Human Body Rhythms in the Development of Non-Invasive Methods of Closed-Loop Adaptive Neurostimulation

Round 1

Reviewer 1 Report

The current review provides an encompassing view of closed-loop sensory stimulation paradigms based on endogenous and non-invasive rhythmic biomarkers. The manuscript provides sufficient background and builds up from traditional open-loop systems to more modern closed-loop approaches. The work further describes many of these systems in the scope of clinical disorders, bringing an appropriate translational perspective to the text. While the review is comprehensive, I have a handful of comments regarding aspects that I feel should be improved. Please see my detailed comments below:

- While the main text of the review (section 4 and table 1) focus on sensory brain stimulation techniques, the Introduction section seems to emphasize direct electrical or magnetic brain stimulation. Overall, I feel that this gives the reader a bit of the wrong impression of the upcoming content. Therefore, given the focus of the review, I strongly urge the authors to steer the Introduction (and Abstract) in a direction that better reflects the sensory (auditory) stimulation paradigms that are described in depth later in the text.

- The current review focuses largely on auditory stimulation approaches, but has largely ignored tactile sensory stimulation techniques that have long been used in closed-loop paradigms. Specifically, vibration or electrical stimulation has shown great promise in closed-loop neuromodulation approaches, and has recently been successfully applied to patient populations (e.g. stroke rehabilitation). I feel that this topic would strongly complement the sensory stimulation paradigms that the authors describe in the current work. Please add a brief description of this concept, with the following references as support.

T Kaufmann et al. (2013) Comparison of tactile, auditory, and visual modality for brain-computer interface use: a case study with a patient in the locked-in state. Frontiers in Neuroscience, 7:129

A. Biasiucci et al. (2018) Brain-actuated functional electrical stimulation elicits lasting arm motor recovery after stroke. Nature Communications, 9:2421

- I think the current review would also benefit from a brief discussion on how EEG-based cognitive engagement/arousal can be used in closed-loop paradigms. Specifically, recent non-invasive brain-computer interface work has found that user engagement can be successfully detected from scalp EEG and can help inform/assess task performance. This type of signal has already been shown to be successfully decoded from non-invasive human brain activity and fits well within the concept of "human endogenous rhythms" that the authors describe. Please briefly describe this topic and add the following references as support:

BJ Edelman et al. (2019). Noninvasive neuroimaging enhances continuous neural tracking for robotic device control. Science Robotics, 4(31):eaaw6844

J Faller et al. (2019). Regulation of arousal via online neurofeedback improves human performance in a demanding sensory-motor task. PNAS, 116:15

- It would be interesting if the authors could comment on the future of closed-loop sensory stimulation paradigms. For example, are there promising new biomarker signals or sensory stimulation modalities that may rise in popularity in the near future? I feel that this prospective outlook would benefit the concluding remarks of the this work.

Author Response

Dear Reviewer #1:

Thank you very much for your positive opinion about our article, profound analysis and very helpful recommendations. We took into account all your recommendations. Our replies are presented point by point below.

1. 1. The current review provides an encompassing view of closed-loop sensory stimulation paradigms based on endogenous and non-invasive rhythmic biomarkers. The manuscript provides sufficient background and builds up from traditional open-loop systems to more modern closed-loop approaches. The work further describes many of these systems in the scope of clinical disorders, bringing an appropriate translational perspective to the text. While the review is comprehensive, I have a handful of comments regarding aspects that I feel should be improved. Please see my detailed comments below:

- While the main text of the review (section 4 and table 1) focus on sensory brain stimulation techniques, the Introduction section seems to emphasize direct electrical or magnetic brain stimulation. Overall, I feel that this gives the reader a bit of the wrong impression of the upcoming content. Therefore, given the focus of the review, I strongly urge the authors to steer the Introduction (and Abstract) in a direction that better reflects the sensory (auditory) stimulation paradigms that are described in depth later in the text.

We have corrected (green) the introduction as follows:

Non-invasive brain stimulation techniques, including transcranial magnetic stimulation, transcranial direct current stimulation, and various kinds of sensory stimulation, are successfully used as therapeutic tool in psychiatry and neurology and are also applied in cognitive neuroscience to study the functioning of the brain. ¹ For example, non-invasive brain stimulation is entering increasingly widespread use as a clinical intervention for neuropsychiatric disorders ^2-3, as a method to understand the neural mechanisms underlying cognition ⁴ and to enhance cognitive rehabilitation after stroke. ⁵ Sensory brain stimulation with various modalities, such as tactile, auditory and visual, could be effectively used in brain-computer interface systems to provide paralyzed patients with an alternative communication channel. ⁶ 

2.- The current review focuses largely on auditory stimulation approaches, but has largely ignored tactile sensory stimulation techniques that have long been used in closed-loop paradigms. Specifically, vibration or electrical stimulation has shown great promise in closed-loop neuromodulation approaches, and has recently been successfully applied to patient populations (e.g. stroke rehabilitation). I feel that this topic would strongly complement the sensory stimulation paradigms that the authors describe in the current work. Please add a brief description of this concept, with the following references as support.

T Kaufmann et al. (2013) Comparison of tactile, auditory, and visual modality for brain-computer interface use: a case study with a patient in the locked-in state. Frontiers in Neuroscience, 7:129

1. Biasiucci et al. (2018) Brain-actuated functional electrical stimulation elicits lasting arm motor recovery after stroke. Nature Communications, 9:2421

- I think the current review would also benefit from a brief discussion on how EEG-based cognitive engagement/arousal can be used in closed-loop paradigms. Specifically, recent non-invasive brain-computer interface work has found that user engagement can be successfully detected from scalp EEG and can help inform/assess task performance. This type of signal has already been shown to be successfully decoded from non-invasive human brain activity and fits well within the concept of "human endogenous rhythms" that the authors describe. Please briefly describe this topic and add the following references as support:

BJ Edelman et al. (2019). Noninvasive neuroimaging enhances continuous neural tracking for robotic device control. Science Robotics, 4(31):eaaw6844

J Faller et al. (2019). Regulation of arousal via online neurofeedback improves human performance in a demanding sensory-motor task. PNAS, 116:15

  We added text, as well as the recommended and other references:

For example, it was shown that the brain-actuated functional electrical stimulation elicits significant, clinically relevant, and lasting motor recovery in chronic stroke survivors due to involvement of the mechanisms of functional neuroplasticity. ¹⁴ Closed-loop vibration stimulation could effectively influence heart rhythm and stabilize the autonomic nervous system. ¹⁵ There are a number of studies demonstrating the advantages of closed-loop electroencephalography (EEG) utilization for human cognitive engagement and regulation of arousal to improve task performance. For example, EEG-based closed-loop system has been recently developed to increase user engagement through a continuous pursuit task and associated training paradigm. ¹⁶ EEG-based closed-loop brain–computer interface is shown to induce dynamically shifting arousal to affect online task performance. ¹⁷

3.- It would be interesting if the authors could comment on the future of closed-loop sensory stimulation paradigms. For example, are there promising new biomarker signals or sensory stimulation modalities that may rise in popularity in the near future? I feel that this prospective outlook would benefit the concluding remarks of the this work.

We added the next sentences to the conclusion:

The most promising seems to be the utilization of complex multimodal feedback from several rhythmic processes of the patient, including heart rate, respiratory rate, and human EEG oscillators. It would make the treatment interventions more personalized and effective.

Sincerely- Alexander Fedotchev and co-authors.

Reviewer 2 Report

1. The aims and contribution of the paper were not clear.
2. There are some grammar issues. The paper needs a whole revision.
3. The analysis method used in the paper was not described carefully.
4. In this study, only 12 volunteers suffering from different etiology pain participated in the study. This number was not enough.
5. The authors stated, “It was shown that after only a single treatment procedure the most significant changes are registered in the level of subjective pain ratings, which dropped by half. Significant pain reduction effects were accompanied by positive shifts in patient’s self-assessments of functional state and mood”, Explain that with the details.
6. Table 1 shows 14 studies were achieved in using automatic closed-loop feedback from human endogenous rhythms for non-invasive adaptive neurostimulation, and six of the 14 studies belong to the author of that paper “fedotchev”. The authors need to cite other studies but not for the authors.
7. The authors did not explore the state of the art carefully, they used seven out of 41 references to the author of that paper “fedotchev” i.e., 17, 18, 33, 35, 36, 40, and 41.
8. The results of the paper are not clear.
9. What are the differences between the previous methods used to close the feedback loop in adaptive neurostimulation and the suggested method?
10. Abstract, introduction, methodology, and conclusions are need to rewrite.

Author Response

Dear Reviewer #2:

Thank you very much for your stern but fair comments and helpful recommendations. We tried to take into account all your recommendations. Our replies are presented point by point below.

1. The aims and contribution of the paper were not clear.

We added the following sentence to the main text::

Present article aims to assess a state of the art in this specific line of research, where the parameters of closed-loop sensory stimulation are automatically modulated by human body rhythmical processes.

1. There are some grammar issues. The paper needs a whole revision.

Yes, we will use special MDPI service.

1. The analysis method used in the paper was not described carefully.

We added the following sentence:

Searches were conducted using OVID (Medline, Health Star, Embase + Embase Classic) and PubMed databases.

1. In this study, only 12 volunteers suffering from different etiology pain participated in the study. This number was not enough.

We agree, but it was a pilot study, and there are examples from the literature, where 10 participants (Choi et al., 2019; Ramirez et al., 2015) and 11 participants (Ehrlich et al., 2019) were used.. Despite the small sample of our patients, the differences found are statistically significant.

5. The authors stated, “It was shown that after only a single treatment procedure the most significant changes are registered in the level of subjective pain ratings, which dropped by half. Significant pain reduction effects were accompanied by positive shifts in patient’s self-assessments of functional state and mood”, Explain that with the details.

 We corrected the text as follows:

Significant pain reduction effects were accompanied by the relaxation reactions of the central nervous system (deepening of respiration, reduction of muscular tension) and positive shifts in patient’s self-assessments of well-being and mood.^.

1. Table 1 shows 14 studies were achieved in using automatic closed-loop feedback from human endogenous rhythms for non-invasive adaptive neurostimulation, and six of the 14 studies belong to the author of that paper “fedotchev”. The authors need to cite other studies but not for the authors.
2. The authors did not explore the state of the art carefully, they used seven out of 41 references to the author of that paper “fedotchev” i.e., 17, 18, 33, 35, 36, 40, and 41.

 Our article is devoted to a specific line of research related to the automatic modulation of sensory stimulations by human rhythmic processes. We were pioneers in this field in 1996, and, in addition to the publications mentioned (Fedotchev, 1996; Salansky et al., 1998), we have a utility model Russian patent (Fedotchev, Bondar, Semenov, 2008) which is used not only by our group in current research, but also in some clinical hospitals in Russia. Nevertheless, the presented mini-review demonstrates that this line of research is being intensively developed not only by our group, but also by many other researchers [ref  27-31, 34-36]. We believe that it would be useful for readers of JPM to familiarize themselves with the state of the art in this specific area.

1. The results of the paper are not clear.
2. What are the differences between the previous methods used to close the feedback loop in adaptive neurostimulation and the suggested method?

The main difference consists of automatic modulation of sensory stimulations by human rhythmic processes. Among the benefits of this approach there are high personalization of treatment, involvement of interoceptive signals and automatic, without conscious efforts of a person, control of therapeutic sensory stimulation. All these aspects are presented in Conclusion section.

1. Abstract, introduction, methodology, and conclusions are need to rewrite.

We corrected the text in accordance with the recommendations: we ordered special MDPI service to improve the text, we added accents in the introduction and conclusion, and added a number of references.

 Sincerely- Alexander Fedotchev and co-authors.

Round 2

Reviewer 2 Report

1. The paper still has a major issue with grammar. The paper needs the whole proofreading.
2. The identity of the paper was not clear. The type of this paper based on the submission type is a review paper, but in the abstract, the authors stated, “The proposed approach has been successfully tested on a model of analgesic electroneurostimulation with automatic control of the parameters of the stimulating current by the patient’s breathing rate”.

This means this is a research article. That sentence must be removed from the abstract because it will confuse the readers.

3. In line 89, the authors used the phrase “previously, 21, 22 we proposed”, instead of that, it is better to say, Fedotchev et. al [21], and Salansky et. al [22] proposed the use of on-line automatic sensory stimulation with the parameters modulated by the patient’s rhythmical processes, such as respiratory rate, heart rate, and electroencephalogram (EEG) rhythms.  
4. The authors have a problem when they referring to previous studies, as shown in line 98, “The clinic-like testing of the proposed approach was carried out on a model”. This sentence needs to rewrite as shown

The clinic-like testing of the proposed approach in [21] was carried out on a model.

5. The authors should know how to refer to the previous studies without confusing the readers.

Author Response

Dear Reviewer #2:

Thank you very much for your comments and highly helpful recommendations. Our responses and corrections are presented point by point below.

1. The paper still has a major issue with grammar. The paper needs the whole proofreading.

We used the MDPI English pre-edit service and corrected the text in accordance with their proofs. Additionally, whole proofreading of the paper was carried out by professional English translator, who made a number of corrections (shown by yellow in the revised paper).

 The identity of the paper was not clear. The type of this paper based on the submission type is a review paper, but in the abstract, the authors stated, “The proposed approach has been successfully tested on a model of analgesic electroneurostimulation with automatic control of the parameters of the stimulating current by the patient’s breathing rate”.

This means this is a research article. That sentence must be removed from the abstract because it will confuse the readers.

We removed this sentence from the abstract.

1. In line 89, the authors used the phrase “previously, 21, 22 we proposed”, instead of that, it is better to say, Fedotchev et. al [21], and Salansky et. al [22] proposed the use of on-line automatic sensory stimulation with the parameters modulated by the patient’s rhythmical processes, such as respiratory rate, heart rate, and electroencephalogram (EEG) rhythms.  

We corrected the phrase as recommended: In order to identify the appropriate way to close the feedback loop in adaptive neurostimulation procedures, Fedotchev, 1996 ²¹ and Salansky et al., 1998 ²² have previously proposed to use on-line automatic sensory stimulation with the parameters modulated by the patient’s own rhythmical processes, such as respiratory rate, heart rate, and electroencephalogram (EEG) rhythms..

 The authors have a problem when they referring to previous studies, as shown in line 98, “The clinic-like testing of the proposed approach was carried out on a model”. This sentence needs to rewrite as shown

The clinic-like testing of the proposed approach in [21] was carried out on a model.

We corrected this sentence in accordance with your recommendation: The clinic-like testing of the approach proposed in ²¹ was carried out on a model of analgesic electroneurostimulation with the automatic control of the parameters of the stimulating current by the patient’s breathing rate.

5. The authors should know how to refer to the previous studies without confusing the readers.

Thank you for your very helpful lesson how to refer to the previous studies.

Sincerely – Alexander Fedotchev & co-authors.

Author Response File: Author Response.pdf