BACKGROUND: Accurate evaluation of level of disorder of consciousness (DOC) is clinically challenging.
OBJECTIVE: This study aimed to establish a distinctive DOC-related pattern (DOCRP) for assessing disease severity and distinguishing unresponsive wakefulness syndrome (UWS) from minimally conscious state (MCS).
METHODS: Fifteen patients with DOC and eighteen health subjects with F-18-fluorodeoxyglucose (F-18-FDG) positron emission tomography (PET) were enrolled in this study. All patients were assessed by Coma Recovery Scale-Revised (CRS-R) and all individuals were randomly divided into two cohorts (Cohort A and B). DOCRP was identified in Cohort A and subsequently validated in Cohort B and A+B. We also assessed the discriminatory power of DOCRP between MCS and UWS.
RESULTS: The DOCRP was characterized bilaterally by relatively decreased metabolism in the medial and lateral frontal lobes, parieto-temporal lobes, cingulate gyrus and caudate, associated with relatively increased metabolism in the cerebellum and brainstem. DOCRP expression exhibited high accuracy in differentiating DOC patients from controls (P<0.0001, AUC=1.000), and furthermore could effectively distinguish MCS from UWS (P=0.037, AUC=0.821, sensitivity: 85.7 %, specificity: 75.0 %). Particularly in the subgroup of DOC patients survived global hypoxic-ischemic brain injury, DOCRP expression exhibited even better discriminatory power between MCS and UWS (P=0.046, AUC=1.000).
CONCLUSIONS: DOCRP might serve as an objective biomarker in distinguishing between UWS and MCS, especially in patients survived global hypoxic-ischemic brain injury.
BACKGROUND: ChiCTR2300073717 (Chinese clinical trial registry site, http://www.chictr.org).

Disorders of Consciousness (DoCs) after severe acquired brain injury involve substantial impairment of cognition and physical functioning, requiring comprehensive rehabilitation and support. Technological interventions, such as immersive Virtual Reality (VR), have shown promising results in promoting neural activity and enhancing cognitive and motor recovery. VR can induce physical sensations that may activate the Autonomic Nervous System (ANS) and induce ANS-regulated responses. This study aimed to investigate the effects of immersive VR on the ANS in patients with DoCs through the analysis of the electrodermal activity (EDA). EDA was measured with a wearable device during a single immersive VR session consisting of static and dynamic videos depicting naturalistic environments. A pilot case-control study was conducted with 12 healthy participants and 12 individuals with DoCs. Results showed higher EDA values in patients than in healthy participants (p = 0.035), suggesting stronger autonomic activation during immersive VR exposure, while healthy subjects, in turn, showed a decrease in EDA values. Our results revealed a significant interaction between conditions and groups (p = 0.003), with patients showing significantly increased EDA values from the baseline compared to dynamic video observation (p = 0.014) and final rest (p = 0.007). These results suggest that immersive VR can elicit sympathetic arousal in patients with DoCs. This study highlights the potential of immersive VR as a tool to strengthen autonomic responses in patients with impaired consciousness.

Ensuring a robust and reliable evaluation of coma deepness and prognostication of neurological outcome is challenging. We propose to develop PET neuroimaging as a new diagnostic and prognosis tool for comatose patients using a recently published methodology to perform functional PET (fPET). This exam permits the quantification of task-specific changes in neuronal metabolism in a single session. The aim of this protocol is to determine whether task-specific changes in glucose metabolism during the acute phase of coma are able to predict recovery at 18 months. Participation will be proposed for all patients coming for a standard PET-CT in our center in order to evaluate global cerebral metabolism during the comatose state. Legally appointed representative consent will be obtained to slightly modify the exam protocol: (1) 18F-fluorodeoxyglucose (18F-FDG) bolus plus continuous infusion instead of a simple bolus and (2) more time under camera to perform dynamic acquisition. Participants will undergo a 55-min fPET session with a 20% bolus + 80% infusion protocol. Two occurrences of three block (5-min rest, 10-min auditory stimulation and 10-min emotional auditory stimulation) will be performed after reaching equilibrium of FDG arterial concentration. We will compare the regional brain metabolism at rest and during the sessions of auditory and emotional auditory stimulation to search for a determinant of coma recovery (18 months of follow-up after the exam). Emotional auditory stimulation should induce an activation of: the auditory cortex, the consciousness areas and the neural circuitry for emotion (function to coma deepness). An activation analysis will be carried out to highlight regional brain activation using dedicated custom-made software based on Python statistical and image processing toolboxes. The association between activation levels and the Coma Recovery Scale-Revisited (CRS-R) will be assessed using multivariate analysis. If successful, the results from this study will help improve coma prognosis evaluation based on the pattern of neuronal metabolism at the onset of the pathology. The study protocol, rationale and methods are described in this paper.

Confirmation of the exact voluntary movements of patients with disorder of consciousness following severe traumatic brain injury (TBI) is difficult because of the associated communication disturbances. In this pilot study, we investigated whether regional brain glucose metabolism assessed by 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) at rest could predict voluntary movement in severe TBI patients, particularly those with sufficient upper limb capacity to use communication devices. We visually and verbally instructed patients to clasp or open their hands. After video capture, three independent rehabilitation therapists determined whether the patients\' movements were voluntary or involuntary. The results were compared with the standardized uptake value in the primary motor cortex, referring to the Penfield\'s homunculus, by resting state by FDG-PET imaged 1 year prior. Results showed that glucose uptake in the left (p = 0.0015) and right (p = 0.0121) proximal limb of the primary motor cortex, based on Penfield\'s homunculus on cerebral cartography, may reflect contralateral voluntary movement. Receiver operating characteristic curve analysis showed that a mean cutoff standardized uptake value of 5.47 ± 0.08 provided the best sensitivity and specificity for differentiating between voluntary and involuntary movements in each area. FDG-PET may be a useful and robust biomarker for predicting long-term recovery of motor function in severe TBI patients with disorders of consciousness.

UNASSIGNED: This study aimed to establish and validate a prediction model for clinical outcomes in patients with prolonged disorders of consciousness (pDOC).
UNASSIGNED: A total of 170 patients with pDOC enrolled in our rehabilitation unit were included and divided into training (n = 119) and validation sets (n = 51). Independent predictors for improved clinical outcomes were identified by univariate and multivariate logistic regression analyses, and a nomogram model was established. The nomogram performance was quantified using receiver operating curve (ROC) and calibration curves in the training and validated sets. A decision curve analysis (DCA) was performed to evaluate the clinical usefulness of this nomogram model.
UNASSIGNED: Univariate and multivariate logistic regression analyses indicated that age, diagnosis at entry, serum albumin (g/L), and pupillary reflex were the independent prognostic factors that were used to construct the nomogram. The area under the curve in the training and validation sets was 0.845 and 0.801, respectively. This nomogram model showed good calibration with good consistency between the actual and predicted probabilities of improved outcomes. The DCA demonstrated a higher net benefit in clinical decision-making compared to treating all or none.
UNASSIGNED: Several feasible, cost-effective prognostic variables that are widely available in hospitals can provide an efficient and accurate prediction model for improved clinical outcomes and support clinicians to offer suitable clinical care and decision-making to patients with pDOC and their family members.

UNASSIGNED: Spinal cord stimulation (SCS) can improve the level of awareness of prolonged disorder of consciousness (pDOC), but its application is restricted due to damage of invasive operation. Short-term spinal cord stimulation (st-SCS) in a minimally invasive manner will better balance the benefits and risks.
UNASSIGNED: This study focuses on the safety and efficacy of st-SCS for pDOC and reveals the modulation characteristics of different frequencies of SCS.
UNASSIGNED: 31 patients received 2-week st-SCS treatment and 3-months follow-up. All patients were divided into two types of frequency treatment groups of 5 Hz and 70 Hz according to the postoperative electroencephalography (EEG) test. The efficacy was assessed based on the revised coma recovery scale (CRS-R).
UNASSIGNED: The results showed a significant increase in CRS-R scores after treatment (Z = -3.668, p < 0.001) without significant adverse effects. Univariate analysis showed that the minimally conscious state minus (MCS-) benefits most from treatment. Furthermore, two frequency have a difference in the time-point of the CRS-R score increase. 5 Hz mainly showed a significant increase in CRS-R score at 2 weeks of treatment (p = 0.027), and 70 Hz additionally showed a delayed effect of a continued significant increase at 1 week after treatment (p = 0.004).
UNASSIGNED: st-SCS was safe and effective in improving patients with pDOC levels of consciousness, and was most effective for MCS-. Both 5 Hz and 70 Hz st-SCS can promote consciousness recovery, with 70 Hz showing a delayed effect in particular.

Due to improvements in medicine, the figures of patients with disorders of consciousness (DoC) are increasing. Diagnostics of DoC and prognostication of rehabilitation outcome is challenging but necessary to evaluate recovery potential and to decide on treatment options. Such decisions should be made by doctors and patients\' surrogates based on medico-ethical principles. Meeting information needs and communicating effectively with caregivers as the patients´ most common surrogate-decision makers is crucial, and challenging when novel tech-nologies are introduced. This qualitative study aims to explore information needs of informal DoC caregivers, how they manage the obtained information and their perceptions and experiences with caregiver-physician communication in facilities that implemented innovative neurodiagnostics studies. In 2021, we conducted semi-structured interviews with nine caregivers of clinically stable DoC patients in two rehabilitation centers in Italy and Germany. Participants were selected based on consecutive purposeful sampling. Caregivers were recruited at the facilities after written informed consent. All interviews were recorded, transcribed verbatim and translated. For analysis, we used reflexive thematic analysis according to Braun & Clarke (2006). Caregivers experienced the conversations emotionally, generally based on the value of the information provided. They reported to seek positive information, comfort and empathy with-in the communication of results of examinations. They needed detailed information to gain a deep understanding and a clear picture of their loved-one\'s condition. The results suggest a mismatch between the perspectives of caregivers and the perspectives of medical profession-als, and stress the need for more elaborate approaches to the communication of results of neu-rodiagnostics studies.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s12152-022-09503-0.

Significant anti-spike protein receptor-binding domain (S-RBD) antibody responses have been demonstrated in patients with chronic disorder of consciousness (DOC) completing a COVID-19 vaccine regime with BNT162b2 (Pfizer-BioNTech). We now provide further prospective data on the immunogenicity of these patients followed by heterologous booster injection with mRNA-1273 (Moderna). These patients were compared with two different demographically comparable healthcare workers (HCW) groups who underwent homologous booster injection with BNT162b2 vaccine or heterologous booster injection with mRNA-1273. Antibody responses were evaluated at 21 days after the administration of the booster dose of vaccination. Results: No severe adverse reactions were reported after each type of vaccination. Heterologous boosting with mRNA-1273 elicited a higher increase of S-RBD IgG levels than homologous boosting with BNT162b2 both in DOC patients and HCW who had previously received two doses of BNT162b2. No significant difference was detected between DOC and HCW patients who received heterologous boosting. Conclusions: Despite the small sample size, our preliminary results suggest that heterologous boosting with mRNA-1273, following initial vaccination with BNT162b2, is safe and tends to be more immunogenic than homologous boosting, either in fragile people or in healthy controls.

OBJECTIVE: In the last year, a large amount of research has investigated the anti-spike protein receptor-binding domain (S-RBD) antibody responses in patients at high risk of developing severe acute respiratory syndrome because of COVID-19 infection. However, no data are available on the chronic disorder of consciousness (DOC).
METHODS: Here, we evaluated anti-S-RBD IgG levels after vaccination in chronic DOC patients compared with demographically matched healthy controls (HC) by indirect chemiluminescence immunoassay. All individuals completed a two-dose-cycle vaccination with Pfizer mRNA vaccine (BNT162b2), and antibody responses were evaluated at 30 and 180 days after the administration of the second dose of vaccination.
RESULTS: We compared 32 DOC patients with 34 demographically matched healthy controls. Both DOC and HC groups showed a similar antibody response at 30 days, whereas at follow-up (180 days) DOC patients were characterized by lower S-RBD IgG levels with respect to controls. Additional multiple regression analyses including demographical and clinical comorbidities as predictors revealed that age was the only factor associated with the decrease in S-RBD IgG levels at follow-up (180 days). Elderly individuals of both groups were characterized by a reduction in the antibody responses with respect to younger individuals.
CONCLUSIONS: Our results show an efficacy seroconversion in DOC patients in the first period after vaccination, which significantly declines over time with respect to healthy controls.

Purpose: SARS-CoV-2 infection can cause the coronavirus disease (COVID), ranging from flu-like symptoms to interstitial pneumonia. Mortality is high in COVID pneumonia and it is the highest among the frailest. COVID could be particularly serious in patients with severe acquired brain injury (SABI), such as those with a disorder of consciousness. We here describe a cohort of patients with a disorder of consciousness exposed to SARS-CoV-2 early after their SABI.Materials and methods: The full cohort of 11 patients with SABI hospitalized in March 2020 in the IRCCS Fondazione Don Gnocchi rehabilitation (Milan, Italy) was recruited. Participants received SARS-CoV-2 testing and different clinical and laboratory data were collected.Results: Six patients contracted SARS-CoV-2 and four of them developed the COVID. Of these, one patient had ground-glass opacities on the chest CT scan, while the remaining three developed consolidations. No patient died and the overall respiratory involvement was mild, requiring in the worst cases low-flow oxygen.Conclusions: Here we report the clinical course of a cohort of patients with SABI exposed to SARS-CoV-2. The infection spread among patients and caused COVID in some of them. Unexpectedly, COVID was moderate, caused at most mild respiratory distress and did not result in fatalities.