Background Apomorphine is a dopaminergic candidate therapy to improve recovery in patients with prolonged disorders of consciousness (PDoC). Behavioural improvements were previously described in non-controlled case series, but its efficacy and neural mechanisms remain largely unknown. This open-label controlled study using multimodal outcome measures investigates the action of apomorphine in severely brain-injured patients. Methods Thirteen PDoC patients received 30-day subcutaneous apomorphine treatment (n = 6) or standard care (control group, n = 7) in a neurological rehabilitation centre between February 2018 and January 2021. The apomorphine group was monitored 30 days before treatment initiation, during treatment and one year after treatment. Primary outcome measure was defined as changes in behavioural diagnosis using the Coma Recovery Scale-Revised (CRS-R). CRS-R index, recovery of new conscious behaviours, DoC-feeling scores, high-density electroencephalography, and fluorodeoxyglucose positron emission tomography were employed as secondary outcome measures. The control group was monitored with repeated CRS-R only. Registration: EudraCT 2018003144-23; Clinicaltrials.gov NCT03623828. Findings Groups (apomorphine vs. control: odds ratio 8.9, 95% CI 3.3-17.8) and study phase (treatment vs. baseline, apomorphine group only: odds ratio 3.9, 95% CI 1.5-10.1) significantly influenced positive changes in behavioural diagnosis. At one-year post-injury, 4/6 patients in the apomorphine group and 1/7 patients in the control group had improved theirdiagnosis. Similarly, CRS-R indexwas significantly influenced by study phase (treatment vs. baseline). All items onthe DoC-feeling score were rated higher after treatment than before by both family and medical staff. Patients in the apomorphine group recovered more conscious behaviours than control patients. Alpha-band whole-brain connectivity and participation coefficient, as well as alpha-band parieto-temporal connectivity and frontal participation coefficient were higher after treatment than at baseline. Whole-brain metabolism increased by a relative mean of 13.8% after treatment compared to baseline, with a significant effect of timing (pre-vs. post-treatment scans) on regional SUV. Interpretation Long-lasting consciousness improvements were observed in patients treated with apomorphine, compared to controls and compared to baseline. Changes in brain connectivity and metabolism were observed after treatment, providing insights into possible neurophysiological mechanisms and target areas. This open-label study confirmed the feasibility and safety of apomorphine treatment, which may represent a key therapeutic option for PDoC. Copyright (c) 2024 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

ABSTRACTThe complex diagnosis of disorders of consciousness (DoC) diagnosis increasingly relies on brain-imaging techniques for their ability to detect residual signs of consciousness in otherwise unresponsive patients. However, few of these techniques have been validated on external datasets. Here, we show that the FDG-PET glucose metabolic index of the best preserved hemisphere has robust in-sample and out-sample performances to diagnose DoC, slightly outperforming EEG-based classification. We further show that a multimodal assessment combining both FDG-PET and EEG not only improved diagnostic performances, but also allowed to identify covert cognition and to predict 6-month responsiveness in initially unresponsive patients. Lastly, we show that DoC heterogeneity reflects a sum of regional cortical metabolic differences, and their corresponding behavioral patterns, rather than a binary contrast between conscious and unconscious states. In total, we show that FDG-PET and EEG provide complementary information on DoC physiopathology and that their combination improves DoC diagnosis and prognostication.

Objective Brain‐injured patients who are unresponsive at the bedside (ie, vegetative state/unresponsive wakefulness syndrome – VS/UWS) may present brain activity similar to patients in minimally conscious state (MCS). This peculiar condition has been termed “non‐behavioural MCS” or “MCS*”. In the present study we aimed to investigate the proportion and underlying brain characteristics of patients in MCS*. Methods Brain 18 F‐fluorodeoxyglucose Positron Emission Tomography (FDG‐PET) was acquired on 135 brain‐injured patients diagnosed in prolonged VS/UWS (n = 48) or MCS (n = 87). From an existing database, relative metabolic preservation in the fronto‐parietal network (measured with standardized uptake value) was visually inspected by three experts. Patients with hypometabolism of the fronto‐parietal network were labelled “VS/UWS”, while its (partial) preservation either confirmed the behavioural diagnosis of “MCS” or, in absence of behavioural signs of consciousness, suggested a diagnosis of “MCS*”. Clinical outcome at 1‐year follow‐up, functional connectivity, grey matter atrophy, and regional brain metabolic patterns were investigated in the three groups (VS/UWS, MCS* and MCS). Results 67% of behavioural VS/UWS presented a partial preservation of brain metabolism (ie, MCS*). Compared to VS/UWS patients, MCS* patients demonstrated a better outcome, global functional connectivity and grey matter preservation more compatible with the diagnosis of MCS. MCS* patients presented lower brain metabolism mostly in the posterior brain regions compared to MCS patients. Interpretation MCS* is a frequent phenomenon that is associated with better outcome and better brain preservation than the diagnosis of VS/UWS. Complementary exams should be provided to all unresponsive patients before taking medical decisions. ANN NEUROL 2021;90:89–100

Background: A significant proportion of brain-injured patients who are unresponsive at the bedside (i.e., unresponsive wakefulness syndrome – UWS) may present brain activity similar to patients in minimally conscious state (MCS). This peculiar condition has been termed “non-behavioural MCS” or “MCS*”. Methods: Brain 18 F-fluorodeoxyglucose Positron Emission Tomography (FDG-PET) was acquired on 135 brain-injured patients diagnosed in prolonged UWS (n=48) or MCS (n=87). Clinical diagnosis was based on repeated Coma Recovery Scale-Revised assessments. Relative metabolic preservation in the fronto-parietal network (measured with standardized uptake value) was evaluated by 3 experts blinded to the clinical diagnosis. Patients with hypometabolism of the fronto-parietal network were labelled UWS, while preservation either confirmed the behavioural diagnosis of MCS or, in absence of behavioural signs of consciousness, suggested a diagnosis of MCS*. The clinical outcome at 1-year follow-up, the functional connectivity (measured with electroencephalography), the grey matter atrophy (assessed with magnetic resonance imaging), and the regional brain metabolic patterns were investigated in the three groups (UWS, MCS* and MCS). Findings: Out of the 48 behavioural UWS patients, 32 (67%) presented a partial preservation of brain metabolism (i.e., MCS*). Compared to the hypometabolic UWS patients, MCS* patients demonstrated a better outcome, higher global functional connectivity in the alpha and theta bands, as well as greater grey matter preservation in the frontal and temporal regions, the fusiform gyrus, and the insula. MCS* patients presented lower brain metabolism mostly in the posterior regions compared to MCS patients. Interpretation: MCS* is a frequent phenomenon that is also associated with a better outcome than the diagnosis of UWS. Complementary exams should be provided to all unresponsive patients before taking medical decisions. Funding Statement: Belgian National Funds for Scientific Research, Human Brain Project SGA3 (No. 945539), DOCMA project (EU-H2020-MSCA–RISE–778234), Belgian Federal Science Policy Office (PRODEX), Bial Foundation, fund Generet, King Baudouin Foundation, AstraZeneca Foundation. Declaration of Interests: The authors declare that there is no conflict of interest regarding the publication of this paper. Ethics Approval Statement: The study was approved by the Ethics Committee of the Faculty of Medicine of the University of Liege. Written informed consent was obtained from healthy controls and patients' legal representatives.

Neurological examination of non-communicating patients relies on a few decisive items that enable the crucial distinction between vegetative state (VS)-also coined unresponsive wakefulness syndrome (UWS)-and minimally conscious state. Over the past 10 years, this distinction has proven its diagnostic value as well as its important prognostic value on consciousness recovery. However, clinicians are currently limited by three factors: (i) the current behavioural repertoire of minimally conscious state items is limited and restricted to a few cognitive domains in the goldstandard revised version of the Coma Recovery Scale; (ii) a proportion of ∼15-20% clinically VS/UWS patients are actually in a richer state than VS/UWS as evidenced by functional brain imaging; and (iii) the neurophysiological and cognitive interpretation of each minimally conscious state item is still unclear and debated. In the current study we demonstrate that habituation of the auditory startle reflex (hASR) tested at bedside constitutes a novel, simple and powerful behavioural sign that can accurately distinguish minimally conscious state from VS/UWS. In addition to enlarging the minimally conscious state items repertoire, and therefore decreasing the low sensitivity of current behavioural measures, we also provide an original and rigorous description of the neurophysiological basis of hASR through a combination of functional (high density EEG and 18F-fluorodeoxyglucose PET imaging) and structural (diffusion tensor imaging MRI) measures. We show that preservation of hASR is associated with the functional and structural integrity of a brain-scale fronto-parietal network, including prefrontal regions related to control of action and inhibition, and meso-parietal areas associated with minimally conscious and conscious states. Lastly, we show that hASR predicts 6-month improvement of consciousness. Taken together, our results show that hASR is a cortically-mediated behaviour, and suggest that it could be a new clinical item to clearly and accurately identify non-communicating patients who are in the minimally conscious state.

Background: There are few available therapeutic options to promote recovery among patients with chronic disorders of consciousness (DOC). Among pharmacological treatments, apomorphine, a dopamine agonist, has exhibited promising behavioral effects and safety of use in small-sample pilot studies. The true efficacy of the drug and its neural mechanism are still unclear. Apomorphine may act through a modulation of the anterior forebrain mesocircuit, but neuroimaging and neurophysiological investigations to test this hypothesis are scarce. This clinical trial aims to (1) assess the treatment effect of subcutaneous apomorphine infusions in patients with DOC, (2) better identify the phenotype of responders to treatment, (3) evaluate tolerance and side effects in this population, and (4) examine the neural networks underlying its modulating action on consciousness. Methods/Design: This study is a prospective double-blind randomized parallel placebo-controlled trial. Forty-eight patients diagnosed with DOC will be randomized to receive a 30-day regimen of either apomorphine hydrochloride or placebo subcutaneous infusions. Patients will be monitored at baseline 30 days before initiation of therapy, during treatment and for 30 days after treatment washout, using standardized behavioral scales (Coma Recovery Scale-Revised, Nociception Coma Scale-Revised), neurophysiological measures (electroencephalography, body temperature, actigraphy) and brain imaging (magnetic resonance imaging, positron emission tomography). Behavioral follow-up will be performed up to 2 years using structured phone interviews. Analyses will look for changes in behavioral status, circadian rhythmicity, brain metabolism, and functional connectivity at the individual level (comparing before and after treatment) and at the group level (comparing apomorphine and placebo arms, and comparing responder and non-responder groups). Discussion: This study investigates the use of apomorphine for the recovery of consciousness in the first randomized placebo-controlled double-blind trial using multimodal assessments. The results will contribute to define the role of dopamine agonists for the treatment of these challenging conditions and identify the neural correlates to their action. Results will bring objective evidence to further assess the modulation of the anterior forebrain mesocircuit by pharmacological agents, which may open new therapeutic perspectives. Clinical Trial Registration: EudraCT n°2018-003144-23; Clinicaltrials.gov n°NCT03623828 (https://clinicaltrials.gov/ct2/show/NCT03623828).

Parkinson's disease (PD) is a progressing neurodegenerative disease predominantly involving the loss of dopamine producing neurons with hallmark symptoms of motor disorders and cognitive, motivational, emotional, and perceptual impairments. Intriguingly, PD can also be connected-often anecdotally-with a sudden burst of artistic creativity, motivation, or changed quality/style of produced art. This has led to growing empirical interest, promising a window into brain function and the unique neurological signature of artists. This topic also fits a growing interest from researchers in other areas, including Alzheimer's or other dementia, which have suggested that specific changes in art production/appraisal may provide a unique basis for therapy, diagnosis, or understanding of these diseases. However, whether PD also shows similar impacts on how we perceive and evaluate art has never been systematically addressed. We compared a cohort of PD patients against age-matched healthy controls, asking participants to rate paintings using scales of liking and beauty and terms pertaining to artworks' formal and conceptual qualities previously designed to provide a rubric for symptom identification. We found no evidence for PD-related differences in liking or beauty. However, PD patients showed higher ratings on assessed "emotionality," potentially relating to the tie between PD, dopamine pathways, and emotion/reward.

Because the human brain consumes a disproportionate fraction of the resting body's energy, positron emission tomography (PET) measurements of absolute glucose metabolism (CMRglc) can serve as disease biomarkers. Global mean normalization (GMN) of PET data reveals disease-based differences from healthy individuals as fractional changes across regions relative to a global mean. To assess the impact of GMN applied to metabolic data, we compared CMRglc with and without GMN in healthy awake volunteers with eyes closed (i.e., control) against specific physiological/clinical states, including healthy/awake with eyes open, healthy/awake but congenitally blind, healthy/sedated with anesthetics, and patients with disorders of consciousness. Without GMN, global CMRglc alterations compared to control were detected in all conditions except in congenitally blind where regional CMRglc variations were detected in the visual cortex. However, GMN introduced regional and bidirectional CMRglc changes at smaller fractions of the quantitative delocalized changes. While global information was lost with GMN, the quantitative approach (i.e., a validated method for quantitative baseline metabolic activity without GMN) not only preserved global CMRglc alterations induced by opening eyes, sedation, and varying consciousness but also detected regional CMRglc variations in the congenitally blind. These results caution the use of GMN upon PET-measured CMRglc data in health and disease.

In this case study, we report the longitudinal and multimodal follow-up of a catastrophic initial presentation of cerebral fat embolism syndrome. We show that despite the initial severity, the cognitive outcome was ultimately very good but with a highly nonlinear time-course and prolonged loss of consciousness (more than 2 months). Repeated clinical assessments and brain-imaging techniques (electroencephalography, event-related potential, 18-Fluoro-Deoxy-Glucose-PET and magnetic resonance imaging) allowed us to monitor and anticipate this dynamic, providing relevant information to guide decision making in front of withdrawal of life-sustaining therapy discussions. This case illustrates the value of multimodal functional imaging in devastating brain injuries.

Event Abstract Back to Event Treating severely brain-injured patients with apomorphine: study protocol for a double blind randomized placebo-controlled trial using behavioral and neuroimaging assessments Leandro R. Sanz1*, Nicolas Lejeune1, 2, 3, Aurore Thibaut1, Séverine Blandiaux1, Johan Stender4, Neal Farber5, Ross D. Zafonte6, 7, 8, Steven Laureys1 and Olivia Gosseries1 1 Coma Science Group, University of Liège, Belgium 2 William Lennox Neurological Hospital Center, Belgium 3 Institute of NeuroScience, Université Catholique de Louvain, Belgium 4 Department of Neuroscience, Faculty of Health Sciences, University of Copenhagen, Denmark 5 NeuroHealing Pharmaceuticals (United States), United States 6 Spaulding Rehabilitation Hospital, United States 7 Massachusetts General Hospital, Harvard Medical School, United States 8 Brigham and Women's Hospital, Harvard Medical School, United States Summary for lay people: Patients who survive coma may develop disorders of consciousness. Treating these patients to improve recovery is extremely challenging. Apomorphine, a drug which stimulates dopamine neurons, exhibits promising clinical effects and safety in preliminary studies. However, its efficacy for the recovery of consciousness in large studies and its neural mechanisms remain to be definitely demonstrated. This trial aims to quantify the efficacy of apomorphine in treating patients with disorders of consciousness and to identify the brain networks it targets, using standardized clinical scales and advanced brain imaging techniques. Confirmatory results would open new and much needed therapeutic options for brain-injured patients. Background: Patients who survive severe brain injury may develop chronic disorders of consciousness. Treating these patients to improve recovery is extremely challenging because of the absence of international guidelines and scarce therapeutic options (Schnakers and Monti, 2017). Among pharmacological treatments, apomorphine, a potent direct non-specific dopamine agonist with a high affinity for D2 receptors, has exhibited promising behavioral effects and safety of use in small-sample pilot studies (Fridman et al., 2009, 2010). However, despite the improvement compared to historical data, the lack of a control group could not eliminate the possibility that the effect was a result of spontaneous recovery, and the true efficacy of apomorphine for the recovery of consciousness remains unclear (Gosseries et al., 2014). In addition, the underlying neural mechanisms of this treatment are still unknown. An upregulation of central thalamic activity through a modulation of the anterior forebrain mesocircuit has been proposed as a possible explanation (Schiff, 2010a, 2010b) but the absence of neuroimaging and neurophysiological data prevent definitive confirmation. This clinical trial aims to 1) verify and quantify the efficacy of apomorphine subcutaneous infusion in patients with disorders of consciousness, 2) better identify the rate and the phenotype of responders to treatment, 3) evaluate tolerance and side effects occurrence in this specific patient population and 4) investigate the neural networks underlying its modulating action on consciousness using multimodal outcome measurements. Methods/design: This study is a prospective double-blind randomized placebo-controlled trial. Forty-eight patients diagnosed with disorders of consciousness (i.e., unresponsive wakefulness syndrome and minimally conscious state) will be randomized to receive a 30-day regimen of either apomorphine hydrochloride or placebo via daily 12-hour subcutaneous infusions. Patients will be monitored at baseline 30 days before initiation of therapy, during treatment and for 30 days after treatment washout, followed by a two-year remote follow-up. In an initial study phase, up to six patients will be treated in an open-label fashion. Behavioral outcome measures will include weekly assessments using standardized scales such as the Coma Recovery Scale – Revised (CRS-R) (Giacino et al., 2004) and the Nociception Coma Scale – Revised (NCS-R) (Chatelle et al., 2012) during the inpatient phase. Tolerance and safety of use will be monitored using a specifically designed Adverse Events Questionnaire filled weekly by the referent physician, from treatment initiation to the end of the inpatient phase. Long-term behavioral follow-up will be performed at 6, 12 and 24 months post-treatment by telephone interview using the Glasgow Outcome Scale – Extended (GOS-E) (Levin et al., 2001) as well as phone-adapted versions of the CRS-R and the Adverse Events Questionnaire. Neurophysiological and neuroimaging measures will complement clinical evaluations and provide data on brain activity. Resting-state high-density electroencephalography (EEG) will be acquired weekly during the whole inpatient phase. In addition, participants will be assessed before and after treatment with Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET), EEG during auditory paradigms and 24-hours EEG recordings. To measure changes in circadian rhythm, body core temperature (Matsumoto et al., 2013) and body movements (Cruse et al., 2013) will be recorded with non-invasive portable devices throughout the whole duration of the inpatient phase (Figure 1). Statistical analyses will be performed blindly to detect changes in behavioral status, circadian rhythmicity, brain metabolism and functional connectivity both at the individual level (comparing before and after treatment) and at the group level (comparing the apomorphine and the placebo arms). Behavioral response will be determined by changes of diagnosis using the CRS-R, and further analyses will also look at changes between the non-responding and the responding patient subgroups. Age, gender, etiology, time since injury and diagnosis will also be included as regressors. Hypotheses: Based on the mesocircuit hypothesis, we postulate a modulation in the activity of the network’s anterior forebrain structures following administration of apomorphine (Figure 2), which will translate into the following changes: 1) A behavioral improvement such that the CRS-R diagnosis and total score will improve in responding patients, while NCS-R scores may also increase, reflecting a higher perception of pain; along with long-term functional recovery measured by sustained higher GOS-E and CRS-R scores at follow-up compared to the placebo group; 2) A relative recovery of sleep-wake cycles measured by a normalization of circadian rhythmicity as well as an increase in total body movements; 3) A metabolic improvement with significant increase of whole-brain glucose uptake, with highest increase of values found in the striatum, thalamus and frontoparietal cortical areas measured with PET; 4) A modulation of dynamic connectivity in response to apomorphine measured by resting-state fMRI analyses (seed-based and whole-brain connectivity measures) and changes of resting-state EEG connectivity metrics (notably increased mean alpha spectral connectivity, participation coefficient and delta modularity). Additionally, we can expect improvements after treatment in less specific measures of recovery such as sleep cycle architecture on 24-hours EEG hypnograms and the probability of consciousness given by a machine learning multivariate classifier derived from EEG recordings during auditory paradigms (Engemann et al., 2015). While improvements can be expected as well in the placebo arm due to spontaneous recovery and placebo effect, we hypothesize that responding patients in the apomorphine arm will exhibit significantly higher increases in these different markers of recovery. Discussion: New multimodal approaches using neurophysiology and neuroimaging allow a more accurate diagnosis of patients with disorders of consciousness but the current available treatments remain inefficient. This study aims to verify the efficacy of apomorphine for the recovery of consciousness in the first randomized placebo-controlled double-blind trial using multimodal measurement methods. The results will contribute to define the role of dopamine agonists in the treatment of this challenging population of patients and help identify the neural underpinnings underlying the modulation of consciousness networks by apomorphine. Notably, this trial is designed to bring objective neuroimaging and neurophysiological evidence to further assess the validity of the mesocircuit hypothesis and its modulation by pharmacological agents, which may open new therapeutic perspectives. Figure 1. Timeline of the study protocol. * : multimodal assessment; Blue segments: inpatient phase; Green segment: outpatient follow-up; CRS-R: Coma Recovery Scale – Revised; NCS-R: Nociception Coma Scale – Revised; EEG: electroencephalography; PET: positron emission tomography; MRI: magnetic resonance imaging; T°: body core temperature; GOS-E: Glasgow Outcome Scale – Extended; Red crosses: 24-hours EEG Figure 2. The mesocircuit hypothesis. (A) Normal wakeful condition. Dopamine neurons in the striatum inhibit the pallidum, which prevents it from inhibiting the thalamus. Thalamic projections activate cortical networks and get positive feedback in return. Excitatory inputs from both the cortex and the thalamus activate the striatum to maintain the loop. (B) Brain injury. Withdrawal of thalamostriatal and corticostriatal projections following widespread neuronal deafferentation leads to reduced activity of the striatum, resulting in an inhibition of thalamic activity and decreased cortical activation. (C) Postulated action of apomorphine (APO) on brain injury. The facilitating action of apomorphine on striatal dopamine neurons could substitute for the missing inputs and restore the inhibitory striatopallidal projections, thus freeing the thalamus and its output towards the cortex. Figure 1 Figure 2 Acknowledgements This work is supported by the University and University Hospital of Liege, the Belgian National Funds for Scientific Research (F.R.S-FNRS), the European Union’s Horizon 2020 Framework Programme for Research and Innovation under the Specific Grant Agreement No. 785907 (Human Brain Project SGA2) and NeuroHealing Pharmaceuticals Inc. L.R.D.S and N.L. are research fellow, A.T. and O.G. are post-doctoral fellow, and S.L. is research director at the F.R.S-FNRS. References Chatelle, C., Majerus, S., Whyte, J., Laureys, S., and Schnakers, C. (2012). A sensitive scale to assess nociceptive pain in patients with disorders of consciousness. J. Neurol. Neurosurg. Psychiatry 83, 1233–1237. doi:10.1136/jnnp-2012-302987. Cruse, D., Thibaut, A., Demertzi, A., Nantes, J. C., Bruno, M. A., Gosseries, O., et al. (2013). Actigraphy assessments of circadian sleep-wake cycles in the Vegetative and Minimally Conscious States. BMC Med. 11, 18. doi:10.1186/1741-7015-11-18. Engemann, D., Raimondo, F., King, J.-R., Jas, M., Gramfort, A., Dehaene, S., et al. (2015). Automated Measurement and Prediction of Consciousness in Vegetative and Minimally Conscious Patients. ICML Work. Stat. Mach. Learn. Neurosci. (Stamlins 2015). Available at: http://www.hal.inserm.fr/hal-01225254/. Fridman, E. A., Calvar, J., Bonetto, M., Gamzu, E., Krimchansky, B. Z., Meli, F., et al. (2009). Fast awakening from minimally conscious state with apomorphine. Brain Inj. 23, 172–177. doi:10.1080/02699050802649662. Fridman, E. A., Krimchansky, B. Z., Bonetto, M., Galperin, T., Gamzu, E. R., Leiguarda, R. C., et al. (2010). Continuous subcutaneous apomorphine for severe disorders of consciousness after traumatic brain injury. Brain Inj. 24, 636–641. doi:10.3109/02699051003610433. Giacino, J. T., Kalmar, K., and Whyte, J. (2004). The JFK Coma Recovery Scale-Revised: Measurement characteristics and diagnostic utility. Arch. Phys. Med. Rehabil. 85, 2020–2029. doi:10.1016/j.apmr.2004.02.033. Gosseries, O., Charland-Verville, V., Thonnard, M., Bodart, O., Laureys, S., and Demertzi, A. (2014). Amantadine, apomorphine and zolpidem in the treatment of disorders of consciousness. Curr. Pharm. Des. 20, 4167–84. doi:10.2174/13816128113196660654. Levin, H. S., Boake, C., Song, J., McCauley, S., Contant, C., Diaz-Marchan, P., et al. (2001). Validity and Sensitivity to Change of the Extended Glasgow Outcome Scale in Mild to Moderate Traumatic Brain Injury. J. Neurotrauma 18, 575–584. doi:10.1089/089771501750291819. Matsumoto, M., Sugama, J., Okuwa, M., Dai, M., Matsuo, J., and Sanada, H. (2013). Non-invasive monitoring of core body temperature rhythms over 72h in 10 bedridden elderly patients with disorders of consciousness in a Japanese hospital: A pilot study. Arch. Gerontol. Geriatr. 57, 428–432. doi:10.1016/j.archger.2013.05.009. Schiff, N. D. (2010a). Recovery of consciousness after brain injury: a mesocircuit hypothesis. Trends Neurosci. 33, 1–9. doi:10.1016/j.tins.2009.11.002. Schiff, N. D. (2010b). Recovery of consciousness after severe brain injury: The role of arousal regulation mechanisms and some speculation on the heart-brain interface. Cleve. Clin. J. Med. 77, 27–33. doi:10.3949/ccjm.77.s3.05. Schnakers, C., and Monti, M. M. (2017). Disorders of consciousness after severe brain injury. Curr. Opin. Neurol. 30, 573–579. doi:10.1097/WCO.0000000000000495. Keywords: disorders of consciousness, dopamine agonist, Apomorphine, minimally conscious state (MCS), unresponsive wakefulness syndrome (UWS), Randomized controlled trial (RCT) Conference: Belgian Brain Congress 2018 — Belgian Brain Council, LIEGE, Belgium, 19 Oct - 19 Oct, 2018. Presentation Type: e-posters Topic: NOVEL STRATEGIES FOR NEUROLOGICAL AND MENTAL DISORDERS: SCIENTIFIC BASIS AND VALUE FOR PATIENT-CENTERED CARE Citation: Sanz LR, Lejeune N, Thibaut A, Blandiaux S, Stender J, Farber N, Zafonte RD, Laureys S and Gosseries O (2019). Treating severely brain-injured patients with apomorphine: study protocol for a double blind randomized placebo-controlled trial using behavioral and neuroimaging assessments. Front. Neurosci. Conference Abstract: Belgian Brain Congress 2018 — Belgian Brain Council. doi: 10.3389/conf.fnins.2018.95.00065 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 28 Aug 2018; Published Online: 17 Jan 2019. * Correspondence: MD. Leandro R Sanz, Coma Science Group, University of Liège, Liège, Liège, 4000, Belgium, leandro.sanz@uliege.be Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Leandro R Sanz Nicolas Lejeune Aurore Thibaut Séverine Blandiaux Johan Stender Neal Farber Ross D Zafonte Steven Laureys Olivia Gosseries Google Leandro R Sanz Nicolas Lejeune Aurore Thibaut Séverine Blandiaux Johan Stender Neal Farber Ross D Zafonte Steven Laureys Olivia Gosseries Google Scholar Leandro R Sanz Nicolas Lejeune Aurore Thibaut Séverine Blandiaux Johan Stender Neal Farber Ross D Zafonte Steven Laureys Olivia Gosseries PubMed Leandro R Sanz Nicolas Lejeune Aurore Thibaut Séverine Blandiaux Johan Stender Neal Farber Ross D Zafonte Steven Laureys Olivia Gosseries Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

INTRODUCTION:Independent component analysis (ICA) has been extensively used for reducing task-free BOLD fMRI recordings into spatial maps and their associated time-courses. The spatially identified independent components can be considered as intrinsic connectivity networks (ICNs) of non-contiguous regions. To date, the spatial patterns of the networks have been analyzed with techniques developed for volumetric data. OBJECTIVE:Here, we detail a graph building technique that allows these ICNs to be analyzed with graph theory. METHODS:First, ICA was performed at the single-subject level in 15 healthy volunteers using a 3T MRI scanner. The identification of nine networks was performed by a multiple-template matching procedure and a subsequent component classification based on the network "neuronal" properties. Second, for each of the identified networks, the nodes were defined as 1,015 anatomically parcellated regions. Third, between-node functional connectivity was established by building edge weights for each networks. Group-level graph analysis was finally performed for each network and compared to the classical network. RESULTS:Network graph comparison between the classically constructed network and the nine networks showed significant differences in the auditory and visual medial networks with regard to the average degree and the number of edges, while the visual lateral network showed a significant difference in the small-worldness. CONCLUSIONS:This novel approach permits us to take advantage of the well-recognized power of ICA in BOLD signal decomposition and, at the same time, to make use of well-established graph measures to evaluate connectivity differences. Moreover, by providing a graph for each separate network, it can offer the possibility to extract graph measures in a specific way for each network. This increased specificity could be relevant for studying pathological brain activity or altered states of consciousness as induced by anesthesia or sleep, where specific networks are known to be altered in different strength.

Understanding loss of consciousness after brain injury poses a practical test for the field of consciousness research, with both clinical and ethical implications. We here discuss three major pathological disorders of consciousness; coma, the unresponsive wakefulness syndrome and the minimally conscious state, which together represent a lesion model for the investigation of human awareness. We review the anatomical and neurophysiological correlates of each condition, and discuss the current findings in context of several theoretical frameworks of consciousness.

Differentiation of the minimally conscious state (MCS) and the unresponsive wakefulness syndrome (UWS) is a persistent clinical challenge [1]. Based on positron emission tomography (PET) studies with [(18)F]-fluorodeoxyglucose (FDG) during sleep and anesthesia, the global cerebral metabolic rate of glucose has been proposed as an indicator of consciousness [2, 3]. Likewise, FDG-PET may contribute to the clinical diagnosis of disorders of consciousness (DOCs) [4, 5]. However, current methods are non-quantitative and have important drawbacks deriving from visually guided assessment of relative changes in brain metabolism [4]. We here used FDG-PET to measure resting state brain glucose metabolism in 131 DOC patients to identify objective quantitative metabolic indicators and predictors of awareness. Quantitation of images was performed by normalizing to extracerebral tissue. We show that 42% of normal cortical activity represents the minimal energetic requirement for the presence of conscious awareness. Overall, the cerebral metabolic rate accounted for the current level, or imminent return, of awareness in 94% of the patient population, suggesting a global energetic threshold effect, associated with the reemergence of consciousness after brain injury. Our data further revealed that regional variations relative to the global resting metabolic level reflect preservation of specific cognitive or sensory modules, such as vision and language comprehension. These findings provide a simple and objective metabolic marker of consciousness, which can readily be implemented clinically. The direct correlation between brain metabolism and behavior further suggests that DOCs can fundamentally be understood as pathological neuroenergetic conditions and provide a unifying physiological basis for these syndromes.

Our understanding of the mechanisms of loss and recovery of consciousness, following severe brain injury or during anesthesia, is changing rapidly. Recent neuroimaging studies have shown that patients with chronic disorders of consciousness and subjects undergoing general anesthesia present a complex dysfunctionality in the architecture of brain connectivity. At present, the global hallmark of impaired consciousness appears to be a multifaceted dysfunctional connectivity pattern with both within-network loss of connectivity in a widespread frontoparietal network and between-network hyperconnectivity involving other regions such as the insula and ventral tegmental area. Despite ongoing efforts, the mechanisms underlying the emergence of consciousness after severe brain injury are not thoroughly understood. Important questions remain unanswered: What triggers the connectivity impairment leading to disorders of consciousness? Why do some patients recover from coma, while others with apparently similar brain injuries do not? Understanding these mechanisms could lead to a better comprehension of brain function and, hopefully, lead to new therapeutic strategies in this challenging patient population.

Background Bedside clinical examinations can have high rates of misdiagnosis of unresponsive wakefulness syndrome (vegetative state) or minimally conscious state. The diagnostic and prognostic usefulness of neuroimaging-based approaches has not been established in a clinical setting. We did a validation study of two neuroimaging-based diagnostic methods: PET imaging and functional MRI (fMRI).Methods For this clinical validation study, we included patients referred to the University Hospital of Lige, Belgium, between January, 2008, and June, 2012, who were diagnosed by our unit with unresponsive wakefulness syndrome, locked-in syndrome, or minimally conscious state with traumatic or non-traumatic causes. We did repeated standardised clinical assessments with the Coma Recovery Scale-Revised (CRS-R), cerebral F-18 -fluorodeoxyglucose (FDG) PET, and fMRI during mental activation tasks. We calculated the diagnostic accuracy of both imaging methods with CRS-R diagnosis as reference. We assessed outcome after 12 months with the Glasgow Outcome Scale-Extended.Findings We included 41 patients with unresponsive wakefulness syndrome, four with locked-in syndrome, and 81 in a minimally conscious state (48=traumatic, 78=non-traumatic; 110=chronic, 16=subacute). F-18-FDG PET had high sensitivity for identification of patients in a minimally conscious state (93%, 95% CI 85-98) and high congruence (85%, 77-90) with behavioural CRS-R scores. The active fMRI method was less sensitive at diagnosis of a minimally conscious state (45%, 30-61) and had lower overall congruence with behavioural scores (63%, 51-73) than PET imaging. F-18-FDG PET correctly predicted outcome in 75 of 102 patients (74%, 64-81), and fMRI in 36 of 65 patients (56%, 43-67). 13 of 41 (32%) of the behaviourally unresponsive patients (ie, diagnosed as unresponsive with CRS-R) showed brain activity compatible with (minimal) consciousness (ie, activity associated with consciousness, but diminished compared with fully conscious individuals) on at least one neuroimaging test; 69% of these (9 of 13) patients subsequently recovered consciousness.Interpretation Cerebral F-18-FDG PET could be used to complement bedside examinations and predict long-term recovery of patients with unresponsive wakefulness syndrome. Active fMRI might also be useful for differential diagnosis, but seems to be less accurate.

In Parkinson's disease (PD) the demonstration of neuropathological disturbances in nigrostriatal and extranigral brain pathways using magnetic resonance imaging remains a challenge. Here, we applied a novel diffusion-weighted imaging approach—track density imaging (TDI). Twenty-seven non-demented Parkinson's patients (mean disease duration: 5 years, mean score on the Hoehn & Yahr scale = 1.5) were compared with 26 elderly controls matched for age, sex, and education level. Track density images were created by sampling each subject's spatially normalized fiber tracks in 1 mm isotropic intervals and counting the fibers that passed through each voxel. Whole-brain voxel-based analysis was performed and significance was assessed with permutation testing. Statistically significant increases in track density were found in the Parkinson's patients, relative to controls. Clusters were distributed in disease-relevant areas including motor, cognitive, and limbic networks. From the lower medulla to the diencephalon and striatum, clusters encompassed the known location of the locus coeruleus and pedunculopontine nucleus in the pons, and from the substantia nigra up to medial aspects of the posterior putamen, bilaterally. The results identified in brainstem and nigrostriatal pathways show a large overlap with the known distribution of neuropathological changes in non-demented PD patients. Our results also support an early involvement of limbic and cognitive networks in Parkinson's disease.

The differentiation of the vegetative or unresponsive wakefulness syndrome (VS/UWS) from the minimally conscious state (MCS) is an important clinical issue. The cerebral metabolic rate of glucose (CMRglc) declines when consciousness is lost, and may reveal the residual cognitive function of these patients. However, no quantitative comparisons of cerebral glucose metabolism in VS/UWS and MCS have yet been reported. We calculated the regional and whole-brain CMRglc of 41 patients in the states of VS/UWS ( n=14), MCS ( n=21) or emergence from MCS (EMCS, n=6), and healthy volunteers ( n=29). Global cortical CMRglc in VS/UWS and MCS averaged 42% and 55% of normal, respectively. Differences between VS/UWS and MCS were most pronounced in the frontoparietal cortex, at 42% and 60% of normal. In brainstem and thalamus, metabolism declined equally in the two conditions. In EMCS, metabolic rates were indistinguishable from those of MCS. Ordinal logistic regression predicted that patients are likely to emerge into MCS at CMRglc above 45% of normal. Receiver-operating characteristics showed that patients in MCS and VS/UWS can be differentiated with 82% accuracy, based on cortical metabolism. Together these results reveal a significant correlation between whole-brain energy metabolism and level of consciousness, suggesting that quantitative values of CMRglc reveal consciousness in severely brain-injured patients.