{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T09:14:30Z","timestamp":1790759670192,"version":"4.1.0"},"reference-count":41,"publisher":"PeerJ","license":[{"start":{"date-parts":[[2019,5,13]],"date-time":"2019-05-13T00:00:00Z","timestamp":1557705600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Levels of consciousness in patients with acute and chronic brain injury are notoriously underestimated. Paradigms based on electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) may detect covert consciousness in clinically unresponsive patients but are subject to logistical challenges and the need for advanced statistical analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To assess the feasibility of automated pupillometry for the detection of command following, we enrolled 20 healthy volunteers and 48 patients with a wide range of neurological disorders, including seven patients in the intensive care unit (ICU), who were asked to engage in mental arithmetic.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Fourteen of 20 (70%) healthy volunteers and 17 of 43 (39.5%) neurological patients, including 1 in the ICU, fulfilled prespecified criteria for command following by showing pupillary dilations during \u22654 of five arithmetic tasks. None of the five sedated and unconscious ICU patients passed this threshold.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Automated pupillometry combined with mental arithmetic appears to be a promising paradigm for the detection of covert consciousness in people with brain injury. We plan to build on this study by focusing on non-communicating ICU patients in whom the level of consciousness is unknown. If some of these patients show reproducible pupillary dilation during mental arithmetic, this would suggest that the present paradigm can reveal covert consciousness in unresponsive patients in whom standard investigations have failed to detect signs of consciousness.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.7717\/peerj.6929","type":"journal-article","created":{"date-parts":[[2019,5,13]],"date-time":"2019-05-13T04:02:08Z","timestamp":1557720128000},"page":"e6929","source":"Crossref","is-referenced-by-count":30,"title":["Automated pupillometry to detect command following in neurological patients: a proof-of-concept study"],"prefix":"10.7717","volume":"7","author":[{"given":"Alexandra","family":"Vassilieva","sequence":"first","affiliation":[{"name":"Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus Harboe","family":"Olsen","sequence":"additional","affiliation":[{"name":"Department of Neuroanesthesiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Costanza","family":"Peinkhofer","sequence":"additional","affiliation":[{"name":"Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark"},{"name":"Medical Faculty, University of Trieste, Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gitte Moos","family":"Knudsen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark"},{"name":"Faculty of Health Sciences and Medicine, University of Copenhagen, Copenhagen, Denmark"},{"name":"Neurobiology Research Unit, Rigshospitalet, Copenhagen University Hospital and Center for Integrated Molecular Brain Imaging, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Kondziella","sequence":"additional","affiliation":[{"name":"Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark"},{"name":"Faculty of Health Sciences and Medicine, University of Copenhagen, Copenhagen, Denmark"},{"name":"Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4443","published-online":{"date-parts":[[2019,5,13]]},"reference":[{"key":"10.7717\/peerj.6929\/ref-1","doi-asserted-by":"publisher","first-page":"5008","DOI":"10.1523\/JNEUROSCI.2433-16.2017","article-title":"Selective modulation of the pupil light reflex by microstimulation of prefrontal cortex","volume":"37","author":"Becket Ebitz","year":"2017","journal-title":"Journal of Neuroscience"},{"issue":"2","key":"10.7717\/peerj.6929\/ref-2","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1007\/s10877-018-0147-y","article-title":"Suppression of pupillary unrest by general anesthesia and propofol sedation","volume":"33","author":"Behrends","year":"2018","journal-title":"Journal of Clinical Monitoring and Computing"},{"key":"10.7717\/peerj.6929\/ref-3","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2017.00688","article-title":"Functional MRI Motor Imagery Tasks to detect command following in traumatic disorders of consciousness","volume":"8","author":"Bodien","year":"2017","journal-title":"Frontiers in Neurology"},{"key":"10.7717\/peerj.6929\/ref-4","doi-asserted-by":"publisher","DOI":"10.4103\/2152-7806.82248","article-title":"Pupillary reactivity as an early indicator of increased intracranial pressure: the introduction of the neurological pupil index","volume":"2","author":"Chen","year":"2011","journal-title":"Surgical Neurology International"},{"key":"10.7717\/peerj.6929\/ref-5","doi-asserted-by":"publisher","first-page":"2088","DOI":"10.1016\/S0140-6736(11)61224-5","article-title":"Bedside detection of awareness in the vegetative state: a cohort study","volume":"378","author":"Cruse","year":"2011","journal-title":"Lancet"},{"key":"10.7717\/peerj.6929\/ref-6","doi-asserted-by":"publisher","first-page":"1058","DOI":"10.1007\/s00415-010-5882","article-title":"Attitudes towards end-of-life issues in disorders of consciousness: a European survey","volume":"258","author":"Demertzi","year":"2011","journal-title":"Journal of Neurology"},{"key":"10.7717\/peerj.6929\/ref-7","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1186\/1471-2377-14-147","article-title":"Assessment of visual fixation in vegetative and minimally conscious states","volume":"14","author":"Di","year":"2014","journal-title":"BMC Neurology"},{"key":"10.7717\/peerj.6929\/ref-8","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1093\/brain\/awx176","article-title":"Early detection of consciousness in patients with acute severe traumatic brain injury","volume":"140","author":"Edlow","year":"2017","journal-title":"Brain"},{"key":"10.7717\/peerj.6929\/ref-9","doi-asserted-by":"publisher","first-page":"1436","DOI":"10.1111\/psyp.12896","article-title":"Pupil size as a measure of within-task learning","volume":"54","author":"Foroughi","year":"2017","journal-title":"Psychophysiology"},{"issue":"9","key":"10.7717\/peerj.6929\/ref-10","doi-asserted-by":"publisher","first-page":"1699","DOI":"10.1212\/WNL.0000000000005926","article-title":"Practice guideline update recommendations summary: disorders of consciousness","volume":"99","author":"Giacino","year":"2018","journal-title":"Neurology"},{"key":"10.7717\/peerj.6929\/ref-11","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1016\/j.concog.2016.10.006","article-title":"EEG and fMRI agree: mental arithmetic is the easiest form of imagery to detect","volume":"48","author":"Harrison","year":"2017","journal-title":"Consciousness and Cognition"},{"key":"10.7717\/peerj.6929\/ref-12","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.bja.2017.10.002","article-title":"Management of perceived devastating brain injury after hospital admission: a consensus statement from stakeholder professional organizations","volume":"120","author":"Harvey","year":"2018","journal-title":"British Journal of Anaesthesia"},{"key":"10.7717\/peerj.6929\/ref-13","volume-title":"Attention and effort","author":"Kahneman","year":"1973"},{"key":"10.7717\/peerj.6929\/ref-14","doi-asserted-by":"publisher","first-page":"1583","DOI":"10.1126\/science.154.3756.1583","article-title":"Pupil diameter and load on memory","volume":"154","author":"Kahneman","year":"1966","journal-title":"Science"},{"key":"10.7717\/peerj.6929\/ref-15","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1016\/j.neuroimage.2013.07.013","article-title":"Single-trial decoding of auditory novelty responses facilitates the detection of residual consciousness","volume":"83","author":"King","year":"2013","journal-title":"NeuroImage"},{"key":"10.7717\/peerj.6929\/ref-16","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1136\/jnnp-2015-310958","article-title":"Preserved consciousness in vegetative and minimal conscious states: systematic review and meta-analysis","volume":"87","author":"Kondziella","year":"2016","journal-title":"Journal of Neurology, Neurosurgery, and Psychiatry"},{"key":"10.7717\/peerj.6929\/ref-17","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1177\/1745691611427305","article-title":"Pupillometry: a window to the preconscious? Perspectives on psychological science","volume":"7","author":"Laeng","year":"2012","journal-title":"Journal of the Association for Psychological Science"},{"key":"10.7717\/peerj.6929\/ref-18","doi-asserted-by":"publisher","first-page":"1242","DOI":"10.1213\/ANE.0000000000000314","article-title":"Portable infrared pupillometry: a review","volume":"120","author":"Larson","year":"2015","journal-title":"Anesthesia and Analgesia"},{"key":"10.7717\/peerj.6929\/ref-19","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1186\/1741-7015-8-68","article-title":"Unresponsive wakefulness syndrome: a new name for the vegetative state or apallic syndrome","volume":"8","author":"Laureys","year":"2010","journal-title":"BMC Medicine"},{"key":"10.7717\/peerj.6929\/ref-20","volume-title":"The pupil: anatomy, physiology, and clinical applications","author":"Loewenfeldt","year":"1999"},{"key":"10.7717\/peerj.6929\/ref-21","doi-asserted-by":"publisher","first-page":"e16","DOI":"10.7717\/peerj-cs.16","article-title":"Workload assessment for mental arithmetic tasks using the task-evoked pupillary response","volume":"1","author":"Marquart","year":"2015","journal-title":"PeerJ"},{"key":"10.7717\/peerj.6929\/ref-22","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1111\/psyp.12772","article-title":"Pupillometry reveals changes in physiological arousal during a sustained listening task","volume":"54","author":"McGarrigle","year":"2017","journal-title":"Psychophysiology"},{"key":"10.7717\/peerj.6929\/ref-23","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1056\/NEJMoa0905370","article-title":"Willful modulation of brain activity in disorders of consciousness","volume":"362","author":"Monti","year":"2010","journal-title":"The New England Journal of Medicine"},{"key":"10.7717\/peerj.6929\/ref-24","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1213\/ANE.0000000000001728","article-title":"Prediction of opioid analgesic efficacy by measurement of pupillary unrest","volume":"124","author":"Neice","year":"2017","journal-title":"Anesthesia & Analgesia"},{"key":"10.7717\/peerj.6929\/ref-25","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1007\/s12028-016-0275-5","article-title":"Early withdrawal decision-making in patients with coma after cardiac arrest: a qualitative study of intensive care clinicians","volume":"25","author":"Ong","year":"2016","journal-title":"Neurocritical Care"},{"key":"10.7717\/peerj.6929\/ref-26","doi-asserted-by":"publisher","DOI":"10.1126\/science.1130197","article-title":"Detecting awareness in the vegetative state","volume":"313","author":"Owen","year":"2006","journal-title":"Science"},{"key":"10.7717\/peerj.6929\/ref-27","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2018.00916","article-title":"Influence of strategic cortical infarctions on pupillary function","volume":"9","author":"Peinkhofer","year":"2018","journal-title":"Frontiers in Neurology"},{"key":"10.7717\/peerj.6929\/ref-28","doi-asserted-by":"publisher","first-page":"14819","DOI":"10.1038\/s41598-018-33202-7","article-title":"Conscious processing of auditory regularities induces a pupil dilation","volume":"8","author":"Quirins","year":"2018","journal-title":"Scientific Reports"},{"key":"10.7717\/peerj.6929\/ref-29","article-title":"R: a language and environment for statistical computing","author":"R Core Team","year":"2017"},{"issue":"10","key":"10.7717\/peerj.6929\/ref-30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/02699052.2017.1327673","article-title":"Probing consciousness in a sensory-disconnected paralyzed patient","volume":"31","author":"Rohaut","year":"2017","journal-title":"Brain Injury"},{"key":"10.7717\/peerj.6929\/ref-31","doi-asserted-by":"publisher","first-page":"1413","DOI":"10.1001\/jamaneurol.2015.2899","article-title":"Cognitive motor dissociation following severe brain injuries","volume":"72","author":"Schiff","year":"2015","journal-title":"JAMA Neurology"},{"key":"10.7717\/peerj.6929\/ref-32","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1080\/13554790902724904","article-title":"Detecting consciousness in a total locked-in syndrome: an active event-related paradigm","volume":"15","author":"Schnakers","year":"2009","journal-title":"Neurocase"},{"key":"10.7717\/peerj.6929\/ref-33","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1186\/1471-2377-9-35","article-title":"Diagnostic accuracy of the vegetative and minimally conscious state: clinical consensus versus standardized neurobehavioral assessment","volume":"9","author":"Schnakers","year":"2009","journal-title":"BMC Neurology"},{"key":"10.7717\/peerj.6929\/ref-34","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/j.neuroimage.2016.06.011","article-title":"Spontaneous pupil dilations during the resting state are associated with activation of the salience network","volume":"139","author":"Schneider","year":"2016","journal-title":"NeuroImage"},{"key":"10.7717\/peerj.6929\/ref-35","doi-asserted-by":"publisher","first-page":"2258","DOI":"10.1093\/brain\/awu141","article-title":"Large scale screening of neural signatures of consciousness in patients in a vegetative or minimally conscious state","volume":"137","author":"Sitt","year":"2014","journal-title":"Brain"},{"key":"10.7717\/peerj.6929\/ref-36","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2015\/179542","article-title":"Pharmacological isolation of cognitive components influencing the pupillary light reflex","volume":"2015","author":"Steinhauer","year":"2015","journal-title":"Journal of Ophthalmology"},{"key":"10.7717\/peerj.6929\/ref-37","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1016\/S0140-6736(14)60042-8","article-title":"Diagnostic precision of PET imaging and functional MRI in disorders of consciousness: a clinical validation study","volume":"384","author":"Stender","year":"2014","journal-title":"Lancet"},{"key":"10.7717\/peerj.6929\/ref-38","doi-asserted-by":"publisher","first-page":"R647","DOI":"10.1016\/j.cub.2013.06.011","article-title":"Pupil responses allow communication in locked-in syndrome patients","volume":"23","author":"Stoll","year":"2013","journal-title":"Current Biology"},{"key":"10.7717\/peerj.6929\/ref-39","doi-asserted-by":"publisher","first-page":"1581","DOI":"10.1503\/cmaj.101786","article-title":"Mortality associated with withdrawal of life-sustaining therapy for patients with severe traumatic brain injury: a Canadian multicentre cohort study","volume":"183","author":"Turgeon","year":"2011","journal-title":"Canadian Medical Association journal = Journal de l\u2019Association Medicale Canadienne"},{"key":"10.7717\/peerj.6929\/ref-40","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fneur.2018.00671","article-title":"Conscious while being considered in an unresponsive wakefulness syndrome for 20 years","volume":"9","author":"Vanhaudenhuyse","year":"2018","journal-title":"Frontiers in Neurology"},{"issue":"1","key":"10.7717\/peerj.6929\/ref-41","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1093\/brain\/awv272","article-title":"Ethical considerations in functional magnetic resonance imaging research in acutely comatose patients","volume":"139","author":"Weijer","year":"2015","journal-title":"Brain: A Journal of Neurology"}],"container-title":["PeerJ"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/peerj.com\/articles\/6929.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/peerj.com\/articles\/6929.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/peerj.com\/articles\/6929.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/peerj.com\/articles\/6929.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,5,13]],"date-time":"2019-05-13T04:02:12Z","timestamp":1557720132000},"score":1,"resource":{"primary":{"URL":"https:\/\/peerj.com\/articles\/6929"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,13]]},"references-count":41,"alternative-id":["10.7717\/peerj.6929"],"URL":"https:\/\/doi.org\/10.7717\/peerj.6929","archive":["CLOCKSS","LOCKSS","Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.7287\/peerj.6929v0.4\/reviews\/1","asserted-by":"object"},{"id-type":"doi","id":"10.7287\/peerj.6929v0.4\/reviews\/2","asserted-by":"object"},{"id-type":"doi","id":"10.7287\/peerj.6929v0.2\/reviews\/2","asserted-by":"object"},{"id-type":"doi","id":"10.7287\/peerj.6929v0.2\/reviews\/1","asserted-by":"object"},{"id-type":"doi","id":"10.7287\/peerj.6929v0.3\/reviews\/2","asserted-by":"object"},{"id-type":"doi","id":"10.7287\/peerj.6929v0.1\/reviews\/2","asserted-by":"object"},{"id-type":"doi","id":"10.7287\/peerj.6929v0.3\/reviews\/1","asserted-by":"object"},{"id-type":"doi","id":"10.7287\/peerj.6929v0.1\/reviews\/1","asserted-by":"object"}],"has-preprint":[{"id-type":"doi","id":"10.1101\/525212","asserted-by":"object"}]},"ISSN":["2167-8359"],"issn-type":[{"value":"2167-8359","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,5,13]]},"article-number":"e6929"}}