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<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Hum. Neurosci.</journal-id>
<journal-title>Frontiers in Human Neuroscience</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Hum. Neurosci.</abbrev-journal-title>
<issn pub-type="epub">1662-5161</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fnhum.2017.00044</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Neuroscience</subject>
<subj-group>
<subject>Mini Review</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Transcranial Direct Current Stimulation over the Dorsolateral Prefrontal Cortex in Schizophrenia: A Quantitative Review of Cognitive Outcomes</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author" corresp="yes">
<name><surname>Mervis</surname> <given-names>Joshua E.</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<xref ref-type="author-notes" rid="fn001"><sup>&#x0002A;</sup></xref>
<uri xlink:href="http://loop.frontiersin.org/people/116053/overview"/>
</contrib>
<contrib contrib-type="author">
<name><surname>Capizzi</surname> <given-names>Riley J.</given-names></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<uri xlink:href="http://loop.frontiersin.org/people/392242/overview"/>
</contrib>
<contrib contrib-type="author">
<name><surname>Boroda</surname> <given-names>Elias</given-names></name>
<xref ref-type="aff" rid="aff2"><sup>2</sup></xref>
<uri xlink:href="http://loop.frontiersin.org/people/305681/overview"/>
</contrib>
<contrib contrib-type="author">
<name><surname>MacDonald</surname> <given-names>Angus W.</given-names> <suffix>III</suffix></name>
<xref ref-type="aff" rid="aff1"><sup>1</sup></xref>
<xref ref-type="aff" rid="aff3"><sup>3</sup></xref>
<uri xlink:href="http://loop.frontiersin.org/people/5442/overview"/>
</contrib>
</contrib-group>
<aff id="aff1"><sup>1</sup><institution>Department of Psychology, University of Minnesota</institution> <country>Minneapolis, MN, USA</country></aff>
<aff id="aff2"><sup>2</sup><institution>Department of Neuroscience, University of Minnesota</institution> <country>Minneapolis, MN, USA</country></aff>
<aff id="aff3"><sup>3</sup><institution>Department of Psychiatry, University of Minnesota Medical School</institution> <country>Minneapolis, MN, USA</country></aff>
<author-notes>
<fn fn-type="edited-by"><p>Edited by: Evangelia G. Chrysikou, University of Kansas, USA</p></fn>
<fn fn-type="edited-by"><p>Reviewed by: Josefien Dedoncker, University Hospital Ghent, Belgium; Hector Arciniega, University of Nevada, Reno, USA</p></fn>
<fn fn-type="corresp" id="fn001"><p>&#x0002A;Correspondence: Joshua E. Mervis <email>mervi004&#x00040;umn.edu</email></p></fn>
</author-notes>
<pub-date pub-type="epub">
<day>02</day>
<month>02</month>
<year>2017</year>
</pub-date>
<pub-date pub-type="collection">
<year>2017</year>
</pub-date>
<volume>11</volume>
<elocation-id>44</elocation-id>
<history>
<date date-type="received">
<day>09</day>
<month>09</month>
<year>2016</year>
</date>
<date date-type="accepted">
<day>20</day>
<month>01</month>
<year>2017</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#x000A9; 2017 Mervis, Capizzi, Boroda and MacDonald.</copyright-statement>
<copyright-year>2017</copyright-year>
<copyright-holder>Mervis, Capizzi, Boroda and MacDonald</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/"><p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p></license>
</permissions>
<abstract><p>Cognitive deficits are a core and disabling feature of psychotic disorders, specifically schizophrenia. Current treatments for impaired cognition in schizophrenia remain insufficient. Recent research suggests transcranial direct current stimulation (tDCS) targeting the dorsolateral prefrontal cortex can potentiate cognitive improvements in healthy individuals and those with psychiatric conditions, such as schizophrenia. However, this burgeoning literature has not been quantitatively evaluated. Through a literature search and quantitative review, we identified 194 papers on tDCS, psychosis, and cognition. Selection criteria included pre/post design and sham control to achieve specific sham-adjusted effect sizes. The 6 retained studies all address schizophrenia populations and include single and repeated stimulation, as well as within and between subject designs. Small positive effects were found for anodal stimulation on behavioral measures of attention and working memory, with tentative findings for cognitive ability and memory. Cathodal stimulation yielded a small positive effect on behaviorally measured cognitive ability. Neurophysiological measures of attention showed a small to medium down-modulation effect for anodal stimulation. Implications of these findings and guidelines for future research are discussed. As revealed by this report, due to the paucity of data available, much remains unknown regarding the clinical efficacy of tDCS in schizophrenia.</p></abstract>
<kwd-group>
<kwd>cognition</kwd>
<kwd>dorsolateral prefrontal cortex</kwd>
<kwd>quantitative review</kwd>
<kwd>Schizophrenia</kwd>
<kwd>transcranial direct current stimulation</kwd>
</kwd-group>
<contract-sponsor id="cn001">University of Minnesota<named-content content-type="fundref-id">10.13039/100007249</named-content></contract-sponsor>
<counts>
<fig-count count="1"/>
<table-count count="1"/>
<equation-count count="2"/>
<ref-count count="46"/>
<page-count count="8"/>
<word-count count="5442"/>
</counts>
</article-meta>
</front>
<body>
<sec sec-type="intro" id="s1">
<title>Introduction</title>
<p>Impaired cognition is a significant and disabling feature of psychotic disorders such as schizophrenia. Deficits in executive functions (working memory, attention, response inhibition) are the most commonly reported, and the most predictive of functional outcome (Green, <xref ref-type="bibr" rid="B18">1996</xref>). Despite the central role of these impairments, current treatments, including pharmacological interventions, have proven ineffective at ameliorating cognitive dysfunction (Fusar-Poli et al., <xref ref-type="bibr" rid="B15">2015</xref>). New or adjunctive treatment options are needed.</p>
<p>A large body of evidence implicates impaired frontal cortical activity as a causal factor in cognitive dysfunction in schizophrenia (Minzenberg et al., <xref ref-type="bibr" rid="B31">2009</xref>). Specifically, hypoactivation of the dorsolateral prefrontal cortex (DLPFC) has been suggested as the core deficit (Potkin et al., <xref ref-type="bibr" rid="B39">2009</xref>; Lesh et al., <xref ref-type="bibr" rid="B27">2011</xref>). Given the pivotal role of the DLPFC in mediating a wide range of executive functions (Niendam et al., <xref ref-type="bibr" rid="B33">2012</xref>), interventions that target this region are of great clinical interest. Non-invasive methods of neuromodulation provide a safe, cost-effective and robust means to enhance DLPFC function.</p>
<p>Transcranial current stimulation (tCS) is a non-invasive neuromodulation technique that uses small, specifically directed electrical currents to alter cortical brain activity (Nitsche and Paulus, <xref ref-type="bibr" rid="B36">2001</xref>). Though there are several forms of tCS, transcranial direct current stimulation (tDCS) has by far been the most commonly employed. TDCS involves the use of two electrodes, a positively charged anode and a negatively charged cathode. Studies in both animals and humans demonstrate that anodal stimulation produces a shift in excitability that depolarizes neurons, while cathodal stimulation has opposite effects (Nitsche and Paulus, <xref ref-type="bibr" rid="B35">2000</xref>; Cambiaghi et al., <xref ref-type="bibr" rid="B7">2010</xref>). Though the mechanisms underlying tDCS are still under investigation, it is postulated that these shifts in excitability are induced by altering membrane polarization at the cellular level (Fritsch et al., <xref ref-type="bibr" rid="B14">2010</xref>; Kronberg et al., <xref ref-type="bibr" rid="B26">2017</xref>). Due to its safety (Bikson et al., <xref ref-type="bibr" rid="B6">2016</xref>), tolerability, and low cost, the use of tDCS has grown substantially. Recent research demonstrates that tDCS targeted to the DLPFC has the ability to potentiate changes in cognition in both healthy individuals (Fregni et al., <xref ref-type="bibr" rid="B13">2005</xref>) and those with various psychiatric conditions, such as schizophrenia (Dedoncker et al., <xref ref-type="bibr" rid="B10">2016</xref>).</p>
<p>As a clinical intervention, the use of tDCS to enhance cognition in schizophrenia is especially promising. Anodal tDCS, directed at the DLPFC, has now been evaluated in several trials as a possible rehabilitation technique or adjunct to existing treatments (Minzenberg and Carter, <xref ref-type="bibr" rid="B30">2012</xref>; Palm et al., <xref ref-type="bibr" rid="B38">2016</xref>). However, research has indicated contradictory effects of stimulation in some patient populations (Berryhill et al., <xref ref-type="bibr" rid="B5">2014</xref>) and differential effects on various cognitive domains are not well understood.</p>
<p>To address these ambiguities, we undertook a quantitative review of studies on tDCS in schizophrenia using the PubMed database and identified 194 articles. This number was reduced to 6 articles after excluding studies on populations without psychosis, without cognitive outcomes, and including only those with a sham stimulation condition to create a sham-adjusted effect size. Study outcomes and heterogeneity of designs were aggregated and variance-weighted.</p>
</sec>
<sec sec-type="methods" id="s2">
<title>Methods</title>
<sec>
<title>Literature search</title>
<p>A literature search was conducted in the PubMed Database searching titles and abstracts for the following key words and Boolean terms: (&#x0201C;psychosis&#x0201D; OR &#x0201C;schizophrenia&#x0201D; OR &#x0201C;schizoaffective disorder&#x0201D; OR &#x0201C;bipolar disorder&#x0201D;) AND (&#x0201C;tDCS&#x0201D; OR &#x0201C;direct current&#x0201D;). Published articles were collected up until May 2016 returning 194 results.</p>
</sec>
<sec>
<title>Eligibility criteria</title>
<p>Criteria for inclusion were: (a) psychosis; (b) randomized and sham-controlled designs; (c) pre-post within-subject or between-subject designs. Duplicates, reviews, case studies, and studies with &#x0003C;3 participants were excluded. Studies were also excluded due to the inability to calculate independent groups pre-post effect sizes (Becker, <xref ref-type="bibr" rid="B4">1988</xref>; Lipsey and Wilson, <xref ref-type="bibr" rid="B28">1993</xref>) See Figure <xref ref-type="fig" rid="F1">1</xref>. Specific study characteristics extracted for discussion are presented in Table <xref ref-type="table" rid="T1">1</xref>. No formal quality assessment was performed.</p>
<fig id="F1" position="float">
<label>Figure 1</label>
<caption><p><bold>Literature Search and Study Eligibility Determination</bold>.</p></caption>
<graphic xlink:href="fnhum-11-00044-g0001.tif"/>
</fig>
<table-wrap position="float" id="T1">
<label>Table 1</label>
<caption><p><bold>Anodal tDCS studies: cognitive domains, measures, and design parameters</bold>.</p></caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th valign="top" align="left"><bold>Study</bold></th>
<th valign="top" align="left"><bold>Measures</bold></th>
<th valign="top" align="left"><bold>Active electrode</bold></th>
<th valign="top" align="left"><bold>Reference electrode</bold></th>
<th valign="top" align="left"><bold>Stimulation target</bold></th>
<th valign="top" align="left"><bold>On/Offline</bold></th>
<th valign="top" align="center"><bold>Amplitude (mA)</bold></th>
<th valign="top" align="center"><bold>Sessions</bold></th>
<th valign="top" align="center"><bold>Unweighted effect size (d<sub>uw</sub>)</bold></th>
<th valign="top" align="center"><bold>Weighted effect size (d<sub>w</sub>)</bold></th>
<th valign="top" align="center"><bold>d<sub>w</sub> Ranking (high/low)</bold></th>
</tr>
</thead>
<tbody>
<tr>
<td valign="top" align="left" colspan="11" style="background-color:#bbbdc0"><bold>ATTENTION</bold></td>
</tr>
<tr>
<td valign="top" align="left">Dunn et al., <xref ref-type="bibr" rid="B11">2016</xref></td>
<td valign="top" align="left">P300 (&#x003BC;V)</td>
<td valign="top" align="left">Fp1/Fp2</td>
<td valign="top" align="left">Upper Arm (R)</td>
<td valign="top" align="left">Bilateral DLPFC</td>
<td valign="top" align="left">Offline</td>
<td valign="top" align="center">1</td>
<td valign="top" align="center">2</td>
<td valign="top" align="char" char=".">0.16</td>
<td valign="top" align="char" char=".">0.78</td>
<td valign="top" align="center">8</td>
</tr>
<tr>
<td valign="top" align="left">Dunn et al., <xref ref-type="bibr" rid="B11">2016</xref></td>
<td valign="top" align="left">Mismatch Negativity (&#x003BC;V)</td>
<td valign="top" align="left">Fp1/Fp2</td>
<td valign="top" align="left">Upper Arm (R)</td>
<td valign="top" align="left">Bilateral DLPFC</td>
<td valign="top" align="left">Offline</td>
<td valign="top" align="center">1</td>
<td valign="top" align="center">2</td>
<td valign="top" align="char" char=".">&#x02212;1.54</td>
<td valign="top" align="char" char=".">&#x02212;4.05</td>
<td valign="top" align="center">22</td>
</tr>
<tr>
<td valign="top" align="left">Mean Effect</td>
<td valign="top" align="left">(Neurophysiological)</td>
<td/>
<td/>
<td/>
<td/>
<td/>
<td/>
<td valign="top" align="char" char=".">&#x02212;0.69</td>
<td valign="top" align="char" char=".">&#x02212;0.44</td>
<td/>
</tr>
<tr>
<td valign="top" align="left">Smith et al., <xref ref-type="bibr" rid="B45">2015</xref></td>
<td valign="top" align="left">MCCB Attention-Vigilance (accuracy)</td>
<td valign="top" align="left">F3</td>
<td valign="top" align="left">Supraorbital (R)</td>
<td valign="top" align="left">Left DLPFC</td>
<td valign="top" align="left">Offline</td>
<td valign="top" align="center">2</td>
<td valign="top" align="center">5</td>
<td valign="top" align="char" char=".">0.49</td>
<td valign="top" align="char" char=".">3.01</td>
<td valign="top" align="center">2</td>
</tr>
<tr>
<td valign="top" align="left">Smith et al., <xref ref-type="bibr" rid="B45">2015</xref></td>
<td valign="top" align="left">MCCB Reasoning/Problem Solving (seconds)</td>
<td valign="top" align="left">F3</td>
<td valign="top" align="left">Supraorbital (R)</td>
<td valign="top" align="left">Left DLPFC</td>
<td valign="top" align="left">Offline</td>
<td valign="top" align="center">2</td>
<td valign="top" align="center">5</td>
<td valign="top" align="char" char=".">0.32</td>
<td valign="top" align="char" char=".">1.99</td>
<td valign="top" align="center">4</td>
</tr>
<tr>
<td valign="top" align="left">Mean Effect</td>
<td valign="top" align="left">(Behavioral)</td>
<td/>
<td/>
<td/>
<td/>
<td/>
<td/>
<td valign="top" align="char" char=".">0.40</td>
<td valign="top" align="char" char=".">0.40</td>
<td/>
</tr>
<tr>
<td valign="top" align="left" colspan="11" style="background-color:#bbbdc0"><bold>MEMORY</bold></td>
</tr>
<tr>
<td valign="top" align="left">Smith et al., <xref ref-type="bibr" rid="B45">2015</xref></td>
<td valign="top" align="left">MCCB Verbal Learning (recall and recognition scores)</td>
<td valign="top" align="left">F3</td>
<td valign="top" align="left">Supraorbital (R)</td>
<td valign="top" align="left">Left DLPFC</td>
<td valign="top" align="left">Offline</td>
<td valign="top" align="center">2</td>
<td valign="top" align="center">5</td>
<td valign="top" align="char" char=".">0.21</td>
<td valign="top" align="char" char=".">1.33</td>
<td valign="top" align="center">7</td>
</tr>
<tr>
<td valign="top" align="left">Smith et al., <xref ref-type="bibr" rid="B45">2015</xref></td>
<td valign="top" align="left">MCCB Visual Learning (recall and recognition scores)</td>
<td valign="top" align="left">F3</td>
<td valign="top" align="left">Supraorbital (R)</td>
<td valign="top" align="left">Left DLPFC</td>
<td valign="top" align="left">Offline</td>
<td valign="top" align="center">2</td>
<td valign="top" align="center">5</td>
<td valign="top" align="char" char=".">0.10</td>
<td valign="top" align="char" char=".">0.55</td>
<td valign="top" align="center">10</td>
</tr>
<tr>
<td valign="top" align="left">Mean Effect</td>
<td/>
<td/>
<td/>
<td/>
<td/>
<td/>
<td/>
<td valign="top" align="char" char=".">0.21</td>
<td valign="top" align="char" char=".">0.16</td>
<td/>
</tr>
<tr>
<td valign="top" align="left" colspan="11" style="background-color:#bbbdc0"><bold>PROCESSING SPEED</bold></td>
</tr>
<tr>
<td valign="top" align="left">Smith et al., <xref ref-type="bibr" rid="B45">2015</xref></td>
<td valign="top" align="left">MCCB Speed of Processing (accuracy)</td>
<td valign="top" align="left">F3</td>
<td valign="top" align="left">Supraorbital (R)</td>
<td valign="top" align="left">Left DLPFC</td>
<td valign="top" align="left">Offline</td>
<td valign="top" align="center">2</td>
<td valign="top" align="center">5</td>
<td valign="top" align="char" char=".">&#x02212;0.18</td>
<td valign="top" align="char" char=".">&#x02212;1.12</td>
<td valign="top" align="center">20</td>
</tr>
<tr>
<td valign="top" align="left">Palm et al., <xref ref-type="bibr" rid="B38">2016</xref></td>
<td valign="top" align="left">Trail-Making Test A (seconds)</td>
<td valign="top" align="left">F3</td>
<td valign="top" align="left">Supraorbital (R)</td>
<td valign="top" align="left">Left DLPFC</td>
<td valign="top" align="left">Offline</td>
<td valign="top" align="center">2</td>
<td valign="top" align="center">10</td>
<td valign="top" align="char" char=".">&#x02212;0.14</td>
<td valign="top" align="char" char=".">&#x02212;0.49</td>
<td valign="top" align="center">17</td>
</tr>
<tr>
<td valign="top" align="left">Palm et al., <xref ref-type="bibr" rid="B38">2016</xref></td>
<td valign="top" align="left">Trail-Making Test B (seconds)</td>
<td valign="top" align="left">F3</td>
<td valign="top" align="left">Supraorbital (R)</td>
<td valign="top" align="left">Left DLPFC</td>
<td valign="top" align="left">Offline</td>
<td valign="top" align="center">2</td>
<td valign="top" align="center">10</td>
<td valign="top" align="char" char=".">0.11</td>
<td valign="top" align="char" char=".">0.41</td>
<td valign="top" align="center">11</td>
</tr>
<tr>
<td valign="top" align="left">Mean Effect</td>
<td/>
<td/>
<td/>
<td/>
<td/>
<td/>
<td/>
<td valign="top" align="char" char=".">&#x02212;0.16</td>
<td valign="top" align="char" char=".">&#x02212;0.16</td>
<td/>
</tr>
<tr>
<td valign="top" align="left" colspan="11" style="background-color:#bbbdc0"><bold>SOCIAL COGNITION</bold></td>
</tr>
<tr>
<td valign="top" align="left">Rassovsky et al., <xref ref-type="bibr" rid="B41">2015</xref></td>
<td valign="top" align="left">TASIT (total score)</td>
<td valign="top" align="left">Fp1/Fp2</td>
<td valign="top" align="left">Upper Arm (R)</td>
<td valign="top" align="left">Bilateral DLPFC</td>
<td valign="top" align="left">Offline</td>
<td valign="top" align="center">1</td>
<td valign="top" align="center">1</td>
<td valign="top" align="char" char=".">&#x02212;0.12</td>
<td valign="top" align="char" char=".">&#x02212;0.59</td>
<td valign="top" align="center">18</td>
</tr>
<tr>
<td valign="top" align="left">Rassovsky et al., <xref ref-type="bibr" rid="B41">2015</xref></td>
<td valign="top" align="left">PONS (total score)</td>
<td valign="top" align="left">Fp1/Fp2</td>
<td valign="top" align="left">Upper Arm (R)</td>
<td valign="top" align="left">Bilateral DLPFC</td>
<td valign="top" align="left">Offline</td>
<td valign="top" align="center">1</td>
<td valign="top" align="center">1</td>
<td valign="top" align="char" char=".">&#x02212;0.13</td>
<td valign="top" align="char" char=".">&#x02212;0.65</td>
<td valign="top" align="center">19</td>
</tr>
<tr>
<td valign="top" align="left">Rassovsky et al., <xref ref-type="bibr" rid="B41">2015</xref></td>
<td valign="top" align="left">FEIT (accuracy)</td>
<td valign="top" align="left">Fp1/Fp2</td>
<td valign="top" align="left">Upper Arm (R)</td>
<td valign="top" align="left">Bilateral DLPFC</td>
<td valign="top" align="left">Offline</td>
<td valign="top" align="center">1</td>
<td valign="top" align="center">1</td>
<td valign="top" align="char" char=".">0.44</td>
<td valign="top" align="char" char=".">2.02</td>
<td valign="top" align="center">3</td>
</tr>
<tr>
<td valign="top" align="left">Rassovsky et al., <xref ref-type="bibr" rid="B41">2015</xref></td>
<td valign="top" align="left">MSCEIT (total score)</td>
<td valign="top" align="left">Fp1/Fp2</td>
<td valign="top" align="left">Upper Arm (R)</td>
<td valign="top" align="left">Bilateral DLPFC</td>
<td valign="top" align="left">Offline</td>
<td valign="top" align="center">1</td>
<td valign="top" align="center">1</td>
<td valign="top" align="char" char=".">0.02</td>
<td valign="top" align="char" char=".">0.08</td>
<td valign="top" align="center">16</td>
</tr>
<tr>
<td valign="top" align="left">Smith et al., <xref ref-type="bibr" rid="B45">2015</xref></td>
<td valign="top" align="left">MCCB Social Cognition (total score)</td>
<td valign="top" align="left">F3</td>
<td valign="top" align="left">Supraorbital (R)</td>
<td valign="top" align="left">Left DLPFC</td>
<td valign="top" align="left">Offline</td>
<td valign="top" align="center">2</td>
<td valign="top" align="center">5</td>
<td valign="top" align="char" char=".">0.26</td>
<td valign="top" align="char" char=".">1.54</td>
<td valign="top" align="center">6</td>
</tr>
<tr>
<td valign="top" align="left">Mean Effect</td>
<td/>
<td/>
<td/>
<td/>
<td/>
<td/>
<td/>
<td valign="top" align="char" char=".">0.14</td>
<td valign="top" align="char" char=".">0.15</td>
<td/>
</tr>
<tr>
<td valign="top" align="left" colspan="11" style="background-color:#bbbdc0"><bold>WORKING MEMORY</bold></td>
</tr>
<tr>
<td valign="top" align="left">Hoy et al., <xref ref-type="bibr" rid="B24">2016</xref><xref ref-type="table-fn" rid="TN1"><sup>&#x0002A;</sup></xref></td>
<td valign="top" align="left">2-back (Letters) (accuracy)</td>
<td valign="top" align="left">F3</td>
<td valign="top" align="left">Supraorbital (R)</td>
<td valign="top" align="left">Left DLPFC</td>
<td valign="top" align="left">Offline<xref ref-type="table-fn" rid="TN3"><sup>&#x0002A;&#x0002A;&#x0002A;</sup></xref></td>
<td valign="top" align="center">2</td>
<td valign="top" align="center">1&#x02013;2</td>
<td valign="top" align="char" char=".">&#x02212;0.46</td>
<td valign="top" align="char" char=".">&#x02212;1.18</td>
<td valign="top" align="center">21</td>
</tr>
<tr>
<td valign="top" align="left">Nienow et al., <xref ref-type="bibr" rid="B34">2016</xref><xref ref-type="table-fn" rid="TN2"><sup>&#x0002A;&#x0002A;</sup></xref></td>
<td valign="top" align="left">2-back (Words) (accuracy)</td>
<td valign="top" align="left">F3</td>
<td valign="top" align="left">Supraorbital (R)</td>
<td valign="top" align="left">Left DLPFC</td>
<td valign="top" align="left">Online</td>
<td valign="top" align="center">1</td>
<td valign="top" align="center">28</td>
<td valign="top" align="char" char=".">0.53</td>
<td valign="top" align="char" char=".">0.24</td>
<td valign="top" align="center">14</td>
</tr>
<tr>
<td valign="top" align="left">Nienow et al., <xref ref-type="bibr" rid="B34">2016</xref><xref ref-type="table-fn" rid="TN2"><sup>&#x0002A;&#x0002A;</sup></xref></td>
<td valign="top" align="left">2-back (Pictures) (accuracy)</td>
<td valign="top" align="left">F3</td>
<td valign="top" align="left">Supraorbital (R)</td>
<td valign="top" align="left">Left DLPFC</td>
<td valign="top" align="left">Online</td>
<td valign="top" align="center">1</td>
<td valign="top" align="center">28</td>
<td valign="top" align="char" char=".">0.58</td>
<td valign="top" align="char" char=".">0.31</td>
<td valign="top" align="center">13</td>
</tr>
<tr>
<td valign="top" align="left">Palm et al., <xref ref-type="bibr" rid="B38">2016</xref></td>
<td valign="top" align="left">Self-Ordered Pointing Task (accuracy)</td>
<td valign="top" align="left">F3</td>
<td valign="top" align="left">Supraorbital (R)</td>
<td valign="top" align="left">Left DLPFC</td>
<td valign="top" align="left">Offline</td>
<td valign="top" align="center">2</td>
<td valign="top" align="center">10</td>
<td valign="top" align="char" char=".">0.19</td>
<td valign="top" align="char" char=".">0.73</td>
<td valign="top" align="center">9</td>
</tr>
<tr>
<td valign="top" align="left">Smith et al., <xref ref-type="bibr" rid="B45">2015</xref></td>
<td valign="top" align="left">MCCB Working Memory (recall score)</td>
<td valign="top" align="left">F3</td>
<td valign="top" align="left">Supraorbital (R)</td>
<td valign="top" align="left">Left DLPFC</td>
<td valign="top" align="left">Offline</td>
<td valign="top" align="center">2</td>
<td valign="top" align="center">5</td>
<td valign="top" align="char" char=".">0.51</td>
<td valign="top" align="char" char=".">3.12</td>
<td valign="top" align="center">1</td>
</tr>
<tr>
<td valign="top" align="left">Mean Effect</td>
<td/>
<td/>
<td/>
<td/>
<td/>
<td/>
<td/>
<td valign="top" align="char" char=".">0.21</td>
<td valign="top" align="char" char=".">0.23</td>
<td/>
</tr>
<tr>
<td valign="top" align="left" colspan="11" style="background-color:#bbbdc0"><bold>COGNITIVE ABILITY</bold></td>
</tr>
<tr>
<td valign="top" align="left">Nienow et al., <xref ref-type="bibr" rid="B34">2016</xref><xref ref-type="table-fn" rid="TN2"><sup>&#x0002A;&#x0002A;</sup></xref></td>
<td valign="top" align="left">MCCB Composite (total score)</td>
<td valign="top" align="left">F3</td>
<td valign="top" align="left">Supraorbital (R)</td>
<td valign="top" align="left">Left DLPFC</td>
<td valign="top" align="left">Online</td>
<td valign="top" align="center">1</td>
<td valign="top" align="center">28</td>
<td valign="top" align="char" char=".">0.14</td>
<td valign="top" align="char" char=".">0.12</td>
<td valign="top" align="center">15</td>
</tr>
<tr>
<td valign="top" align="left">Rassovsky et al., <xref ref-type="bibr" rid="B41">2015</xref></td>
<td valign="top" align="left">MCCB Composite (total score)</td>
<td valign="top" align="left">Fp1/Fp2</td>
<td valign="top" align="left">Upper Arm (R)</td>
<td valign="top" align="left">Bilateral DLPFC</td>
<td valign="top" align="left">Offline</td>
<td valign="top" align="center">1</td>
<td valign="top" align="center">1</td>
<td valign="top" align="char" char=".">0.07</td>
<td valign="top" align="char" char=".">0.34</td>
<td valign="top" align="center">12</td>
</tr>
<tr>
<td valign="top" align="left">Smith et al., <xref ref-type="bibr" rid="B45">2015</xref></td>
<td valign="top" align="left">MCCB Composite (total score)</td>
<td valign="top" align="left">F3</td>
<td valign="top" align="left">Supraorbital (R)</td>
<td valign="top" align="left">Left DLPFC</td>
<td valign="top" align="left">Offline</td>
<td valign="top" align="center">2</td>
<td valign="top" align="center">5</td>
<td valign="top" align="char" char=".">0.30</td>
<td valign="top" align="char" char=".">1.89</td>
<td valign="top" align="center">5</td>
</tr>
<tr>
<td valign="top" align="left">Mean Effect</td>
<td/>
<td/>
<td/>
<td/>
<td/>
<td/>
<td/>
<td valign="top" align="char" char=".">0.17</td>
<td valign="top" align="char" char=".">0.20</td>
<td/>
</tr>
</tbody>
</table>
<table-wrap-foot>
<p><italic>All studies stimulated for 20 min at a time, electrode area was 35 cm<sup>2</sup> for all but Smith et al. (<xref ref-type="bibr" rid="B45">2015</xref>) which was 5.08 cm<sup>2</sup></italic>.</p>
<fn id="TN1">
<label>&#x0002A;</label>
<p><italic>Randomized between sessions for transcranial alternating, direct, and sham current stimulation. Only tDCS and sham conditions included in review</italic>.</p></fn>
<fn id="TN2">
<label>&#x0002A;&#x0002A;</label>
<p><italic>Includes cognitive remediation training (48 h) for both tDCS and sham groups</italic>.</p></fn>
<fn id="TN3">
<label>&#x0002A;&#x0002A;&#x0002A;</label>
<p><italic>Study includes stimulation concurrent to task, although effect sizes were calculated from pre-post assessments</italic>.</p></fn>
</table-wrap-foot>
</table-wrap>
</sec>
<sec>
<title>Quantitative review</title>
<sec>
<title>Effect sizes</title>
<p>Effect sizes were calculated by combining elements of repeated measures and independent groups designs as described by previous meta-analytic work (Becker, <xref ref-type="bibr" rid="B4">1988</xref>; Morris and DeShon, <xref ref-type="bibr" rid="B32">2002</xref>, Equation 6):</p>
<disp-formula id="E1"><mml:math id="M1"><mml:mtable columnalign='left'><mml:mtr><mml:mtd><mml:mi>d</mml:mi><mml:mo>=</mml:mo><mml:mfrac><mml:mrow><mml:mi>S</mml:mi><mml:mi>t</mml:mi><mml:mi>i</mml:mi><mml:mi>m</mml:mi><mml:mi>u</mml:mi><mml:mi>l</mml:mi><mml:mi>a</mml:mi><mml:mi>t</mml:mi><mml:mi>i</mml:mi><mml:mi>o</mml:mi><mml:mi>n</mml:mi><mml:mtext>&#x02009;</mml:mtext><mml:mi>M</mml:mi><mml:mi>e</mml:mi><mml:mi>a</mml:mi><mml:msub><mml:mi>n</mml:mi><mml:mrow><mml:mi>p</mml:mi><mml:mi>o</mml:mi><mml:mi>s</mml:mi><mml:mi>t</mml:mi></mml:mrow></mml:msub><mml:mo>&#x02212;</mml:mo><mml:mtext>&#x02009;</mml:mtext><mml:mi>S</mml:mi><mml:mi>t</mml:mi><mml:mi>i</mml:mi><mml:mi>m</mml:mi><mml:mi>u</mml:mi><mml:mi>l</mml:mi><mml:mi>a</mml:mi><mml:mi>t</mml:mi><mml:mi>i</mml:mi><mml:mi>o</mml:mi><mml:mi>n</mml:mi><mml:mtext>&#x02009;</mml:mtext><mml:mi>M</mml:mi><mml:mi>e</mml:mi><mml:mi>a</mml:mi><mml:msub><mml:mi>n</mml:mi><mml:mrow><mml:mi>b</mml:mi><mml:mi>a</mml:mi><mml:mi>s</mml:mi><mml:mi>e</mml:mi><mml:mi>l</mml:mi><mml:mi>i</mml:mi><mml:mi>n</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:mrow><mml:mrow><mml:mi>S</mml:mi><mml:mi>t</mml:mi><mml:mi>i</mml:mi><mml:mi>m</mml:mi><mml:mi>u</mml:mi><mml:mi>l</mml:mi><mml:mi>a</mml:mi><mml:mi>t</mml:mi><mml:mi>i</mml:mi><mml:mi>o</mml:mi><mml:mi>n</mml:mi><mml:mtext>&#x02009;</mml:mtext><mml:mi>S</mml:mi><mml:msub><mml:mi>D</mml:mi><mml:mrow><mml:mi>b</mml:mi><mml:mi>a</mml:mi><mml:mi>s</mml:mi><mml:mi>e</mml:mi><mml:mi>l</mml:mi><mml:mi>i</mml:mi><mml:mi>n</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:mfrac></mml:mtd></mml:mtr><mml:mtr><mml:mtd><mml:mtext>&#x000A0;&#x000A0;&#x000A0;&#x000A0;&#x000A0;&#x000A0;&#x000A0;</mml:mtext><mml:mo>&#x02212;</mml:mo><mml:mtext>&#x02009;</mml:mtext><mml:mfrac><mml:mrow><mml:mi>S</mml:mi><mml:mi>h</mml:mi><mml:mi>a</mml:mi><mml:mi>m</mml:mi><mml:mtext>&#x02009;</mml:mtext><mml:mi>M</mml:mi><mml:mi>e</mml:mi><mml:mi>a</mml:mi><mml:msub><mml:mi>n</mml:mi><mml:mrow><mml:mi>p</mml:mi><mml:mi>o</mml:mi><mml:mi>s</mml:mi><mml:mi>t</mml:mi></mml:mrow></mml:msub><mml:mo>&#x02212;</mml:mo><mml:mtext>&#x02009;</mml:mtext><mml:mi>S</mml:mi><mml:mi>h</mml:mi><mml:mi>a</mml:mi><mml:mi>m</mml:mi><mml:mtext>&#x02009;</mml:mtext><mml:mi>M</mml:mi><mml:mi>e</mml:mi><mml:mi>a</mml:mi><mml:msub><mml:mi>n</mml:mi><mml:mrow><mml:mi>b</mml:mi><mml:mi>a</mml:mi><mml:mi>s</mml:mi><mml:mi>e</mml:mi><mml:mi>l</mml:mi><mml:mi>i</mml:mi><mml:mi>n</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:mrow><mml:mrow><mml:mi>S</mml:mi><mml:mi>h</mml:mi><mml:mi>a</mml:mi><mml:mi>m</mml:mi><mml:mtext>&#x02009;</mml:mtext><mml:mi>S</mml:mi><mml:msub><mml:mi>D</mml:mi><mml:mrow><mml:mi>b</mml:mi><mml:mi>a</mml:mi><mml:mi>s</mml:mi><mml:mi>e</mml:mi><mml:mi>l</mml:mi><mml:mi>i</mml:mi><mml:mi>n</mml:mi><mml:mi>e</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:mfrac></mml:mtd></mml:mtr></mml:mtable></mml:math></disp-formula>
<p>Baseline standard deviations are assumed to be more comparable across studies before different treatments are applied. Sham-adjustment is important because research has observed non-zero changes in control groups (sham) over time (Lipsey and Wilson, <xref ref-type="bibr" rid="B28">1993</xref>; Carlson and Schmidt, <xref ref-type="bibr" rid="B8">1999</xref>).</p>
</sec>
<sec>
<title>Sampling variance</title>
<p>Sampling variance calculations were selected to match the combined effect size (Becker, <xref ref-type="bibr" rid="B4">1988</xref>), drawn from Morris and DeShon (<xref ref-type="bibr" rid="B32">2002</xref>), computing each group&#x00027;s variance separately (Equation A1) and adding them together, where <italic>df</italic> &#x0003D; n&#x02212;1, <italic>d</italic> is the effect size, and <italic>c</italic> is the bias function <inline-formula><mml:math id="M2"><mml:mn>1</mml:mn><mml:mo>-</mml:mo><mml:mfrac><mml:mrow><mml:mn>3</mml:mn></mml:mrow><mml:mrow><mml:mn>4</mml:mn><mml:mi>d</mml:mi><mml:mi>f</mml:mi><mml:mo>-</mml:mo><mml:mn>1</mml:mn></mml:mrow></mml:mfrac></mml:math></inline-formula> (Equation 23):</p>
<disp-formula id="E2"><mml:math id="M3"><mml:mtable columnalign="left"><mml:mtr><mml:mtd><mml:mi>s</mml:mi><mml:mi>a</mml:mi><mml:mi>m</mml:mi><mml:mi>p</mml:mi><mml:mi>l</mml:mi><mml:mi>i</mml:mi><mml:mi>n</mml:mi><mml:mi>g</mml:mi><mml:mtext>&#x000A0;</mml:mtext><mml:mi>v</mml:mi><mml:mi>a</mml:mi><mml:mi>r</mml:mi><mml:mi>i</mml:mi><mml:mi>a</mml:mi><mml:mi>n</mml:mi><mml:mi>c</mml:mi><mml:mi>e</mml:mi><mml:mtext>&#x000A0;</mml:mtext><mml:mo>=</mml:mo><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mfrac><mml:mrow><mml:mn>1</mml:mn></mml:mrow><mml:mrow><mml:mi>n</mml:mi></mml:mrow></mml:mfrac></mml:mrow><mml:mo>)</mml:mo></mml:mrow><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mfrac><mml:mrow><mml:mi>d</mml:mi><mml:mi>f</mml:mi></mml:mrow><mml:mrow><mml:mi>d</mml:mi><mml:mi>f</mml:mi><mml:mo>-</mml:mo><mml:mn>2</mml:mn></mml:mrow></mml:mfrac></mml:mrow><mml:mo>)</mml:mo></mml:mrow><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mn>1</mml:mn><mml:mtext>&#x000A0;</mml:mtext><mml:mo>&#x0002B;</mml:mo><mml:mtext>&#x000A0;</mml:mtext><mml:mi>n</mml:mi><mml:mo>&#x0002A;</mml:mo><mml:msup><mml:mrow><mml:mi>d</mml:mi></mml:mrow><mml:mrow><mml:mn>2</mml:mn></mml:mrow></mml:msup></mml:mrow><mml:mo>)</mml:mo></mml:mrow><mml:mo>-</mml:mo><mml:mfrac><mml:mrow><mml:msup><mml:mrow><mml:mi>d</mml:mi></mml:mrow><mml:mrow><mml:mn>2</mml:mn></mml:mrow></mml:msup></mml:mrow><mml:mrow><mml:msup><mml:mrow><mml:mi>c</mml:mi><mml:mrow><mml:mo stretchy="false">(</mml:mo><mml:mrow><mml:mi>d</mml:mi><mml:mi>f</mml:mi></mml:mrow><mml:mo stretchy="false">)</mml:mo></mml:mrow></mml:mrow><mml:mrow><mml:mn>2</mml:mn></mml:mrow></mml:msup></mml:mrow></mml:mfrac></mml:mtd></mml:mtr></mml:mtable></mml:math></disp-formula>
<p>Meta-analytic procedures detailed in Lipsey and Wilson (<xref ref-type="bibr" rid="B29">2001</xref>) and Morris and DeShon (<xref ref-type="bibr" rid="B32">2002</xref>) were used to calculate weights as the inverse of the squared standard error for each effect size. Variance-weighted mean effect sizes (d<sub>W</sub>) and mean effect sizes without weights (d<sub>UW</sub>) should be interpreted carefully as not all studies examined each cognitive domain discussed. There are an inadequate number of measures in each domain to detect a significant effect for a specific hypothesis (e.g., <italic>Z</italic>-test), even if sample-dependent measures are treated as sample-independent.</p>
</sec>
</sec>
</sec>
<sec id="s3">
<title>Effect sizes for cognition</title>
<p>Sham-adjusted effect sizes for anodal stimulation are reported in Table <xref ref-type="table" rid="T1">1</xref>. As a complement to effect sizes, ranks for variance-weighted effect sizes are also included in the table, with larger, positive descriptive effects ranked highest and the rest in descending order. Confidence intervals are included below as a measure of variability. For comparison to the greater literature (without any specific hypothesis testing) effect sizes are discussed according to Cohen&#x00027;s conventions of 0.2, 0.5, and 0.8 as putative measures for small, medium, and large descriptive, non-inferential effects (Cohen, <xref ref-type="bibr" rid="B9">1992</xref>). These distinctions were originally a proposed route for accurate foresight in power analysis and are not strictly indicative of clinical efficacy (Abelson, <xref ref-type="bibr" rid="B1">1985</xref>; Prentice and Miller, <xref ref-type="bibr" rid="B40">1992</xref>). Results from other areas provide a benchmark: small classes rather than large had an effect of 0.20 on educational achievement (Hedges and Stock, <xref ref-type="bibr" rid="B20">1983</xref>), therapy for test anxiety in college students showed an effect of 0.58 on anxiety and test performance (Harris, <xref ref-type="bibr" rid="B19">1988</xref>). Other effects beneath Cohen&#x00027;s conventions that may be worth implementing include individualized education program&#x00027;s effects on achievement at 0.10 (Bangert-Drowns et al., <xref ref-type="bibr" rid="B3">1983</xref>) and 0.17 (Hood, <xref ref-type="bibr" rid="B21">1991</xref>). Therefore, these conventions should not underrepresent the importance of the effects of stimulation.</p>
<sec>
<title>Overview</title>
<p>The 194 studies were screened according to inclusion and exclusion criteria at title, abstract, and full text levels and subsequently reduced to 6 studies for quantitative review. A flow diagram indicating successive exclusion is provided in Figure <xref ref-type="fig" rid="F1">1</xref>. Although, search terms were determined in order to garner citations involving psychosis, it is important to note that our search rendered only populations diagnosed with schizophrenia and schizoaffective disorder. All studies evaluated individuals with schizophrenia; three included schizoaffective disorder. All articles meeting eligibility criteria stimulated the DLPFC. Cathodal stimulation is reported where applicable or omitted from results when not. Domains of cognition included in the retained articles are discussed herein.</p>
</sec>
<sec>
<title>Attention</title>
<p>Smith et al. (<xref ref-type="bibr" rid="B45">2015</xref>) reported the only behavioral measures of attention, with a variant of the continuous performance task. The mean effect size for anodal stimulation was small to medium (d<sub>w</sub> &#x0003D; 0.40, 95% CI: &#x02212;0.15, 0.96; d<sub>uw</sub> &#x0003D; 0.40). No behavioral measures were used with cathodal stimulation in the studies reviewed. Only Dunn et al. (<xref ref-type="bibr" rid="B11">2016</xref>) included neurophysiological measures of attention and error, using an auditory oddball task to elicit event related potentials, specifically P300 and mismatch negativity. Different effects were observed between the anodal stimulation group (d<sub>w</sub> &#x0003D; &#x02212;0.44, 95% CI: &#x02212;1.17, 0.28; d<sub>uw</sub> &#x0003D; &#x02212;0.69) and the cathodal stimulation group (d<sub>w</sub> &#x0003D; 0.10, 95% CI: &#x02212;.53, 0.73; d<sub>uw</sub> &#x0003D; 0.10). These neurophysiological outcomes are included for the purposes of the review, yet are not a part of other calculated mean effects.</p>
</sec>
<sec>
<title>Memory</title>
<p>Only Smith et al. (<xref ref-type="bibr" rid="B45">2015</xref>) included measures for memory with a letter-number span task. The mean anodal effect was marginal to small (d<sub>w</sub> &#x0003D; 0.16, 95% CI: &#x02212;.41, 0.73; d<sub>uw</sub> &#x0003D; 0.21).</p>
</sec>
<sec>
<title>Processing speed</title>
<p>Two studies employed symbol-coding tasks to measure processing speed. The mean anodal effect for processing speed was marginal (d<sub>w</sub> &#x0003D; &#x02212;0.16, 95% CI: &#x02212;.78, 0.46; d<sub>uw</sub> &#x0003D; &#x02212;0.16).</p>
</sec>
<sec>
<title>Social cognition</title>
<p>The mean anodal effect for social cognition was marginal (d<sub>w</sub> &#x0003D; 0.15, 95% CI: &#x02212;0.44, 0.75; d<sub>uw</sub> &#x0003D; 0.14) as calculated from two studies that included the same broad measure (Mayer-Salovey-Caruso Emotional Intelligence Test). For cathodal conditions, the effect (d<sub>w</sub> &#x0003D; 0.06, 95% CI: &#x02212;0.39, 0.51; d<sub>uw</sub> &#x0003D; 0.06) was calculated as the mean effect for all measures included in the one study that examined social cognition (Rassovsky et al., <xref ref-type="bibr" rid="B41">2015</xref>; see Table <xref ref-type="table" rid="T1">1</xref>).</p>
</sec>
<sec>
<title>Working memory</title>
<p>The mean anodal effect for working memory was small (d<sub>w</sub> &#x0003D; 0.23, 95% CI: &#x02212;0.31, 0.77; d<sub>uw</sub> &#x0003D; 0.21). The effect was calculated from four studies using n-back tasks to measure working memory (variants of the N-Back task). Two of these studies carried out anodal tDCS concurrent with administration of the working memory task (Hoy et al., <xref ref-type="bibr" rid="B24">2016</xref>; Nienow et al., <xref ref-type="bibr" rid="B34">2016</xref>). Nienow et al. (<xref ref-type="bibr" rid="B34">2016</xref>) used picture and word n-backs to avoid direct practice effects from treatment sessions. The combined interpretation suggests a small effect at this time. The variance-weighted mean effect without Nienow et al. and Hoy et al. is almost double, but still a small effect (d<sub>w</sub> &#x0003D; 0.39, 95% CI: &#x02212;0.23, 1.01; d<sub>uw</sub> &#x0003D; 0.35). These three studies were particularly low in variability, which also explains the difference between weighted and unweighted effect sizes when Nienow et al. is excluded.</p>
</sec>
<sec>
<title>Cognitive ability</title>
<p>Across three studies, the mean anodal effect for general cognitive ability was small to marginal (d<sub>w</sub> &#x0003D; 0.20, 95% CI: &#x02212;0.37, 0.76; d<sub>uw</sub> &#x0003D; 0.17). Although, one of the studies included here also employed cognitive remediation in tandem with tDCS (Nienow et al., <xref ref-type="bibr" rid="B34">2016</xref>), this summary category also has the advantage of using the same measure (Matrics Consensus Cognitive Battery; Nuechterlein and Green, <xref ref-type="bibr" rid="B37">2006</xref>). Only Rassovsky et al. (<xref ref-type="bibr" rid="B41">2015</xref>) included a cathodal stimulation condition, for which the effect size was small (d<sub>w</sub> &#x0003D; 0.29, 95% CI: &#x02212;0.61, 1.18; d<sub>uw</sub> &#x0003D; 0.29). For the studies without a direct measure for general cognitive ability (Hoy et al., <xref ref-type="bibr" rid="B24">2016</xref>; Palm et al., <xref ref-type="bibr" rid="B38">2016</xref>), effect sizes within the studies were averaged as a general measure. Including the additional studies, general cognitive ability showed a marginal mean weighted effect for anodal stimulation (d<sub>w</sub> &#x0003D; 0.06, 95% CI: &#x02212;0.41, 0.52; d<sub>uw</sub> &#x0003D; 0.06).</p>
</sec>
</sec>
<sec id="s4">
<title>Effect sizes for studies by methods used</title>
<p>Unless otherwise noted, methodological issues are discussed across all domains and are not specific. Examining bilateral stimulation through the two studies that used such a montage (Rassovsky et al., <xref ref-type="bibr" rid="B41">2015</xref>; Dunn et al., <xref ref-type="bibr" rid="B11">2016</xref>) resulted in different effects for behavioral and neurophysiological outcomes. For the purposes of this review, bilateral stimulation refers to montages containing two stimulating electrodes of the same polarity with a separate, third electrode serving as the reference electrode. Therefore, they were not averaged so as to not understate their differences, nor were confidence intervals reported. These effects were positive and small to marginal for mean behavioral outcomes in Rassovsky et al. (<xref ref-type="bibr" rid="B41">2015</xref>; d<sub>w</sub> &#x0003D; 0.24, d<sub>uw</sub> &#x0003D; 0.05) with anodal stimulation and with cathodal stimulation medium to marginal (d<sub>w</sub> &#x0003D; 0.51, d<sub>uw</sub> &#x0003D; 0.11). For neurophysiological outcomes (event related potential measures of P300 and mismatch negativity), the mean effects of anodal stimulation were negative and medium to large (d<sub>w</sub> &#x0003D; &#x02212;1.64; d<sub>uw</sub> &#x0003D; &#x02212;0.69), whereas cathodal stimulation resulted in a marginal to near-medium effect (d<sub>w</sub> &#x0003D; 0.48, d<sub>uw</sub> &#x0003D; 0.10; Dunn et al., <xref ref-type="bibr" rid="B11">2016</xref>). These divergent effects likely result from different results within the study, particularly given a large negative effect for one measure as seen in Table <xref ref-type="table" rid="T1">1</xref>. Unilateral anodal stimulation (d<sub>w</sub> &#x0003D; 0.06, 95% CI: &#x02212;0.48, 61; d<sub>uw</sub> &#x0003D; 0.23) was used by four studies (Smith et al., <xref ref-type="bibr" rid="B45">2015</xref>; Hoy et al., <xref ref-type="bibr" rid="B24">2016</xref>; Nienow et al., <xref ref-type="bibr" rid="B34">2016</xref>; Palm et al., <xref ref-type="bibr" rid="B38">2016</xref>) with behavioral outcomes and yielded marginal to small effect sizes calculated using the average of all effects in each behavioral study. Only one study (Hoy et al., <xref ref-type="bibr" rid="B24">2016</xref>) showed a negative finding in this area, but that study only included a single measure (working memory).</p>
<p>Current intensity was also examined for differences in effects between 1 and 2 mA stimulation on behavioral outcomes and was only conducted for anodal stimulation. Based on two studies (Rassovsky et al., <xref ref-type="bibr" rid="B41">2015</xref>; Nienow et al., <xref ref-type="bibr" rid="B34">2016</xref>), marginal to small effects were found for 1 mA stimulation (d<sub>w</sub> &#x0003D; 0.09, 95% CI: &#x02212;0.76, 0.93; d<sub>uw</sub> &#x0003D; 0.24). Based on three studies (Smith et al., <xref ref-type="bibr" rid="B45">2015</xref>; Hoy et al., <xref ref-type="bibr" rid="B24">2016</xref>; Palm et al., <xref ref-type="bibr" rid="B38">2016</xref>), marginal effects were observed for 2 mA stimulation (d<sub>w</sub> &#x0003D; 0.04, 95% CI: &#x02212;0.51, 0.60; d<sub>uw</sub> &#x0003D; &#x02212;0.05). Only one study, which was excluded for only using a post-test, did have multiple amplitudes (Hoy et al., <xref ref-type="bibr" rid="B22">2014</xref>) and only found improvements for the 2 mA anodal stimulation.</p>
<p>The number of active stimulation sessions constitutes another methodological difference common in the literature. Two studies (Rassovsky et al., <xref ref-type="bibr" rid="B41">2015</xref>; Hoy et al., <xref ref-type="bibr" rid="B24">2016</xref>) using a single session of anodal tDCS found marginal to small negative effects (d<sub>w</sub> &#x0003D; &#x02212;0.13, 95% CI: &#x02212;0.85, 0.59; d<sub>uw</sub> &#x0003D; &#x02212;0.20) that appear driven by one study, highlighting the challenge of summarizing the literature at this time. Three studies (Smith et al., <xref ref-type="bibr" rid="B45">2015</xref>; Nienow et al., <xref ref-type="bibr" rid="B34">2016</xref>; Palm et al., <xref ref-type="bibr" rid="B38">2016</xref>) using more than one session of anodal tDCS, ranging from 5 to 28 sessions showed a positive marginal to small effect (d<sub>w</sub> &#x0003D; 0.19, 95% CI: &#x02212;0.42, 0.80; d<sub>uw</sub> &#x0003D; 0.24). Currently, a direct trend has not been identified between the amount of stimulation sessions and cognitive enhancement. Such empirical evidence would prompt establishing an accepted dose of stimulation.</p>
<p>The most studied areas of cognition with tDCS in psychosis are working memory, attention, and cognitive ability (Smith et al., <xref ref-type="bibr" rid="B45">2015</xref>; Hoy et al., <xref ref-type="bibr" rid="B24">2016</xref>; Nienow et al., <xref ref-type="bibr" rid="B34">2016</xref>; Palm et al., <xref ref-type="bibr" rid="B38">2016</xref>). This may be due to their overall importance in the literature for the treatment of cognitive deficits in psychosis. Variety exists in measurement time points used in study designs, for example, post-test only (Hoy et al., <xref ref-type="bibr" rid="B22">2014</xref>, <xref ref-type="bibr" rid="B23">2015</xref>), or stimulation concurrent to task and assessment (Vercammen et al., <xref ref-type="bibr" rid="B46">2011</xref>; Schretlen et al., <xref ref-type="bibr" rid="B44">2014</xref>; Reinhart et al., <xref ref-type="bibr" rid="B42">2015a</xref>,<xref ref-type="bibr" rid="B43">b</xref>). This is an especially pertinent source of variability as recent research has demonstrated that tDCS effects are highly state dependent (Elmasry et al., <xref ref-type="bibr" rid="B12">2015</xref>; Gill et al., <xref ref-type="bibr" rid="B16">2015</xref>; Dedoncker et al., <xref ref-type="bibr" rid="B10">2016</xref>), suggesting that the combination of a task with stimulation might yield greater modulation of cognitive domains. As an example, one of our reviewed studies (Nienow et al., <xref ref-type="bibr" rid="B34">2016</xref>) used stimulation concurrent with cognitive remediation and found positive effects. Another important source of variability may stem from differences in the overall electrode montage. It has been shown that even minor changes in placement of the reference electrode affect the distribution and intensity of electrical current (Bai et al., <xref ref-type="bibr" rid="B2">2014</xref>).</p>
</sec>
<sec id="s5">
<title>Summary</title>
<p>This report captures the current state of the literature as it pertains to the cognitive outcomes from tDCS targeted at the DLPFC in schizophrenia. Although, none of the effects observed in this small sample rule-out the possibility of null effects, we were able to quantitatively summarize current knowledge and provide the central tendency of the effects on cognitive outcomes following tDCS over the DLPFC. Small effects of anodal stimulation were observed on behavioral measures of attention and working memory. More tentative small effects were observed for cognitive ability and memory, with marginal effects observed on processing speed. Cathodal stimulation paired with behavioral outcomes suggested a small effect on cognitive ability and a marginal one for social cognition, though this area of the literature is currently underdeveloped.</p>
<p>Neurophysiological measures were restricted to attention and were associated with a small to medium negative effect for anodal stimulation that is driven by a strong modulation of mismatch negativity (Dunn et al., <xref ref-type="bibr" rid="B11">2016</xref>). A marginal effect for cathodal stimulation was also found. A closer reading of that study suggests minor differences in negative symptoms at baseline in the anodal stimulation group. However, another study not indexed in the PubMed database showed a null finding for several neurophysiological measures (Knechtel et al., <xref ref-type="bibr" rid="B25">2014</xref>) included in Dunn et al. (<xref ref-type="bibr" rid="B11">2016</xref>).</p>
<p>Bilateral stimulation with behavioral measures seems to produce tentative small effects with anodal stimulation and medium effects with cathodal. Behavioral measures with a unilateral montage were only assessed with anodal stimulation, which appears to produce either marginal or small effects. More research in unilateral stimulation is important, even though it is more commonly used than bilateral stimulation. Future reviews might seek to address the more specific placement of active or reference electrodes according to the international 10&#x02013;20 system or more detailed schemas where available.</p>
<p>For behavioral outcomes, no particular current intensity seemed critical for modulation with anodal stimulation. Some studies incorporate an alternating current condition and find promising effects (G&#x000F6;der et al., <xref ref-type="bibr" rid="B17">2013</xref>; Hoy et al., <xref ref-type="bibr" rid="B24">2016</xref>). The number of anodal stimulation sessions differed such that a single session of stimulation showed a marginal to small negative effect, whereas multiple sessions showed a marginal to small positive effect.</p>
<p>One general limitation of this review is that the overall and domain-specific weighted averages for cognition must be interpreted carefully, as the sample size and statistical dependence of measures makes inference premature, and few studies report power analyses. Researchers must report means and standard deviations for all groups and time points or other statistics to aid in producing effect sizes. Additionally, few authors studying cognition with multiple measurement time points use neurophysiological measures. One of the largest discrepancies in this review emerges from that fact. With anodal stimulation, behavioral measures of attention showed small, non-significant improvements, but neurophysiological measures showed a decline with a near-medium effect size. More studies using neurophysiologically grounded outcomes (i.e., EEG, fMRI) are critical to understanding the efficacy of tDCS as a potential modulator for cognition in schizophrenia.</p>
<p>This review of tDCS over the DLPFC in schizophrenia highlights methodological heterogeneity that reflects no current gold standard. Although, the review was conducted without specific hypothesis testing, a positive effect is observed for anodal stimulation on several domains of behaviorally measured cognition, with a negative effect on neurophysiologically measured attention. Some support exists for a positive effect of cathodal stimulation on cognition with measures that are behavioral. Future research with larger sample sizes and combined behavioral and neurophysiological outcomes in the same studies are needed to push the field forward.</p>
</sec>
<sec id="s6">
<title>Author contributions</title>
<p>JM co-designed the project, conducted the analysis, and wrote all drafts of the manuscript. RC co-designed the project, supervised data collection, assisted in the analysis, and co-wrote manuscript drafts. EB provided conceptual guidance on project design and co-wrote all drafts of the manuscript. AM designed the project, supervised data analysis, and co-wrote all drafts of the manuscript.</p>
</sec>
<sec id="s7">
<title>Funding</title>
<p>This project was funded by a Graduate Summer Research Fellowship from the Department of Psychology at the University of Minnesota and a Sambol Family Foundation Grant to JM.</p>
<sec>
<title>Conflict of interest statement</title>
<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
</sec>
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