Most of Clinically Unresponsive Patients Present Richer Brain Activity than Expected: Lessons from a Multimodal Neuroimaging Study

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.