Elwell, C

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Functional Neuroimaging in PatientsWith Disorders of Consciousness:Caution AdvisedPrognostication in patients with disorders of con-sciousness is a complex clinical problem, which canbe impacted by multiple factors. The current approach tothe assessment of patients with disorders of conscious-ness involves standardized behavioral examinations.Functional neuroimaging investigates evidence of neuralresponses in the absence of behavioral signs. In 2006, theearliest study reporting the use of neuroimaging in apatient with disordered consciousness used a functionalmagnetic resonance imaging (fMRI) mental imagery taskto suggest the presence of residual cognitive capability ina patient diagnosed as being in a vegetative state, nowreferred to as unresponsive wakefulness state.1 Sincethen, fMRI2 and electroencephalography (EEG)3 havebeen used to provide evidence of preserved cognitiveprocesses in patients in varying states of consciousness.These and other studies have helped to define cognitivemotor dissociation (evidence of command followingduring a motor imagery task)4 and higher-order cortexmotor dissociation (association cortex responses duringlanguage and music stimuli).5Most recently, the optical neuroimaging techniquefunctional near-infrared spectroscopy (fNIRS) has beenused to investigate neural responses in patients withdisorders of consciousness.6 fNIRS measures the hemo-dynamic response to neural activity using a methodsimilar to pulse oximetry. It uses multiple sources anddetectors (optodes) to noninvasively measure the absorp-tion of near-infrared light through the skull and producemaps of regional cerebral oxygenation. Like fMRI, fNIRSmeasures the dynamics of oxygen delivery resulting fromlocalized neuronal activation.7 Simultaneous EEG-fNIRSstudies deliver the possibility of a direct bedside measureof neurovascular coupling,8 and multimodal (although notnecessarily simultaneous) imaging protocols are now beingproposed for use in patients with disorders of conscious-ness. Kazazian et al9 described a protocol, which willcombine fMRI, EEG, and fNIRS studies across the first10 days postinjury in 350 acutely brain-injured patients,with follow-up imaging at 12 months. The physiologicalsignals measured by fMRI, EEG, and fNIRS as well asother factors relevant to the clinical use of these techniquesare shown in Table 1.It is clear that functional neuroimaging technologiesare contributing new perspectives to the assessmentof disorders of consciousness beyond those accessiblethrough clinical behavioral assessments.10 To date, studieshave broadly been limited to clinical settings with theappropriate level of technical expertise and supportinfrastructure. However, continuing innovations in, andthe availability of, low-cost wearable neuroimaging tech-nologies (especially fNIRS) are likely to expand their usewhen studying patients in the acute and chronic phases ofdisordered consciousness. It is, therefore, timely to con-sider the array of context-specific challenges in dataacquisition, analysis, and interpretation presented by theadvent of this new horizon of functional neuroimaging,and to provide recommendations for addressing thesechallenges.DATA ACQUISITIONThe choice of imaging technique is informed bymultiple factors including availability, cost, practical im-plementation in the required clinical setting, and thecondition of the patient (Table 1). EEG and fNIRS areseen as more practical and cost-efficient alternatives tofMRI (also negating the need for transfer to aneuroimaging suite) with EEG providing a direct (ratherthan vascular-based) marker of neural activity. However,EEG measures can be impacted by electrically noisyenvironments, especially in the intensive care unit. Theaccuracy of fNIRS measurements can be influenced byintracranial blood, cerebral edema, blood contaminationof the cerebrospinal fluid, and skull integrity, all of whichalter the optical geometry of the head. Moreover, evenwith the improved engineering of wearable systems, headmovement, jaw clenching, and changes to the coupling ofEEG electrodes and fNIRS optodes with the skull surfacewill produce signal artifacts, which may be stimulus-related.Study protocols for eliciting neuronal responses havenecessarily been derived from those tested in small cohortsof healthy participants, so special consideration must begiven to their translation into clinical studies of disordersof consciousness. To enable cross-study comparisons,protocols need to be standardized while also being lin-guistically, culturally, and clinically appropriate for in-dividual patients (eg, those with dementia, deafness,aphasia, pain, and delirium).Data AnalysesThe analysis of functional neuroimaging datapresents specific challenges even under the controlledenvironment of studies in healthy volunteers. Standard-ized and validated analysis pipelines are essential todeal with movement artifacts, stimulus-related changesin systemic physiology (eg, scalp blood flow andblood pressure, which impact fNIRS measures), andinadequate signal-to-noise. Determining statisticallyDOI: 10.1097/ANA.0000000000000920The author has no conflicts of interest to declare.Address correspondence to: Clare Elwell, PhD. E-mail: c.elwell@ucl.ac.uk.Copyright © 2023 The Author(s). Published by Wolters Kluwer Health,Inc. This is an open access article distributed under the terms of theCreative Commons Attribution-Non Commercial-No DerivativesLicense 4.0 (CCBY-NC-ND), where it is permissible to downloadand share the work provided it is properly cited. The work cannot bechanged in any way or used commercially without permission from thejournal.EDITORIALSJ Neurosurg Anesthesiol  Volume 35, Number 3, July 2023 www.jnsa.com | 257Downloaded from http://journals.lww.com/jnsa by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 07/18/2023significant findings at a group level in conscious volun-teers and extrapolating these to an individual patient in apotentially dynamic state of arousal and consciousnessare nontrivial. Advanced machine and deep learningtechniques may aid the extraction of meaningful andreliable neuronal responses in patients with disorders ofconsciousness, but the scarcity of available data fromthese types of clinical studies impacts their usefulness inthe short term.Data Interpretation and Impact on ClinicalDecision MakingThe medical and ethical considerations of usingfunctional imaging techniques for prognostication in pa-tients with disorders of consciousness are wide-ranging.11The relationship between cognitive motor dissociation orhigher order cortex motor dissociation with consciousnessor potential for consciousness remains unclear, especiallywhen ~25% of healthy participants do not demonstrate theexpected functional neuroimaging responses when per-forming motor imagery tasks.5 More recent studies haveused functional neuroimaging data to suggest the re-classification of patients from the unresponsive wakeful-ness state to a minimally conscious state and/or theintroduction of the classification of minimally consciousstate* to denote a dissociation between behavioral diag-nosis and neuroimaging findings.12Of utmost importance is the impact of functionalneuroimaging on the ongoing management of patientswith disorders of consciousness and, specifically, the like-lihood of functional neuroimaging being used to guidetime-sensitive decisions regarding withdrawal of life-sus-taining treatment or provision of neurorehabilitationservices. The limited outcome data from current studiesimpedes the prognostic value of functional neuroimagingdata in this context, especially when one study in a rela-tively large (n = 16) cohort of patients found no associ-ation between early fMRI and EEG responses and6-month outcomes.5 Evidence of neural responses onfunctional imaging may delay decisions to withdrawtreatment and allow more time to assess recovery poten-tial. In contrast, functional neuroimaging findings maymake it more likely that life-sustaining treatment iscontinued even if the potential for a degree of recoverythat would be acceptable to the patient (which will differbetween individuals) has not changed. Moreover, in anenvironment of prognostic uncertainty, relatives can viewthe technological intervention of functional neuroimagingas a magic bullet of recovery prediction, so communica-tion about the potential impact, or not, on the clinicalmanagement of their loved one must be handled carefully.Opportunities for Future ResearchAs with all translation research, impactful clinicaladvances depend upon close collaboration and meaningfultwo-way communication between disciplines. In this case,physicists and engineers developing functional neuro-imaging technologies and clinical specialists managingpatients with disorders of consciousness must work to-gether to ensure sufficient attention is paid to the clinicalcontext and consequences of the functional neuroimagingmeasures, as well as to the methodological, im-plementation and data interpretation issues associatedwith the different technologies.As innovations in the bioengineering of neuro-imaging systems focus on democratizing how, when, andwhere the brain can be imaged, we should also acknowl-edge the need for systems to be optimized for specificclinical applications and for data analysis and inter-pretation methods to be aligned for specific patientgroups. In addition, there is a clear need for appropriatelyfunded multicentre outcome studies, which should focuson the relationship between evidence of covert con-sciousness and meaningful functional outcomes.Much work is needed to understand the role offunctional neuroimaging in the clinical management ofpatients with disorders of consciousness before thesetechniques can be used to reliably guide prognostication.Although functional neuroimaging has real potential inthis area, caution is advised. The stakes for this new era ofbrain imaging and the patients it may serve are high.Clare Elwell, PhDDepartment of Medical Physics and BiomedicalEngineering, University College London, UKREFERENCES1. Owen A, Coleman M, Boly M, et al. Detecting awareness in thevegetative state. Science. 2006;313:1401. doi:10.1126/science.1130197TABLE 1. Comparison of Three Functional Neuroimaging TechniquesfMRI EEG fNIRSPhysiological signal measured BOLD Potential difference ΔHbO2 and ΔHHbPenetration depth Whole head Brain cortex Brain cortexSpatial resolution (cm) 0.3 mm voxels 5-9 2-3Temporal resolution (Hz) 1-3 > 1000 Up to 10Limitations for use in clinicalsettingsMetal implants/pacemakers/transferto imaging suiteElectrically noisyenvironmentsBrain injury-related changes inoptical geometryWearable No Yes YesCost High Low LowBOLD indicates blood oxygenation level-dependent; EEG, electrocorticography; fMRI, functional magnetic resonance imaging; fNIRS, functional near-infraredspectroscopy; HbO2, oxyhemoglobin; HHb, deoxyhemoglobin.Editorials J Neurosurg Anesthesiol  Volume 35, Number 3, July 2023258 | www.jnsa.com Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.Downloaded from http://journals.lww.com/jnsa by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 07/18/20232. Kazazian K, Norton L, Gofton T, et al. Cortical function in acutesevere traumatic brain injury and at recovery: a longitudinal fMRIcase study. Brain. 2020;10:604. doi:10.3390/brainsci100906043. Claassen J, Doyle K, Matory A, et al. Detection of brain activationin unresponsive patients with acute brain injury. N Engl J Med.2019;380:2497–2505. doi:10.1056/NEJMoa18127574. Schiff N. Cognitive motor dissociation following severe braininjuries. JAMA Neurol. 2015;72:1413–1415. doi:10.1001/jamaneurol.2015.28995. Edlow B, Chatelle C, Spencer C, et al. Early detection of conscious-ness in patients with acute severe traumatic brain injury. Brain.2017;140:2399–2414. doi:10.1093/brain/awx1766. Chen H, Miao G, wang S, et al. Disturbed functional connectivityand topological properties of the frontal lobe in minimally consciousstate based on resting-state fNIRS. Front Neurosci. 2023;17:1118395.doi:10.3389/fnins.2023.11183957. Pinti P, Tachtsidis I, Hamilton A, et al. The present and future offunctional near-infrared spectroscopy (fNIRS) for cognitive neuro-science. Ann NY Acad Sci. 2020;1464:5–29. doi:10.1016/j.cobme.2017.09.0118. Othman M, Bhattacharya M, Moller K, et al. Resting -state NIRS-EEG in unresponsive patients with acute brain injury: a proof-of-concept study. Neurocrit Care. 2021;34:31–44. doi:10.1007/s12028-020-00971-x9. Kazazian K, Norton L, Laforge G, et al. Improving diagnosis andprognosis in acute severe brain injury: a multimodal imagingprotocol. Front Neurol. 2023;12:757219. doi:10.3389/fneur.2021.75721910. Alnagger N, Cardone P, Martial C, et al. The current and futurecontribution of neuroimaging to the understanding of disorders ofconsciousness. Presse Med. 2023;52:104163. doi:10.1016/j.lpm.2022.10416311. Rohaut B, Eliseyev A, Claassen J. Uncovering consciousness inunresponsive ICU patients: technical, medical and ethical consid-erations. Crit Care. 2019;23:78. doi:10.1186/s13054-019-2370-412. Thibaut A, Panda R, Annen J, et al. Preservation of brain activity inunresponsive patients identifies MCS star. Ann Neurol. 2021;90:89–100. doi:10.1002/ana.26095Journal of Neurosurgical AnesthesiologyEditorial BoardOn behalf of the Journal of Neurosurgical Anesthesi-ology Editorial team, I would like to acknowledge thecontributions of colleagues who have recently retired fromthe Editorial Board after many years of service to thejournal: Drs Federico Bilotta, Ansgar Brambrink, IanHerrick, Vesna Jevtovic-Todorovic, Masahiko Kawaguchi,and Irene Rozet. Their contributions have been pivotal tothe development and governance of JNA, and I thank themfor their service to the journal and to our specialty.I also take this opportunity to welcome the followingnew members of the Editorial Board: Drs William Gross,Laura Hemmer, Amie Hoefnagel, Bhiken Naik, andMatt Whalin. I am grateful for their willingness to takeon this important role among their many other commit-ments, and look forward to working with them over thenext 3 years.Martin SmithEditor-in-ChiefThe author has no conflicts of interest to disclose.DOI: 10.1097/ANA.0000000000000924J Neurosurg Anesthesiol  Volume 35, Number 3, July 2023 EditorialsCopyright © 2023 Wolters Kluwer Health, Inc. All rights reserved. www.jnsa.com | 259Downloaded from http://journals.lww.com/jnsa by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 07/18/2023

Functional Neuroimaging in Patients with Disorders of Consciousness: Caution Advised

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Functional Neuroimaging in Patients with Disorders of Consciousness: Caution Advised

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