Motor cortex stimulation for Parkinson's disease: a modelling study
Identifieur interne : 000D90 ( Main/Corpus ); précédent : 000D89; suivant : 000D91Motor cortex stimulation for Parkinson's disease: a modelling study
Auteurs : Daphne G M. Zwartjes ; Tjitske Heida ; Hans K P. Feirabend ; Marcus L F. Janssen ; Veerle Visser-Vandewalle ; Hubert C F. Martens ; Peter H. VeltinkSource :
- Journal of Neural Engineering [ 1741-2560 ] ; 2012-10.
Abstract
Chronic motor cortex stimulation (MCS) is currently being investigated as a treatment method for Parkinson's disease (PD). Unfortunately, the underlying mechanisms of this treatment are unclear and there are many uncertainties regarding the most effective stimulation parameters and electrode configuration. In this paper, we present a MCS model with a 3D representation of several axonal populations. The model predicts that the activation of either the basket cell or pyramidal tract (PT) type axons is involved in the clinical effect of MCS. We propose stimulation protocols selectively targeting one of these two axon types. To selectively target the basket cell axons, our simulations suggest using either cathodal or bipolar stimulation with the electrode strip placed perpendicular rather than parallel to the gyrus. Furthermore, selectivity can be increased by using multiple cathodes. PT type axons can be selectively targeted with anodal stimulation using electrodes with large contact sizes. Placing the electrode epidurally is advisable over subdural placement. These selective protocols, when practically implemented, can be used to further test which axon type should be activated for clinically effective MCS and can subsequently be applied to optimize treatment. In conclusion, this paper increases insight into the neuronal population involved in the clinical effect of MCS on PD and proposes strategies to improve this therapy.
Url:
DOI: 10.1088/1741-2560/9/5/056005
Links to Exploration step
ISTEX:586106634EA3ADCD5B24A82FE916C9425CB3F011Le document en format XML
<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title>Motor cortex stimulation for Parkinson's disease: a modelling study</title><author><name sortKey="Zwartjes, Daphne G M" sort="Zwartjes, Daphne G M" uniqKey="Zwartjes D" first="Daphne G M" last="Zwartjes">Daphne G M. Zwartjes</name><affiliation><mods:affiliation>MIRA Institute for Biomedical Engineering and Technical Medicine, Biomedical Signals and Systems Group, University of Twente, Enschede, The Netherlands</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: d.g.m.zwartjes@utwente.nl</mods:affiliation></affiliation></author><author><name sortKey="Heida, Tjitske" sort="Heida, Tjitske" uniqKey="Heida T" first="Tjitske" last="Heida">Tjitske Heida</name><affiliation><mods:affiliation>MIRA Institute for Biomedical Engineering and Technical Medicine, Biomedical Signals and Systems Group, University of Twente, Enschede, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Feirabend, Hans K P" sort="Feirabend, Hans K P" uniqKey="Feirabend H" first="Hans K P" last="Feirabend">Hans K P. Feirabend</name><affiliation><mods:affiliation>Department of Anatomy & Embryology, Leiden University Medical Center, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Janssen, Marcus L F" sort="Janssen, Marcus L F" uniqKey="Janssen M" first="Marcus L F" last="Janssen">Marcus L F. Janssen</name><affiliation><mods:affiliation>Department of Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands</mods:affiliation></affiliation><affiliation><mods:affiliation>European Graduate School of Neuroscience (EURON), Maastricht, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Visser Vandewalle, Veerle" sort="Visser Vandewalle, Veerle" uniqKey="Visser Vandewalle V" first="Veerle" last="Visser-Vandewalle">Veerle Visser-Vandewalle</name><affiliation><mods:affiliation>Department of Neurosurgery, Maastricht University Medical Center, Maastricht, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Martens, Hubert C F" sort="Martens, Hubert C F" uniqKey="Martens H" first="Hubert C F" last="Martens">Hubert C F. Martens</name><affiliation><mods:affiliation>SapiensSteering Brain Stimulation, Eindhoven, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Veltink, Peter H" sort="Veltink, Peter H" uniqKey="Veltink P" first="Peter H" last="Veltink">Peter H. Veltink</name><affiliation><mods:affiliation>MIRA Institute for Biomedical Engineering and Technical Medicine, Biomedical Signals and Systems Group, University of Twente, Enschede, The Netherlands</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:586106634EA3ADCD5B24A82FE916C9425CB3F011</idno><date when="2012" year="2012">2012</date><idno type="doi">10.1088/1741-2560/9/5/056005</idno><idno type="url">https://api.istex.fr/document/586106634EA3ADCD5B24A82FE916C9425CB3F011/fulltext/pdf</idno><idno type="wicri:Area/Main/Corpus">000D90</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">Motor cortex stimulation for Parkinson's disease: a modelling study</title><author><name sortKey="Zwartjes, Daphne G M" sort="Zwartjes, Daphne G M" uniqKey="Zwartjes D" first="Daphne G M" last="Zwartjes">Daphne G M. Zwartjes</name><affiliation><mods:affiliation>MIRA Institute for Biomedical Engineering and Technical Medicine, Biomedical Signals and Systems Group, University of Twente, Enschede, The Netherlands</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: d.g.m.zwartjes@utwente.nl</mods:affiliation></affiliation></author><author><name sortKey="Heida, Tjitske" sort="Heida, Tjitske" uniqKey="Heida T" first="Tjitske" last="Heida">Tjitske Heida</name><affiliation><mods:affiliation>MIRA Institute for Biomedical Engineering and Technical Medicine, Biomedical Signals and Systems Group, University of Twente, Enschede, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Feirabend, Hans K P" sort="Feirabend, Hans K P" uniqKey="Feirabend H" first="Hans K P" last="Feirabend">Hans K P. Feirabend</name><affiliation><mods:affiliation>Department of Anatomy & Embryology, Leiden University Medical Center, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Janssen, Marcus L F" sort="Janssen, Marcus L F" uniqKey="Janssen M" first="Marcus L F" last="Janssen">Marcus L F. Janssen</name><affiliation><mods:affiliation>Department of Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands</mods:affiliation></affiliation><affiliation><mods:affiliation>European Graduate School of Neuroscience (EURON), Maastricht, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Visser Vandewalle, Veerle" sort="Visser Vandewalle, Veerle" uniqKey="Visser Vandewalle V" first="Veerle" last="Visser-Vandewalle">Veerle Visser-Vandewalle</name><affiliation><mods:affiliation>Department of Neurosurgery, Maastricht University Medical Center, Maastricht, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Martens, Hubert C F" sort="Martens, Hubert C F" uniqKey="Martens H" first="Hubert C F" last="Martens">Hubert C F. Martens</name><affiliation><mods:affiliation>SapiensSteering Brain Stimulation, Eindhoven, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Veltink, Peter H" sort="Veltink, Peter H" uniqKey="Veltink P" first="Peter H" last="Veltink">Peter H. Veltink</name><affiliation><mods:affiliation>MIRA Institute for Biomedical Engineering and Technical Medicine, Biomedical Signals and Systems Group, University of Twente, Enschede, The Netherlands</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Journal of Neural Engineering</title><idno type="ISSN">1741-2560</idno><idno type="eISSN">1741-2552</idno><imprint><publisher>IOP Publishing</publisher><date type="published" when="2012-10">2012-10</date><biblScope unit="volume">9</biblScope><biblScope unit="issue">5</biblScope></imprint><idno type="ISSN">1741-2560</idno></series><idno type="istex">586106634EA3ADCD5B24A82FE916C9425CB3F011</idno><idno type="DOI">10.1088/1741-2560/9/5/056005</idno><idno type="href">http://stacks.iop.org/JNE/9/056005</idno><idno type="ArticleID">jne434133</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1741-2560</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">Chronic motor cortex stimulation (MCS) is currently being investigated as a treatment method for Parkinson's disease (PD). Unfortunately, the underlying mechanisms of this treatment are unclear and there are many uncertainties regarding the most effective stimulation parameters and electrode configuration. In this paper, we present a MCS model with a 3D representation of several axonal populations. The model predicts that the activation of either the basket cell or pyramidal tract (PT) type axons is involved in the clinical effect of MCS. We propose stimulation protocols selectively targeting one of these two axon types. To selectively target the basket cell axons, our simulations suggest using either cathodal or bipolar stimulation with the electrode strip placed perpendicular rather than parallel to the gyrus. Furthermore, selectivity can be increased by using multiple cathodes. PT type axons can be selectively targeted with anodal stimulation using electrodes with large contact sizes. Placing the electrode epidurally is advisable over subdural placement. These selective protocols, when practically implemented, can be used to further test which axon type should be activated for clinically effective MCS and can subsequently be applied to optimize treatment. In conclusion, this paper increases insight into the neuronal population involved in the clinical effect of MCS on PD and proposes strategies to improve this therapy.</div></front></TEI><istex><corpusName>iop</corpusName><author><json:item><name>Daphne G M Zwartjes</name><affiliations><json:string>MIRA Institute for Biomedical Engineering and Technical Medicine, Biomedical Signals and Systems Group, University of Twente, Enschede, The Netherlands</json:string><json:string>E-mail: d.g.m.zwartjes@utwente.nl</json:string></affiliations></json:item><json:item><name>Tjitske Heida</name><affiliations><json:string>MIRA Institute for Biomedical Engineering and Technical Medicine, Biomedical Signals and Systems Group, University of Twente, Enschede, The Netherlands</json:string></affiliations></json:item><json:item><name>Hans K P Feirabend</name><affiliations><json:string>Department of Anatomy & Embryology, Leiden University Medical Center, The Netherlands</json:string></affiliations></json:item><json:item><name>Marcus L F Janssen</name><affiliations><json:string>Department of Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands</json:string><json:string>European Graduate School of Neuroscience (EURON), Maastricht, The Netherlands</json:string></affiliations></json:item><json:item><name>Veerle Visser-Vandewalle</name><affiliations><json:string>Department of Neurosurgery, Maastricht University Medical Center, Maastricht, The Netherlands</json:string></affiliations></json:item><json:item><name>Hubert C F Martens</name><affiliations><json:string>SapiensSteering Brain Stimulation, Eindhoven, The Netherlands</json:string></affiliations></json:item><json:item><name>Peter H Veltink</name><affiliations><json:string>MIRA Institute for Biomedical Engineering and Technical Medicine, Biomedical Signals and Systems Group, University of Twente, Enschede, The Netherlands</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>87.80.y</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>87.19.X</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>87.19.L</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>02.70.Dh</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>87.19.R</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>motor cortex stimulation</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Parkinson's disease</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>model</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>pyramidal neurons</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>basket cells</value></json:item></subject><language><json:string>eng</json:string></language><abstract>Chronic motor cortex stimulation (MCS) is currently being investigated as a treatment method for Parkinson's disease (PD). Unfortunately, the underlying mechanisms of this treatment are unclear and there are many uncertainties regarding the most effective stimulation parameters and electrode configuration. In this paper, we present a MCS model with a 3D representation of several axonal populations. The model predicts that the activation of either the basket cell or pyramidal tract (PT) type axons is involved in the clinical effect of MCS. We propose stimulation protocols selectively targeting one of these two axon types. To selectively target the basket cell axons, our simulations suggest using either cathodal or bipolar stimulation with the electrode strip placed perpendicular rather than parallel to the gyrus. Furthermore, selectivity can be increased by using multiple cathodes. PT type axons can be selectively targeted with anodal stimulation using electrodes with large contact sizes. Placing the electrode epidurally is advisable over subdural placement. These selective protocols, when practically implemented, can be used to further test which axon type should be activated for clinically effective MCS and can subsequently be applied to optimize treatment. In conclusion, this paper increases insight into the neuronal population involved in the clinical effect of MCS on PD and proposes strategies to improve this therapy.</abstract><qualityIndicators><score>8.032</score><pdfVersion>1.4</pdfVersion><pdfPageSize>595 x 842 pts (A4)</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>10</keywordCount><abstractCharCount>1445</abstractCharCount><pdfWordCount>7236</pdfWordCount><pdfCharCount>42884</pdfCharCount><pdfPageCount>12</pdfPageCount><abstractWordCount>211</abstractWordCount></qualityIndicators><title>Motor cortex stimulation for Parkinson's disease: a modelling study</title><genre><json:string>research-article</json:string></genre><host><volume>9</volume><issn><json:string>1741-2560</json:string></issn><issue>5</issue><genre></genre><language><json:string>unknown</json:string></language><eissn><json:string>1741-2552</json:string></eissn><title>Journal of Neural Engineering</title></host><publicationDate>2012</publicationDate><copyrightDate>2012</copyrightDate><doi><json:string>10.1088/1741-2560/9/5/056005</json:string></doi><id>586106634EA3ADCD5B24A82FE916C9425CB3F011</id><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/586106634EA3ADCD5B24A82FE916C9425CB3F011/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/586106634EA3ADCD5B24A82FE916C9425CB3F011/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/586106634EA3ADCD5B24A82FE916C9425CB3F011/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a">Motor cortex stimulation for Parkinson's disease: a modelling study</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>IOP Publishing</publisher><availability><p>IOP</p></availability><date>2012-08-10</date></publicationStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">Motor cortex stimulation for Parkinson's disease: a modelling study</title><author><persName><forename type="first">Daphne G M</forename><surname>Zwartjes</surname></persName><email>d.g.m.zwartjes@utwente.nl</email><affiliation>MIRA Institute for Biomedical Engineering and Technical Medicine, Biomedical Signals and Systems Group, University of Twente, Enschede, The Netherlands</affiliation></author><author><persName><forename type="first">Tjitske</forename><surname>Heida</surname></persName><affiliation>MIRA Institute for Biomedical Engineering and Technical Medicine, Biomedical Signals and Systems Group, University of Twente, Enschede, The Netherlands</affiliation></author><author><persName><forename type="first">Hans K P</forename><surname>Feirabend</surname></persName><affiliation>Department of Anatomy & Embryology, Leiden University Medical Center, The Netherlands</affiliation></author><author><persName><forename type="first">Marcus L F</forename><surname>Janssen</surname></persName><affiliation>Department of Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands</affiliation><affiliation>European Graduate School of Neuroscience (EURON), Maastricht, The Netherlands</affiliation></author><author><persName><forename type="first">Veerle</forename><surname>Visser-Vandewalle</surname></persName><affiliation>Department of Neurosurgery, Maastricht University Medical Center, Maastricht, The Netherlands</affiliation></author><author><persName><forename type="first">Hubert C F</forename><surname>Martens</surname></persName><affiliation>SapiensSteering Brain Stimulation, Eindhoven, The Netherlands</affiliation></author><author><persName><forename type="first">Peter H</forename><surname>Veltink</surname></persName><affiliation>MIRA Institute for Biomedical Engineering and Technical Medicine, Biomedical Signals and Systems Group, University of Twente, Enschede, The Netherlands</affiliation></author></analytic><monogr><title level="j">Journal of Neural Engineering</title><idno type="pISSN">1741-2560</idno><idno type="eISSN">1741-2552</idno><imprint><publisher>IOP Publishing</publisher><date type="published" when="2012-10"></date><biblScope unit="volume">9</biblScope><biblScope unit="issue">5</biblScope></imprint></monogr><idno type="istex">586106634EA3ADCD5B24A82FE916C9425CB3F011</idno><idno type="DOI">10.1088/1741-2560/9/5/056005</idno><idno type="href">http://stacks.iop.org/JNE/9/056005</idno><idno type="ArticleID">jne434133</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2012-08-10</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>Chronic motor cortex stimulation (MCS) is currently being investigated as a treatment method for Parkinson's disease (PD). Unfortunately, the underlying mechanisms of this treatment are unclear and there are many uncertainties regarding the most effective stimulation parameters and electrode configuration. In this paper, we present a MCS model with a 3D representation of several axonal populations. The model predicts that the activation of either the basket cell or pyramidal tract (PT) type axons is involved in the clinical effect of MCS. We propose stimulation protocols selectively targeting one of these two axon types. To selectively target the basket cell axons, our simulations suggest using either cathodal or bipolar stimulation with the electrode strip placed perpendicular rather than parallel to the gyrus. Furthermore, selectivity can be increased by using multiple cathodes. PT type axons can be selectively targeted with anodal stimulation using electrodes with large contact sizes. Placing the electrode epidurally is advisable over subdural placement. These selective protocols, when practically implemented, can be used to further test which axon type should be activated for clinically effective MCS and can subsequently be applied to optimize treatment. In conclusion, this paper increases insight into the neuronal population involved in the clinical effect of MCS on PD and proposes strategies to improve this therapy.</p></abstract><textClass><keywords scheme="keyword"><list><head>article-type</head><item><term>Paper</term></item></list></keywords></textClass><textClass><keywords scheme="keyword"><list><head>author-pacs</head><item><term>87.80.y</term></item><item><term>87.19.X</term></item><item><term>87.19.L</term></item><item><term>02.70.Dh</term></item><item><term>87.19.R</term></item></list></keywords></textClass><textClass><keywords scheme="keyword"><list><head>Keywords</head><item><term>motor cortex stimulation</term></item><item><term>Parkinson's disease</term></item><item><term>model</term></item><item><term>pyramidal neurons</term></item><item><term>basket cells</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2012-08-10">Created</change><change when="2012-10">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/586106634EA3ADCD5B24A82FE916C9425CB3F011/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus iop not found" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="ISO-8859-1" </istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v3.0 20080202//EN" URI="http://ej.iop.org/dtd/nlm-3.0/journalpublishing3.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article"><front><journal-meta><journal-id journal-id-type="publisher-id">jne</journal-id><journal-id journal-id-type="coden">JNEIEZ</journal-id><journal-title-group><journal-title>Journal of Neural Engineering</journal-title><abbrev-journal-title abbrev-type="IOP">JNE</abbrev-journal-title><abbrev-journal-title abbrev-type="publisher">J. Neural Eng.</abbrev-journal-title></journal-title-group><issn pub-type="ppub">1741-2560</issn><issn pub-type="epub">1741-2552</issn><publisher><publisher-name>IOP Publishing</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="publisher-id">jne434133</article-id><article-id pub-id-type="doi">10.1088/1741-2560/9/5/056005</article-id><article-id pub-id-type="manuscript">434133</article-id><article-categories><subj-group subj-group-type="article-type"><subject>Paper</subject></subj-group></article-categories><title-group><article-title>Motor cortex stimulation for Parkinson's disease: a modelling study</article-title><alt-title alt-title-type="ascii">Motor cortex stimulation for Parkinson's disease: a modelling study</alt-title><alt-title alt-title-type="short">Motor cortex stimulation for Parkinson's disease: a modelling study</alt-title><alt-title alt-title-type="short-ascii">Motor cortex stimulation for Parkinson's disease: a modelling study</alt-title></title-group><contrib-group content-type="all"><contrib contrib-type="author"><name><surname>Zwartjes</surname><given-names>Daphne G M</given-names></name><xref ref-type="aff" rid="jne434133af1">1</xref><xref ref-type="aff" rid="jne434133em1"></xref></contrib><contrib contrib-type="author"><name><surname>Heida</surname><given-names>Tjitske</given-names></name><xref ref-type="aff" rid="jne434133af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Feirabend</surname><given-names>Hans K P</given-names></name><xref ref-type="aff" rid="jne434133af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Janssen</surname><given-names>Marcus L F</given-names></name><xref ref-type="aff" rid="jne434133af3">3</xref><xref ref-type="aff" rid="jne434133af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Visser-Vandewalle</surname><given-names>Veerle</given-names></name><xref ref-type="aff" rid="jne434133af5">5</xref></contrib><contrib contrib-type="author"><name><surname>Martens</surname><given-names>Hubert C F</given-names></name><xref ref-type="aff" rid="jne434133af6">6</xref></contrib><contrib contrib-type="author"><name><surname>Veltink</surname><given-names>Peter H</given-names></name><xref ref-type="aff" rid="jne434133af1">1</xref></contrib><aff id="jne434133af1"><label>1</label><institution>MIRA Institute for Biomedical Engineering and Technical Medicine, Biomedical Signals and Systems Group, University of Twente</institution>, Enschede, <country>The Netherlands</country></aff><aff id="jne434133af2"><label>2</label><institution>Department of Anatomy & Embryology, Leiden University Medical Center</institution>, <country>The Netherlands</country></aff><aff id="jne434133af3"><label>3</label><institution>Department of Neuroscience, Maastricht University Medical Center</institution>, Maastricht, <country>The Netherlands</country></aff><aff id="jne434133af4"><label>4</label><institution>European Graduate School of Neuroscience (EURON)</institution>, Maastricht, <country>The Netherlands</country></aff><aff id="jne434133af5"><label>5</label><institution>Department of Neurosurgery, Maastricht University Medical Center</institution>, Maastricht, <country>The Netherlands</country></aff><aff id="jne434133af6"><label>6</label><institution>Sapiens—Steering Brain Stimulation, Eindhoven</institution>, <country>The Netherlands</country></aff><ext-link ext-link-type="email" id="jne434133em1">d.g.m.zwartjes@utwente.nl</ext-link><author-comment content-type="short-author-list"><p>D G M Zwartjes <italic>et al</italic></p></author-comment></contrib-group><pub-date pub-type="ppub"><month>10</month><year>2012</year></pub-date><pub-date pub-type="epub"><day>10</day><month>8</month><year>2012</year></pub-date><volume>9</volume><issue>5</issue><elocation-id content-type="artnum">056005</elocation-id><supplementary-material content-type="colour-figures"></supplementary-material><history><date date-type="received"><day>24</day><month>5</month><year>2012</year></date><date date-type="accepted"><day>19</day><month>7</month><year>2012</year></date></history><permissions><copyright-statement>© 2012 IOP Publishing Ltd</copyright-statement><copyright-year>2012</copyright-year></permissions><self-uri xlink:href="http://stacks.iop.org/JNE/9/056005"></self-uri><abstract><title>Abstract</title><p>Chronic motor cortex stimulation (MCS) is currently being investigated as a treatment method for Parkinson's disease (PD). Unfortunately, the underlying mechanisms of this treatment are unclear and there are many uncertainties regarding the most effective stimulation parameters and electrode configuration. In this paper, we present a MCS model with a 3D representation of several axonal populations. The model predicts that the activation of either the basket cell or pyramidal tract (PT) type axons is involved in the clinical effect of MCS. We propose stimulation protocols selectively targeting one of these two axon types. To selectively target the basket cell axons, our simulations suggest using either cathodal or bipolar stimulation with the electrode strip placed perpendicular rather than parallel to the gyrus. Furthermore, selectivity can be increased by using multiple cathodes. PT type axons can be selectively targeted with anodal stimulation using electrodes with large contact sizes. Placing the electrode epidurally is advisable over subdural placement. These selective protocols, when practically implemented, can be used to further test which axon type should be activated for clinically effective MCS and can subsequently be applied to optimize treatment. In conclusion, this paper increases insight into the neuronal population involved in the clinical effect of MCS on PD and proposes strategies to improve this therapy.</p></abstract><kwd-group kwd-group-type="author-pacs"><kwd>87.80.−y</kwd><kwd>87.19.X−</kwd><kwd>87.19.L−</kwd><kwd>02.70.Dh</kwd><kwd>87.19.R−</kwd></kwd-group><kwd-group kwd-group-type="author"><kwd>motor cortex stimulation</kwd><kwd>Parkinson's disease</kwd><kwd>model</kwd><kwd>pyramidal neurons</kwd><kwd>basket cells</kwd></kwd-group><counts><page-count count="12"></page-count></counts><custom-meta-group><custom-meta><meta-name>ccc</meta-name><meta-value>1741-2560/12/056005+12$33.00</meta-value></custom-meta><custom-meta><meta-name>printed</meta-name><meta-value>Printed in the UK & the USA</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec id="jne434133s1"><label>1.</label><title>Introduction</title><p>Stimulation of the brain is increasingly used to treat Parkinson's disease (PD) and stimulation of the basal ganglia, deep brain stimulation (DBS), has become a widely accepted therapy for PD [<xref ref-type="bibr" rid="jne434133bib1">1</xref>]. Chronic motor cortex stimulation (MCS) is a less invasive therapy, which was initially used for the treatment of chronic pain [<xref ref-type="bibr" rid="jne434133bib2">2</xref>], but has now also been studied as a PD treatment, especially for patients who are not eligible for DBS or refuse this treatment [<xref ref-type="bibr" rid="jne434133bib3">3</xref>, <xref ref-type="bibr" rid="jne434133bib4">4</xref>].</p><p>From a review of the literature and their own clinical data, Cioni <italic>et al</italic> [<xref ref-type="bibr" rid="jne434133bib5">5</xref>] conclude that MCS may relieve all three main symptoms of PD (akinesia, rigidity, tremor), but results vary widely. Currently, MCS protocols for PD comprise either cathodal or bipolar stimulation [<xref ref-type="bibr" rid="jne434133bib3">3</xref>–<xref ref-type="bibr" rid="jne434133bib12">12</xref>]. There are, however, many uncertainties about the most effective stimulation parameters and electrode configuration. It is, for example, not known whether subdural or epidural stimulation should be used [<xref ref-type="bibr" rid="jne434133bib10">10</xref>–<xref ref-type="bibr" rid="jne434133bib12">12</xref>] and which electrode orientation relative to the gyrus is optimal [<xref ref-type="bibr" rid="jne434133bib4">4</xref>, <xref ref-type="bibr" rid="jne434133bib7">7</xref>, <xref ref-type="bibr" rid="jne434133bib10">10</xref>–<xref ref-type="bibr" rid="jne434133bib13">13</xref>].</p><p>Since the mechanisms of MCS in the treatment of PD are not clear, information on how to optimize treatment is lacking. Several theories exist about the neuronal populations that are involved: (1) the involvement of the axons projecting to the hyperdirect pathway from the cortex to the subthalamic nucleus (STN) through which STN activity can be modulated (figure <xref ref-type="fig" rid="jne434133f1">1</xref>(a)) [<xref ref-type="bibr" rid="jne434133bib3">3</xref>]. In cats, it has been shown that these axonal projections originate from the pyramidal tract (PT) type cells [<xref ref-type="bibr" rid="jne434133bib14">14</xref>] (figure <xref ref-type="fig" rid="jne434133f1">1</xref>(b)), but this has not been studied in rats and monkeys yet [<xref ref-type="bibr" rid="jne434133bib15">15</xref>]. (2) The axons projecting to the direct and indirect pathway (figure <xref ref-type="fig" rid="jne434133f1">1</xref>(a)) can also modulate basal ganglia activity [<xref ref-type="bibr" rid="jne434133bib3">3</xref>, <xref ref-type="bibr" rid="jne434133bib4">4</xref>, <xref ref-type="bibr" rid="jne434133bib7">7</xref>, <xref ref-type="bibr" rid="jne434133bib13">13</xref>]. These pathways presumably originate from intratelecenphalic (IT) type pyramidal cells in the motor cortex [<xref ref-type="bibr" rid="jne434133bib15">15</xref>, <xref ref-type="bibr" rid="jne434133bib16">16</xref>] and project to the striatum, or more particularly the lateral putamen [<xref ref-type="bibr" rid="jne434133bib17">17</xref>], and then to the STN (figure <xref ref-type="fig" rid="jne434133f1">1</xref>(b)). (3) The involvement of the inhibitory axonal population [<xref ref-type="bibr" rid="jne434133bib7">7</xref>, <xref ref-type="bibr" rid="jne434133bib12">12</xref>, <xref ref-type="bibr" rid="jne434133bib13">13</xref>, <xref ref-type="bibr" rid="jne434133bib18">18</xref>], i.e. the basket cells, which have long axons running parallel to the pial surface [<xref ref-type="bibr" rid="jne434133bib19">19</xref>] (figure <xref ref-type="fig" rid="jne434133f1">1</xref>(b)). As the basket cells have multiple synaptic contacts on the pyramidal neurons [<xref ref-type="bibr" rid="jne434133bib19">19</xref>], they can strongly inhibit this population and thereby modulate the cortico-basal ganglia loops. Additional networks in the cortex are formed by excitatory projections from the pyramidal neurons to the basket cells and other pyramidal neurons in different cortical layers [<xref ref-type="bibr" rid="jne434133bib19">19</xref>]. Based on these theories, activation of three axonal populations has been suggested to play a role in MCS treatment for PD, namely basket cell axons, PT and IT type pyramidal axons.</p><fig id="jne434133f1" fig-type="pgwide"><label>Figure 1.</label><caption id="jne434133fc1"><p>(a) The neuronal pathways from the cortex through the basal ganglia and thalamus back to the cortex. (b) A schematic representation of the axonal populations that have been suggested to play a role in the mechanisms of MCS for PD treatment: basket cell axons, which have inhibitory properties, are mainly located in layer III and V; PT type pyramidal axons, being excitatory and composing the hyperdirect pathway, originate from deep layer V [<xref ref-type="bibr" rid="jne434133bib34">34</xref>]; IT type pyramidal axons, which are also excitatory and compose the direct and indirect pathway. Their somas are located in layer III, superficial and deep layer V [<xref ref-type="bibr" rid="jne434133bib34">34</xref>] (those located in deep layer V are not considered, since their relatively small diameter makes them less excitable than PT type axons at similar locations).</p></caption><graphic id="jne434133f1_eps" content-type="print" xlink:href="jne434133f1_pr.eps"></graphic><graphic id="jne434133f1_online" content-type="online" xlink:href="jne434133f1_online.jpg"></graphic></fig><p>To optimize treatment, it is important to know which axonal population is primarily involved in the clinical effect of MCS on PD. We propose a modelling approach using a finite element volume conduction model in combination with an axon model, similar to previously developed models for MCS [<xref ref-type="bibr" rid="jne434133bib20">20</xref>–<xref ref-type="bibr" rid="jne434133bib25">25</xref>] and DBS [<xref ref-type="bibr" rid="jne434133bib26">26</xref>–<xref ref-type="bibr" rid="jne434133bib29">29</xref>]. We extended previous MCS models by: considering axons with different orientations and at different depths in the grey matter (figure <xref ref-type="fig" rid="jne434133f1">1</xref>(b)); including new anatomical data on the diameters of the myelinated fibre populations [<xref ref-type="bibr" rid="jne434133bib30">30</xref>]; using realistic models of PT and IT type pyramidal axons including axon collaterals [<xref ref-type="bibr" rid="jne434133bib19">19</xref>, <xref ref-type="bibr" rid="jne434133bib31">31</xref>]; modelling axons in 3D space.</p><p>The aim is to determine which axonal populations are activated during clinically effective MCS treatment for PD using this computational model. Secondly, we will employ the model to determine protocols that selectively target these populations.</p><p>Although this paper is aimed at chronic MCS for PD, the outcome can also be useful for other applications, such as MCS for pain and stroke treatment and acute MCS to target the STN or GPi motor regions during DBS surgery [<xref ref-type="bibr" rid="jne434133bib32">32</xref>, <xref ref-type="bibr" rid="jne434133bib33">33</xref>].</p></sec><sec id="jne434133s2"><label>2.</label><title>Methods</title><sec id="jne434133s2-1"><label>2.1.</label><title>Volume conduction model</title><p>A 3D finite element volume conduction model of the MC including a current controlled stimulation electrode was developed using COMSOL Multiphysics (v3.4, COMSOL, Inc., Burlington, MA, USA). In addition, an axon model was developed in Matlab (MathWorks, Natick, MA, USA), using a finite impedance single cable model, which was virtually positioned in the MC.</p><p>The modelled MC geometry included the scalp, skull, dura mater, cerebrospinal fluid, grey matter and white matter (figure <xref ref-type="fig" rid="jne434133f2">2</xref>, table <xref ref-type="table" rid="jne434133t1">1</xref>). Since quasi-static conditions can be assumed [<xref ref-type="bibr" rid="jne434133bib35">35</xref>], the electrical potential field was calculated by solving Poisson's equation. Boundary conditions were based on a realistic head model [<xref ref-type="bibr" rid="jne434133bib36">36</xref>], since Grant and Lowery showed that it is inadequate to use a simple cubic block grounded on the exterior boundaries for the representation of distant tissue. They propose a realistic model with electric insulation at the exterior boundaries and a ground located at the approximate location of the reference electrode. As only relative voltage values are of concern for the cable models of the axon, the reference electrode was set to 0 V. Their head model has an ellipsoid shape and incorporates a two-layered representation of the scalp, a three-layered representation of the skull and the cerebrospinal fluid. We replicated this model and added the dura mater. Subsequently, the realistic model was simplified by converting the ellipsoid shape of the head to a block (figure <xref ref-type="fig" rid="jne434133f2">2</xref>). Furthermore, outside the area of interest, which is an area of about 30 mm around the electrode, the different shells representing the scalp, skull, dura mater and cerebrospinal fluid were converted to one layer. The effective conductivity of this layer was chosen such that the electric potential (in the grey matter right beneath the stimulation electrode) and impedance in the simplified model differed less than 2% from the electric potential and impedance in the realistic version. The boundary conditions in the realistic model and simplified model were similar, i.e. exterior boundaries were electrically insulated and the reference electrode was set to 0 V. During monopolar stimulation, the reference electrode was located on the case of the implantable pulse generator (IPG; figure <xref ref-type="fig" rid="jne434133f2">2</xref>) [<xref ref-type="bibr" rid="jne434133bib3">3</xref>, <xref ref-type="bibr" rid="jne434133bib4">4</xref>, <xref ref-type="bibr" rid="jne434133bib6">6</xref>, <xref ref-type="bibr" rid="jne434133bib8">8</xref>–<xref ref-type="bibr" rid="jne434133bib11">11</xref>]. During bipolar stimulation, one of the remaining electrode contacts was used as a reference. Like Manola <italic>et al</italic> [<xref ref-type="bibr" rid="jne434133bib21">21</xref>], we set the conductance of the dura mater to a value that gives an impedance matching to the mean empirical value of ∼1000 Ω during bipolar stimulation. This resulted in a conductance of 0.055 S m<sup>−1</sup>, which is in between the values of 0.065 S m<sup>−1</sup> proposed by Manola <italic>et al</italic> [<xref ref-type="bibr" rid="jne434133bib21">21</xref>] and 0.03 S m<sup>−1</sup> used by Struijk <italic>et al</italic> [<xref ref-type="bibr" rid="jne434133bib37">37</xref>]. The conductance of the ‘distant tissue’ representing tissue in between the brain and clavicle, where the case of the IPG is located, was determined by matching the model impedance during monopolar stimulation to the mean empirical value of ∼750 Ω [<xref ref-type="bibr" rid="jne434133bib21">21</xref>]. The finite element model was 19 × 16 × 17 cm<sup>3</sup> and it was solved for 9.2 × 10<sup>4</sup> tetrahedral elements using a linear solver, conjugate gradients, with preconditioning of an algebraic multigrid solver. The finest mesh is located in the electrode contact where the mesh elements had an average volume of 0.041 mm<sup>3</sup>. The mesh element volume increased to an average of 412 mm<sup>3</sup> in the roughest meshed structure; the brain tissue. Increasing the overall resolution approximately twofold resulted in a less than 2% difference of the electric potential in the grey matter beneath the stimulation electrode.</p><fig id="jne434133f2" fig-type="pgwide"><label>Figure 2.</label><caption id="jne434133fc2"><p>The finite element volume conduction model of the motor cortex with surrounding structures during epidural stimulation when the case of the IPG is used as a reference. On the left, the entire model, which is derived from a realistic head model, is shown. The area around the electrode, encompassed by dashed lines, is shown in more detail on the right. The layer around the brain represents the scalp, skull, dura mater and cerebro spinal fluid. The distant tissue represents the tissue in between the brain and clavicle, where the IPG is located. The entire model has the following dimensions: 192.1 × 157.1 × 167.1 mm.</p></caption><graphic id="jne434133f2_eps" content-type="print" xlink:href="jne434133f2_pr.eps"></graphic><graphic id="jne434133f2_online" content-type="online" xlink:href="jne434133f2_online.jpg"></graphic></fig><table-wrap id="jne434133t1" content-type="pgwide"><label>Table 1.</label><caption id="jne434133tc1"><p>Parameters volume conduction model.</p></caption><table><colgroup><col align="left"></col><col align="left"></col><col align="left"></col></colgroup><thead><tr><th align="left">Geometry</th><th align="left">dimensions (mm)</th><th align="left">Conductivity (S m<sup>−1</sup>)</th></tr></thead><tbody><tr><td>Skin</td><td><italic>y</italic> = 2.4 [<xref ref-type="bibr" rid="jne434133bib38">38</xref>]</td><td>0.00087 [<xref ref-type="bibr" rid="jne434133bib39">39</xref>]</td></tr><tr><td>Fat</td><td><italic>y</italic> = 3.1 [<xref ref-type="bibr" rid="jne434133bib38">38</xref>]</td><td>0.042 [<xref ref-type="bibr" rid="jne434133bib39">39</xref>]</td></tr><tr><td>Skull inner layer</td><td><italic>y</italic> = 3 [<xref ref-type="bibr" rid="jne434133bib37">37</xref>]</td><td>0.076 [<xref ref-type="bibr" rid="jne434133bib39">39</xref>]</td></tr><tr><td>Skull outer layers</td><td><italic>y</italic> = 0.8 and <italic>y</italic> = 0.8 [<xref ref-type="bibr" rid="jne434133bib37">37</xref>]</td><td>0.02 [<xref ref-type="bibr" rid="jne434133bib39">39</xref>]</td></tr><tr><td>Dura mater</td><td>0.36 [<xref ref-type="bibr" rid="jne434133bib18">18</xref>]</td><td>0.055</td></tr><tr><td>Electrode insulation</td><td><italic>xyz</italic> = 8 × 1.8 × 44</td><td>0.0001 [<xref ref-type="bibr" rid="jne434133bib21">21</xref>]</td></tr><tr><td>Electrode contact</td><td>diameter = 2.3 or 4; height = 0.4</td><td>6 · 10<sup>7</sup></td></tr><tr><td>Cerebrospinal fluid</td><td><italic>y</italic> = 3.1 [<xref ref-type="bibr" rid="jne434133bib21">21</xref>]</td><td>1.6 [<xref ref-type="bibr" rid="jne434133bib40">40</xref>]</td></tr><tr><td>Grey matter</td><td><italic>y</italic> = 3.7 [<xref ref-type="bibr" rid="jne434133bib21">21</xref>]</td><td>0.36 [<xref ref-type="bibr" rid="jne434133bib21">21</xref>]</td></tr><tr><td>Precentral gyrus</td><td><italic>x</italic> = 11.7 [<xref ref-type="bibr" rid="jne434133bib21">21</xref>]</td><td></td></tr><tr><td>Central sulcus</td><td><italic>xy</italic> = 2.3 × 16.4 [<xref ref-type="bibr" rid="jne434133bib21">21</xref>]</td><td></td></tr><tr><td>Precentral sulcus</td><td><italic>xy</italic> = 2.7 × 15.6 [<xref ref-type="bibr" rid="jne434133bib21">21</xref>]</td><td></td></tr><tr><td>White matter</td><td><italic>xyz</italic> = 54 × 30.4 × 50</td><td><italic>x</italic> = 0.083; <italic>y</italic> = 0.6; <italic>z</italic> = 0.083 [<xref ref-type="bibr" rid="jne434133bib21">21</xref>]</td></tr><tr><td>Layer around the brain</td><td><italic>xyz</italic> = 192.1 × 157.1 × 167.1</td><td>0.0004</td></tr><tr><td>Distant tissue</td><td><italic>xyz</italic> = 40 × 13.56 × 40</td><td>0.048</td></tr><tr><td>Brain tissue</td><td><italic>xyz</italic> = 165 × 130 × 140</td><td>0.27 [<xref ref-type="bibr" rid="jne434133bib41">41</xref>]</td></tr></tbody></table></table-wrap></sec><sec id="jne434133s2-2"><label>2.2.</label><title>Axon model</title><p>Instead of an entire neuron, only the axon was modelled since axons are the key neuronal components responding to MCS, i.e. the component that primarily causes the output activity of the stimulated structure [<xref ref-type="bibr" rid="jne434133bib20">20</xref>, <xref ref-type="bibr" rid="jne434133bib42">42</xref>, <xref ref-type="bibr" rid="jne434133bib43">43</xref>]. The axon was modelled as a single cable model with the myelin having a finite resistance and capacitance; details can be found in [<xref ref-type="bibr" rid="jne434133bib44">44</xref>, <xref ref-type="bibr" rid="jne434133bib45">45</xref>]. The parameters applied in the axon model are listed in table <xref ref-type="table" rid="jne434133t2">2</xref>. Details on the ion channel and leakage conductances are presented in the <xref ref-type="sec" rid="jne434133app1">appendix</xref>.</p><table-wrap id="jne434133t2"><label>Table 2.</label><caption id="jne434133tc2"><p>Parameters axon model.</p></caption><table><colgroup><col align="left"></col><col align="left"></col></colgroup><thead><tr><th align="left">Parameter</th><th align="left">Value</th></tr></thead><tbody><tr><td>Neuron resting potential</td><td>−0.084 V [<xref ref-type="bibr" rid="jne434133bib46">46</xref>]</td></tr><tr><td>Intracellular resistivity</td><td> 0.4 Ωm [<xref ref-type="bibr" rid="jne434133bib47">47</xref>]</td></tr><tr><td>Membrane capacitance</td><td> 0.028 F m<sup>−2</sup> [<xref ref-type="bibr" rid="jne434133bib48">48</xref>]</td></tr><tr><td>Myelin membrane capacitance</td><td> 0.0005 F m<sup>−2</sup> [<xref ref-type="bibr" rid="jne434133bib49">49</xref>]</td></tr><tr><td>Myelin membrane conductance</td><td> 5 S m<sup>−2</sup> [<xref ref-type="bibr" rid="jne434133bib49">49</xref>]</td></tr></tbody></table></table-wrap><p>The following boundary conditions were used in the axon model: at the start and end of the axons, the next ‘virtual’ compartment was assumed to have the same membrane potential value as the boundary compartment. This ensures that no action potentials will be generated by boundary effects. Activation of an axon was defined when the membrane potential of one of the nodes was raised by 70 mV from the rest potential.</p><p>Different types of axons are located in the motor cortex. Since we are interested in those that might be involved in the clinical effect of MCS on PD, we modelled the basket cell, PT and IT type axons (figure <xref ref-type="fig" rid="jne434133f1">1</xref>). We assume that the direct and indirect pathways are (solely) innervated by IT type axons. Although one study argues that the PT type axons provide the main input to the direct pathway [<xref ref-type="bibr" rid="jne434133bib50">50</xref>], recent work [<xref ref-type="bibr" rid="jne434133bib15">15</xref>, <xref ref-type="bibr" rid="jne434133bib16">16</xref>] indicates that the IT type axons are the most important input. The inhibitory double bouquet cells and chandelier cells, which have axons oriented perpendicular to the pial surface, were not modelled as their axons run alongside pyramidal axons, which typically have a larger diameter [<xref ref-type="bibr" rid="jne434133bib51">51</xref>] and are, therefore, more excitable.</p><p>The inhibitory axonal population was represented by basket cell axons, which were modelled as long axons running parallel to the pial surface at depths of 1950 µm and 850 µm from the pial surface, being halfway the fifth and the third layer, respectively ([<xref ref-type="bibr" rid="jne434133bib19">19</xref>]; figure <xref ref-type="fig" rid="jne434133f3">3</xref>, red and orange). These axons were placed in 91 <italic>xy</italic>-planes spaced 0.33 mm apart in <italic>z</italic>-direction: −15 to +15 mm from the middle in between the two electrode contacts. Thereby, 3D populations of 91 basket cell axons in both the fifth and third layer were obtained. The pyramidal axons (the PT and IT type axons) were placed such that the soma (which was not modelled) would lie at distances of 2125, 1775 and 1125 µm from the pial surface. These depths correspond to the PT axon at three-fourth of layer V, and the IT axons at one-fourth of layer V and three-fourth of layer III, respectively. Furthermore, they were placed in the <italic>xy</italic>-plane in three different ways (figure <xref ref-type="fig" rid="jne434133f3">3</xref>): (1) a vertical axon right beneath the stimulation electrode on the crown of the gyrus (blue); (2) a diagonal axon running through the lip (purple); and (3) a horizontal axon running through the sulcus bank (green) [<xref ref-type="bibr" rid="jne434133bib24">24</xref>]. They were also placed in <italic>z</italic>-direction from −15 to +15 mm, using 31 <italic>xy</italic>-planes spaced 1 mm apart, obtaining a population of 93 PT type axons in layer V, 93 IT type axons in both layer III and V. The pyramidal axons were represented by a main axon and an axon collateral [<xref ref-type="bibr" rid="jne434133bib19">19</xref>, <xref ref-type="bibr" rid="jne434133bib31">31</xref>] (figure <xref ref-type="fig" rid="jne434133f3">3</xref>). Two types of axon collaterals were used, both lying parallel to the pial surface but oriented differently with respect to the medial–lateral and anterior–posterior axis (figure <xref ref-type="fig" rid="jne434133f3">3</xref>). Each pyramidal axon model was modelled using collateral type 1 or 2 and a 50% presence of both types was assumed. It was checked that the pyramidal axon model produced results consistent with several experimental studies [<xref ref-type="bibr" rid="jne434133bib18">18</xref>, <xref ref-type="bibr" rid="jne434133bib32">32</xref>, <xref ref-type="bibr" rid="jne434133bib52">52</xref>].</p><fig id="jne434133f3" fig-type="pgwide"><label>Figure 3.</label><caption id="jne434133fc3"><p>The motor cortex in which the basket cell axon, PT and IT type pyramidal axon models are shown: basket axons in layer III (orange) and layer V (red); pyramidal axons (blue, purple and green). The pyramidal axons in one layer of one type are shown. In reality there is the PT type in layer V and IT type in layer III and V. The different colours represent three orientations. The pyramidal axons are modelled using a main axon and axon collaterals type 1 and 2. For illustrative purposes, the three pyramidal axons with collaterals are shown with a small distance in between the collaterals type 1, but in reality they overlie one another. Only one <italic>xy</italic>-plane is shown for each axonal type, while multiple planes in <italic>z</italic>-direction were modelled.</p></caption><graphic id="jne434133f3_eps" content-type="print" xlink:href="jne434133f3_pr.eps"></graphic><graphic id="jne434133f3_online" content-type="online" xlink:href="jne434133f3_online.jpg"></graphic></fig><p>The diameters of the basket cell axon models were retrieved from Feirabend <italic>et al</italic> [<xref ref-type="bibr" rid="jne434133bib30">30</xref>]. They assessed the diameter of the myelinated fibre population, which they define as the thickness of the axon including the myelin sheets, in the human motor cortex. The axon diameter in our model is defined similarly. Only fibres with a diameter above 5 µm were considered by Feirabend <italic>et al</italic> because thinner fibres are less interesting since they become increasingly difficult to activate. They distinguished diameters between differently oriented axons and between axons at different depths in the grey matter. As basket cell axons are mainly located in layer III and V [<xref ref-type="bibr" rid="jne434133bib19">19</xref>], we used the axon diameters found at depths corresponding to the middle of both layers: the basket cell axon has an average diameter of 5.4 µm in layer III and 5.7 µm in layer V.</p><p>The diameters of the pyramidal axons were derived from average diameters measured in human and the ratio between the axon diameters of different neuron types found in rat. The average diameter of perpendicularly oriented axons in the human motor cortex is 7.1 µm [<xref ref-type="bibr" rid="jne434133bib30">30</xref>]. We differentiated different neuron types and neurons at different depths, by using ratios of soma sizes found in the rat motor cortex [<xref ref-type="bibr" rid="jne434133bib34">34</xref>], which were converted to axon diameters using the relation between axon and soma diameters [<xref ref-type="bibr" rid="jne434133bib51">51</xref>]. The following diameters were used: 10.6, 5.1 and 5.7 µm for PT type axons in layer V and IT type axons in layer III and V, respectively. The axon collaterals of these perpendicular axons ran parallel to the pial surface. The diameters of these collaterals were based on the diameter-ratio between parallel and perpendicular axon diameters in human 0.85:1 [<xref ref-type="bibr" rid="jne434133bib30">30</xref>]. This gave collateral diameters of 9.0, 4.5 and 4.8 µm for the PT type axons in layer V and IT type axons in layer III and V, respectively.</p></sec><sec id="jne434133s2-3"><label>2.3.</label><title>Simulations</title><p>The simulations consisted of two parts: defining which axonal populations are activated during clinically effective MCS for PD; and proposing stimulation protocols to target these populations selectively. In both parts, the effect of the stimulation protocols was assessed by determining the activation threshold for each individual axon and subsequent computation of the activation fraction. The activation fraction is defined as the percentage of activated axons from the total amount of axons we modelled in our 3D population. Assuming that, within a volume of 8.2 ⋅ 10<sup>3</sup> mm<sup>3</sup> an equal number of each axon type exists, i.e. 91 basket cell axons in both layer III and V, 93 IT type axons in both layer III and V, and 93 PT type axons. Results were obtained within clinically relevant stimulation amplitudes, which are up to 8 V [<xref ref-type="bibr" rid="jne434133bib7">7</xref>]. Considering impedances of 750 and 1000 Ω during monopolar and bipolar stimulation, respectively [<xref ref-type="bibr" rid="jne434133bib21">21</xref>], this corresponds to 10.7 and 8 mA.</p><p>The first part of the simulations assess which neuronal populations are activated during clinically effective MCS treatment. This will be done by studying the effects of cortical stimulation on the earlier proposed axonal populations: the basket cell, PT and IT type axons. The clinically effective stimulation protocols are epidural cathodal and bipolar stimulation (table <xref ref-type="table" rid="jne434133t3">3</xref>). The effect of monopolar anodal stimulation has not been studied on humans as this is not possible due to the design of the present IPGs [<xref ref-type="bibr" rid="jne434133bib12">12</xref>].</p><table-wrap id="jne434133t3" content-type="pgwide"><label>Table 3.</label><caption id="jne434133tc3"><p>MCS protocols.</p></caption><table><colgroup><col align="left"></col></colgroup><tbody><tr><td><inline-formula><tex-math></tex-math><inline-graphic xlink:href="jne434133ieqn1.gif"></inline-graphic></inline-formula></td></tr></tbody></table><table-wrap-foot><fn><p>The first row shows clinically used MCS protocols [<xref ref-type="bibr" rid="jne434133bib3">3</xref>–<xref ref-type="bibr" rid="jne434133bib12">12</xref>]. The remaining rows show the variations on the clinical protocols, which are assessed to find selective stimulation protocols. Each variation is numbered. The change relative to the clinical protocols is shaded.</p></fn><fn id="jne434133t3fn1"><label>a</label><p>Strip orientation relatively to the gyrus.</p></fn><fn id="jne434133t3fn2"><label>b</label><p>Electrode configurations: ‘+’ is anode, ‘−’ is cathode and ‘o’ is not active. When multiple cathodes were used, the current was divided between the contacts.</p></fn></table-wrap-foot></table-wrap><p>In the second part, we looked for selective MCS protocols by varying the position and orientation of the strip, the contact size and the distance between the contacts, the stimulation type, i.e. anodal/cathodal/bipolar, and the number of cathodes (table <xref ref-type="table" rid="jne434133t3">3</xref>).</p></sec></sec><sec id="jne434133s3"><label>3.</label><title>Results</title><sec id="jne434133s3-1"><label>3.1.</label><title>Axonal populations activated during clinically effective MCS for PD</title><p>The activation fractions during clinically effective stimulation protocols (table <xref ref-type="table" rid="jne434133t3">3</xref>, first row) are shown in figures <xref ref-type="fig" rid="jne434133f4">4</xref>(a) and (b). The activation fraction of the basket cell axons was largest during cathodal stimulation, but the PT type pyramidal axons were also activated. The IT type pyramidal axons were activated at a threshold of 13.5 mA, which is beyond the clinical range of stimulation amplitudes used during MCS. During bipolar stimulation, all axon types were activated, but the activation fractions of basket cell and PT type axons were larger than those of IT type axons. Furthermore, a larger fraction of the more superficially located basket cells in layer III were activated than those in layer V in both stimulation protocols.</p><fig id="jne434133f4" fig-type="pgwide"><label>Figure 4.</label><caption id="jne434133fc4"><p>The activation fractions of different axonal populations that are believed to be involved in the mechanisms of MCS on PD. The clinically used stimulation protocols, epidural cathodal (a) and bipolar (b) stimulation, were modelled.</p></caption><graphic id="jne434133f4_eps" content-type="print" xlink:href="jne434133f4_pr.eps"></graphic><graphic id="jne434133f4_online" content-type="online" xlink:href="jne434133f4_online.jpg"></graphic></fig><p>To get more insight into how the activation spreads in the cortex, the spreading of the basket cell axon activation is depicted in figure <xref ref-type="fig" rid="jne434133f5">5</xref>. This distribution is slightly asymmetrical, because of the location of the reference electrode which influences the gradient of the potential field.</p><fig id="jne434133f5" fig-type="pgwide"><label>Figure 5.</label><caption id="jne434133fc5"><p>The spreading of the activation of the basket cell axons in layer III during cathodal and bipolar epidural stimulation. Note that for illustrative reasons the basket cell axons are depicted on the surface of the gyrus, while they are modelled at a depth corresponding to the middle of the third cortical layer.</p></caption><graphic id="jne434133f5_eps" content-type="print" xlink:href="jne434133f5_pr.eps"></graphic><graphic id="jne434133f5_online" content-type="online" xlink:href="jne434133f5_online.jpg"></graphic></fig><p>The activation of the axons was initiated at different nodes during different stimulation protocols. The following results were found for axons activated within the clinically used range of stimulation amplitudes. During anodal stimulation, excitation of the vertical pyramidal axons (figure <xref ref-type="fig" rid="jne434133f3">3</xref>, blue) started close to the boundary of the grey and white matter on the main axon. During cathodal stimulation, excitation of the vertical pyramidal axons (figure <xref ref-type="fig" rid="jne434133f3">3</xref>, blue) initiated at the axon collaterals close to the main axon, while the diagonal and horizontal pyramidal axons (figure <xref ref-type="fig" rid="jne434133f3">3</xref>, purple and green) were activated first at nodes located in the bending part of the main axon. During cathodal stimulation, basket cell axons (figure <xref ref-type="fig" rid="jne434133f3">3</xref>, orange and red) were activated first on the node in the horizontal part of the axon closest to the stimulation electrode. When considering bipolar stimulation, the locations of activation on the axons beneath the anode were similar to monopolar anodal stimulation, and beneath the cathode similar to monopolar cathodal stimulation.</p></sec><sec id="jne434133s3-2"><label>3.2.</label><title>Establishing more selective stimulation protocols</title><p>An extensive number of protocols were assessed in order to achieve more selective stimulation. The results of our model described above indicate that the basket cell and PT type pyramidal axonal populations are excited in all clinically effective MCS protocols, while IT type pyramidal axons are not activated in all effective protocols. Therefore, we assume that the activation of IT type pyramidal axons is not involved in the clinical effect of MCS on PD and further assess selective stimulation of basket cell axons and PT type pyramidal axons.</p><p>First, we assessed the two clinically applied protocols and varied the electrode configuration with an anode (table <xref ref-type="table" rid="jne434133t3">3</xref>—variation 1; figure <xref ref-type="fig" rid="jne434133f6">6</xref>). It is shown that cathodal stimulation most selectively activates basket cell axons, while PT type axons are selectively targeted using anodal stimulation. Using these electrode configurations as a starting point, more selective stimulation protocols will be developed.</p><fig id="jne434133f6"><label>Figure 6.</label><caption id="jne434133fc6"><p>The two clinically applied stimulation protocols (table <xref ref-type="table" rid="jne434133t3">3</xref>) and a variation in the electrode configuration, i.e. monopolar anodal stimulation (variation 1). Each point represents the activation fraction for a certain stimulation amplitude, which increases from 1 to 10 mA, in steps of 1 mA. Basket cell axons are most selectively activated during cathodal stimulation, while anodal stimulation selectively targets the PT type pyramidal axons.</p></caption><graphic id="jne434133f6_eps" content-type="print" xlink:href="jne434133f6_pr.eps"></graphic><graphic id="jne434133f6_online" content-type="online" xlink:href="jne434133f6_online.jpg"></graphic></fig><sec id="jne434133s3-2-1"><label>3.2.1.</label><title>Basket cell axons</title><p>The cathodal stimulation protocol most selectively stimulated basket cell axons (figure <xref ref-type="fig" rid="jne434133f6">6</xref>). As IT type axons were not activated at all during this stimulation protocol (figure <xref ref-type="fig" rid="jne434133f4">4</xref>(a)), the selectivity of basket cell axons against PT type axons was investigated further. Variations 5–9 (table <xref ref-type="table" rid="jne434133t3">3</xref>) were assessed.</p><p>Selective stimulation of basket cell axons can be improved by using multiple cathodes (variation 5; figure <xref ref-type="fig" rid="jne434133f7">7</xref>(a)). The optimal location and number of cathodes depended on the required basket cell activation fraction. For higher fractions, multiple cathodes are preferable, while for lower fractions a single cathode or two separate cathodes offer the best selectivity. A second approach to stimulate the basket cell axons more selectively was by using bipolar stimulation while placing the electrode strip perpendicular to the gyrus over the central sulcus with the cathode on top of the gyrus (variation 8). Compared to the cathodal stimulation protocol, the basket cell axons were activated more selectively relatively to the PT type axons (figure <xref ref-type="fig" rid="jne434133f7">7</xref>(b)). Bipolar stimulation with the contacts placed closer to each other or further apart (variation 6) did not give a higher selective activation of the basket cell axons. The electrode location (epidural/subdural; variation 7) and contact diameter (variation 9) had little influence on selectivity of basket cell axons relatively to the PT population.</p><fig id="jne434133f7" fig-type="pgwide"><label>Figure 7.</label><caption id="jne434133fc7"><p>The following variations on the cathodal stimulation protocol provided more selective stimulation of the basket cell axons relatively to the PT type pyramidal axons. Each point represents the activation fraction for a certain stimulation amplitude, which increases from 1 to 10 mA, in steps of 1 mA. (a) The activation fraction for a varying number of epidurally placed cathodes (variation 5). For basket cell axon activation fractions up to ∼20%, one cathode or two separate cathodes offered the highest selectivity. For larger activation fractions, two adjacent cathodes resulted in increased selectivity, and for fractions above 41% three cathodes was the best choice. (b) The perpendicular bipolar protocol with the cathode placed over the gyrus (variation 8) provided more selective stimulation of basket cell axons than the cathodal stimulation protocol.</p></caption><graphic id="jne434133f7_eps" content-type="print" xlink:href="jne434133f7_pr.eps"></graphic><graphic id="jne434133f7_online" content-type="online" xlink:href="jne434133f7_online.jpg"></graphic></fig></sec><sec id="jne434133s3-2-2"><label>3.2.2.</label><title>PT type pyramidal axons</title><p>Figure <xref ref-type="fig" rid="jne434133f6">6</xref> shows that anodal stimulation (variation 1) offers the highest selectivity for PT type pyramidal axons activation. As basket cell axons are not activated at all within the clinically relevant stimulation amplitudes during anodal stimulation, the selectivity of PT type against IT type pyramidal axons is explored further. Variations 1–4 and 6 were assessed. Increased selectivity of PT type axon stimulation can be achieved by increasing the contact size (variation 4; figure <xref ref-type="fig" rid="jne434133f8">8</xref>(a)). Using subdural rather than epidural stimulation resulted in a lower selectivity toward PT type axons (variation 2; figure <xref ref-type="fig" rid="jne434133f8">8</xref>(b)). This selectivity was also decreased when using bipolar stimulation (variation 3) with the anode on top of the gyrus and the strip placed perpendicular to the gyrus over the sulcus and when using bipolar stimulation with the contacts spaced closer to each other or further away (variation 6).</p><fig id="jne434133f8" fig-type="pgwide"><label>Figure 8.</label><caption id="jne434133fc8"><p>(a) The selectivity of the activation of PT type against IT type pyramidal axons during anodal stimulation increased with a larger contact size (variation 4). Each point represents the activation fraction for a certain stimulation amplitude, which increases from 1 to 10 mA, in steps of 1 mA. (b) PT type axons were activated more selectively during epidural stimulation than during subdural stimulation. The activation fraction for increasing stimulation amplitudes from 0.1 to 1 mA, in steps of 0.1 mA, are shown.</p></caption><graphic id="jne434133f8_eps" content-type="print" xlink:href="jne434133f8_pr.eps"></graphic><graphic id="jne434133f8_online" content-type="online" xlink:href="jne434133f8_online.jpg"></graphic></fig></sec></sec></sec><sec id="jne434133s4"><label>4.</label><title>Discussion</title><sec id="jne434133s4-1"><label>4.1.</label><title>Axonal population responsible for clinically effective MCS on PD</title><p>We examined the activation of several axonal populations in order to identify the populations activated during clinically effective MCS treatment for PD. We found that IT type pyramidal axons were not activated during all clinically effective stimulation protocols, while both basket cell axons and PT type pyramidal axons were activated. This suggests that it is unlikely that the activation of IT type axons is responsible for the clinical effect MCS has on PD. Our model predicts that either the activation of basket cell axons or PT type pyramidal axon is involved in this clinical effect.</p><p>Activation of the basket cell axons supports the theory that the inhibitory axonal population plays an important role in the clinical effect of MCS on PD [<xref ref-type="bibr" rid="jne434133bib7">7</xref>, <xref ref-type="bibr" rid="jne434133bib12">12</xref>, <xref ref-type="bibr" rid="jne434133bib13">13</xref>, <xref ref-type="bibr" rid="jne434133bib18">18</xref>]. However, since the pyramidal neurons that innervate the hyperdirect, direct and indirect pathways are inhibited by the basket cells, theories suggesting the involvement of these pathways are also likely true [<xref ref-type="bibr" rid="jne434133bib3">3</xref>, <xref ref-type="bibr" rid="jne434133bib4">4</xref>, <xref ref-type="bibr" rid="jne434133bib7">7</xref>, <xref ref-type="bibr" rid="jne434133bib13">13</xref>]. These network properties are important as chronic MCS is performed by applying a continuous train of pulses instead of just a single pulse as in our model. The result of train stimulation is a cumulative sum of the facilitating and inhibitory effects; thus, the effect of stimulation trains may depend on whether facilitation or inhibition dominates the response to single stimuli [<xref ref-type="bibr" rid="jne434133bib18">18</xref>]. The main hypothesis on the mechanisms of DBS concerns prevention of the transmission of the pathologic network activity generated in the cortico-basal-ganglia-thalamo-cortical loop [<xref ref-type="bibr" rid="jne434133bib53">53</xref>]. Likewise, the basket cells have inhibitory properties and can thereby reduce the loop-gain in the motor cortex, which could prevent transmission of the pathological activity in these loops.</p><p>Activation of the PT type pyramidal axons agrees with theories suggesting modulation of the hyperdirect pathway to play a role in the mechanisms of MCS [<xref ref-type="bibr" rid="jne434133bib3">3</xref>], but as these axons innervate other pyramidal axons, excitation of the direct and indirect pathways could also explain the clinical effect [<xref ref-type="bibr" rid="jne434133bib4">4</xref>, <xref ref-type="bibr" rid="jne434133bib7">7</xref>, <xref ref-type="bibr" rid="jne434133bib13">13</xref>].</p></sec><sec id="jne434133s4-2"><label>4.2.</label><title>Establishing more selective stimulation protocols</title><p>Since our model predicts that either the basket cell axons or the PT type pyramidal axons are highly likely candidates for the clinical effect, activation of these axonal populations with a higher selectivity was assessed. Selective targeting of the population involved in the clinical effect could improve the effect of the treatment.</p><p>Based on the modelling results, cathodal epidural stimulation, often used to treat PD, is the protocol that most selectively targets the basket cell axons. The following protocols can increase this selectivity even further: the use of multiple cathodes either adjacent or with an inactive contact in between; applying bipolar stimulation rather than cathodal stimulation with the electrode strip placed perpendicular to the gyrus and the cathode overlying the gyrus. The contact size of the electrode contacts and the use of epidural rather than subdural stimulation did not influence selectivity toward basket cell axons during cathodal stimulation.</p><p>According to our model, selective stimulation of PT type pyramidal axons can be achieved by anodal epidural stimulation using electrodes with large contact sizes. Selective stimulation of the PT type axons was reduced when using subdural stimulation and bipolar stimulation with the strip oriented parallel as well as perpendicular to the gyrus.</p><p>In the future, these new protocols should be tested experimentally with evaluation of the effect on motor symptoms using clinical rating scales [<xref ref-type="bibr" rid="jne434133bib54">54</xref>] and objective movement measurements [<xref ref-type="bibr" rid="jne434133bib55">55</xref>]. This could help to confine which axonal population, i.e. basket cell axons or PT type pyramidal axons, should be activated in order to achieve clinically effective stimulation for the treatment of PD. The selective protocols could offer means to improve this treatment.</p></sec><sec id="jne434133s4-3"><label>4.3.</label><title>Comparison to previous modelling studies</title><p>Assessing the location at which the axon was excited, we found that during anodal stimulation excitation generally started at a node close to the grey and white matter boundary. This is in agreement with earlier modelling studies [<xref ref-type="bibr" rid="jne434133bib24">24</xref>, <xref ref-type="bibr" rid="jne434133bib25">25</xref>]. Like Salvador <italic>et al</italic> [<xref ref-type="bibr" rid="jne434133bib31">31</xref>], we found that during cathodal stimulation, the action potential was generated at the axon collateral in the vertical pyramidal axon (figure <xref ref-type="fig" rid="jne434133f3">3</xref>, blue). They indicated that with large diameter differences between the main and collateral axon, the action potential did not propagate from the collateral to the main axon. However when considering diameter differences consistent with our model, they did see propagation to the main axon, which is similar to our findings. In addition, they also found activation to be started on a node at the bend of the main axon in the diagonal and horizontal pyramidal axons (figure <xref ref-type="fig" rid="jne434133f3">3</xref>, purple and green). Furthermore, during cathodal stimulation the basket cell axons were activated in the nodes closest to the electrode at the horizontal part of the main axon, which is similar to Manola's findings [<xref ref-type="bibr" rid="jne434133bib24">24</xref>]. During bipolar stimulation, axons beneath the anode and cathode were activated at similar locations compared to monopolar stimulation. This is in agreement with the findings of Holsheimer <italic>et al</italic> [<xref ref-type="bibr" rid="jne434133bib56">56</xref>], who argued that bipolar stimulation with the electrodes at least 10 mm apart is actually bifocal.</p><p>Our model shows that anodal stimulation favours activation of axons running perpendicular to the pial surface, i.e. pyramidal axons (figure <xref ref-type="fig" rid="jne434133f6">6</xref>), which is in agreement with a previous model study on MCS for pain [<xref ref-type="bibr" rid="jne434133bib24">24</xref>]. Cathodal stimulation selectively activates basket cell axons, which run parallel to the pial. This is also in agreement with the study of Manola <italic>et al</italic> [<xref ref-type="bibr" rid="jne434133bib24">24</xref>]. In contrast, our results also show activation of the vertical pyramidal axons (figure <xref ref-type="fig" rid="jne434133f3">3</xref>, blue), which were not activated in Manola's study. This is caused by the inclusion of axon collaterals in the pyramidal axon model.</p></sec><sec id="jne434133s4-4"><label>4.4.</label><title>Model limitations</title><p>In our model, we simulated single pulse stimulation. As the clinical application of MCS encompasses high frequency chronic stimulation, network properties are involved [<xref ref-type="bibr" rid="jne434133bib18">18</xref>]. The final effect of the stimulation depends on parameters such as the number of synaptic contacts and their strengths, as well as the axon density. These parameters are, except for certain axon density parameters [<xref ref-type="bibr" rid="jne434133bib30">30</xref>], not yet sufficiently available. Therefore, we looked at activation fractions of different axonal populations relatively to one another. Second, we used a fixed CSF-layer thickness, while the thickness depends on the brain location and is different per person. This will probably influence model outcomes [<xref ref-type="bibr" rid="jne434133bib21">21</xref>] and it could therefore be included in patient specific models in the future. Third, the axon was modelled without a soma and dendrites, while both influence the axon boundary node. This may have introduced a small difference in the results, especially in the pyramidal axons which have somas close to the electrode contact. Fourth, although the diameters were for a large part based on human data, the ratios between the PT and IT type axon diameters were based on rat data, as no human data was available on this. Finally, the basket cell axons were modelled running parallel to the pial surface in the <italic>xy</italic>-plane, while they also run in <italic>z</italic>-direction (figure <xref ref-type="fig" rid="jne434133f3">3</xref>). This likely has the largest influence on the results of bipolar stimulation parallel to the gyrus, which will probably excite basket cell axons running in <italic>z</italic>-direction relatively more easily. This would provide better selective stimulation of basket cell axons than anticipated in our current model, which is in favour of the hypothesis that these axon type is involved in clinically effective stimulation.</p></sec></sec><sec id="jne434133s5"><label>5.</label><title>Conclusions</title><p>Our computational model predicts that the clinical effect of MCS in the treatment of PD is related to the activation of either the inhibitory basket cell axonal population or the excitatory PT type pyramidal axons. Selective stimulation of the basket cell axonal population can be achieved using cathodal, rather than anodal stimulation. When bipolar stimulation is applied, the electrode strip is preferably placed over the sulcus perpendicular to the gyrus. Furthermore, selective stimulation of the basket cell axons can be increased by the use of multiple cathodes. PT type pyramidal axons can be selectively targeted using anodal stimulation with electrodes having large contact sizes. Epidural stimulation is advisable over subdural stimulation. To further confine which population is involved in the clinical effect of MCS, protocols selectively targeting one of both axonal populations can be tested for their effect on PD. Such selective stimulation protocols could also improve MCS for PD. In conclusion, this study provides more insight into the neuronal population involved in the clinical effect of chronic MCS on PD and proposes strategies to improve this therapy.</p></sec></body><back><ack><title>Acknowledgments</title><p>The authors would like to thank S Canavero for the helpful discussions. The authors gratefully acknowledge the support of the BrainGain in Smart Mix Programme of the Netherlands Ministry of Economic Affairs and the Netherlands Ministry of Education, Culture and Science.</p></ack><app-group id="jne434133app"><app id="jne434133app1"><label>Appendix.</label><p>The axon model [<xref ref-type="bibr" rid="jne434133bib46">46</xref>] at 37 °C.</p><p>Gating variables, with the gating coefficients α and β in s-1 and the membrane potential at the node, <italic>V<sub>n</sub></italic>, in V. <disp-formula id="jne434133ueq1"><tex-math></tex-math><graphic xlink:href="jne434133ueq1.gif"></graphic></disp-formula></p><p>The ionic currents and leakage are in A m<sup>−2</sup>.</p><p><italic>Sodium current</italic><disp-formula id="jne434133ueq2"><tex-math></tex-math><graphic xlink:href="jne434133ueq2.gif"></graphic></disp-formula><disp-formula id="jne434133ueq3"><tex-math></tex-math><graphic xlink:href="jne434133ueq3.gif"></graphic></disp-formula></p><p><italic>Fast potassium current</italic><disp-formula id="jne434133ueq4"><tex-math></tex-math><graphic xlink:href="jne434133ueq4.gif"></graphic></disp-formula></p><p><italic>Slow potassium current</italic><disp-formula id="jne434133ueq5"><tex-math></tex-math><graphic xlink:href="jne434133ueq5.gif"></graphic></disp-formula></p><p><italic>Leakage current</italic><disp-formula id="jne434133ueq6"><tex-math></tex-math><graphic xlink:href="jne434133ueq6.gif"></graphic></disp-formula></p><p>Sodium permeability, <italic>P</italic><sub>Na</sub> = 7.04 · 10<sup>−5</sup> m s<sup>−1</sup></p><p>Sodium ion valency, <italic>z</italic> = 1</p><p>Faraday's constant, <italic>F</italic> = 96485 C mol<sup>−1</sup></p><p>Gas constant, <italic>R</italic> = 8.3144 J K*mol<sup>−1</sup></p><p>Temperature, <italic>T</italic> = 310 K</p><p>Intracellular Na concentration, Na<italic><sub>i</sub></italic> = 18 mM</p><p>Extracellular Na concentration, Na<italic><sub>o</sub></italic> = 154 mM</p><p>Potassium equilibrium potential, <italic>V<sub>k</sub></italic> = −0.0887 V</p><p>Leakage equilibrium potential, <italic>V<sub>L</sub></italic> = −0.084 V</p><p>Fast <italic>K</italic> conductance, <italic>g</italic><sub>Kf</sub> = 300 S m<sup>−2</sup></p><p>Slow <italic>K</italic> conductance, <italic>g</italic><sub>Ks</sub> = 600 S m<sup>−2</sup></p><p>Leak conductance, <italic>g<sub>L</sub></italic> = 400 S m<sup>−2</sup>.</p></app></app-group><ref-list content-type="numerical"><title>References</title><ref id="jne434133bib1"><label>1</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Benabid</surname><given-names>A L</given-names></name></person-group><year>2003</year><article-title>Deep brain stimulation for Parkinson's disease</article-title><source>Curr. Opin. Neurobiol.</source><volume>13</volume><fpage>696</fpage><lpage>706</lpage><page-range>696–706</page-range><pub-id pub-id-type="doi">10.1016/j.conb.2003.11.001</pub-id></element-citation></ref><ref id="jne434133bib2"><label>2</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tsubokawa</surname><given-names>T</given-names></name><name><surname>Katayama</surname><given-names>Y</given-names></name><name><surname>Yamamoto</surname><given-names>T</given-names></name><name><surname>Hirayama</surname><given-names>T</given-names></name><name><surname>Koyama</surname><given-names>S</given-names></name></person-group><year>1991</year><article-title>Treatment of thalamic pain by chronic motor cortex stimulation</article-title><source>PACE-Pacing Clin. Electrophysiol.</source><volume>14</volume><fpage>131</fpage><lpage>134</lpage><page-range>131–4</page-range><pub-id pub-id-type="doi">10.1111/j.1540-8159.1991.tb04058.x</pub-id></element-citation></ref><ref id="jne434133bib3"><label>3</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Pagni</surname><given-names>C A</given-names></name><etal></etal></person-group><year>2005</year><article-title>Extradural motor cortex stimulation (EMCS) for Parkinson's disease. History and first results by the study group of the Italian neurosurgical society</article-title><source>Acta Neurochir.</source><volume>S93</volume><fpage>113</fpage><lpage>119</lpage><page-range>113–9</page-range><pub-id pub-id-type="doi">10.1007/3-211-27577-0</pub-id></element-citation></ref><ref id="jne434133bib4"><label>4</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cioni</surname><given-names>B</given-names></name></person-group><year>2007</year><article-title>Motor cortex stimulation for Parkinson's disease</article-title><source>Acta Neurochir.</source><volume>S97</volume><fpage>233</fpage><lpage>238</lpage><page-range>233–8</page-range><pub-id pub-id-type="doi">10.1007/978-3-211-33081-4</pub-id></element-citation></ref><ref id="jne434133bib5"><label>5</label><element-citation publication-type="book"><person-group person-group-type="author"><name><surname>Cioni</surname><given-names>B</given-names></name><name><surname>Bentivoglio</surname><given-names>A</given-names></name><name><surname>De Simone</surname><given-names>C</given-names></name><name><surname>Fasano</surname><given-names>A</given-names></name><name><surname>Piano</surname><given-names>C</given-names></name><name><surname>Policicchio</surname><given-names>D</given-names></name><name><surname>Perotti</surname><given-names>V</given-names></name><name><surname>Meglio</surname><given-names>M</given-names></name></person-group><year>2009</year><source>Invasive Cortical Stimulation for Parkinson's Disease and Movement Disordered</source><person-group person-group-type="editor"><name><surname>Canavero</surname><given-names>S</given-names></name></person-group><publisher-loc>New York</publisher-loc><publisher-name>Nova Science</publisher-name></element-citation></ref><ref id="jne434133bib6"><label>6</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Canavero</surname><given-names>S</given-names></name><name><surname>Paolotti</surname><given-names>R</given-names></name></person-group><year>2000</year><article-title>Extradural motor cortex stimulation for advanced Parkinson's disease: case report</article-title><source>Mov. Disord.</source><volume>15</volume><fpage>169</fpage><lpage>171</lpage><page-range>169–71</page-range><pub-id pub-id-type="doi">10.1002/1531-8257(200001)15:1<169::AID-MDS1030>3.0.CO;2-W</pub-id></element-citation></ref><ref id="jne434133bib7"><label>7</label><element-citation publication-type="book"><person-group person-group-type="author"><name><surname>Meglio</surname><given-names>M</given-names></name><name><surname>Cioni</surname><given-names>B</given-names></name></person-group><year>2009</year><source>Textbook of Stereotactic and Functional Neurosurgery</source><volume>vol 7</volume><person-group person-group-type="editor"><name><surname>Lozano</surname><given-names>A M</given-names></name><etal></etal></person-group><publisher-loc>Berlin</publisher-loc><publisher-name>Springer</publisher-name><fpage>1679</fpage><lpage>1690</lpage><page-range>pp 1679–90</page-range><pub-id pub-id-type="doi">10.1007/978-3-540-69960-6</pub-id></element-citation></ref><ref id="jne434133bib8"><label>8</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Drouot</surname><given-names>X</given-names></name><etal></etal></person-group><year>2004</year><article-title>Functional recovery in a primate model of Parkinson's disease following motor cortex stimulation</article-title><source>Neuron</source><volume>44</volume><fpage>769</fpage><lpage>778</lpage><page-range>769–78</page-range><pub-id pub-id-type="doi">10.1016/j.neuron.2004.11.023</pub-id></element-citation></ref><ref id="jne434133bib9"><label>9</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Fasano</surname><given-names>A</given-names></name><name><surname>Piano</surname><given-names>C</given-names></name><name><surname>De Simone</surname><given-names>C</given-names></name><name><surname>Cioni</surname><given-names>B</given-names></name><name><surname>Di Giuda</surname><given-names>D</given-names></name><name><surname>Zinno</surname><given-names>M</given-names></name><name><surname>Daniele</surname><given-names>A</given-names></name><name><surname>Meglio</surname><given-names>M</given-names></name><name><surname>Giordano</surname><given-names>A</given-names></name><name><surname>Bentivoglio</surname><given-names>A</given-names></name></person-group><year>2008</year><article-title>High frequency extradural motor cortex stimulation transiently improves axial symptoms in a patient with Parkinson's disease</article-title><source>Mov. Disord.</source><volume>23</volume><fpage>1916</fpage><lpage>1919</lpage><page-range>1916–9</page-range><pub-id pub-id-type="doi">10.1002/mds.21977</pub-id></element-citation></ref><ref id="jne434133bib10"><label>10</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Arle</surname><given-names>J E</given-names></name><name><surname>Apetauerova</surname><given-names>D</given-names></name><name><surname>Zani</surname><given-names>J</given-names></name><name><surname>Deletis</surname><given-names>D V</given-names></name><name><surname>Penney</surname><given-names>D L</given-names></name><name><surname>Hoit</surname><given-names>D</given-names></name><name><surname>Gould</surname><given-names>C</given-names></name><name><surname>Shils</surname><given-names>J L</given-names></name></person-group><year>2008</year><article-title>Motor cortex stimulation in patients with Parkinson disease: 12-month follow-up in 4 patients</article-title><source>J. Neurosurg.</source><volume>109</volume><fpage>133</fpage><lpage>139</lpage><page-range>133–9</page-range><pub-id pub-id-type="doi">10.3171/JNS/2008/109/7/0133</pub-id></element-citation></ref><ref id="jne434133bib11"><label>11</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gutierrez</surname><given-names>J C</given-names></name><name><surname>Seijo</surname><given-names>F J</given-names></name><name><surname>Alcarez Vega</surname><given-names>M A</given-names></name><name><surname>Fernandez Gonzalez</surname><given-names>F</given-names></name><name><surname>Lozano Aragoneses</surname><given-names>B</given-names></name><name><surname>Blazquez</surname><given-names>M</given-names></name></person-group><year>2009</year><article-title>Therapeutic extradural cortical stimulation for Parkinson's disease: report of six cases and review of the literature</article-title><source>Clin. Neurol. Neurosurg.</source><volume>111</volume><fpage>703</fpage><lpage>707</lpage><page-range>703–7</page-range><pub-id pub-id-type="doi">10.1016/j.clineuro.2009.06.006</pub-id></element-citation></ref><ref id="jne434133bib12"><label>12</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Arle</surname><given-names>J E</given-names></name><name><surname>Shils</surname><given-names>J L</given-names></name></person-group><year>2008</year><article-title>Motor cortex stimulation for pain and movement disorders</article-title><source>Neurotherapeutics</source><volume>5</volume><fpage>37</fpage><lpage>49</lpage><page-range>37–49</page-range><pub-id pub-id-type="doi">10.1016/j.nurt.2007.11.004</pub-id></element-citation></ref><ref id="jne434133bib13"><label>13</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cioni</surname><given-names>B</given-names></name><name><surname>Meglio</surname><given-names>M</given-names></name><name><surname>Perotti</surname><given-names>V</given-names></name><name><surname>De Bonis</surname><given-names>P</given-names></name><name><surname>Montano</surname><given-names>N</given-names></name></person-group><year>2007</year><article-title>Neurophysiological aspect of chronic motor cortex stimulation</article-title><source>Clin. Neurophysiol.</source><volume>37</volume><fpage>441</fpage><lpage>447</lpage><page-range>441–7</page-range><pub-id pub-id-type="doi">10.1016/j.neucli.2007.10.007</pub-id></element-citation></ref><ref id="jne434133bib14"><label>14</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Giuffrida</surname><given-names>R</given-names></name><name><surname>Li Volsi</surname><given-names>G</given-names></name><name><surname>Maugeri</surname><given-names>G</given-names></name><name><surname>Percivalle</surname><given-names>V</given-names></name></person-group><year>1985</year><article-title>Influences of pyramidal tract on the subthalamic nucleus in the subthalamic nucleus of the cat</article-title><source>Neurosci. Lett.</source><volume>54</volume><fpage>231</fpage><lpage>235</lpage><page-range>231–5</page-range><pub-id pub-id-type="doi">10.1016/S0304-3940(85)80084-7</pub-id></element-citation></ref><ref id="jne434133bib15"><label>15</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mathai</surname><given-names>A</given-names></name><name><surname>Smith</surname><given-names>S</given-names></name></person-group><year>2011</year><article-title>The corticostriatal and corticosubthalamic pathways: two entries, one target. So what?</article-title><source>Front. Syst. Neurosci.</source><volume>5</volume><fpage>64</fpage><pub-id pub-id-type="doi">10.3389/fnsys.2011.00064</pub-id></element-citation></ref><ref id="jne434133bib16"><label>16</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ballion</surname><given-names>B</given-names></name><name><surname>Mallet</surname><given-names>N</given-names></name><name><surname>Bézard</surname><given-names>E</given-names></name><name><surname>Lanciego</surname><given-names>J L</given-names></name><name><surname>Gonon</surname><given-names>F</given-names></name></person-group><year>2008</year><article-title>Intratelencephalic corticostriatal neurons equally excite striatonigral and striatopallidal neurons and their discharge activity is selectively reduced in experimental parkinsonism</article-title><source>Eur. J. Neurosci.</source><volume>27</volume><fpage>2313</fpage><lpage>2321</lpage><page-range>2313–21</page-range><pub-id pub-id-type="doi">10.1111/j.1460-9568.2008.06192.x</pub-id></element-citation></ref><ref id="jne434133bib17"><label>17</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Takada</surname><given-names>M</given-names></name><name><surname>Tokuno</surname><given-names>H</given-names></name><name><surname>Nambu</surname><given-names>A</given-names></name><name><surname>Inase</surname><given-names>M</given-names></name></person-group><year>1998</year><article-title>Corticostriatal projections from the somatic motor areas of the frontal cortex in the macaque monkey: segregation versus overlap of input zones from the primary motor cortex, the supplementary motor area, and the premotor cortex</article-title><source>Exp. Brain Res.</source><volume>120</volume><fpage>114</fpage><lpage>128</lpage><page-range>114–28</page-range><pub-id pub-id-type="doi">10.1007/s002210050384</pub-id></element-citation></ref><ref id="jne434133bib18"><label>18</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hanajima</surname><given-names>R</given-names></name><name><surname>Ashby</surname><given-names>P</given-names></name><name><surname>Lang</surname><given-names>A E</given-names></name><name><surname>Lozano</surname><given-names>A M</given-names></name></person-group><year>2002</year><article-title>Effects of acute stimulation through contacts placed on the motor cortex for chronic stimulation</article-title><source>Clin. Neurophysiol.</source><volume>113</volume><fpage>635</fpage><lpage>641</lpage><page-range>635–41</page-range><pub-id pub-id-type="doi">10.1016/S1388-2457(02)00042-1</pub-id></element-citation></ref><ref id="jne434133bib19"><label>19</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Nieuwenhuys</surname><given-names>R</given-names></name></person-group><year>1994</year><article-title>The neocortex. An overview of its evolutionary development, structural organization and synaptology</article-title><source>Anat. Embryol.</source><volume>190</volume><fpage>307</fpage><lpage>337</lpage><page-range>307–37</page-range><pub-id pub-id-type="doi">10.1007/BF00187291</pub-id></element-citation></ref><ref id="jne434133bib20"><label>20</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Manola</surname><given-names>L</given-names></name><name><surname>Holsheimer</surname><given-names>J</given-names></name></person-group><year>2007</year><article-title>Motor cortex stimulation: role of computer modelling</article-title><source>Acta Neurochir.</source><volume>S97</volume><fpage>497</fpage><lpage>503</lpage><page-range>497–503</page-range><pub-id pub-id-type="doi">10.1007/978-3-211-33081-4</pub-id></element-citation></ref><ref id="jne434133bib21"><label>21</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Manola</surname><given-names>L</given-names></name><name><surname>Roelofsen</surname><given-names>B H</given-names></name><name><surname>Holsheimer</surname><given-names>J</given-names></name><name><surname>Marani</surname><given-names>E</given-names></name><name><surname>Geelen</surname><given-names>J A</given-names></name></person-group><year>2005</year><article-title>Modelling motor cortex stimulation for chronic pain control: electrical potential field, activating functions and responses of simple nerve fibre models</article-title><source>Med. Biol. Eng. Comput.</source><volume>43</volume><fpage>335</fpage><lpage>343</lpage><page-range>335–43</page-range><pub-id pub-id-type="doi">10.1007/BF02345810</pub-id></element-citation></ref><ref id="jne434133bib22"><label>22</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Silva</surname><given-names>S</given-names></name><name><surname>Basser</surname><given-names>P J</given-names></name><name><surname>Miranda</surname><given-names>P C</given-names></name></person-group><year>2008</year><article-title>Elucidating the mechanisms and loci of neuronal excitation of transcranial magnetic stimulation using a finite element model of cortical sulcus</article-title><source>Clin. Neurophysiol.</source><volume>119</volume><fpage>2405</fpage><lpage>2413</lpage><page-range>2405–13</page-range><pub-id pub-id-type="doi">10.1016/j.clinph.2008.07.248</pub-id></element-citation></ref><ref id="jne434133bib23"><label>23</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wongsarnpigoon</surname><given-names>A</given-names></name><name><surname>Grill</surname><given-names>W M</given-names></name></person-group><year>2008</year><article-title>Computational modeling of epidural cortical stimulation</article-title><source>J. Neural Eng.</source><volume>5</volume><fpage>443</fpage><lpage>454</lpage><page-range>443–54</page-range><pub-id pub-id-type="doi">10.1088/1741-2560/5/4/009</pub-id></element-citation></ref><ref id="jne434133bib24"><label>24</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Manola</surname><given-names>L</given-names></name><name><surname>Holsheimer</surname><given-names>J</given-names></name><name><surname>Veltink</surname><given-names>P H</given-names></name><name><surname>Buitenweg</surname><given-names>J R</given-names></name></person-group><year>2007</year><article-title>Anodal vs cathodal stimulation of motor cortex: a modeling study</article-title><source>Clin. Neurophysiol.</source><volume>118</volume><fpage>464</fpage><lpage>474</lpage><page-range>464–74</page-range><pub-id pub-id-type="doi">10.1016/j.clinph.2006.09.012</pub-id></element-citation></ref><ref id="jne434133bib25"><label>25</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wongsarnpigoon</surname><given-names>A</given-names></name><name><surname>Grill</surname><given-names>W M</given-names></name></person-group><year>2012</year><article-title>Computer-based model of epidural motor cortex stimulation: effects of electrode position and geometry on activation of cortical neurons</article-title><source>Clin. Neurophysiol.</source><volume>123</volume><fpage>160</fpage><lpage>172</lpage><page-range>160–72</page-range><pub-id pub-id-type="doi">10.1016/j.clinph.2011.06.005</pub-id></element-citation></ref><ref id="jne434133bib26"><label>26</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>McIntyre</surname><given-names>C C</given-names></name><name><surname>Mori</surname><given-names>S</given-names></name><name><surname>Sherman</surname><given-names>D L</given-names></name><name><surname>Thakor</surname><given-names>N V</given-names></name><name><surname>Vitek</surname><given-names>J L</given-names></name></person-group><year>2004</year><article-title>Electric field and stimulating influence generated by deep brain stimulation of the subthalamic nucleus</article-title><source>Clin. Neurophysiol.</source><volume>115</volume><fpage>589</fpage><lpage>595</lpage><page-range>589–95</page-range><pub-id pub-id-type="doi">10.1016/j.clinph.2003.10.033</pub-id></element-citation></ref><ref id="jne434133bib27"><label>27</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sotiropoulos</surname><given-names>S N</given-names></name><name><surname>Steinmetz</surname><given-names>P N</given-names></name></person-group><year>2007</year><article-title>Assessing the direct effects of deep brain stimulation using embedded axon models</article-title><source>J. Neural Eng.</source><volume>4</volume><fpage>107</fpage><lpage>119</lpage><page-range>107–19</page-range><pub-id pub-id-type="doi">10.1088/1741-2560/4/2/011</pub-id></element-citation></ref><ref id="jne434133bib28"><label>28</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Butson</surname><given-names>C R</given-names></name><name><surname>McIntyre</surname><given-names>C C</given-names></name></person-group><year>2008</year><article-title>Current steering to control the volume of tissue activated during deep brain stimulation</article-title><source>Brain Stimul.</source><volume>1</volume><fpage>7</fpage><lpage>15</lpage><page-range>7–15</page-range><pub-id pub-id-type="doi">10.1016/j.brs.2007.08.004</pub-id></element-citation></ref><ref id="jne434133bib29"><label>29</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Frankemolle</surname><given-names>A M M</given-names></name><name><surname>Wu</surname><given-names>J</given-names></name><name><surname>Noecker</surname><given-names>A M</given-names></name></person-group><year>2010</year><article-title>Reversing cognitive-motor impairments in Parkinson's disease patients using a computational modelling approach to deep brain stimulation programming</article-title><source>Brain</source><volume>133</volume><fpage>746</fpage><lpage>761</lpage><page-range>746–61</page-range><pub-id pub-id-type="doi">10.1093/brain/awp315</pub-id></element-citation></ref><ref id="jne434133bib30"><label>30</label><element-citation publication-type="communication"><person-group person-group-type="author"><name><surname>Feirabend</surname><given-names>H K P</given-names></name><etal></etal></person-group><year>2011</year><comment>personal communication</comment></element-citation></ref><ref id="jne434133bib31"><label>31</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Salvador</surname><given-names>R</given-names></name><name><surname>Silva</surname><given-names>S</given-names></name><name><surname>Basser</surname><given-names>P J</given-names></name><name><surname>Miranda</surname><given-names>P C</given-names></name></person-group><year>2011</year><article-title>Determining which mechanisms lead to activation in the motor cortex: a modeling study of transcranial magnetic stimulation using realistic stimulus waveforms and sulcal geometry</article-title><source>Clin. Neurophysiol.</source><volume>122</volume><fpage>748</fpage><lpage>758</lpage><page-range>748–58</page-range><pub-id pub-id-type="doi">10.1016/j.clinph.2010.09.022</pub-id></element-citation></ref><ref id="jne434133bib32"><label>32</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Janssen</surname><given-names>M L F</given-names></name><name><surname>Zwartjes</surname><given-names>D G M</given-names></name><name><surname>Temel</surname><given-names>Y</given-names></name><name><surname>Van Kranen-Mastenbroek</surname><given-names>V</given-names></name><name><surname>Duits</surname><given-names>A</given-names></name><name><surname>Bour</surname><given-names>L J</given-names></name><name><surname>Veltink</surname><given-names>P H</given-names></name><name><surname>Heida</surname><given-names>T</given-names></name><name><surname>Visser-Vandewalle</surname><given-names>V</given-names></name></person-group><year>2012</year><article-title>Subthalamic neuronal responses to cortical stimulation</article-title><source>Mov. Disord.</source><volume>27</volume><fpage>435</fpage><lpage>438</lpage><page-range>435–8</page-range><pub-id pub-id-type="doi">10.1002/mds.24053</pub-id></element-citation></ref><ref id="jne434133bib33"><label>33</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Nishibayashi</surname><given-names>H</given-names></name><name><surname>Ogura</surname><given-names>M</given-names></name><name><surname>Kakishita</surname><given-names>K</given-names></name><name><surname>Tanaka</surname><given-names>S</given-names></name><name><surname>Tachibana</surname><given-names>Y</given-names></name><name><surname>Nambu</surname><given-names>A</given-names></name><name><surname>Kita</surname><given-names>H</given-names></name><name><surname>Itakura</surname><given-names>T</given-names></name></person-group><year>2011</year><article-title>Cortically evoked responses of human pallidal neurons recorded during stereotactic surgery</article-title><source>Mov. Disord.</source><volume>26</volume><fpage>469</fpage><lpage>476</lpage><page-range>469–76</page-range><pub-id pub-id-type="doi">10.1002/mds.23502</pub-id></element-citation></ref><ref id="jne434133bib34"><label>34</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Reiner</surname><given-names>A</given-names></name><name><surname>Jiao</surname><given-names>Y</given-names></name><name><surname>Del Mar</surname><given-names>N</given-names></name><name><surname>Laverghettam</surname><given-names>A V</given-names></name><name><surname>Lei</surname><given-names>W</given-names></name></person-group><year>2003</year><article-title>Differential morphology of pyramidal tract-type and intratelencephalically projecting-type corticostriatal neurons and their intrastriatal terminals in rat</article-title><source>J. Comp. Neurol.</source><volume>457</volume><fpage>420</fpage><lpage>440</lpage><page-range>420–40</page-range><pub-id pub-id-type="doi">10.1002/cne.10541</pub-id></element-citation></ref><ref id="jne434133bib35"><label>35</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Plonsey</surname><given-names>R</given-names></name><name><surname>Heppner</surname><given-names>D B</given-names></name></person-group><year>1967</year><article-title>Considerations of quasi-stationarity in electrophysiological systems</article-title><source>Bull. Math. Biophys.</source><volume>29</volume><fpage>657</fpage><lpage>664</lpage><page-range>657–64</page-range><pub-id pub-id-type="doi">10.1007/BF02476917</pub-id></element-citation></ref><ref id="jne434133bib36"><label>36</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Grant</surname><given-names>P F</given-names></name><name><surname>Lowery</surname><given-names>M M</given-names></name></person-group><year>2009</year><article-title>Electric field distribution in a finite-volume head model of deep brain stimulation</article-title><source>Med. Eng. Phys.</source><volume>31</volume><fpage>1095</fpage><lpage>1103</lpage><page-range>1095–103</page-range><pub-id pub-id-type="doi">10.1016/j.medengphy.2009.07.006</pub-id></element-citation></ref><ref id="jne434133bib37"><label>37</label><element-citation publication-type="book"><article-title>International Commission of Radiological Protection 1975</article-title><source>Report of the Task Group on Reference Man</source><volume>vol 23</volume><publisher-loc>London</publisher-loc><publisher-name>Pergamon</publisher-name></element-citation></ref><ref id="jne434133bib38"><label>38</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Scheufler</surname><given-names>O</given-names></name><name><surname>Kania</surname><given-names>N M</given-names></name><name><surname>Heinrichs</surname><given-names>C M</given-names></name><name><surname>Exner</surname><given-names>K</given-names></name></person-group><year>2003</year><article-title>Hyperplasia of the subcutaneous adipose tissue is the primary histopathologic abnormality in lipedematous scalp</article-title><source>Am. J. Dermatopathol.</source><volume>25</volume><fpage>248</fpage><lpage>252</lpage><page-range>248–52</page-range><pub-id pub-id-type="doi">10.1097/00000372-200306000-00010</pub-id></element-citation></ref><ref id="jne434133bib39"><label>39</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gabriel</surname><given-names>S</given-names></name><name><surname>Lau</surname><given-names>R W</given-names></name><name><surname>Gabriel</surname><given-names>C</given-names></name></person-group><year>1996</year><article-title>The dielectric properties of biological tissues: III. Parametric models for the dielectric spectrum of tissues</article-title><source>Phys. Med. Biol.</source><volume>41</volume><fpage>2271</fpage><lpage>2293</lpage><page-range>2271–93</page-range><pub-id pub-id-type="doi">10.1088/0031-9155/41/11/003</pub-id></element-citation></ref><ref id="jne434133bib40"><label>40</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Baumann</surname><given-names>S B</given-names></name><name><surname>Wozny</surname><given-names>D R</given-names></name><name><surname>Kelly</surname><given-names>S K</given-names></name><name><surname>Meno</surname><given-names>F M</given-names></name></person-group><year>1997</year><article-title>The electrical conductivity of human cerebrospinal fluid at body temperature</article-title><source>IEEE Trans. Biomed. Eng.</source><volume>44</volume><fpage>220</fpage><lpage>223</lpage><page-range>220–3</page-range><pub-id pub-id-type="doi">10.1109/10.554770</pub-id></element-citation></ref><ref id="jne434133bib41"><label>41</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ranck</surname><given-names>J B</given-names></name><name><surname>BeMent</surname><given-names>S L</given-names></name></person-group><year>1965</year><article-title>The specific impedance of the dorsal columns of the cat: an anisotropic medium</article-title><source>Exp. Neurol.</source><volume>11</volume><fpage>451</fpage><lpage>463</lpage><page-range>451–63</page-range><pub-id pub-id-type="doi">10.1016/0014-4886(65)90059-2</pub-id></element-citation></ref><ref id="jne434133bib42"><label>42</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Nowak</surname><given-names>L G</given-names></name><name><surname>Bullier</surname><given-names>J</given-names></name></person-group><year>1998</year><article-title>Axons, but not cell bodies, are activated by electrical stimulation in cortical gray matter I. Evidence from chronaxie measurements</article-title><source>Exp. Brain Res.</source><volume>118</volume><fpage>477</fpage><lpage>488</lpage><page-range>477–88</page-range><pub-id pub-id-type="doi">10.1007/s002210050304</pub-id></element-citation></ref><ref id="jne434133bib43"><label>43</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Nowak</surname><given-names>L G</given-names></name><name><surname>Bullier</surname><given-names>J</given-names></name></person-group><year>1998</year><article-title>Axons, but not cell bodies, are activated by electrical stimulation in cortical gray matter: II. Evidence from selective inactivation of cell bodies and axon initial segments</article-title><source>Exp. Brain Res.</source><volume>118</volume><fpage>489</fpage><lpage>500</lpage><page-range>489–500</page-range><pub-id pub-id-type="doi">10.1007/s002210050305</pub-id></element-citation></ref><ref id="jne434133bib44"><label>44</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>McNeal</surname><given-names>D R</given-names></name></person-group><year>1976</year><article-title>Analysis of a model for excitation of myelinated nerve</article-title><source>IEEE Trans. Biomed. Eng.</source><volume>BME-23</volume><fpage>329</fpage><lpage>337</lpage><page-range>329–37</page-range><pub-id pub-id-type="doi">10.1109/TBME.1976.324593</pub-id></element-citation></ref><ref id="jne434133bib45"><label>45</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Richardson</surname><given-names>A G</given-names></name><name><surname>McIntyre</surname><given-names>C C</given-names></name><name><surname>Grill</surname><given-names>W M</given-names></name></person-group><year>2000</year><article-title>Modeling the effects of electric fields on nerve fibres: influence of the myelin sheath</article-title><source>Med. Biol. Eng. Comput. <named-content content-type="jnl-part">07-2000</named-content></source><volume>38</volume><fpage>438</fpage><lpage>446</lpage><page-range>438–46</page-range><pub-id pub-id-type="doi">10.1007/BF02345014</pub-id></element-citation></ref><ref id="jne434133bib46"><label>46</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Schwarz</surname><given-names>J R</given-names></name><name><surname>Reid</surname><given-names>G</given-names></name><name><surname>Bostock</surname><given-names>H</given-names></name></person-group><year>1995</year><article-title>Action potentials and membrane currents in the human node of Ranvier</article-title><source>Pflugers Arch.</source><volume>430</volume><fpage>283</fpage><lpage>292</lpage><page-range>283–92</page-range><pub-id pub-id-type="doi">10.1007/BF00374660</pub-id></element-citation></ref><ref id="jne434133bib47"><label>47</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Foster</surname><given-names>K R</given-names></name><name><surname>Bidinger</surname><given-names>J M</given-names></name><name><surname>Carpenter</surname><given-names>D O</given-names></name></person-group><year>1976</year><article-title>The electrical resistivity of cytoplasm</article-title><source>Biophys. J.</source><volume>16</volume><fpage>991</fpage><lpage>1001</lpage><page-range>991–1001</page-range><pub-id pub-id-type="doi">10.1016/S0006-3495(76)85750-5</pub-id></element-citation></ref><ref id="jne434133bib48"><label>48</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wesselink</surname><given-names>W A</given-names></name><name><surname>Holsheimer</surname><given-names>J</given-names></name><name><surname>Boom</surname><given-names>H B K</given-names></name></person-group><year>1999</year><article-title>A model of the electrical behaviour of myelinated sensory nerve fibres based on human data</article-title><source>Med. Biol. Eng. Comput.</source><volume>37</volume><fpage>228</fpage><lpage>235</lpage><page-range>228–35</page-range><pub-id pub-id-type="doi">10.1007/BF02513291</pub-id></element-citation></ref><ref id="jne434133bib49"><label>49</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Huxley</surname><given-names>A F</given-names></name><name><surname>Stämpfli</surname><given-names>R</given-names></name></person-group><year>1949</year><article-title>Evidence for saltatory conduction in peripheral myelinated nerve fibers</article-title><source>J. Physiol.</source><volume>108</volume><fpage>315</fpage><lpage>339</lpage><page-range>315–39</page-range></element-citation></ref><ref id="jne434133bib50"><label>50</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lei</surname><given-names>W</given-names></name><name><surname>Jiao</surname><given-names>Y</given-names></name><name><surname>Del Mar</surname><given-names>N</given-names></name><name><surname>Reiner</surname><given-names>A</given-names></name></person-group><year>2004</year><article-title>Evidence for differential cortical input to direct pathway versus indirect pathway striatal projection neurons in rats</article-title><source>J. Neurosci.</source><volume>24</volume><fpage>8289</fpage><lpage>8299</lpage><page-range>8289–99</page-range><pub-id pub-id-type="doi">10.1523/JNEUROSCI.1990-04.2004</pub-id></element-citation></ref><ref id="jne434133bib51"><label>51</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sloper</surname><given-names>J J</given-names></name><name><surname>Powell</surname><given-names>T P S</given-names></name></person-group><year>1979</year><article-title>A study of the axon initial segment and proximal axon of neurons in the primate motor and somatic sensory cortices</article-title><source>Phil. Trans. R. Soc. Lond. <named-content content-type="jnl-part">B</named-content> Bio. Sci.</source><volume>285</volume><fpage>173</fpage><lpage>197</lpage><page-range>173–97</page-range><pub-id pub-id-type="doi">10.1098/rstb.1979.0004</pub-id></element-citation></ref><ref id="jne434133bib52"><label>52</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lefaucheur</surname><given-names>J P</given-names></name><name><surname>Holsheimer</surname><given-names>J</given-names></name><name><surname>Goujon</surname><given-names>C</given-names></name><name><surname>Keravel</surname><given-names>Y</given-names></name><name><surname>Nguyen</surname><given-names>J</given-names></name></person-group><year>2010</year><article-title>Descending volleys generated by efficacious epidural motor cortex stimulation in patients with chronic neuropathic pain</article-title><source>Exp. Neurol.</source><volume>223</volume><fpage>609</fpage><lpage>614</lpage><page-range>609–14</page-range><pub-id pub-id-type="doi">10.1016/j.expneurol.2010.02.008</pub-id></element-citation></ref><ref id="jne434133bib53"><label>53</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>McIntyre</surname><given-names>C C</given-names></name><name><surname>Hahn</surname><given-names>P J</given-names></name></person-group><year>2010</year><article-title>Network perspectives on the mechanisms of deep brain stimulation</article-title><source>Neurobiol. Dis.</source><volume>38</volume><fpage>329</fpage><lpage>337</lpage><page-range>329–37</page-range><pub-id pub-id-type="doi">10.1016/j.nbd.2009.09.022</pub-id></element-citation></ref><ref id="jne434133bib54"><label>54</label><element-citation publication-type="book"><person-group person-group-type="author"><name><surname>Fahn</surname><given-names>S</given-names></name><name><surname>Elton</surname><given-names>R L</given-names></name></person-group><year>1987</year><source>Recent Developments in Parkinson's Disease</source><person-group person-group-type="editor"><name><surname>Fahn</surname><given-names>S</given-names></name><name><surname>Marsden</surname><given-names>C D</given-names></name><etal></etal></person-group><publisher-loc>New York</publisher-loc><publisher-name>Macmillan</publisher-name><fpage>153</fpage><lpage>164</lpage><page-range>pp 153–64</page-range></element-citation></ref><ref id="jne434133bib55"><label>55</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zwartjes</surname><given-names>D G M</given-names></name><name><surname>Heida</surname><given-names>T</given-names></name><name><surname>van Vugt</surname><given-names>J P</given-names></name><name><surname>Geelen</surname><given-names>J A</given-names></name><name><surname>Veltink</surname><given-names>P H</given-names></name></person-group><year>2010</year><article-title>Ambulatory monitoring of activities and motor symptoms in Parkinson's disease</article-title><source>IEEE Trans. Biomed. Eng.</source><volume>57</volume><fpage>2778</fpage><lpage>2786</lpage><page-range>2778–86</page-range><pub-id pub-id-type="doi">10.1109/TBME.2010.2049573</pub-id></element-citation></ref><ref id="jne434133bib56"><label>56</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Holsheimer</surname><given-names>J</given-names></name><name><surname>Nguyen</surname><given-names>J</given-names></name><name><surname>Lefaucheur</surname><given-names>J P</given-names></name><name><surname>Manola</surname><given-names>L</given-names></name></person-group><year>2007</year><article-title>Cathodal, anodal or bifocal stimulation of the motor cortex in the management of chronic pain?</article-title><source>Acta Neurochir.</source><volume>S97</volume><fpage>57</fpage><lpage>66</lpage><page-range>57–66</page-range><pub-id pub-id-type="doi">10.1007/978-3-211-33081-4</pub-id></element-citation></ref></ref-list></back></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Motor cortex stimulation for Parkinson's disease: a modelling study</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Motor cortex stimulation for Parkinson's disease: a modelling study</title></titleInfo><name type="personal"><namePart type="given">Daphne G M</namePart><namePart type="family">Zwartjes</namePart><affiliation>MIRA Institute for Biomedical Engineering and Technical Medicine, Biomedical Signals and Systems Group, University of Twente, Enschede, The Netherlands</affiliation><affiliation>E-mail: d.g.m.zwartjes@utwente.nl</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Tjitske</namePart><namePart type="family">Heida</namePart><affiliation>MIRA Institute for Biomedical Engineering and Technical Medicine, Biomedical Signals and Systems Group, University of Twente, Enschede, The Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Hans K P</namePart><namePart type="family">Feirabend</namePart><affiliation>Department of Anatomy & Embryology, Leiden University Medical Center, The Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Marcus L F</namePart><namePart type="family">Janssen</namePart><affiliation>Department of Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands</affiliation><affiliation>European Graduate School of Neuroscience (EURON), Maastricht, The Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Veerle</namePart><namePart type="family">Visser-Vandewalle</namePart><affiliation>Department of Neurosurgery, Maastricht University Medical Center, Maastricht, The Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Hubert C F</namePart><namePart type="family">Martens</namePart><affiliation>SapiensSteering Brain Stimulation, Eindhoven, The Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Peter H</namePart><namePart type="family">Veltink</namePart><affiliation>MIRA Institute for Biomedical Engineering and Technical Medicine, Biomedical Signals and Systems Group, University of Twente, Enschede, The Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><subject><genre>article-type</genre><topic>Paper</topic></subject><originInfo><publisher>IOP Publishing</publisher><dateIssued encoding="w3cdtf">2012-10</dateIssued><dateCreated encoding="w3cdtf">2012-08-10</dateCreated><copyrightDate encoding="w3cdtf">2012</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>Chronic motor cortex stimulation (MCS) is currently being investigated as a treatment method for Parkinson's disease (PD). Unfortunately, the underlying mechanisms of this treatment are unclear and there are many uncertainties regarding the most effective stimulation parameters and electrode configuration. In this paper, we present a MCS model with a 3D representation of several axonal populations. The model predicts that the activation of either the basket cell or pyramidal tract (PT) type axons is involved in the clinical effect of MCS. We propose stimulation protocols selectively targeting one of these two axon types. To selectively target the basket cell axons, our simulations suggest using either cathodal or bipolar stimulation with the electrode strip placed perpendicular rather than parallel to the gyrus. Furthermore, selectivity can be increased by using multiple cathodes. PT type axons can be selectively targeted with anodal stimulation using electrodes with large contact sizes. Placing the electrode epidurally is advisable over subdural placement. These selective protocols, when practically implemented, can be used to further test which axon type should be activated for clinically effective MCS and can subsequently be applied to optimize treatment. In conclusion, this paper increases insight into the neuronal population involved in the clinical effect of MCS on PD and proposes strategies to improve this therapy.</abstract><subject><genre>author-pacs</genre><topic>87.80.y</topic><topic>87.19.X</topic><topic>87.19.L</topic><topic>02.70.Dh</topic><topic>87.19.R</topic></subject><subject><genre>Keywords</genre><topic>motor cortex stimulation</topic><topic>Parkinson's disease</topic><topic>model</topic><topic>pyramidal neurons</topic><topic>basket cells</topic></subject><relatedItem type="host"><titleInfo><title>Journal of Neural Engineering</title></titleInfo><genre type="Journal">journal</genre><identifier type="ISSN">1741-2560</identifier><identifier type="eISSN">1741-2552</identifier><identifier type="PublisherID">jne</identifier><part><date>2012</date><detail type="volume"><caption>vol.</caption><number>9</number></detail><detail type="issue"><caption>no.</caption><number>5</number></detail><extent unit="pages"><total>12</total></extent></part></relatedItem><identifier type="istex">586106634EA3ADCD5B24A82FE916C9425CB3F011</identifier><identifier type="DOI">10.1088/1741-2560/9/5/056005</identifier><identifier type="href">http://stacks.iop.org/JNE/9/056005</identifier><identifier type="ArticleID">jne434133</identifier><accessCondition type="use and reproduction" contentType="copyright">2012 IOP Publishing Ltd</accessCondition><recordInfo><recordContentSource>IOP</recordContentSource></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Sante/explor/ParkinsonV1/Data/Main/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000D90 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Corpus/biblio.hfd -nk 000D90 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Sante
|area= ParkinsonV1
|flux= Main
|étape= Corpus
|type= RBID
|clé= ISTEX:586106634EA3ADCD5B24A82FE916C9425CB3F011
|texte= Motor cortex stimulation for Parkinson's disease: a modelling study
}}
| This area was generated with Dilib version V0.6.23. |  |