{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T23:57:50Z","timestamp":1783468670201,"version":"3.55.0"},"reference-count":134,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,9,13]],"date-time":"2020-09-13T00:00:00Z","timestamp":1599955200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Delirium, an acute alteration in mental status characterized by confusion, inattention and a fluctuating level of arousal, is a common problem in critically ill patients. Delirium prolongs hospital stay and is associated with higher mortality. The pathophysiology of delirium has not been fully elucidated. Neuroinflammation and neurotransmitter imbalance seem to be the most important factors for delirium development. In this review, we present the most important pathomechanisms of delirium in critically ill patients, such as neuroinflammation, neurotransmitter imbalance, hypoxia and hyperoxia, tryptophan pathway disorders, and gut microbiota imbalance. A thorough understanding of delirium pathomechanisms is essential for effective prevention and treatment of this underestimated pathology in critically ill patients.<\/jats:p>","DOI":"10.3390\/medicina56090469","type":"journal-article","created":{"date-parts":[[2020,9,13]],"date-time":"2020-09-13T21:11:32Z","timestamp":1600031492000},"page":"469","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Pathomechanisms of Non-Traumatic Acute Brain Injury in Critically Ill Patients"],"prefix":"10.3390","volume":"56","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0449-2375","authenticated-orcid":false,"given":"Wojciech","family":"Dabrowski","sequence":"first","affiliation":[{"name":"Department of Anaesthesiology and Intensive Care, Medical University of Lublin, 20-954 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1001-0080","authenticated-orcid":false,"given":"Dorota","family":"Siwicka-Gieroba","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology and Intensive Care, Medical University of Lublin, 20-954 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malgorzata","family":"Gasinska-Blotniak","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology and Intensive Care, Medical University of Lublin, 20-954 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2193-1512","authenticated-orcid":false,"given":"Sami","family":"Zaid","sequence":"additional","affiliation":[{"name":"Department of Anaesthesia, Al-Emadi-Hospital Doha, P.O. Box 5804 Doha, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maja","family":"Jezierska","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology and Intensive Care, Medical University of Lublin, 20-954 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0618-2488","authenticated-orcid":false,"given":"Cezary","family":"Pakulski","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology, Intensive Therapy and Emergency Medicine, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shawniqua","family":"Williams Roberson","sequence":"additional","affiliation":[{"name":"Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center, Vanderbilt University Medical Center, 1211, Nashville, TN 37232, USA"},{"name":"Department of Neurology, Vanderbilt University Medical Center, 1211, Nashville, TN 37232, USA"},{"name":"Department of Biomedical Engineering, Vanderbilt University, 1211, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene","family":"Wesley Ely","sequence":"additional","affiliation":[{"name":"Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center, Vanderbilt University Medical Center, 1211, Nashville, TN 37232, USA"},{"name":"Geriatric Research, Education and Clinical Center (GRECC), Tennessee Valley Veterans Affairs Healthcare System, 1310, Nashville, TN 37212, USA"},{"name":"Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, 1211, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8430-1369","authenticated-orcid":false,"given":"Katarzyna","family":"Kotfis","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology, Intensive Therapy and Acute Intoxications, Pomeranian Medical University, 70-111 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders, American Psychiatric Pub. [5th ed.].","DOI":"10.1176\/appi.books.9780890425596"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"European Delirium Association, and American Delirium Society (2014). The DSM-5 criteria, level of arousal and delirium diagnosis: Inclusiveness is safer. BMC Med., 12, 141\u2013148.","DOI":"10.1186\/s12916-014-0141-2"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2311","DOI":"10.1097\/CCM.0b013e3181f85759","article-title":"Delirium duration and mortality in lightly sedated, mechanically ventilated intensive care patients","volume":"38","author":"Shehabi","year":"2010","journal-title":"Crit. Care Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1001\/jama.291.14.1753","article-title":"Delirium as a Predictor of Mortality in Mechanically Ventilated Patients in the Intensive Care Unit","volume":"291","author":"Ely","year":"2004","journal-title":"JAMA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"160","DOI":"10.5603\/AIT.a2018.0011","article-title":"ICU delirium\u2014A diagnostic and therapeutic challenge in the intensive care unit","volume":"50","author":"Kotfis","year":"2018","journal-title":"Anaesthesiol. Intensive Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1513\/AnnalsATS.201910-764OC","article-title":"Delirium Severity Trajectories and Outcomes in ICU Patients: Defining a Dynamic Symptom Phenotype","volume":"17","author":"Lindroth","year":"2020","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e480","DOI":"10.1097\/CCM.0000000000004313","article-title":"Association of Hypoactive and Hyperactive Delirium with Cognitive Function After Critical Illness","volume":"48","author":"Hayhurst","year":"2020","journal-title":"Crit. Care Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1002\/gps.4823","article-title":"Delirium pathophysiology: An updated hypothesis of the etiology of acute brain failure","volume":"33","author":"Maldonado","year":"2018","journal-title":"Int. J. Geriatr. Psychiatry"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.ccc.2017.03.013","article-title":"Acute brain failure: Pathophysiology, diagnosis, management and sequelae of delirium","volume":"33","author":"Maldonado","year":"2017","journal-title":"Crit. Care Clin."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"127","DOI":"10.4037\/ajcc2019874","article-title":"Delirium Monitoring: Yes or No? That Is The Question","volume":"28","author":"Marra","year":"2019","journal-title":"Am. J. Crit. Care"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.bpa.2012.07.003","article-title":"Epidemiology and risk factors for delirium across hospital settings","volume":"26","author":"Vasilevskis","year":"2012","journal-title":"Best Pr. Res. Clin. Anaesthesiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"352","DOI":"10.4103\/psychiatry.IndianJPsychiatry_583_18","article-title":"Delirium in medical intensive care units: Incidence, subtypes, risk factors, and outcome","volume":"61","author":"Sampath","year":"2019","journal-title":"Indian J. Psychiatry"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1038\/jcbfm.1995.72","article-title":"Ion channel involvement in anoxic depolarization induced by cardiac arrest un rat brain","volume":"15","author":"Xie","year":"1995","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4914","DOI":"10.1523\/JNEUROSCI.18-13-04914.1998","article-title":"Induction of Caspase-3-Like Protease May Mediate Delayed Neuronal Death in the Hippocampus after Transient Cerebral Ischemia","volume":"18","author":"Chen","year":"1998","journal-title":"J. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"227","DOI":"10.2217\/fnl.10.1","article-title":"Microglia in ischemic brain injury","volume":"5","author":"Weinstein","year":"2010","journal-title":"Future Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/s40560-016-0167-y","article-title":"Decreases in cerebral saturation in patients with septic shock are associated with increased risk of death: A prospective observational single center study","volume":"4","author":"Funk","year":"2016","journal-title":"J. Intensiv. Care"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1164\/rccm.201111-2025OC","article-title":"Faculty Opinions recommendation of The adult respiratory distress syndrome cognitive outcomes study: Long-term neuropsychological function in survivors of acute lung injury","volume":"185","author":"Mikkelsen","year":"2012","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1164\/rccm.200406-763OC","article-title":"Two-Year Cognitive, Emotional, and Quality-of-Life Outcomes in Acute Respiratory Distress Syndrome","volume":"171","author":"Hopkins","year":"2005","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7006","DOI":"10.18632\/aging.103058","article-title":"Intra-operative hyperoxia and the risk of delirium in eldery patients after cardiac surgery","volume":"12","author":"Kupiec","year":"2020","journal-title":"Aging"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13054-020-2800-3","article-title":"Brain BOLD MRI O2 and CO2 stress testing: Implications for perioperative neurocognitive disorder following surgery","volume":"24","author":"Mutch","year":"2020","journal-title":"Crit. Care"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1186\/s13054-014-0711-x","article-title":"Arterial hyperoxia and mortality in critically ill patients: A systematic review and meta-analysis","volume":"18","author":"Damiani","year":"2014","journal-title":"Crit. Care"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Terraneo, L., and Samaja, M. (2017). Comparative Response of Brain to Chronic Hypoxia and Hyperoxia. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18091914"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.nbd.2004.07.019","article-title":"Oxygen causes cell death in the developing brain","volume":"17","author":"Bittigau","year":"2004","journal-title":"Neurobiol. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.freeradbiomed.2016.12.039","article-title":"Intraoperative cerebral oxygenation, oxidative injury, and delirium following cardiac surgery","volume":"103","author":"Lopez","year":"2017","journal-title":"Free Radic. Biol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.freeradbiomed.2003.10.024","article-title":"Isomer-specific contractile effects of a series of synthetic F2-isoprostanes on retinal and cerebral microvasculature","volume":"36","author":"Hou","year":"2004","journal-title":"Free Radic. Biol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"10077","DOI":"10.3390\/ijms160510077","article-title":"Peripheral Blood Lymphocyte Subsets (CD4+, CD8+ T Cells, NK Cells) in Patients with Cardiovascular and Neurological Complications after Carotid Endarterectomy","volume":"16","author":"Kotfis","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1186\/s12974-016-0528-4","article-title":"Systemic pro-inflammatory response facilitates the development of cerebral edema during short hypoxia","volume":"13","author":"Song","year":"2016","journal-title":"J. Neuroinflamm."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.coph.2015.10.009","article-title":"Neuro-immune dysfunction during brain aging: New insights in microglial cell regulation","volume":"26","author":"Matt","year":"2016","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.bbr.2015.11.003","article-title":"Cerebral mast cells contribute to postoperative cognitive dysfunction by promoting blood brain barrier disruption","volume":"298","author":"Zhang","year":"2016","journal-title":"Behav. Brain Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Skelly, D.T., Hennessy, E., Dansereau, M.-A., and Cunningham, C. (2013). A Systematic Analysis of the Peripheral and CNS Effects of Systemic LPS, IL-1\u0392, TNF-\u03b1 and IL-6 Challenges in C57BL\/6 Mice. PLoS ONE, 8.","DOI":"10.1371\/annotation\/90c76048-2edd-4315-8404-4d9d8cbd411e"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1080\/10623320390272299","article-title":"Interferon (IFN)-beta 1a and IFN-beta 1b block IFN-gamma disinterration of endothelial junction integrity and barrier","volume":"10","author":"Minagar","year":"2003","journal-title":"Endothelium"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.bbrc.2018.11.021","article-title":"IFN-\u03b3, IL-17A, or zonulin rapidly increase the permeability of the blood-brain and small intestinal epithelial barriers: Relevance for neuro-inflammatory diseases","volume":"507","author":"Rahman","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1002\/glia.20467","article-title":"Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration","volume":"55","author":"Qin","year":"2007","journal-title":"Glia"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/978-1-4939-9658-2_2","article-title":"Morphology of Microglia across Contexts of Health and Disease","volume":"2034","author":"Savage","year":"2019","journal-title":"Methods Mol. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/nrneurol.2014.38","article-title":"Microglial priming in neurodegenerative disease","volume":"10","author":"Perry","year":"2014","journal-title":"Nat. Rev. Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2675","DOI":"10.3389\/fimmu.2019.02675","article-title":"Orthopedic Surgery Triggers Attention Deficits in a Delirium-Like Mouse Model","volume":"10","author":"Velagapudi","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"5219","DOI":"10.1073\/pnas.0600506103","article-title":"Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia","volume":"103","author":"Pavlov","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.12740\/PP\/60139","article-title":"Effects of statins on delirium following cardiac surgery\u2014Vidence from literature","volume":"49","author":"Mariscalco","year":"2015","journal-title":"Psychiatr. Pol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.ccc.2018.11.008","article-title":"Melatonin in Critical Care","volume":"35","author":"Marra","year":"2019","journal-title":"Crit. Care Clin."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"59","DOI":"10.2174\/1570159X15666170703101816","article-title":"Statins and the Brain: More than Lipid Lowering Agents?","volume":"17","author":"Fracassi","year":"2019","journal-title":"Curr. Neuropharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.1111\/j.1532-5415.2008.01851.x","article-title":"Time-Course of Cytokines during Delirium in Elderly Patients with Hip Fractures","volume":"56","author":"Korevaar","year":"2008","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1007\/s00401-010-0674-1","article-title":"The neuroinflammatory hypothesis of delirium","volume":"119","author":"Cerejeira","year":"2010","journal-title":"Acta Neuropathol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1080\/08820139.2017.1373898","article-title":"Anesthetic Immunomodulation of the Neuroinflammation in Postoperative Cognitive Dysfunction","volume":"46","author":"Umholtz","year":"2017","journal-title":"Immunol. Investig."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Jardine, K.H., Wideman, C.E., MacGregor, C., Sgarbossa, C., Orr, D., Mitchnick, K.A., and Winters, B.D. (2020). Activation of cortical M1 muscarinic receptors and related intracellular signaling is necessary for reactivation-induced object memory updating. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-65836-x"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6288","DOI":"10.1523\/JNEUROSCI.4673-11.2012","article-title":"Prior pathology in the basal forebrain cholinergic system predisposes to inflammation-induced working memory deficits: Reconciling inflammatory and cholinergic hypotheses of delirium","volume":"32","author":"Field","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1111\/j.1471-4159.2009.06524.x","article-title":"Reductions of acetylcholine release and nerve growth factor expression are correlated with memory impairment induced by interleukin-1\u03b2 administrations: Effects of omega-3 fatty acid EPA treatment","volume":"112","author":"Taepavarapruk","year":"2010","journal-title":"J. Neurochem."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Adam, E.H., Haas, V., Lindau, S., Zacharowski, K., and Scheller, B. (2020). Cholinesterase alterations in delirium after cardiosurgery: A German monocentric prospective study. BMJ Open, 10.","DOI":"10.1136\/bmjopen-2019-031212"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"John, M., Ely, E.W., Halfkann, D., Schoen, J., Sedemund-Adib, B., Klotz, S., Radtke, F., Stehr, S., and Hueppe, M. (2017). Acetylcholinesterase and butyrylcholinesterase in cardiosurgical patients with postoperative delirium. J. Intensiv. Care, 5.","DOI":"10.1186\/s40560-017-0224-1"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/0163-7258(94)90041-8","article-title":"Dopamine receptors: Molecular biology, biochemistry and behalioural aspects","volume":"64","author":"Jackson","year":"1994","journal-title":"Pharmacol. Ther."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/S0165-6147(00)89044-6","article-title":"Novel dopamine receptors half a decade later","volume":"16","author":"Sokoloff","year":"1995","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1038\/sj.bjp.0704982","article-title":"Oxidative and non-oxidative mechanisms of neuronal cel death and apoptosis by 1-3,4-dihydroxyphenylalanine (L-dopa) and dopamine","volume":"137","author":"Pedrosa","year":"2002","journal-title":"Br. J. Pharmacol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1007\/s00210-018-1534-0","article-title":"The modulatory role of accumbens and hippocampus D2 receptors in anxiety and memory","volume":"391","author":"Nasehi","year":"2018","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1016\/S0306-4522(98)00261-9","article-title":"Role of accumbens and cortical dopamine receptors in the regulation of cortical acetycholine release","volume":"88","author":"Moore","year":"1999","journal-title":"Neuroscience"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.hlc.2015.09.012","article-title":"Dopamine Administration is a Risk Factor for Delirium in Patients Undergoing Coronary Artery Bypass Surgery","volume":"25","author":"Yilmaz","year":"2016","journal-title":"Heart Lung Circ."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1093\/alcalc\/agx090","article-title":"Treatment of alcohol-induced psychotic disorder (alcoholic hallucinosis)\u2014A systematic review","volume":"53","author":"Masood","year":"2018","journal-title":"Alcohol Alcohol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"4943","DOI":"10.2174\/1381612821666150914121624","article-title":"GABA Receptors: Pharmacological Potential and Pitfalls","volume":"21","author":"Jembrek","year":"2015","journal-title":"Curr. Pharm. Des."},{"key":"ref_57","first-page":"269","article-title":"The association of plasma gamma-aminobutyric acid concentration with postoperative delirium in critically ill patients","volume":"16","author":"Yoshitaka","year":"2014","journal-title":"Crit. Care Resusc."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/164_2017_56","article-title":"GABA Receptors and the Pharmacology of Sleep","volume":"253","author":"Wisden","year":"2019","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.1002\/jnr.21325","article-title":"Neuroinflammation and regulation of glial glutamate uptake in neurological disorders","volume":"85","author":"Tilleux","year":"2007","journal-title":"J. Neurosci. Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"S310","DOI":"10.1038\/sj.bjp.0707509","article-title":"Role of the brain-derived neutrophic factor at glutamateric synapses","volume":"153","author":"Carvalho","year":"2008","journal-title":"Br. J. Pharmacol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1093\/bja\/aex103","article-title":"Association of intraoperative changes in brain-derived neurotrophic factor and postoperative delirium in older adults","volume":"119","author":"Wyrobek","year":"2017","journal-title":"Br. J. Anaesth."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.neuron.2014.09.034","article-title":"The neurology of mTOR","volume":"84","author":"Lipton","year":"2014","journal-title":"Neuron"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1097\/FBP.0000000000000279","article-title":"Neural activity, memory, and dementias: Serotonergic markers","volume":"28","author":"Meneses","year":"2017","journal-title":"Behav. Pharmacol."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Rebholz, H., Friedman, E., and Castello, J. (2018). Alterations of Expression of the Serotonin 5-HT4 Receptor in Brain Disorders. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19113581"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.bbr.2007.12.006","article-title":"Cognitive dysfunction in neuropsychiatric disorders: Selected serotonin receptor subtypes as therapeutic targets","volume":"195","author":"Terry","year":"2008","journal-title":"Behav. Brain Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1176\/ajp.148.6.705","article-title":"The serotonin syndrome","volume":"148","author":"Sternbach","year":"1991","journal-title":"Am. J. Psychiatry"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1038\/jcbfm.2011.11","article-title":"Age and sex effects on 5-HT4receptors in the human brain: A [11C]SB207145 PET study","volume":"31","author":"Madsen","year":"2011","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"574","DOI":"10.2174\/1570159X15666170913110426","article-title":"Neuroinflammation and the Immune-Kynurenine Pathway in Anxiety Disorders","volume":"16","author":"Kim","year":"2018","journal-title":"Curr. Neuropharmacol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"533","DOI":"10.2174\/1570159X15666171123201142","article-title":"Imaging the Role of Inflammation in Mood and Anxiety-related Disorders","volume":"16","author":"Felger","year":"2018","journal-title":"Curr. Neuropharmacol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1007\/s11011-007-9064-3","article-title":"Tryptophan, adenosine, neurodegeneration and neuroprotection","volume":"22","author":"Stone","year":"2007","journal-title":"Metab. Brain Dis."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"603","DOI":"10.2174\/1389450043345209","article-title":"Neuroprotection against ischemic\/hypoxic brain damage: Blockers of ionotropic glutamate receptor and voltage sensitive calcium channels","volume":"5","author":"Schurr","year":"2004","journal-title":"Curr. Drug Targets"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Dobelis, P., Staley, K.J., and Cooper, D.C. (2012). Lack of modulation of nicotinic acetylcholine alpha-7 receptor currents by kynurenic acid in adult hippocampal interneurons. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0041108"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Dabrowski, W., Kwiecie\u0144, J.M., Rola, R., Klapec, M., Stanisz, G.J., Kotli\u0144ska-Hasiec, E., Oakden, W., Janik, R., Coote, M., and Frey, B.N. (2015). Prolonged Subdural Infusion of Kynurenic Acid Is Associated with Dose-Dependent Myelin Damage in the Rat Spinal Cord. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0142598"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1101\/gad.307918.117","article-title":"Kynurenic acid accumulation underlies learning and memory impairment associated with aging","volume":"32","author":"Vohra","year":"2018","journal-title":"Genes Dev."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"10592","DOI":"10.1523\/JNEUROSCI.1107-14.2014","article-title":"Reduction of Brain Kynurenic Acid Improves Cognitive Function","volume":"34","author":"Kozak","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.jneuroim.2018.03.007","article-title":"HIV, prospective memory, and cerebrospinal fluid concentrations of quinolinic acid and phosphorylated Tau","volume":"319","author":"Anderson","year":"2018","journal-title":"J. Neuroimmunol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1093\/brain\/awh130","article-title":"CSF quinolinic acid levels are determined by local HIV infection: Cross-sectional analysis and modelling of dynamics following antiretroviral therapy","volume":"127","author":"Valle","year":"2004","journal-title":"Brain"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"204","DOI":"10.2478\/v10039-010-0023-6","article-title":"Kynurenine and its metabolites in Alzheimer\u2019s sidease patients","volume":"55","author":"Gulaj","year":"2010","journal-title":"Adv. Med. Sci."},{"key":"ref_79","first-page":"1178646919877883","article-title":"Kynurenines, Neuropsychiatric Symptoms, and Cognitive Prognosis in Patients with Mild Dementia","volume":"12","author":"Solvang","year":"2019","journal-title":"Int. J. Tryptophan Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1002\/phar.2392","article-title":"Intensive care unit delirium in surgical patients is associated with upreguloation in tryptophan metabolism","volume":"40","author":"Voils","year":"2020","journal-title":"Pharmacotherapy"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1017\/neu.2016.69","article-title":"Inflammation and depression: A causal or coincidental link to the pathophysiology?","volume":"30","author":"Leonard","year":"2018","journal-title":"Acta Neuropsychiatr."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2516","DOI":"10.1096\/fasebj.5.11.1907934","article-title":"Relationship between interferon-gamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism","volume":"5","author":"Taylor","year":"1991","journal-title":"FASEB J."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1042\/BST0351287","article-title":"Neurotoxicity of tryptophan metabolites","volume":"35","author":"Smith","year":"2007","journal-title":"Biochem. Soc. Trans."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1007\/s00109-007-0229-7","article-title":"IDO expression in the brain: A double-edged sword","volume":"85","author":"Kwidzinski","year":"2007","journal-title":"J. Mol. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"e734","DOI":"10.1097\/CCM.0000000000004469","article-title":"Endothelial Activation, Acute Kidney Injury, and Cognitive Impairment in Pediatric Severe Malaria","volume":"48","author":"Ouma","year":"2020","journal-title":"Crit. Care Med."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Tao, X., Yan, M., Wang, L., Zhou, Y., Wang, Z., Xia, T., Liu, X.-M., Pan, R.-L., and Chang, Q. (2020). Homeostasis Imbalance of Microglia and Astrocytes Leads to Alteration in the Metabolites of the Kynurenine Pathway in LPS-Induced Depressive-Like Mice. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21041460"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.cell.2015.03.033","article-title":"Gut microbiota: The link to your second brain","volume":"161","author":"Ridaura","year":"2015","journal-title":"Cell"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1172\/JCI76304","article-title":"Gut\/brain axis and the microbiota","volume":"125","author":"Mayer","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"S12","DOI":"10.1038\/518S13a","article-title":"Mental Health: Thinking from the Gut","volume":"518","author":"Schmidt","year":"2015","journal-title":"Nature"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1007\/s11883-014-0454-9","article-title":"The Effects of Gastrointestinal Surgery on Gut Microbiota: Potential Contribution to Improved Insulin Sensitivity","volume":"16","year":"2014","journal-title":"Curr. Atheroscler. Rep."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"4150","DOI":"10.3748\/wjg.v21.i14.4150","article-title":"Changes in the colon microbiota and intestinal cytokine gene expression following minimal intestinal surgery","volume":"21","author":"Lapthorne","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Lederer, A.-K., Pisarski, P., Kousoulas, L., Fichtner-Feigl, S., Hess, C., and Huber, R. (2017). Postoperative changes of the microbiome: Are surgical complications related to the gut flora? A systematic review. BMC Surg., 17.","DOI":"10.1186\/s12893-017-0325-8"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1111\/cns.13103","article-title":"Abnormal composition of gut microbiota contributes to delirium-like behaviors after abdominal surgery in mice","volume":"25","author":"Zhang","year":"2019","journal-title":"CNS Neurosci. Ther."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1965","DOI":"10.18632\/aging.102736","article-title":"Anesthesia and surgery induce age-dependent changes in behaviors and microbiota","volume":"12","author":"Liufu","year":"2020","journal-title":"Aging"},{"key":"ref_95","unstructured":"Kitsios, G., Fair, K., Xie, M., Shah, F., Fitch, A., Rapport, S., Huwe, J., Alexander, S., Morris, A., and Girard, T.D. (2018). Gut microbiome dysbiosis and delirium in mechanically ventilated adults patients: A prospective cohort study. Critical Care: Microbiome, Genetics, and Other Biomarkers in Acute Critical Illness, American Thoracic Society."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Liskiewicz, P., Kaczmarczyk, M., Misiak, B., Wronski, M., Baba-Kubis, A., Skonieczna-Zydecka, K., Marlicz, W., Bienkowski, P., Misera, A., and Pelka-Wysiecka, J. (2020). Analysis of gut microbiota and intestinal integrity markers of inpatients with major depressive disorder. Prog. Neuropharmacol. Biol. Psychiatry, 19.","DOI":"10.1016\/j.pnpbp.2020.110076"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"3329","DOI":"10.2147\/NDT.S188340","article-title":"Possible association of Firmicutes in the gut microbiota of patients with major depressive disorder","volume":"14","author":"Huang","year":"2018","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1056\/NEJM199903043400901","article-title":"A multicomponent intervention to prevent delirium in hospitalized ilder patients","volume":"340","author":"Inouye","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1097\/CCM.0b013e3182783b72","article-title":"Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit","volume":"41","author":"Barr","year":"2013","journal-title":"Crit. Care Med."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"e1111","DOI":"10.1097\/CCM.0000000000002640","article-title":"Worldwide survey of the \u201cAssessing pain, both spontaneous awakening and breathing trialsm choice of drugs, delirium monitoring\/management, early exercise\/mobility, and family empowerment\u201d (ABCDEF) bundle reply","volume":"45","author":"Morandi","year":"2017","journal-title":"Crit. Care Med."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1097\/ACO.0b013e3283445382","article-title":"The complex interplay between delirium, sedation, and early mobility during critical illness: Applications in the trauma unit","volume":"24","author":"Banerjee","year":"2011","journal-title":"Curr. Opin. Anaesthesiol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.jcrc.2016.02.024","article-title":"Cerebral oximetry as a biomarker of postoperative delirium in cardiac surgery patients","volume":"34","author":"Mailhot","year":"2016","journal-title":"J. Crit. Care"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1111\/anae.14056","article-title":"Cerebral oximetry and postoperative delirium after cardiac surgery: A randomised, controlled trial","volume":"72","author":"Lei","year":"2017","journal-title":"Anaesthesia"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1007\/s12630-018-1065-7","article-title":"Intraoperative cerebral oximetry-based management for optimizing perioperative outcomes: A meta-analysis of randomized controlled trials","volume":"65","author":"Healy","year":"2018","journal-title":"Can. J. Anesth."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"2512","DOI":"10.1177\/0271678X18803081","article-title":"Dysfunctional cerebral autoregulation is associated with delirium in critically ill adults","volume":"39","author":"Lee","year":"2019","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1007\/s10877-017-0049-4","article-title":"Correction to: The oxygen reserve index (ORI): A new tool to monitor oxygen therapy","volume":"32","author":"Scheeren","year":"2018","journal-title":"J. Clin. Monit."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1097\/CM9.0000000000000625","article-title":"Oxygen reserve index, a new method of monitoring oxygenation status: What do we need to know?","volume":"133","author":"Chen","year":"2020","journal-title":"Chin. Med. J."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1164\/rccm.201710-1995OC","article-title":"Low-dose nocturnal dexmedetomidyne prevents ICU delirium. A randomized, placebo-controlles trial","volume":"197","author":"Skrobik","year":"2018","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1378\/chest.15-0525","article-title":"Delirium and Circadian Rhythm of Melatonin During Weaning From Mechanical Ventilation: An ancillary study of a weaning trial","volume":"148","author":"Dessap","year":"2015","journal-title":"Chest"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1111\/j.0001-5172.2004.00401.x","article-title":"Abolished circadian rhythm of melatonin secretion in sedated and artificially ventilated intensive care patients","volume":"48","author":"Olofsson","year":"2004","journal-title":"Acta Anaesthesiol. Scand."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1002\/phar.2222","article-title":"Effectiveness of Melatonin for the Prevention of Intensive Care Unit Delirium","volume":"39","author":"Baumgartner","year":"2019","journal-title":"J. Hum. Pharmacol. Drug Ther."},{"key":"ref_112","first-page":"325","article-title":"Studies of the 24 h rhythm of melatonin in man","volume":"13","author":"Weitzman","year":"1978","journal-title":"J. Neural Transm. Suppl."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"4303","DOI":"10.1210\/jc.2003-030460","article-title":"Melatonin phase-shifts humen circadiad rhythms with no evidence of changes in the duration of endogenous melatonin secretion or the 24-h production of reproductive hormones","volume":"88","author":"Rajaratnam","year":"2003","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1746","DOI":"10.1007\/s00134-007-0727-7","article-title":"Evidence of altered cortisol metabolism in critically ill patients: A prospective study","volume":"33","author":"Venkatesh","year":"2007","journal-title":"Intensiv. Care Med."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.bbr.2015.04.017","article-title":"Inflammation and increased IDO in hippocampus contribute to depression-like behaviour induced by estrogen deficiency","volume":"288","author":"Xu","year":"2015","journal-title":"Behav. Brain Res."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"571","DOI":"10.2174\/13894501113149990154","article-title":"Inflammation, serotonin and major depression","volume":"14","author":"Rotella","year":"2013","journal-title":"Curr. Drug Targets"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1016\/j.bbr.2017.05.064","article-title":"Behavioral, inflammatory and neurochemical disturbances in LPS and UCMS-induced mouse models of depression","volume":"364","author":"Zhao","year":"2019","journal-title":"Behav. Brain Res."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1097\/NMD.0000000000000969","article-title":"The Association Between Symptoms of Anxiety, Depression, and Cardiovascular Risk Factors: Rresults from an Italian cross-sectional study","volume":"207","author":"Rioli","year":"2019","journal-title":"J. Nerv. Ment. Dis."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1771","DOI":"10.2147\/CIA.S227755","article-title":"Characteristic, risk factor and outcome of early-onset delirium in elderly patients with first ever acute ischemic stroke\u2014A prospective observational cohort study","volume":"14","author":"Kotfis","year":"2019","journal-title":"Clin. Interv. Aging"},{"key":"ref_120","doi-asserted-by":"crossref","unstructured":"Li, L.-Q., Wang, C., Fang, M.-D., Xu, H.-Y., Lu, H.-L., and Zhang, H.-Z. (2019). Effects of Dexamethasone on Post-Operative Cognitive Dysfunction and Delirium in Adults Following General Anaesthesia: A Meta-Analysis of Randomised Controlled Trials. BMC Anesthesiol., 19.","DOI":"10.1186\/s12871-019-0783-x"},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Lally, L., McCarthy, G.M., and Meehan, K. (2017). Hyperactive delirium following administration of intra-articular corticosteroid. BMJ Case Rep., 2017.","DOI":"10.1136\/bcr-2016-217483"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.bbi.2016.11.006","article-title":"Statins prevent cognitive impairment after sepsis by reverting neuroinflammation, and microcirculatory\/endothelial dysfunction","volume":"60","author":"Reis","year":"2017","journal-title":"Brain Behav. Immun."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/j.ebiom.2018.10.021","article-title":"Surgery, neuroinflammation and cognitive impairment","volume":"37","author":"Alam","year":"2018","journal-title":"EBioMedicine"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1007\/s12028-016-0290-6","article-title":"Simvastatin therapy in the acute stage of traumatic brain injury attenuates brain trauma-induced depression-like behaviour in rats by reducing neuroinflammation in the hippocampus","volume":"26","author":"Lim","year":"2017","journal-title":"Neurocrit. Care"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1899","DOI":"10.1097\/CCM.0000000000000398","article-title":"Statins and Delirium During Critical Illness","volume":"42","author":"Morandi","year":"2014","journal-title":"Crit. Care Med."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1007\/s00134-018-5310-x","article-title":"Does this critically ill patient with delirium require any drug treatment?","volume":"45","author":"Salluh","year":"2019","journal-title":"Intensiv. Care Med."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1097\/CCM.0000000000001411","article-title":"Preventing ICU Subsyndromal Delirium Conversion to Delirium With Low-Dose IV Haloperidol: A double-blind, placebo-controlles pilot study","volume":"44","author":"Skrobik","year":"2016","journal-title":"Crit. Care Med."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1080\/15360288.2018.1513434","article-title":"Comparison of haloperidol, non-haloperidol antipsychotics, and no pharnmacotherapy for the management of delirium in an inpatient geriatric palliative care population","volume":"32","author":"Felton","year":"2018","journal-title":"J. Pain Palliat. Care Pharmacother."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/j.psym.2015.09.008","article-title":"Valproic Acid for Treatment of Hyperactive or Mixed Delirium: Rationale and Literature Review","volume":"56","author":"Sher","year":"2015","journal-title":"Psychosomatics"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"e825","DOI":"10.1097\/CCM.0000000000003299","article-title":"Clinical practice guidelines for the prevention and management of pain, agitation\/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU","volume":"46","author":"Devlin","year":"2018","journal-title":"Crit. Care Med."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"2506","DOI":"10.1056\/NEJMoa1808217","article-title":"Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness","volume":"379","author":"Girard","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1097\/01.pra.0000450319.21859.6d","article-title":"QTc Prolongation with Antipsychotics: Is routine ECG monitoring recommended?","volume":"20","author":"Shah","year":"2014","journal-title":"J. Psychiatr. Pract."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1176\/appi.neuropsych.14080190","article-title":"Adjunctive Valproic Acid in Management-Refractory Hyperactive Delirium: A Case Series and Rationale","volume":"27","author":"Sher","year":"2015","journal-title":"J. Neuropsychiatry Clin. Neurosci."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.2174\/1570159X17666190617100707","article-title":"Highlighting the Role of Cognitive and Brain Reserve in the Substance use Disorder Field","volume":"17","author":"Cutuli","year":"2019","journal-title":"Curr. Neuropharmacol."}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/56\/9\/469\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:09:36Z","timestamp":1760177376000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/56\/9\/469"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,13]]},"references-count":134,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["medicina56090469"],"URL":"https:\/\/doi.org\/10.3390\/medicina56090469","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,13]]}}}