The involvement of the human prefrontal cortex in the emergence of visual awareness

Reviewer #1 (Public Review):

This is a clear and rigorous study of intracranial EEG signals in the prefrontal cortex during a visual awareness task. The results are convincing and worthwhile, and strengths include the use of several complementary analysis methods and clear results. The only methodological weakness is the relatively small sample size of only 6 participants compared to other studies in the field. Interpretation weaknesses that can easily be addressed are claims that their task removes the confound of report (it does not), and claims of primacy in showing early prefrontal cortical involvement in visual perception using intracranial EEG (several studies already have shown this). Also the shorter reaction times for perceived vs not perceived stimuli (confident vs not confident responses) has been described many times previously and is not a new result.

Reviewer #2 (Public Review):

The authors attempt to address a long-standing controversy in the study of the neural correlates of visual awareness, namely whether neurons in prefrontal cortex are necessarily involved in conscious perception. Several leading theories of consciousness propose a necessary role for (at least some sub-regions of) PFC in basic perceptual awareness (e.g., global neuronal workspace theory, higher order theories), while several other leading theories posit that much of the previously reported PFC contributions to perceptual awareness may have been confounded by task-based cognition that co-varied between the aware and unaware reports (e.g., recurrent processing theory, integrated information theory). By employing intracranial EEG in human patients and a threshold detection task on low-contrast visual stimuli, the authors assessed the timing and location of neural populations in PFC that are differentially activated by stimuli that are consciously perceived vs. not perceived. Overall, the reported results support the view that certain regions of PFC do contribute to visual awareness, but at time-points earlier than traditionally predicted by GNWT and HOTs.

Major strengths of this paper include the straightforward visual threshold detection task including the careful calibration of the stimuli and the separate set of healthy control subjects used for validation of the behavioral and eye tracking results, the high quality of the neural data in six epilepsy patients, the clear patterns of differential high gamma activity and temporal generalization of decoding for seen versus unseen stimuli, and the authors' interpretation of these results within the larger research literature on this topic. This study appears to have been carefully conducted, the data were analyzed appropriately, and the overall conclusions seem warranted given the main patterns of results.

Weaknesses include the saccadic reaction time results and the potential flaws in the design of the reporting task. This is not a "no report" paradigm, rather, it's a paradigm aimed at balancing the post-perceptual cognitive and motor requirements between the seen and unseen trials. On each trial, subjects/patients either perceived the stimulus or not, and had to briefly maintain this "yes/no" judgment until a fixation cross changed color, and the color change indicated how to respond (saccade to the left or right). Differences in saccadic RTs (measured from the time of the fixation color change to moving the eyes to the left or right response square) were evident between the seen and unseen trials (faster for seen). If the authors' design achieved what they claim on page 3, "the report behaviors were matched between the two awareness states ", then shouldn't we expect no differences in saccadic RTs between the aware and unaware conditions? The fact that there were such differences may indicate differences in post-perceptual cognition during the time between the stimulus and the response cue. Alternatively, the RT difference could reflect task-strategies used by subjects/patients to remember the response mapping rules between the perception and the color cue (e.g., if the YES+GREEN=RIGHT and YES+RED=LEFT rules were held in memory, while the NO mappings were inferred secondarily rather than being actively held in memory). This saccadic RT result should be better explained in the context of the goals of this particular reporting-task.

Nevertheless, the current results do help advance our understanding of the contribution of PFC to visual awareness. These results, when situated within the larger context of the rapidly developing literature on this topic (using "no report" paradigms), e.g., the recent studies by Vishne et al. (2023) Cell Reports and the Cogitate consortium (2023) bioRxiv, provide converging evidence that some sub-regions of PFC contribute to visual awareness, but at latencies earlier than originally predicted by proponents of, especially, global neuronal workspace theory.

Reviewer #3 (Public Review):

The authors report a study in which they use intracranial recordings to dissociate subjectively aware and subjectively unaware stimuli, focusing mainly on prefrontal cortex. Although this paper reports some interesting findings (the videos are very nice and informative!) the interpretation of the data is unfortunately problematic for several reasons. I will detail my main comments below. If the authors address these comments well, I believe the paper may provide an interesting contribution to further specifying the neural mechanisms important for conscious access (in line with Gaillard et al., Plos Biology 2009).

The main problem with the interpretation of the data is that the authors have NOT used a so-called "no-report paradigm". The idea of no report paradigms is that subjects passively view a certain stimulus without the instruction to "do something with it", e.g., detect the stimulus, immediately or later in time. Because of the confusion of this term, specifically being related to the "act of reporting", some have argued we should use the term no-cognition paradigm instead (Block, TiCS, 2019, see also Pitts et al., Phil Trans B 2018). The crucial aspect is that, in these types of paradigms, the critical stimulus should be task-irrelevant and thus not be associated with any task (immediately or later). Because in this experiment subjects were instructed to detect the gratings when cued 600 ms later in time, the stimuli are task relevant, they have to be reported about later and therefore trigger all kinds of (known and potentially unknown) cognitive processes at the moment the stimuli are detected in real-time (so stimulus-locked). You could argue that the setup of this delayed response task excludes some very specific report related processes (e.g., the preparation of an eye-movement), which is good, however this is usually not considered the main issue. For example when comparing masked versus unmasked stimuli (Gaillard et al., 2009 Plos Biology), these conditions usually also both contain responses but these response related processes are "averaged out" in the specific contrasts (unmasked > masked). In this paper, RT differences between conditions (that are present in this dataset) are taken care of by using this delayed response in this paper, which is a nice feature for that and is not the case for the above example set-up.

Given the task instructions, and this being merely a delayed-response task, it is to be expected that prefrontal cortex shows stronger activity for subjectively aware versus subjectively unaware stimuli. Unfortunately, given the nature of this task, the novelty of the findings is severely reduced. The authors cannot claim that prefrontal cortex is associated with "visual awareness", or what people have called phenomenal consciousness (this is the goal of using no-cognition paradigms). The only conclusion that can be drawn is that prefrontal cortex activity is associated with accessing sensory input: and hence conscious access. This less novel observation has been shown many times before and there is also little disagreement about this issue between different theories of consciousness (e.g., global workspace theory and local recurrency theories both agree on this).

The best solution at this point seems to rewrite the paper entirely in light of this. My advice would be to state in the introduction that the authors investigate conscious access using iEEG and then not refer too much to no-cognition paradigm or maybe highlight some different strategies about using task-irrelevant stimuli (see Canales-Johnson et al., Plos Biology 2023; Hesse et al., eLife 2020; Hatamimajoumerd et al Curr Bio 2022; Alilovic et al., Plos Biology 2023; Pitts et al., Frontiers 2014; Dwarakanth et al., Neuron 2023 and more). Obviously, the authors should then also not claim that their results solve debates about theories regarding visual awareness (in the "no-cognition" sense, or phenomenal consciousness), for example in relation to the debate about the "front or the back of the brain", because the data do not inform that discussion. Basically, the authors can just discuss their results in detail (related to timing, frequency, synchronization etc) and relate the different signatures that they have observed to conscious access.

I think the authors have to discuss the Gaillard et al PLOS Biology 2009 paper in much more detail. Gaillard et al also report a study related to conscious access contrasting unmasked and masked stimuli using iEEG. In this paper they also report ERP, time frequency and phase synchronization results (and even Granger causality). Because of the similarities in approach, I think it would be important to directly compare the results presented in that paper with results presented here and highlight the commonalities and discrepancies in the Discussion.

In the Gaillard paper they report a figure plotting the percentage of significant frontal electrodes across time (figure 4A) in which it can be seen that significant electrodes emerge after approximately 250 ms in PFC as well. It would be great if the authors could make a similar figure to compare results. In the current paper there are much more frontal electrode contacts than in the Gaillard paper, so that is interesting in itself.

In my opinion, some of the most interesting results are not highlighted: the findings that subjectively unaware stimuli show increased activations in the prefrontal cortex as compared to stimulus absent trials (e.g., Figure 4D). Previous work has shown PFC activations to masked stimuli (e.g., van Gaal et al., J Neuroscience 2008, 2010; Lau and Passigngham J Neurosci 2007) as well as PFC activations to subjectively unaware stimuli (e.g., King, Pescetelli, and Dehaene, Neuron 2016) and this is a very nice illustration of that with methods having more detailed spatial precision. Although potentially interesting, I wonder about the objective detection performance of the stimuli in this task. So please report objective detection performance for the patients and the healthy subjects, using signal detection theoretic d'. This gives the reader an idea of how good subjects were in detecting the presence/absence of the gratings. Likely, this reveals far above chance detection performance and in that case I would interpret these findings as "PFC activation to stimuli indicated as subjectively unaware" and not unconscious stimuli. See Stein et al., Plos Biology 2021 for a direct comparison of subjectively and objectively unaware stimuli.

In Figure 7 of the paper the authors want to make the case that the contrast does not differ between subjectively aware stimuli and subjectively unaware stimuli. However so far they've done the majority of their analyses across subjects, and for this analysis the authors only performed within-subject tests, which is not a fair comparison imo. Because several P values are very close to significance I anticipate that a test across subjects will clearly show that the contrast level of the subjectively aware stimuli is higher than of the subjectively unaware stimuli, at the group level. A solution to this would be to subselect trials from one condition (NA) to match the contrast of the other condition (NU), and thereby create two conditions that are matched in contrast levels of the stimuli included. Then do all the analyses on the matched conditions.

Related, Figure 7B is confusing and the results are puzzling. Why is there such a strong below chance decoding on the diagonal? (also even before stimulus onset) Please clarify the goal and approach of this analysis and also discuss/explain better what they mean.

I was somewhat surprised by several statements in the paper and it felt that the authors may not be aware of several intricacies in the field of consciousness. For example a statement like the following "Consciousness, as a high-level cognitive function of the brain, should have some similar effects as other cognitive functions on behavior (for example, saccadic reaction time). With this question in mind, we carefully searched the literature about the relationship between consciousness and behavior; surprisingly, we failed to find any relevant literature." This is rather problematic for at least two reasons. First, not everyone would agree that consciousness is a high-level cognitive function and second there are many papers arguing for a certain relationship between consciousness and behavior (Dehaene and Naccache, 2001 Cognition; van Gaal et al., 2012, Frontiers in Neuroscience; Block 1995, BBS; Lamme, Frontiers in Psychology, 2020; Seth, 2008 and many more). Further, the explanation for the reaction time differences in this specific case is likely related to the fact that subjects' confidence in that decision is much higher in the aware trials than in the unaware trials, hence the speeded response for the first. This is a phenomenon that is often observed if one explores the "confidence literature". Although the authors have not measured confidence I would not make too much out of this RT difference.

I would be interested in a lateralized analysis, in which the authors compare the PFC responses and connectivity profiles using PLV as a factor of stimulus location (thus comparing electrodes contralateral to the presented stimulus and electrodes ipsilateral to the presented stimulus). If possible this may give interesting insights in the mechanism of global ignition (global broadcasting), supposing that for contralateral electrodes information does not have to cross from one hemisphere to another, whereas for ipsilateral electrodes that is the case (which may take time). Gaillard et al refer to this issue as well in their paper, and this issue is sometimes discussed regarding to Global workspace theory. This would add novelty to the findings of the paper in my opinion.