In their submitted manuscript “Modulation of auditory novelty processing by dexmedetomidine and natural sleep: A human intracranial electrophysiology study”, Nourski and colleagues seek to investigate the effects of dexmedetomidine on auditory novelty processing, having investigated this in their previous work using propofol. To carry this out, they had subjects perform an auditory novelty task while underdoing presurgical monitoring for epilepsy surgery with implanted with intracranial electrodes. They had subjects listen to auditory stimuli that deviated either in local or global structure and they examined neural responses in both low frequency and high gamma.
Their results are quite similar to their previous work, in that they show responses in core auditory regions that are similar across states, but responses in higher order areas are diminished both during drowsiness and under sedation. Further, low frequency responses were more distributed than high gamma responses.
In general, this is a well carried out study by a strong group if scientists. I think it would benefit from a more overall interpretation to link the hypothesized mechanisms to the findings, as well as some other minor issues (see below).
1. What is the link between GABAa and LD vs GD (and the anatomy)? This should be motivated better to motivate the experiment and findings better.
2. Generally, the motivation should be fleshed out more clearly. The motivation is a bit unclear as it stands as compared to the author’s previous work (aside from using a different sedative to replicate).
3. Figure 4: wider anatomical activation of HG for unresponsive vs awake local deviance. Why?
4. Relatedly, what does the Figure 4C/D look like for HG? I understand the lack of prevalence outside of auditory areas, but what about within the auditory areas? It would be useful to know if this is a feature of the AEPs only or the HG as well.
5. It could be helpful to perform a latency analysis of the peaks? Could tell us how much of non-auditory areas is efferent connections from auditory regions vs local processing.
6. Page 13: “…with LGD effects occurring simultaneously in multiple brain areas.” How do you know they are simultaneous?
7. It would be helpful to perform an analysis comparing the propofol to the dexmedetomidine directly.
8. Further, it would be useful to characterize the background signals as well between proposal and dexmedetomidine as well as between dexmedetomidine and sleep. Are there similarities/differences?

I thank the authors for their careful and thorough consideration of my comments and suggestions. They have all been addressed. I now believe that this manuscript will make a great addition to the literature!