radial ESWT because of his spasticity, has not needed any related medication since then, particularly no injection of BTX-A, and therefore has a special interest in correct reporting about ESWT in the literature. All authors are actively involved in ESWT research (<xref ref-type="bibr" rid="B2">2</xref>&#x02013;<xref ref-type="bibr" rid="B5">5</xref>).</p>
<p><bold>Both focused extracorporeal shock waves (fESWs) and radial extracorporeal shock waves (rESWs) used in ESWT have phases of positive and negative pressure and can generate cavitation</bold>.</p>
<p><xref ref-type="fig" rid="F1">Figure 1A</xref> of this commentary shows the waveforms of fESWs and rESWs provided in Figure 1 in Guo et al. (<xref ref-type="bibr" rid="B1">1</xref>); <xref ref-type="fig" rid="F1">Figures 1B</xref>, <xref ref-type="fig" rid="F1">C</xref> show real waveforms of fESWs published in the literature (<xref ref-type="bibr" rid="B3">3</xref>, <xref ref-type="bibr" rid="B6">6</xref>); and <xref ref-type="fig" rid="F1">Figure 1D</xref> shows real waveforms of rESWs published in the literature (<xref ref-type="bibr" rid="B7">7</xref>). These published waveforms differ from the illustrations in Guo et al. (<xref ref-type="bibr" rid="B1">1</xref>). Specifically, after an initial phase of positive pressure (black arrows in <xref ref-type="fig" rid="F1">Figures 1A</xref>&#x02013;<xref ref-type="fig" rid="F1">D</xref>) followed by a necessary phase of negative pressure (red arrows in <xref ref-type="fig" rid="F1">Figures 1A</xref>&#x02013;<xref ref-type="fig" rid="F1">D</xref>; note that a pressure wave absent a tensile phase is not possible) both fESWs and rESWs can show a second phase of positive pressure (green arrows in <xref ref-type="fig" rid="F1">Figures 1B</xref>&#x02013;<xref ref-type="fig" rid="F1">D</xref>) followed by a second phase of negative pressure (blue arrows in <xref ref-type="fig" rid="F1">Figures 1C</xref>, <xref ref-type="fig" rid="F1">D</xref>). Of note, the article by Guo et al. (<xref ref-type="bibr" rid="B1">1</xref>) is not the only one that shows incorrect representations of the waveforms of fESWs and rESWs. An equally incorrect representation of rESWs (pressure wave absent a tensile phase) can also be found, for example, in Figure 26.2 in Zwerver et al. (<xref ref-type="bibr" rid="B8">8</xref>).</p>
<fig id="F1" position="float">
<label>Figure 1</label>
<caption><p>Waveform characteristics of focused and radial extracorporeal shock waves as illustrated in (<xref ref-type="bibr" rid="B1">1</xref>) <bold>(A)</bold> and published in (<xref ref-type="bibr" rid="B3">3</xref>, <xref ref-type="bibr" rid="B6">6</xref>, <xref ref-type="bibr" rid="B7">7</xref>) <bold>(B&#x02013;D)</bold>, as well as cavitation fields (yellow arrows) generated by focused <bold>(E)</bold> and radial <bold>(F)</bold> extracorporeal shock waves (<xref ref-type="bibr" rid="B4">4</xref>, <xref ref-type="bibr" rid="B5">5</xref>). Details are in the text. The yellow asterisk in <bold>(F)</bold> indicates the applicator of the handpiece of the rESWT device used. <bold>(A)</bold> was taken from (<xref ref-type="bibr" rid="B1">1</xref>) published under the CC-BY license; <bold>(B)</bold> was taken from (<xref ref-type="bibr" rid="B6">6</xref>) with permission from the publisher<xref ref-type="fn" rid="fn0001"><sup>1</sup></xref>; and <bold>(C&#x02013;F)</bold> were taken from (<xref ref-type="bibr" rid="B3">3</xref>)/(<xref ref-type="bibr" rid="B7">7</xref>)/(<xref ref-type="bibr" rid="B4">4</xref>)/(<xref ref-type="bibr" rid="B5">5</xref>) published under the CC-BY license (<xref ref-type="bibr" rid="B3">3</xref>), the CC BY 2.0 license (<xref ref-type="bibr" rid="B4">4</xref>), or the CC BY 4.0 license (<xref ref-type="bibr" rid="B5">5</xref>, <xref ref-type="bibr" rid="B7">7</xref>), respectively. The publications (<xref ref-type="bibr" rid="B3">3</xref>&#x02013;<xref ref-type="bibr" rid="B5">5</xref>) are from the senior author of this commentary (CS).</p></caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fneur-14-1281684-g0001.tif"/>
</fig>
<p>Of particular note, both fESWs and rESWs can generate cavitation as a consequence of the negative pressure. This is shown for fESWs in <xref ref-type="fig" rid="F1">Figure 1E</xref> taken from (<xref ref-type="bibr" rid="B4">4</xref>) and for rESWs in <xref ref-type="fig" rid="F1">Figure 1F</xref> taken from (<xref ref-type="bibr" rid="B5">5</xref>); both publications (<xref ref-type="bibr" rid="B4">4</xref>, <xref ref-type="bibr" rid="B5">5</xref>) are from the senior author of this commentary (CS). In contrast, the illustration of the waveform of rESWs provided by Guo et al. (<xref ref-type="bibr" rid="B1">1</xref>) (<xref ref-type="fig" rid="F1">Figure 1A</xref>) does not show any negative pressure, which would prevent the formation of cavitation bubbles.</p>
<p>Furthermore, according to the International Standard IEC 61846 (<xref ref-type="bibr" rid="B9">9</xref>) the rise time of shock waves is defined at the focus as the time taken for the instantaneous acoustic pressure to increase from 10 to 90% of the peak-positive acoustic pressure, which is different from the illustration provided by Guo et al. (<xref ref-type="bibr" rid="B1">1</xref>) in which the rise time is indicated as the time taken for the instantaneous acoustic pressure to increase from approximately 14&#x02013;100% of the peak-positive acoustic pressure (<xref ref-type="fig" rid="F1">Figure 1A</xref>).</p>
<p>Moreover, extracorporeal shock waves are not characterized by symmetry and a slow, disproportionally large, pressure rise before the onset of the shock front as suggested by the presentation in Guo et al. (<xref ref-type="bibr" rid="B1">1</xref>) (<xref ref-type="fig" rid="F1">Figure 1A</xref>). Rather <xref ref-type="fig" rid="F1">Figures 1B</xref>&#x02013;<xref ref-type="fig" rid="F1">D</xref> show the correct, asymmetrical waveforms of fESWs and rESWs from real measurements according to IEC 61846 (<xref ref-type="bibr" rid="B9">9</xref>).</p>
<p><bold>Some fESWT devices used in contemporary ESWT generate true shock waves, whereas others do not</bold>.</p>
<p>Guo et al. (<xref ref-type="bibr" rid="B1">1</xref>) stated that &#x0201C;as an acoustic wave, fESW is characterized by its high pressure of more than 1,000 bar (100 MPa), an extremely short rise time (&#x0003C;10 ns), a short duration (&#x0003C;10 ms), and a broad frequency spectrum (16&#x02013;20 MHz)&#x0201D;. This description of fESWs is very similar to an earlier description provided by Ogden et al. (<xref ref-type="bibr" rid="B10">10</xref>): &#x0201C;A shock wave is a sonic pulse that has certain physical characteristics. There is a high peak pressure, sometimes more than 100 MPa (500 bar), but more often approximately 50&#x02013;80 MPa, a fast initial rise in pressure during a period of &#x0003C;10 ns, a low tensile amplitude (up to 10 MPa), a short life cycle of &#x0007E;10 &#x003BC;s, and a broad frequency spectrum, typically in the range of 16 Hz to 20 MHz.&#x0201D; Of note, in Ogden et al. (<xref ref-type="bibr" rid="B10">10</xref>) the life cycle of fESWs was correctly given as &#x0007E;10 &#x003BC;s, which is in line with the waveforms shown in <xref ref-type="fig" rid="F1">Figures 1B</xref>, <xref ref-type="fig" rid="F1">C</xref>, whereas Guo et al. (<xref ref-type="bibr" rid="B1">1</xref>) defined the duration of fESWs &#x0003C;10 ms which is 1,000 times longer.</p>
<p>Furthermore, Ogden et al. (<xref ref-type="bibr" rid="B10">10</xref>) provided the frequency range of fESWs correctly as 16 Hz to 20 MHz, whereas the frequency range provided by Guo et al. (<xref ref-type="bibr" rid="B1">1</xref>) of 16&#x02013;20 MHz is not correct.</p>
<p>The waveform shown in <xref ref-type="fig" rid="F1">Figure 1C</xref> of the piezoelectric fESWT applicator F10G4 (Richard Wolf, Knittlingen, Germany) operated at highest machine settings is in line with the definition provided by Ogden et al. (<xref ref-type="bibr" rid="B10">10</xref>), whereas the waveform shown in <xref ref-type="fig" rid="F1">Figure 1B</xref> of the electromagnetic fESWT device Duolith SD1 (Storz Medical, T&#x000E4;gerwillen, Switzerland) operated at highest machine settings is not. Figure 1C in Guo et al. (<xref ref-type="bibr" rid="B1">1</xref>) shows the focused handpiece of the Duolith SD1 device (Storz Medical). Waveform characteristics of the fESWs generated by the Duolith SD1 device (Storz Medical) were reported in 2007 in (<xref ref-type="bibr" rid="B6">6</xref>) as follows: maximum pressure 42.7 MPa, rise time 8&#x02013;500 ns, no formation of true shock waves for any machine settings.</p>
<p><bold>Like fESWs, rESWs can possess non-linearity</bold>.</p>
<p>Guo et al. (<xref ref-type="bibr" rid="B1">1</xref>) stated that &#x0201C;unlike fESW, radial extracorporeal shock wave (rESW) does not possess the shock wave characteristics of a short rise time, a high peak pressure, and non-linearity&#x0201D;. In contrast to this description, Cleveland et al. (<xref ref-type="bibr" rid="B11">11</xref>) demonstrated already in 2007 non-linear distortion of the rESWs generated using the rESWT device Swiss DolorClast (Electro Medical Systems, Nyon, Switzerland) (<xref ref-type="fig" rid="F1">Figure 1D</xref>). However, the non-linear distortion was not strong enough to result in a shock front. Of note, this is different from the description by Guo et al. (<xref ref-type="bibr" rid="B1">1</xref>) that rESWs do not possess non-linearity. Furthermore, Cleveland et al. (<xref ref-type="bibr" rid="B11">11</xref>) reported a rise time of 800 ns of the rESWs generated by the Swiss DolorClast (Electro Medical Systems), which is not too different from the 500 ns reported in (<xref ref-type="bibr" rid="B6">6</xref>) for the Duolith SD1 (Storz Medical) at low machine settings.</p>
<p><bold>A scientifically correct classification of shock waves used in contemporary ESWT would have to distinguish between focused shock waves, focused pressure waves and radial pressure waves</bold>.</p>
<p>Guo et al. (<xref ref-type="bibr" rid="B1">1</xref>) stated that &#x0201C;some scholars even call &#x02018;rESW&#x00027; &#x02018;radial pressure waves&#x00027; because rESW uses the energy generated from compressed gas to drive the bullet body to the treated tissue area in a pulsed manner&#x0201D;. In this regard it is of note that Cleveland et al. (<xref ref-type="bibr" rid="B11">11</xref>) reported that piezoelectric and electromagnetic fESWT sources (such as the F10G4 device from Richard Wolf and the Duolith SD1 device from Storz Medical) use focusing but do not generate shock waves at the source. Rather, they rely on non-linear propagation distortion to produce a shock along the path to the focus. For mid and high-amplitude settings, the waveforms are shocked and the peak amplitudes and rise times are comparable to those of electrohydraulic sources (as shown in <xref ref-type="fig" rid="F1">Figure 1C</xref> for the F10G4 device from Richard Wolf). However, at low-amplitude settings the waveforms do not contain shocks (<xref ref-type="bibr" rid="B11">11</xref>), as demonstrated by Perez et al. (<xref ref-type="bibr" rid="B6">6</xref>) for the Duolith SD1 (Storz Medical) at any machine settings (<xref ref-type="fig" rid="F1">Figure 1B</xref>). Therefore, it would be correct to distinguish between true focused shock waves (<xref ref-type="fig" rid="F1">Figure 1C</xref>), focused pressure waves (<xref ref-type="fig" rid="F1">Figure 1B</xref>) and radial pressure waves (<xref ref-type="fig" rid="F1">Figure 1D</xref>). However, for several good reasons, this is not done in the literature. One of these reasons is that differences in molecular and cellular mechanisms of action between true focused shock waves and focused pressure waves were not reported in the literature.</p></sec>
<sec id="s2">
<title>2 Discussion</title>
<p>It is beyond the scope of this commentary to discuss to what extent the incorrect and misleading description of the principles of ESWT in the article by Guo et al. (<xref ref-type="bibr" rid="B1">1</xref>) had influence on the other sections of their article. In our opinion the readers of Frontiers in Neurology should be informed that the principles of ESWT are different than outlined in the article by Guo et al. (<xref ref-type="bibr" rid="B1">1</xref>), and the molecular and cellular mechanisms of action of fESWs and rESWs on nervous tissue presented by Guo et al. (<xref ref-type="bibr" rid="B1">1</xref>) are incomplete. Our recent publication (<xref ref-type="bibr" rid="B2">2</xref>) provides a comprehensive review of the molecular and cellular mechanisms of action of fESWs and rESWs on nervous tissue, and Figures 1, 2 in (<xref ref-type="bibr" rid="B12">12</xref>) [also published by the senior author of this commentary (CS)] provide an overview on the physical mechanisms of generating fESWs and rESWs.</p></sec>
<sec sec-type="author-contributions" id="s3">
<title>Author contributions</title>
<p>LJ: Conceptualization, Formal analysis, Investigation, Validation, Writing &#x02013; review &#x00026; editing. TW: Conceptualization, Formal analysis, Investigation, Validation, Writing &#x02013; review &#x00026; editing. CS: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing &#x02013; original draft.</p></sec>
</body>
<back>
<sec sec-type="funding-information" id="s4">
<title>Funding</title>
<p>The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.</p>
</sec>
<ack><p>This commentary article has been made available as preprint (<xref ref-type="bibr" rid="B13">13</xref>).</p>
</ack>
<sec sec-type="COI-statement" id="conf1">
<title>Conflict of interest</title>
<p>CS served as consultant for Electro Medical Systems (Nyon, Switzerland) until December 2017, and has received funding from Electro Medical Systems for conducting basic research into rESWT at his lab. However, Electro Medical Systems had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
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