Recovery of consciousness and cognition after general anesthesia in humans

  1. George A Mashour
  2. Ben JA Palanca
  3. Mathias Basner
  4. Duan Li
  5. Wei Wang
  6. Stefanie Blain-Moraes
  7. Nan Lin
  8. Kaitlyn Maier
  9. Maxwell Muench
  10. Vijay Tarnal
  11. Giancarlo Vanini
  12. E Andrew Ochroch
  13. Rosemary Hogg
  14. Marlon Schwartz
  15. Hannah Maybrier
  16. Randall Hardie
  17. Ellen Janke
  18. Goodarz Golmirzaie
  19. Paul Picton
  20. Andrew R McKinstry-Wu
  21. Michael S Avidan
  22. Max B Kelz

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Abstract

Understanding how the brain recovers from unconsciousness can inform neurobiological theories of consciousness and guide clinical investigation. To address this question, we conducted a multicenter study of 60 healthy humans, half of whom received general anesthesia for 3 hr and half of whom served as awake controls. We administered a battery of neurocognitive tests and recorded electroencephalography to assess cortical dynamics. We hypothesized that recovery of consciousness and cognition is an extended process, with differential recovery of cognitive functions that would commence with return of responsiveness and end with return of executive function, mediated by prefrontal cortex. We found that, just prior to the recovery of consciousness, frontal-parietal dynamics returned to baseline. Consistent with our hypothesis, cognitive reconstitution after anesthesia evolved over time. Contrary to our hypothesis, executive function returned first. Early engagement of prefrontal cortex in recovery of consciousness and cognition is consistent with global neuronal workspace theory.

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  1. Version published to 10.7554/elife.59525 on eLife
  2. eLife

    ###Reviewer #3:

    General Assessment:

    The paper investigates the recovery of neurocognitive function after general anaesthesia, a topic of clinical and scientific interest, and not well investigated to date. It's concisely written and its conceptual structure easy to follow.

    The study is well controlled, and uses a wide range of neurocognitive tests to assess different aspects of cognition.

    The main findings, that executive function recovers before other potentially more basic aspects of cognition, supported by a similarly early return of frontal cortical dynamics, and essentially unperturbed sleep-wake cycles, suggest neurocognitive resilience to general anaesthesia with isoflurane in healthy individuals.

    These findings are novel and, although cannot be generalised beyond anaesthetic agent isoflurane, will be of interest to clinical anaesthesiologists, healthy individuals undergoing isoflurane-based general anaesthesia, and researchers investigating the relationship between consciousness and cognition.

    Major Comments:

    More in-depth and critical description of cognitive functions investigated, and of motivation for hypothesis is needed in the introduction.

    -First, the reason for hypothesised recovery sequence of cognitive functions is unclear. E.g. it's unclear that attention and executive functions are at opposite ends of this proposed hierarchy, or if so what type/aspect of 'attention' is investigated. Similarly scanning and tracking does not refer to a cognitively- or psychologically-motivated distinct function (top of page 5).

    -The link between cognitive functions and tests used to assess these is unclear in this section. E.g., 5 functions are linked to 6 behavioural tests.

    -The descriptions in the methods section do not help to clarify the relationships; e.g., the Motor Praxis Task (MP) task linked to complex scanning and visual tracking in the introduction, is described to measure sensorimotor speed. Similar concerns apply to the others.

    Details of analyses and results are hard to follow and need to be made more transparent, and comprehensive.

    -Results described in the two paragraphs of page 9 do not match those summarised on Table 1, as suggested. Is this a case of mistaken table, or is this table capturing other results? If so, results in page 9 need to be summarised in table form.

    -Results in 2nd paragraph of page 7 are very scantily described, and a summary table with full disclosure of test statistic values is needed.

    -Figures 2 and 3 lack signposting of statistical significance, a missed opportunity given the rich information provided. E.g., it's impossible to visualise when performance in each task reconstitutes, or matches control level.

    -While AM is showcased, it would be useful to learn about the relative timing of baseline recovery of the other tasks (& related cognitive functions) to one another, to fully evaluate the reconstitution of the proposed cognitive hierarchy.

    -Similarly, more transparent Bayesian analyses results would be helpful. As it stands, the figures do not convey well the type of analyses performed, nor do they give sufficient statistical details.

    -The lack of these details make it hard for another team to attempt to replicate these tests and results, as depicted in the paper itself.

    -Additional info can be placed in SI.

    More context and critical analyses is needed on the interpretation of the main finding, of executive function (based on performance of abstract matching (AM) task) reconstitution after loss of consciousness.

    -In page 5, the authors state the isoflurane is used because of slower offset relative to other anaesthetics, that would allow observation of differential recovery of function. This suggests slower recovery, than with other, more commonly used agents for anaesthesia studies, e.g. propofol. However, in page 13 the authors suggest that residual isoflurane levels are predicted to be 1-4 times lower than hypnotic agents, e.g., propofol, used in other studies where early recovery of executive function was not observed, therefore accounting for robust return of cortical dynamics in the current study. These statements appear to be in contradiction.

    -It's worth considering whether task differences serve as confounds that drive the early recovery of performance in the AM task, e.g., stronger salience, more engaging etc.

  3. eLife

    ###Reviewer #2:

    In this work cognitive assessment after isoflurane anaesthesia shows that several cognitive domains are impaired in speed of response and accuracy but dynamics of recovery are not the same for all domains. Specifically, tests related to executive functions recovered faster than others, against the authors' expectations.

    These results are important as they help to understand the dynamics of recovery of the cognitive systems after being challenged pharmacologically. The dynamics of a complex system (the brain) coming back to functioning in full is assessed both cognitively and neurally.

    I think this paper requires some clarifications, some more analyses and further discussion. One important result is the assessment of the dynamics of cognitive recovery after unconsciousness and its parallels with local and global complexity measures. As I was reading the paper I thought there would be a combined analyses to address the dependencies between complexity measured before, in unconsciousness and ROC to the behavioural outcomes. How does the level of complexity before even getting sedated or the complexity reached during unconsciousness influences the degree or speed of recovery? Please let me know if this sounds too post-hoc for you since it feels like an important and meaningful question to pose to the data for me.

    Am I correct in interpreting that you have calculated the LZC over the global topography? It would be important to clarify this point, differentiate from the other variant, and reflect that in the theoretical interpretation to avoid misunderstanding and subsequent unnecessary criticism. Two different variants of LZ complexity have been described: one that quantifies local, channel-wise complexity (LZS/LZSUM) and one that quantifies the complexity of the global topography of the scalp over time (LZC). These two variants appear to occasionally track different aspects of consciousness (Comsa 2018, thesis and Schartner et al., 2017). Specifically from Comsa's thesis "To compute the Lempel-Ziv complexity of EEG data, the concatenation of a signal consisting of channel values over time can be performed either channel-by-channel or observation-by-observation, where an observation consists of the values of all channels at a single point in time. The interpretation of the two complexity flavours is slightly different: the former case reflects the local, temporal signal diversity in individual channel values over time, whereas the latter captures the spatial diversity of the global landscape of neural activity. In some of the above studies, a different flavour appears to have worked best in different contexts: for example, the spatial variant in anaesthesia (Schartner et al., 2015), and the temporal variant in psychedelic states (Schartner et al., 2017). These different interpretations have not been thoroughly explored so far and it is not clear which variant best fits with the original theoretical framework that indicates neural information diversity as a key element for the emergence of consciousness".

    It would be a good idea to ask the question of no differences between cognitive scores before isoflurane and after several hours (three hours?), and compare to the control group in a statistically robust manner. If the aim is to claim full return-to-normal then a test to trust the no-difference would offer the answer. Please consider a statistical model that allows you to test the "return to normal" of cognitive capacities appropriately, maybe a Bayesian framework like the NLMM used but including some measure of the trust in the no-differences. It may be that the authors consider the CI values enough, in that case please express the results in terms of strength of these?

    I think a rerun of the stats asking for the effect size or bayes factor or any other parameter that would allow for an impression of the strength of the effect would go a long way in interpreting the results. Currently there seems to be a reliance on the p value (in the text), that does not reflect the strength of an effect.

    Further to this, supplementary material with the single subject dynamics of recovery would paint a true picture of the variance and variability of the results. We have gained great insight about the differential impact of sedatives in the last few years in the transition of consciousness. Here a couple of examples:

    https://www.pnas.org/content/110/12/E1142 https://www.sciencedirect.com/science/article/pii/S1053811920301142#bib68 and even one of our own https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1004669

    In particular you might want to take a look at a recent reanalysis of our data of mild sedation by Bola and collaborators (https://www.biorxiv.org/content/10.1101/444281v2.full ) where they analyse the eeg using measures of diversity and complexity that are particularly relevant for the interpretation of your results.

    In the discussion there is the need for a section where the theoretical justification for the use of PE and LCZ. How is this better or complementary to power, connectivity and other measures used in EEG to discuss consciousness and sedation needs to be addressed so the readers get a more contextualised picture of why using these measures may shield better results, why they may be better for interpretation of the loss, maintenance and recovery of consciousness.

  4. eLife

    ###Reviewer #1:

    This study examines the impact of general anaesthesia on cognitive function and, in parallel on a set of EEG indices. In particular, the authors seek to establish the order in which different cognitive abilities are recovered as consciousness is restored. One group of volunteers were placed under general anaesthetic (isoflurane) for 3 hours while a comparison control group participated in active walking during the corresponding period. Both groups then undertook cognitive testing at 30 minute intervals for 3 hours. The results suggest that, contrary to the authors hypotheses, executive functions were the first to recover and this was accompanied by a restoration of frontal EEG dynamics.

    Overall I think this is a potentially valuable study of interest to the field however my current enthusiasm is dampened by a number of apparently major issues.

    First and foremost is that the author's do not clearly define or operationalise the term 'recovery'. A Bayesian regression approach is described in the Methods section but the information provided does not explain to me how recovery is defined or established. As the authors themselves note, the potential for practice effects to confound any recovery estimates is a critical concern here and I remain to be convinced that it has been addressed.

    Relatedly, there is the concern that these cognitive tests may differ quite markedly in their difficulty for potentially trivial reasons. I do not see any analyses that would address the possibility that some tasks may simply be more sensitive to cognitive perturbations than others e.g. if performance is close to or at ceiling in the control group.

    The EEG analyses are potentially interesting too but the authors do not provide any rationale for focussing in on these particular metrics. In addition, the fact that the EEG trends are never linked to the cognitive ones limits the conclusions that can be drawn here.

    On the more minor side, the authors do not provide any rationale for their starting hypotheses. Their prediction that vigilance would be the first function to recover is not at all intuitive for me. Can the authors cite previous literature to back up this prediction?

    In addition, if the authors prefer to position the Results before the Methods then they should ensure that there is sufficient detail in the Results to allow the reader to understand the experiment. For example, they should not have to read the Methods to be told that there were two separate groups and that the control group exercised prior to cognitive testing.

  5. eLife

    ##Preprint Review

    This preprint was reviewed using eLife’s Preprint Review service, which provides public peer reviews of manuscripts posted on bioRxiv for the benefit of the authors, readers, potential readers, and others interested in our assessment of the work. This review applies only to version 1 of the manuscript. Redmond G O'Connell (Trinity College Dublin) served as the Reviewing Editor.

    ###Summary:

    The three reviewers agreed that the paper reports results that are important as they appear to offer novel insights into the dynamics of cognitive recovery following loss of consciousness; an area that has been relatively under-investigated to date. However all three reviewers also highlighted some significant concerns regarding aspects of the study rationale and methodology.

  6. Version published to 10.1101/2020.05.28.121269 on bioRxiv