De Lucia, Marzia

Oddo, Mauro

Rossetti, Andrea O.

Simonin, Alexandre

Tzovara, Athina

English

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LETTERTOTHEEDITORReply: Neural detection of complex sound sequences or of statistical regularities inthe absence of consciousness?Athina Tzovara,1,2 Alexandre Simonin,3 Mauro Oddo,4 Andrea O. Rossetti3 andMarzia De Lucia11 Laboratoire de Recherche en Neuroimagerie (LREN), Department of Clinical Neuroscience, Lausanne University and UniversityHospital, Lausanne, CH-1011, Switzerland2 Department of Psychiatry, Psychotherapy, and Psychosomatics, University of Zurich, CH-8032, Switzerland3 Department of Clinical Neurosciences, University Hospital, Lausanne, CH-1011, Switzerland4 Adult Intensive Care Medicine, CH-1011, Lausanne University Hospital, SwitzerlandCorrespondence to: Marzia De Lucia,Laboratoire de Recherche en Neuroimagerie (LREN),Department of Clinical Neuroscience,Lausanne University and University Hospital,Lausanne, CH-1011, SwitzerlandE-mail: Marzia.De-Lucia@chuv.chSir,We read with interest the letter by Naccache and col-leagues (2015) on our recent paper showing unconsciousprocessing of global auditory regularities. We thank theEditor for the opportunity to provide further detailsabout our results especially in the context of a growinginterest around the interpretation of the global effect indisorders of consciousness (Piarulli et al., 2015) and insleep research (Strauss et al., 2015).Naccache and colleagues questioned the reliability of theconclusion of our paper arguing that previous studies havenever shown a global effect unless healthy controls/patientswere aware of the global regularity violation. In this con-text, they propose a different interpretation of our studyalong three lines: (i) the observed effect is not ‘global’because it does not have the characteristic features previ-ously reported in the literature in terms of latency(4300ms) and associated EEG component (i.e. P300)both in controls and in patients; (ii) the reported effectmight be driven by violation detection between twoconsecutive sounds and not at the level of groups ofsounds as required by a true global discrimination; and(iii) comatose patients showing the global effect were infact conscious.Global effect in healthycontrolsIn response to the ﬁrst point, we should ﬁrst clarify that thelatencies of the observed global effect in control subjectsare indeed in accordance with what was reported previ-ously in the literature (i.e. Fig. 4 in Bekinschtein et al.,2009) as all subjects exhibited discriminative periods after300ms post-stimulus onset (Fig. 1). We have never re-ported that the global discrimination ‘. . . occurred duringthe early time period (0–250ms) following the onset of theirregular sound’ as claimed in the letter. In our study the0–250ms time periods were the result of the topographicconsistency test (Koenig and Melie-Garcı´a, 2010), whichquantiﬁes the presence of an evoked response to thesounds independently of the auditory discrimination ana-lysis and therefore of the global effect (Supplementary ma-terial in Tzovara et al., 2015). Also, in accordance withprevious literature (Bekinschtein et al., 2009; King et al.,2013), we have shown that active controls outperform thepassive listeners both in terms of decoding performance andnumber of individuals with signiﬁcant global discrimination(Tzovara et al., 2015). Nevertheless, as Naccache anddoi:10.1093/brain/awv186 BRAIN 2015: 138; 1–4 | e396Advance Access publication July 2, 2015 The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.For Permissions, please email: journals.permissions@oup.comcolleagues pointed out, the total number of subjects with asigniﬁcant decoding result is lower compared to previousstudies (King et al., 2013). Several reasons can explain thisdiscrepancy. First, we tested the global effect in a relativelyold cohort of subjects, age-matched to the coma patients(i.e. mean age: 62  2 years for the passive and 56  2 forthe active group) differently to previous studies thatincluded only young controls—i.e. mean age: 27  3years in Bekinschtein et al. (2009) and 23  1 or 25  5years in King et al. (2013). Second, in our study we imple-mented a global paradigm based on changes in the sounds’duration while all previous studies have been based onchanges in pitch. The perceptual detection of duration de-viants is more challenging compared to pitch deviants,Figure 1 Auditory evoked potentials and discriminative time periods in active controls. (A and B) Exemplar auditory evokedpotentials (AEPs) recorded at the Cz electrode and global field power in response to global standard and global deviant sequence of five sounds.The detection of the global regularity in this active control manifests as a sustained difference in the response to the global violation as shown byboth the auditory evoked potential and global field power representations. (C) A summary of the discriminative periods in response to globalstandards and global deviants, as revealed by the decoding analysis of the four active subjects with significant results. Each horizontal line displaysthe discriminative periods revealed by the decoding algorithm in each of the six shuffles in the data set. The onset (time 0) refers to the beginningof the fifth sound of the group of five. All subjects exhibited at least one discriminative time period after 300 ms post-stimulus onset. Thewaveforms plotted in A and B correspond to the first subject of C (Subj 1).e396 | BRAIN 2015: 138; 1–4 Letter to the Editorproviding in our study an accuracy of perceptual detectionranging between 55 and 92% in active controls. Third, thesigniﬁcance of our decoding results is based on a strictstatistical criterion entailing a comparison between thetrue decoding performance and the distribution of thevalues obtained after reshufﬂing the data 500 times.Previous studies were either based on univariate statisticsat the single electrode level (for example as reported inBekinschtein et al., 2009 or Faugeras et al., 2011), or ondecoding results statistically assessed at the group level,without within-subject permutations (King et al., 2013).Global effect in comatosepatientsTo our knowledge, our study was the ﬁrst to explore globalauditory discrimination in post-anoxic patients treated withtherapeutic hypothermia and pharmacological sedation;therefore, our data cannot be readily compared to resultsobtained in vegetative and minimally conscious patients(King et al., 2013) in terms of latencies and associatedstereotypical waveforms. Nevertheless, as in this previousstudy, we did control whether the global discriminationwas driven by a somehow trivial violation detection atthe level of two adjacent sounds and typically eliciting amismatch negativity response (MMN). Indeed, we haveshown that the global effect in comatose patients persistedin the unfavourable context where global deviant soundsdid not correspond to local deviant ones (Supplementarymaterial in Tzovara et al., 2015). This control analysis sug-gests that the global discrimination was not trivially drivenby an MMN modulation. We therefore do not believe thatour results may correspond to an unconscious modulationof the early MMN by the statistical regularities, but thatthey reﬂect detection of global regularities, previously asso-ciated only with a classic P3b component, observed duringconscious access to the auditory stimuli.Consciousness levelassessment in patientsThe patients included in the present study were all treatedwith mild therapeutic hypothermia and analgo-sedation:they were thus not only in coma following cardiac arrestbut also under midazolam at sedative doses (i.e. 0.1mg/kg/h). To provide a clinical parallel, similar doses are commonlyused also to treat patients in status epilepticus, where comainduction is part of the therapeutic armamentarium (Rossettiand Lowenstein, 2011). Naccache and colleagues correctlymention that curarisation is used during therapeutic hypo-thermia, but this is only intermittent and occurs only to coun-teract marked shivering (Oddo and Rossetti, 2014), thereforeallowing—together with the clinical EEG—a periodic assess-ment of the state of patients; moreover it is never administeredafter return to normal temperature. Under such conditions, allclinical evidence was in accordance with a complete absenceof any sign of arousal, a necessary condition for consciousprocessing (Laureys et al., 2004). The complete absence ofarousal was inferred with the Sedation-Agitation and ComaGlasgow Scale that provided the lowest scores at least duringhypothermia (see Table 1 in Tzovara et al., 2015). Our pa-tients were intubated, with eyes closed, and not arousable bypotent painful stimuli, fulﬁlling the deﬁnition of coma(Laureys et al., 2004). On the basis of this clinical evidence,one can conclude that the patients included in the study wereindeed unconscious, at least during hypothermia.In summary, we believe that our experimental evidencestrongly supports the existence of an automatic mechanismfor global regularity detection, which is modulated by taskdemands. This mechanism appears preserved even in theabsence of any conscious perception of the stimuli, andirrespective of an MMN response.Previous literature has mainly focused on patients in areduced consciousness state for a prolonged period of time(Bekinschtein et al., 2009; Faugeras et al., 2011; King et al.,2013), when general neural functions have likely deterio-rated (Tzovara et al., 2013). We speculate that previousstudies may have been looking at the tail of an ongoingprocess (Piarulli et al., 2015), and at a point where a globaleffect is no longer present.We would like to ﬁnish this letter by thanking Naccacheand colleagues for stimulating a scientiﬁc discussion that mayenhance the understanding of cerebral processes during con-sciousness impairment, and renew our proposal to them todirectly compare our two versions of the global paradigms onthe same patients, in early coma and chronic stage.FundingThis work was supported by the ‘Service Projets etOrganisation Strate´giques’ of the University Hospital ofLausanne (Project number 29062-1144 to M.D.L.) andthe Swiss National Science Foundation (grant numberCR32I3_143780 to A.O.R).ReferencesBekinschtein TA, Dehaene S, Rohaut B, Tadel F, Cohen L, NaccacheL. Neural signature of the conscious processing of auditory regula-rities. Proc Natl Acad Sci USA 2009; 106: 1672–7.Faugeras F, Rohaut B, Weiss N, Bekinschtein TA, Galanaud D,Puybasset L, et al. Probing consciousness with event-related poten-tials in the vegetative state. Neurology 2011; 77: 264–8.King JR, Faugeras F, Gramfort A, Schurger A, El Karoui I, Sitt JD,et al. Single-trial decoding of auditory novelty responses facili-tates the detection of residual consciousness. Neuroimage 2013;83: 726–38.Koenig T, Melie-Garcı´a L. A method to determine the presence ofaveraged event-related ﬁelds using randomization tests. BrainTopogr 2010; 23: 233–42.Laureys S, Owen AM, Schiff ND. Brain functin in coma, vegetativestate, and related disorders. Lancet 2004; 3: 537–46.Letter to the Editor BRAIN 2015: 138; 1–4 | e396Naccache L, King J-R, Sitt J, Engemann D, El Karoui I, Rohaut Bet al. Neural detection of complex sound sequences or of statisticalregularities in the absence of consciousness? Brain 2015; in press.Oddo M, Rossetti AO. Early multimodal outcome prediction aftercardiac arrest in patients treated with hypothermia. Crit Care Med2014; 42: 1340–7.Piarulli A, Charland-Verville V, Laureys S. Neural detection of com-plex sound sequences in the absence of consciousness. Brain 2015;138: 1129–37.Rossetti AO, Lowenstein DH. Management of refractory status epilep-ticus in adults: Still more questions than answers. Lancet Neurol2011; 10: 922–30.Strauss M, Sitt JD, King J-R, Elbaz M, Azizi L, Buiatti M, et al.Disruption of hierarchical predictive coding during sleep. ProcNatl Acad Sci 2015; 12: E1353–62.Tzovara A, Rossetti AO, Spierer L, Grivel J, Murray MM, Oddo M,et al. Progression of auditory discrimination based on neural decod-ing predicts awakening from coma. Brain 2013; 136: 81–9.Tzovara A, Simonin A, Oddo M, Rossetti AO, De Lucia M. Neuraldetection of complex sound sequences in the absence of conscious-ness. Brain 2015; 138: 1160–6.e396 | BRAIN 2015: 138; 1–4 Letter to the Editor

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