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Objective: Clinical assessment of consciousness relies on behavioural assessments, which have several limitations. Hence, disorder of consciousness (DOC) patients are often misdiagnosed. In this work, we aimed to compare the repetitive assessment of consciousness performed with a clinical behavioural and a Brain-Computer Interface (BCI) approach., Materials and Methods: For 7 weeks, sixteen DOC patients participated in weekly evaluations using both the Coma Recovery Scale-Revised (CRS-R) and a vibrotactile P300 BCI paradigm. To use the BCI, patients had to perform an active mental task that required detecting specific stimuli while ignoring other stimuli. We analysed the reliability and the efficacy in the detection of command following resulting from the two methodologies., Results: Over repetitive administrations, the BCI paradigm detected command following before the CRS-R in seven patients. Four clinically unresponsive patients consistently showed command following during the BCI assessments., Conclusion: Brain-Computer Interface active paradigms might contribute to the evaluation of the level of consciousness, increasing the diagnostic precision of the clinical bedside approach., Significance: The integration of different diagnostic methods leads to a better knowledge and care for the DOC., Competing Interests: RS was a Marie Skłodowska-Curie fellow (H2020- MSCAIF- 2018- Project number: 841116) at g.tec Medical Engineering GmbH. RX and AH were g.tec Medical Engineering GmbH employees. CG was CEO of g.tec Medical Engineering GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Spataro, Xu, Xu, Mandalà, Allison, Ortner, Heilinger, La Bella and Guger.)

Mutations in Fused-in-Sarcoma (FUS) gene involving the nuclear localization signal (NLS) domain lead to juvenile-onset Amyotrophic Lateral Sclerosis (ALS). The mutant protein mislocalizes to the cytoplasm, incorporating it into Stress Granules (SG). Whether SGs are the first step to the formation of stable FUS-containing aggregates is still unclear. In this work, we used acute and chronic stress paradigms to study the SG dynamics in a human SH-SY5Y neuroblastoma cell line carrying a deletion of the NLS domain of the FUS protein (homozygous: ΔNLS -/- ; heterozygous: ΔNLS +/- ). Wild-type (WT) cells served as controls. We evaluated the subcellular localization of the mutant protein through immunoblot and immunofluorescence, in basal conditions and after acute stress and chronic stress with sodium arsenite (NaAsO 2 ). Cells were monitored for up to 24 h after rescue. FUS was expressed in both nucleus and cytoplasm in the ΔNLS +/- cells, whereas it was primarily cytoplasmic in the ΔNLS -/- . Acute NaAsO 2 exposure induced SGs: at rescue,>90% of ΔNLS cells showed abundant FUS-containing if compared to less than 5% of the WT cells. The proportion of FUS-positive SGs remained 15-20% at 24 h in mutant cells. Cycloheximide did not abolish the long-lasting SGs in mutant cells. Chronic exposure to NaAsO 2 did not induce significant SGs formation. A wealth of research has demonstrated that ALS-associated FUS mutations at the C-terminus facilitate the incorporation of the mutant protein into SGs. We have shown here that mutant FUS-containing SGs tend to fail to dissolve after stress, facilitating a liquid-to-solid phase transition. The FUS-containing inclusions seen in the dying motor neurons might therefore directly derive from SGs. This might represent an attractive target for future innovative therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Notaro, Messina and La Bella.)

Persons diagnosed with disorders of consciousness (DOC) typically suffer from motor and cognitive disabilities. Recent research has shown that non-invasive brain-computer interface (BCI) technology could help assess these patients' cognitive functions and command following abilities. 20 DOC patients participated in the study and performed 10 vibro-tactile P300 BCI sessions over 10 days with 8-12 runs each day. Vibrotactile tactors were placed on the each patient's left and right wrists and one foot. Patients were instructed, via earbuds, to concentrate and silently count vibrotactile pulses on either their left or right wrist that presented a target stimulus and to ignore the others. Changes of the BCI classification accuracy were investigated over the 10 days. In addition, the Coma Recovery Scale-Revised (CRS-R) score was measured before and after the 10 vibro-tactile P300 sessions. In the first run, 10 patients had a classification accuracy above chance level (>12.5%). In the best run, every patient reached an accuracy ≥60%. The grand average accuracy in the first session for all patients was 40%. In the best session, the grand average accuracy was 88% and the median accuracy across all sessions was 21%. The CRS-R scores compared before and after 10 VT3 sessions for all 20 patients, are showing significant improvement ( p = 0.024). Twelve of the twenty patients showed an improvement of 1 to 7 points in the CRS-R score after the VT3 BCI sessions (mean: 2.6). Six patients did not show a change of the CRS-R and two patients showed a decline in the score by 1 point. Every patient achieved at least 60% accuracy at least once, which indicates successful command following. This shows the importance of repeated measures when DOC patients are assessed. The improvement of the CRS-R score after the 10 VT3 sessions is an important issue for future experiments to test the possible therapeutic applications of vibro-tactile and related BCIs with a larger patient group., (Copyright © 2020 Murovec, Heilinger, Xu, Ortner, Spataro, La Bella, Miao, Jin, Chatelle, Laureys, Allison and Guger.)

Patients with locked-in syndrome (LIS) are typically unable to move or communicate and can be misdiagnosed as patients with disorders of consciousness (DOC). Behavioral assessment scales are limited in their ability to detect signs of consciousness in this population. Recent research has shown that brain-computer interface (BCI) technology could supplement behavioral scales and allows to establish communication with these severely disabled patients. In this study, we compared the vibro-tactile P300 based BCI performance in two groups of patients with LIS of different etiologies: stroke ( n = 6) and amyotrophic lateral sclerosis (ALS) ( n = 9). Two vibro-tactile paradigms were administered to the patients to assess conscious function and command following. The first paradigm is called vibrotactile evoked potentials (EPs) with two tactors (VT2), where two stimulators were placed on the patient's left and right wrist, respectively. The patients were asked to count the rare stimuli presented to one wrist to elicit a P300 complex to target stimuli only. In the second paradigm, namely vibrotactile EPs with three tactors (VT3), two stimulators were placed on the wrists as done in VT2, and one additional stimulator was placed on his/her back. The task was to count the rare stimuli presented to one wrist, to elicit the event-related potentials (ERPs). The VT3 paradigm could also be used for communication. For this purpose, the patient had to count the stimuli presented to the left hand to answer "yes" and to count the stimuli presented to the right hand to answer "no." All patients except one performed above chance level in at least one run in the VT2 paradigm. In the VT3 paradigm, all 6 stroke patients and 8/9 ALS patients showed at least one run above chance. Overall, patients achieved higher accuracies in VT2 than VT3. LIS patients due to ALS exhibited higher accuracies that LIS patients due to stroke, in both the VT2 and VT3 paradigms. These initial data suggest that controlling this type of BCI requires specific cognitive abilities that may be impaired in certain sub-groups of severely motor-impaired patients. Future studies on a larger cohort of patients are needed to better identify and understand the underlying cortical mechanisms of these differences.

Persons diagnosed with disorders of consciousness (DOC) typically suffer from motor disablities, and thus assessing their spared cognitive abilities can be difficult. Recent research from several groups has shown that non-invasive brain-computer interface (BCI) technology can provide assessments of these patients' cognitive function that can supplement information provided through conventional behavioral assessment methods. In rare cases, BCIs may provide a binary communication mechanism. Here, we present results from a vibrotactile BCI assessment aiming at detecting command-following and communication in 12 unresponsive wakefulness syndrome (UWS) patients. Two different paradigms were administered at least once for every patient: (i) VT2 with two vibro-tactile stimulators fixed on the patient's left and right wrists and (ii) VT3 with three vibro-tactile stimulators fixed on both wrists and on the back. The patients were instructed to mentally count either the stimuli on the left or right wrist, which may elicit a robust P300 for the target wrist only. The EEG data from -100 to +600 ms around each stimulus were extracted and sub-divided into 8 data segments. This data was classified with linear discriminant analysis (using a 10 × 10 cross validation) and used to calibrate a BCI to assess command following and YES/NO communication abilities. The grand average VT2 accuracy across all patients was 38.3%, and the VT3 accuracy was 26.3%. Two patients achieved VT3 accuracy ≥80% and went through communication testing. One of these patients answered 4 out of 5 questions correctly in session 1, whereas the other patient answered 6/10 and 7/10 questions correctly in sessions 2 and 4. In 6 other patients, the VT2 or VT3 accuracy was above the significance threshold of 23% for at least one run, while in 4 patients, the accuracy was always below this threshold. The study highlights the importance of repeating EEG assessments to increase the chance of detecting command-following in patients with severe brain injury. Furthermore, the study shows that BCI technology can test command following in chronic UWS patients and can allow some of these patients to answer YES/NO questions.

Many patients with locked-in syndrome (LIS) or complete locked-in syndrome (CLIS) also need brain-computer interface (BCI) platforms that do not rely on visual stimuli and are easy to use. We investigate command following and communication functions of mindBEAGLE with 9 LIS, 3 CLIS patients and three healthy controls. This tests were done with vibro-tactile stimulation with 2 or 3 stimulators (VT2 and VT3 mode) and with motor imagery (MI) paradigms. In VT2 the stimulators are fixed on the left and right wrist and the participant has the task to count the stimuli on the target hand in order to elicit a P300 response. In VT3 mode an additional stimulator is placed as a distractor on the shoulder and the participant is counting stimuli either on the right or left hand. In motor imagery mode the participant is instructed to imagine left or right hand movement. VT3 and MI also allow the participant to answer yes and no questions. Healthy controls achieved a mean assessment accuracy of 100% in VT2, 93% in VT3, and 73% in MI modes. They were able to communicate with VT3 (86.7%) and MI (83.3%) after 2 training runs. The patients achieved a mean accuracy of 76.6% in VT2, 63.1% in VT3, and 58.2% in MI modes after 1-2 training runs. 9 out of 12 LIS patients could communicate by using the vibro-tactile P300 paradigms (answered on average 8 out of 10 questions correctly) and 3 out of 12 could communicate with the motor imagery paradigm (answered correctly 4,7 out of 5 questions). 2 out of the 3 CLIS patients could use the system to communicate with VT3 (90 and 70% accuracy). The results show that paradigms based on non-visual evoked potentials and motor imagery can be effective for these users. It is also the first study that showed EEG-based BCI communication with CLIS patients and was able to bring 9 out of 12 patients to communicate with higher accuracies than reported before. More importantly this was achieved within less than 15-20 min.

Locked-in Amyotrophic Lateral Sclerosis (ALS) patients are fully dependent on caregivers for any daily need. At this stage, basic communication and environmental control may not be possible even with commonly used augmentative and alternative communication devices. Brain Computer Interface (BCI) technology allows users to modulate brain activity for communication and control of machines and devices, without requiring a motor control. In the last several years, numerous articles have described how persons with ALS could effectively use BCIs for different goals, usually spelling. In the present study, locked-in ALS patients used a BCI system to directly control the humanoid robot NAO (Aldebaran Robotics, France) with the aim of reaching and grasping a glass of water. Four ALS patients and four healthy controls were recruited and trained to operate this humanoid robot through a P300-based BCI. A few minutes training was sufficient to efficiently operate the system in different environments. Three out of the four ALS patients and all controls successfully performed the task with a high level of accuracy. These results suggest that BCI-operated robots can be used by locked-in ALS patients as an artificial alter-ego, the machine being able to move, speak and act in his/her place.