EEG-Neurofeedback Targeting Gamma Oscillations at the Parieto-Occipital Region Reduces Pain Perception

Reviewer #1 (Public review):

Summary:

The authors investigate whether EEG neurofeedback (NFB) can be used to increase spontaneous parieto-occipital gamma oscillations and thereby reduce experimentally induced pain. Healthy participants were randomly assigned to active or sham neurofeedback and completed three consecutive neurofeedback blocks with concurrent EEG measurements and phasic painful stimulation. The study addresses a relevant question regarding the causal role of spontaneous gamma oscillations in pain perception and the potential of neurofeedback as a non-pharmacological pain intervention. While the reported findings appear consistent with an association between increased gamma power and reduced pain in a subset of participants, the current analyses do not provide sufficient support for the strong causal conclusions drawn by the authors.

Strengths:

(1) The study addresses an important and timely research question with potential implications for EEG-based neurofeedback approaches to pain modulation.

(2) The sample size is relatively large for an experimental EEG neurofeedback study and includes a sham-control condition.

(3) The manuscript is generally well written and clearly organized.

(3) The authors address an important methodological concern regarding EMG contamination of gamma-band activity by including additional EMG recordings in a subset of participants.

Weaknesses:

(1) The manuscript frequently presents the relationship between spontaneous gamma oscillations and pain perception as established fact. Given the continuing debate regarding the functional significance of EEG gamma oscillations in pain processing, these statements should be moderated.

(2) The responder analysis is the most serious methodological concern. Participants in the active group were retrospectively classified as "responders" based on increased gamma power after neurofeedback, and only these participants appear to have been included in the primary analyses and matched to sham participants. As only 23 of 44 participants (52%) met this criterion, the responder rate alone does not demonstrate successful neurofeedback-induced gamma modulation. More importantly, selecting participants based on the outcome variable and subsequently testing that same outcome constitutes circular analysis (double dipping), invalidating the statistical inference. Consequently, the reported effects should be interpreted as an association within a post hoc selected subgroup rather than evidence that neurofeedback increased gamma activity and reduced pain.

(3) The criterion for successful neurofeedback-induced gamma modulation was not prespecified. It is therefore unclear whether successful modulation was defined by the responder classification, the main effect of session, the group × session interaction, or one of the post hoc comparisons.

(4) Several methodological details reduce the reproducibility and replicability of the study. The spectral analysis does not clearly describe how trial-wise power estimates were aggregated within participants before group-level analyses, and the preprocessing pipeline includes manual ICA-based artifact rejection without specifying the criteria used for component selection. In addition, the analysis pipeline and custom neurofeedback software should be made publicly available to enable independent reproduction and verification of the reported findings.

(5) The neurofeedback implementation also raises questions. Updating the feedback only once per second using a 2-s sliding window results in discontinuous visual feedback that may reduce feedback quality and could introduce visually evoked activity. In addition, the viewing distance of approximately 30 cm likely required substantial eye movements while following the moving feedback object.

(6) The muscle-confound analysis is insufficiently documented. EMG recordings were acquired only in the second cohort, but the manuscript does not clearly state how many participants contributed to this analysis or whether responder selection was performed before or after restricting the sample. These details should be explicitly reported.

Reviewer #2 (Public review):

Summary:

The authors investigated whether neurofeedback (NFB) training targeting spontaneous gamma oscillations (30-60 Hz) at the parieto-occipital region (Pz electrode) could reduce experimental pain perception. They randomized 88 healthy participants to active or sham NFB groups across two cohorts (44 each). Active NFB consisted of real-time feedback based on participants' own gamma power; sham NFB consisted of the preceding participant's gamma power. Participants completed three ~16-min sessions, and approximately 52% of active NFB participants showed increased gamma power in session 3 and were considered responders. Analyses restricted to these 23 responders (matched with 23 sham controls) showed reduced pain intensity, unpleasantness, and laser-evoked potential (LEP) amplitudes, with a significant negative correlation between gamma power and pain intensity after session 3.

Strengths:

(1) The distinction between spontaneous and stimulus-evoked gamma oscillations in pain processing is theoretically important.

(2) The rationale for targeting spontaneous gamma via NFB is clearly articulated.

(3) The study was sham-controlled, and the blinding was adequate.

(4) The authors commendably ran a second cohort (n=44) with simultaneous posterior neck EMG recording to address the critical concern of muscle artifact contamination of gamma, in response to a previous review

Weaknesses:

(1) The most critical issue is about the exclusion of non-responders from the analysis. I find this problematic, as the reasoning becomes circular (selecting the participants who managed to increased gamma and then asking whether gamma NFB influenced pain), effect sizes are inflated, and the selection itself may introduce biases. For example, the responders may differ from the non-responders with respect to other characteristics (better attention skills, better self-regulation, etc). It would be more principled to present the results for the entire sample and only present the responder analysis as a secondary analysis. In the preregistration, the responder-only analysis was not mentioned.

(2) Another critical point is about the causal claims made in the abstract, introduction, and discussion. Given that the current results provide only correlational evidence in a subsample, the language should be revised to avoid overinterpretation. If the authors can demonstrate a significant mediation effect (NFB group -> gamma change -> pain change), they may be able to argue that increases in gamma activity mediate the observed reduction in pain.

Minor points:

(1) For the sham procedure, the authors used the preceding participant's gamma data for feedback. This raises two questions: How was this handled for the first participant? Did the authors check the discrepancy between actual gamma and presented gamma in the sham NFB group?

(2) Was baseline gamma power comparable between groups?

Reviewer #3 (Public review):

Summary:

The authors aimed to test whether spontaneous gamma-band oscillations over the parieto-occipital region can be volitionally upregulated using EEG neurofeedback, and whether this upregulation reduces subsequent pain perception and nociceptive-evoked brain responses. Gamma-band activity has been repeatedly associated with pain processing, but most available evidence remains correlational, and previous attempts to modulate pain-related gamma activity using non-invasive stimulation have not produced robust analgesic effects. The present study therefore addresses an important question: whether real-time neurofeedback may provide a more effective way to train endogenous gamma activity and thereby influence pain.

Strengths:

A major strength of the study is the use of an active/sham neurofeedback design. The authors also combine subjective pain ratings with laser-evoked potentials, which provides converging behavioural and neurophysiological outcome measures. The manuscript is clearly written overall, and the study addresses a question of broad interest for pain neuroscience and neurofeedback research.

Weaknesses:

A number of aspects limit the strength of the conclusions. The first and most important issue concerns the interpretation of scalp gamma-band activity. Gamma-band oscillations recorded with scalp EEG are difficult to measure reliably, are not observable in all participants, and can be strongly affected by muscle activity. The authors acknowledge this issue and include posterior neck EMG, but the control remains limited. A lack of correlation between one posterior neck EMG channel and Pz gamma power is not sufficient to exclude muscle contamination, especially because gamma-band artifacts can arise from multiple muscle groups and may not be well captured by a single EMG channel. This is particularly important because changes in posture, facial tension, breathing, and arousal could all influence high-frequency scalp activity.

Second, the evidence for a causal relationship between parieto-occipital gamma activity and pain perception should be interpreted cautiously. The authors show that gamma power increased in approximately half of the active neurofeedback participants and that these responders showed reduced pain ratings and laser-evoked potentials. However, because the main analgesic effect is tied to responder classification, it remains difficult to separate the specific effect of gamma upregulation from broader individual differences in task engagement, suggestibility, relaxation ability, attentional state, or neurofeedback learning capacity.

A third limitation concerns the control condition and blinding. Participants were reportedly blinded to group allocation, and the credibility ratings appear similar between groups, which is reassuring. However, it is not clear whether the experimenters were also blinded during data collection and interaction with participants. This matters because neurofeedback studies are particularly vulnerable to expectancy.

The choice of the two neurofeedback scenarios requires clearer justification. The manuscript describes a deep ocean scene followed by a seaside scene with relaxation instructions, but it is not clear why these two scenarios were selected, and whether they were matched for attentional engagement and affective content. This is not a minor point, because both groups showed reductions in pain ratings after the entire neurofeedback procedure.

The comparison with tACS is interesting but currently underdeveloped. The authors suggest that neurofeedback may succeed where gamma-frequency tACS failed because it allows real-time, personalized, self-regulatory modulation of ongoing activity. This is plausible, but the manuscript should discuss this distinction more deeply. Neurofeedback may not simply be a different way of modulating gamma; it may recruit volitional control, attentional engagement, immersion, expectation, etc. These mechanisms could be central to the observed pain reduction and may partly explain why neurofeedback effects differ from those of externally applied stimulation.

Overall, this is an interesting study that introduces a promising neurofeedback approach for experimental pain modulation. The findings are encouraging, especially the convergence between subjective ratings and laser-evoked potentials in responders. However, the conclusions should be tempered. The current evidence supports the feasibility of training gamma-band activity in a subset of participants and suggests that successful training is associated with reduced experimental pain.

Author response:

Reviewer #1 (Public review):

R1-Q1: The manuscript frequently presents the relationship between spontaneous gamma oscillations and pain perception as established fact. Given the continuing debate regarding the functional significance of EEG gamma oscillations in pain processing, these statements should be moderated.

We thank the reviewer for raising this important and thoughtful point. We agree that the relationship between spontaneous gamma oscillations and pain perception remains a matter of active debate, and we will moderate these statements throughout the manuscript. We will acknowledge the ongoing debate and present the gamma-pain relationship as an active area of investigation rather than settled fact.

R1-Q2: The responder analysis is the most serious methodological concern. Participants in the active group were retrospectively classified as 'responders' based on increased gamma power after neurofeedback, and only these participants appear to have been included in the primary analyses and matched to sham participants. As only 23 of 44 participants (52%) met this criterion, the responder rate alone does not demonstrate successful neurofeedback-induced gamma modulation. More importantly, selecting participants based on the outcome variable and subsequently testing that same outcome constitutes circular analysis (double dipping), invalidating the statistical inference. Consequently, the reported effects should be interpreted as an association within a post hoc selected subgroup rather than evidence that neurofeedback increased gamma activity and reduced pain.

We appreciate this careful critique. We wish to clarify the rationale behind our analytical approach and address the concern.

A well-established finding in the neurofeedback literature is that a substantial proportion of participants are "non-learners" — individuals who, despite receiving real feedback, fail to achieve effective control over the targeted neural activity. This is not a failure of the intervention, but reflects individual differences in neurofeedback learning capacity. Our core research question is therefore: "Among individuals who can successfully learn to upregulate gamma oscillations, does this upregulation reduce pain perception and nociceptive brain responses?"

To address the circularity concern and improve transparency, we will make the following revisions:

- We will reframe the wording from "NFB increases gamma and reduces pain" to "Successful gamma upregulation via NFB is associated with reduced pain in those who achieve it." All causal language will be replaced with appropriately cautious, correlation-based terminology.

- We will report full-sample results for completeness.

R1-Q3: The criterion for successful neurofeedback-induced gamma modulation was not prespecified. It is therefore unclear whether successful modulation was defined by the responder classification, the main effect of session, the group × session interaction, or one of the post hoc comparisons.

We thank the reviewer for requesting this clarification. We will specify the exact criterion in the revised manuscript, i.e., a participant was classified as a responder if their post-intervention gamma power minus pre-intervention gamma power was positive (i.e., an increase in gamma power following the neurofeedback intervention).

R1-Q4: Several methodological details reduce the reproducibility and replicability of the study. The spectral analysis does not clearly describe how trial-wise power estimates were aggregated within participants before group-level analyses, and the preprocessing pipeline includes manual ICA-based artifact rejection without specifying the criteria used for component selection. In addition, the analysis pipeline and custom neurofeedback software should be made publicly available to enable independent reproduction and verification of the reported findings.

We thank the reviewer for these constructive suggestions. We will supplement and refine the methodological details in the revised manuscript, and we will make the analysis code and the experimental program (including the custom neurofeedback software) publicly available via an open repository.

R1-Q5: Updating the feedback only once per second using a 2-s sliding window results in discontinuous visual feedback that may reduce feedback quality and could introduce visually evoked activity. In addition, the viewing distance of approximately 30 cm likely required substantial eye movements while following the moving feedback object.

We will discuss the limitations of the discontinuous visual feedback and the viewing distance in the revised manuscript. We acknowledge these as valid methodological concerns and will address them as limitations in the Discussion.

R1-Q6: The muscle-confound analysis is insufficiently documented. EMG recordings were acquired only in the second cohort, but the manuscript does not clearly state how many participants contributed to this analysis or whether responder selection was performed before or after restricting the sample. These details should be explicitly reported.

We thank the reviewer for pointing out that the description of the muscle-confound analysis was insufficiently detailed. In the revised manuscript, we will clarify the EMG analysis procedures and explicitly report: (a) the exact number of participants contributing to the EMG analysis; (b) the cohort from which they were drawn; and (c) whether responder selection was performed before or after restricting the sample for EMG analysis.

Reviewer #2 (Public review):

R2-Q1: The most critical issue is about the exclusion of non-responders from the analysis. I find this problematic, as the reasoning becomes circular (selecting the participants who managed to increase gamma and then asking whether gamma NFB influenced pain), effect sizes are inflated, and the selection itself may introduce biases. For example, the responders may differ from the non-responders with respect to other characteristics (better attention skills, better self-regulation, etc). It would be more principled to present the results for the entire sample and only present the responder analysis as a secondary analysis. In the preregistration, the responder-only analysis was not mentioned.

As detailed in our response to R1-Q2, the responder analysis reflects a conceptually motivated subgroup defined by successful neurofeedback learning — a well-documented challenge in NFB research where many participants are non-learners. Our central question is whether successful gamma upregulation (among those capable of achieving it) is associated with pain reduction. We will make this rationale explicit in the revised manuscript. We will also: (a) transparently report full-sample results; (b) discuss potential biases introduced by subgroup selection (e.g., differences in attention, self-regulation); and (c) acknowledge the lack of preregistration for the responder analysis.

R2-Q2: Another critical point is about the causal claims made in the abstract, introduction, and discussion. Given that the current results provide only correlational evidence in a subsample, the language should be revised to avoid overinterpretation. If the authors can demonstrate a significant mediation effect (NFB group → gamma change → pain change), they may be able to argue that increases in gamma activity mediate the observed reduction in pain.

We will substantially revise the language throughout the manuscript to avoid causal claims. We also plan to conduct a formal mediation analysis (NFB group → gamma change → pain change) to test whether changes in gamma activity statistically mediate the observed pain reduction.

R2-Q3: For the sham procedure, the authors used the preceding participant's gamma data for feedback. This raises two questions: How was this handled for the first participant? Did the authors check the discrepancy between actual gamma and presented gamma in the sham NFB group?

We thank the reviewer for raising this point, and we will clarify both points in the revised manuscript. (a) Because group assignment was randomized, the first participant could in principle have been assigned to the sham group. To prepare for this possibility, we collected EEG data from one participant in advance (equivalent to pilot data) to serve as the sham feedback signal, had the first participant been assigned to the sham group. In the actual experiment, however, the first participant was randomly assigned to the active group, so this pre-collected dataset was never used. (b) We will also compare the discrepancy between actual gamma power and the sham feedback signal in the sham group, and report this result in the revised manuscript.

R2-Q4: Was baseline gamma power comparable between groups?

We thank the reviewer for this suggestion. We will report and compare baseline gamma power between the active and sham groups in the revised manuscript.

Reviewer #3 (Public review):

R3-Q1: Gamma-band oscillations recorded with scalp EEG are difficult to measure reliably, are not observable in all participants, and can be strongly affected by muscle activity. The authors acknowledge this issue and include posterior neck EMG, but the control remains limited. A lack of correlation between one posterior neck EMG channel and Pz gamma power is not sufficient to exclude muscle contamination, especially because gamma-band artifacts can arise from multiple muscle groups and may not be well captured by a single EMG channel. This is particularly important because changes in posture, facial tension, breathing, and arousal could all influence high-frequency scalp activity.

We thank the reviewer for this important suggestion. We will revise the manuscript to discuss more explicitly the inherent difficulty of recording pure gamma-band oscillations with scalp EEG. We will acknowledge that scalp gamma is not reliably observable in all participants, is vulnerable to contamination from multiple muscle sources, and that a single posterior neck EMG channel provides only limited control. We will also discuss the possibility that changes in posture, facial tension, breathing, and arousal may contribute to high-frequency scalp activity.

R3-Q2: The evidence for a causal relationship between parieto-occipital gamma activity and pain perception should be interpreted cautiously. The authors show that gamma power increased in approximately half of the active neurofeedback participants and that these responders showed reduced pain ratings and laser-evoked potentials. However, because the main analgesic effect is tied to responder classification, it remains difficult to separate the specific effect of gamma upregulation from broader individual differences in task engagement, suggestibility, relaxation ability, attentional state, or neurofeedback learning capacity.

We appreciate the reviewer's careful consideration of this point. We will temper our conclusions, presenting the current evidence as demonstrating the feasibility of gamma-band neurofeedback training in a subset of participants and an association between successful training and pain reduction, rather than a demonstrated causal relationship. We will discuss individual differences (attention, suggestibility, relaxation ability, neurofeedback learning capacity) as potential confounds that cannot be fully disentangled from gamma-specific effects.

R3-Q3: It is not clear whether the experimenters were also blinded during data collection and interaction with participants. This matters because neurofeedback studies are particularly vulnerable to expectancy.

We will clarify that the study employed a single-blind design: participants were unaware of their group assignment. We will state this clearly in the revised manuscript.

R3-Q4: The choice of the two neurofeedback scenarios requires clearer justification. The manuscript describes a deep ocean scene followed by a seaside scene with relaxation instructions, but it is not clear why these two scenarios were selected, and whether they were matched for attentional engagement and affective content. This is not a minor point, because both groups showed reductions in pain ratings after the entire neurofeedback procedure.

We will provide a stronger rationale for the selection of the two neurofeedback video scenarios. We will also place greater emphasis on the pain reduction observed in both groups, acknowledging the substantial nonspecific analgesic effects associated with the procedure.

R3-Q5: The comparison with tACS is interesting but currently underdeveloped. The authors suggest that neurofeedback may succeed where gamma-frequency tACS failed because it allows real-time, personalized, self-regulatory modulation of ongoing activity. This is plausible, but the manuscript should discuss this distinction more deeply. Neurofeedback may not simply be a different way of modulating gamma; it may recruit volitional control, attentional engagement, immersion, expectation, etc. These mechanisms could be central to the observed pain reduction and may partly explain why neurofeedback effects differ from those of externally applied stimulation.

We thank the reviewer for this insightful comment. We will expand the discussion of why neurofeedback may produce effects beyond those achieved by gamma-frequency tACS. In particular, we will elaborate on the potential contributions of volitional control, attentional engagement, immersion, expectation, and self-regulatory processes, and discuss how these factors may be central to the observed pain reduction rather than merely incidental to the gamma modulation.

R3-Q6: Overall, this is an interesting study that introduces a promising neurofeedback approach for experimental pain modulation. The findings are encouraging, especially the convergence between subjective ratings and laser-evoked potentials in responders. However, the conclusions should be tempered. The current evidence supports the feasibility of training gamma-band activity in a subset of participants and suggests that successful training is associated with reduced experimental pain.

We thank the reviewer for this balanced assessment. We fully agree that the conclusions should be tempered, and we will revise the manuscript accordingly to reflect that the current evidence supports feasibility and association rather than established causal efficacy.

Summary

In summary, the planned revisions include:

(i) full-sample results reported;

(ii) moderating causal language throughout and adding a formal mediation analysis;

(iii) clearly specifying the responder criterion and adding this to the preregistration;

(iv) providing complete methodological documentation and publicly releasing all analysis code;

(v) expanding the Discussion to address limitations regarding scalp gamma measurement, EMG control, visual feedback, viewing distance, single-blind design, NFB scenario rationale, and nonspecific effects;

(vi) adding analyses on baseline gamma comparability and sham-feedback discrepancy.