PONE-D-21-31557Neural and behavioral adaptations to frontal theta neurofeedback training

PLOS ONE

Dear Dr. Kerick,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

1) In lines 54-55 authors postulated that neurofeedback (NF) "is a highly attention-demanding task that must be learned through extended deliberate practice like many skills." This is not in accordance with the fact that in their experiment they only give 5 sessions. This should be discussed. Even in operant conditioning learning that compromises survival, such a small number of sessions does not make learning happen; It is difficult then to believe that it happens when life is not threatened ...

2) lines 82-100: Up-regulation of Fmθ has been used to improve the cognitive performance in healthy young subjects. Up-regulation of Fmθ protocol should not be confused with the protocol to promote REDUCTION in theta power, used by Becerra et al. (2012), in which the subjects were older adults at risk of cognitive decline (evidenced by an excess of theta power for their age, when compared with normative values). Please review the rationale of this last paper.In this study, a lead was selected in each subject to give the NF. Although in 7 of 14 subjects a frontal lead was selected (in 3 from the experimental group and in 4 from the control group), Fz was never selected; i.e., no subject was down-regulated Fmθ. Therefore, the sentence in lines 98-100 ("Taken together, there is preliminary evidence that either up regulating or down-regulating Fmθ can potentially promote gains in executive performance of some tasks) is not true.A crucial point in this regard is that these older adults had excess theta at rest, and must be undergoing some compensatory process to correct this abnormality, since their cognitive performance is normal; while the Fmθ protocol of the other studies mentioned has been applied mainly to young subjects for whom the normality / abnormality of their EEG is unknown. 3) lines 105-108: Considering that accurate contingent feedback linking response and reward is required for optimal learning to occur, it’s difficult to disentangle whether NF training-related differences are due to reinforcement learning based on contingent reward mechanisms or increased/decreased theta power levels per se, or both.I consider that this paragraph forms the cornerstone of this study. Consequently, it must be very clearly formulated. In previous studies, two groups have been considered: an experimental group, in which Fmθ has been up-regulated, and a control sham group.  It is difficult to consider separately the theta increase at Fz lead and the accuracy of contingent feedback. Therefore I ask the authors to take in consideration the following facts to rephrase their research question:     • In the experimental group, there are:             o increased  θ power at Fz             o accurate contingent feedback to ensure optimal learning     • In the control group,:             o no optimal learning can be ensured because there is not an accurate contingent feedbackIf authors consider that the previous facts are incorrect, please explain why. 4) lines 113-114: "Another key limitation of existing NF studies, including those targeting Fmθ, is that they modulate neural activity only in one direction (either solely up-modulation or solely down-modulation)." The authors should explain why they do it; that is, their rationale based on EEG activity during attention tasks (Gevins et al., 1997). 5) It must be made very clearly established that this doubt about the placebo sham treatment is only applicable to the Fmθ protocol. However, when using protocols other than this one, the argument that attention could be the one that increased theta activity in Fz has no place. 6) I agree with Reviewer 2 that it is difficult to reach the conclusions the authors reach from the results presented. Perhaps by assembling the results in another way, the authors' conclusion could be accepted, but it is not clear to me in the current form. 7) Not having solved this point (6), it is difficult to form an opinion of the Discussion.

Please submit your revised manuscript by Feb 24 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Thalia Fernandez, Ph.D.

Academic Editor

PLOS ONE

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JA: Research was sponsored by the Army Research Laboratory and was accomplished under Cooperative Agreement Number W911NF-21-2-0097. The views and conclusions contained in this document are those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of the Army Research Laboratory or the U.S. Government. The U.S. Government is authorized to reproduce and distribute reprints for Government purposes notwithstanding any copyright notation herein.

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Additional Editor Comments:

1) In lines 54-55 authors postulated that neurofeedback (NF) "is a highly attention-demanding task that must be learned through extended deliberate practice like many skills." This is not in accordance with the fact that in their experiment they only give 5 sessions.

2) lines 82-100: Up-regulation of Fmθ has been used to improve the cognitive performance in healthy young subjects. Up-regulation of Fmθ protocol should not be confused with the protocol to promote REDUCTION in theta power, used by Becerra et al. (2012), in which the subjects were older adults at risk of cognitive decline (evidenced by an excess of theta power for their age, when compared with normative values). Please review the rationale of this last paper.

In this study, a lead was selected in each subject to give the NF. Although in 7 of 14 subjects a frontal lead was selected (in 3 from the experimental group and in 4 from the control group), Fz was never selected; i.e., no subject was down-regulated Fmθ. Therefore, the sentence in lines 98-100 ("Taken together, there is preliminary evidence that either up regulating or down-regulating Fmθ can potentially promote gains in executive performance of some tasks) is not true.

A crucial point in this regard is that these older adults had excess theta at rest, and must be undergoing some compensatory process to correct this abnormality, since their cognitive performance is normal; while the Fmθ protocol of the other studies mentioned has been applied mainly to young subjects for whom the normality / abnormality of their EEG is unknown.

3) lines 105-108: Considering that accurate contingent feedback linking response and reward is required for optimal learning to occur, it’s difficult to disentangle whether NF training-related differences are due to reinforcement learning based on contingent reward mechanisms or increased/decreased theta power levels per se, or both.

I consider that this paragraph forms the cornerstone of this study. Consequently, it must be very clearly formulated. In previous studies, two groups have been considered: an experimental group, in which Fmθ has been up-regulated, and a control sham group. It is difficult to consider separately the theta increase at Fz lead and the accuracy of contingent feedback. Therefore I ask the authors to take in consideration the following facts to rephrase their research question:

• In the experimental group, there are:

o increased θ power at Fz

o accurate contingent feedback to ensure optimal learning

• In the control group,:

o no optimal learning can be ensured because there is not an accurate contingent feedback

If authors consider that the previous facts are incorrect, please explain why.

4) lines 113-114: "Another key limitation of existing NF studies, including those targeting Fm�, is that they modulate neural activity only in one direction (either solely up-modulation or solely down-modulation)." The authors should explain why they do it; that is, their rationale based on EEG activity during attention tasks (Gevins et al., 1997).

5) It must be made very clearly established that this doubt about the placebo sham treatment is only applicable to the Fm protocol. However, when using protocols other than this one, the argument that attention could be the one that increased theta activity in Fz has no place.

6) I agree with Reviewer 2 that it is difficult to reach the conclusions the authors reach from the results presented. Perhaps by assembling the results in another way, the authors' conclusion could be accepted, but it is not clear to me in the current form.

7) Not having solved this point, it is difficult to form an opinion of the Discussion.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #3: No

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: In literature, there is no consensus of how to design aт ultimate neurofeedback study: what EEG parameter to train, what instruction to give, what a comparison neurofeedback option (SHAM?) to use, and what behavioral/neuronal indexes apply to measure the changes.

This study uses a good rational for selection a neurofeedback study: 1) a frontal midline theta rhythm (4-7 Hz) measured at FCz selected as a neurofeedback parameter. 2) No specific instruction was done to modulate the parameter. 3) Reaction time in shooting task (SH) and EEG spectra were used to measure pre-post differences. 4) Two groups with the two types of NF procedures: a) steadily increase theta – INC, and b) alternatively increase/decrease theta - ALT. The study required a lot of hard work of skilled professionals.

However, looking at the results presented in Fig. 4-10, I can’t say that the results are impressive. My impression is that no differences between the groups are found. To prove the opposite (the one that the authors claim in the text), the authors should try to assemble the results in a different and condensed way.

Further, if we accept the results as positive (i.e. the study shows changes between the groups in EEG spectra and behavioral parameters) the Discussion is worth to read.

Reviewer #2: This study encompasses de comparison between two different neurofeedback protocols (increase of Theta and increase/decrease Theta) which aimed at assessing the specificity of NF training overcoming the methodological difficulties of sham and placebo groups.

The authors did a great job, the methods are clear, and the analyses are very good. Just in case, the authors might be interested in the Bayesian LM (i.e. https://pubmed.ncbi.nlm.nih.gov/33486138/)

Here my minor comments:

Intro:

L 93 The authors state that less NF research were down to down training Theta band, however there is a large literature in ADHD which in fact trained down-regulation, although mainly together with up-regulation of the Beta band. This might be mentioned. Here a new reference

Arnold, L. Eugene, Martijn Arns, Justin Barterian, Rachel Bergman, Sarah Black, C. Keith Conners, Shea Connor, u. a. „Double-Blind Placebo-Controlled Randomized Clinical Trial of Neurofeedback for Attention-Deficit/Hyperactivity Disorder With 13 Month Follow-Up“. Journal of the American Academy of Child & Adolescent Psychiatry, 25. August 2020. https://doi.org/10.1016/j.jaac.2020.07.906.

Methods and discussion: Are clear and well written. However, I miss the question regarding specificity and I would recommend performing an additional analysis, which takes into account the block, and session wise learning (i.e. blocke wise / session wise slope on Task performance) and introduce this into the model of the No-go Task. As far as I understood, this was not made. It would add important evidence (or not) of specify of the training which is an important topic.

Reviewer #3: The research question of this study is quite interesting.

However, the proposed methodology does not answer the question. The major problem is that the hypotheses are false, i.e., they are presented as mutually exclusive when, in fact, they are not.

I present some issues that the authors should consider:

INTRODUCTION

- There are several conceptual inaccuracies throughout the introduction. The scope of NF training (i.e., the operant conditioning of brain activity) should be kept in mind in order to avoid mereological fallacies (e.g. lines 67 - 68: NF does NOT train executive control, it trains changes in brain activity, which are not equivalent).

- The authors present a very poor review of previous research regarding fmTheta NF. Only 3 previous studies are shown. More importantly, the 3 studies follow very different rationales:

1. Enriquez-Geppert et al., 2014. They sought to increase fmTheta using NF based on task-induced theta, which is very different to resting-state, task-independent theta activity.

2. Brandmeyer & Delorme, 2020. They also sought to increase fmTheta using NF based on the characteristics of task-specific brain activity, that is, during meditation.

3. Becerra et al., 2012. The description of this article in the introduction is mistaken. Moreover, the rationale behind the NFB treatment has nothing to do with the task-specific fmTheta activity.

- Lines 106-108: “(…)it’s difficult to disentangle whether NF training-related differences are due to reinforcement learning based on contingent reward mechanisms or increased/decreased theta power levels per se, or both.” They are not mutually exclusive. Contingency is a condition for learning to occur. Increases or decreases in theta activity may be a consequence of training (which always involves contingency) or a byproduct of changes in another variable.

- Lines 108-112: The concepts of contingency and learning are inaccurate. The need that the authors mention to implement control conditions with contingent reward is not supported by the previous ideas.

OVERALL PROBLEMS:

- EEG was recorded exclusively during NF training, which may not reflect the EEG activity of the individuals at rest.

- As the authors stated “It is a highly attention-demanding task that must be learned through extended deliberate practice like many skills” (lines 54-55). For this reason, 5 sessions may be insufficient for the actual NF learning to occur.

- Learning curves for each individual should be taken into consideration to decide wether the participant actually learned to modify what the NF protocol intended to modify.

- The change in fmTheta may actually be due to the SH task or the rich and novelty of the VR. The NF protocol could have nothing to do with it.

- An adequate methodology should include, at least, 2 other control groups: One that receives contingent reinforcement for the reduction of fmTheta and another group that receives SHAM feedback. Only then can the research question be truly addressed.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Mauricio González-López

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PONE-D-21-31557R1Neural and behavioral adaptations to frontal theta neurofeedback trainingPLOS ONE

Dear Dr. Kerick,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

The reviewers and I think that the authors have improved the manuscript substantially, meanly the Introduction. However, the current version of the manuscript does not fully ready for publication yet.

Although the response letter addressed the reviewers comments, the manuscript still does not reflect what was written in the response letter.  I suggest that the authors indicate precisely the lines of the document in which these changes are reflected.

The most serious problem of the article is the very small number of sessions. It is a pity that only 5 sessions have been applied, because in my opinion they are insufficient to reach a conclusion. Please review Alatorre-Cruz et al. (2022). In the penultimate paragraph of their discussion ("A strength of our study is that 30 sessions of treatment were applied...") reference is made to John Garcia's classic work on Pavlovian flavor conditioning. Even in extreme cases of survival, it is sometimes not possible to establish learning with a few training sessions. The experiment carried out in this paper is not related to survival. Therefore, although the exposed theory is interesting, it should be handled as a proof of concept without trying to reach conclusions based on the experiment. The Discussion must be much more critical regarding this weakness of the study.

There are attached some suggestions that could help improve the introduction.

Please submit your revised manuscript by Jul 18 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Thalia Fernandez, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments:

The reviewers and I think that the authors have improved the manuscript substantially, meanly the Introduction. However, the current version of the manuscript does not fully ready for publication yet.

Although the response letter addressed the reviewers comments, the manuscript still does not reflect what was written in the response letter. I suggest that the authors indicate precisely the lines of the document in which these changes are reflected.

The most serious problem of the article is the very small number of sessions. It is a pity that only 5 sessions have been applied, because in my opinion they are insufficient to reach a conclusion. Please review Alatorre-Cruz et al. (2022). In the penultimate paragraph of their discussion ("A strength of our study is that 30 sessions of treatment were applied...") reference is made to John Garcia's classic work on Pavlovian flavor conditioning. Even in extreme cases of survival, it is sometimes not possible to establish learning with a few training sessions. The experiment carried out in this paper is not related to survival. Therefore, although the exposed theory is interesting, it should be handled as a proof of concept without trying to reach conclusions based on the experiment. The Discussion must be much more critical regarding this weakness of the study.

Here are some suggestions that could help improve the introduction:

Introduction

1.- Neurofeedback (NF) is a psychophysiological training, therefore there must be scientific evidence of a clear relationship between the particular neurophysiological marker targeted by neurofeedback and the behavioral or cognitive process being studied. This is not clear in the description of NF the authors give.

2.- line 51 & 55

"involves defining: i) the general goal;..."

"Depending on one’s goals, training..."

researcher's goal regarding what? conduct? EEG? another thing?

3.- line 87-90

"For example, Enriquez-Geppert et al., (2014) found that N-back and task-switching performance improved pre-post training in both NF and sham groups, but to a greater extent in the NF group; however, performance on stop-signal and Stroop tasks did not change as a function of real or sham training."

If both groups improved their performance, this improvement is not an exclusive consequence of operant conditioning. What happened in the Sham group could be a consequence of other factors (see Alatorre et al 2022).

4.- lines 94-100

"Less research has used NF to promote decreases in theta power. In one study using this protocol, older participants instructed to sustain decreased levels of theta power, presented as the lead where theta/alpha ratios were most abnormally high (in 6 of 14 total subjects a frontal lead was identified), the NF group exhibited higher performance gains on verbal comprehension and verbal IQ relative to a random feedback group, but no differences were observed on executive IQ (Becerra et al., 2011). Taken together, there is preliminary evidence that either up-regulating or down-regulating Fm� can potentially promote gains in executive performance of some tasks."

I invite the authors to review the article by Alatorre-Cruz et al. (2022), recently published by the same research group as Becerra et al. (2012). I consider that it is very important to highlight that the healthy older adults in both articles had an electroencephalographic risk of developing cognitive impairment (MCI or dementia); that risk consisted of having an abnormally high value of absolute power theta. This marks a big difference between the two types of participants that are pointed out: some are healthy young adults (it is not known if theta activity is normal or not) and others are clinically healthy older adults with abnormal theta activity. In the former, the objective is to improve performance but in the latter, the objective is to prevent cognitive deterioration.

The authors talk about the theta/alpha ratio, but this seems to be an error because it is not directly related to the study' rationale and is not mentioned by Alatorre-Cruz et al., who said they are replicating the Becerra experiment and evaluating a 1-year follow-up.

5.- lines 105-108

"Considering that accurate contingent feedback linking response and reward is required for optimal learning to occur (Sterman & Egner, 2006), it’s difficult to disentangle whether NF training-related differences are due to reinforcement learning based on contingent reward mechanisms or increased/decreased theta power levels per se, or both. Contingent reward enables the accurate coupling of top-down goals and bottom-up stimulus processing (error monitoring and control) that may account for the learning differences observed in previous sham control studies. However, a need exists to implement control conditions in which accurate contingent reward is also inherent in the training and consistent with experimental NF training conditions. However, a need exists to implement control conditions in which accurate contingent reward is also inherent in the training and consistent with experimental NF training conditions."

I exhort to the authors to better explain the ideas because I do not understand. The conclusions that are given throughout the paragraph are not derived from what has been said previously.

6.- lines 113- 117

"Another key limitation of existing NF studies, including those targeting Fm�, is that they modulate neural activity only in one direction (either solely up-modulation or solely down-modulation). However, to support adaptive behavior in real-world situations, neural activity must exhibit dynamic variability such that activation and inhibition must be coordinated in response to varied internal/external demands. "

References are required

7.- lines 123-127

" In these views, it is not sustained increases or decreases in theta (or any other neural process) that are most optimal for adaptive cognitive performance. Rather, dynamically shifting between increasing and decreasing activity (up and down modulation) might promote more efficient neural adaptations in support of superior executive control performance."

Is this the authors' interpretation of what was previously said or are there experiments that prove it?

8.- lines 128-131

Representing another key issue, analogous to the above on sham control issues, the Fm� activation targeted by NF is often confounded with the neural functions required to modulate brain responses in NF protocols. Specifically, NF is an attention-demanding task requiring the activation of frontal executive control networks during training irrespective of the frequency or region targeted by feedback

It is not clear "the Fm� activation targeted by NF is often confounded with the neural functions required to modulate brain responses in NF protocols."

9.- line 141:

"This possibility obscures extant findings on Fm��modulation, such that observed effects of Fm��modulation on the brain and performance may not be driven by NF per se (i.e. reinforcement learning) but instead by differences in cognitive control strategies and effort levels when attempting NF (i.e. theta activation)"

When authors say "(i.e. reinforcement learning)" are they referring to "operant conditioning"? Terms must be used precisely. Operant conditioning can be done using reinforcers or punishments.

10.- lines 180-189

" We tested two competing hypotheses regarding the effects of NF training on concomitant levels of Fm��power. If Fm��changes are due to reinforcement learning afforded by accurate contingent feedback, then the INC group should exhibit greater increases within and across training sessions. If Fm��changes are due to greater executive task demands associated with task-switching of top-down goals, then the ALT group should exhibit greater increases within and across training sessions. Assuming that Fm��is effectively shaped by reinforcement learning in both groups, we also hypothesized that the ALT group will improve at a greater rate on the Go-NoGo shooting task over sessions. Furthermore, we hypothesized higher Fm��power in the ALT group during performance of the Go-NoGo task over sessions, suggesting more refined task specificity and context dependent adaptations, or more specific dynamics-to-function mapping, in the ALT group."

Please try to explain more clearly the rationale of these hypotheses.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #3: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #3: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #3: No

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I think that the authors have improved the manuscript substantially. I also think that the field needs to see the results of this important study.

Reviewer #3: The authors have addressed in an adequate manner the reviewers comments in their response letter. The aim of the study seems more clear to me now.

However, the manuscript still does not reflect what was written in the response letter to the reviewers. The issue of mereological fallacy is still found throughout the manuscript (e.g. lines 67 & 70).

Please make sure that the whole manuscript is coherent with the answers that you have provided to the reviewers.

Moreover, I encourage the author to include the results of the comparison between responders and non-responders. Even though you have found no differences, this is an important issue, because it is directñy related to your research question.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #3: Yes: Mauricio González-López

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Attachments

Attachment

Submitted filename: R1 comments.docx

PONE-D-21-31557R2Neural and behavioral adaptations to frontal theta neurofeedback training

PLOS ONE

Dear Dr. Kerick,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Taking into consideration Reviewer 3's comments, the authors could discuss as a weakness of their project the fact that the hypotheses they considered are not mutually exclusive. Being the current document a proof of concept, mainly due to the small sample size, it is reasonable to assume that performing the experiment will overcome this weakness. Please consider making it explicit in the title that this is a proof of concept.

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Thalia Fernandez, Ph.D.

Academic Editor

PLOS ONE

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Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #3: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #3: Partly

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #3: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #3: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #3: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #3: This paper addresses the question of whether the previously reported increases in FM-theta activity as a consequence of neurofeedback training could be actually attributed to the actual feedback procedure (i.e., administering a contingent reward to ongoing changes in fm-theta increases during training) or if they could be a consequence of non-specific executive control processes involved in NFB training.

In order to answer the research question, the authors aimed to test two competing hypotheses regarding the effects of NFB training on fm-theta power:

1. If Fm-theta changes are due to self-regulation afforded by accurate contingent feedback, then the INC group should exhibit greater increases within and across training sessions, and

2. If, on the other hand, Fm-theta increases more in the ALT group or no differences are observed between groups, then self-regulation based on accurate contingent reward mechanisms underlying reinforcement learning would be challenged.

If this were taken to be true, then it would involve that actual operant learning as a consequence of providing contingent feedback and the non-specific executive control processes are mutually exclusive, which is not the case. The increases in fm-theta could also be a result of a combination of these factors or they could also be attributable to another variable altogether (for example expectancy, i.e., placebo effect). Moreover, the ALT group could actually get better at increasing fm-theta activity because contingent feedback provides them with better contextual cues to achieve discrimination of their own neurophysiological state.

Also, the authors should keep in mind that an actual increase in behavior is necessary for a stimulus to be a reinforcer, contingency alone is not sufficient to establish the functionality of a stimulus as a reward (reinforcer). That is, for the feedback to actually be a reinforcer, one must see an increase in the behavior that is pretended to be reinforced.

Since the experimental design assumes the hypotheses to be mutually exclusive, the research method proposed by the authors does not adequately address their research question.

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Reviewer #3: Yes: Mauricio González-López

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Neural and behavioral adaptations to frontal theta neurofeedback training: A proof of concept study

PONE-D-21-31557R3

Dear Dr. Kerick,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Thalia Fernandez, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #3: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #3: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #3: (No Response)

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #3: Yes: Mauricio González-López

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