The Many Unknowns of Partial Sensory Disconnection during Sleep: A Review of the Literature

Round 1

Reviewer 1 Report

This is a well-written and interesting review article regarding the physiological bases of sensory disconnection during sleep. Below are my comments and suggestions.

- Sleep-related sensory disconnection is never clearly defined. Moreover, throughout the manuscript, the authors seem to refer to and apply different definitions of sensory disconnection, according to behavioral responses, the appearance of arousals (or awakenings), or brain activity changes related to sensory processing (with or without accompanying arousals). The authors may consider better describing in the introduction the definition (or definitions) they intend to apply.

- The review discusses the significance of slow waves and spindles for sensory disconnection. K-complexes are never mentioned even though they represent a typical electrophysiological response to sensory stimuli during NREM sleep and are thought to have an important role in sensory disconnection.

- Page 7. "Serotoninergic neurons in the dorsal raphe continue to respond to acoustic stimuli during slow wave sleep [93], contrary to LC neurons [78] and dopaminergic neurons of the substantial nigra [94]". I feel this sentence may be misleading since the cited references indicate an attenuated rather than an absent response of LC and SN neurons during SWS.

- The manuscript contains a small number of typos. Here are a few that I noted:

Page 1. "[...] we sleep for many hours every day, and so do all other animals carefully study [studied] so far."

Page 7. "[S]serotoninergic activity inhibits the processing of visual stimuli in thalamus and cortex."

Page 8. "[...] many intriguing observations come from old studies in which few neurons very [were?] recorded."

Author Response

Reviewer 1.

This is a well-written and interesting review article regarding the physiological bases of sensory disconnection during sleep. Below are my comments and suggestions.

RE: Thank you for this general assessment.

- Sleep-related sensory disconnection is never clearly defined. Moreover, throughout the manuscript, the authors seem to refer to and apply different definitions of sensory disconnection, according to behavioral responses, the appearance of arousals (or awakenings), or brain activity changes related to sensory processing (with or without accompanying arousals). The authors may consider better describing in the introduction the definition (or definitions) they intend to apply.

RE: Thank you for this comment. We now provide a definition of sensory disconnection during sleep at the beginning of the main text. We also clarify how the underlying mechanisms are assessed by measuring local neuronal responses, either local field potentials or firing responses in specific neuronal groups.

“By sensorimotor disconnection we mean that relative to waking, during sleep the ability to respond to a stimulus is reduced, i.e. the “arousal threshold” is increased. The arousal threshold is usually assessed in humans by measuring the ability to produce a behavioral response, such as pushing a button or providing a verbal response, often in association with the analysis of the global brain response as detected by the scalp EEG. Orienting responses or other complex behaviors are rarely used in animals, where the arousal threshold is measured by the ability of the stimulus to cause a shift in behavioral state, an “awakening”, as detected by the scalp EEG. Awakening from NREM sleep is usually defined as a clear switch in the EEG from the high amplitude low frequency pattern to the low amplitude and high frequency pattern, while awakening from REM sleep requires an increase in muscle tone.”

“Paradoxically, however, the neural mechanisms responsible for sensory disconnection during sleep are still unclear, and most of the available evidence is restricted to the auditory system. Two main approaches have been used to understand these mechanisms: evoked potentials (evoked “responses”) and evoked unit activity. These measures of neuronal responsiveness are taken in specific brain regions, i.e. they are local, and they are usually compared in 3 conditions: subjects are awake when stimulated, they are asleep and do not wake up in response to the stimulus, or they do wake up. Evoked responses are usually collected using scalp EEG (or magnetoencephalography, or functional MRI) recordings or with invasive, deep intracortical local field potential (LFP) recordings. Evoked responses reflect mainly the synaptic input, not the firing output, which is why the analysis of unit activity is also critical to study sensory disconnection.”

- The review discusses the significance of slow waves and spindles for sensory disconnection. K-complexes are never mentioned even though they represent a typical electrophysiological response to sensory stimuli during NREM sleep and are thought to have an important role in sensory disconnection.

RE: We have now added a section on K complexes, although to our knowledge very few studies have tested whether a stimulus given during a K complex leads to changes in arousal threshold. We cite, however, a few studies assessing BOLD responses and EEG responses during and after K complexes.

“Together, these studies show that sounds reach the input layer of A1 equally well in waking and NREM sleep, but their transmission to supragranular and infragranular layers, as well as the feedforward transmission to higher order cortices, are compromised. During NREM sleep this effect likely depends on the occurrence of OFF periods, which impair corticocortical communication [20], an hypothesis that is consistent with the fact that higher SWA leads to higher auditory arousal threshold [5; 6]. It is also in line with an early report that a motor response (thumb press) is unlikely to occur if the tone is delivered during a K complex [21; 22], and with more recent findings that spontaneous and evoked K complexes are associated with an increase in power in the low frequencies, although region-specific effects are present [23; 24].”

“One EEG/fMRI study found that sounds elicit BOLD responses in thalamus and primary auditory cortex when delivered in waking as well as when given during NREM sleep without causing an awakening [11]. In sleep, the responses are smaller and more variable when sounds are given during spindles, and larger and extending to broader cortical areas if the sound elicits a K complex, a large slow wave that reflects the presence of bistability in the thalamocortical system [11].”

- Page 7. "Serotoninergic neurons in the dorsal raphe continue to respond to acoustic stimuli during slow wave sleep [93], contrary to LC neurons [78] and dopaminergic neurons of the substantial nigra [94]". I feel this sentence may be misleading since the cited references indicate an attenuated rather than an absent response of LC and SN neurons during SWS.

RE: The sentence has been edited as follows:

“Serotoninergic neurons in the dorsal raphe continue to respond to acoustic stimuli during slow wave sleep [93], contrary to LC neurons [78] and dopaminergic neurons of the substantia nigra [94] whose response is greatly attenuated compared to waking.”

- The manuscript contains a small number of typos. Here are a few that I noted:

RE: Thank you, all typos have been corrected.

Page 1. "[...] we sleep for many hours every day, and so do all other animals carefully study [studied] so far."

Page 7. "[S]serotoninergic activity inhibits the processing of visual stimuli in thalamus and cortex."

Page 8. "[...] many intriguing observations come from old studies in which few neurons very [were?] recorded."

Author Response File: Author Response.docx

Reviewer 2 Report

This was a well written review of the literature on sensory disconnection during sleep. I have no comments or suggestions for authors.

Author Response

Reviewer 2.

This was a well written review of the literature on sensory disconnection during sleep. I have no comments or suggestions for authors.

RE: Thank you for this general assessment.

Author Response File: Author Response.docx

Reviewer 3 Report

1. The type of review should be mentioned in the title.

2.  Could the authors do a table with the sensory disconnections in sleep? The reviewer believes this will lead to a quick understanding of the authors’ ideas.

3. Could the authors provide diagrams or figures of the mechanisms being proposed? The reviewer believes including diagrams will lead to a better comprehension of the manuscript.

1. What is the main question addressed by the research?

This literature review addresses sensory disconnection during sleep.

2. Do you consider the topic original or relevant in the field? Does it address a specific gap in the field?

The topic is not original, but it is relevant to the field of the pathophysiology of the sleep cycle.

3. What does it add to the subject area compared with other published material?

Provide a broad spectrum of different types of sensory disconnections.

4. What specific improvements should the authors consider regarding the methodology? What further controls should be considered?

The reviewer believes that this is not pertinent to the present study.

5. Are the conclusions consistent with the evidence and arguments presented, and do they address the main question posed?

The reviewer believes that this is not pertinent to the present study.

6. Are the references appropriate?

Yes, the references are appropriate. And, the auto-citation index is of 5-6%.

7. Please include any additional comments on the tables and figures.
The reviewer believes that including figures and tables as described above would significantly improve the quality of the manuscript.

Author Response

Reviewer 3.

1. The type of review should be mentioned in the title.

RE: We now state that this is a  review of the literature.

2.  Could the authors do a table with the sensory disconnections in sleep? The reviewer believes this will lead to a quick understanding of the authors’ ideas
3. Could the authors provide diagrams or figures of the mechanisms being proposed? The reviewer believes including diagrams will lead to a better comprehension of the manuscript.

 RE: It is difficult to prepare a table with the cited literature. However, we have added a schematic figure with the main take home-messages of this review. 

1. What is the main question addressed by the research?

This literature review addresses sensory disconnection during sleep.

2. 
   Do you consider the topic original or relevant in the field? Does itaddress a specific gap in the field?

The topic is not original, but it is relevant to the field of the pathophysiology of the sleep cycle.

3. 
   What does it add to the subject area compared with other publishedmaterial?

Provide a broad spectrum of different types of sensory disconnections.

4. 
   What specific improvements should the authors consider regarding themethodology? What further controls should be considered?

The reviewer believes that this is not pertinent to the present study.

5. 
   Are the conclusions consistent with the evidence and arguments presented,and do they address the main question posed?

The reviewer believes that this is not pertinent to the present study.

6. 
   Are the references appropriate?

Yes, the references are appropriate. And, the auto-citation index is of 5-6%.

7. 
   Please include any additional comments on the tables and figures.
   The reviewer believes that including figures and tables as described above would significantly improve the quality of the manuscript.

RE: It is difficult to prepare a table, because the cited literature is quite scattered. However, we have added a schematic figure with the main take home-messages of this review. 

Author Response File: Author Response.docx