{"id":26766,"date":"2024-01-03T21:38:06","date_gmt":"2024-01-03T19:38:06","guid":{"rendered":"https:\/\/hho-bulgaria.com\/h2-rich-water-and-caffeine-for-alertness-in-sleep-deprived-coffee-drinkers\/"},"modified":"2024-01-29T21:40:17","modified_gmt":"2024-01-29T19:40:17","slug":"h2-rich-water-and-caffeine-for-alertness-in-sleep-deprived-coffee-drinkers","status":"publish","type":"post","link":"https:\/\/hho-bulgaria.com\/en\/h2-rich-water-and-caffeine-for-alertness-in-sleep-deprived-coffee-drinkers\/","title":{"rendered":"H2-rich Water and Caffeine for Alertness in Sleep-Deprived Coffee Drinkers"},"content":{"rendered":"<div class=\"jig-ncbiinpagenav\" data-jigconfig=\"smoothScroll: false, allHeadingLevels: ['h2'], headingExclude: ':hidden,.nomenu'\" id=\"ui-ncbiinpagenav-1\">\n<div class=\"fm-sec half_rhythm no_top_margin\">\n<div class=\"fm-flexbox\">\n<div class=\"fm-citation\">\n<div class=\"citation-default\">\n<div class=\"part1\"><span role=\"menubar\"><a href=\"#\" role=\"menuitem\" aria-expanded=\"false\" aria-haspopup=\"true\">Food Sci Nutr.<\/a><\/span> 2021 Sep; 9(9): 5139\u20135145. <\/div>\n<div class=\"part2\"><span class=\"fm-vol-iss-date\">Published online 2021 Jul 19. <\/span>  <span class=\"doi\"><span>doi:&nbsp;<\/span><a href=\"\/\/doi.org\/10.1002%2Ffsn3.2480\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=8441318&amp;issue-id=390094&amp;journal-id=2357&amp;FROM=Article%7CFront%20Matter&amp;TO=Content%20Provider%7CCrosslink%7CDOI\">10.1002\/fsn3.2480<\/a><\/span><\/div>\n<\/div>\n<\/div>\n<div class=\"fm-ids\">\n<div class=\"fm-citation-pmcid\"><span class=\"fm-citation-ids-label\">PMCID: <\/span><span>PMC8441318<\/span><\/div>\n<div class=\"fm-citation-pmid\">PMID: <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/34532023\">34532023<\/a><\/div>\n<\/div>\n<\/div>\n<h1 class=\"content-title\">Hydrogen\u2010rich water and caffeine for alertness and brain metabolism in sleep\u2010deprived habitual coffee drinkers<\/h1>\n<div class=\"half_rhythm\">\n<div class=\"contrib-group fm-author\"><a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Todorovic%20N%5BAuthor%5D\" id=\"fsn32480-cr-0001\" class=\"affpopup\" co-rid=\"_co_idm139975545624592\" co-class=\"co-affbox\">Nikola Todorovic<\/a>,<sup><br \/>\n1<br \/>\n<\/sup> <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Zanini%20D%5BAuthor%5D\" id=\"fsn32480-cr-0002\" class=\"affpopup\" co-rid=\"_co_idm139975541004960\" co-class=\"co-affbox\">Dragana Zanini<\/a>,<sup><br \/>\n1<br \/>\n<\/sup> <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Stajer%20V%5BAuthor%5D\" id=\"fsn32480-cr-0003\" class=\"affpopup\" co-rid=\"_co_idm139975541002352\" co-class=\"co-affbox\">Valdemar Stajer<\/a>,<sup><br \/>\n1<br \/>\n<\/sup> <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Korovljev%20D%5BAuthor%5D\" id=\"fsn32480-cr-0004\" class=\"affpopup\" co-rid=\"_co_idm139975540559616\" co-class=\"co-affbox\">Darinka Korovljev<\/a>,<sup><br \/>\n1<br \/>\n<\/sup> <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Ostojic%20J%5BAuthor%5D\" id=\"fsn32480-cr-0005\" class=\"affpopup\" co-rid=\"_co_idm139975540557008\" co-class=\"co-affbox\">Jelena Ostojic<\/a>,<sup><br \/>\n1<br \/>\n<\/sup> and  <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Ostojic%20SM%5BAuthor%5D\" id=\"fsn32480-cr-0006\" class=\"affpopup\" co-rid=\"_co_idm139975587337600\" co-class=\"co-affbox\">Sergej M. Ostojic<\/a><sup><img decoding=\"async\" src=\"\/corehtml\/pmc\/pmcgifs\/corrauth.gif\" alt=\"corresponding author\"><\/sup><sup><br \/>\n1<br \/>\n,<\/sup><sup><br \/>\n2<br \/>\n<\/sup><\/div>\n<div style=\"display:none\" class=\"contrib-group aff-tip\">\n<div id=\"_co_idm139975545624592\">\n<h3 class=\"no_margin\">Nikola Todorovic<\/h3>\n<p>\n<sup><br \/>\n1<br \/>\n<\/sup><br \/>\nApplied Bioenergetics Lab,<br \/>\nFaculty of Sport and PE,<br \/>\nUniversity of Novi Sad,<br \/>\nNovi Sad<br \/>\nSerbia\n<\/p>\n<div>Find articles by <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Todorovic%20N%5BAuthor%5D\">Nikola Todorovic<\/a><\/div>\n<\/div>\n<div id=\"_co_idm139975541004960\">\n<h3 class=\"no_margin\">Dragana Zanini<\/h3>\n<p>\n<sup><br \/>\n1<br \/>\n<\/sup><br \/>\nApplied Bioenergetics Lab,<br \/>\nFaculty of Sport and PE,<br \/>\nUniversity of Novi Sad,<br \/>\nNovi Sad<br \/>\nSerbia\n<\/p>\n<div>Find articles by <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Zanini%20D%5BAuthor%5D\">Dragana Zanini<\/a><\/div>\n<\/div>\n<div id=\"_co_idm139975541002352\">\n<h3 class=\"no_margin\">Valdemar Stajer<\/h3>\n<p>\n<sup><br \/>\n1<br \/>\n<\/sup><br \/>\nApplied Bioenergetics Lab,<br \/>\nFaculty of Sport and PE,<br \/>\nUniversity of Novi Sad,<br \/>\nNovi Sad<br \/>\nSerbia\n<\/p>\n<div>Find articles by <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Stajer%20V%5BAuthor%5D\">Valdemar Stajer<\/a><\/div>\n<\/div>\n<div id=\"_co_idm139975540559616\">\n<h3 class=\"no_margin\">Darinka Korovljev<\/h3>\n<p>\n<sup><br \/>\n1<br \/>\n<\/sup><br \/>\nApplied Bioenergetics Lab,<br \/>\nFaculty of Sport and PE,<br \/>\nUniversity of Novi Sad,<br \/>\nNovi Sad<br \/>\nSerbia\n<\/p>\n<div>Find articles by <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Korovljev%20D%5BAuthor%5D\">Darinka Korovljev<\/a><\/div>\n<\/div>\n<div id=\"_co_idm139975540557008\">\n<h3 class=\"no_margin\">Jelena Ostojic<\/h3>\n<p>\n<sup><br \/>\n1<br \/>\n<\/sup><br \/>\nApplied Bioenergetics Lab,<br \/>\nFaculty of Sport and PE,<br \/>\nUniversity of Novi Sad,<br \/>\nNovi Sad<br \/>\nSerbia\n<\/p>\n<div>Find articles by <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Ostojic%20J%5BAuthor%5D\">Jelena Ostojic<\/a><\/div>\n<\/div>\n<div id=\"_co_idm139975587337600\">\n<h3 class=\"no_margin\">Sergej M. Ostojic<\/h3>\n<p>\n<sup><br \/>\n1<br \/>\n<\/sup><br \/>\nApplied Bioenergetics Lab,<br \/>\nFaculty of Sport and PE,<br \/>\nUniversity of Novi Sad,<br \/>\nNovi Sad<br \/>\nSerbia\n<\/p>\n<p>\n<sup><br \/>\n2<br \/>\n<\/sup><br \/>\nFaculty of Health Sciences,<br \/>\nUniversity of Pecs,<br \/>\nPecs<br \/>\nHungary\n<\/p>\n<div>Find articles by <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Ostojic%20SM%5BAuthor%5D\">Sergej M. Ostojic<\/a><\/div>\n<\/div>\n<\/div>\n<\/div>\n<div class=\"half_rhythm\">\n<div class=\"togglers fm-copyright-license\"><a href=\"#\" class=\"pmctoggle\" rid=\"idm139975587596768_ai\">Author information<\/a> <a href=\"#\" class=\"pmctoggle\" rid=\"idm139975587596768_an\">Article notes<\/a> <a href=\"#\" class=\"pmctoggle\" rid=\"idm139975587596768_cpl\">Copyright and License information<\/a> <a href=\"\/pmc\/about\/disclaimer\/\" style=\"margin-left: 1em\">PMC Disclaimer<\/a><\/div>\n<div class=\"fm-authors-info hide half_rhythm\" id=\"idm139975587596768_ai\" style=\"display:none\">\n<div class=\"fm-affl\" id=\"fsn32480-aff-0001\">\n<sup><br \/>\n1<br \/>\n<\/sup><br \/>\nApplied Bioenergetics Lab,<br \/>\nFaculty of Sport and PE,<br \/>\nUniversity of Novi Sad,<br \/>\nNovi Sad<br \/>\nSerbia\n<\/div>\n<div class=\"fm-affl\" id=\"fsn32480-aff-0002\">\n<sup><br \/>\n2<br \/>\n<\/sup><br \/>\nFaculty of Health Sciences,<br \/>\nUniversity of Pecs,<br \/>\nPecs<br \/>\nHungary\n<\/div>\n<div><span class=\"fm-affl\">Sergej M. Ostojic, <\/span><span class=\"fm-affl\"><span class=\"email-label\">Email: <\/span><a href=\"mailto:dev@null\" data-email=\"sr.ude.ssehc@cijotso.jegres\" class=\"oemail\">sr.ude.ssehc@cijotso.jegres<\/a><\/span>.<\/div>\n<div><sup><img decoding=\"async\" src=\"\/corehtml\/pmc\/pmcgifs\/corrauth.gif\" alt=\"corresponding author\"><\/sup>Corresponding author.<\/div>\n<div id=\"correspondenceTo\"><sup>*<\/sup><strong>Correspondence<\/strong><br \/>\nSergej M. Ostojic, Applied Bioenergetics Lab, Faculty of Sport and Physical Education, University of Novi Sad, Lovcenska 16, Novi Sad 21000, Serbia.<br \/>\nEmail: <a href=\"mailto:dev@null\" data-email=\"sr.ude.ssehc@cijotso.jegres\" class=\"oemail\">sr.ude.ssehc@cijotso.jegres<\/a><br \/>\n\n<\/div>\n<\/div>\n<div class=\"fm-article-notes hide half_rhythm\" id=\"idm139975587596768_an\" style=\"display:none\">\n<div class=\"fm-pubdate half_rhythm\">Received 2021 Feb 15; Revised 2021 Jun 20; Accepted 2021 Jul 7.<\/div>\n<\/div>\n<div class=\"permissions half_rhythm hide\" id=\"idm139975587596768_cpl\" style=\"display:none\">\n<div class=\"fm-copyright half_rhythm\"><a href=\"\/pmc\/about\/copyright\/\">Copyright<\/a> \u00a9 2021 The Authors. <em>Food Science &amp; Nutrition<\/em> published by Wiley Periodicals LLC.<\/div>\n<div class=\"license half_rhythm\">This is an open access article under the terms of the <a href=\"https:\/\/creativecommons.org\/licenses\/by\/4.0\/\" data-ga-action=\"click_feat_suppl\" ref=\"reftype=extlink&amp;article-id=8441318&amp;issue-id=390094&amp;journal-id=2357&amp;FROM=Article%7CFront%20Matter&amp;TO=External%7CLink%7CURI\" target=\"_blank\" rel=\"noopener\">http:\/\/creativecommons.org\/licenses\/by\/4.0\/<\/a> License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.<\/div>\n<\/div>\n<\/div>\n<div id=\"pmclinksbox\" class=\"links-box whole_rhythm hidden\" role=\"complementary\" aria-label=\"Related or updated information about this article.\"><\/div>\n<\/div>\n<div class=\"sec\"><\/div>\n<div id=\"ass-data\" class=\"tsec fm-sec whole_rhythm\" data-section=\"Featured_PMC_Datacitation\">\n<h2 class=\"nomenu\">Associated Data<\/h2>\n<dl data-length=\"172\" class=\"box-data-avail whole_rhythm no_bottom_margin\">\n<dt><a href=\"#\" rid=\"data-avl-stmnt\" data-ga-action=\"click_feat_toggler\" data-ga-label=\"Data Availability Statement\" class=\"pmctoggle\">Data Availability Statement<\/a><\/dt>\n<dd id=\"data-avl-stmnt\" style=\"display: none;\">\n<p class=\"p p-first-last\">The data that support the findings of this study have already been included in the manuscript. Raw data are available from the corresponding author upon reasonable request.<\/p>\n<\/dd>\n<\/dl>\n<\/div>\n<div id=\"fsn32480-abs-0001\" lang=\"en\" class=\"tsec sec\">\n<div class=\"goto jig-ncbiinpagenav-goto-container\"><span role=\"menubar\"><a class=\"tgt_dark page-toc-label jig-ncbiinpagenav-goto-heading\" href=\"#\" title=\"Go to other sections in this page\" role=\"menuitem\" aria-expanded=\"false\" aria-haspopup=\"true\">Go to:<\/a><\/span><\/div>\n<h2 class=\"head no_bottom_margin ui-helper-clearfix\" id=\"fsn32480-abs-0001title\">Abstract<\/h2>\n<p><!--article-meta--><\/p>\n<div>\n<p class=\"p p-first-last\">The main aim of this randomized\u2010controlled cross\u2010over interventional trial was to assess the acute effects of taking a single dose of hydrogen\u2010rich water (HRW), and compare it with caffeine, HRW plus caffeine, and control water, for alertness, brain metabolism, brain and oxygen saturation, and self\u2010reported adverse events in healthy men and women who were habitual coffee drinkers and were sleep\u2010deprived for 24&nbsp;hr. Sixteen apparently healthy young adults (8 men and 8 women; age 24.0&nbsp;\u00b1&nbsp;3.5&nbsp;years) were allocated in a cross\u2010over design to receive a single\u2010dose drink of HRW (8&nbsp;ppm), caffeine (50&nbsp;mg), HRW plus caffeine, or control drink (tap water) in the morning after 24\u2010hr sleep deprivation and 12\u2010hr fasting. The primary and secondary outcomes were assessed at baseline (pre\u2010intervention) and 15\u2010min follow\u2010up. Significantly less time was needed to complete trail\u2010making test after both HRW and HRW plus caffeine compared with the control drink (<em>p<\/em>&nbsp;&lt;&nbsp;.05). The number of errors in the symbol digit modalities test was significantly lower after drinking HRW or caffeine than control drink (<em>p<\/em>&nbsp;&lt;&nbsp;.05). Both HRW and caffeine significantly increased the choline\u2010to\u2010creatine ratio in several brain regions (frontal white and gray matter), while HRW and the combination intervention also affected brain metabolism in the paracentral brain. No participants reported any side effects from any intervention. The attention enhancement driven by HRW appears along with changes in brain metabolism. Being generally recognized as a safe intervention, hydrogen could be thus recommended as a novel intervention that upholds attention in stressed conditions, with its metabolic footprint likely different from caffeine.<\/p>\n<\/div>\n<div class=\"sec\"><strong class=\"kwd-title\">Keywords: <\/strong><span class=\"kwd-text\">alertness, brain metabolism, choline\u2010to\u2010creatine ratio, hydrogen, sleep<\/span><\/div>\n<\/div>\n<div id=\"fsn32480-abs-0002\" lang=\"en\" class=\"tsec sec\">\n<h2 class=\"headless nomenu\"><\/h2>\n<p><!--article-meta--><\/p>\n<div>\n<p class=\"p p-first-last\">Drinking a single dose of hydrogen\u2010rich water (HRW) improves alertness in sleep\u2010deprived young men and women. The attention enhancement driven by HRW appears to go with notable changes in brain metabolism, illustrated by higher choline\u2010to\u2010creatine ratio levels in the frontal and paracentral brain. Being a harmless intervention, HRW could be thus recommended as a novel food intervention that upholds attention in stressed conditions, with its metabolic footprint likely different from caffeine.<\/p>\n<div class=\"boxed-text-box whole_rhythm hide-overflow\" id=\"fsn32480-blkfxd-0001\">\n<div class=\"figure\" data-largeobj=\"\" data-largeobj-link-rid=\"largeobj_idm139975545162832\"><img decoding=\"async\" loading=\"lazy\" class=\"fig-image\" alt=\"An external file that holds a picture, illustration, etc.\nObject name is FSN3-9-5139-g004.jpg\" title=\"An external file that holds a picture, illustration, etc.\nObject name is FSN3-9-5139-g004.jpg\" src=\"https:\/\/hho-bulgaria.com\/wp-content\/uploads\/2024\/01\/FSN3-9-5139-g004.jpg\"><\/div>\n<\/div>\n<\/div>\n<\/div>\n<div id=\"fsn32480-sec-0001\" class=\"tsec sec\">\n<div class=\"goto jig-ncbiinpagenav-goto-container\"><a class=\"tgt_dark page-toc-label jig-ncbiinpagenav-goto-heading\" href=\"#\" title=\"Go to other sections in this page\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Go to:<\/a><\/div>\n<h2 class=\"head no_bottom_margin ui-helper-clearfix\" id=\"fsn32480-sec-0001title\">1.\u2003INTRODUCTION<\/h2>\n<p class=\"p p-first-last\">Molecular hydrogen (dihydrogen, H<sub>2<\/sub>) is a novel biotherapeutic gas that appears effective in various health conditions. Hydrogen\u2010rich water (HRW: also known as hydrogen\u2010infused water) emerges as the most common vehicle to deliver dihydrogen in biomedicine, and over 1,500 studies published during the past decade or so confirm the favorable effects of drinking HRW in both animal and human trials (for a detailed review see Yang et&nbsp;al.,&nbsp;<sup><a href=\"#fsn32480-bib-0022\" rid=\"fsn32480-bib-0022\" class=\" bibr popnode\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">2020<\/a><\/sup>). Due to its pleiotropic biological activity and ability to easily cross the blood\u2010brain barrier (Ohta <sup><a href=\"#fsn32480-bib-0014\" rid=\"fsn32480-bib-0014\" class=\" bibr popnode\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">2012<\/a><\/sup>), HRW was found to ameliorate patient\u2010reported scores in Parkinson&#8217;s disease (Yoritaka et&nbsp;al.,&nbsp;<sup><a href=\"#fsn32480-bib-0023\" rid=\"fsn32480-bib-0023\" class=\" bibr popnode\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">2013<\/a><\/sup>), increase mood, anxiety, and autonomic nerve function in daily life (Mizuno et&nbsp;al.,&nbsp;<sup><a href=\"#fsn32480-bib-0013\" rid=\"fsn32480-bib-0013\" class=\" bibr popnode\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">2018<\/a><\/sup>) and reduce the presence and severity of symptoms of mild traumatic brain injury (Javorac et al. <sup><a href=\"#fsn32480-bib-0008\" rid=\"fsn32480-bib-0008\" class=\" bibr popnode\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">2019<\/a><\/sup>). The beneficial effects of dihydrogen in neurology are attributed to its role in neurometabolic processes, including bioenergetics, anti\u2010oxygenation, anti\u2010inflammation, and anti\u2010apoptosis, (Iketani &amp; Ohsawa,&nbsp;<sup><a href=\"#fsn32480-bib-0007\" rid=\"fsn32480-bib-0007\" class=\" bibr popnode\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">2017<\/a><\/sup&gt;; Ostojic,&nbsp;<sup><a href=\"#fsn32480-bib-0017\" rid=\"fsn32480-bib-0017\" class=\" bibr popnode\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">2017<\/a><\/sup>). However, no human studies so far have evaluated the immediate impact of dihydrogen on brain metabolism. We recently found that HRW is superior to caffeine, a well\u2010known cognitive enhancer, to improve orientation\u2010specific alertness in healthy men and women (Zanini et&nbsp;al.,&nbsp;<sup><a href=\"#fsn32480-bib-0024\" rid=\"fsn32480-bib-0024\" class=\" bibr popnode\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">2020<\/a><\/sup>). A limited number of brain\u2010specific outcomes and biomarkers used in this pilot trial require additional investigation to compare HRW and caffeine for brain function. Therefore, the main aim of the present study was to evaluate the acute effects of drinking single\u2010dose HRW, and compare it with caffeine, HRW plus caffeine, and control water (no dihydrogen and caffeine) for alertness, brain metabolism, brain and oxygen saturation, and self\u2010reported adverse events in healthy men and women who were sleep\u2010deprived for 24&nbsp;hr.<\/p>\n<\/div>\n<div id=\"fsn32480-sec-0002\" class=\"tsec sec\">\n<div class=\"goto jig-ncbiinpagenav-goto-container\"><a class=\"tgt_dark page-toc-label jig-ncbiinpagenav-goto-heading\" href=\"#\" title=\"Go to other sections in this page\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Go to:<\/a><\/div>\n<h2 class=\"head no_bottom_margin ui-helper-clearfix\" id=\"fsn32480-sec-0002title\">2.\u2003METHODS<\/h2>\n<div id=\"fsn32480-sec-0003\" class=\"sec sec-first\">\n<h3 id=\"fsn32480-sec-0003title\">2.1. Participants<\/h3>\n<p class=\"p p-first-last\">Sixteen healthy adults (8 men and 8 women; age 24.0&nbsp;\u00b1&nbsp;3.5&nbsp;years, body mass index 23.5&nbsp;\u00b1&nbsp;2.4&nbsp;cm) signed an informed consent to voluntarily participate in this randomized\u2010controlled cross\u2010over interventional trial. Inclusion criteria were as follows: age 18 to 30&nbsp;years, healthy body mass index (<em>e.g<\/em>., 18.5 to 25.0&nbsp;kg\/m<sup>2<\/sup>), no current chronic diseases or acute disorders, habitual coffee drinking, and sleep deprivation of 24&nbsp;hr. Exclusion criteria included a previous history of dietary supplement use during the four weeks before the study commences and caffeine intake 12&nbsp;hr before the trial. The minimal sample size (<em>n<\/em>&nbsp;=&nbsp;16) was calculated using power analysis (G*Power 3.1), with the effect&#8217;s size set at 0.50 (medium effect), alpha error probability 0.05, and power 0.80 for four groups, and eight measurements of study outcomes. The primary outcome was the change in reaction time for the attention network test (see below) at baseline and 15\u2010min postadministration. The study design was approved by the local IRB at the University of Novi Sad (# 2\u2010CFHRW\/2020), with the study systematized following the Declaration of Helsinki and International Conference of Harmonization Efficacy Guidelines E6.<\/p>\n<\/div>\n<div id=\"fsn32480-sec-0004\" class=\"sec\">\n<h3 id=\"fsn32480-sec-0004title\">2.2. Experimental interventions<\/h3>\n<p class=\"p p-first\">All volunteers were allocated in a cross\u2010over design to receive a single\u2010dose drink of HRW, caffeine, HRW plus caffeine, or control drink in the morning after 24\u2010hr sleep deprivation and 12\u2010hr fasting. The composition of each drink is presented in Figure&nbsp;<a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC8441318\/figure\/fsn32480-fig-0001\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"fsn32480-fig-0001\" rid-ob=\"ob-fsn32480-fig-0001\" co-legend-rid=\"lgnd_fsn32480-fig-0001\" rel=\"noopener\"><span>1<\/span><\/a>, with all experimental interventions produced by dissolving specific tablets\/powders into a cup of lukewarm water (500&nbsp;ml). HRW and nonhydrogen producing magnesium tablets were provided by HRW Natural Health Products Inc. (New Westminster, BC, Canada), and caffeine anhydrous powder was purchased by Proteos (Zagreb, Croatia). Dihydrogen in HRW was produced by the following reaction: Mg + H<sub>2<\/sub>O \u2192 H<sub>2<\/sub> + Mg(OH)<sub>2<\/sub>, with magnesium used in HRW was elemental magnesium. The content of dihydrogen in all experimental drinks was measured by gas chromatography, as previously described (Zanini et&nbsp;al.,&nbsp;<sup><a href=\"#fsn32480-bib-0024\" rid=\"fsn32480-bib-0024\" class=\" bibr popnode\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">2020<\/a><\/sup>). All drinks were similar in appearance, texture, and sensory characteristics, and normalized for total magnesium amount. A wash\u2010out period of 7&nbsp;days was set to prevent the residual effects of interventions across study periods.<\/p>\n<p><!--fig ft0--><!--fig mode=article f1--><\/p>\n<div class=\"fig iconblock whole_rhythm\" id=\"fsn32480-fig-0001\" co-legend-rid=\"lgnd_fsn32480-fig-0001\"><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC8441318\/figure\/fsn32480-fig-0001\/\" target=\"figure\" rid-figpopup=\"fsn32480-fig-0001\" rid-ob=\"ob-fsn32480-fig-0001\" rel=\"noopener\"><!--fig\/graphic|fig\/alternatives\/graphic mode=\"anchored\" m1--><\/p>\n<div class=\"figure\" data-largeobj=\"\" data-largeobj-link-rid=\"largeobj_idm139975542749328\"><img decoding=\"async\" loading=\"lazy\" class=\"fig-image\" alt=\"An external file that holds a picture, illustration, etc.\nObject name is FSN3-9-5139-g001.jpg\" title=\"An external file that holds a picture, illustration, etc.\nObject name is FSN3-9-5139-g001.jpg\" src=\"https:\/\/hho-bulgaria.com\/wp-content\/uploads\/2024\/01\/FSN3-9-5139-g001.jpg\"><\/div>\n<p><\/a><\/p>\n<div class=\"largeobj-link align_right\" id=\"largeobj_idm139975542749328\" style=\"display: none;\"><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC8441318\/figure\/fsn32480-fig-0001\/\" target=\"figure\" rid-figpopup=\"fsn32480-fig-0001\" rid-ob=\"ob-fsn32480-fig-0001\" rel=\"noopener\"><\/a><a target=\"object\" rel=\"noopener\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC8441318\/figure\/fsn32480-fig-0001\/?report=objectonly\">Open in a separate window<\/a><\/div>\n<div class=\"icnblk_cntnt\" id=\"lgnd_fsn32480-fig-0001\">\n<div><a class=\"figpopup\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC8441318\/figure\/fsn32480-fig-0001\/\" target=\"figure\" rid-figpopup=\"fsn32480-fig-0001\" rid-ob=\"ob-fsn32480-fig-0001\" rel=\"noopener\">FIGURE 1<\/a><\/div>\n<p><!--caption a7--><\/p>\n<div class=\"caption\">\n<p>The composition of experimental interventions. HRW\u2014ahydrogen\u2010rich water<\/p>\n<\/div>\n<\/div>\n<\/div>\n<p class=\"p\">Sleep deprivation was secured by keeping participants awake in a sleep quarantine room within FSPE Applied Bioenergetics Lab under continuous control of research staff for 24&nbsp;hr before the experimental drinks\u2019 intervention. Outcomes assessed at baseline (pre\u2010intervention) and 15\u2010min follow\u2010up were visual analogue scale (VAS) for alertness (Srivastava et&nbsp;al.,&nbsp;<sup><a href=\"#fsn32480-bib-0020\" rid=\"fsn32480-bib-0020\" class=\" bibr popnode\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">2013<\/a><\/sup>), and the attention network test (ANT) with subscales for alerting, orienting, and executive control (Macleod et&nbsp;al.,&nbsp;<sup><a href=\"#fsn32480-bib-0012\" rid=\"fsn32480-bib-0012\" class=\" bibr popnode\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">2010<\/a><\/sup>). Trail\u2010making test A was also employed as an indicator of visual scanning, graphomotor speed, and executive function (Llin\u00e0s\u2010Regl\u00e0 et&nbsp;al.,&nbsp;<sup><a href=\"#fsn32480-bib-0011\" rid=\"fsn32480-bib-0011\" class=\" bibr popnode\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">2017<\/a><\/sup>), along with symbol digit modalities test (SDMT) (Smith, <sup><a href=\"#fsn32480-bib-0019\" rid=\"fsn32480-bib-0019\" class=\" bibr popnode\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">2000<\/a><\/sup>). Brain oxygenation (SbO<sub>2<\/sub>) and hemoglobin index (tHb) in the prefrontal cortex was monitored with 4\u2010optode (680\u2013800&nbsp;nm) functional near\u2010infrared spectroscopy sensor (Fortiori Design LLC, Hutchinson, Minnesota), while peripheral capillary oxygen saturation (SpO<sub>2<\/sub>) was monitored with fingertip oximeter (Barrington Diagnostics, Barrington, IN). Magnetic resonance imaging and spectroscopy were performed on a 1.5&nbsp;T Siemens Avanto scanner (Erlangen, Germany), using matrix head coil (receiver coil) in circularly polarized mode as previously described (Ostojic et&nbsp;al.,&nbsp;<sup><a href=\"#fsn32480-bib-0018\" rid=\"fsn32480-bib-0018\" class=\" bibr popnode\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">2017<\/a><\/sup>). Water\u2010suppressed proton 2D Spectroscopic Imaging (CSI) and single\u2010voxel data sets were acquired with point\u2010resolved spectroscopy TR\/TE of 1500\/135&nbsp;ms. The first CSI slab [field of view (FOV) 160&nbsp;\u00d7&nbsp;160 \u00d7 160&nbsp;mm; voxel of interest (VOI) 80&nbsp;\u00d7&nbsp;80 \u00d7 80&nbsp;mm, thickness 10&nbsp;mm] was positioned parallel to the axial images, immediately above the corpus callosum along the anterior\u2013posterior commissure, to encompass the semioval white matter and the cortical gray matter. The number of phase\u2010encoding steps (scan resolution) was 12 in all directions (R\u2010L, A\u2010P, and F\u2010H). The number of reconstructed spectra (interpolation resolution) was 12 in all directions, resulting in a VOI of 10&nbsp;\u00d7&nbsp;10 \u00d7 10&nbsp;mm. Twelve phase\u2010encoding steps and reconstructed spectra were recorded, resulting in a VOI of 8&nbsp;\u00d7&nbsp;8 \u00d7 15&nbsp;mm. The number of acquisitions was 4, with a scan time of 7&nbsp;min 12&nbsp;s for each CSI acquisition. A nonwater\u2010suppressed CSI and SVS data were also obtained with the same geometrical parameters (e.g., one average for CSI, sixty\u2010four averages for SVS) to provide an internal water reference for the absolute quantification of relevant metabolic ratios. The weighted phase\u2010encoding scheme was applied. Interfering signal contributions from areas outside the VOI were suppressed by six saturation regions, manually positioned along each VOI margin. The homogeneity of the magnetic field was optimized using manual shimming. Special care has been taken to position each region of interest in the exact location for all subjects to achieve the highest possible level of reproducibility. Spectra were evaluated from 12 individual voxels: six areas were located in bilateral parasagittal anterior, middle, and posterior cortices, characterized primarily by frontal, paracentral, and parietal mesial gray matter, and six were in lateral anterior, middle, and posterior regions containing predominantly frontal, precentral, and parietal white matter (Figure&nbsp;<a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC8441318\/figure\/fsn32480-fig-0002\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"fsn32480-fig-0002\" rid-ob=\"ob-fsn32480-fig-0002\" co-legend-rid=\"lgnd_fsn32480-fig-0002\" rel=\"noopener\"><span>2<\/span><\/a>). A total of 285 spectra were analyzed in this study. The CSI raw data were evaluated using a commercially available spectral analysis software package (Syngo Multi\u2010Modality Workplace, version VE23A, Siemens, Erlangen, Germany). The postprocessing protocol included water reference processing by averaging 20 adjacent points, removing the residual water signal from the spectrum by subtracting it from the time signal and frequency shift correction of the water signal, Hanning filter 512&nbsp;ms width, Zero filling from 512 to 1,024 data points, and Fourier transformation. Signals for creatine (3.04&nbsp;ppm), choline (3.2&nbsp;ppm), and NAA (2.02&nbsp;ppm) were quantified using Gaussian curve fittings. The choline\u2010to\u2010creatine and choline\u2010to\u2010<em>N<\/em>\u2010acetyl aspartate (NAA) ratios were calculated from areas under the respective signals. The area of water signal for each processed voxel was assessed from the scan without water suppression. The quantification of the SVS data was performed offline in the time domain using the jMRUI software package. For metabolite spectra processing, the remaining water signal was removed using an HLSVD filter, and amplitudes of choline, creatine, and NAA signals were calculated with the AMARES method (Vanhamme et al. <sup><a href=\"#fsn32480-bib-0021\" rid=\"fsn32480-bib-0021\" class=\" bibr popnode\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">1997<\/a><\/sup>). The amplitude of the water signal for each processed voxel was assessed from the scan without water suppression. Mono\u2010exponential spin\u2010lattice and spin\u2010spin relaxation were assumed, and published values of T1 and T2 relaxation times of water and respective metabolites measured at 1.5&nbsp;T in the gray and white matter of healthy volunteers were used for relaxation corrections (Bajzik et al. <sup><a href=\"#fsn32480-bib-0001\" rid=\"fsn32480-bib-0001\" class=\" bibr popnode\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">2008<\/a><\/sup>). The volunteers were also instructed to report any side effects of each intervention (<em>e.g<\/em>., palpitations, gut disturbances, and headache) throughout the study with an open\u2010ended questionnaire.<\/p>\n<p><!--fig ft0--><!--fig mode=article f1--><\/p>\n<div class=\"fig iconblock whole_rhythm\" id=\"fsn32480-fig-0002\" co-legend-rid=\"lgnd_fsn32480-fig-0002\"><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC8441318\/figure\/fsn32480-fig-0002\/\" target=\"figure\" rid-figpopup=\"fsn32480-fig-0002\" rid-ob=\"ob-fsn32480-fig-0002\" rel=\"noopener\"><!--fig\/graphic|fig\/alternatives\/graphic mode=\"anchored\" m1--><\/p>\n<div class=\"figure\" data-largeobj=\"\" data-largeobj-link-rid=\"largeobj_idm139975538545904\"><img decoding=\"async\" loading=\"lazy\" class=\"fig-image\" alt=\"An external file that holds a picture, illustration, etc.\nObject name is FSN3-9-5139-g003.jpg\" title=\"An external file that holds a picture, illustration, etc.\nObject name is FSN3-9-5139-g003.jpg\" src=\"https:\/\/hho-bulgaria.com\/wp-content\/uploads\/2024\/01\/FSN3-9-5139-g003.jpg\"><\/div>\n<p><\/a><\/p>\n<div class=\"largeobj-link align_right\" id=\"largeobj_idm139975538545904\" style=\"display: none;\"><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC8441318\/figure\/fsn32480-fig-0002\/\" target=\"figure\" rid-figpopup=\"fsn32480-fig-0002\" rid-ob=\"ob-fsn32480-fig-0002\" rel=\"noopener\"><\/a><a target=\"object\" rel=\"noopener\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC8441318\/figure\/fsn32480-fig-0002\/?report=objectonly\">Open in a separate window<\/a><\/div>\n<div class=\"icnblk_cntnt\" id=\"lgnd_fsn32480-fig-0002\">\n<div><a class=\"figpopup\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC8441318\/figure\/fsn32480-fig-0002\/\" target=\"figure\" rid-figpopup=\"fsn32480-fig-0002\" rid-ob=\"ob-fsn32480-fig-0002\" rel=\"noopener\">FIGURE 2<\/a><\/div>\n<p><!--caption a7--><\/p>\n<div class=\"caption\">\n<p>Location of the individual voxels (blue square) evaluated during the study<\/p>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<div id=\"fsn32480-sec-0005\" class=\"sec sec-last\">\n<h3 id=\"fsn32480-sec-0005title\">2.3. Statistical analyses<\/h3>\n<p class=\"p p-first-last\">Friedman test was used to establish whether significant differences existed between different experimental drinks over time of intervention (baseline versus. 15\u2010min postadministration), with post hoc test used to identify differences between individual sample pairs. Data were analyzed using SPSS Statistics for Mac Version 24.0 (IBM, Armonk, NY), with the significance level set at <em>p<\/em>&nbsp;&lt;.05.<\/p>\n<\/div>\n<\/div>\n<div id=\"fsn32480-sec-0006\" class=\"tsec sec\">\n<div class=\"goto jig-ncbiinpagenav-goto-container\"><a class=\"tgt_dark page-toc-label jig-ncbiinpagenav-goto-heading\" href=\"#\" title=\"Go to other sections in this page\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Go to:<\/a><\/div>\n<h2 class=\"head no_bottom_margin ui-helper-clearfix\" id=\"fsn32480-sec-0006title\">3.\u2003RESULTS<\/h2>\n<p class=\"p p-first\">All volunteers completed all four trials, with no participants reported any side effect of each intervention. Changes in alertness biomarkers were depicted in Table&nbsp;<a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC8441318\/table\/fsn32480-tbl-0001\/\" target=\"table\" class=\"fig-table-link figpopup\" rid-figpopup=\"fsn32480-tbl-0001\" rid-ob=\"ob-fsn32480-tbl-0001\" co-legend-rid=\"\" rel=\"noopener\"><span>1<\/span><\/a>. A significant treatment versus. time interaction was found for reaction time, trail\u2010making test duration, and SDMT outcomes (<em>p<\/em>&nbsp;&lt;.05). In particular, a mean change in reaction time at 15\u2010min follow\u2010up was different between caffeine and HRW (<em>p<\/em>&nbsp;&lt;.05), and caffeine and HRW plus caffeine (<em>p<\/em>&nbsp;&lt;.05). A significantly less time was needed to complete trail\u2010making test after both HRW and HRW plus caffeine compared with the control drink (<em>p<\/em>&nbsp;&lt;.05). Finally, the number of errors in the SDMT test was significantly lower after drinking HRW or caffeine than control drink (<em>p<\/em>&nbsp;&lt;.05). No differences were found for SbO2, tHb, and SpO2 during the trial (<em>p<\/em>&nbsp;&gt;.05).<\/p>\n<p><!--table ft1--><!--table-wrap mode=\"anchored\" t5--><\/p>\n<div class=\"table-wrap anchored whole_rhythm\" id=\"fsn32480-tbl-0001\">\n<h3>TABLE 1<\/h3>\n<p><!--caption a7--><\/p>\n<div class=\"caption\">\n<p>Changes in alertness and oxygenation outcomes during the study<\/p>\n<\/div>\n<div class=\"xtable\">\n<table frame=\"hsides\" rules=\"groups\" class=\"rendered small default_table\">\n<thead valign=\"top\">\n<tr style=\"border-bottom:solid 1px #000000\">\n<th align=\"left\" rowspan=\"2\" valign=\"top\" colspan=\"1\"><\/th>\n<th align=\"left\" rowspan=\"2\" valign=\"top\" colspan=\"1\">Baseline<\/th>\n<th align=\"left\" colspan=\"4\" style=\"border-bottom:solid 1px #000000\" valign=\"top\" rowspan=\"1\">At 15\u2010min follow\u2010up<\/th>\n<th align=\"left\" style=\"border-bottom:solid 1px #000000\" valign=\"top\" rowspan=\"1\" colspan=\"1\">\n<em>P *<\/em>\n<\/th>\n<th align=\"left\" style=\"border-bottom:solid 1px #000000\" valign=\"top\" rowspan=\"1\" colspan=\"1\">Post hoc<\/th>\n<\/tr>\n<tr style=\"border-bottom:solid 1px #000000\">\n<th align=\"left\" valign=\"top\" rowspan=\"1\" colspan=\"1\">Control<\/th>\n<th align=\"left\" valign=\"top\" rowspan=\"1\" colspan=\"1\">Caffeine<\/th>\n<th align=\"left\" valign=\"top\" rowspan=\"1\" colspan=\"1\">HRW<\/th>\n<th align=\"left\" valign=\"top\" rowspan=\"1\" colspan=\"1\">HRW +Caffeine<\/th>\n<th align=\"left\" valign=\"top\" rowspan=\"1\" colspan=\"1\"><\/th>\n<th align=\"left\" valign=\"top\" rowspan=\"1\" colspan=\"1\"><\/th>\n<\/tr>\n<\/thead>\n<tbody>\n<tr>\n<td align=\"left\" rowspan=\"1\" colspan=\"1\">VAS alertness (score)<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">4.5&nbsp;\u00b1&nbsp;2.6<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">5.3&nbsp;\u00b1&nbsp;2.2<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">5.0&nbsp;\u00b1&nbsp;2.4<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">5.6&nbsp;\u00b1&nbsp;2.3<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">6.5&nbsp;\u00b1&nbsp;1.9<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">0.095<\/td>\n<td align=\"left\" rowspan=\"1\" colspan=\"1\">\u2010<\/td>\n<\/tr>\n<tr>\n<td align=\"left\" rowspan=\"1\" colspan=\"1\">ANT alerting (ms)<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">37.0&nbsp;\u00b1&nbsp;26.7<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">45.6&nbsp;\u00b1&nbsp;32.4<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">43.6&nbsp;\u00b1&nbsp;30.3<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">35.3&nbsp;\u00b1&nbsp;37.1<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">40.3&nbsp;\u00b1&nbsp;32.7<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">0.802<\/td>\n<td align=\"left\" rowspan=\"1\" colspan=\"1\">\u2010<\/td>\n<\/tr>\n<tr>\n<td align=\"left\" rowspan=\"1\" colspan=\"1\">ANT orienting (ms)<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">37.6&nbsp;\u00b1&nbsp;27.2<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">46.1&nbsp;\u00b1&nbsp;28.5<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">46.3&nbsp;\u00b1&nbsp;22.5<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">42.6&nbsp;\u00b1&nbsp;25.9<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">46.8&nbsp;\u00b1&nbsp;25.6<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">0.963<\/td>\n<td align=\"left\" rowspan=\"1\" colspan=\"1\">\u2010<\/td>\n<\/tr>\n<tr>\n<td align=\"left\" rowspan=\"1\" colspan=\"1\">ANT executive control (ms)<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">143.2&nbsp;\u00b1&nbsp;57.7<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">153.3&nbsp;\u00b1&nbsp;62.7<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">127.4&nbsp;\u00b1&nbsp;35.1<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">136.1&nbsp;\u00b1&nbsp;88.6<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">107.3&nbsp;\u00b1&nbsp;42.2<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">0.070<\/td>\n<td align=\"left\" rowspan=\"1\" colspan=\"1\">\u2010<\/td>\n<\/tr>\n<tr>\n<td align=\"left\" rowspan=\"1\" colspan=\"1\">Reaction time (ms)<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">567.3&nbsp;\u00b1&nbsp;81.2<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">586.9&nbsp;\u00b1&nbsp;76.5<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">578.7&nbsp;\u00b1&nbsp;71.7<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">609.4&nbsp;\u00b1&nbsp;68.7<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">626.9&nbsp;\u00b1&nbsp;90.4<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">0.041<\/td>\n<td align=\"left\" rowspan=\"1\" colspan=\"1\">\n<sup>d e<\/sup>\n<\/td>\n<\/tr>\n<tr>\n<td align=\"left\" rowspan=\"1\" colspan=\"1\">Test accuracy (%)<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">96.6&nbsp;\u00b1&nbsp;3.4<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">94.4&nbsp;\u00b1&nbsp;9.9<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">98.6&nbsp;\u00b1&nbsp;1.3<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">97.9&nbsp;\u00b1&nbsp;3.1<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">98.6&nbsp;\u00b1&nbsp;1.4<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">0.072<\/td>\n<td align=\"left\" rowspan=\"1\" colspan=\"1\">\u2010<\/td>\n<\/tr>\n<tr>\n<td align=\"left\" rowspan=\"1\" colspan=\"1\">Trail\u2010making test A (ms)<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">21.6&nbsp;\u00b1&nbsp;5.0<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">22.8&nbsp;\u00b1&nbsp;5.1<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">19.3&nbsp;\u00b1&nbsp;7.3<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">16.6&nbsp;\u00b1&nbsp;4.9<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">17.0&nbsp;\u00b1&nbsp;3.7<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">0.001<\/td>\n<td align=\"left\" rowspan=\"1\" colspan=\"1\">\n<sup>b c<\/sup>\n<\/td>\n<\/tr>\n<tr>\n<td align=\"left\" rowspan=\"1\" colspan=\"1\">SDMT (number of symbols)<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">53.2&nbsp;\u00b1&nbsp;7.3<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">58.6&nbsp;\u00b1&nbsp;6.1<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">61.2&nbsp;\u00b1&nbsp;8.7<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">62.9&nbsp;\u00b1&nbsp;9.7<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">59.1&nbsp;\u00b1&nbsp;10.5<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">0.045<\/td>\n<td align=\"left\" rowspan=\"1\" colspan=\"1\">\n<sup>a b<\/sup>\n<\/td>\n<\/tr>\n<tr>\n<td align=\"left\" rowspan=\"1\" colspan=\"1\">SDMT (errors)<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">1.1&nbsp;\u00b1&nbsp;2.5<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">1.3&nbsp;\u00b1&nbsp;2.0<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">0.6&nbsp;\u00b1&nbsp;0.7<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">0.7&nbsp;\u00b1&nbsp;0.9<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">1.1&nbsp;\u00b1&nbsp;0.9<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">0.297<\/td>\n<td align=\"left\" rowspan=\"1\" colspan=\"1\">\u2010<\/td>\n<\/tr>\n<tr>\n<td align=\"left\" rowspan=\"1\" colspan=\"1\">Brain oxygenation (%)<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">67.5&nbsp;\u00b1&nbsp;6.0<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">62.4&nbsp;\u00b1&nbsp;6.6<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">63.7&nbsp;\u00b1&nbsp;9.0<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">63.1&nbsp;\u00b1&nbsp;8.1<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">60.7&nbsp;\u00b1&nbsp;5.8<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">0.592<\/td>\n<td align=\"left\" rowspan=\"1\" colspan=\"1\">\u2010<\/td>\n<\/tr>\n<tr>\n<td align=\"left\" rowspan=\"1\" colspan=\"1\">Total hemoglobin (umol\/L)<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">13.0&nbsp;\u00b1&nbsp;0.1<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">12.9&nbsp;\u00b1&nbsp;0.2<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">13.0&nbsp;\u00b1&nbsp;0.2<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">13.0&nbsp;\u00b1&nbsp;0.2<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">12.9&nbsp;\u00b1&nbsp;0.3<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">0.803<\/td>\n<td align=\"left\" rowspan=\"1\" colspan=\"1\">\u2010<\/td>\n<\/tr>\n<tr>\n<td align=\"left\" rowspan=\"1\" colspan=\"1\">Peripheral oxygen saturation (%)<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">98.5&nbsp;\u00b1&nbsp;0.7<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">98.5&nbsp;\u00b1&nbsp;0.5<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">98.1&nbsp;\u00b1&nbsp;1.4<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">98.3&nbsp;\u00b1&nbsp;1.2<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">98.7&nbsp;\u00b1&nbsp;0.5<\/td>\n<td align=\"center\" rowspan=\"1\" colspan=\"1\">0.899<\/td>\n<td align=\"left\" rowspan=\"1\" colspan=\"1\">\u2010<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<\/div>\n<div class=\"largeobj-link align_right\" id=\"largeobj_idm139975551484272\"><a target=\"object\" rel=\"noopener\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC8441318\/table\/fsn32480-tbl-0001\/?report=objectonly\">Open in a separate window<\/a><\/div>\n<div class=\"tblwrap-foot\">Note<\/p>\n<div id=\"fsn32480-note-0001\">\n<p class=\"p p-first-last\">Values are mean \u00b1 <em>SD<\/em>.<\/p>\n<\/div>\n<div id=\"fsn32480-note-0002\">\n<p class=\"p p-first-last\">Abbreviations: ANT, attention network test;<sup>b<\/sup>, control versus. HRW; <sup>c<\/sup>, mcontrol versus. HRW plus caffeine; <sup>d<\/sup>, caffeine versus. HRW; <sup>e<\/sup>, caffeine versus. HRW plus caffeine;HRW, hydrogen\u2010rich water. * <em>P<\/em> value from two\u2010way mixed ANOVA (treatment versus. time interaction). Post hoc superscript indicates a significant difference at <em>p<\/em>&nbsp;&lt;.05 for the following sample pairs: <sup>a<\/sup>, control versus. caffeine; SDMT, symbol digit modalities test; VAS, visual analogue scale.<\/p>\n<\/div>\n<\/div>\n<div class=\"small permissions half_rhythm\"><\/div>\n<\/div>\n<p class=\"p\">Figure&nbsp;<a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC8441318\/figure\/fsn32480-fig-0003\/\" target=\"figure\" class=\"fig-table-link figpopup\" rid-figpopup=\"fsn32480-fig-0003\" rid-ob=\"ob-fsn32480-fig-0003\" co-legend-rid=\"lgnd_fsn32480-fig-0003\" rel=\"noopener\"><span>3<\/span><\/a> depicts changes in brain metabolic ratios across twelve different brain locations. It appears that a significant treatment versus. time interaction was found for the changes in the choline\u2010to\u2010creatine ratio in 9 out of 12 regions (<em>p<\/em>&nbsp;&lt;.05). Caffeine significantly increased the choline\u2010to\u2010creatine ratio comparing to control drink in 5 locations (<em>p<\/em>&nbsp;&lt;.05), HRW significantly increased the ratio in 8 locations (<em>p<\/em>&nbsp;&lt;.05), and HRW plus caffeine significantly increased the ratio in 8 locations (<em>p<\/em>&nbsp;&lt;.05). Besides, a combination was superior to HRW to increase the choline\u2010to\u2010creatine ratio in left frontal gray matter (<em>p<\/em>&nbsp;&lt;.05). No differences were found between interventions for the choline\u2010to\u2010NAA ratio across the trial (<em>p<\/em>&nbsp;&gt;.05).<\/p>\n<p><!--fig ft0--><!--fig mode=article f1--><\/p>\n<div class=\"fig iconblock whole_rhythm\" id=\"fsn32480-fig-0003\" co-legend-rid=\"lgnd_fsn32480-fig-0003\"><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC8441318\/figure\/fsn32480-fig-0003\/\" target=\"figure\" rid-figpopup=\"fsn32480-fig-0003\" rid-ob=\"ob-fsn32480-fig-0003\" rel=\"noopener\"><!--fig\/graphic|fig\/alternatives\/graphic mode=\"anchored\" m1--><\/p>\n<div class=\"figure\" data-largeobj=\"\" data-largeobj-link-rid=\"largeobj_idm139975547461504\"><img decoding=\"async\" loading=\"lazy\" class=\"fig-image\" alt=\"An external file that holds a picture, illustration, etc.\nObject name is FSN3-9-5139-g002.jpg\" title=\"An external file that holds a picture, illustration, etc.\nObject name is FSN3-9-5139-g002.jpg\" src=\"https:\/\/hho-bulgaria.com\/wp-content\/uploads\/2024\/01\/FSN3-9-5139-g002.jpg\"><\/div>\n<p><\/a><\/p>\n<div class=\"largeobj-link align_right\" id=\"largeobj_idm139975547461504\" style=\"display: none;\"><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC8441318\/figure\/fsn32480-fig-0003\/\" target=\"figure\" rid-figpopup=\"fsn32480-fig-0003\" rid-ob=\"ob-fsn32480-fig-0003\" rel=\"noopener\"><\/a><a target=\"object\" rel=\"noopener\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC8441318\/figure\/fsn32480-fig-0003\/?report=objectonly\">Open in a separate window<\/a><\/div>\n<div class=\"icnblk_cntnt\" id=\"lgnd_fsn32480-fig-0003\">\n<div><a class=\"figpopup\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC8441318\/figure\/fsn32480-fig-0003\/\" target=\"figure\" rid-figpopup=\"fsn32480-fig-0003\" rid-ob=\"ob-fsn32480-fig-0003\" rel=\"noopener\">FIGURE 3<\/a><\/div>\n<p><!--caption a7--><\/p>\n<div class=\"caption\">\n<p>Changes in the choline\u2010to\u2010creatine ratio (blue) and choline\u2010to\u2010N\u2010acetyl aspartate (NAA) ratio (orange) in 12 various brain regions during the study. Y\u2010axis labels absolute values for metabolic ratios; each bar indicates changes from baseline to 15\u2010min follow\u2010up. Asterisk (*) indicates a significant difference at <em>p<\/em>&nbsp;&lt;.05 between the experimental drink and control drink; # indicates a significant difference at <em>p<\/em>&nbsp;&lt;.05 between hydrogen\u2010rich water (HRW) and HRW plus caffeine<\/p>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<div id=\"fsn32480-sec-0007\" class=\"tsec sec\">\n<div class=\"goto jig-ncbiinpagenav-goto-container\"><a class=\"tgt_dark page-toc-label jig-ncbiinpagenav-goto-heading\" href=\"#\" title=\"Go to other sections in this page\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Go to:<\/a><\/div>\n<h2 class=\"head no_bottom_margin ui-helper-clearfix\" id=\"fsn32480-sec-0007title\">4.\u2003DISCUSSION<\/h2>\n<p class=\"p p-first\">The present study corroborated preliminary findings that hydrogen\u2010rich water could acutely affect biomarkers of alertness in sleep\u2010deprived men and women. Specifically, HRW was superior to control drink to improve trail\u2010making and SDMT performance, while caffeine outperformed HRW for reaction time. The effects seen here were accompanied by changes in brain metabolism. Both HRW and caffeine significantly increased the choline\u2010to\u2010creatine ratio in several brain regions (<em>e.g<\/em>., frontal white and gray matter), while HRW and the combination intervention also affected brain metabolism in the paracentral brain. These findings suggest that HRW and caffeine probably affect different domains of alertness and stimulate metabolism in separate brain segments when administered acutely in sleep\u2010deprived volunteers.<\/p>\n<p>During the past decade or so, molecular hydrogen has emerged as an innovative agent in human neuroscience and clinical neurology. The effects of this simple biomedical gas on brain performance have been evaluated in a handful of interventional trials, spanning from brain trauma to neurodegenerative and cerebrovascular diseases. For instance, hydrogen improved the brain MRI indices in the acute brain stem infarct sites (Ono et&nbsp;al.,&nbsp;<sup><a href=\"#fsn32480-bib-0015\" rid=\"fsn32480-bib-0015\" class=\" bibr popnode\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">2011<\/a><\/sup>), positively affected patient\u2010reported scores in Parkinson&#8217;s disease (Yoritaka et&nbsp;al.,&nbsp;<sup><a href=\"#fsn32480-bib-0023\" rid=\"fsn32480-bib-0023\" class=\" bibr popnode\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">2013<\/a><\/sup>), attenuated the stroke severity in patients with cerebral infarction (Ono et&nbsp;al.,&nbsp;<sup><a href=\"#fsn32480-bib-0016\" rid=\"fsn32480-bib-0016\" class=\" bibr popnode\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">2017<\/a><\/sup>), increased mood, anxiety, and autonomic nerve function in healthy volunteers (Mizuno et&nbsp;al.,&nbsp;<sup><a href=\"#fsn32480-bib-0013\" rid=\"fsn32480-bib-0013\" class=\" bibr popnode\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">2018<\/a><\/sup>), reduced the presence and severity of symptoms of mild traumatic brain injury (Javorac et al. 2019), and improved cognitive function in community\u2010dwelling older women (Korovljev et&nbsp;al.,&nbsp;<sup><a href=\"#fsn32480-bib-0009\" rid=\"fsn32480-bib-0009\" class=\" bibr popnode\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">2020<\/a><\/sup>). Although those studies showed promising results of medium\u2010 to long\u2010term intervention with hydrogen on various indices of brain function, few trials endeavored to evaluate short\u2010term effects of hydrogen on brain performance. Besides, no neuroimaging studies so far evaluated the immediate effects of hydrogen on brain metabolism in separate brain areas involved in perception, executive function, and connectivity, or contrast hydrogen with other brain\u2010stimulating agents. Our group&#8217;s previous pilot investigation was arguably the first interventional study that compared the acute effects of single\u2010dose HRW and caffeine on brain performance among healthy men and women who were sleep\u2010deprived for 24&nbsp;hr (Zanini et&nbsp;al.,&nbsp;<sup><a href=\"#fsn32480-bib-0024\" rid=\"fsn32480-bib-0024\" class=\" bibr popnode\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">2020<\/a><\/sup>). Both interventions acutely affected markers of alertness, yet caffeine induced a drop in alerting and executive control at 15\u2010min follow\u2010up, while HRW caused a reduction in the orientation at postadministration. Although no differences were found between interventions for all evaluated outcomes of alertness, the authors suggested that HRW and caffeine might have impacted different alertness domains, with dihydrogen improving orienting to sensory stimulation. In contrast, caffeine alters awareness and executive attention. The current study findings extend previous research by showing stimulating effects of acute dihydrogen and caffeine intake on brain performance and metabolism in stressed individuals, with HRW having appeared to tackle different brain regions compared with caffeine. We reported no significant differences in alertness outcomes among interventions, yet subjectively reported scores for alertness, executive control, and test accuracy strongly tended to be improved by all three experimental interventions at follow\u2010up, with HRW plus caffeine being the most prominent. Despite that, HRW and HRW plus caffeine were superior to control drink to complete trail\u2010making tests in a shorter time, suggesting improved visual attention and task switching for both interventions. In addition, both caffeine and HRW were better than control drink to complete SDMT, perhaps due to intervention\u2010driven stimulation of attention, perceptual speed, motor speed, and visual scanning reported previously (Zanini et&nbsp;al.,&nbsp;<sup><a href=\"#fsn32480-bib-0024\" rid=\"fsn32480-bib-0024\" class=\" bibr popnode\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">2020<\/a><\/sup>). Interestingly, reaction time was different for caffeine versus. both HRW and HRW plus caffeine, with all interventions provoked a delay in reaction time at 15\u2010min follow\u2010up. To our knowledge, this is the first human study that evaluated the acute effects of dihydrogen on brain metabolism. We found that the ameliorated brain function induced by HRW and caffeine appears to be accompanied by brain tissue metabolism adjustments. For instance, caffeine and HRW increased the choline\u2010to\u2010creatine ratio, an indicator of brain viability, in frontal bilateral white and gray matter, while HRW (and HRW plus caffeine) additionally elevated the ratio in the paracentral brain. This suggests that both interventions may positively affect region\u2010specific brain metabolism linked to executive functions, attention, and problem\u2010solving (frontal and prefrontal lobules), while HRW perhaps can also target brain regions relevant for orienting (paracentral lobule). A correlation between cognition and region\u2010specific choline\/creatine ratio has been confirmed previously (Ben Salem et&nbsp;al.,&nbsp;<sup><a href=\"#fsn32480-bib-0002\" rid=\"fsn32480-bib-0002\" class=\" bibr popnode\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">2008<\/a><\/sup>), with trail\u2010making test results appears to be relevant not only for the frontal areas but also for more remote areas such as the thalamus, the insula, and the deep periventricular white matter. Also, we found that the combination of HRW and caffeine was equivalent or better than individual components for several alertness outcomes and brain metabolism indices. This perhaps suggests that HRW and caffeine could be consumed together while each component affects various domains of attention and brain metabolism.<\/p>\n<p>Caffeine withdrawal should also be considered for study findings interpretation, with people experiencing caffeine withdrawal often experience symptoms such as headache, dizziness, fatigue, brain fog, and negative mood (Heatherley,&nbsp;<sup><a href=\"#fsn32480-bib-0005\" rid=\"fsn32480-bib-0005\" class=\" bibr popnode\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">2011<\/a><\/sup>). The control group and HRW group could possibly be experiencing caffeine withdrawal symptoms while HRW might have some effect on caffeine withdrawal symptoms; future studies should recruit experimental subjects who do not habitually drink or eat caffeine or similar substances, such as theophylline.&nbsp;In addition, caffeine acts primarily on adenosine receptors (Costenla et&nbsp;al.,&nbsp;<sup><a href=\"#fsn32480-bib-0003\" rid=\"fsn32480-bib-0003\" class=\" bibr popnode\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">2010<\/a><\/sup>), which may cause nerve cells to speed up, since adenosine primarily causes drowsiness, and the caffeine blocks adenosine from the receptors, so the nerve cells tend to speed up and causes an alerting response.&nbsp;HRW might also interact with adenosine receptors, and this interaction should be investigated in future research. Finally, a recent study indicated that regular caffeine intake can cause minor gray matter atrophy, although it is reversible with caffeine cessation (Lin et&nbsp;al.,&nbsp;<sup><a href=\"#fsn32480-bib-0010\" rid=\"fsn32480-bib-0010\" class=\" bibr popnode\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">2021<\/a><\/sup&gt;); this requires monitoring of structural brain changes in subsequent interventional studies with caffeine and caffeine\u2010free beverages.<\/p>\n<p class=\"p p-last\">The study strengths include the use of randomized\u2010controlled cross\u2010over design for administering HRW, and the relatively robust methodology to evaluate both participant\u2010 and clinician\u2010reported brain function outcomes. Our study is limited by containing a sample of young healthy subjects, so exploration on the effects of acute HRW administration in older adults or clinical populations with brain diseases is needed in order to ascertain benefits for these populations. Further studies should enroll these critical groups and perhaps evaluate the role of prolonged dihydrogen intake in experimental and clinical neurology.<\/p>\n<\/div>\n<div id=\"fsn32480-sec-0008\" class=\"tsec sec\">\n<div class=\"goto jig-ncbiinpagenav-goto-container\"><a class=\"tgt_dark page-toc-label jig-ncbiinpagenav-goto-heading\" href=\"#\" title=\"Go to other sections in this page\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Go to:<\/a><\/div>\n<h2 class=\"head no_bottom_margin ui-helper-clearfix\" id=\"fsn32480-sec-0008title\">5.\u2003CONCLUSION<\/h2>\n<p class=\"p p-first-last\">Drinking a single dose of hydrogen\u2010rich water improves trail\u2010making test performance and reduces the number of errors in symbol digit modalities test in coffee habituated sleep\u2010deprived young adults. The attention enhancement driven by HRW appears to go with notable changes in brain metabolism, illustrated by higher choline\u2010to\u2010creatine ratio levels in the frontal and paracentral brain. Being generally recognized as safe intervention (Food and Drug Administration., <sup><a href=\"#fsn32480-bib-0004\" rid=\"fsn32480-bib-0004\" class=\" bibr popnode\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">2014<\/a><\/sup>), hydrogen could be thus recommended as a novel intervention that upholds attention in stressed conditions, with its metabolic footprint likely different from caffeine.<\/p>\n<\/div>\n<div id=\"fsn32480-sec-0010\" class=\"tsec sec\">\n<div class=\"goto jig-ncbiinpagenav-goto-container\"><a class=\"tgt_dark page-toc-label jig-ncbiinpagenav-goto-heading\" href=\"#\" title=\"Go to other sections in this page\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Go to:<\/a><\/div>\n<h2 class=\"head no_bottom_margin ui-helper-clearfix\" id=\"fsn32480-sec-0010title\">CONFLICTS OF INTEREST<\/h2>\n<p class=\"p p-first-last\">The authors declare no conflicts of interest.<\/p>\n<\/div>\n<div id=\"fsn32480-sec-0011\" class=\"tsec sec\">\n<div class=\"goto jig-ncbiinpagenav-goto-container\"><a class=\"tgt_dark page-toc-label jig-ncbiinpagenav-goto-heading\" href=\"#\" title=\"Go to other sections in this page\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Go to:<\/a><\/div>\n<h2 class=\"head no_bottom_margin ui-helper-clearfix\" id=\"fsn32480-sec-0011title\">ETHICAL APPROVAL<\/h2>\n<p class=\"p p-first-last\">The study was approved by the local IRB at the University of Novi Sad (# 2\u2010CFHRW\/2020), with the study systematized following the Declaration of Helsinki and International Conference of Harmonization Efficacy Guidelines E6.<\/p>\n<\/div>\n<div id=\"fsn32480-sec-0009\" class=\"tsec sec\">\n<div class=\"goto jig-ncbiinpagenav-goto-container\"><a class=\"tgt_dark page-toc-label jig-ncbiinpagenav-goto-heading\" href=\"#\" title=\"Go to other sections in this page\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Go to:<\/a><\/div>\n<h2 class=\"head no_bottom_margin ui-helper-clearfix\" id=\"fsn32480-sec-0009title\">ACKNOWLEDGMENTS<\/h2>\n<div class=\"sec\">\n<p>This work was supported by the Serbian Ministry of Education, Science and Technological Development (# 175037); the Provincial Secretariat for Higher Education and Scientific Research (# 142\u2010451\u20103097); the Faculty of Sport and Physical Education, Novi Sad; the Center for Health, Exercise and Sport Sciences, Belgrade, and HRW Natural Health Products Inc.<\/p>\n<\/div>\n<\/div>\n<div id=\"notes-a.i.c\" class=\"tsec sec\">\n<div class=\"goto jig-ncbiinpagenav-goto-container\"><a class=\"tgt_dark page-toc-label jig-ncbiinpagenav-goto-heading\" href=\"#\" title=\"Go to other sections in this page\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Go to:<\/a><\/div>\n<h2 class=\"head no_bottom_margin ui-helper-clearfix\" id=\"notes-a.i.ctitle\">Notes<\/h2>\n<p>\n<span class=\"mixed-citation\" id=\"fsn32480-cit-1001\">Todorovic, N., Zanini, D., Stajer, V., Korovljev, D., Ostojic, J., &amp; Ostojic, S. M. (2021). <span class=\"ref-title\">Hydrogen\u2010rich water and caffeine for alertness and brain metabolism in sleep\u2010deprived habitual coffee drinkers<\/span>. <span class=\"ref-journal\">Food Science &amp; Nutrition<\/span>, <span class=\"ref-vol\">9<\/span>, 5139\u20135145. 10.1002\/fsn3.2480<br \/>\n [<a href=\"\/\/doi.org\/10.1002%2Ffsn3.2480\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=8441318&amp;issue-id=390094&amp;journal-id=2357&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CCrosslink%7CDOI\">CrossRef<\/a>] <span class=\"nowrap\">[<a href=\"https:\/\/scholar.google.com\/scholar_lookup?journal=Food+Science+&amp;+Nutrition&amp;title=Hydrogen\u2010rich+water+and+caffeine+for+alertness+and+brain+metabolism+in+sleep\u2010deprived+habitual+coffee+drinkers&amp;volume=9&amp;publication_year=2021&amp;pages=5139-5145&amp;doi=10.1002\/fsn3.2480&amp;\" target=\"_blank\" rel=\"noopener noreferrer\" ref=\"reftype=other&amp;article-id=8441318&amp;issue-id=390094&amp;journal-id=2357&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span>\n<\/p>\n<\/div>\n<div id=\"fsn32480-sec-0013\" class=\"tsec bk-sec\">\n<div class=\"goto jig-ncbiinpagenav-goto-container\"><a class=\"tgt_dark page-toc-label jig-ncbiinpagenav-goto-heading\" href=\"#\" title=\"Go to other sections in this page\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Go to:<\/a><\/div>\n<h2 class=\"head no_bottom_margin ui-helper-clearfix\" id=\"fsn32480-sec-0013title\">DATA AVAILABILITY STATEMENT<\/h2>\n<p><!--\/article\/back\/sec\/--><\/p>\n<p class=\"p p-first-last\">The data that support the findings of this study have already been included in the manuscript. Raw data are available from the corresponding author upon reasonable request.<\/p>\n<\/div>\n<div id=\"fsn32480-bibl-0001\" class=\"tsec sec\">\n<div class=\"goto jig-ncbiinpagenav-goto-container\"><a class=\"tgt_dark page-toc-label jig-ncbiinpagenav-goto-heading\" href=\"#\" title=\"Go to other sections in this page\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Go to:<\/a><\/div>\n<h2 class=\"head no_bottom_margin ui-helper-clearfix\" id=\"fsn32480-bibl-0001title\">REFERENCES<\/h2>\n<div class=\"ref-list-sec sec\" id=\"reference-list\">\n<ul class=\"back-ref-list\" style=\"list-style-type:decimal;\">\n<li id=\"fsn32480-bib-0001\"><span class=\"mixed-citation\" id=\"fsn32480-cit-0001\">Bajzik, G., Auer, T., Bogner, P., Aradi, M., Kotek, G., Repa, I., Doczi, T., &amp; Schwarcz, A. 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ref=\"reftype=other&amp;article-id=8441318&amp;issue-id=390094&amp;journal-id=2357&amp;FROM=Article%7CCitationRef&amp;TO=Content%20Provider%7CLink%7CGoogle%20Scholar\" role=\"button\" aria-expanded=\"false\" aria-haspopup=\"true\">Google Scholar<\/a>]<\/span><\/span><\/li>\n<\/ul>\n<\/div>\n<\/div>\n<div style=\"display: none; width: 200px; top: -100px; left: -100px;\" aria-live=\"assertive\" aria-hidden=\"true\" class=\"ui-helper-reset ui-ncbipopper-wrapper ui-ncbilinksmenu\">\n<ul id=\"ui-ncbiinpagenav-2\">\n<li><a href=\"#fsn32480-abs-0001title\">Abstract<\/a><\/li>\n<li><a href=\"#fsn32480-sec-0001title\">1.\u2003INTRODUCTION<\/a><\/li>\n<li><a href=\"#fsn32480-sec-0002title\">2.\u2003METHODS<\/a><\/li>\n<li><a href=\"#fsn32480-sec-0006title\">3.\u2003RESULTS<\/a><\/li>\n<li><a href=\"#fsn32480-sec-0007title\">4.\u2003DISCUSSION<\/a><\/li>\n<li><a href=\"#fsn32480-sec-0008title\">5.\u2003CONCLUSION<\/a><\/li>\n<li><a href=\"#fsn32480-sec-0010title\">CONFLICTS OF INTEREST<\/a><\/li>\n<li><a href=\"#fsn32480-sec-0011title\">ETHICAL APPROVAL<\/a><\/li>\n<li><a href=\"#fsn32480-sec-0009title\">ACKNOWLEDGMENTS<\/a><\/li>\n<li><a href=\"#notes-a.i.ctitle\">Notes<\/a><\/li>\n<li><a href=\"#fsn32480-sec-0013title\">DATA AVAILABILITY STATEMENT<\/a><\/li>\n<li><a href=\"#fsn32480-bibl-0001title\">REFERENCES<\/a><\/li>\n<\/ul>\n<\/div>\n<\/div>\n","protected":false},"excerpt":{"rendered":"<p>Hydrogen-rich water and caffeine for alertness and brain metabolism in sleep-deprived habitual coffee drinkers<\/p>\n","protected":false},"author":1,"featured_media":17899,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[130],"tags":[],"disease":[895],"body-organ":[1019],"applications":[680],"test_subjects":[1519],"report-topic":[1283],"class_list":["post-26766","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-hydrogen-health","disease-sleep-deprivation-2","body-organ-brain-2","applications-ingestion-2","test_subjects-human-2","report-topic-fatigue-2"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.3 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>H2-rich Water and Caffeine for Alertness in Sleep-Deprived Coffee Drinkers<\/title>\n<meta name=\"description\" content=\"Hydrogen-rich water and caffeine for alertness and brain metabolism in sleep-deprived habitual coffee drinkers\" 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