Connecting Circuits with Networks in Addiction Neuroscience: A Salience Network Perspective

Round 1

Reviewer 1 Report

In this review, Cushnie et al., provide a well-rounded reconciliation of human neuroimaging studies of the salience network (SN) with circuit-level investigations in animal models. This is an important contribution as more work is needed in bridging the gap between these levels of explanation. I find the paper to be generally well-written with a few exceptions. I have a few comments about the general conceptualization of the salience network and about the functions attributed to it, as well as some additional papers I suggest to the authors.

1.     A general comment is that the current numbering and breakdown sections (8!) makes the reading a bit laborious and gives the vague sense that this is a dissertation chapter rather than an article. I suggest at the very least to consolidate sections 1, 2, and 3, which read as an introduction. I also see advantages to sections 4 and 5 into a broad “Anatomy and function” section, and then leaving sections 6 and 7 as separate sections.

2.     In section 2, where the authors discuss functional networks, the two paragraphs should more clearly make the distinction between intrinsic functional connectivity (resting state) and task-based connectivity studies (particularly thinking of an audience coming from a circuits background rather than a human neuroimaging background).

3.     The description of the functional roles of the Anterior Insula Cortex (AIC) is a bit imprecise. Activity in the AIC has been shown to represent important attributes of outcomes and stimuli such as magnitude, uncertainty, and skewness. The AIC is also known for its importance in social decision-making and in decision-making under uncertainty and risk. More recent investigations using electrophysiological recordings in macaques in the AIC have shown an important role for encoding the subjective value of outcomes (both rewards and losses) in a relative rather than absolute way, suggesting a role for integrating value and relevant information about the context. I append a list of suggested readings at the end of my review.

4.     A broader comment, and one that perhaps is not necessarily an issue with this specific manuscript but rather with the entire neuroimaging field, is that while the concept of a SN is generally accepted, there are limitations in that taxonomy as is clear from previous comment. A computational understanding of the role of the AIC and the ACC will probably help us move past a purely descriptive classification of this network as doing “salience”. I am not suggesting that you do away with the term SN, but in light of very significant efforts in developing a more thorough explanation of what these areas are doing, I would suggest adding a comment about the limitations of that term.

5.     Another notable limitation that affects the neuroimaging field is the possible artifacts brought about by the Insula’s anatomical relation to the Middle Cerebral Artery. While this is perhaps a comment that goes beyond the scope of this review, it is my opinion that it could contribute to the Insula’s preeminent role in so many neuroimaging studies.

6.     Minor comments about readability:

a.     Page 6 line 301. The final sentence starting with “Interestingly, […]” is very hard to parse. What are you trying to say?

b.     Page 8 line 398. In the final sentence starting with “However, […]” there is a bad usage of the comma after the word “marmoset”. Consider re-writing the sentence to improve clarity.

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

This review describes brain circuits, especially the role of the silence network (SN), in addiction. The literature review looks reasonably comprehensive. I have a few comments:

(i) Since the authors’ focus is on the salience network, this should be mentioned in the title of the paper. At this point, the title is a bit vague and hard to understand.

(ii) The connection of the SN to addiction neuroscience in the human brain, even though looks good, lacks in depth. The connection of brain circuits to addiction in other species is completely missing.

(iii) Some very important references are missing, which should be added to improve depth of the literature review.

[1] Jilka SR, Scott G, Ham T, Pickering A, Bonnelle V, Braga RM, Leech R, Sharp DJ. 2014. Damage to the Salience Network and interactions with the Default Mode Network. The Journal of Neuroscience 34:10798–10807.

[2] Chao, TH.H., Lee, B., Hsu, LM., Cerri, D.H., Zhang, WT., Wang, TW., Ryali, S., Menon, V., Shih, YY.I. Neuronal dynamics of the default mode network and anterior insular cortex: intrinsic properties and modulation by salient stimuli. Science Advances, 2023.

[3] Chiarello C, Vazquez D, Felton A, Leonard CM. 2013. Structural asymmetry of anterior insula: behavioral correlates and individual differences. Brain and Language 126:109–122.

[4] A. Das, J. Myers, R. Mathura, B. Shofty, B. A. Metzger, K. Bijanki, C. Wu, J. Jacobs, S. A. Sheth,"Spontaneous neuronal oscillations in the human insula are hierarchically organized traveling waves," eLife, 2022.

[5] Menon, V., Gallardo, G., Pinsk, MA., Nguyen, VD, Li, JR., Cai, W., Wassermann, D. Microstructural organization of human insula is linked to its macrofunctional circuitry and predicts cognitive control. eLife, 2020.

[6] A. Das, V. Menon,"Spatiotemporal Integrity and Spontaneous Nonlinear Dynamic Properties of the Salience Network Revealed by Human Intracranial Electrophysiology: A Multicohort Replication," Cereb Cortex., 2020.

Author Response

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Author Response File: Author Response.pdf

Reviewer 3 Report

The authors provide a well written and interesting review regarding the SN and recent studies that examine potential interactions with other regions, all in the context of addiction. We note that there are an increasing number of recent reviews about insula (e.g. 34461066, 36917821). Thus, some aspects of the present review are more redundant, but the descriptions of studies related to interactions of SN with other regions is of value.

Major concern:

Some of the statements seem oversimplified, and with only scant interaction with what has been examined in the field, and overall there is the concern that readers outside of the field will come away with an incorrect idea of what is “known” about SN. Thus the review comes across as covering too much, with thin addressing of key points that should be discussed more. Indeed, the first sections looking at connectivity patterns have been addressed at length elsewhere, while the later sections, which are more novel and in need of addressing are underaddressed.

Other specific points

Line75 DLP is listed as sometimes being a part of the SN, and yet Seeley 2007 (cited there) shows DLP is in the ECN that has very different functional role. Since this is meant to be a more general review, the authors should add more discussion of when DLP (VLP, SMA etc) might be within SN, and when it would be a very different circuit that the SN regulates. Sridharan 2008 also considers DLP separate from SN. Clearly the different networks interact in important ways. Perhaps a few examples of when DLP is or is not SN would be very helpful.

Lines140-160 some of the description seems overly simplified. E.g. AIC is linked to empathy, but there is considerable nuance. Similarly, viscerosensory paragraph ends with novelty, somewhat a non-sequitur.

Line 214 Gratton reference is not in citations’

Line 290s noting less SN activation during abstinence, and insula lesion reducing addiction: how does this relate to studies described earlier in the review of decreased SN volume with addiction, related to impulsivity etc? This seems to be a contradiction.

Line 302-304 presumably “effect is stronger” is in reference to insula lesion?

Line 310-320 The point of DA relation to SN is incompletely addressed. E.g. 22764248 shows SN dopamine in relation to self control, an important observation along with a larger literature. In addition, Nora Volkow’s lab has extensive studies of dopamine changes with SUD (and Heinz lab for AUD), including shifts in the relationship between cortical areas and striatal dopamine release.

Line 359 Tsai 2020 is cited above, but is missing here as an important study comparing rodent vs primate AIC regions and their similar and different connections.

Line 399 “and the marmoset” seems like and incomplete sentence

Paragraph starting l457: Sentence fragment l461-463. Also, the implication that circuit specificity comes through transgenic animals overlooks a great number of studies using an intersectional virus approach (i.e. retrograde Cre in the projection target region, DIO-linked inhibitory DREADD in the cell body area). Virus is mentioned but this paragraph is confusing and incomplete.

Line 509. Serotonin is introduced without rationale

Paragraph 516 and on: parts here seem overstated. Menon study as described does not address ECN, and thus extending conclusion to triple model seems premature.

Author Response

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Round 2

Reviewer 2 Report

The authors have well addressed my concerns. I do not have any further comments.

Reviewer 3 Report

Very nice review! Line 665 has work (CITE)