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<meta name="DC.Title" content="Functional MRI Shows Altered Deactivation and a Corresponding Decrease in Functional Connectivity of the Default Mode Network in Patients with Gliomas" />
<meta name="DC.Identifier" content="10.3174/ajnr.A7138" />
<meta name="DC.Date" content="2021-08-01" />
<meta name="DC.Publisher" content="American Journal of Neuroradiology" />
<meta name="DC.Rights" content="© 2021 by American Journal of Neuroradiology" />
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<meta name="DC.Description" content="BACKGROUND AND PURPOSE: The default mode network normally decreases in activity during externally directed tasks. Although default mode network connectivity is disrupted in numerous brain pathologies, default mode network deactivation has not been studied in patients with brain tumors. We investigated default mode network deactivation with language task–based fMRI by measuring the anticorrelation of a critical default mode network node, the posterior cingulate cortex, in patients with gliomas and controls; furthermore, we examined default mode network functional connectivity in these patients with task-based and resting-state fMRI.

MATERIALS AND METHODS: In 10 healthy controls and 30 patients with gliomas, the posterior cingulate cortex was identified on task-based fMRI and was used as an ROI to create connectivity maps from task-based and resting-state fMRI data. We compared the average correlation in each default mode network region between patients and controls for each correlation map and stratified patients by tumor location, hemisphere, and grade.

RESULTS: Patients with gliomas ( P = .001) and, in particular, patients with tumors near the posterior default mode network ( P &lt; .001) showed less posterior cingulate cortex anticorrelation in task-based fMRI than controls. Patients with both left- and right-hemisphere tumors, as well as those with grade IV tumors, showed significantly lower posterior cingulate cortex anticorrelation than controls ( P = .02, .03, and &lt;.001, respectively). Functional connectivity in each default mode network region was not significantly different between task-based and resting-state maps.

CONCLUSIONS: Task-based fMRI showed impaired deactivation of the default mode network in patients with gliomas. The functional connectivity of the default mode network in both task-based and resting-state fMRI in patients with gliomas using the posterior cingulate cortex identified in task-based fMRI as an ROI for seed-based correlation analysis has strong overlap.

BOLD
:   blood oxygen level–dependent
DMN
:   default mode network
FC
:   functional connectivity
IPL
:   inferior parietal lobule
LIPL
:   left inferior parietal lobule
mPFC
:   medial prefrontal cortex
PCC
:   posterior cingulate cortex
RIPL
:   right inferior parietal lobule
rs-fMRI
:   resting-state fMRI
tb-fMRI
:   task-based fMRI" />
<meta name="DC.Contributor" content="Y.M. Maniar" />
<meta name="DC.Contributor" content="K.K. Peck" />
<meta name="DC.Contributor" content="M. Jenabi" />
<meta name="DC.Contributor" content="M. Gene" />
<meta name="DC.Contributor" content="A.I. Holodny" />
<meta name="article:published_time" content="2021-08-01" />
<meta name="article:section" content="Functional" />
<meta name="citation_title" content="Functional MRI Shows Altered Deactivation and a Corresponding Decrease in Functional Connectivity of the Default Mode Network in Patients with Gliomas" />
<meta name="citation_abstract" lang="en" content="&lt;h3&gt;BACKGROUND AND PURPOSE:&lt;/h3&gt;
&lt;p&gt;The default mode network normally decreases in activity during externally directed tasks. Although default mode network connectivity is disrupted in numerous brain pathologies, default mode network deactivation has not been studied in patients with brain tumors. We investigated default mode network deactivation with language task–based fMRI by measuring the anticorrelation of a critical default mode network node, the posterior cingulate cortex, in patients with gliomas and controls; furthermore, we examined default mode network functional connectivity in these patients with task-based and resting-state fMRI.&lt;/p&gt;&lt;h3&gt;MATERIALS AND METHODS:&lt;/h3&gt;
&lt;p&gt;In 10 healthy controls and 30 patients with gliomas, the posterior cingulate cortex was identified on task-based fMRI and was used as an ROI to create connectivity maps from task-based and resting-state fMRI data. We compared the average correlation in each default mode network region between patients and controls for each correlation map and stratified patients by tumor location, hemisphere, and grade.&lt;/p&gt;&lt;h3&gt;RESULTS:&lt;/h3&gt;
&lt;p&gt;Patients with gliomas (&lt;i&gt;P&lt;/i&gt; = .001) and, in particular, patients with tumors near the posterior default mode network (&lt;i&gt;P&lt;/i&gt; &amp;lt; .001) showed less posterior cingulate cortex anticorrelation in task-based fMRI than controls. Patients with both left- and right-hemisphere tumors, as well as those with grade IV tumors, showed significantly lower posterior cingulate cortex anticorrelation than controls (&lt;i&gt;P&lt;/i&gt; = .02, .03, and &amp;lt;.001, respectively). Functional connectivity in each default mode network region was not significantly different between task-based and resting-state maps.&lt;/p&gt;&lt;h3&gt;CONCLUSIONS:&lt;/h3&gt;
&lt;p&gt;Task-based fMRI showed impaired deactivation of the default mode network in patients with gliomas. The functional connectivity of the default mode network in both task-based and resting-state fMRI in patients with gliomas using the posterior cingulate cortex identified in task-based fMRI as an ROI for seed-based correlation analysis has strong overlap.&lt;/p&gt;" />
<meta name="citation_journal_title" content="American Journal of Neuroradiology" />
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<meta name="citation_publication_date" content="2021/08/01" />
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<meta name="citation_volume" content="42" />
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<meta name="citation_section" content="Functional" />
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<meta name="citation_author" content="Y.M. Maniar" />
<meta name="citation_author_institution" content="aFrom the Department of Radiology (Y.M.M., K.K.P., M.J., M.G., A.I.H.), Memorial Sloan Kettering Cancer Center, New York, New York" />
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<meta name="citation_author_institution" content="bDepartment of Medical Physics (K.K.P.), Memorial Sloan Kettering Cancer Center, New York, New York" />
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<meta name="citation_author" content="M. Jenabi" />
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<meta name="citation_author" content="M. Gene" />
<meta name="citation_author_institution" content="aFrom the Department of Radiology (Y.M.M., K.K.P., M.J., M.G., A.I.H.), Memorial Sloan Kettering Cancer Center, New York, New York" />
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<meta name="twitter:title" content="Functional MRI Shows Altered Deactivation and a Corresponding Decrease in Functional Connectivity of the Default Mode Network in Patients with Gliomas" />
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<meta name="twitter:description" content="BACKGROUND AND PURPOSE: The default mode network normally decreases in activity during externally directed tasks. Although default mode network connectivity is disrupted in numerous brain pathologies, default mode network deactivation has not been studied in patients with brain tumors. We investigated default mode network deactivation with language task–based fMRI by measuring the anticorrelation of a critical default mode network node, the posterior cingulate cortex, in patients with gliomas and controls; furthermore, we examined default mode network functional connectivity in these patients with task-based and resting-state fMRI.

MATERIALS AND METHODS: In 10 healthy controls and 30 patients with gliomas, the posterior cingulate cortex was identified on task-based fMRI and was used as an ROI to create connectivity maps from task-based and resting-state fMRI data. We compared the average correlation in each default mode network region between patients and controls for each correlation map and stratified patients by tumor location, hemisphere, and grade.

RESULTS: Patients with gliomas ( P = .001) and, in particular, patients with tumors near the posterior default mode network ( P &lt; .001) showed less posterior cingulate cortex anticorrelation in task-based fMRI than controls. Patients with both left- and right-hemisphere tumors, as well as those with grade IV tumors, showed significantly lower posterior cingulate cortex anticorrelation than controls ( P = .02, .03, and &lt;.001, respectively). Functional connectivity in each default mode network region was not significantly different between task-based and resting-state maps.

CONCLUSIONS: Task-based fMRI showed impaired deactivation of the default mode network in patients with gliomas. The functional connectivity of the default mode network in both task-based and resting-state fMRI in patients with gliomas using the posterior cingulate cortex identified in task-based fMRI as an ROI for seed-based correlation analysis has strong overlap.

BOLD
:   blood oxygen level–dependent
DMN
:   default mode network
FC
:   functional connectivity
IPL
:   inferior parietal lobule
LIPL
:   left inferior parietal lobule
mPFC
:   medial prefrontal cortex
PCC
:   posterior cingulate cortex
RIPL
:   right inferior parietal lobule
rs-fMRI
:   resting-state fMRI
tb-fMRI
:   task-based fMRI" />
<meta name="og-title" property="og:title" content="Functional MRI Shows Altered Deactivation and a Corresponding Decrease in Functional Connectivity of the Default Mode Network in Patients with Gliomas" />
<meta name="og-url" property="og:url" content="http://ajnr-stage2.stage.highwire.org/content/42/8/1505" />
<meta name="og-site-name" property="og:site_name" content="American Journal of Neuroradiology" />
<meta name="og-description" property="og:description" content="BACKGROUND AND PURPOSE: The default mode network normally decreases in activity during externally directed tasks. Although default mode network connectivity is disrupted in numerous brain pathologies, default mode network deactivation has not been studied in patients with brain tumors. We investigated default mode network deactivation with language task–based fMRI by measuring the anticorrelation of a critical default mode network node, the posterior cingulate cortex, in patients with gliomas and controls; furthermore, we examined default mode network functional connectivity in these patients with task-based and resting-state fMRI.

MATERIALS AND METHODS: In 10 healthy controls and 30 patients with gliomas, the posterior cingulate cortex was identified on task-based fMRI and was used as an ROI to create connectivity maps from task-based and resting-state fMRI data. We compared the average correlation in each default mode network region between patients and controls for each correlation map and stratified patients by tumor location, hemisphere, and grade.

RESULTS: Patients with gliomas ( P = .001) and, in particular, patients with tumors near the posterior default mode network ( P &lt; .001) showed less posterior cingulate cortex anticorrelation in task-based fMRI than controls. Patients with both left- and right-hemisphere tumors, as well as those with grade IV tumors, showed significantly lower posterior cingulate cortex anticorrelation than controls ( P = .02, .03, and &lt;.001, respectively). Functional connectivity in each default mode network region was not significantly different between task-based and resting-state maps.

CONCLUSIONS: Task-based fMRI showed impaired deactivation of the default mode network in patients with gliomas. The functional connectivity of the default mode network in both task-based and resting-state fMRI in patients with gliomas using the posterior cingulate cortex identified in task-based fMRI as an ROI for seed-based correlation analysis has strong overlap.

BOLD
:   blood oxygen level–dependent
DMN
:   default mode network
FC
:   functional connectivity
IPL
:   inferior parietal lobule
LIPL
:   left inferior parietal lobule
mPFC
:   medial prefrontal cortex
PCC
:   posterior cingulate cortex
RIPL
:   right inferior parietal lobule
rs-fMRI
:   resting-state fMRI
tb-fMRI
:   task-based fMRI" />
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    <div class="highwire-article-citation highwire-citation-type-highwire-article node92387--5" data-node-nid="92387" id="top-node-92387--6921419952" data-pisa="ajnr;42/8/1505" data-pisa-master="ajnr;ajnr.A7138" data-apath="/ajnr/42/8/1505.atom" data-hw-author-tooltip-instance="highwire_author_tooltip"><div class="highwire-cite highwire-cite-highwire-article highwire-citation-jcore-article-title-complete clearfix has-author-tooltip highwire-citation-highwire-article-top-a">
  
  
      <div class="highwire-cite-overline"><span  class="highwire-cite-metadata-article-type highwire-cite-metadata">Research Article</span><span class="separator-pipe"></span><span  class="highwire-cite-metadata-art-cat highwire-cite-metadata"><span class="wrapper">Functional</span></span></div>
  
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      <h1 class="highwire-cite-title" id="page-title">Functional MRI Shows Altered Deactivation and a Corresponding Decrease in Functional Connectivity of the Default Mode Network in Patients with Gliomas</h1>  
    	<div class="highwire-cite-authors"><span  class="highwire-citation-authors"><span class="highwire-citation-author first" data-delta="0">Y.M. Maniar</span>, <span class="highwire-citation-author" data-delta="1">K.K. Peck</span>, <span class="highwire-citation-author" data-delta="2">M. Jenabi</span>, <span class="highwire-citation-author" data-delta="3">M. Gene</span> and <span class="highwire-citation-author" data-delta="4">A.I. Holodny</span></span></div>
  
    	<div class="highwire-cite-metadata"><span  class="highwire-cite-metadata-journal highwire-cite-metadata">American Journal of Neuroradiology </span><span  class="highwire-cite-metadata-date highwire-cite-metadata">August 2021,  </span><span  class="highwire-cite-metadata-volume highwire-cite-metadata">42 </span><span  class="highwire-cite-metadata-issue highwire-cite-metadata">(8) </span><span  class="highwire-cite-metadata-pages highwire-cite-metadata">1505-1512; </span><span  class="highwire-cite-metadata-doi highwire-cite-metadata">DOI: https://doi.org/10.3174/ajnr.A7138 </span></div>
  
  
  
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<div id="hw-article-author-popups-top-node-92387--6921419952" style="display: none;"><div class="author-tooltip-0"><div class="author-tooltip-name">Y.M. Maniar </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>a</span>From the Department of Radiology (Y.M.M., K.K.P., M.J., M.G., A.I.H.), Memorial Sloan Kettering Cancer Center, New York, New York</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&amp;gs_type=author&amp;author%5B0%5D=Y.M.%2BManiar%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Maniar%20Y&amp;link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link"><a href="/search/author1%3AY.M.%2BManiar%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-orcid-link last"><a href="https://orcid.org/0000-0001-9286-0005" target="_blank" class="" data-icon-position="" data-hide-link-title="0">ORCID record for Y.M. Maniar</a></li></ul></div><div class="author-tooltip-1"><div class="author-tooltip-name">K.K. Peck </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>a</span>From the Department of Radiology (Y.M.M., K.K.P., M.J., M.G., A.I.H.), Memorial Sloan Kettering Cancer Center, New York, New York</div><div class='author-affiliation'><span class='nlm-sup'>b</span>Department of Medical Physics (K.K.P.), Memorial Sloan Kettering Cancer Center, New York, New York</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&amp;gs_type=author&amp;author%5B0%5D=K.K.%2BPeck%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Peck%20K&amp;link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link"><a href="/search/author1%3AK.K.%2BPeck%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-orcid-link last"><a href="https://orcid.org/0000-0002-9841-3078" target="_blank" class="" data-icon-position="" data-hide-link-title="0">ORCID record for K.K. Peck</a></li></ul></div><div class="author-tooltip-2"><div class="author-tooltip-name">M. Jenabi </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>a</span>From the Department of Radiology (Y.M.M., K.K.P., M.J., M.G., A.I.H.), Memorial Sloan Kettering Cancer Center, New York, New York</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&amp;gs_type=author&amp;author%5B0%5D=M.%2BJenabi%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Jenabi%20M&amp;link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link"><a href="/search/author1%3AM.%2BJenabi%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-orcid-link last"><a href="https://orcid.org/0000-0002-2456-0737" target="_blank" class="" data-icon-position="" data-hide-link-title="0">ORCID record for M. Jenabi</a></li></ul></div><div class="author-tooltip-3"><div class="author-tooltip-name">M. Gene </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>a</span>From the Department of Radiology (Y.M.M., K.K.P., M.J., M.G., A.I.H.), Memorial Sloan Kettering Cancer Center, New York, New York</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&amp;gs_type=author&amp;author%5B0%5D=M.%2BGene%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Gene%20M&amp;link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link"><a href="/search/author1%3AM.%2BGene%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-orcid-link last"><a href="https://orcid.org/0000-0001-9516-5155" target="_blank" class="" data-icon-position="" data-hide-link-title="0">ORCID record for M. Gene</a></li></ul></div><div class="author-tooltip-4"><div class="author-tooltip-name">A.I. Holodny </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>a</span>From the Department of Radiology (Y.M.M., K.K.P., M.J., M.G., A.I.H.), Memorial Sloan Kettering Cancer Center, New York, New York</div><div class='author-affiliation'><span class='nlm-sup'>c</span>Department of Radiology (A.I.H.), Weill Medical College of Cornell University, New York, New York</div><div class='author-affiliation'><span class='nlm-sup'>d</span>Department of Neuroscience (A.I.H.), Weill-Cornell Graduate School of the Medical Sciences, New York, New York</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&amp;gs_type=author&amp;author%5B0%5D=A.I.%2BHolodny%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Holodny%20A&amp;link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link"><a href="/search/author1%3AA.I.%2BHolodny%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-orcid-link last"><a href="https://orcid.org/0000-0002-1159-2705" target="_blank" class="" data-icon-position="" data-hide-link-title="0">ORCID record for A.I. 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    <div class="highwire-markup"><div xmlns="http://www.w3.org/1999/xhtml" data-highwire-cite-ref-tooltip-instance="highwire_reflinks_tooltip" class="content-block-markup" xmlns:xhtml="http://www.w3.org/1999/xhtml"><div class="article abstract-view "><span class="highwire-journal-article-marker-start"></span><div class="section abstract" id="abstract-2"><h2>Abstract</h2><div id="sec-1" class="subsection"><p id="p-2"><strong>BACKGROUND AND PURPOSE:</strong> The default mode network normally decreases in activity during externally directed tasks. Although default mode network connectivity is disrupted in numerous brain pathologies, default mode network deactivation has not been studied in patients with brain tumors. We investigated default mode network deactivation with language task–based fMRI by measuring the anticorrelation of a critical default mode network node, the posterior cingulate cortex, in patients with gliomas and controls; furthermore, we examined default mode network functional connectivity in these patients with task-based and resting-state fMRI.</p></div><div id="sec-2" class="subsection"><p id="p-3"><strong>MATERIALS AND METHODS:</strong> In 10 healthy controls and 30 patients with gliomas, the posterior cingulate cortex was identified on task-based fMRI and was used as an ROI to create connectivity maps from task-based and resting-state fMRI data. We compared the average correlation in each default mode network region between patients and controls for each correlation map and stratified patients by tumor location, hemisphere, and grade.</p></div><div id="sec-3" class="subsection"><p id="p-4"><strong>RESULTS:</strong> Patients with gliomas (<em>P</em> = .001) and, in particular, patients with tumors near the posterior default mode network (<em>P</em> &lt; .001) showed less posterior cingulate cortex anticorrelation in task-based fMRI than controls. Patients with both left- and right-hemisphere tumors, as well as those with grade IV tumors, showed significantly lower posterior cingulate cortex anticorrelation than controls (<em>P</em> = .02, .03, and &lt;.001, respectively). Functional connectivity in each default mode network region was not significantly different between task-based and resting-state maps.</p></div><div id="sec-4" class="subsection"><p id="p-5"><strong>CONCLUSIONS:</strong> Task-based fMRI showed impaired deactivation of the default mode network in patients with gliomas. The functional connectivity of the default mode network in both task-based and resting-state fMRI in patients with gliomas using the posterior cingulate cortex identified in task-based fMRI as an ROI for seed-based correlation analysis has strong overlap.</p></div></div><div class="section glossary" id="glossary-1"><h2 class="">ABBREVIATIONS:</h2><dl id="def-list-1"><dt id="def-item-1">BOLD<span class="def-item-dt-sep"></span></dt><dd>blood oxygen level–dependent<span class="def-item-dd-sep"></span></dd><dt id="def-item-2">DMN<span class="def-item-dt-sep"></span></dt><dd>default mode network<span class="def-item-dd-sep"></span></dd><dt id="def-item-3">FC<span class="def-item-dt-sep"></span></dt><dd>functional connectivity<span class="def-item-dd-sep"></span></dd><dt id="def-item-4">IPL<span class="def-item-dt-sep"></span></dt><dd>inferior parietal lobule<span class="def-item-dd-sep"></span></dd><dt id="def-item-5">LIPL<span class="def-item-dt-sep"></span></dt><dd>left inferior parietal lobule<span class="def-item-dd-sep"></span></dd><dt id="def-item-6">mPFC<span class="def-item-dt-sep"></span></dt><dd>medial prefrontal cortex<span class="def-item-dd-sep"></span></dd><dt id="def-item-7">PCC<span class="def-item-dt-sep"></span></dt><dd>posterior cingulate cortex<span class="def-item-dd-sep"></span></dd><dt id="def-item-8">RIPL<span class="def-item-dt-sep"></span></dt><dd>right inferior parietal lobule<span class="def-item-dd-sep"></span></dd><dt id="def-item-9">rs-fMRI<span class="def-item-dt-sep"></span></dt><dd>resting-state fMRI<span class="def-item-dd-sep"></span></dd><dt id="def-item-10">tb-fMRI<span class="def-item-dt-sep"></span></dt><dd>task-based fMRI</dd></dl></div><ul class="copyright-statement"><li class="fn" id="copyright-statement-1">© 2021 by American Journal of Neuroradiology</li></ul><span class="highwire-journal-article-marker-end"></span></div><span class="related-urls"></span></div><a href="http://ajnr-stage2.stage.highwire.org/content/42/8/1505.full" class="hw-link hw-link-article-full-text" data-icon-position="" data-hide-link-title="0">View Full Text</a></div>  </div>

  
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        	<div class="highwire-cite-metadata"><span  class="highwire-cite-metadata-volume highwire-cite-metadata">Vol. 42</span>, <span  class="highwire-cite-metadata-issue highwire-cite-metadata">Issue 8 </span><div  class="highwire-cite-metadata-pubdate highwire-cite-metadata">1 Aug 2021 </div></div>
      
      
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