OVERALL ASSESSMENT:
This manuscript presents a compelling and well-executed study on the modulation of auditory novelty processing under dexmedetomidine sedation and natural sleep, using intracranial electrophysiology in neurosurgical patients. The study addresses an important question in neuroscience, particularly in the context of identifying neural signatures of consciousness and the effects of different states of arousal on sensory processing. The authors provide a thorough analysis of the data, and the results are presented in a clear and detailed manner. The study is innovative and contributes significantly to the field by comparing the effects of dexmedetomidine (an alpha-2 adrenergic agonist) with natural sleep, and by replicating previous findings with propofol. Overall, the manuscript is well-written, methodologically sound, and the findings are of high relevance to both clinical and basic neuroscience.

MAJOR COMMENTS:
1) Sample Size and Generalizability:
The study includes a relatively small number of participants (11 patients), which is understandable given the nature of intracranial recordings in neurosurgical patients and the complicated experimental setup. However, this partially limits the generalizability of the findings, particularly when interpreting the results in the context of consciousness and neural correlates of conscious perception. For example the limited number of occipital and parietal contacts, while not critical when looking at the auditory evoked potentials alone, could be a limitation when discussing broader implications for consciousness (e.g., the "front vs. back" debate in conscious perception). The authors should acknowledge this limitation and discuss how the relative absence of these regions might influence the interpretation of the results.

2) Single-Subject Data:
Given the small sample size, it would be beneficial to include more detailed single-subject data in the supplementary materials. This would allow readers to better assess the consistency of the findings across individuals and provide a clearer picture of the variability in responses. Showing representative contacts for each subject could enhance the transparency and robustness of the results.

3) Bipolar vs. Monopolar Recordings:
The manuscript does not explicitly state whether the recordings were bipolar or monopolar. This is an important methodological detail, as it can influence the interpretation of the data. The authors should clarify this point and discuss any potential implications for the results.

4) SEEG vs. ECoG:
The authors acknowledge that the study is limited by the use of both SEEG and ECoG in different patients. This is a valid concern, as the two methods have different spatial resolutions and sensitivities. I recommend that the authors perform additional analyses to address this issue, such as analyzing SEEG and ECoG data separately or using mixed statistical models that account for this variability. This would strengthen the validity of the conclusions.

5) Responses in Sedation vs. Wakefulness:
The observation that some contacts showed responses in sedation or unresponsive states but not in wakefulness is intriguing and somewhat counterintuitive. The authors should comment on this finding and provide examples in the supplementary materials. This could help clarify whether these responses are genuine or possibly artifacts of the recording or analysis methods.

6) High Gamma Responses Without AEP:
The authors note that some sites showed high gamma responses without concomitant AEP novelty effects. This is unusual, as one would expect postsynaptic activity (reflected in AEP) to underlie high gamma responses. The authors should discuss this finding in more detail, considering potential explanations such as statistical thresholds or methodological factors. This could be addressed by revisiting the statistical methods or providing additional examples in the supplementary materials.

7) Differences Between Dexmedetomidine and Sleep:
The authors highlight a notable difference between dexmedetomidine and sleep experiments, where the AEP LD effect prevalence did not decrease with drowsiness in the sleep experiment. This could be due to sampling bias, as the two conditions were tested in different subjects. The authors should discuss this limitation and consider referencing recent work by Zelmann et al. (2023, Neuron), which may provide additional context for this finding.

8) Auditory Awareness vs. Consciousness:
I would use the term auditory awareness or auditory conscious perception throughout the text instead of the general term consciousness. The manuscript addresses questions specifically associated with auditory perception, not to consciousness in general.

9) Open Data:
I believe in open data and open science, and I always recommend sharing data on open platforms whenever feasible. This practice ensures that research results are reproducible and, particularly in the case of intracerebral recordings in humans, represents an invaluable source of new scientific knowledge for the future of science itself and for the patients who enable us to publish using their data.

MINOR COMMENTS:
- Line 207: The manuscript states that electrodes were implanted in "5 participants out of 12," but the total number of participants is 11. This discrepancy should be corrected.
- Trial Rejection Procedure: The manuscript does not mention whether a trial rejection procedure was performed to exclude artifacts or noisy trials. This should be clarified in the methods section.
- Figure 4: The authors should consider adding panels for high gamma responses in Figure 4c and 4d. While the absence of responses is informative, showing the areas that do not respond could provide a more complete picture of the data.
- Supplementary Figure 4: The legend for Supplementary Figure 4 is confusing. The different symbol shapes denote participants, but the colors represent target hit rates. This should be clarified to avoid misinterpretation.
- Line 570: The authors should cite Zelmann et al. (2023, Neuron, DOI: 10.1016/j.neuron.2023.08.007) when discussing the differences between dexmedetomidine and sleep experiments.
Cite Hayat et al. 2022, Nat Naurosc, DOI:10.1038/s41593-022-01107-4, when concluding that auditory cortex continues to monitor the environment following loss of consciousness

CONCLUSION:
This manuscript presents a valuable contribution to the field of auditory processing and consciousness research. The study is well-designed, and the results are presented clearly and thoroughly. While there are some limitations related to sample size and methodological variability, the authors have addressed these issues thoughtfully. With the suggested revisions, this manuscript will be a strong addition to the literature. I recommend acceptance after significant, but minor revisions.

Andrea Pigorini

The authors have addressed properly all my concerns.
All the Best
Andrea Pigorini