<?xml version="1.0" encoding="utf8"?>
 <!DOCTYPE article PUBLIC "-//NLM//DTD JATS (Z39.96) Journal Publishing DTD v1.0 20120330//EN" "http://jats.nlm.nih.gov/publishing/1.0/JATS-journalpublishing1.dtd"> <article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" article-type="review-article" dtd-version="1.0" xml:lang="en">
  <front>
    <journal-meta>
      <journal-id journal-id-type="publisher-id">JARH</journal-id>
      <journal-title-group>
        <journal-title>Journal of Aging Research And Healthcare</journal-title>
      </journal-title-group>
      <issn pub-type="epub">2474-7785</issn>
      <publisher>
        <publisher-name>Open Access Pub</publisher-name>
        <publisher-loc>United States</publisher-loc>
      </publisher>
    </journal-meta>
    <article-meta>
      <article-id pub-id-type="doi">10.14302/issn.2474-7785.jarh-21-3935</article-id>
      <article-id pub-id-type="publisher-id">JARH-21-3935</article-id>
      <article-categories>
        <subj-group>
          <subject>review-article</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Photobiomodulation, Depression, Anxiety, and Cognition </article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="author">
          <name>
            <surname>Ray</surname>
            <given-names>Marks</given-names>
          </name>
          <xref ref-type="aff" rid="idm1843069932">1</xref>
          <xref ref-type="aff" rid="idm1843070652">*</xref>
        </contrib>
      </contrib-group>
      <aff id="idm1843069932">
        <label>1</label>
        <addr-line>Department of Health and Behavior Studies, Teachers College, Columbia University, New York, NY 10027, USA.</addr-line>
      </aff>
      <aff id="idm1843070652">
        <label>*</label>
        <addr-line>Corresponding author</addr-line>
      </aff>
      <author-notes>
        <corresp>
    
    Ray Marks, <addr-line>Department of Health and Behavior Studies, Teachers College, Columbia University, New York, NY 10027, USA</addr-line><email>rm226@tc.columbia.edu</email></corresp>
        <fn fn-type="conflict" id="idm1849932452">
          <p>The authors have declared that no competing interests exist.</p>
        </fn>
      </author-notes>
      <pub-date pub-type="epub" iso-8601-date="2021-08-23">
        <day>23</day>
        <month>8</month>
        <year>2021</year>
      </pub-date>
      <volume>4</volume>
      <issue>1</issue>
      <fpage>30</fpage>
      <lpage>42</lpage>
      <history>
        <date date-type="received">
          <day>18</day>
          <month>08</month>
          <year>2021</year>
        </date>
        <date date-type="accepted">
          <day>21</day>
          <month>08</month>
          <year>2021</year>
        </date>
        <date date-type="online">
          <day>23</day>
          <month>08</month>
          <year>2021</year>
        </date>
      </history>
      <permissions>
        <copyright-statement>© </copyright-statement>
        <copyright-year>2021</copyright-year>
        <copyright-holder>Ray Marks</copyright-holder>
        <license xlink:href="http://creativecommons.org/licenses/by/4.0/" xlink:type="simple">
          <license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p>
        </license>
      </permissions>
      <self-uri xlink:href="http://openaccesspub.org/jarh/article/1688">This article is available from http://openaccesspub.org/jarh/article/1688</self-uri>
      <abstract>
        <sec id="idm1842934700">
          <title>Background</title>
          <p>Anxiety and depression are key                  barriers to healthy aging and greatly heighten the risk for many negative health issues that seriously impact life quality<bold>.</bold></p>
        </sec>
        <sec id="idm1842935348">
          <title>Aim</title>
          <p>This mini review examines the potential of low level laser treatments or photobiomodulation               therapy for ameliorating severe anxiety and                 depression in older adults.</p>
        </sec>
        <sec id="idm1842935996">
          <title>Methods and Procedures</title>
          <p>Articles that adressed the current topic of interest extracted from PUBMED and Google Scholar were carefully and presented in                narrative form.  </p>
        </sec>
        <sec id="idm1842933980">
          <title>Results</title>
          <p>Photobiomodulation therapy appears to be a safe efficacious modality for ameliorating various degrees of anxiety and depression and for improving cognition, and is supported by several well                       established mechanisms of action at the molecular, cellular, and tissue levels.</p>
        </sec>
        <sec id="idm1842935276">
          <title>Conclusion</title>
          <p> More research to examine who might benefit most from this form of therapy, and in what respect in this area of growing global concern and few intervention options is strongly warranted. </p>
        </sec>
      </abstract>
      <kwd-group>
        <kwd>Aging</kwd>
        <kwd>Anxiety</kwd>
        <kwd>Cognition</kwd>
        <kwd>Depression</kwd>
        <kwd>Low Level Laser</kwd>
        <kwd>Low Level Light Therapy</kwd>
        <kwd>Near Infrared Radiation</kwd>
        <kwd>Transcranial Photobiomodulation Therapy</kwd>
        <kwd>Treatment</kwd>
      </kwd-group>
      <counts>
        <fig-count count="1"/>
        <table-count count="0"/>
        <page-count count="13"/>
      </counts>
    </article-meta>
  </front>
  <body>
    <sec id="idm1842934196" sec-type="intro">
      <title>Introduction</title>
      <p>Depression among the elderly is now                   considered among the leading and most disabling health challenges facing the older population, and will be the foremost disabler by 2030 <xref ref-type="bibr" rid="ridm1843230260">1</xref><xref ref-type="bibr" rid="ridm1843231196">2</xref>. However, its management and current treatments offer many challenges, and have many limitations <xref ref-type="bibr" rid="ridm1843310468">3</xref><xref ref-type="bibr" rid="ridm1843086644">4</xref><xref ref-type="bibr" rid="ridm1843084268">5</xref>. Anxiety, the most common mental health concern among older adults <xref ref-type="bibr" rid="ridm1843075316">6</xref>, and one often associated with                  depression, is also a common debilitating state of fears that commonly impacts health behaviors                 negatively and significantly. Among the various                   strategies for intervening in this regard, a form of low level laser known as photo biomodulation therapy or PBM, which can be applied transcranially and that                           appears to safely activate selected brain pathways and tissues involved in mood disturbances, has been                   advocated for some time <xref ref-type="bibr" rid="ridm1843078844">7</xref><xref ref-type="bibr" rid="ridm1843056844">8</xref><xref ref-type="bibr" rid="ridm1843060876">9</xref><xref ref-type="bibr" rid="ridm1843049892">10</xref>.</p>
      <p>This does not negate other forms of                    intervention that do exist, but is studied because it may fill a gap in areas where these more mainstream             interventions do not help to directly alleviate the highly negative impact of various forms of persistent anxiety, which often accompanies depression, nor pathways inducing associated feelings of sadness, helplessness, loss of interest in self-care as well as pleasure in daily activities in a practical as well as possibly in an                  observable functional and neural context <xref ref-type="bibr" rid="ridm1843049892">10</xref>. On the other hand, multiple studies support the idea that the perpetuation of unrelieved states of suffering, including feelings of hopelessness, and low self-worth, may in turn, increase or produce unwanted stress and                   frustration levels, while adversely impacting coping ability, sleep, energy levels, and appetite, as well as serving as a risk factor for bone loss and osteoporotic fractures <xref ref-type="bibr" rid="ridm1843043556">11</xref>, as well as cardiovascular disease <xref ref-type="bibr" rid="ridm1843041036">12</xref>. In contrast, transcranial photobiomodulation <sup>TPBM</sup> light energy applications, which commonly involve the               delivery of various forms of low level red light spectra via the skull to the brain, appears to have direct effects on brain tissue physiology thought to underpin                   depression, such as inflammation <xref ref-type="bibr" rid="ridm1843053996">13</xref> that may help to alleviate the immense suffering experienced by the chronically anxious and/or depressed older individual, while affording them a heightened sense of emotional control, plus a sense of optimism about possible                  changes that might yet occur with the steady                         application of one or more forms of therapy over time. This use of nonthermal levels of visible or near infrared light for treating depression and anxiety in turn, may be expected to not only mediate the biology and pathways related to the risk and progression of these conditions via photochemical mechanisms <xref ref-type="bibr" rid="ridm1843049892">10</xref><xref ref-type="bibr" rid="ridm1843053996">13</xref>, but may also indirectly prevent the onset of, or reduce the risk of acquiring any excess or secondary chronic illness            burden, injurious tissue degeneration or damage, and/or other adverse life events and losses, including               mobility losses and falls associated with aging that           often in turn, heighten depression and anxiety <xref ref-type="bibr" rid="ridm1843043556">11</xref><xref ref-type="bibr" rid="ridm1843024108">14</xref>. In addition, there may be fewer social            disruptions, along with fewer associated medical visits. At the same time, self-management practices may be more readily accomplished, adhered to, and effective. On the other hand, a failure to alleviate protracted                   unrelenting bouts of anxiety and depression, may foster excess pain experiences, and possible substance abuse, along with a greater likelihood of premature death, higher rates of inflammation, blood pressure issues, memory challenges, and a decreased desire for physical                     activities often recommended for intervening on                 depression and anxiety <xref ref-type="bibr" rid="ridm1843018420">15</xref>.</p>
      <p>In light of the severe impact of excessive                  anxiety and depression as mentioned above, plus its detrimental impact on motivation, as well as health seeking and promoting behaviors, and that evidence shows many factors underpinning depression and              anxiety are amenable to therapy and prevention <xref ref-type="bibr" rid="ridm1843053996">13</xref>, this mini review elected to selectively focus on the known benefits of applying photo biomodulation              therapy in the context of anxiety, depression, and                  possible memory challenges in older adults that might serve to place the individual in a more salient stage of ‘preparedness’ to partake in self-care and be responsive to other forms of non-pharmacologic therapy given the lack of safe forms of practical intervention to ameliorate these conditions in this regard. While other modes of intervention such as meditation may be helpful in this respect, it is possible that some cases of severe chronic mood conditions need to be overcome first by more direct interventions such as those produced by TPBM. Since quality of life may be severely jeopardized by      chronic mood disorders, as well as cognitive challenges that may be reversible, it was believed line of research would prove fruitful to examine.</p>
    </sec>
    <sec id="idm1842932180" sec-type="materials">
      <title>Materials and Methods</title>
      <p>To attain the aims of this review, we attempted to locate salient data housed on PUBMED and GOOGLE SCHOLAR using the key terms, <italic>transcranial</italic><italic>photobiomodulation/lower level laser therapy </italic>and           <italic>depression/anxiety/older adults</italic>. All forms of publication were deemed acceptable if they addressed the topics of interest noted above and there were no yearly or               methodological restrictions. The most salient articles  related to the transcranial use of photobiomodulation therapy, rather than systemic approaches, were duly    examined and those that were noteworthy are presented in narrative form. All modes of application employed in the various research studies were accepted as valid, as were all definitions of anxiety and depression. Moreover, since the article was designed to serve as a general one to introduce the topic, rather than a systematic review,  it did not consider any of the currently reported research endeavors in depth, but rather the goals was to present a snapshot of the prevailing trends in this realm and the potential of this modality for clinical purposes. As per Hamblin <xref ref-type="bibr" rid="ridm1843049892">10</xref><xref ref-type="bibr" rid="ridm1843014172">16</xref>, the term photobiomodulation, which refers to the use of red or near-infrared light to stimulate, heal, regenerate, and protect tissues was used                             predominantly in this brief review. Also termed low level laser light or therapy in the past, as well as simply                  photobiomodulation to describe the therapeutic process these technical terms are used interchangeably in this report. For a succinct review of recent controlled clinical        trials, the articles by de Oliviera Foncesca et al. <xref ref-type="bibr" rid="ridm1843018420">15</xref>, Askalsky and Iosifescu <xref ref-type="bibr" rid="ridm1843310468">3</xref> and Hamblin <xref ref-type="bibr" rid="ridm1843049892">10</xref><xref ref-type="bibr" rid="ridm1843014172">16</xref> are               recommended. </p>
    </sec>
    <sec id="idm1842931964">
      <title>Search Results  </title>
      <sec id="idm1842932252">
        <title>General Observations </title>
        <p>Depressive and anxiety disorders have been shown to be associated with premature or advanced                 biological aging and consequently to adversely impact life quality adversely, as well as somatic health <xref ref-type="bibr" rid="ridm1843009924">17</xref>.                     Treatments with antidepressant medication or running therapy, however, found to be effective for many with mood and anxiety disorders <xref ref-type="bibr" rid="ridm1843009924">17</xref>, are unlikely to be safe in all respects, for example, if the individual is frail <xref ref-type="bibr" rid="ridm1842988292">18</xref>, or they have a high falls risk profile, or if the medications employed produce unwanted side effects, such as obesity. As well, existing antidepressants not only have               burdensome side effects, but are only partially effective in many cases, and relapse is frequently observed <xref ref-type="bibr" rid="ridm1843310468">3</xref>.  For vulnerable older adults who cannot exercise readily and do not respond favorably to antidepressant medications, it appears that non-thermal non-invasive applications of visible or near infrared light transcranial                                neuro-stimulation may be able to stimulate or inhibit   targeted biological cells and tissues that undermine                        emotional health via a reproducible photochemical mechanism <xref ref-type="bibr" rid="ridm1843049892">10</xref><xref ref-type="bibr" rid="ridm1843014172">16</xref>. </p>
        <p>Indeed, since poorly treated anxiety and               depression can cause immense suffering, family                     disruptions, and disability, while worsening the outcomes of many medical illnesses, and/or increasing mortality rates, it appears very important to be able to offer                  vulnerable older adults a minimally invasive and safe  possible therapeutic option <xref ref-type="bibr" rid="ridm1842986420">19</xref>. It is increasingly             essential as well to consider that poorly treated                   depression or anxiety or both can be expected to increase the risk for comorbid diseases, negative inflammatory responses, negative cognitions, health behaviors, and   negative immunity associated changes <xref ref-type="bibr" rid="ridm1842980732">20</xref>. </p>
        <p>On the other hand, if an individual who has been severely immobilized by their depression or anxiety symptoms can experience some relief in a short time frame from repeated bout of photo biomodulation                therapy that may be accompanied by important cognitive improvements, they may be more readily motivated                towards pursuing physical activity and other                              recommended self-help approaches.</p>
      </sec>
      <sec id="idm1842932540">
        <title>What the Research on Photobiomodulation Shows</title>
        <p>​For over 20 years, and despite their varied modes of research and photobiomodulation application strategies, most published data support the utility of this form of therapy for reversing or reducing the severity of anxiety and depression. In addition, several mechanism of action have been affirmed in multiple studies for both those that influence depression as well as                               anxiety <xref ref-type="bibr" rid="ridm1842996572">21</xref><xref ref-type="bibr" rid="ridm1842970316">22</xref>.</p>
        <p>In addition to the findings of positive behavioral effects of chronically stimulating rats using cortical infra red stimulation, plus favorable neurogenic cortical            hippocampus tissue changes <xref ref-type="bibr" rid="ridm1842964412">23</xref>, one controlled clinical trial similarly observed that low level laser applications were indeed able to enhance the effects of cognitive training approaches applied to depressed subjects <xref ref-type="bibr" rid="ridm1842976076">24</xref>. Another <xref ref-type="bibr" rid="ridm1842971180">25</xref>, showed that while participants generally reported more positive affective states than negative, overall affect improved significantly in the treated group when compared to the placebo control group. These data were taken to imply that transcranial laser stimulation is a potentially useful non-invasive and efficacious                  approach for purposes of fostering brain functions such as those related to the cognitive and emotional                       dimensions. Moreover, the mode of application may be manipulated to foster differential outcomes, with some more profound than others <xref ref-type="bibr" rid="ridm1842937812">26</xref>, or effects comparable to more time consuming interventions as far as anxiety is concerned <xref ref-type="bibr" rid="ridm1842933852">27</xref>.  </p>
        <p>​Shiffler et al. <xref ref-type="bibr" rid="ridm1843056844">8</xref> further showed post                    stimulation psychological benefits two and four weeks following but a single treatment of near infrared light  applied to the forehead in a pilot study of 10 patients with major depression and anxiety. Indeed, in this first study to examine major depressive disorder patients, normally a fairly intractable condition, both the depression and anxiety symptoms experienced previously by the                 participants were readily alleviated at two weeks              post-irradiation. At the end of four weeks, 6/10 patients experienced a remission in their depression and 7/10 experienced remission of their anxiety. </p>
        <p>​In the study by Tanaka et al. <xref ref-type="bibr" rid="ridm1842964412">23</xref> who evaluated the antidepressant and anxiolytic effects of infrared                   radiation in a randomized controlled trial using an                experimental animal model, this group similarly found chronic infrared radiation exposure tended to decrease the indicators of depression as well as anxiety-like               behavior employed in the study. As well, selected                   histological assays of the hippocampus showed                    favorable responses in both acutely and chronically               exposed infrared radiation groups compared to the               tissue samples of the control group. These results were taken to indicate that chronic infrared radiation may be able to produce comparable antidepressant- and                 anxiolytic-like effects in the human situation.</p>
        <p>​Other findings relative to anxiety benefits are cited by Brochado et al. <xref ref-type="bibr" rid="ridm1842933852">27</xref> and Yang et al. <xref ref-type="bibr" rid="ridm1842929964">28</xref> and tend to echo and provide further support for the efficacy of photo biomodulation stimulation effects for mitigating chronic anxiety states. In addition, Gabel et al. <xref ref-type="bibr" rid="ridm1842925068">29</xref> who applied photo biomodulation to the back and thighs as an adjunct to physical therapy for chronic pain, also found the patients experienced improvements in                   concurrent depression. Kerppers et al. <xref ref-type="bibr" rid="ridm1842922116">30</xref> too, who studied the use of TPBM found this mode of intervention to decrease anxiety and depression, as well as increasing brain activity as a whole. Using an animal model of                   depression, Mohammed <xref ref-type="bibr" rid="ridm1842918156">31</xref> similarly found laser                  irradiation to successfully ameliorate depression                  induced by reserpine, which was deemed indicative of the potentially beneficial anti-depressant effects of                 low-level infrared laser irradiation on tissues associated with depression in normal and healthy animal brain     tissues.</p>
        <p>In addition, TPBM appears to enhance frontal lobe cognitive activity <xref ref-type="bibr" rid="ridm1842911820">33</xref><xref ref-type="bibr" rid="ridm1842939036">34</xref>, as well as improving     neuron metabolic capacity. As well, when examined              independently in depressed humans, or in combination with coenzyme Q<sub>10,</sub> this approach appears to reduce      oxidative stress, neuro-inflammation, and cell death            associated with depression <xref ref-type="bibr" rid="ridm1842888228">35</xref>. Alone or in                              combination with other interventions, TPBM may hence prove very helpful clinically for ameliorating the severity of symptoms in selected cases of major depression or       reactive depression, among other cognitive impairments experienced at high rates among the elderly.</p>
        <p>According to dos Santos Cardosa <xref ref-type="bibr" rid="ridm1842881604">36</xref> TPBM also has the potential to improve brain energy metabolism as well helping to control damaging inflammatory processes found to prevail among the aged and that contributes to their oftentimes declining cognitive brain functions.              Accordingly, studies in humans have specifically shown that this form of therapy does tend to improve                          electrophysiological brain response activity and cognitive functions such as attention, learning, memory and mood among older adults. </p>
        <p>Importantly, too, Cassano et al. <xref ref-type="bibr" rid="ridm1842877500">37</xref>, who                investigated the tolerability and efficacy of near infrared applications in selected cases diagnosed as having major depression found those who received this form of                  treatment appeared to tolerate this well without any             serious adverse events. Other data show low level infra red rays applied to the frontal region of the skull in              depressed and anxious adults may not only help to            reverse neurotransmitter imbalances, but may foster             cerebral blood flow and metabolic processes in different areas of the brain-found deficient in depressed elders <xref ref-type="bibr" rid="ridm1842875124">38</xref>, such as the frontal lobe <xref ref-type="bibr" rid="ridm1842870444">39</xref>. Photo biomodulation also appears to improve any present mitochondrial                dysfunction, as well as oxidative stress mechanisms and neuroinflammation. Improvements in any impaired        neurogenesis functions (i.e., ability to regenerate and/or grow nerves/neurons); are other explanations for its              efficacy.</p>
        <p>These post stimulation consistently observed increases in regional blood flow in the brain of depressed individuals subjected to TPBM and others may thus               augment cerebral energy metabolism, a contributing                factor to depressive manifestations <xref ref-type="bibr" rid="ridm1842866052">40</xref>, while their                apparent antidepressant effect coupled with the enhanced blood flow in turn, potentially contributes to the                     increased chances of the patient experiencing some                degree of recovery from persistent mood disorders and impaired cognitions <xref ref-type="bibr" rid="ridm1842881604">36</xref><xref ref-type="bibr" rid="ridm1842866052">40</xref>.</p>
        <p>It is also known that red light therapy can foster the release of nitric oxide, a vasodilator, that could help improve circulation to selectively irradiated cortical areas, while near infra red light spectra may help to                    specifically activate antioxidant mechanisms that reduce damaging oxidative stresses. According to Xu et al. <xref ref-type="bibr" rid="ridm1842861516">41</xref> depression like behaviors can also be reduced in response to photobiomodulation applications given their observed ability to impact on neurotransmitter abnormalities and promote mitochondrial function in the prefrontal cortex. According to Xu et al. <xref ref-type="bibr" rid="ridm1842861516">41</xref>, red light therapy                                also stimulates neurogenesis and synaptogeneisis and protects against cell death by improving levels of                    brain-derived neurotrophic factor. As indicated in                        multiple, studies conducted in different animal models and in humans, TPBM appears to not only have the power to improve cerebral metabolic activity as well as blood flow <xref ref-type="bibr" rid="ridm1842857052">42</xref>, and ATP production, but to also enhance                     anti-inflammatory and antioxidant pathway influences, which are known to prevail in the context of various            degrees of depression and distress <xref ref-type="bibr" rid="ridm1843310468">3</xref><xref ref-type="bibr" rid="ridm1843060876">9</xref>.</p>
        <p>The application of the TPBM is hence not only a promising approach for the treatment of a wide range of neuropsychiatric disorders, including disorders                       characterized by poor regulation of emotion such as                  major depressive disorder <xref ref-type="bibr" rid="ridm1842911820">33</xref><xref ref-type="bibr" rid="ridm1842888228">35</xref><xref ref-type="bibr" rid="ridm1842866052">40</xref><xref ref-type="bibr" rid="ridm1842844804">43</xref><xref ref-type="bibr" rid="ridm1842837892">44</xref><xref ref-type="bibr" rid="ridm1842835012">45</xref>, but the clear demonstration of the multiple relevant mechanisms of action explaining its observed impact on cerebral                  cortical tissues and cells, greatly strengthen the credibility of the current therapeutic observations <xref ref-type="bibr" rid="ridm1843014172">16</xref>. Moreover, this is seen to occur regardless of method of stimulation and target tissues examined, and even though the              techniques of application vary, they all essentially direct light, typically in the near infra red range of the spectrum to the brain through the skull, where they appear to                 readily activate numerous desirable cellular, circulatory, and anti-inflammatory processes. There are hence                     currently a wide range of related clinical trials in this promising realm, including those targeting major             depressive disorder, generalized anxiety disorder,                 dementia, traumatic brain injury and post-traumatic stress disorder to support its more widespread usage and utility <xref ref-type="bibr" rid="ridm1843078844">7</xref><xref ref-type="bibr" rid="ridm1843049892">10</xref><xref ref-type="bibr" rid="ridm1843014172">16</xref><xref ref-type="bibr" rid="ridm1842844804">43</xref><xref ref-type="bibr" rid="ridm1842837892">44</xref><xref ref-type="bibr" rid="ridm1842835012">45</xref>.</p>
        <p>As well, new methods of application, such as those that utilize an intranasal mode have become an attractive and potentially useful option for the treatment of a variety of potentially reversible brain conditions because evidence to date shows that nostril-based                applications can improve blood rheology, and cerebral blood flow, that may produce results equivalent to those observed when using peripheral intravenous laser           irradiation procedures <xref ref-type="bibr" rid="ridm1842828388">46</xref>. Theoretically, these light rays can also be expected to stimulate cortical                   mitochondrial respiratory chain components, as well as significantly increasing cerebral blood flow <xref ref-type="bibr" rid="ridm1843310468">3</xref><xref ref-type="bibr" rid="ridm1842857052">42</xref> and neurogenesis <xref ref-type="bibr" rid="ridm1842824356">47</xref>. Its anti-apoptotic, anti-inflammatory, and antioxidative responses, may also provide for pain relief, often a key contributor to the presence of                persistent anxiety and depressive states.  Xioran et al. <xref ref-type="bibr" rid="ridm1842820036">48</xref> also highlights the promise of various forms of light therapy for potentially improving brain activity patterns in those diseases or situations affected by brain                    dysfunction and/or injury and that may engender               depression and anxiety states. In addition, Salgado et al. <xref ref-type="bibr" rid="ridm1842857052">42</xref> report transcranial low level light therapy applied with an LED device (light-emitting diode device—627 nm, 70 mW/cm<xref ref-type="bibr" rid="ridm1843231196">2</xref>, 10 J/cm<xref ref-type="bibr" rid="ridm1843231196">2</xref>, for a total of 2 minutes) to the frontal and parietal encephalic regions of elderly individuals, twice weekly for 4 weeks, increased blood flow velocity in the middle and basilar cerebral arteries. This suggested that the procedure might prove to be a useful form of prophylactic therapy in the elderly                population, who are commonly affected by age                       associated vascular and cognitive alterations often found in cases with chronic depression and as supported by Gutiérrez-Menéndez et al. <xref ref-type="bibr" rid="ridm1842835012">45</xref>. It may also enhance excitatory synaptic transmission <xref ref-type="bibr" rid="ridm1842845092">50</xref>, despite the           presence of any already apparently compromised                integrity of the frontal-limbic networks implicated in depression, as well as frequent observations of                     volumetric hippocampus, anterior cingulate cortex,                  prefrontal cortex, striatum, and amygdale reductions, as well as compromised white matter integrity <xref ref-type="bibr" rid="ridm1842769172">51</xref>, and the favorable effects can potentially be sustained with bilateral prefrontal sited applications delivered                      intermittently over time <xref ref-type="bibr" rid="ridm1842835012">45</xref>.</p>
        <p>In sum, as discussed by Urquhart et al. <xref ref-type="bibr" rid="ridm1842763124">52</xref>    photobiomodulation applications of low-power,                     high-fluence light in the red to near-infrared range (usually between 630-1100 nm) are found to modulate cortical mitochondrial respiratory pathways and other salient neural mechanisms implicated in depression and anxiety among the elderly in a non-destructive and                non-thermal manner. While enhancing cerebral                      oxygenation and cognitive function, among other                 positive attributes including metabolic and                                hemodynamic alterations in the brain, it appears                photobiomoduation applications can activate key                 neuroprotective mechanisms, while enhancing                     cognitions. Although initially viewed quite skeptically for some time <xref ref-type="bibr" rid="ridm1843049892">10</xref><xref ref-type="bibr" rid="ridm1843014172">16</xref>, multiple current reviews and studies by various groups tend to support this form of therapy as consistently promising and helpful in safely alleviating depression, anxiety, and cognitive                            dysfunction. It also appears that TPBM as applied to   alleviating intractable bouts of depression and anxiety may also reduce the extent of any persistent mood states through its positive influence on pain, wound healing, muscle function, and aesthetic applications <xref ref-type="bibr" rid="ridm1843018420">15</xref>. </p>
      </sec>
    </sec>
    <sec id="idm1842930380" sec-type="discussion">
      <title>Discussion</title>
      <p>Depression and anxiety, major health issues impacting older adults negatively and significantly                remain extremely challenging to eliminate. This review discusses findings concerning the possible role of                  photobiomodulation, a form of light therapy that utilizes non-ionizing light sources, including lasers, light                       emitting diodes, or broadband light to treat brain                tissues, while providing a safe means of modulating brain activity without any irreversible damage in this regard <xref ref-type="bibr" rid="ridm1842820036">48</xref>. According to Gutiérrez-Menéndez et al. <xref ref-type="bibr" rid="ridm1842835012">45</xref> and an increasing number of researchers <xref ref-type="bibr" rid="ridm1843014172">16</xref>,                      photobiomodulation, a non invasive brain modulation technique that can be applied in different formats, shows considerable promise in this regard for being able to stimulate, preserve and regenerate cells and tissues,    including mitochondrial photon absorption, function, and integrity, while activating signaling pathways,                transcription factors and protective genes, and                        anti-inflammatory mechanisms <xref ref-type="bibr" rid="ridm1842824356">47</xref><xref ref-type="bibr" rid="ridm1842762044">53</xref> associated with depressive symptoms and others <xref ref-type="bibr" rid="ridm1843078844">7</xref>. </p>
      <p>
        <xref ref-type="fig" rid="idm1850396828">Figure 1</xref>
      </p>
      <fig id="idm1850396828">
        <label>Figure 1.</label>
        <caption>
          <title> Schematic of hypothesized benefits that may accrue from applications of transcranial                                    photobiomodulation TPBM to cases suffering from protracted anxiety and/or depression plus cognitive                             dysfunction</title>
        </caption>
        <graphic xlink:href="images/image1.jpg" mime-subtype="jpg"/>
      </fig>
      <p>Older adults were the specific focus in this             review, given the high prevalence rates of mood            disorders in this group, including those with Alzheimer’s disease <xref ref-type="bibr" rid="ridm1842824356">47</xref>, which may worsen with unrelieved albeit preventable depression symptoms. A high number of depressed older adults with memory loss may not be amenable to psychotherapy or alternate mainstream forms of therapy, such as exercise. As well, as opposed to pharmacotherapy, which may only have a limited impact in severe cases, Disner et al. <xref ref-type="bibr" rid="ridm1842976076">24</xref> note low-level light therapy with transcranial laser is a non-invasive form of therapy that can be applied selectively to the prefrontal lobe to reduce depression and anxiety symptoms through its ability to foster a state of potentially                      sustainable neuro enhancement <xref ref-type="bibr" rid="ridm1842835012">45</xref>. Additional                research further shows features of depression, including impaired neuronal metabolism, chronic pain, and                    various degrees of cognition, may indeed be modified favorably by this approach. </p>
      <p>Kerppers et al <xref ref-type="bibr" rid="ridm1842922116">30</xref> -who examined transcranial                    photobiomodulation in an effort to heighten  neural             activity in anxious and/or depressed younger subjects did find this modality was able to stimulate brain          activity. This was also the view of Maiello et al. <xref ref-type="bibr" rid="ridm1842970316">22</xref> and Cassano et al. <xref ref-type="bibr" rid="ridm1842837892">44</xref>. Moreover, the fact that red and near infra red light stimuli can be selectively modulated and adjusted non invasively to effect cognitive targets                    associated with declines in emotional health  and                      impaired psychological status <xref ref-type="bibr" rid="ridm1842760316">54</xref> is expected to help minimize or reduce the complex challenges of excess distress attributable to mood disturbances and their oftentimes disabling immobilizing ramifications and negative health consequences <xref ref-type="bibr" rid="ridm1843014172">16</xref>. Indeed, numerous studies that do exist all tend to show that in agreement with the known structural and dysfunctional alterations of the brain in depression and anxiety states, this non invasive form of light stimulation does consistently                appear to mitigate various degrees of mood                                disturbances, effectively and significantly, and can                 reverse abnormalities, including those associated with severe depression states, as well as cognitions deemed irreversible. In addition, these improvements can be      explained by observable related changes in one or more brain sites, molecular pathways, and neural processes implicated in mediating one or both of these disabling psychological conditions <xref ref-type="bibr" rid="ridm1842844804">43</xref>. These include, but are not limited to favorable impacts on mitochondrial                          metabolism and other pathways relevant to major                depressive disorders. In addition, studies on animal models indicate the benefits from this form of therapy appear to be comparable to those achieved by                 antidepressant medications. Clinical studies also                  indicate good tolerability.</p>
      <p>Taken as a whole, and even if studies to the            contrary have not been published, in accord with              Hamblin <xref ref-type="bibr" rid="ridm1843049892">10</xref><xref ref-type="bibr" rid="ridm1843014172">16</xref> and others <sup>eg.</sup><xref ref-type="bibr" rid="ridm1842754844">55</xref>, photo                          biomodulation, a novel form of light therapy that utilizes non-ionizing light sources, including lasers, light             emitting diodes, or broadband light, does appear to be a highly promising safe means of modulating brain                 cortical activity in simulated as well as clinical                      depression and anxiety without any observable damage when delivered transcranially <xref ref-type="bibr" rid="ridm1842844804">43</xref>. Also associated with cognitive improvements, memory, and behavioral                 improvements, including attenuation of depression and anxiety, and increased cortical oxygenation, the                   application of TPBM may be especially helpful for                alleviating suffering in older adults who cannot exercise readily, take medications, or interact effectively clinically or in a group <xref ref-type="bibr" rid="ridm1842754844">55</xref>, especially those with cognitive                  challenges and frail elders with multiple morbidities. Thus future work to validate these preliminary findings, as well as clarifying the apparent clinical value of TPBM for larger more diverse samples that may lead to more targeted and successful therapies is strongly warranted. As well, the role of TPBM as an adjunctive therapeutic tool should be examined. In the interim, since many         current intervention approaches, it appears that subject to careful patient evaluation concerning the nature and etiology of any prevailing chronic mood disturbances, the carefully construed and monitored application of TPBM can be expected to safely reduce feelings of excess anxiety <xref ref-type="bibr" rid="ridm1842749444">56</xref> and depression <xref ref-type="bibr" rid="ridm1842835012">45</xref> to some degree, with minimal risk, regardless of age and extent of the severity of one or more mood disturbances. To shed more light on the potential for TPBM and its implications on health status as a whole, testing whether such an application yield important parallel improvements in parameters related to the function of the musculoskeletal and                                     cardiorespiratory systems, plus the immune system will be valuable. Whether bone health, the degree of sleep and life quality, and  the extent of premature or biological aging attributable to inflammation can be attenuated is also of possible value to ascertain <xref ref-type="bibr" rid="ridm1843009924">17</xref><xref ref-type="bibr" rid="ridm1842754844">55</xref><xref ref-type="bibr" rid="ridm1842744692">57</xref> and may be highly informative. Moreover, identifying whether targeted and repeated TPBM applications can foster a stronger desire among patients towards self care and other positive behaviors, as well as a greater ability to adhere to health recommendations and to feel efficacious in achieving favorable health and active aging outcomes in the short and long-term time periods could prove invaluable. </p>
      <p>In the interim, and in line with growing                   evidence from multiple sources, the transcranial              application of diverse forms of delivering low level laser light therapy to the prefrontal cotical region of               depressed animals and humans appears to offer a              consistently efficacious result as far as producing measureable favorable organic changes in the stimulated neural tissues and structures that are vital to emotional regulation and wellbeing. Furthermore, and importantly, the currently demonstrated benefits of TPBM may be expected to heighten favorable outcome expectations and thus more positive perspectives for many older adults-in general, especially in light of the unfavorable stance often accompanying the stigma of depression and anxiety, in addition to widespread ageism issues and perspectives, plus vulnerability to the use of                            psychotropic drugs. To further affirm and advance its clinical value, however, more comparative studies, as well as dose response and other studies assessing the degree to which TPBM can act as an effective approach for enhancing mainstream intervention approaches such as exercise, counseling, pharmacologic and stress                  control approaches may be insightful. Finally, in terms of cost benefit analyses, it appears the low monetary and energy costs of TPBM, along with its ease of usage might be better exploited in terms of its possible value for             reducing the immense degree of suffering, as well as unwanted consequences of depression, such as               cardiovascular disease <xref ref-type="bibr" rid="ridm1842774140">58</xref>, and more recently              COVID-19, among the growing older adult population, if more clinical evidence from long-term prospective            studies of various degrees of distress in healthy and chronically impaired older adults are forthcoming.</p>
      <p>Indeed, by providing hope to many, as opposed to despair, along with cost savings to elder care                     organizations, health policy makers, and governmental agencies, the apparent merits of TPBM should be studied sooner rather than later by all those in the health field who seek to advance elder care and raise older adults life quality, while preventing undue suffering and              emotional pain in a cost-effective and safe manner.</p>
      <p>Attributes or factors and parameters that may impact or influence efficacy and outcomes in clinical and preclinical studies of TPBM that should be carefully               examined in light of their possible differential effects on the quantity of light absorbed, and hence on the desired outcomes include:</p>
      <p>the degree of prevailing irradiance </p>
      <p>treatment timing and repetition </p>
      <p>pulse attributes and wavelength/light color </p>
      <p>the degree of fluence</p>
      <p>power density effects</p>
      <p>Other mediating or moderating factors that can be examined to gain further insight into the efficacy of TPBM for intervening in depression and anxiety are the characteristics of the subject, and application site <sup>s</sup>, the methods of applying the light stimuli, and the                             prevailing degree of emotional and neural                                                                      dysfunction <xref ref-type="bibr" rid="ridm1843049892">10</xref><xref ref-type="bibr" rid="ridm1843018420">15</xref><xref ref-type="bibr" rid="ridm1843014172">16</xref><xref ref-type="bibr" rid="ridm1842733964">59</xref><xref ref-type="bibr" rid="ridm1842729644">60</xref>. Others not well studied to date are the role of: 1) caregiver empathy and knowledge; 2) patient attributes and beliefs; 3) general health status; 4) living conditions; 5) social support; 6) degree of follow up evaluations.</p>
      <p>Successful results may also depend on the                   ability of the provider to personalize any recommended phototherapy application, as well as follow up plans and timely carefully construed evaluations.</p>
      <p>In the meantime, the work to date not only                 embodies, but is consistent with the                                              contemporary paradigm shift away from dysregulation of single neurotransmitter systems in cases of                          depression towards circuit level abnormalities                         impacting function across multiple brain regions and neurotransmitter systems that is comparable to the             actions of antidepressant medications <xref ref-type="bibr" rid="ridm1842844804">43</xref><xref ref-type="bibr" rid="ridm1842760316">54</xref>, as well as efforts to foster successful aging. Combining                       transcranially induced light therapy alongside                                                     antidepressant and/or other medications and                         educational approaches can also be expected to help speed up the rate at which possible beneficial outcomes are realized. Moreover, those treated optimally will                 undoubtedly tend to experience better overall health status, sleep quality, and a higher life quality than those who do not – all things considered <xref ref-type="bibr" rid="ridm1843231196">2</xref><xref ref-type="bibr" rid="ridm1842727268">61</xref><sup> 62</sup>.</p>
      <p>In this regard, although ignored for many years, it appears hard to refute the idea that TPBM is a                    potentially effective, sustainable, safe, and compatible intervention mode for purposes of offsetting the                     immense suffering attributable to the presence and risk of multiple cognitive and health challenges faced by many elderly, if not all. Its optimal value too, which may yet be untapped, appears to merit considerable attention in this regard, and is strongly encouraged.  </p>
    </sec>
    <sec id="idm1842862020" sec-type="conclusions">
      <title>Conclusions                                                                                                                             </title>
      <p>Transcranial</p>
      <p>photobiomodulation therapy, a novel non-invasive form of neuromodulatory stimulation is emerging as a viable adjunct to alleviating the                    disabling cognitive states of anxiety and depressive, highly prevalent among the elderly.</p>
      <p>Demonstrated to minimize depression and               anxiety symptoms favorably and safely and with good tolerability and on the basis of multiple empirically              derived mechanisms of impact, the approach seems highly promising for fostering more optimal healthy    aging and personalized care in many respects. </p>
      <p>More research to carefully examine how this strategy can be optimized for both prophylactic as well as therapeutic purposes and who will benefit and why will hence likely prove highly fruitful for countering this growing burdensome mental health epidemic among older adults, but its present application, where                         indicated, which is engendering positive results on a consistent bases, should not be overlooked.</p>
    </sec>
  </body>
  <back>
    <ref-list>
      <ref id="ridm1843230260">
        <label>1.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Malhi</surname>
            <given-names>G S</given-names>
          </name>
          <name>
            <surname>Mann</surname>
            <given-names>J J</given-names>
          </name>
          <date>
            <year>2018</year>
          </date>
          <source>Depression. Lancet</source>
          <volume>392</volume>
          <issue>10161</issue>
          <fpage>2299</fpage>
          <lpage>2312</lpage>
          <pub-id pub-id-type="doi">10.1016/S0140-6736(18)31948-2</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1843231196">
        <label>2.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Blazer</surname>
            <given-names>D G</given-names>
          </name>
          <article-title>Depression in late life: review and commentary</article-title>
          <date>
            <year>2003</year>
          </date>
          <source>J Gerontol A Biol Sci Med Sci</source>
          <volume>58</volume>
          <issue>3</issue>
          <fpage>249</fpage>
          <lpage>265</lpage>
          <pub-id pub-id-type="doi">10.1093/gerona/58.3.m249</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1843310468">
        <label>3.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Askalsky</surname>
            <given-names>P</given-names>
          </name>
          <name>
            <surname>Iosifescu</surname>
            <given-names>D V</given-names>
          </name>
          <article-title>Transcranial photobiomodulation for the management of depression: current perspectives</article-title>
          <date>
            <year>2019</year>
          </date>
          <source>Neuropsychiatr Dis Treat</source>
          <volume>22</volume>
          <issue>15</issue>
          <fpage>3255</fpage>
          <lpage>3272</lpage>
          <pub-id pub-id-type="doi">10.2147/NDT.S188906</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1843086644">
        <label>4.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Zis</surname>
            <given-names>P</given-names>
          </name>
          <name>
            <surname>Daskalaki</surname>
            <given-names>A</given-names>
          </name>
          <name>
            <surname>Bountouni</surname>
            <given-names>I</given-names>
          </name>
          <name>
            <surname>Sykioti</surname>
            <given-names>P</given-names>
          </name>
          <name>
            <surname>Varrassi</surname>
            <given-names>G</given-names>
          </name>
          <article-title>Depression and chronic pain in the elderly: links and management challenges</article-title>
          <date>
            <year>2017</year>
          </date>
          <source>Clin Interv Aging</source>
          <volume>21</volume>
          <issue>12</issue>
          <fpage>709</fpage>
          <lpage>720</lpage>
          <pub-id pub-id-type="doi">10.2147/CIA.S113576</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1843084268">
        <label>5.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Mitchell</surname>
            <given-names>P B</given-names>
          </name>
          <name>
            <surname>Harvey</surname>
            <given-names>S B</given-names>
          </name>
          <article-title>Depression and the older medical patient--when and how to intervene</article-title>
          <date>
            <year>2014</year>
          </date>
          <source>Maturitas</source>
          <volume>79</volume>
          <issue>2</issue>
          <fpage>153</fpage>
          <lpage>9</lpage>
          <pub-id pub-id-type="doi">10.1016/j.maturitas.2014.05.010</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1843075316">
        <label>6.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Scinto</surname>
            <given-names>K</given-names>
          </name>
          <name>
            <surname>Wick</surname>
            <given-names>J Y</given-names>
          </name>
          <article-title>Anxiety disorders in older people</article-title>
          <date>
            <year>2020</year>
          </date>
          <source>Sr Care Pharm</source>
          <volume>35</volume>
          <issue>5</issue>
          <fpage>198</fpage>
          <lpage>206</lpage>
          <pub-id pub-id-type="doi">10.4140/TCP.n.2020.198</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1843078844">
        <label>7.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Hennessy</surname>
            <given-names>M</given-names>
          </name>
          <name>
            <surname>Hamblin</surname>
            <given-names>M R</given-names>
          </name>
          <article-title>Photobiomodulation and the brain: a new paradigm</article-title>
          <date>
            <year>2017</year>
          </date>
          <source>J Opt</source>
          <volume>19</volume>
          <issue>1</issue>
          <fpage>013003</fpage>
        </mixed-citation>
      </ref>
      <ref id="ridm1843056844">
        <label>8.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Schiffer</surname>
            <given-names>F</given-names>
          </name>
          <name>
            <surname>Johnston</surname>
            <given-names>A L</given-names>
          </name>
          <name>
            <surname>Ravichandran</surname>
            <given-names>C</given-names>
          </name>
          <name>
            <surname>Polcari</surname>
            <given-names>A</given-names>
          </name>
          <name>
            <surname>Teicher</surname>
            <given-names>M H</given-names>
          </name>
          <article-title>Psychological benefits 2 and 4 weeks after a single treatment with near infrared light to the forehead: a pilot study of 10 patients with major depression and anxiety</article-title>
          <date>
            <year>2009</year>
          </date>
          <source>Behav Brain Funct</source>
          <volume>5</volume>
          <fpage>46</fpage>
        </mixed-citation>
      </ref>
      <ref id="ridm1843060876">
        <label>9.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Salehpour</surname>
            <given-names>F</given-names>
          </name>
          <name>
            <surname>Mahmoudi</surname>
            <given-names>J</given-names>
          </name>
          <name>
            <surname>Kamari</surname>
            <given-names>F</given-names>
          </name>
          <name>
            <surname>Sadigh-</surname>
            <given-names>Eteghad S</given-names>
          </name>
          <name>
            <surname>Rasta</surname>
            <given-names>S H</given-names>
          </name>
          <article-title>Brain photobiomodulation therapy: a narrative review</article-title>
          <date>
            <year>2018</year>
          </date>
          <source>Mol Neurobiol</source>
          <volume>55</volume>
          <issue>8</issue>
          <fpage>6601</fpage>
          <lpage>6636</lpage>
          <pub-id pub-id-type="doi">10.1007/s12035-017-0852-4</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1843049892">
        <label>10.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Hamblin</surname>
            <given-names>M R</given-names>
          </name>
          <article-title>Shining light on the head: photobiomodulation for brain disorders</article-title>
          <date>
            <year>2016</year>
          </date>
          <source>BBA Clin</source>
          <volume>6</volume>
          <fpage>113</fpage>
          <lpage>124</lpage>
        </mixed-citation>
      </ref>
      <ref id="ridm1843043556">
        <label>11.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Zhou</surname>
            <given-names>J</given-names>
          </name>
          <name>
            <surname>Xue</surname>
            <given-names>Y</given-names>
          </name>
          <article-title>Depression, falls, and osteoporotic fractures</article-title>
          <date>
            <year>2020</year>
          </date>
          <source>Osteoporos Int</source>
          <volume>31</volume>
          <issue>6</issue>
          <fpage>1175</fpage>
        </mixed-citation>
      </ref>
      <ref id="ridm1843041036">
        <label>12.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Raič</surname>
            <given-names>M</given-names>
          </name>
          <article-title>Depression and heart diseases: leading health problems</article-title>
          <date>
            <year>2017</year>
          </date>
          <source>Psychiatr Danub</source>
          <volume>29</volume>
          <issue>4</issue>
          <fpage>770</fpage>
          <lpage>777</lpage>
        </mixed-citation>
      </ref>
      <ref id="ridm1843053996">
        <label>13.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Berk</surname>
            <given-names>M</given-names>
          </name>
          <name>
            <surname>Williams</surname>
            <given-names>L J</given-names>
          </name>
          <name>
            <surname>Jacka</surname>
            <given-names>F N</given-names>
          </name>
          <name>
            <surname>O'Neil</surname>
            <given-names>A</given-names>
          </name>
          <name>
            <surname>Pasco</surname>
            <given-names>J A</given-names>
          </name>
          <article-title>So depression is an inflammatory disease, but where does the inflammation come from?</article-title>
          <date>
            <year>2013</year>
          </date>
          <source>BMC Med</source>
          <volume>11</volume>
          <fpage>200</fpage>
        </mixed-citation>
      </ref>
      <ref id="ridm1843024108">
        <label>14.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Iaboni</surname>
            <given-names>A</given-names>
          </name>
          <name>
            <surname>Flint</surname>
            <given-names>A J</given-names>
          </name>
          <article-title>The complex interplay of depression and falls in older adults: a clinical review</article-title>
          <date>
            <year>2013</year>
          </date>
          <source>Am J Geriatr Psychiatry</source>
          <volume>21</volume>
          <issue>5</issue>
          <fpage>484</fpage>
          <lpage>92</lpage>
          <pub-id pub-id-type="doi">10.1016/j.jagp.2013.01.008</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1843018420">
        <label>15.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>de</surname>
            <given-names>Oliveira LDSSCB</given-names>
          </name>
          <name>
            <surname>Souza</surname>
            <given-names>E C</given-names>
          </name>
          <name>
            <surname>RAS</surname>
            <given-names>Rodrigues</given-names>
          </name>
          <name>
            <surname>Fett</surname>
            <given-names>C A</given-names>
          </name>
          <name>
            <surname>Piva</surname>
            <given-names>A B</given-names>
          </name>
          <article-title>The effects of physical activity on anxiety, depression, and quality of life in elderly people living in the community. Trends Psychiatry Psychother</article-title>
          <date>
            <year>2019</year>
          </date>
          <volume>41</volume>
          <issue>1</issue>
          <fpage>36</fpage>
          <lpage>42</lpage>
          <pub-id pub-id-type="doi">10.1590/2237-6089-2017-0129</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1843014172">
        <label>16.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Hamblin</surname>
            <given-names>M R</given-names>
          </name>
          <article-title>Photobiomodulation or low-level laser therapy</article-title>
          <date>
            <year>2016</year>
          </date>
          <source>J Biophotonics.9(11-12):</source>
          <fpage>1122</fpage>
          <lpage>1124</lpage>
        </mixed-citation>
      </ref>
      <ref id="ridm1843009924">
        <label>17.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Lever-van</surname>
            <given-names>Milligen BA</given-names>
          </name>
          <name>
            <surname>Verhoeven</surname>
            <given-names>J E</given-names>
          </name>
          <name>
            <surname>Schmaal</surname>
            <given-names>L</given-names>
          </name>
          <name>
            <surname>van</surname>
            <given-names>Velzen LS</given-names>
          </name>
          <name>
            <surname>Révész</surname>
            <given-names>D</given-names>
          </name>
          <article-title>The impact of depression and anxiety treatment on biological aging and metabolic stress: study protocol of the MOod treatment with antidepressants or running (MOTAR) study</article-title>
          <date>
            <year>2019</year>
          </date>
          <source>BMC Psychiatry</source>
          <volume>19</volume>
          <issue>1</issue>
          <fpage>425</fpage>
        </mixed-citation>
      </ref>
      <ref id="ridm1842988292">
        <label>18.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Vaughan</surname>
            <given-names>L</given-names>
          </name>
          <name>
            <surname>Corbin</surname>
            <given-names>A L</given-names>
          </name>
          <name>
            <surname>Goveas</surname>
            <given-names>J S</given-names>
          </name>
          <article-title>Depression and frailty in later life: a systematic review</article-title>
          <date>
            <year>2015</year>
          </date>
          <source>Clin Interv Aging</source>
          <volume>10</volume>
          <fpage>1947</fpage>
          <lpage>58</lpage>
        </mixed-citation>
      </ref>
      <ref id="ridm1842986420">
        <label>19.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Casey</surname>
            <given-names>D A</given-names>
          </name>
          <article-title>Depression in older adults: a treatable medical condition</article-title>
          <date>
            <year>2017</year>
          </date>
          <source>Prim Care</source>
          <volume>44</volume>
          <issue>3</issue>
          <fpage>499</fpage>
          <lpage>510</lpage>
          <pub-id pub-id-type="doi">10.1016/j.pop.2017.04.007</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1842980732">
        <label>20.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Morimoto</surname>
            <given-names>S S</given-names>
          </name>
          <name>
            <surname>Alexopoulos</surname>
            <given-names>G S</given-names>
          </name>
          <article-title>Immunity, aging, and geriatric depression</article-title>
          <date>
            <year>2011</year>
          </date>
          <source>Psychiatr Clin North Am</source>
          <volume>34</volume>
          <issue>2</issue>
          <fpage>437</fpage>
          <lpage>49</lpage>
          <pub-id pub-id-type="doi">10.1016/j.psc.2011.02.006</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1842996572">
        <label>21.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Eshaghi</surname>
            <given-names>E</given-names>
          </name>
          <name>
            <surname>Sadigh-Eteghad</surname>
            <given-names>S</given-names>
          </name>
          <name>
            <surname>Mohaddes</surname>
            <given-names>G</given-names>
          </name>
          <name>
            <surname>Rasta</surname>
            <given-names>S H</given-names>
          </name>
          <article-title>Transcranial photobiomodulation prevents anxiety and depression via changing serotonin and nitric oxide levels in brain of depression model mice: A study of three different doses of 810 laser. Lasers Surg Med</article-title>
          <date>
            <year>2019</year>
          </date>
          <volume>51</volume>
          <issue>7</issue>
          <fpage>634</fpage>
          <lpage>642</lpage>
          <pub-id pub-id-type="doi">10.1002/lsm.23082</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1842970316">
        <label>22.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Maiello</surname>
            <given-names>M</given-names>
          </name>
          <name>
            <surname>Losiewicz</surname>
            <given-names>O M</given-names>
          </name>
          <name>
            <surname>Bui</surname>
            <given-names>E</given-names>
          </name>
          <name>
            <surname>Spera</surname>
            <given-names>V</given-names>
          </name>
          <name>
            <surname>Hamblin</surname>
            <given-names>M R</given-names>
          </name>
          <article-title>Transcranial Photobiomodulation with near-infrared light for generalized anxiety disorder: a pilot study. Photobiomodul Photomed Laser Surg</article-title>
          <date>
            <year>2019</year>
          </date>
          <volume>37</volume>
          <issue>10</issue>
          <fpage>644</fpage>
          <lpage>650</lpage>
          <pub-id pub-id-type="doi">10.1089/photob.2019.4677</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1842964412">
        <label>23.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Tanaka</surname>
            <given-names>Y</given-names>
          </name>
          <name>
            <surname>Akiyoshi</surname>
            <given-names>J</given-names>
          </name>
          <name>
            <surname>Kawahara</surname>
            <given-names>Y</given-names>
          </name>
          <name>
            <surname>Ishitobi</surname>
            <given-names>Y</given-names>
          </name>
          <name>
            <surname>Hatano</surname>
            <given-names>K</given-names>
          </name>
          <article-title>Infrared radiation has potential antidepressant and anxiolytic effects in animal model of depression and anxiety</article-title>
          <date>
            <year>2010</year>
          </date>
          <source>Brain Stimul</source>
          <volume>4</volume>
          <issue>2</issue>
          <fpage>71</fpage>
          <lpage>6</lpage>
          <pub-id pub-id-type="doi">10.1016/j.brs.2010.04.001</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1842976076">
        <label>24.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Disner</surname>
            <given-names>S G</given-names>
          </name>
          <name>
            <surname>Beevers</surname>
            <given-names>C G</given-names>
          </name>
          <name>
            <surname>Gonzalez-Lima</surname>
            <given-names>F</given-names>
          </name>
          <article-title>Transcranial laser stimulation as neuroenhancement for attention bias modification in adults with elevated depression symptoms</article-title>
          <date>
            <year>2016</year>
          </date>
          <source>Brain Stimul</source>
          <volume>9</volume>
          <issue>5</issue>
          <fpage>780</fpage>
          <lpage>787</lpage>
          <pub-id pub-id-type="doi">10.1016/j.brs.2016.05.009</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1842971180">
        <label>25.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Barrett</surname>
            <given-names>D W</given-names>
          </name>
          <name>
            <surname>Gonzalez-Lima</surname>
            <given-names>F</given-names>
          </name>
          <article-title>Transcranial infrared laser stimulation produces beneficial cognitive and emotional effects in humans</article-title>
          <date>
            <year>2013</year>
          </date>
          <source>Neuroscience</source>
          <volume>230</volume>
          <fpage>13</fpage>
          <lpage>23</lpage>
          <pub-id pub-id-type="doi">10.1016/j.neuroscience.2012.11.016</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1842937812">
        <label>26.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Henderson</surname>
            <given-names>T A</given-names>
          </name>
          <name>
            <surname>Morries</surname>
            <given-names>L D</given-names>
          </name>
          <article-title>Multi-watt near-infrared phototherapy for the treatment of comorbid depression: an open-label single-arm study. Front Psychiatry</article-title>
          <date>
            <year>2017</year>
          </date>
          <volume>8</volume>
          <fpage>187</fpage>
        </mixed-citation>
      </ref>
      <ref id="ridm1842933852">
        <label>27.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Brochado</surname>
            <given-names>F T</given-names>
          </name>
          <name>
            <surname>Jesus</surname>
            <given-names>L H</given-names>
          </name>
          <name>
            <surname>Carrard</surname>
            <given-names>V C</given-names>
          </name>
          <name>
            <surname>Freddo</surname>
            <given-names>A L</given-names>
          </name>
          <name>
            <surname>Chaves</surname>
            <given-names>K D</given-names>
          </name>
          <article-title>Comparative effectiveness of photobiomodulation and manual therapy alone or combined in TMD patients: a randomized clinical trial. Braz Oral Res</article-title>
          <date>
            <year>2018</year>
          </date>
          <volume>32</volume>
          <fpage>50</fpage>
        </mixed-citation>
      </ref>
      <ref id="ridm1842929964">
        <label>28.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Yang</surname>
            <given-names>L</given-names>
          </name>
          <name>
            <surname>Wu</surname>
            <given-names>C</given-names>
          </name>
          <name>
            <surname>Tucker</surname>
            <given-names>L</given-names>
          </name>
          <name>
            <surname>Dong</surname>
            <given-names>Y</given-names>
          </name>
          <name>
            <surname>Li</surname>
            <given-names>Y</given-names>
          </name>
          <article-title>Photobiomodulation therapy attenuates anxious-depressive-like behavior in the TgF344 rat model. J Alzheimers Dis</article-title>
          <date>
            <year>2021</year>
          </date>
        </mixed-citation>
      </ref>
      <ref id="ridm1842925068">
        <label>29.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Gabel</surname>
            <given-names>C P</given-names>
          </name>
          <name>
            <surname>Petrie</surname>
            <given-names>S R</given-names>
          </name>
          <name>
            <surname>Mischoulon</surname>
            <given-names>D</given-names>
          </name>
          <name>
            <surname>Hamblin</surname>
            <given-names>M R</given-names>
          </name>
          <name>
            <surname>Yeung</surname>
            <given-names>A</given-names>
          </name>
          <article-title>Case control series for the effect of photobiomodulation in patients with low back pain and concurrent depression. Laser Ther</article-title>
          <date>
            <year>2018</year>
          </date>
          <volume>27</volume>
          <issue>3</issue>
          <fpage>167</fpage>
          <lpage>173</lpage>
          <pub-id pub-id-type="doi">10.5978/islsm.27_18-OR-18</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1842922116">
        <label>30.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Kerppers</surname>
            <given-names>F K</given-names>
          </name>
          <name>
            <surname>Dos</surname>
            <given-names>Santos KMMG</given-names>
          </name>
          <name>
            <surname>MER</surname>
            <given-names>Cordeiro</given-names>
          </name>
          <name>
            <surname>MC</surname>
            <given-names>da Silva Pereira</given-names>
          </name>
          <name>
            <surname>Barbosa</surname>
            <given-names>D</given-names>
          </name>
          <article-title>Study of transcranial photobiomodulation at 945-nm wavelength: anxiety and depression. Lasers Med Sci</article-title>
          <date>
            <year>2020</year>
          </date>
          <volume>35</volume>
          <issue>9</issue>
          <fpage>1945</fpage>
          <lpage>1954</lpage>
          <pub-id pub-id-type="doi">10.1007/s10103-020-02983-7</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1842918156">
        <label>31.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Mohammed</surname>
            <given-names>H S</given-names>
          </name>
          <article-title>Transcranial low-level infrared laser irradiation ameliorates depression induced by reserpine in rats</article-title>
          <date>
            <year>2016</year>
          </date>
          <source>Lasers Med Sci</source>
          <volume>31</volume>
          <issue>8</issue>
          <fpage>1651</fpage>
          <lpage>1656</lpage>
          <pub-id pub-id-type="doi">10.1007/s10103-016-2033-5</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1842913764">
        <label>32.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Chan</surname>
            <given-names>A S</given-names>
          </name>
          <name>
            <surname>Lee</surname>
            <given-names>T L</given-names>
          </name>
          <name>
            <surname>Yeung</surname>
            <given-names>M K</given-names>
          </name>
          <name>
            <surname>Hamblin</surname>
            <given-names>M R</given-names>
          </name>
          <article-title>Photobiomodulation improves the frontal cognitive function of older adults</article-title>
          <date>
            <year>2019</year>
          </date>
          <source>Int J Geriatric Psychiatry</source>
          <volume>34</volume>
          <issue>2</issue>
          <fpage>369</fpage>
          <lpage>377</lpage>
        </mixed-citation>
      </ref>
      <ref id="ridm1842911820">
        <label>33.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Salehpour</surname>
            <given-names>F</given-names>
          </name>
          <name>
            <surname>Rasta</surname>
            <given-names>S H</given-names>
          </name>
          <article-title>The potential of transcranial photobiomodulation therapy for treatment of major depressive disorder</article-title>
          <date>
            <year>2017</year>
          </date>
          <source>Rev Neurosci</source>
          <volume>28</volume>
          <issue>4</issue>
          <fpage>441</fpage>
          <lpage>453</lpage>
          <pub-id pub-id-type="doi">10.1515/revneuro-2016-0087</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1842939036">
        <label>34.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Salehpour</surname>
            <given-names>F</given-names>
          </name>
          <name>
            <surname>Farajdokht</surname>
            <given-names>F</given-names>
          </name>
          <name>
            <surname>Cassano</surname>
            <given-names>P</given-names>
          </name>
          <name>
            <surname>Sadigh-Eteghad</surname>
            <given-names>S</given-names>
          </name>
          <name>
            <surname>Erfani</surname>
            <given-names>M</given-names>
          </name>
          <article-title>Near-infrared photobiomodulation combined with coenzyme Q10 for depression in a mouse model of restraint stress: reduction in oxidative stress, neuro inflammation, and apoptosis</article-title>
          <date>
            <year>2018</year>
          </date>
          <source>Brain Res Bull</source>
          <volume>144</volume>
          <fpage>213</fpage>
          <lpage>222</lpage>
          <pub-id pub-id-type="doi">10.1016/j.brainresbull.2018.10.010</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1842888228">
        <label>35.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Cassano</surname>
            <given-names>P</given-names>
          </name>
          <name>
            <surname>Petrie</surname>
            <given-names>S R</given-names>
          </name>
          <name>
            <surname>Hamblin</surname>
            <given-names>M R</given-names>
          </name>
          <name>
            <surname>Henderson</surname>
            <given-names>T A</given-names>
          </name>
          <name>
            <surname>Iosifescu</surname>
            <given-names>D V</given-names>
          </name>
          <article-title>Review of transcranial photobiomodulation for major depressive disorder: targeting brain metabolism, inflammation, oxidative stress, and neurogenesis</article-title>
          <date>
            <year>2016</year>
          </date>
          <source>Neurophotonics</source>
          <volume>3</volume>
          <issue>3</issue>
          <fpage>031404</fpage>
        </mixed-citation>
      </ref>
      <ref id="ridm1842881604">
        <label>36.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>F</surname>
            <given-names>dos Santos Cardoso</given-names>
          </name>
          <name>
            <surname>Gonzalez-Lima</surname>
            <given-names>F</given-names>
          </name>
          <name>
            <surname>da</surname>
            <given-names>Silva SG</given-names>
          </name>
          <article-title>Photobiomodulation for the aging brain. Ageing Res Rev</article-title>
          <date>
            <year>2021</year>
          </date>
          <source>Jul</source>
          <volume>26</volume>
          <fpage>101415</fpage>
        </mixed-citation>
      </ref>
      <ref id="ridm1842877500">
        <label>37.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Cassano</surname>
            <given-names>P</given-names>
          </name>
          <name>
            <surname>Cusin</surname>
            <given-names>C</given-names>
          </name>
          <name>
            <surname>Mischoulon</surname>
            <given-names>D</given-names>
          </name>
          <name>
            <surname>Hamblin</surname>
            <given-names>M R</given-names>
          </name>
          <name>
            <surname>L</surname>
            <given-names>De Taboada</given-names>
          </name>
          <article-title>Near-infrared transcranial radiation for major depressive disorder: proof of concept study</article-title>
          <date>
            <year>2015</year>
          </date>
          <source>Psychiatry</source>
          <fpage>352979</fpage>
        </mixed-citation>
      </ref>
      <ref id="ridm1842875124">
        <label>38.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Matsuo</surname>
            <given-names>K</given-names>
          </name>
          <name>
            <surname>Kato</surname>
            <given-names>T</given-names>
          </name>
          <name>
            <surname>Fukuda</surname>
            <given-names>M</given-names>
          </name>
          <name>
            <surname>Kato</surname>
            <given-names>N</given-names>
          </name>
          <article-title>Alteration of hemoglobin oxygenation in the frontal region in elderly depressed patients as measured by near-infrared spectroscopy</article-title>
          <date>
            <year>2000</year>
          </date>
          <source>J Neuropsychiatry Clin Neurosci</source>
          <volume>12</volume>
          <issue>4</issue>
          <fpage>465</fpage>
          <lpage>471</lpage>
          <pub-id pub-id-type="doi">10.1176/jnp.12.4.465</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1842870444">
        <label>39.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Fonseca</surname>
            <given-names>M O</given-names>
          </name>
          <name>
            <surname>Soares</surname>
            <given-names>C P</given-names>
          </name>
          <name>
            <surname>Joaquim</surname>
            <given-names>R M</given-names>
          </name>
          <name>
            <surname>Veras</surname>
            <given-names>A B</given-names>
          </name>
          <article-title>Transcranial photobiomodulation in the treatment of major depression</article-title>
          <date>
            <year>2019</year>
          </date>
          <source>Clin Psychiatry</source>
          <volume>5</volume>
          <issue>1</issue>
          <fpage>1</fpage>
        </mixed-citation>
      </ref>
      <ref id="ridm1842866052">
        <label>40.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Cao</surname>
            <given-names>X</given-names>
          </name>
          <name>
            <surname>Li</surname>
            <given-names>L P</given-names>
          </name>
          <name>
            <surname>Wang</surname>
            <given-names>Q</given-names>
          </name>
          <name>
            <surname>Wu</surname>
            <given-names>Q</given-names>
          </name>
          <name>
            <surname>Hu</surname>
            <given-names>H H</given-names>
          </name>
          <article-title>Astrocyte-derived ATP modulates depressive-like behaviors</article-title>
          <date>
            <year>2013</year>
          </date>
          <source>Nat Med</source>
          <volume>19</volume>
          <issue>6</issue>
          <fpage>773</fpage>
          <lpage>777</lpage>
          <pub-id pub-id-type="doi">10.1038/nm.3162</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1842861516">
        <label>41.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Xu</surname>
            <given-names>Z</given-names>
          </name>
          <name>
            <surname>Guo</surname>
            <given-names>X</given-names>
          </name>
          <name>
            <surname>Yang</surname>
            <given-names>Y</given-names>
          </name>
          <name>
            <surname>Tucker</surname>
            <given-names>D</given-names>
          </name>
          <name>
            <surname>Lu</surname>
            <given-names>Y</given-names>
          </name>
          <article-title>Low-level laser irradiation improves depression-like behaviors in mice</article-title>
          <date>
            <year>2017</year>
          </date>
          <source>Mol Neurobiol</source>
          <volume>54</volume>
          <issue>6</issue>
          <fpage>4551</fpage>
          <lpage>4559</lpage>
          <pub-id pub-id-type="doi">10.1007/s12035-016-9983-2</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1842857052">
        <label>42.</label>
        <mixed-citation xlink:type="simple" publication-type="book">
          <name>
            <surname>ASI</surname>
            <given-names>Salgado</given-names>
          </name>
          <name>
            <surname>Cidral-Filho</surname>
            <given-names>F J</given-names>
          </name>
          <name>
            <surname>Martins</surname>
            <given-names>D F</given-names>
          </name>
          <name>
            <surname>Kerppers</surname>
            <given-names>Parreira RB</given-names>
          </name>
          <article-title>Cerebral blood flow in the elderly: impact of photobiomodulation</article-title>
          <date>
            <year>2019</year>
          </date>
          <chapter-title>In Photobiomodulation in the Brain</chapter-title>
          <fpage>473</fpage>
          <lpage>477</lpage>
          <publisher-name>Academic Press</publisher-name>
        </mixed-citation>
      </ref>
      <ref id="ridm1842844804">
        <label>43.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Caldieraro</surname>
            <given-names>M A</given-names>
          </name>
          <name>
            <surname>Cassano</surname>
            <given-names>P</given-names>
          </name>
          <article-title>Transcranial and systemic photobiomodulation for major depressive disorder: A systematic review of efficacy, tolerability and biological mechanisms</article-title>
          <date>
            <year>2019</year>
          </date>
          <source>J Affect Disord</source>
          <volume>243</volume>
          <fpage>262</fpage>
          <lpage>273</lpage>
          <pub-id pub-id-type="doi">10.1016/j.jad.2018.09.048</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1842837892">
        <label>44.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Cassano</surname>
            <given-names>P</given-names>
          </name>
          <name>
            <surname>Petrie</surname>
            <given-names>S R</given-names>
          </name>
          <name>
            <surname>Mischoulon</surname>
            <given-names>D</given-names>
          </name>
          <name>
            <surname>Cusin</surname>
            <given-names>C</given-names>
          </name>
          <name>
            <surname>Katnani</surname>
            <given-names>H</given-names>
          </name>
          <article-title>Transcranial Photobiomodulation for the treatment of major depressive disorder. the ELATED-2 pilot trial. Photomed Laser Surg</article-title>
          <date>
            <year>2018</year>
          </date>
          <volume>36</volume>
          <issue>12</issue>
          <fpage>634</fpage>
          <lpage>646</lpage>
          <pub-id pub-id-type="doi">10.1089/pho.2018.4490</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1842835012">
        <label>45.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Gutiérrez-Menéndez</surname>
            <given-names>A</given-names>
          </name>
          <name>
            <surname>Marcos-Nistal</surname>
            <given-names>M</given-names>
          </name>
          <name>
            <surname>Méndez</surname>
            <given-names>M</given-names>
          </name>
          <name>
            <surname>Arias</surname>
            <given-names>J L</given-names>
          </name>
          <article-title>Photobiomodulation as a promising new tool in the management of psychological disorders: A systematic review</article-title>
          <date>
            <year>2020</year>
          </date>
          <source>Neurosci Biobehav Rev</source>
          <volume>119</volume>
          <fpage>242</fpage>
          <lpage>254</lpage>
          <pub-id pub-id-type="doi">10.1016/j.neubiorev.2020.10.002</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1842828388">
        <label>46.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Salehpour</surname>
            <given-names>F</given-names>
          </name>
          <name>
            <surname>Gholipour-Khalili</surname>
            <given-names>S</given-names>
          </name>
          <name>
            <surname>Farajdokht</surname>
            <given-names>F</given-names>
          </name>
          <name>
            <surname>Kamari</surname>
            <given-names>F</given-names>
          </name>
          <name>
            <surname>Walski</surname>
            <given-names>T</given-names>
          </name>
          <article-title>Therapeutic potential of intranasal photobiomodulation therapy for neurological and neuropsychiatric disorders: a narrative review</article-title>
          <date>
            <year>2020</year>
          </date>
          <source>Rev Neurosci</source>
          <volume>31</volume>
          <issue>3</issue>
          <fpage>269</fpage>
          <lpage>286</lpage>
          <pub-id pub-id-type="doi">10.1515/revneuro-2019-0063</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1842824356">
        <label>47.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Yang</surname>
            <given-names>M</given-names>
          </name>
          <name>
            <surname>Yang</surname>
            <given-names>Z</given-names>
          </name>
          <name>
            <surname>Wang</surname>
            <given-names>P</given-names>
          </name>
          <name>
            <surname>Sun</surname>
            <given-names>Z</given-names>
          </name>
          <article-title>Current application and future directions of photo biomodulation in central nervous diseases. Neural Regen Res</article-title>
          <date>
            <year>2021</year>
          </date>
          <volume>16</volume>
          <issue>6</issue>
          <fpage>1177</fpage>
          <lpage>1185</lpage>
          <pub-id pub-id-type="doi">10.4103/1673-5374.300486</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1842820036">
        <label>48.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Li</surname>
            <given-names>X</given-names>
          </name>
          <name>
            <surname>Liu</surname>
            <given-names>C</given-names>
          </name>
          <name>
            <surname>Wang</surname>
            <given-names>R</given-names>
          </name>
          <article-title>Light modulation of brain and development of relevant equipment</article-title>
          <date>
            <year>2020</year>
          </date>
          <volume>1</volume>
          <fpage>29</fpage>
          <lpage>41</lpage>
        </mixed-citation>
      </ref>
      <ref id="ridm1842814996">
        <label>49.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Zhang</surname>
            <given-names>D</given-names>
          </name>
          <name>
            <surname>Shen</surname>
            <given-names>Q</given-names>
          </name>
          <name>
            <surname>Wu</surname>
            <given-names>X</given-names>
          </name>
          <name>
            <surname>Xing</surname>
            <given-names>D</given-names>
          </name>
          <article-title>Photobiomodulation therapy ameliorates glutamatergic dysfunction in mice with chronic unpredictable mild stress-induced depression. Oxid Med Cell Longev</article-title>
          <date>
            <year>2021</year>
          </date>
          <fpage>6678276</fpage>
        </mixed-citation>
      </ref>
      <ref id="ridm1842845092">
        <label>50.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Gujral</surname>
            <given-names>S</given-names>
          </name>
          <name>
            <surname>Aizenstein</surname>
            <given-names>H</given-names>
          </name>
          <name>
            <surname>Reynolds</surname>
            <given-names>CF 3rd</given-names>
          </name>
          <name>
            <surname>Butters</surname>
            <given-names>M A</given-names>
          </name>
          <name>
            <surname>Erickson</surname>
            <given-names>K I</given-names>
          </name>
          <article-title>Exercise effects on depression: Possible neural mechanisms</article-title>
          <date>
            <year>2017</year>
          </date>
          <source>Gen Hosp Psychiatry</source>
          <volume>49</volume>
          <fpage>2</fpage>
          <lpage>10</lpage>
          <pub-id pub-id-type="doi">10.1016/j.genhosppsych.2017.04.012</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1842769172">
        <label>51.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Urquhart</surname>
            <given-names>E L</given-names>
          </name>
          <name>
            <surname>Wanniarachchi</surname>
            <given-names>H</given-names>
          </name>
          <name>
            <surname>Wang</surname>
            <given-names>X</given-names>
          </name>
          <name>
            <surname>Gonzalez-Lima</surname>
            <given-names>F</given-names>
          </name>
          <name>
            <surname>Alexandrakis</surname>
            <given-names>G</given-names>
          </name>
          <article-title>Transcranial photobiomodulation-induced changes in human brain functional connectivity and network metrics mapped by whole-head functional near-infrared spectroscopy in vivo</article-title>
          <date>
            <year>2020</year>
          </date>
          <source>Biomed Opt Express</source>
          <volume>11</volume>
          <issue>10</issue>
          <fpage>5783</fpage>
          <lpage>5799</lpage>
          <pub-id pub-id-type="doi">10.1364/BOE.402047</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1842763124">
        <label>52.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Ramezani</surname>
            <given-names>F</given-names>
          </name>
          <name>
            <surname>Neshasteh-Riz</surname>
            <given-names>A</given-names>
          </name>
          <name>
            <surname>Ghadaksaz</surname>
            <given-names>A</given-names>
          </name>
          <name>
            <surname>Fazeli</surname>
            <given-names>S M</given-names>
          </name>
          <name>
            <surname>Janzadeh</surname>
            <given-names>A</given-names>
          </name>
          <article-title>Mechanistic aspects of photobiomodulation therapy in the nervous system. Lasers in Med Sci.pp.1-8</article-title>
          <date>
            <year>2021</year>
          </date>
        </mixed-citation>
      </ref>
      <ref id="ridm1842762044">
        <label>53.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Hare</surname>
            <given-names>B D</given-names>
          </name>
          <name>
            <surname>Duman</surname>
            <given-names>R S</given-names>
          </name>
          <article-title>Prefrontal cortex circuits in depression and anxiety: contribution of discrete neuronal populations and target regions</article-title>
          <date>
            <year>2020</year>
          </date>
          <source>Mol Psychiatry</source>
          <volume>25</volume>
          <issue>11</issue>
          <fpage>2742</fpage>
          <lpage>2758</lpage>
          <pub-id pub-id-type="doi">10.1038/s41380-020-0685-9</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1842760316">
        <label>54.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Pinto</surname>
            <given-names>A P</given-names>
          </name>
          <name>
            <surname>Guimarães</surname>
            <given-names>C L</given-names>
          </name>
          <name>
            <surname>GADS</surname>
            <given-names>Souza</given-names>
          </name>
          <name>
            <surname>Leonardo</surname>
            <given-names>P S</given-names>
          </name>
          <name>
            <surname>MFD</surname>
            <given-names>Neves</given-names>
          </name>
          <article-title>Sensory-motor and cardiorespiratory sensory rehabilitation associated with transcranial photobiomodulation in patients with central nervous system injury: trial protocol for a single-center, randomized, double-blind, and controlled clinical trial</article-title>
          <date>
            <year>2019</year>
          </date>
          <source>Medicine (Baltimore)</source>
          <volume>98</volume>
          <issue>25</issue>
          <fpage>15851</fpage>
        </mixed-citation>
      </ref>
      <ref id="ridm1842754844">
        <label>55.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Yuan</surname>
            <given-names>Y</given-names>
          </name>
          <name>
            <surname>Cassano</surname>
            <given-names>P</given-names>
          </name>
          <name>
            <surname>Pias</surname>
            <given-names>M</given-names>
          </name>
          <name>
            <surname>Fang</surname>
            <given-names>Q</given-names>
          </name>
          <article-title>Transcranial photobiomodulation with near-infrared light from childhood to elderliness: simulation of dosimetry</article-title>
          <date>
            <year>2020</year>
          </date>
          <source>Neurophotonics</source>
          <volume>7</volume>
          <issue>1</issue>
          <fpage>015009</fpage>
        </mixed-citation>
      </ref>
      <ref id="ridm1842749444">
        <label>56.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Ribeiro</surname>
            <given-names>O</given-names>
          </name>
          <name>
            <surname>Teixeira</surname>
            <given-names>L</given-names>
          </name>
          <name>
            <surname>Araújo</surname>
            <given-names>L</given-names>
          </name>
          <name>
            <surname>Rodríguez-Blázquez</surname>
            <given-names>C</given-names>
          </name>
          <name>
            <surname>Calderón-Larrañaga</surname>
            <given-names>A</given-names>
          </name>
          <article-title>Anxiety, depression and quality of life in older adults: trajectories of influence across age</article-title>
          <date>
            <year>2020</year>
          </date>
          <source>Int J Environ Res Public Health</source>
          <volume>17</volume>
          <issue>23</issue>
          <fpage>9039</fpage>
        </mixed-citation>
      </ref>
      <ref id="ridm1842744692">
        <label>57.</label>
        <mixed-citation xlink:type="simple" publication-type="book">
          <name>
            <surname>Almeida</surname>
            <given-names>O P</given-names>
          </name>
          <name>
            <surname>Ford</surname>
            <given-names>A H</given-names>
          </name>
          <name>
            <surname>Hankey</surname>
            <given-names>G J</given-names>
          </name>
          <name>
            <surname>Golledge</surname>
            <given-names>J</given-names>
          </name>
          <name>
            <surname>Yeap</surname>
            <given-names>B B</given-names>
          </name>
          <article-title>Depression, antidepressants and the risk of cardiovascular events and death in older men</article-title>
          <date>
            <year>2019</year>
          </date>
          <chapter-title>Maturitas.;128:</chapter-title>
          <fpage>4</fpage>
          <lpage>9</lpage>
          <pub-id pub-id-type="doi">10.1016/j.maturitas.2019.06.009</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1842774140">
        <label>58.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Tsai</surname>
            <given-names>S R</given-names>
          </name>
          <name>
            <surname>Hamblin</surname>
            <given-names>M R</given-names>
          </name>
          <article-title>Biological effects and medical applications of infrared radiation</article-title>
          <date>
            <year>2017</year>
          </date>
          <source>J Photochem Photobiol B</source>
          <volume>170</volume>
          <fpage>197</fpage>
          <lpage>207</lpage>
          <pub-id pub-id-type="doi">10.1016/j.jphotobiol.2017.04.014</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1842733964">
        <label>59.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Zein</surname>
            <given-names>R</given-names>
          </name>
          <name>
            <surname>Selting</surname>
            <given-names>W</given-names>
          </name>
          <name>
            <surname>Hamblin</surname>
            <given-names>M R</given-names>
          </name>
          <article-title>Review of light parameters and photobiomodulation efficacy: dive into complexity</article-title>
          <date>
            <year>2018</year>
          </date>
          <source>J Biomed Opt</source>
          <volume>23</volume>
          <issue>12</issue>
          <fpage>1</fpage>
          <lpage>17</lpage>
          <pub-id pub-id-type="doi">10.1117/1.JBO.23.12.120901</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1842729644">
        <label>60.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Hamblin</surname>
            <given-names>M BermanMH</given-names>
          </name>
          <name>
            <surname>Chazo</surname>
            <given-names>P</given-names>
          </name>
          <article-title>Photobiomodulation and Other Light Stimulation Procedures. doi: 10.1016/B978-0-12-803726-3.00004-3. In: Rhythmic Stimulation Procedures in Neuromodulation</article-title>
          <date>
            <year>2017</year>
          </date>
          <source>Chapter</source>
          <volume>4</volume>
          <pub-id pub-id-type="doi">10.1016/B978-0-12-803726-3.00004-3</pub-id>
        </mixed-citation>
      </ref>
      <ref id="ridm1842727268">
        <label>61.</label>
        <mixed-citation xlink:type="simple" publication-type="journal">
          <name>
            <surname>Heiskanen</surname>
            <given-names>V</given-names>
          </name>
          <name>
            <surname>Pfiffner</surname>
            <given-names>M</given-names>
          </name>
          <name>
            <surname>Partonen</surname>
            <given-names>T</given-names>
          </name>
          <article-title>Sunlight and health: shifting the focus from vitamin D3 to photobiomodulation by red and near-infrared light. Ageing Res Rev</article-title>
          <date>
            <year>2020</year>
          </date>
          <volume>61</volume>
          <fpage>101089</fpage>
        </mixed-citation>
      </ref>
    </ref-list>
  </back>
</article>
