Multiscale dynamical characterization of cortical brain states: from synchrony to asynchrony

Reviewer #1 (Public review):

Summary:

In the paper, the authors review literature on synchronous activity, its relationship to brain state, and the multi-scale mechanisms underlying it.

Strengths:

The overall strength of the paper is the wide range of information reviewed, and the diversity of perspectives/approaches it brings together.

Weaknesses:

However, this strength is also the source of its major weaknesses - namely, that the overall structure lacks clarity, and there are inconsistencies throughout. Overall, in the opinion of this reviewer, the manuscript reads as disorganized and incomplete. Major and minor points are delineated below.

Major points:

(1) Most of the text in many figures was too small to read.

(2) Terminology is inconsistent throughout the manuscript. What is the difference between slow oscillations and delta waves? Sometimes the term slow waves is used instead. For sleep state, sometimes the term SWS is used, sometimes non-REM. Similarly, "spindle activity" is not defined, but simply stated as if the reader knows. This brings up two issues: (a) the manuscript should be clearer and more consistent about its terminology, and (b) it's unclear who is the intended readership of the review - is it a pedagogical review for people outside the field of sleep and slow oscillations, or is it meant to be a consensus statement for readers who are already in the field in which a pressing concern has been addressed? It seems part way between these two, and as a result, is ineffective at either goal.

(3) I suggest the authors look again at the overall structure and flow of the review... many sections feel redundant, and it's unclear how they fit together into a single review.

(4) There are many speculative statements in the review that are not justified or explained sufficiently for the reader. For example: "While highly regular slow waves in vivo suggest a single mechanism of generation, namely local cortical circuits, irregular cycles are compatible with a larger role of subcortical nuclei, ..."; "The involvement of different cortical areas and subcortical nuclei can form the basis of these different roles in memory.". For these statements, I assume the relationship between slow wave statistics, subcortical nuclei, and memory either has been written about before, and then should be cited and summarized, or is a novel claim of the authors, which then should be explained and defended rather than stated. There are other similar examples, and I suggest the authors go through the manuscript and make sure that it's clear what is a novel claim of the authors vs a cited claim, and make sure that both are sufficiently justified for the reader.

(5) An especially notable example can be found in the section on the role of the thalamus, where the authors state that they "hold that slow oscillations are fundamentally cortical". However, this section is far too short, and very little evidence is provided to back up this claim. Please review the ways in which the thalamus modulates, and, e.g., ways in which up-down is similar/different without the thalamus.

Reviewer #2 (Public review):

Summary:

In this review article, the authors discuss the correlated dynamical states associated with distinct cognitive states, including those associated with anesthesia and sleep. They present evidence that these states are primarily cortically generated, and demonstrate the properties of these dynamical states at different levels, from the microscale dynamics in individual neurons to the macroscale dynamics across the brain.

Strengths:

Multiple groups have been adding to this field over the past decades, and therefore, a review of this literature is very helpful. This review collates a large amount of the literature within this field into a single document, which should make it a valuable resource within this area of neuroscience.

Weaknesses:

Unfortunately, this review does not seem to be a balanced viewpoint of the field in question. Although there are a lot of authors in the review, it feels as if they are from a common school of thought. The authors provide only a single perspective on these dynamical states, focusing on the perspective of wave-like electrical dynamics across the cortex. Their perspective is embedded in methods such as EEG and LFP recordings. This makes the work hard to interpret outside of the field in which the authors reside. Indeed, the review seems intended for a more specialized audience.

In addition, the article reads more like a catalog of prior studies as opposed to a true synthesis across the large volume of data in this field that highlights links across multiple sources. Hence, it does not seem to provide a novel way of understanding the dynamics involved in cognitive state transitions.

We have included more details on these general comments below:

Major Comments:

(1) The authors have written this review as if it were intended for an audience who is already familiar with these topics. They do not define many of the terms that they introduce within the review, including concepts like complexity, metastability, and oscillations that are fundamental to the concepts that the authors are introducing. Though these may seem like first principles concepts to the authors, they often introduce assumptions that may be unfamiliar to the general reader. For example, are slow wave oscillations periodic? A naïve reader may assume that oscillations - characterized by their frequency - should be somewhat periodic, but that is often not the case. For a journal with a general biological science readership, it would be particularly helpful for each of these terms to be formally defined and characterized.

(2) It would be helpful for the authors to reframe their work in different perspectives and to incorporate all the literature on the dynamics of cortical brain states, and not simply the work that is most familiar to them. As one example, the authors do not discuss cell-type-specific changes in brain state during anesthesia and in altered states of consciousness (including dissociative states and hallucinatory states). There is recent work in this vein (Suzuki and Larkum, 2020; Vesuna et al, 2020; Bharioke, Munz et al, 2023), and yet the authors do not discuss these papers.

(3) Given the authors' clear, extensive knowledge of their field, it would also be extremely helpful for the authors to reframe fundamental concepts in terms of neuronal population activity, trajectory analyses, etc. This would enable a more general audience to better understand their work.

(4) The authors have one section focused on thalamic contributions to cortical wave-like activity. This is a cursory treatment of a subject that is quite controversial in the field. It would be helpful if the authors could provide a more balanced consideration of all the evidence regarding potential thalamocortical interactions and their role in wave-like activity.

(5) The authors present many computational models and describe the results of simulations with these different models. However, this doesn't provide the reader with intuition about what each model adds or removes from the true biological picture. It would be helpful for the authors to provide some intuition about the assumptions and constraints that underlie each model.

(6) The authors state that "The main mechanism [of slow oscillatory dynamics] consists of a combination of two ingredients: the recurrent connectivity, which maintains the excitability in the network, and adaptation, an activity-dependent fatigue variable that provides inhibitory feedback". They make this statement as a fact, yet they don't provide much justification for it. Additionally, it's not clear that any other possible combination of ingredients would be able to produce slow oscillatory dynamics.

(7) The authors often define one concept in terms of other equally complex concepts. For example: "EIA (excitatory-inhibitory with adaptation) cortical circuits then display the typical slow-fast dynamics of relaxation oscillators". The reader would need an explanation of slow-fast dynamics and relaxation oscillators to understand this line, neither of which is provided in the text.

(8) When discussing sleep, the authors do not discuss REM sleep, focusing on slow-wave non-REM sleep. It would be helpful if the authors could at least frame the full sleep cycle and discuss why they are focusing on one part of it.

(9) The authors introduce the concept of sleep spindles without any explanation.