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.