The challenge of controlling an auditory BCI in the case of severe motor disability.

BACKGROUND: The locked-in syndrome (LIS), due to a lesion in the pons, impedes communication. This situation can also be met after some severe brain injury or in advanced Amyotrophic Lateral Sclerosis (ALS). In the most severe condition, the persons cannot communicate at all because of a complete oculomotor paralysis (Complete LIS or CLIS). This even prevents the detection of consciousness. Some studies suggest that auditory brain-computer interface (BCI) could restore a communication through a « yes-no¼ code. METHODS: We developed an auditory EEG-based interface which makes use of voluntary modulations of attention, to restore a yes-no communication code in non-responding persons. This binary BCI uses repeated speech sounds (alternating "yes" on the right ear and "no" on the left ear) corresponding to either frequent (short) or rare (long) stimuli. Users are instructed to pay attention to the relevant stimuli only. We tested this BCI with 18 healthy subjects, and 7 people with severe motor disability (3 "classical" persons with locked-in syndrome and 4 persons with ALS). RESULTS: We report online BCI performance and offline event-related potential analysis. On average in healthy subjects, online BCI accuracy reached 86% based on 50 questions. Only one out of 18 subjects could not perform above chance level. Ten subjects had an accuracy above 90%. However, most patients could not produce online performance above chance level, except for two people with ALS who obtained 100% accuracy. We report individual event-related potentials and their modulation by attention. In addition to the classical P3b, we observed a signature of sustained attention on responses to frequent sounds, but in healthy subjects and patients with good BCI control only. CONCLUSIONS: Auditory BCI can be very well controlled by healthy subjects, but it is not a guarantee that it can be readily used by the target population of persons in LIS or CLIS. A conclusion that is supported by a few previous findings in BCI and should now trigger research to assess the reasons of such a gap in order to propose new and efficient solutions. CLINICAL TRIAL REGISTRATIONS: No. NCT02567201 (2015) and NCT03233282 (2013).

Infraclinical detection of voluntary attention in coma and post-coma patients using electrophysiology.

OBJECTIVE: Early functional evaluation and prognosis of patients with disorders of consciousness is a major challenge that clinical assessments alone cannot solve. Objective measures of brain activity could help resolve this uncertainty. We used electroencephalogram at bedside to detect voluntary attention with a paradigm previously validated in healthy subjects. METHODS: Using auditory-oddball sequences, our approach rests on detecting known attentional modulations of Event Related Potentials that reflect compliance with verbal instructions. Sixty-eight unresponsive patients were tested in their first year after coma onset (37 coma and 31 first year post-coma patients). Their evolution 6 months after the test was considered. RESULTS: Fourteen of the 68 patients, showed a positive response. Nine were in a coma and 5 in a minimally conscious state (MCS). Except for one who died early, all responders evolved to exit-MCS within 6 months (93%), while 35 (65%) among non-responders only. CONCLUSIONS: Among those patients for whom the outcome is highly uncertain, 21% responded positively to this simple but cognitively demanding test. Strikingly, some coma patients were among responders. SIGNIFICANCE: The proposed paradigm revealed cognitive-motor dissociation in some coma patients. This ability to sustain attention on demand predicted awakening within 6 months and represents an immediately useful information for relatives and caregivers.

Auditory attention alterations in migraine: A behavioral and MEG/EEG study.

OBJECTIVES: To evaluate alterations of top-down and/or bottom-up attention in migraine and their cortical underpinnings. METHODS: 19 migraineurs between attacks and 19 matched control participants performed a task evaluating jointly top-down and bottom-up attention, using visually-cued target sounds and unexpected task-irrelevant distracting sounds. Behavioral responses and magneto- and electro-encephalography signals were recorded. Event-related potentials and fields were processed and source reconstruction was applied to event-related fields. RESULTS: At the behavioral level, neither top-down nor bottom-up attentional processes appeared to be altered in migraine. However, migraineurs presented heightened evoked responses following distracting sounds (orienting component of the N1 and Re-Orienting Negativity, RON) and following target sounds (orienting component of the N1), concomitant to an increased recruitment of the right temporo-parietal junction. They also displayed an increased effect of the cue informational value on target processing resulting in the elicitation of a negative difference (Nd). CONCLUSIONS: Migraineurs appear to display increased bottom-up orienting response to all incoming sounds, and an enhanced recruitment of top-down attention. SIGNIFICANCE: The interictal state in migraine is characterized by an exacerbation of the orienting response to attended and unattended sounds. These attentional alterations might participate to the peculiar vulnerability of the migraine brain to all incoming stimuli.

The auditory oddball paradigm revised to improve bedside detection of consciousness in behaviorally unresponsive patients.

Active paradigms requiring subjects to engage in a mental task on request have been developed to detect consciousness in behaviorally unresponsive patients. Using auditory ERPs, the active condition consists in orienting patient's attention toward oddball stimuli. In comparison with passive listening, larger P300 in the active condition identifies voluntary processes. However, contrast between these two conditions is usually too weak to be detected at the individual level. To improve test sensitivity, we propose as a control condition to actively divert the subject's attention from the auditory stimuli with a mental imagery task that has been demonstrated to be within the grasp of the targeted patients: navigate in one's home. Twenty healthy subjects were presented with a two-tone oddball paradigm in the three following condition: (a) passive listening, (b) mental imagery, (c) silent counting of deviant stimuli. Mental imagery proved to be more efficient than passive listening to lessen P300 response to deviant tones as compared with the active counting condition. An effect of attention manipulation (oriented vs. diverted) was observed in 19/20 subjects, of whom 18 showed the expected P300 effect and 1 showed an effect restricted to the N2 component. The only subject showing no effect also proved insufficient engagement in the tasks. Our study demonstrated the efficiency of diverting attention using mental imagery to improve the sensitivity of the active oddball paradigm. Using recorded instructions and requiring a small number of electrodes, the test was designed to be conveniently and economically used at the patient's bedside.

Increased Evoked Potentials to Arousing Auditory Stimuli during Sleep: Implication for the Understanding of Dream Recall.

High dream recallers (HR) show a larger brain reactivity to auditory stimuli during wakefulness and sleep as compared to low dream recallers (LR) and also more intra-sleep wakefulness (ISW), but no other modification of the sleep macrostructure. To further understand the possible causal link between brain responses, ISW and dream recall, we investigated the sleep microstructure of HR and LR, and tested whether the amplitude of auditory evoked potentials (AEPs) was predictive of arousing reactions during sleep. Participants (18 HR, 18 LR) were presented with sounds during a whole night of sleep in the lab and polysomnographic data were recorded. Sleep microstructure (arousals, rapid eye movements (REMs), muscle twitches (MTs), spindles, KCs) was assessed using visual, semi-automatic and automatic validated methods. AEPs to arousing (awakenings or arousals) and non-arousing stimuli were subsequently computed. No between-group difference in the microstructure of sleep was found. In N2 sleep, auditory arousing stimuli elicited a larger parieto-occipital positivity and an increased late frontal negativity as compared to non-arousing stimuli. As compared to LR, HR showed more arousing stimuli and more long awakenings, regardless of the sleep stage but did not show more numerous or longer arousals. These results suggest that the amplitude of the brain response to stimuli during sleep determine subsequent awakening and that awakening duration (and not arousal) is the critical parameter for dream recall. Notably, our results led us to propose that the minimum necessary duration of an awakening during sleep for a successful encoding of dreams into long-term memory is approximately 2 min.

BCI in patients with disorders of consciousness: clinical perspectives.

The reestablishment of communication is one of the main goals for patients with disorders of consciousness (DOC). It is now established that many DOC patients retain the ability to process stimuli of varying complexity even in the absence of behavioural response. Motor impairment, fatigue, attention disorders might contribute to the difficulty of communication in this population. Brain-computer interfaces (BCI) might be helpful in restoring some communication ability in these patients. After a definition of the different disorders of consciousness that might benefit from BCI, brain markers able to detect cognitive processes and awareness in the absence of behavioural manifestation are described. Can these markers be willfully modulated and used to restore communication in DOC patients? In order to answer this question, three paradigmatic articles using either functional imaging or electrophysiology are critically analysed with regard to clinical applications. It appears that the use of fMRI is limited from a clinical point of view, whereas the EEG seems more feasible with possible BCI applications at the patient's bedside. However, at this stage, several limitations are pointed out: the lack of awareness in itself, the lack of sensitivity of the technique, atypical pattern of brain activity in brain damaged patients. The challenge is now to select the best candidates, to improve the efficiency, portability and cost of these techniques. Although this innovative technology may concern a minority of DOC patients, it might offer the possibility to restore or improve communication to heavily disabled patients and meanwhile detect a signature of awareness.

MMN and novelty P3 in coma and other altered states of consciousness: a review.

In recent decades, there has been a growing interest in the assessment of patients in altered states of consciousness. There is a need for accurate and early prediction of awakening and recovery from coma. Neurophysiological assessment of coma was once restricted to brainstem auditory and primary cortex somatosensory evoked potentials elicited in the 30 ms range, which have both shown good predictive value for poor coma outcome only. In this paper, we review how passive auditory oddball paradigms including deviant and novel sounds have proved their efficiency in assessing brain function at a higher level, without requiring the patient's active involvement, thus providing an enhanced tool for the prediction of coma outcome. The presence of an MMN in response to deviant stimuli highlights preserved automatic sensory memory processes. Recorded during coma, MMN has shown high specificity as a predictor of recovery of consciousness. The presence of a novelty P3 in response to the subject's own first name presented as a novel (rare) stimulus has shown a good correlation with coma awakening. There is now a growing interest in the search for markers of consciousness, if there are any, in unresponsive patients (chronic vegetative or minimally conscious states). We discuss the different ERP patterns observed in these patients. The presence of novelty P3, including parietal components and possibly followed by a late parietal positivity, raises the possibility that some awareness processes are at work in these unresponsive patients.

Attention orienting dysfunction with preserved automatic auditory change detection in migraine.

OBJECTIVE: To investigate automatic event-related potentials (ERPs) to an auditory change in migraine patients. METHODS: Auditory ERPs were recorded in 22 female patients suffering from menstrually-related migraine and in 20 age-matched control subjects, in three sessions: in the middle of the menstrual cycle, before and during menses. In each session, 200 trains of tone-bursts each including two duration deviants were presented in a passive listening condition. RESULTS: In all sessions, duration deviance elicited a mismatch negativity (MMN) showing no difference between the two groups. However, migraine patients showed an increased N1 orienting component to all incoming stimuli and a prolonged N2b to deviance. They also presented a different modulation of P3a amplitude along the menstrual cycle, which tended to normalise during migraine attacks. None of the studied ERP components showed a default of habituation. CONCLUSIONS: This passive paradigm highlighted increased automatic attention orienting to auditory changes but normal auditory sensory processing in migraineurs. SIGNIFICANCE: Our observations suggest normal auditory processing up to attention triggering but enhanced activation of attention-related frontal networks in migraineurs.

Brain reactivity differentiates subjects with high and low dream recall frequencies during both sleep and wakefulness.

The neurophysiological correlates of dreaming remain unclear. According to the "arousal-retrieval" model, dream encoding depends on intrasleep wakefulness. Consistent with this model, subjects with high and low dream recall frequency (DRF) report differences in intrasleep awakenings. This suggests a possible neurophysiological trait difference between the 2 groups. To test this hypothesis, we compared the brain reactivity (evoked potentials) of subjects with high (HR, N = 18) and low (LR, N = 18) DRF during wakefulness and sleep. During data acquisition, the subjects were presented with sounds to be ignored (first names randomly presented among pure tones) while they were watching a silent movie or sleeping. Brain responses to first names dramatically differed between the 2 groups during both sleep and wakefulness. During wakefulness, the attention-orienting brain response (P3a) and a late parietal response were larger in HR than in LR. During sleep, we also observed between-group differences at the latency of the P3a during N2 and at later latencies during all sleep stages. Our results demonstrate differences in the brain reactivity of HR and LR during both sleep and wakefulness. These results suggest that the ability to recall dreaming is associated with a particular cerebral functional organization, regardless of the state of vigilance.

Alpha reactivity to complex sounds differs during REM sleep and wakefulness.

We aimed at better understanding the brain mechanisms involved in the processing of alerting meaningful sounds during sleep, investigating alpha activity. During EEG acquisition, subjects were presented with a passive auditory oddball paradigm including rare complex sounds called Novels (the own first name - OWN, and an unfamiliar first name - OTHER) while they were watching a silent movie in the evening or sleeping at night. During the experimental night, the subjects' quality of sleep was generally preserved. During wakefulness, the decrease in alpha power (8-12 Hz) induced by Novels was significantly larger for OWN than for OTHER at parietal electrodes, between 600 and 900 ms after stimulus onset. Conversely, during REM sleep, Novels induced an increase in alpha power (from 0 to 1200 ms at all electrodes), significantly larger for OWN than for OTHER at several parietal electrodes between 700 and 1200 ms after stimulus onset. These results show that complex sounds have a different effect on the alpha power during wakefulness (decrease) and during REM sleep (increase) and that OWN induce a specific effect in these two states. The increased alpha power induced by Novels during REM sleep may 1) correspond to a short and transient increase in arousal; in this case, our study provides an objective measure of the greater arousing power of OWN over OTHER, 2) indicate a cortical inhibition associated with sleep protection. These results suggest that alpha modulation could participate in the selection of stimuli to be further processed during sleep.

Alpha reactivity to first names differs in subjects with high and low dream recall frequency.

Studies in cognitive psychology showed that personality (openness to experience, thin boundaries, absorption), creativity, nocturnal awakenings, and attitude toward dreams are significantly related to dream recall frequency (DRF). These results suggest the possibility of neurophysiological trait differences between subjects with high and low DRF. To test this hypothesis we compared sleep characteristics and alpha reactivity to sounds in subjects with high and low DRF using polysomnographic recordings and electroencephalography (EEG). We acquired EEG from 21 channels in 36 healthy subjects while they were presented with a passive auditory oddball paradigm (frequent standard tones, rare deviant tones and very rare first names) during wakefulness and sleep (intensity, 50 dB above the subject's hearing level). Subjects were selected as High-recallers (HR, DRF = 4.42 ± 0.25 SEM, dream recalls per week) and Low-recallers (LR, DRF = 0.25 ± 0.02) using a questionnaire and an interview on sleep and dream habits. Despite the disturbing setup, the subjects' quality of sleep was generally preserved. First names induced a more sustained decrease in alpha activity in HR than in LR at Pz (1000-1200 ms) during wakefulness, but no group difference was found in REM sleep. The current dominant hypothesis proposes that alpha rhythms would be involved in the active inhibition of the brain regions not involved in the ongoing brain operation. According to this hypothesis, a more sustained alpha decrease in HR would reflect a longer release of inhibition, suggesting a deeper processing of complex sounds than in LR during wakefulness. A possibility to explain the absence of group difference during sleep is that increase in alpha power in HR may have resulted in awakenings. Our results support this hypothesis since HR experienced more intra sleep wakefulness than LR (30 ± 4 vs. 14 ± 4 min). As a whole our results support the hypothesis of neurophysiological trait differences in high and low-recallers.

What is the specificity of the response to the own first-name when presented as a novel in a passive oddball paradigm? An ERP study.

One's own first-name is a special stimulus: one's attention is more likely captured by hearing one's own first-name than by hearing another first-name. Previous event-related potential (ERP) studies demonstrated that this special stimulus produces differential responses both in active and in passive condition. Such results suggest that passively hearing one's own first-name triggers processing levels generally activated by the explicit detection of stimuli. This questions about the particular power of the own first-name to automatically orient attention, but no study investigated the specific response to this special stimulus in a paradigm designed to study automatic attention orienting. In this ERP study, we compared the responses elicited by the own first-name (OWN) and one unfamiliar first-name (OTHER) presented, rarely, randomly and at the same frequency among repetitive tones (i.e., as novel stimuli in an oddball paradigm) while subjects (N=36) were watching a silent movie with subtitles. We tested at what latency the responses to OWN and OTHER diverge, and whether OWN modulates the brain orienting response (novelty P3). Data analysis showed specific responses to OWN after 300 ms. OWN only evoked a central negativity (320 ms) and a parietal positivity (550 ms). However, OWN had no significant effect on the brain orienting response (260 ms). Our results confirm that the own first-name does elicit a late specific brain response. However, they challenge the idea that in passive condition, the own first-name is systematically more powerful than another first-name to orient attention when it is heard unexpectedly.

Exacerbated attention orienting to auditory stimulation in migraine patients.

OBJECTIVE: To investigate long-term (LTH) and short-term (STH) habituation of auditory event-related potentials (ERPs) during a migraine cycle, using a classic habituation paradigm. METHODS: In 22 patients suffering from menstrually-related migraine and in 20 age-matched control subjects, auditory ERPs were recorded in 3 sessions: in the middle of the menstrual cycle, before menses, and during menses. In 12 patients, a migraine attack occurred during one of the peri-menses sessions. In each session, 200 trains of stimuli were presented, with an average of 10 stimuli per train. RESULTS: In response to the first stimuli of the trains, migraineurs exhibited in all sessions a larger orienting component of N1 than matched controls and a larger P3a in the interictal session, which normalized during attacks. They also showed a residual orienting component in response to the subsequent stimuli inside the trains. In contrast, the sensory component of N1 showed no difference between the two groups, with similar STH and LTH. CONCLUSIONS: Migraineurs show an exacerbated attention orienting to auditory stimulation, without any habituation deficit. SIGNIFICANCE: Previous migraine studies reported interictal habituation deficits of ERPs, but demonstrated in the auditory modality only in paradigms testing intensity dependence. Previous and current results can be interpreted as an increased attention orienting, possibly relying on an abnormal involvement of frontal cortex in auditory processing.

Event-related potentials (MMN and novelty P3) in permanent vegetative or minimally conscious states.

OBJECTIVE: To assess markers of cognition, if any, in patients in a permanent vegetative state (PVS). METHODS: Event-related potential (ERP) mapping was performed on 27 patients in permanent (4-261 months after coma onset) vegetative (PVS, n=16) or minimally conscious states (MCS, n=11) due to anoxia (n=18) or other aetiologies (n=9). Mismatch negativity (MMN) to duration-deviant tones and novelty P3 (nP3) to the subject's own name were recorded according to a paradigm previously validated in healthy volunteers and comatose patients. SEPs, MLAEPs and BAEPs were also recorded. RESULTS: MMN was present in 5/27 and nP3 in 7/27 patients. ERPs were not related to the time from coma onset and not different in MCS and in PVS. Normal SEPs and MLAEPs, and present nP3s were less frequent in anoxia than in other aetiologies. CONCLUSIONS: Irrespective of their clinical assessment, a few patients are likely to process sound deviance (MMN) or novelty (nP3), mainly when their state is not due to anoxia. SIGNIFICANCE: Some PVS patients may be able to put certain awareness marker processes to work. The diagnostic criteria for PVS or MCS, currently based on mere behaviour, should also include functional brain investigations, such as ERPs, related to the aetiology.

Novelty P3 elicited by the subject's own name in comatose patients.

OBJECTIVE: To assess patterns of novelty P3 elicited by the subject's own name (SON) in comatose patients and to compare SON novelty P3 prognostic value with that of mismatch negativity (MMN). METHODS: A passive oddball paradigm, previously validated in healthy subjects, including duration deviants and SON presented as a novel was applied in 50 severe comatose patients on average 20 days after coma onset. The outcome was assessed 3 months after coma onset. RESULTS: MMN to deviants was found in 14/50 patients and a central-parietal P3 to SON was found in 21/50 patients. In 12 patients, a parietal component (P3b) was also clearly present in the late part of P3. Four patients showed an MMN but no P3. Eleven patients had a novelty P3, with a late parietal component for 5 of them, but no MMN. The presence of a P3 was highly correlated with awakening. Compared to MMN, P3 showed as large a specificity for awakening (0.85). It showed a much higher sensitivity (0.71 versus 0.42). All but one patient with P3b woke up. CONCLUSIONS: The use of novelty P3 elicited by SON increases the prognostic value of MMN alone and improves the assessment of comatose patients by demonstrating the activation of higher-level cognitive functions in some of them. It shows that unconsciously perceived stimuli are processed and activate brain areas similarly to consciously perceived stimuli. SIGNIFICANCE: SON as a novel in an MMN design can be used to increase the prognostic value of ERPs in comatose patients and to assess unconscious cognitive processes in uncommunicative patients.

Odd sound processing in the sleeping brain.

How does the sleeping brain process external stimuli, and in particular, up to which extent does the sleeping brain detect and process modifications in its sensory environment? In order to address this issue, we investigated brain reactivity to simple auditory stimulations during sleep in young healthy subjects. Electroencephalogram signal was acquired continuously during a whole night of sleep while a classical oddball paradigm with duration deviance was applied. In all sleep stages, except Sleep Stage 4, a mismatch negativity (MMN) was unquestionably found in response to deviant tones, revealing for the first time preserved sensory memory processing during almost the whole night. Surprisingly, during Sleep Stage 2 and paradoxical sleep, both P3a-like and P3b-like components were identified after the MMN, whereas a P3a alone followed the MMN in wakefulness and in Sleep Stage 1. This totally new result suggests elaborated processing of external stimulation during sleep. We propose that the P3b-like response could be associated to an active processing of the deviant tone in the dream's consciousness.

Subject's own name as a novel in a MMN design: a combined ERP and PET study.

With a view to elaborating a clinical tool to assess cognitive functions in brain-damaged patients, we had previously displayed characteristic patterns of ERPs (32 electrodes) in awake healthy persons in response to their own name (SON) presented as a novel in a passive oddball paradigm. In the present combined ERP and PET study, in an attempt to identify brain correlates of duration MMN and response to SON uttered by a familiar (FV) or an unknown voice (NFV), we used a block design protocol as close as possible to the aforementioned SON protocol. ERP data showed robust duration MMN and novelty P3 in response to SON similar to our previous results. The PET technique did not allow true MMN generators to be disclosed, but blocks with duration deviants elicited an increase of activation in the right temporal pole as compared with the control condition with no deviants, supporting the hypothesis of right hemispheric dominance in early sound discrimination. For SON contrasts, robust cerebral blood flow activation present over temporal, frontal and parietal cortices, in the hippocampus and in the precuneus could be associated with speech, novelty and self-recognition processing. Familiar and unfamiliar voices activated the prefrontal cortex differently, suggesting different retrieval processes, although corresponding ERP responses could not be differentiated.

Separate neural processing of timbre dimensions in auditory sensory memory.

Timbre is a multidimensional perceptual attribute of complex tones that characterizes the identity of a sound source. Our study explores the representation in auditory sensory memory of three timbre dimensions (acoustically related to attack time, spectral centroid, and spectrum fine structure), using the mismatch negativity (MMN) component of the auditory event-related potential. MMN is elicited by a discriminable change in a sound sequence and reflects the detection of the discrepancy between the current stimulus and traces in auditory sensory memory. The stimuli used in the present study were carefully controlled synthetic tones. MMNs were recorded after changes along each of the three timbre dimensions and their combinations. Additivity of unidimensional MMNs and dipole modeling results suggest partially separate MMN generators for different timbre dimensions, reflecting their mainly separate processing in auditory sensory memory. The results expand to timbre dimensions a property of separation of the representation in sensory memory that has already been reported between basic perceptual attributes (pitch, loudness, duration, and location) of sound sources.

Brain responses to a subject's own name uttered by a familiar voice.

Hearing one's own first name automatically elicits a robust electrophysiological response, even in conditions of reduced consciousness like sleep. In a search for objective clues to superior cognitive functions in comatose patients, we looked for an optimal auditory stimulation paradigm mobilizing a large population of neurons. Our hypothesis was that wider ERPs would be obtained in response to the subject's own name (SON) when a familiar person uttered it. In 15 healthy awake volunteers, we tested a passive oddball paradigm with three different novels presented with the same probability (P = 0.02): SON uttered by a familiar voice (FV) or by an unknown voice (NFV) and a non-vocal stimulus (NV) which preserved most of the physical characteristics of SON FV. ERP (32 electrodes) and scalp current density (SCD) maps were analyzed. SON appeared to generate more robust responses related to involuntary attention switching (MMN/N2b, novelty P3) than NV. When uttered by a familiar person, the SON elicited larger response amplitudes in the late phase of novelty P3 (after 300 ms). Most important differences were found in the late slow waves where two components could be temporally and spatially dissociated. A larger parietal component for FV than for NFV suggested deeper high-level processing, even if the subjects were not required to explicitly differentiate or recognize the voices. This passive protocol could therefore provide a valuable tool for clinicians to test residual superior cognitive functions in uncooperative patients.