Altered brain dynamics index levels of arousal in complete locked-in syndrome.

Complete locked-in syndrome (CLIS) resulting from late-stage amyotrophic lateral sclerosis (ALS) is characterised by loss of motor function and eye movements. The absence of behavioural indicators of consciousness makes the search for neuronal correlates as possible biomarkers clinically and ethically urgent. EEG-based measures of brain dynamics such as power-law exponent (PLE) and Lempel-Ziv complexity (LZC) have been shown to have explanatory power for consciousness and may provide such neuronal indices for patients with CLIS. Here, we validated PLE and LZC (calculated in a dynamic way) as benchmarks of a wide range of arousal states across different reference states of consciousness (e.g., awake, sleep stages, ketamine, sevoflurane). We show a tendency toward high PLE and low LZC, with high intra-subject fluctuations and inter-subject variability in a cohort of CLIS patients with values graded along different arousal states as in our reference data sets. In conclusion, changes in brain dynamics indicate altered arousal in CLIS. Specifically, PLE and LZC are potentially relevant biomarkers to identify or diagnose the arousal level in CLIS and to determine the optimal time point for treatment, including communication attempts.

Spelling interface using intracortical signals in a completely locked-in patient enabled via auditory neurofeedback training.

Patients with amyotrophic lateral sclerosis (ALS) can lose all muscle-based routes of communication as motor neuron degeneration progresses, and ultimately, they may be left without any means of communication. While others have evaluated communication in people with remaining muscle control, to the best of our knowledge, it is not known whether neural-based communication remains possible in a completely locked-in state. Here, we implanted two 64 microelectrode arrays in the supplementary and primary motor cortex of a patient in a completely locked-in state with ALS. The patient modulated neural firing rates based on auditory feedback and he used this strategy to select letters one at a time to form words and phrases to communicate his needs and experiences. This case study provides evidence that brain-based volitional communication is possible even in a completely locked-in state.

Brain Computer Interfaces for Assisted Communication in Paralysis and Quality of Life.

The rapid evolution of Brain-Computer Interface (BCI) technology and the exponential growth of BCI literature during the past 20 years is a consequence of increasing computational power and the achievements of statistical learning theory and machine learning since the 1960s. Despite this rapid scientific progress, the range of successful clinical and societal applications remained limited, with some notable exceptions in the rehabilitation of chronic stroke and first steps towards BCI-based assisted verbal communication in paralysis. In this contribution, we focus on the effects of noninvasive and invasive BCI-based verbal communication on the quality of life (QoL) of patients with amyotrophic lateral sclerosis (ALS) in the locked-in state (LIS) and the completely locked-in state (CLIS). Despite a substantial lack of replicated scientific data, this paper complements the existing methodological knowledge and focuses future investigators' attention on (1) Social determinants of QoL and (2) Brain reorganization and behavior. While it is not documented in controlled studies that the good QoL in these patients is a consequence of BCI-based neurorehabilitation, the proposed determinants of QoL might become the theoretical background needed to develop clinically more useful BCI systems and to evaluate the effects of BCI-based communication on QoL for advanced ALS patients and other forms of severe paralysis.

Binary Semantic Classification Using Cortical Activation with Pavlovian-Conditioned Vestibular Responses in Healthy and Locked-In Individuals.

To develop a more reliable brain-computer interface (BCI) for patients in the completely locked-in state (CLIS), here we propose a Pavlovian conditioning paradigm using galvanic vestibular stimulation (GVS), which can induce a strong sensation of equilibrium distortion in individuals. We hypothesized that associating two different sensations caused by two-directional GVS with the thoughts of "yes" and "no" by individuals would enable us to emphasize the differences in brain activity associated with the thoughts of yes and no and hence help us better distinguish the two from electroencephalography (EEG). We tested this hypothesis with 11 healthy and 1 CLIS participant. Our results showed that, first, conditioning of GVS with the thoughts of yes and no is possible. And second, the classification of whether an individual is thinking "yes" or "no" is significantly improved after the conditioning, even in the absence of subsequent GVS stimulations. We observed average classification accuracy of 73.0% over 11 healthy individuals and 85.3% with the CLIS patient. These results suggest the establishment of GVS-based Pavlovian conditioning and its usability as a noninvasive BCI.

EEG power spectral density in locked-in and completely locked-in state patients: a longitudinal study.

Persons with their eye closed and without any means of communication is said to be in a completely locked-in state (CLIS) while when they could still open their eyes actively or passively and have some means of communication are said to be in locked-in state (LIS). Two patients in CLIS without any means of communication, and one patient in the transition from LIS to CLIS with means of communication, who have Amyotrophic Lateral Sclerosis were followed at a regular interval for more than 1 year. During each visit, resting-state EEG was recorded before the brain-computer interface (BCI) based communication sessions. The resting-state EEG of the patients was analyzed to elucidate the evolution of their EEG spectrum over time with the disease's progression to provide future BCI-research with the relevant information to classify changes in EEG evolution. Comparison of power spectral density (PSD) of these patients revealed a significant difference in the PSD's of patients in CLIS without any means of communication and the patient in the transition from LIS to CLIS with means of communication. The EEG of patients without any means of communication is devoid of alpha, beta, and higher frequencies than the patient in transition who still had means of communication. The results show that the change in the EEG frequency spectrum may serve as an indicator of the communication ability of such patients.

Neurophysiological aspects of the completely locked-in syndrome in patients with advanced amyotrophic lateral sclerosis.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) patients in completely locked-in syndrome (CLIS) are incapable of expressing themselves, and their state of consciousness and awareness is difficult to evaluate. Due to the complete paralysis included paralysis of eye muscles, any assessment of the perceptual and psychophysiological state can only be implemented in passive experimental paradigms with neurophysiological recordings. METHODS: Four patients in CLIS were investigated in several experiments including resting state, visual stimulation (eyes open vs eyes closed), auditory stimulation (modified local-global paradigm), somatosensory stimulation (electrical stimulation of the median nerve), and during sleep. RESULTS: All patients showed altered neurophysiological metrics, but a unique and common pattern could not be found between patients. However, slowing of the electroencephalography (EEG) and attenuation or absence of alpha wave activity was common in all patients. In two of the four patients, a slow dominant frequency emerged at 4 Hz with synchronized EEG at all channels. In the other two patients slowing of EEG appears less synchronized. EEGs between eyes open and eyes closed were significantly different in all patients. The dominant slow frequency during the day changes during slow-wave sleep (supposedly sleep stage 3) to even slower frequencies below 2 Hz. Somatosensory evoked potentials (SEPs) were absent or significantly altered in comparison to healthy subjects, similarly for auditory evoked potentials (AEPs). CONCLUSIONS: The heterogeneity of the results underscores the fact that no single neurophysiological index is available to assess psychophysiological states in unresponsive ALS patients in CLIS. This caveat may also be valid for the assessment of cognitive processes; a functioning BCI can be the solution. SIGNIFICANCE: Most of the studies of the neurophysiology of ALS patients focused on the early stage of the disease, and there are very few studies on the late stage when patients are completely paralyzed with no means of communication (i.e., CLIS). This study provides quantitative metrics of different neurophysiological aspects of these patients.

A dataset of EEG and EOG from an auditory EOG-based communication system for patients in locked-in state.

The dataset presented here contains recordings of electroencephalogram (EEG) and electrooculogram (EOG) from four advanced locked-in state (LIS) patients suffering from ALS (amyotrophic lateral sclerosis). These patients could no longer use commercial eye-trackers, but they could still move their eyes and used the remnant oculomotor activity to select letters to form words and sentences using a novel auditory communication system. Data were recorded from four patients during a variable range of visits (from 2 to 10), each visit comprised of 3.22 ± 1.21 days and consisted of 5.57 ± 2.61 sessions recorded per day. The patients performed a succession of different sessions, namely, Training, Feedback, Copy spelling, and Free spelling. The dataset provides an insight into the progression of ALS and presents a valuable opportunity to design and improve assistive and alternative communication technologies and brain-computer interfaces. It might also help redefine the course of progression in ALS, thereby improving clinical judgement and treatment.

Electroencephalography of completely locked-in state patients with amyotrophic lateral sclerosis.

Patients in completely locked-in state (CLIS) due to amyotrophic lateral sclerosis (ALS) lose the control of each and every muscle of their body rendering them motionless and without any means of communication. Though some studies have attempted to develop brain-computer interface (BCI)-based communication methods with CLIS patients, little information is available of the neuroelectric brain activity of CLIS patients. However, because of the difficulties with and often loss of communication, the neuroelectric signature may provide some indications of the state of consciousness in these patients. We recorded electroencephalography (EEG) signals from 10 CLIS patients during resting state and compared their power spectral densities with those of healthy participants in fronto-central, central, and centro-parietal channels. The results showed significant power reduction in the high alpha, beta, and gamma bands in CLIS patients, indicating the dominance of slower EEG frequencies in their oscillatory activity. This is the first study showing group-level EEG change of CLIS patients, though the reason for the observed EEG change cannot be concluded without any reliable communication methods with this population.

Neuropsychological and neurophysiological aspects of brain-computer-interface (BCI) control in paralysis.

Brain-computer interfaces (BCIs) aim to help paralysed patients to interact with their environment by controlling external devices using brain activity, thereby bypassing the dysfunctional motor system. Some neuronal disorders, such as amyotrophic lateral sclerosis (ALS), severely impair the communication capacity of patients. Several invasive and non-invasive brain-computer interfaces (BCIs), most notably using electroencephalography (EEG), have been developed to provide a means of communication to paralysed patients. However, except for a few reports, all available BCI literature for the paralysed (mostly ALS patients) describes patients with intact eye movement control, i.e. patients in a locked-in state (LIS) but not a completely locked-in state (CLIS). In this article we will discuss: (1) the fundamental neuropsychological learning factors and neurophysiological factors determining BCI performance in clinical applications; (2) the difference between LIS and CLIS; (3) recent development in BCIs for communication with patients in the completely locked-in state; (4) the effect of BCI-based communication on emotional well-being and quality of life; and (5) the outlook and the methodology needed to provide a means of communication for patients who have none. Thus, we present an overview of available studies and recent results and try to anticipate future developments which may open new doors for BCI communication with the completely paralysed.

Auditory Electrooculogram-based Communication System for ALS Patients in Transition from Locked-in to Complete Locked-in State.

Patients in the transition from locked-in (i.e., a state of almost complete paralysis with voluntary eye movement control, eye blinks or twitches of face muscles, and preserved consciousness) to complete locked-in state (i.e., total paralysis including paralysis of eye-muscles and loss of gaze-fixation, combined with preserved consciousness) are left without any means of communication. An auditory communication system based on electrooculogram (EOG) was developed to enable such patients to communicate. Four amyotrophic lateral sclerosis patients in transition from locked-in state to completely locked-in state, with ALSFRS-R score of 0, unable to use eye trackers for communication, learned to use an auditory EOG-based communication system. The patients, with eye-movement amplitude between the range of ±200µV and ±40µV, were able to form complete sentences and communicate independently and freely, selecting letters from an auditory speller system. A follow-up of one year with one patient shows the feasibility of the proposed system in long-term use and the correlation between speller performance and eye-movement decay. The results of the auditory speller system have the potential to provide a means of communication to patient populations without gaze fixation ability and with low eye-movement amplitude range.

Open Software/Hardware Platform for Human-Computer Interface Based on Electrooculography (EOG) Signal Classification.

Electrooculography (EOG) signals have been widely used in Human-Computer Interfaces (HCI). The HCI systems proposed in the literature make use of self-designed or closed environments, which restrict the number of potential users and applications. Here, we present a system for classifying four directions of eye movements employing EOG signals. The system is based on open source ecosystems, the Raspberry Pi single-board computer, the OpenBCI biosignal acquisition device, and an open-source python library. The designed system provides a cheap, compact, and easy to carry system that can be replicated or modified. We used Maximum, Minimum, and Median trial values as features to create a Support Vector Machine (SVM) classifier. A mean of 90% accuracy was obtained from 7 out of 10 subjects for online classification of Up, Down, Left, and Right movements. This classification system can be used as an input for an HCI, i.e., for assisted communication in paralyzed people.

Sleep in the completely locked-in state (CLIS) in amyotrophic lateral sclerosis.

Persons in the completely locked-in state (CLIS) suffering from amyotrophic lateral sclerosis (ALS) are deprived of many zeitgebers of the circadian rhythm: While cognitively intact, they are completely paralyzed, eyes mostly closed, with artificial ventilation and artificial nutrition, and social communication extremely restricted or absent. Polysomnographic recordings in eight patients in CLIS, however, revealed the presence of regular episodes of deep sleep during night time in all patients. It was also possible to distinguish an alpha-like state and a wake-like state. Classification of rapid eye movement (REM) sleep is difficult because of absent eye movements and absent muscular activity. Four out of eight patients did not show any sleep spindles. Those who have spindles also show K-complexes and thus regular phases of sleep stage 2. Thus, despite some irregularities, we found a surprisingly healthy sleep pattern in these patients.

Semantic and BCI-performance in completely paralyzed patients: Possibility of language attrition in completely locked in syndrome.

Patients with completely locked-in syndrome (CLIS) are incapable of any voluntary muscle movement and do not have any means of communication. Recently functional near infrared spectroscopy (fNIRS) based brain computer interface (BCI) has been successfully used to enable communication with these patients. The developed fNIRS-BCI system relies on the intactness of language comprehension in these patients in all dimensions of language. Interwoven language and motor cortex in brain, and lack of muscular activity in long run, can cause language attrition due to complete immobility in CLIS patients. In this study we have investigated effects of semantic content of sentences presented to a CLIS patient on the performance of the BCI system during a YES/NO paradigm. Comparison of communication success rate in BCI classification between different semantic categories indicate that semantic content of sentences presented to a CLIS patient can affect the BCI performance. Affected concepts are mostly associated with executive words. These findings can be beneficial towards development of more reliable communication device for patients in CLIS. In addition, these results may assist in elucidating the cognitive changes in completely paralyzed patients with the passage of time since the onset of total immovability.

Correction: Brain-Computer Interface-Based Communication in the Completely Locked-In State.

[This corrects the article DOI: 10.1371/journal.pbio.1002593.].

A 20-Questions-Based Binary Spelling Interface for Communication Systems.

Brain computer interfaces (BCIs) enables people with motor impairments to communicate using their brain signals by selecting letters and words from a screen. However, these spellers do not work for people in a complete locked-in state (CLIS). For these patients, a near infrared spectroscopy-based BCI has been developed, allowing them to reply to "yes"/"no" questions with a classification accuracy of 70%. Because of the non-optimal accuracy, a usual character-based speller for selecting letters or words cannot be used. In this paper, a novel spelling interface based on the popular 20-questions-game has been presented, which will allow patients to communicate using only "yes"/"no" answers, even in the presence of poor classification accuracy. The communication system is based on an artificial neural network (ANN) that estimates a statement thought by the patient asking less than 20 questions. The ANN has been tested in a web-based version with healthy participants and in offline simulations. Both results indicate that the proposed system can estimate a patient's imagined sentence with an accuracy that varies from 40%, in the case of a "yes"/"no" classification accuracy of 70%, and up to 100% in the best case. These results show that the proposed spelling interface could allow patients in CLIS to express their own thoughts, instead of only answer to "yes"/"no" questions.

Brain-Computer Interface-Based Communication in the Completely Locked-In State.

Despite partial success, communication has remained impossible for persons suffering from complete motor paralysis but intact cognitive and emotional processing, a state called complete locked-in state (CLIS). Based on a motor learning theoretical context and on the failure of neuroelectric brain-computer interface (BCI) communication attempts in CLIS, we here report BCI communication using functional near-infrared spectroscopy (fNIRS) and an implicit attentional processing procedure. Four patients suffering from advanced amyotrophic lateral sclerosis (ALS)-two of them in permanent CLIS and two entering the CLIS without reliable means of communication-learned to answer personal questions with known answers and open questions all requiring a "yes" or "no" thought using frontocentral oxygenation changes measured with fNIRS. Three patients completed more than 46 sessions spread over several weeks, and one patient (patient W) completed 20 sessions. Online fNIRS classification of personal questions with known answers and open questions using linear support vector machine (SVM) resulted in an above-chance-level correct response rate over 70%. Electroencephalographic oscillations and electrooculographic signals did not exceed the chance-level threshold for correct communication despite occasional differences between the physiological signals representing a "yes" or "no" response. However, electroencephalogram (EEG) changes in the theta-frequency band correlated with inferior communication performance, probably because of decreased vigilance and attention. If replicated with ALS patients in CLIS, these positive results could indicate the first step towards abolition of complete locked-in states, at least for ALS.

Brain-computer interfaces for communication and rehabilitation.

Brain-computer interfaces (BCIs) use brain activity to control external devices, thereby enabling severely disabled patients to interact with the environment. A variety of invasive and noninvasive techniques for controlling BCIs have been explored, most notably EEG, and more recently, near-infrared spectroscopy. Assistive BCIs are designed to enable paralyzed patients to communicate or control external robotic devices, such as prosthetics; rehabilitative BCIs are designed to facilitate recovery of neural function. In this Review, we provide an overview of the development of BCIs and the current technology available before discussing experimental and clinical studies of BCIs. We first consider the use of BCIs for communication in patients who are paralyzed, particularly those with locked-in syndrome or complete locked-in syndrome as a result of amyotrophic lateral sclerosis. We then discuss the use of BCIs for motor rehabilitation after severe stroke and spinal cord injury. We also describe the possible neurophysiological and learning mechanisms that underlie the clinical efficacy of BCIs.