Conscious processing of global and local auditory irregularities causes differentiated heartbeat-evoked responses

  1. Diego Candia-Rivera
  2. Federico Raimondo
  3. Pauline Pérez
  4. Lionel Naccache
  5. Catherine Tallon-Baudry
  6. Jacobo D Sitt

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    Motivated by previous demonstrations that cognitive modulation of heart beat evoked responses (HER) might distinguish minimally consciousness state and unresponsive wakefulness syndrome patients, the present work sought to determine whether contextual processing of auditory regularities (local-global paradigm) differentially affects HER in these patient groups. The results provide preliminary evidence for the usefulness of EEG and oddball paradigms in informing diagnosis of the state of consciousness. This paper will be of interest to those researchers studying signs of consciousness in post-comatose patients and more broadly to those studying brain-body interactions. However, some aspects of the study design and data analysis need to be clarified, particularly as these affect the conclusions that can be drawn.

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Abstract

Recent research suggests that brain-heart interactions are associated with perceptual and self-consciousness. In this line, the neural responses to visceral inputs have been hypothesized to play a leading role in shaping our subjective experience. This study aims to investigate whether the contextual processing of auditory irregularities modulates both direct neuronal responses to the auditory stimuli (ERPs) and the neural responses to heartbeats, as measured with heartbeat-evoked responses (HERs). HERs were computed in patients with disorders of consciousness, diagnosed with a minimally conscious state or unresponsive wakefulness syndrome. We tested whether HERs reflect conscious auditory perception, which can potentially provide additional information for the consciousness diagnosis. EEG recordings were taken during the local-global paradigm, which evaluates the capacity of a patient to detect the appearance of auditory irregularities at local (short-term) and global (long-term) levels. The results show that local and global effects produce distinct ERPs and HERs, which can help distinguish between the minimally conscious state and unresponsive wakefulness syndrome patients. Furthermore, we found that ERP and HER responses were not correlated suggesting that independent neuronal mechanisms are behind them. These findings suggest that HER modulations in response to auditory irregularities, especially local irregularities, may be used as a novel neural marker of consciousness and may aid in the bedside diagnosis of disorders of consciousness with a more cost-effective option than neuroimaging methods.

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  1. Version published to 10.7554/elife.75352 on eLife
  2. eLife

    Author Response

    Reviewer #1 (Public Review):

    The work in this study builds on previous studies by some of the same authors and aims to test whether the heartbeat evoked response was modulated by the local/global auditory regularities and whether this differed in post-comatose patients with different contagiousness diagnosis. The authors report that during the global effect there were differences between the MCS and UWS patients.

    The study is well constructed and analysed and has data from 148 participants (although the maximum in anyone group was 59). The reporting of the results is excellent and the conclusions are supported by the results presented. This study and the results presented are discussed as evidence that EEG based techniques maybe a low cost diagnostic tool for consciousness in post-comatose patients, although it should be stressed that here no classification of diagnostics was performed on the EEG data.

    One potential weakness was the relationship between the design of the experiment and the analysis pathway for the results. If I have understood correctly the experimental design the auditory regularity changed on whether the local/global regularity was standard/deviant. In the analysis the differences between all conditions in which the local or global regularity were compared between the standard and deviant trials. This difference was then compared between MCS and UWS patient groups. For these analyses the results for the health and emerging MCS were not included. If this is correct it would be interesting to understand the motivation for this. Relatedly, it would be good to clarify if the effects reported were corrected for the multiple planned contrasts and if not why they should not be corrected.

    Thanks for the appreciation and constructive comments to our work. The misdiagnosis of MCS/UWS patients in the clinical practice occurs because of misdetection of covert consciousness given the absence of overt behavioral signs of consciousness. Therefore, the main motivation of our study is to contribute to a better distinction between those two patients’ groups.

    We have modified the introduction to clarify that the objective of the paper is to show in major detail the group differences between MCS and UWS patients:

    "In this study, we analyze HERs following the presentation of auditory irregularities, with special regard on distinguishing UWS (n=40) and MCS (n=46) patients. Note that the automated classification of this cohort was previously performed in another study (Raimondo et al., 2017). Therefore, our aim is to characterize the group-wise differences between UWS and MCS patients that may allow a multi-dimensional cognitive evaluation to infer the presence of consciousness (Sergent et al., 2017), but also complement the bedside diagnosis performed with neuroimaging methods that capture neural correlates of covert consciousness (Sanz et al., 2021)."

    Reviewer #2 (Public Review):

    The goal of this study was to determine whether heartbeat-evoked responses measured at the scalp level with EEG, which followed regularity violations, could potential help inform the diagnosis of patients with altered states of consciousness.

    The authors use high density EEG and an oddball paradigm that probes violations of both local and global regularities. Four groups were considered including unresponsive wakefulness syndrome patents, minimally consciousness patients, emerging minimally consciousness patients and healthy controls. A difference was found between unresponsive and minimally conscious patients in the amplitude of the heartbeat evoked responses measure with EEG following a sound that violated a global regularity. Similarly, differences were found between the variance of these responses between the two above mentioned groups (N=58 and N=59), but no differences were found in relation to the healthy control group, which appear to be "in between" the two other groups (at least for global effect of HER). I thought this was a little counterintuitive and raises some questions about what this neural signature can tell us about the state of consciousness. Having said that, the healthy control sample was very small, more than 5 times smaller (only N=11).

    Thanks to the reviewer for their comments. As described above, distinguishing between MCS/UWS patients is one of the main challenges in the clinical practice. We have modified the manuscript to show the differences between these two patients’ groups. Further data on EMCS and healthy participants is not included in this revision because of the new inclusion criteria.

    In general, I thought the Discussion section was a little light on the implications of the findings, what they tell us about the brain mechanisms of consciousness and their different levels/states. A question is raised about whether it is necessary to lock EEG to heartbeats to find differences between patients. The data appeared to say that this is not the case but the discussion does not appear to reflect that very clearly.

    We have enriched the discussion to comment on the relation of HERs in perception:

    "Our results contribute to the extensive experimental evidence showing that brain-heart interactions, as measured with HERs, are related to perceptual awareness (Azzalini et al., 2019; Skora et al., 2022). For instance, neural responses to heartbeats correlate with perception in a visual detection task (Park et al., 2014). Further evidence exists on somatosensory perception, where a higher detection of somatosensory stimuli occurs when the cardiac cycle is in diastole and it is reflected in HERs (Al et al., 2020). Evidence on heart transplanted patients shows that the ability of heartbeats sensation is reduced after surgery and recovered after one year, with the evolution of the heartbeats sensation recovery reflected in the neural responses to heartbeats as well (Salamone et al., 2020). The responses to heartbeats also covary with self-perception: bodily-self-identification of the full body (Park et al., 2016), and face (Sel et al., 2017), and the self-relatedness of spontaneous thoughts (Babo-Rebelo et al., 2016) and imagination (Babo-Rebelo et al., 2019). Moreover, brain-heart interactions measured from heart rate variability correlate with conscious auditory perception as well (Banellis and Cruse, 2020; Pérez et al., 2021; Pfeiffer and Lucia, 2017)."

    Reviewer #3 (Public Review):

    I found the results very interesting but wondered why the ERP results for the global vs. local effects are not reported. This analysis is mentioned in the methods section, but I do not find it in the results. Is this what is shown in the mid row in panel D? If yes, it should be made clearer. Is there a significant local and global deviant response in each patient group?

    We thank the reviewer for their appreciation of our work and their comments.

    We have reported the new results showing clustered effects in both ERPs and HERs.

    Additionally, eyeballing Figure 1, there are a few potential issues that may be affecting the conclusion re HER:

    (1) Panel D top: it seems that the orange trace (MCS) is largely the same in both the "Local" and "global" condition. But the blue trace (UWS) shows a larger negative going deflection in the "global" case. Put differently, the UWS, but not MCS patients appear to generate a different response to the Global effect relative to the local effect. Is this the case?

    We have separated the Figure 1 into 3 new figures to clarify on the results. And we also provide a more detailed description of our results.

    In brief, our results show that MCS may have a distinctive response to global and local effects. We have included new correlation analysis in which we show that the responses to global and local effects are uncorrelated (Table 2):

    With respect to the “negative” responses in UWS. Note that the measured effect correspond to a linear combination of evoked potentials, e.g.: global effect = mean(global deviants) – mean(global standard). Therefore, the negative group-wise response may imply that global standard responses are larger than global deviants. We have included in Table 1 the statistical tests to show whether the responses to local and global effects are different from zero:

    (2) There are some MCS subjects that appear to show a global effect that is larger than that observed in EMCS and healthy controls. How do you interpret these data?

    We have included in the discussion a paragraph in which we discuss on the outliers:

    "Note that outliers are expected in disorders of consciousness and exact physiological characterization of the different levels of consciousness remains challenging. First, the standard assessment of consciousness based on behavioral measures has shown a high rate of misdiagnosis in MCS and UWS (Stender et al., 2014). The cause of the misdiagnosis of consciousness arises because consciousness does not necessarily translate into overt behavior (Hermann et al., 2021). Unresponsive and minimally conscious patients, namely non-behavioral MCS (Thibaut et al., 2021), represent the main diagnostic challenge in clinical practice. Second, some of these patients suffer from conditions that may translate to no response to stimuli, even in presence of consciousness. For instance, when they suffer from constant pain, fluctuations in arousal levels, or sensory impairments caused by brain damage (Chennu et al., 2013). Third, these patients were recorded in clinical setups, which may lead to a lower signal-to-noise ratio, and lead to biased measurements in evoked potentials (Clayson et al., 2013)."

    (3) How do you interpret the negative average HER data shown by many UWS patients?

    As mentioned above, the negative HER is a result of a linear combination of different HER-based markers (deviants minus standard).

  3. eLife

    eLife assessment

    Motivated by previous demonstrations that cognitive modulation of heart beat evoked responses (HER) might distinguish minimally consciousness state and unresponsive wakefulness syndrome patients, the present work sought to determine whether contextual processing of auditory regularities (local-global paradigm) differentially affects HER in these patient groups. The results provide preliminary evidence for the usefulness of EEG and oddball paradigms in informing diagnosis of the state of consciousness. This paper will be of interest to those researchers studying signs of consciousness in post-comatose patients and more broadly to those studying brain-body interactions. However, some aspects of the study design and data analysis need to be clarified, particularly as these affect the conclusions that can be drawn.

  4. eLife

    Reviewer #1 (Public Review):

    The work in this study builds on previous studies by some of the same authors and aims to test whether the heartbeat evoked response was modulated by the local/global auditory regularities and whether this differed in post-comatose patients with different contagiousness diagnosis. The authors report that during the global effect there were differences between the MCS and UWS patients.

    The study is well constructed and analysed and has data from 148 participants (although the maximum in anyone group was 59). The reporting of the results is excellent and the conclusions are supported by the results presented. This study and the results presented are discussed as evidence that EEG based techniques maybe a low cost diagnostic tool for consciousness in post-comatose patients, although it should be stressed that here no classification of diagnostics was performed on the EEG data.

    One potential weakness was the relationship between the design of the experiment and the analysis pathway for the results. If I have understood correctly the experimental design the auditory regularity changed on whether the local/global regularity was standard/deviant. In the analysis the differences between all conditions in which the local or global regularity were compared between the standard and deviant trials. This difference was then compared between MCS and UWS patient groups. For these analyses the results for the health and emerging MCS were not included. If this is correct it would be interesting to understand the motivation for this. Relatedly, it would be good to clarify if the effects reported were corrected for the multiple planned contrasts and if not why they should not be corrected.

  5. eLife

    Reviewer #2 (Public Review):

    The goal of this study was to determine whether heartbeat-evoked responses measured at the scalp level with EEG, which followed regularity violations, could potencial help inform the diagnosis of patients with altered states of consciousness.

    The authors use high density EEG and an oddball paradigm that probes violations of both local and global regularities. Four groups were considered including unresponsive wakefulness syndrome patents, minimally consciousness patients, emerging minimally consciousness patients and healthy controls. A difference was found between unresponsive and minimally conscious patients in the amplitude of the heartbeat evoked responses measure with EEG following a sound that violated a global regularity. Similarly, differences were found between the variance of these responses between the two above mentioned groups (N=58 and N=59), but no differences were found in relation to the healthy control group, which appear to be "in between" the two other groups (at least for global effect of HER). I thought this was a little counterintuitive and raises some questions about what this neural signature can tell us about the state of consciousness. Having said that, the healthy control sample was very small, more than 5 times smaller (only N=11).

    In general, I thought the Discussion section was a little light on the implications of the findings, what they tell us about the brain mechanisms of consciousness and their different levels/states. A question is raised about whether it is necessary to lock EEG to heartbeats to find differences between patients. The data appeared to say that this is not the case but the discussion does not appear to reflect that very clearly.

  6. eLife

    Reviewer #3 (Public Review):

    I found the results very interesting but wondered why the ERP results for the global vs. local effects are not reported. This analysis is mentioned in the methods section, but I do not find it in the results. Is this what is shown in the mid row in panel D? If yes, it should be made clearer. Is there a significant local and global deviant response in each patient group?

    Additionally, eyeballing Figure 1, there are a few potential issues that may be affecting the conclusion re HER:

    (1) Panel D top: it seems that the orange trace (MCS) is largely the same in both the "Local" and "global" condition. But the blue trace (UWS) shows a larger negative going deflection in the "global" case. Put differently, the UWS, but not MCS patients appear to generate a different response to the Global effect relative to the local effect. Is this the case?
    (2) There are some MCS subjects that appear to show a global effect that is larger than that observed in EMCS and healthy controls. How do you interpret these data?
    (3) How do you interpret the negative average HER data shown by many UWS patients?

  7. Version published to 10.1101/2021.10.27.21265539v2 on medRxiv
  8. Version published to 10.1101/2021.10.27.21265539v1 on medRxiv