Basic discriminative and semantic processing in patients in the vegetative and minimally conscious state

    Basic discriminative and semantic processing in patients in the vegetative and minimally conscious state Helena Erlbeck, Ruben G.L. Real, Boris Kotchoubey, Donatella Mattia, Jakob Bargak, Andrea K¨ubler PII: DOI: Reference:

S0167-8760(16)30908-4 doi: 10.1016/j.ijpsycho.2016.12.012 INTPSY 11219

To appear in:

International Journal of Psychophysiology

Received date: Revised date: Accepted date:

21 July 2016 3 December 2016 28 December 2016

Please cite this article as: Erlbeck, Helena, Real, Ruben G.L., Kotchoubey, Boris, Mattia, Donatella, Bargak, Jakob, K¨ ubler, Andrea, Basic discriminative and semantic processing in patients in the vegetative and minimally conscious state, International Journal of Psychophysiology (2016), doi: 10.1016/j.ijpsycho.2016.12.012

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Basic discriminative and semantic processing in patients in the vegetative and minimally conscious state

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Erlbeck, Helena1, Real, Ruben G. L.1,5, Kotchoubey, Boris2, Mattia, Donatella3, Bargak, Jakob4, & Kübler, Andrea1 University of Würzburg, Institute of Psychology, Marcusstraße 9-11, 97070 Würzburg, Germany 2 University of Tübingen, Institute of Medical Psychology and Behavioral Neurobiology, Otfried-Müller-Straße 25, 72076 Tübingen, Germany 3 Neuroelectrical Imaging and BCI Laboratory, IRCCS, Fondazione Santa Lucia, Via Ardeatina, 306, 00142 Rome, Italy 4 Clinic for Intensive Care, Wieseneckstraße 24, 90571 Schwaig bei Nürnberg, Germany 5 Georg-August-University, Institute of Medical Psychology and Medical Sociology, Waldweg 37, 37073 Göttingen, Germany

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Email

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Erlbeck, Helena – [email protected] Real, Ruben G. L. – [email protected] Kotchoubey, Boris – [email protected] Mattia, Donatella – [email protected] Bargak, Jakob – [email protected] Kübler, Andrea – [email protected]

Correspondence should be addressed to: Andrea Kübler University of Würzburg, Institute of Psychology Marcusstraße 9-11 Würzburg, Germany Phone: +49 931 31-80179 Fax: +49 931 31-87059 E-mail: [email protected]

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1 Abstract Patients who survive injuries to the brain following accidents or diseases often acquire a

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disorder of consciousness (DOC). Assessment of the state of consciousness in these patients is difficult since they are usually incapable of reproducible motor movements. The application

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of event-related potentials (ERP) recorded via EEG constitutes one promising approach to complement the assessment of cognitive functions in DOC patients. For these assessments, a

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hierarchical approach was suggested which means that paradigms aiming at higher order ERPs are only presented if early responses were found. In this study, 19 behaviorally unre-

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sponsive or low-responsive DOC patients were presented with three auditory paradigms using passive instructions. The paradigms aimed at eliciting the Mismatch Negativity (MMN) and

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N400 and were applied at two time points. One oddball paradigm (MMN) and two semantic

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paradigms (word-pairs: N400 Words; sentences: N400 Sentences) were included. The majori-

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ty of patients (n=15) did not show any response to the stimulation. In the MMN paradigm, an MMN was identified in two patients, in the N400 Words paradigm, only an N1 was identified in one patient, and in the N400 Sentences paradigm, a late positive complex (LPC) was identi-

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fied in two patients. These data contradict the hierarchical approach since the LPC was identified in patients who did not exhibit an MMN. They further support the notion that even higher information processing as addressed with the N400 paradigms is preserved in a minority of DOC patients. Thus, in this sample, around 10% of the DOC patients exhibited indicators of preserved consciousness.

Key words: Event-related potentials, disorders of consciousness, vegetative state, minimally conscious state, Mismatch Negativity, N400

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2 Introduction In the past decades, medical progress has led to an increasing number of survivals after

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traumatic and hypoxic brain injuries following accidents, stroke or cardio-vascular diseases. However, some surviving patients remain in altered states of consciousness and are often in-

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capable of communication that is usually based on muscular activity. Estimating the level of consciousness in these patients is difficult and is further impeded by a lack of standardized

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methods independent of behavioral responses. The use of event-related potentials (ERP) measured by EEG is one promising tool to complement the clinical assessment of cognitive

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functions associated with attention and consciousness (Kotchoubey, 2015; Sitt et al., 2014). Albeit being often low or non-responsive in terms of behavioral reactions, patients with

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disorders of consciousness (DOC) can exhibit various levels of consciousness. DOC encom-

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pass the minimally conscious state (MCS, Giacino et al., 2002), the vegetative state (VS, Jen-

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nett & Plum, 1972), coma, and brain death (Bernat, 2006). The present study focuses on MCS and VS patients. VS is defined as wakefulness without awareness meaning that these patients show signs of wakefulness like sleep-wake-cycles including phases of eye-opening but are

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still assumed to be unaware of themselves and their environment (Jennett & Plum, 1972). VS patients exhibit reflex movements to touch, pain, bright light, or noise. However, no reproducible reactions following commands can be observed (Laureys et al., 2010). In contrast, MCS patients do show signs of awareness such as reproducible reactions, gaze following, or yes/no gestures (Bernat, 2006). However, these behaviors are inconsistent and may occur on some days, but not on others. Thus, diagnosis of MCS is especially difficult and largely depends on the current status of the patient. A medical condition that can easily be confused with DOC is the locked-in state (LIS). Like patients in VS, LIS patients are unable to move or speak, but are consciously aware of 3

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themselves and their environment (Smith & Delargy, 2005). LIS patients can be completely locked-in with no means of communication but full awareness, or incompletely locked-in with

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preserved movements, such as eye gaze or single fingers (Smith & Delargy, 2005). Thus, LIS patients can easily be misdiagnosed as VS or MCS or even comatose if only judged by their

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behavioral responses.

However, the differentiation between LIS and VS or MCS is not the only difficulty.

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Numerous studies have provided evidence for different degrees of awareness also in VS patients (i.e. Daltrozzo, 2006; Kotchoubey et al., 2005; Menon et al., 1998; Owen et al., 2006).

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The patients assessed in these studies showed preserved cognitive functioning in response to auditory stimulation that could, in some cases, also indicate preserved consciousness. Thus,

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patients diagnosed with these DOC are not necessarily completely unaware of their environ-

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ment. High rates of misdiagnosis of patients in VS have been published repeatedly (i.e. An-

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drews, Murphy, Munday, & Littlewood, 1996; Schnakers et al., 2009). In addition, DOC patients do not remain in a constant state of consciousness for an unlimited time but experience eminent fluctuation of vigilance (Bernat, 2006). Thus, patients may be able to follow com-

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mands on one day, but not on others, complicating a correct diagnosis. Two candidate ERPs for the assessment of the level of consciousness in DOC patients are the Mismatch Negativity (MMN) and the N400. The MMN belongs to a group of ERPs referred to as N200 (Sutton, Braren, Zubin, & John, 1965). MMN is associated with automatic processing irrespective of attention and is typically elicited in an oddball paradigm comprising one stimulus which occurs frequently (standard), and one that differs from this standard and occurs rarely and unpredictably (deviant). In the auditory domain, an MMN appears in response to deviants that vary in one or more stimulus features such as frequency, intensity, duration, or location (for a review, see Näätänen, Paavilainen, Rinne, & Alho, 2007). The MMN 4

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occurs in a latency range of 100-250 ms after deviant onset and is quantified by subtracting the ERP response elicited by the standards from that elicited by the deviants (Duncan et al.,

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2009).

The N400 occurs as slow monophasic negativity between 200 and 600 ms and is mainly

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regarded as a specific response to violations of semantic expectations (Kutas & Hillyard, 1980). It occurs in response to congruent versus incongruent sentence endings (Kutas, 1987;

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Kutas & Hillyard, 1984), and related versus unrelated word-pairs (Bentin, McCarthy, & Wood, 1985; Hagoort, Brown, & Swaab, 1996), as well as to line drawings completing a sen-

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tence (Ganis, Kutas, & Sereno, 1996), incongruent endings of picture stories (West & Holcomb, 2002), and inappropriate objects in video films (Sitnikova, Kuperberg, & Holcomb,

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2003).

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The existence of MMN or N400 in DOC patients indicates residual information pro-

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cessing and the ability to discriminate between different stimuli: An MMN indicates the preserved automated recognition of deviant stimuli based on traces in sensory memory, thus representing basic processes. The existence of an N400 is a sign for complex, but partially auto-

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mated linguistic information processing (Risetti et al., 2013). Elicitation of these components might be caused by preserved networks of a functional metabolism in the brain (Schiff et al., 2002). Previous studies indicated that the presence of an MMN or N400 may indicate future awakening from coma and VS (Daltrozzo, Wioland, Mutschler, & Kotchoubey, 2007; Faran, Vatine, Lazary, Birbaumer, & Kotchoubey, 2006; Fischer, Luaute, Adeleine, & Morlet, 2004; Steppacher et al., 2013; Wijnen, van Boxtel, Eilander, & Gelder, 2007). N400 effects have been found to indicate preserved semantic processing in some DOC patients (Kotchoubey et al., 2005; Schoenle & Witzke, 2004).

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In comparison to healthy participants, persons with closed head injuries have reduced N200 amplitudes, both visually and auditorily (Duncan, Kosmidis, & Mirsky, 2005). Other

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studies, however, found no differences in auditory N200 between healthy participants and patients with mild brain injuries (Potter, Bassett, Jory, & Barrett, 2001; Sivák et al., 2008).

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Smaller auditory N400 amplitudes were found in patients with traumatic brain injuries as compared to healthy persons (Knuepffer, Murdoch, Lloyd, Lewis, & Hinchliffe, 2012). Also

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Münte and Heinze (1994) reported diminished and delayed auditory N400 responses after closed head injury. In their study, a clear N400 component was only identifiable in response

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to sentences, but not to word-primes, thus, indicating a potential benefit of sentence based stimulus material.

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As a consequence, albeit playing an important role in the assessment of DOC patients,

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ERPs are often altered following injuries of the brain. Diminished amplitudes and prolonged

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latencies can complicate the identification of the relevant deflections, thus fostering the need for a comparison of ERPs within patients across different paradigms. ERPs have long been discussed for their general benefit in the assessment of cognitive

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functioning in DOC patients, complementing a mere behavioral assessment. However, measurements in clinical environments are subject to several constraints, like limited attention span of the patient and limited time available for testing. Thus, a hierarchical approach for those investigations was proposed. According to this approach, the presence of simple processing mechanisms such as the N1-P2 complex is a prerequisite for more complex processes and later components like MMN and P300 as well as responses to semantic material such as N400 and P600, finally presupposing volitional decisions (Kotchoubey et al., 2005; Owen et al., 2005; Owen et al., 2006). Following this approach, recordings using complex paradigms could be skipped if no ERPs emerged in reaction to simple stimuli. Kübler and Kotchoubey 6

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(2007) suggested a five steps procedure: (1) recording of resting state EEG and auditory evoked potentials to rule out the possibility of hearing loss, (2) stimulation using passive par-

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adigms aiming at the elicitation of MMN/P300 (oddball) and N400/P600 (semantic material), (3) stimulation with the same paradigms as in (2) with the additional task to specifically con-

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centrate on certain stimuli, i.e. counting the odds, (4) volitional tasks, i.e. imagination of movements according to certain stimuli, and (5) decision making using brain-computer inter-

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faces (BCI), i.e. answering yes/no questions.

In essence, the hierarchical approach postulates a procedure starting with paradigms to

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ensure intact hearing, slowly proceeding to more complex stimulation and terminating with the attempt to establish communication through conscious decision between different options.

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Following this procedure can save time and resources but presumes the absence of higher or-

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der information processing if no signs of simple discrimination abilities can be found. In a re-

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cent study, Rohaut and colleagues (2015) found patterns supporting this theory: The late ERP components LPC and the global effect were only found in patients who had also exhibited intact P1 and MMN responses. The global effect describes the ability to recognize global regu-

al., 2009).

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larities within a longer series of tones consisting of standards and deviants (Bekinschtein et

To further establish ERPs as a means to better determine the state of consciousness in nonresponsive patients diagnosed with VS or MCS, we investigated the MMN and N400 to answer the following questions: Firstly, how many patients in VS or MCS show the respective ERPs in general? Secondly, does the pattern of arising ERPs follow the hierarchical approach, thus, do all patients exhibiting an N400 also present with an MMN? Thirdly, is there a connection between behavioral measures and emerging ERPs? Fourthly, do the paradigms differ in their potential to elicit the respective components? 7

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It is predicted that at least some patients in VS and MCS show ERPs in response to auditory stimulation (Kotchoubey et al., 2005). Further, ERPs are expected to be altered in their

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physiology, i.e. latency and polarity (Perrin et al., 2006; Pokorny et al., 2013a).

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3 Methods and Materials

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3.1 Participants

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EEG was recorded in 19 behaviorally unresponsive or low-responsive DOC patients (11

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males) at the Clinic for Intensive Care in Schwaig and Hersbruck in Bavaria/Germany. The patients were between 31 and 69 years of age (M = 50.74, SD = 13.75 years) and all meas-

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urements were carried out at bedside. The interval between the incident and the measurement was between 3 and 141 months (M = 72.32, SD = 39.81 months). Written informed consent

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was provided by the legal representatives of the patients after they were informed about the study. Sixteen patients were examined twice within an interval of two to eight weeks (t1 and

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t2). A second measurement was undertaken whenever possible to account for potential shifts

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in arousal and awareness. The remaining three could not be visited a second time because their health status had declined. Immediately before each measurement, the Coma Recovery

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Scale revised (CRS-R; Giacino, Kalmar, & Whyte, 2004) was used for behavioral assessment of the state of consciousness. Thirteen patients were diagnosed with VS. Three patients exhib-

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ited signs for MCS in at least one measurement and three more patients attained the level of exit MCS in at least one measurement. Important demographic data and the exact diagnosis at each time of measurement are listed in Table 1. The study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethical Review Board of the Medical Faculty, University of Würzburg.

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3.2 Experimental procedure and stimuli The experiment comprised three paradigms that were named according to the ERP they

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aimed at eliciting: MMN, N400 Words, and N400 Sentences (Erlbeck, Kübler, Kotchoubey, & Veser, 2014). The MMN paradigm comprised 1000 three-component harmonic sounds of

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440+880+1760 Hz, with 900 standard stimuli with a duration of 50 ms and 100 deviant stimuli with a duration of 20 ms and fall/rise time of 5 ms. The stimulus onset asynchrony (SOA)

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between the onset of two successive tones was 350 ms. The first five tones were always standards and a deviant was always followed by a standard.

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The N400 Words paradigm comprised 100 semantically related (mountain-valley) and 100 semantically unrelated word-pairs (place-bravery), resulting in 400 words altogether. The

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inter-stimulus interval (ISI) was 300 ms within and 1200 ms between the word-pairs. The

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word-pairs were defined in a pre-experiment in which 45 healthy participants rated the rela-

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tion of various word-pairs. Only related word-pairs with a prime strength above 90% and unrelated word-pairs with a prime strength below 10% were selected for the resulting paradigm. The same words were used for the related and unrelated condition, such that each word was

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presented twice.

The N400 Sentences paradigm comprised 200 short sentences of which 100 ended with a correct word (e.g., “The eel is a fish.”) and 100 with a factually incorrect word (e.g., “The eel is a bird.”). The ISI between the sentences was 1200 ms. The sentences were selected in the same pre-experiment as the word-pairs. The participants rated the sentences as correct or incorrect and only sentences which were rated with a certainty above 90% were included. All correct end words also appeared as incorrect end words. All stimuli were spoken by a young female German native speaker with a clear voice free of any dialect inflexion. All sounds in

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the semantic paradigms had a sampling rate of 44.1 kHz, a resolution of 32 bits and were presented at a sound level of 70 dB.

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Each paradigm was presented once with the following passive instruction given in Ger-

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man: “You will now hear a tone sequence including one frequent and one rare tone/a list of

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word-pairs of which some belong together and some do not/a list of sentences of which some make sense and some do not. Please listen.” All paradigms were presented within a single ses-

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sion with short breaks in-between. Absolute recording time was approximately 45 minutes. Paradigms were presented in a pseudorandom order. If patients appeared to be drowsy during

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the course of the experiment, the recording was interrupted and the Arousal Facilitation Protocol of the CRS-R was administered to re-establish a minimum of arousal.

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All auditory stimuli were presented via pneumatic transducer in-ear headphones (3M™

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E-A-RTONE™ Insert Earphone 3A ABR, 50 ohm) equipped with foam eartips (Etymotic re-

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search, inc., eartips for ER-3 & ER-5). In addition to the paradigms presented herein, the patients were also presented with a P300 paradigm using a passive and a focused task. Results of these analyses are presented

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elsewhere (Real et al., 2015).

3.3 Material and data acquisition Thirty-one active electrodes were placed according to the international 10-20 system with a g.tec system and g.recorder (g.tec, Graz, Austria) at the following scalp sites: F8, F4, Fz, F3, F7, FC6, FC2, FC1, FC5, T8, C4, Cz, C3, T7, CP6, CP2, CP1, CP5, P8, P4, Pz, P3, P7, O2, O1, and on the left and right mastoids. The ground electrode was placed at AFz and the data were online referenced to the nose. Four additional electrodes were attached to the two external canthi, as well as above and below the right eye, to monitor eye movements 11

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(EOG). The EEG and EOG had a sampling rate of 512 Hz and were online band-pass filtered

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between 0.01 Hz and 250 Hz.

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3.4 Data pre-processing and analysis

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EEG data were pre-processed and analyzed with Brain Vision Analyzer, Version 2.0.4.368 (Brain Products GmbH, Gilching, Germany). Statistical calculations were per-

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formed in SPSS 17.0 (SPSS Inc., IL).

The EEG data were re-referenced to the linked mastoids and offline band-pass filtered

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between 0.1 and 25 Hz (time constant 15.91549, 12 dB/oct). The ocular channels were bipolarized into vertical and horizontal EOG. Epochs were created from -100 to 500 ms for the

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MMN paradigm and from -200 to 1000 for the N400 paradigms. In the MMN paradigm, only

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the standard epochs directly preceding the deviant epoch were selected to ensure comparable numbers of epochs in both conditions. Time windows from -100 to 0 ms for the MMN para-

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digm and -200 to 0 for the N400 paradigms were used as a baseline. Eye movement artefacts were corrected using a regression-based procedure (Gratton, Coles, & Donchin, 1983) and all

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trials containing signal changes of ± 100 µV were excluded from further analysis. Finally, grand averages were obtained for each patient. A dataset was included into analyses if at least 40 % of the trials remained after preprocessing. In all paradigms, difference waves were obtained by subtracting the standards/related word-pairs/correct sentences from the deviants/unrelated word-pairs/incorrect sentences. The relevant time windows for all analyses were defined for each patient and paradigm individually. First, all grand averages were screened visually to define any distinct deflection. Every paradigm aimed at eliciting a specific ERP. However, in patients, also unexpected ERPs may arise (Neumann & Kotchoubey, 2004b; Pokorny et al., 2013b). Therefore, each waveform 12

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was carefully inspected independently from the ERP the paradigm aimed at. Subsequently, local negative maxima were automatically detected in the time intervals defined by visual in-

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spection. In the next step, mean amplitudes under the curve of the difference waves in an interval of 100 ms (MMN paradigm) or 200 ms (N400 paradigms) around that peak were ex-

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ported and an ANOVA including the factors stimulus (standard vs. deviant), region (frontal, central, parietal), and laterality (left, middle, right) was conducted. For these statistical anal-

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yses, the electrodes F3, Fz, F4, C3, Cz, C4, P3, Pz and P4 were selected (Duncan et al., 2009). For all ANOVAs, the Greenhouse-Geisser corrected results are reported (Greenhouse &

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Geisser, 1959) since the assumption of sphericity was violated in all the analyses and values of epsilon were smaller than .75, which is the recommended threshold for application of the

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Greenhouse-Geisser correction (Girden, 1992). For significant interactions, post-hoc compari-

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plemented in SPPS 17.0.

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sons were conducted using the SIDAK correction procedure for multiple comparisons as im-

The presence of an ERP was judged according to two criteria: First, the visual detection of a distinct deflection and secondly, a significant or marginally significant effect of stimulus

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in the ANOVA (main effect or interaction). While the visual detection was mandatory, the significant statistical results were optional for the reporting of an ERP. Thus, ERPs are still reported if the ANOVA did not reveal a significant result, because significance can be impeded by high variance in the signal which is common in patients. This method was chosen because data recorded in patients may exhibit noise and thus a large variance, potentially masking relevant effects.

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4 Results Altogether, 35 datasets from 19 patients were processed. However, the data of the sec-

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ond measurement of P14 had to be excluded due to a poor signal-to-noise ratio, resulting in 34

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datasets that entered statistical and visual analyses.

4.1 MMN

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In P11 at t1 (diagnosis: exit MCS), a distinct negative deflection was elicited at frontal and central electrodes between 100 and 200 ms. The ANOVA did not yield a significant result

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which could be due to a large standard deviation of the curves. Amplitudes elicited by the deviant were negative, amplitudes elicited by the standard were positive. The deflection was in-

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terpreted as an MMN and is depicted in Figure 1. In P17 at t1 (diagnosis: VS), a distinct nega-

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tive deflection was elicited at frontal and central electrodes between 150 and 300 ms. The ANOVA yielded marginally significant results for the main effect of stimulus (F(1, 99) =

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3.11, p = .081) and the interaction of stimulus and region (F(2, 198) = 2.78, p = .091). Amplitudes elicited by the deviant were negative, amplitudes elicited by the standard were positive.

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The deflection was interpreted as an MMN and is depicted in Figure 2. In all other patients, visual inspection did not reveal any deflection that could be interpreted as an MMN. Figure 3 depicts the EEG recorded in P18 (t2) as an example. The deflection was not judged as an ERP because it already started just before the stimulus and thus, cannot be elicited by the paradigm.

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4.2 N400 Words In the N400 Words paradigm, data of P01 at t1, P06 at t2, P07 and P19 could not be an-

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alyzed due to an insufficient number of trials after pre-processing. Thus, 29 datasets from 17 patients entered analyses.

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In none of the patients, an N400 was detected visually. In P06 at t1 (diagnosis: VS), a distinct negative deflection was elicited at all electrodes between 50 and 150 ms. The deflec-

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tion was interpreted as N1. Since it was elicited by standards and deviants simultaneously, no ANOVA investigating of potential effect of stimulus was calculated. The deflection is depict-

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ed in Figure 4. In all other patients, visual inspection did not reveal any deflection that could

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be interpreted as an ERP. Figure 5 depicts the EEG recorded in P16 (t2) as an example.

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4.3 N400 Sentences

In the N400 Sentences paradigm, data of P01 at t1, of P02, P03, P06, P10, P13, and P19 at t2, respectively, as well as data of P07 and P14 could not be analyzed due to an insufficient number of trials after pre-processing. Thus, 25 datasets of 17 patients entered analyses. No N400 was observed in the visual analysis. However, in P05, a distinct positive deflection was observed in both measurements. At t1 (diagnosis: VS), this deflection was located frontally and occurred between 500 and 800 ms and peaked at about 650 ms. The ANOVA revealed a significant interaction of stimulus and region (F(2, 166) = 4.35, p = .021). Post-hoc comparisons showed that the difference between amplitudes elicited by standards and devi15

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ants was significant over frontal areas (p = .021), marginally significant over parietal areas (p = .095), and non-significant over central areas. Amplitudes elicited by standards were nega-

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tive, amplitudes elicited by deviants were positive. At t2 (diagnosis: VS), this deflection had a fronto-central location, occurred between 200 and 600 ms and peaked at about 450 ms. The

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ANOVA revealed a marginally significant main effect of stimulus (F(1, 68) = 3.37, p = .071) and a marginally significant interaction of stimulus and region (F(2, 136) = 3.27, p = .072).

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Post-hoc comparisons revealed significant differences between amplitudes elicited by standards and deviants over frontal areas (p = .046) while this difference was marginally significant

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centrally (p = .070) and non-significant parietally. Amplitudes elicited by the deviant were positive, amplitudes elicited by the standard were negative. These ERP responses were inter-

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preted as varieties of a late positive complex (LPC). The LPC elicited at t1 is depicted in Fig-

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ure 6.

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In P18 at t2 (diagnosis: VS), a distinct positive deflection over all sites was observed between 200 and 600 ms and peaked at about 500 ms. The deflection was also interpreted as an LPC and is depicted in Figure 7. In the ANOVA, amplitudes differed marginally significantly

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(F(1, 39) = 3.06, p = .088) as a function of stimulus. Amplitudes elicited by deviants were positive, amplitudes elicited by standards were negative. In all other patients, visual inspection did not reveal any deflection that could be interpreted as an ERP. Figure 5 depicts the brain activity recorded in P16 (t2) as an example.

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4.4 CRS and ERPs The CRS comprised assessment in six domains (auditory, visual, motor, verbal, com-

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munication, arousal) with 23 tasks and observations in total. Eleven of the checkpoints indicated MCS and two indicated emergence from MCS. Two patients exhibited signs of MCS at

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one time of measurement (P03 t1, P09 t1). One patient exhibited signs for MCS in both measurements (P14), but the data of the second measurement were not included in the statistical

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and visual analysis because of a poor signal-to-noise ratio. Two more patients exhibited signs of emergence from MCS at one time of measurement (P02 t1, P11 t1), however, no second

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measurement could be undertaken in P11. One patient exhibited signs for emergence from MCS in the first measurement and signs for MCS in the second (P06). In only one of these pa-

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tients (P11), an MMN was found, in none of them an N400 could be identified. In addition, an

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N1 was identified in the N400 Words paradigm in P06 at t1. However, the patient who exhib-

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ited two ERPs within one single measurement (P18 t2) had a low CRS total score of 5 at that time and was diagnosed as VS. Four of the patients who exhibited ERPs were diagnosed with

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VS at that time of measurement.

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5 Discussion and summary The goal of the present study was to investigate the elicitation of ERPs in DOC patients.

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Auditory stimulation using oddball and semantic paradigms resulted in an MMN and a late positive component in four of the 19 patients and N1 in one patient. Table 2 descriptively

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summarizes the results in all patients.

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insert table 2 around here

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The hierarchical approach (Kotchoubey et al., 2005; Kübler & Kotchoubey, 2007; Ow-

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en et al., 2005) is an appealing idea to limit strenuous measuring time to a minimum and to

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work efficiently in clinical settings where time is a limited resource. Complex paradigms would only have to be applied to patients that have shown positive responses to simple stimulus material (Kotchoubey et al., 2005). In the present sample, P05 exhibited a presumed LPC

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in both measurements but no MMN in either measurement. An N1 component, representing basic processing of auditory stimuli, was only identified in one patient in the N400 Words paradigm. Thus, the present results do not support the hierarchical approach. However, since positive findings of ERPs were generally rare in the present sample, their absolute number is not sufficient to draw a final conclusion. In addition, Kotchoubey and colleagues themselves reported patterns contradicting their hierarchical approach (2005). They report that even though they found more responses in simple paradigms compared to more complex ones, this rule was not valid for all patients included in the study. The authors concluded that varying levels of attentional awareness may be one reason for these irregularities. Variation in wake18

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fulness was also observed in the present study. The experimenters thoroughly monitored the patients during measurements and administered the Arousal Facilitation Protocol of the CRS-

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R to re-establish a minimum of arousal, whenever it seemed necessary. However, the exact estimation of the level of awareness remains impossible and it may, thus, have had an effect

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on the recorded ERPs. Furthermore, ERP findings in DOC patients are always subject to specific lesions in the brain. The present sample comprised a large portion of hypoxic patients

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with no specification of the side or location of the lesion. It may thus be possible, that brain areas associated with, e.g., semantic processing was damaged, distorting the results. There-

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fore, although the present results do not support the hierarchical approach, further investigation including more homogenous samples are advisable. Rohaut and colleagues (2015) pro-

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vided results consistent with the hierarchical approach in VS and MCS patients in a very re-

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cent study.

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The existence or absence of ERPs in DOC patients need to be interpreted with great care. On the one hand, responses in passive paradigms cannot be considered a proof of consciousness, but only reveal that a relevant brain network is still able to process the incoming

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stimulation (Boly et al., 2007). On the other hand, Jones and colleagues (2000) for example did not find any auditory evoked potential in two patients who had shown behaviorally clear signs of discriminative hearing. A more reliable proof consists in the application of paradigms including specific instructions or volitional tasks. However, patients who exhibit responses to passive stimulation might be consciously aware, but still unable to understand and follow complex instructions (Kübler & Kotchoubey, 2007). In the present study, the N400 Words paradigm did not elicit an ERP apart from a N100 in a single patient. This might be due to the passive instruction used since also in healthy participants, no visually identifiable N400 was present in the N400 Words paradigm when a pas19

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sive instruction was applied, while a prominent N400 arose in response to a focused instruction (Erlbeck et al., 2014). Previous results support the hypothesis that focused instructions

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lead to more ERPs also in DOC patients (Real et al., 2015). In addition, Münte and Heinze (1994) reported before that more ERP responses were found for sentence-based stimulus ma-

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terial compared to word-pairs and also studies reporting a high prevalence of N400 in DOC patients (e.g. Steppacher et al., 2013) applied sentence-based stimulus material. As a conse-

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quence, the sentence-based stimulation and the usage of focused instructions appears to be more suitable. However, this may also put more attentional demands on the patients.

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ERPs in DOC patients can differ substantially from ERPs in healthy participants. Latency range of components might be delayed (Perrin et al., 2006; Schnakers et al., 2008) and

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even inversed ERPs have been reported before: Negative deflections in P300 paradigm, for

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example, may indicate a delayed MMN instead of the expected P300 (Kotchoubey, 2005;

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Pokorny et al., 2013a). In the present study, unexpected ERPs were detected in the semantic paradigms, but not in the MMN paradigm. In the N400 Sentences paradigm, positive components were identified and in the N400 Words paradigm, only an N1 was present. An LPC can

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be elicited by various kinds of syntactic, grammatical, and semantic violations (Münte, Heinze, Matzke, Wieringa, & Johannes, 1998). For example, a P600 was assumed to occur in response to grammatical and syntactic errors only (Osterhout & Holcomb, 1992), but recent studies have also shown P600 to semantic violations (van Herten, Kolk, & Chwilla, 2005) and especially in patients, both, N400 and P600, should be regarded as a sign of some language comprehension (Neumann & Kotchoubey, 2004a). Thus, the present results underline that it is important to analyze each paradigm for different ERPs and to not focus on a certain latency range or polarity. Even though unexpected ERPs are no proof of awareness or consciousness

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as such, their existence might still indicate stimulus processing and support future measurements with and encourage treatment of the respective patient.

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Although ERPs has been found in the present study, their mere presence does not prove that the patients are consciously aware (Chennu & Bekinschtein, 2012). In research with

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healthy participants, a reliable MMN is also elicited without any attention to the stimuli (i.e. Folstein & van Petten, 2007; Muller-Gass, Stelmack, & Campbell, 2005; Näätänen, 1990).

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There is considerable debate about the role of attention and awareness in the elicitation of the N400 in semantic paradigms. Even brain responses to factually wrong sentences do not un-

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ambiguously indicate conscious processing of these stimuli (Kotchoubey et al., 2014). However, the presence of ERPs in DOC patients has repeatedly proven to be an indicator of recov-

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ery (i.e. Daltrozzo et al., 2007; Faran et al., 2006; Steppacher et al., 2013). In fact, the strong

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connection of the presence of ERPs and recovery from coma suggests that attention and con-

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sciousness, albeit being two separate constructs, do share some cognitive processes and neural mechanisms (Chennu & Bekinschtein, 2012). Altogether, the response rate in our sample was low, which might be attributed to the

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chronic state (≥ 30 months) of all patients except P07 (3 months) and P17 (8 months). Kübler and Birbaumer speculated that such long a duration of a state lacking immediate reinforcement of thoughts (e.g., the wish for the room to be heated up may be fulfilled later and thus, not contingent on the thought, or not at all) may lead to extinction of goal-directed behavior (Kübler & Birbaumer, 2008). If this were true, patients with chronic DOC might have difficulties to follow the instructions of the experimenter even if some conscious awareness may still be present. The LPC is an indicator of higher order cognitive processing and the fact that it was repeatedly found in P05 diagnosed with VS indicated that this patient may indeed have

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been falsely diagnosed. Follow-up tests, also with other paradigms would have been needed to confirm this result, but could not be performed within the present study.

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Patient 14 was diagnosed with “Guillàn-Barré Syndrome with very limited signs of awareness”, which was confirmed by our CRS assessment. According to the neurologist, the

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patient has been in this state since more than 3 years, which may lead to cognitive decline or an extinction of goal directed behavior.

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The problem of using psychophysiological paradigms to estimate the presence of conscious awareness or residual cognitive processing in non-responsive patients, was discussed

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recently by Cruse and colleagues (Cruse, Gantner, Soddu, & Owen, 2014). In order to make reliable decisions on the basis of such paradigms a “ground truth” (p. 1198) or base-rate

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would be necessary, which is impossible to establish because healthy subjects, in who con-

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scious awareness can be taken for granted, information processing is different from that in

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DOC patients and, thus, a healthy sample can only serve as a proxy for comparison with DOC patients. On the other hand, in DOC patients the “ground truth” cannot be assessed due to the inherent problem of the diagnosis, which includes non-responsiveness or ambiguous respons-

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es to stimulation. Consequently, sensitivity and specificity of the paradigms can only be estimated and remain error prone. One remedy to this problem is multiple assessments with regards to time (several measurements with the same method at several time points) and methods (e.g., a combination of EEG and fMRI). Our study did not include several methods, but 3 different EEG paradigms and two time points of assessment. Thus, we partially fulfilled the guidelines recommended by Cruse and colleagues (p. 1200). The present study has some limitations. Firstly, only patients from two subsidiaries of a single clinic and only patients who showed at least minimal responses in reaction to sensory stimulation (such as eye opening following touch) were included. Thus, the results presented 22

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herein may not be generalizable to other patients in other clinics. Secondly, all but two patients had been diagnosed with a DOC for several years. It is often stated that the probability

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of recovery and regaining consciousness decreases with increasing duration of coma or VS (e.g. Bricolo, Turazzi, & Feriotti, 1980; Tirschwell, 2006). Therefore, it is likely that the pa-

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tients included in this study may have been less likely to respond to stimulation and exhibited less and smaller ERPs in comparisons to other less chronic patients. In addition, the sample

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used in the present study was heterogeneous comprising VS, MCS and even exit MCS patients. Thus, no reliable conclusions for a specific group of patients can be drawn. Thirdly, a

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high number of recordings had to be excluded in the N400 Sentences paradigm due to noisy data. This contamination with artifacts might be random noise from electrical devices but it is

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also possible that the auditory stimuli provoked artifacts from eye movements or muscular re-

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actions. Regardless of the source of the artifacts, fewer datasets were included in the analyses

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compared to the other paradigms. Thus, it might be possible that more ERPs to the N400 Sentences paradigm could have been found if the signal-to-noise ratio was better. Fourthly, results of the visual analyses were considered most important because statistical analyses can be

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complicated by various factors: Usually, only a specific time window is included in the statistical analyses, possibly missing deflections in a different time interval. Furthermore, significance of results can be missed due to high variance. In most patients who exhibited statistically significant results in the predefined window, visual inspection did not reveal an ERP. This ambiguity was caused by drifts and artifacts that can only be identified visually. However, also visual analysis may by faulty. In any case, in a patient setting it seems most appropriate to minimize type II errors (missing an existing effect) and to accept an increased type I error (stating an effect that is not present). Thus, visually detected deflections were also interpreted when statistics were not significant. Finally, it is by now well known that ERP paradigms 23

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alone often lead to negative or ambiguous results in DOC patients (e.g. Real et al., 2015). However, when the study started in 2009 the respective situation was different and ERP para-

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digms were considered a possible and valuable approach to estimate the level of conscious-

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ness in patients with DOC.

5.1 Conclusion

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The present results demonstrated ERPs in five of 19 DOC patients (4 VS and 1 MCS). Thus, it could be shown that also VS patients do exhibit some degree of cognitive functioning

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including semantic processing of spoken sentences. A close observation of those patients and regular re-assessment of their state of consciousness is recommended.

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It could be shown that high CRS scores may be an indicator for the presence of ERPs,

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but low CRS scores do not exclude ERPs. Thus, the CRS remains an important tool in the assessment of patients but does require residual motor functions that can be impaired in DOC

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patients. A correct diagnosis requires prolonged periods of observation, profound training and repeated assessment (Childs, Mercer, & Childs, 1993; Kotchoubey et al., 2005). The record-

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ing of ERPs may complement the behavioral assessment and provide indicators of the patients’ cognitive functioning. All paradigms were designed such that a sufficient number of stimuli is delivered while keeping the overall duration at a minimum. An ERP distinguishing deviants from standards was elicited in at least one patient in each paradigm except the N400 Words paradigm. To summarize, the present study allows for the following conclusions: a) Behaviorally unresponsive patients may exhibit ERPs indicating some preserved information processing irrespective of behavioral assessments.

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b) When presenting semantic material to patients, sentences should be preferred over word-pairs.

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c) The lack of an ERP in the N400 Words paradigm supports the results of Erlbeck and colleagues (2014), emphasizing the importance of active instructions.

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d) ERPs in DOC patients may be delayed of reversed polarity adding to the difficulty

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of interpretation.

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6 Acknowledgements We thank the staff of the Clinic for Intensive Care in Schwaig and Hersbruck for their

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support and the patients and their families for taking part in this study.

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7 Funding and financial disclosure This work was supported by the European ICT Programme Project FP7-247919. The

use that may be made of the information contained therein.

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text reflects solely the views of its authors. The European Commission is not liable for any

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Dr. Erlbeck, Dr. Real, Dr. Mattia, Dr. Kotchoubey, Dr. Bargak, and Dr. Kübler reported no actual or potential financial interests or potential conflicts within three years of beginning

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the submitted work.

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hypoxia bleeding basal ganglia bleeding basal ganglia trauma hypoxia hypoxia hypoxia, infarcts hypoxia hypoxia trauma hypoxia hypoxia hypoxia Guillain-Barré syndrome intracerebral bleeding hypoxia meningitis trauma ischemic stroke

lesion side

unspecified left right left unspecified unspecified bilateral unspecified unspecified bilateral unspecified unspecified unspecified unspecified left unspecified bilateral bilateral unspecified

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47 50 58 35 69 59 53 31 66 30 52 32 26 63 64 52 61 66 50

diagnosis

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f m m m m f f f f m f m m f f m m m m

CRS t2 4 6 0 4 2 13* N/A 2 1 4 N/A N/A 4 6* 4 2 4 5 6

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P01 P02 P03 P04 P05 P06 P07 P08 P09 P10 P11 P12 P13 P14 P15 P16 P17 P18 P19

CRS t1 3 12✝ 5* 3 3 13✝ 2 3 6* 4 22✝ 2 3 14* 6 5 5 3 3

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Table 1: months since onset 101 63 30 82 57 39 3 119 135 44 80 113 77 39 141 68 8 70 104

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Table 1: Demographic data of the patient sample: Sex (f-female, m-male), age at the time of measurement, coma recovery scale (CRS) full scores at the first (t1) and second (t2) measurement, if applicable, short diagnosis, side of the lesions and months since onset. The symbol * represents the diagnosis minimally conscious state (MCS), the symbol ✝ represents exit from MCS, no symbol represents vegetative state (VS).

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diagnosis VS VS exit MCS VS MCS VS VS VS VS VS exit MCS MCS VS VS VS MCS VS VS VS exit MCS VS VS VS MCS MCS VS VS VS VS VS VS VS VS VS VS

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code measurement P01 t1 t2 P02 t1 t2 P03 t1 t2 P04 t1 t2 P05 t1 t2 P06 t1 t2 P07 t1 P08 t1 t2 P09 t1 t2 P10 t1 t2 P11 t1 P12 t1 P13 t1 t2 P14 t1 t2 P15 t1 t2 P16 t1 t2 P17 t1 t2 P18 t1 t2 P19 t1 t2

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Table 2: Summary of results in all patients. The table lists each patient, the time of measurement and the respective diagnosis at that time together with the identified event-related potential (ERP). Diagnoses differentiate between minimally conscious state (MCS) and vegetative state (VS)

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Figure 1: Distinct negative deflection elicited in the MMN paradigm in P11 (t1) at Fz and Cz between 100 and 200 ms.

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Figure 2: Distinct negative deflection elicited in the MMN paradigm in P17 (t1) at Fz and Cz between 150 and 300 ms. Figure 3: EEG recorded in P18 (t2) at Fz and Cz in the MMN paradigm. The signal cannot be interpreted as an ERP.

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Figure 4: EEG recorded in P06 (t2) at Cz and Pz in the N400 Words paradigm. The distinct negative deflection between 50-150 ms could be interpreted as an N1.

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Figure 5: EEG recorded in P16 (t2) at Cz and Pz in the N400 Words paradigm. The signal could not be interpreted as an ERP.

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Figure 6: A distinct positive deflection elicited in the N400 Sentences paradigm in P05 (t1) at Fz between 400 and 800 ms.

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Figure 7: A distinct positive deflection elicited in the N400 Sentences paradigm in P18 (t2) at Fz, Cz, and Pz between 200 and 600 ms.

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Figure 8: EEG recorded in P15 (t1) at Cz and Pz in the N400 Sentences paradigm. The signal cannot be interpreted as an ERP.

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Highlights  Behaviorally unresponsive patients may exhibit ERPs indicating some preserved information processing.  Behaviorally unresponsive patients may exhibit some degree of semantic processing of spoken sentences.  High CRS scores may indicate the presence of ERPs, but low CRS scores do not exclude ERPs.  When presenting semantic material to patients, sentences should be preferred over word-pairs.  ERPs in DOC patients may be delayed and of reversed polarity adding to the difficulty of interpretation.

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