The neural dynamics of positive and negative expectations of pain

Reviewer #1 (Public Review):

Summary:

In this important paper, the authors investigate the temporal dynamics of expectation of pain using a combined fMRI-EEG approach. More specifically, by modifying the expectations of higher or lower pain on a trial-to-trial basis, they report that expectations largely share the same set of activations before the administration of the painful stimulus, and that the coding of the valence of the stimulus is observed only after the nociceptive input has been presented. fMRI-informed EEG analysis suggested that the temporal sequence of information processing involved the Dorsolateral prefrontal cortex (DLPFC), the anterior insula, and the anterior cingulate cortex. The strength of evidence is convincing, and the methods are solid, but a few alternative interpretations about the findings related to the control group, as well as a more in-depth discussion on the correlations between the BOLD and EEG signals would strengthen the manuscript.

Strengths:

In line with open science principles, the article presents the data and the results in a complete and transparent fashion.

From a theoretical standpoint, the authors make a step forward in our understanding of how expectations modulate pain by introducing a combination of spatial and temporal investigation. It is becoming increasingly clear that our appraisal of the world is dynamic, guided by previous experiences, and mapped on a combination of what we expect and what we get. New research methods, questions, and analyses are needed to capture these evolving processes.

Weaknesses:

The control condition is not so straightforward. Across the manuscript it is defined as "no expectation", and in the legend of Figure 1 it is mentioned that the third state would be "no prediction". However, it is difficult to conceive that participants would not have any expectations or predictions. Indeed, in the description of the task it is mentioned that participants were instructed that they would receive stimuli during "intermediate sensitive states". The results of the pain scores and expectations might support the idea that the control condition is situated in between the placebo and nocebo conditions. However, since this control condition was not part of the initial conditioning, and = participants had no reference to previous stimuli, one might expect that some ratings might have simply "regressed to the mean" for a lack of previous experience.

General considerations and reflections:

Inducing expectations in the desired direction is not a straightforward task, and results might depend on the exact experimental conditions and the comparison group. In this sense, the authors' choice of having 3 groups of positive, negative, and "neutral" expectations is to be praised. On the other hand, also control groups form their expectations, and this can constitute a confounder in every experiment using expectation manipulation, if not appropriately investigated.

In addition, although fMRI is still (probably) the best available tool we have to understand the spatial representation of cortical processing, limitations about not only the temporal but even the spatial resolution should be acknowledged. Given the anatomical and physiological complexity of the cortical connections, as we know from the animal world, it is still well possible that subcircuits are activated also for positive and negative expectations, but cannot be observed due to the limitation of our techniques. Indeed, on an empirical/evolutionary basis it would remain unclear why we should have a system that waits for the valence of a stimulus to show differential responses.

Also, moving in a dimension of network and graph theory, one would not expect single areas to be responsible for distinct processes, but rather that they would integrate information in a shared way, potentially with different feedback and feedforward communications. As such, it becomes more difficult to assume the insula is a center for coding potential pain, perhaps more of a node in a system that signals potential dangers for the integrity of the body.

The authors analyze the EEG signal between 0.5 to 128 Hz, finding significant results in the correlation between single-trial BOLD and EEG activity in the higher gamma range (see Figure 6 panel C). It would be interesting to understand the rationale for including such high frequencies in the signal, and the interpretation of the significant correlation in the high gamma range.

Reviewer #2 (Public Review):

I think this is a very promising paper. The combination of EEG and fMRI is unique and original. However, I also have some suggestions that I think could help improve the manuscript.

This manuscript reports the findings of an EEG-fMRI study (n = 50) on the effects of expectations on pain. The combination of EEG with fMRI is extremely original and well-suited to study the transition from expectation to perception. However, I think that the current treatment of the data, as well as the way that the manuscript is currently written, does not fully capitalize on the potential of this unique dataset. Several findings are presented but there is currently no clear message coming out of this manuscript.

First, one positive point is that the experimental manipulation clearly worked. However, it should be noted that the instructions used are not typical of studies on placebo/nocebo. Participants were not told that the stimulations would be of higher/lower intensity. Rather, they were told that objective intensities were held constant, but that EEG recordings could be used to predict whether they would perceive the stimulus as more or less intense. I think that this is an interesting way to manipulate expectations, but there could have been more justification in the introduction for why the authors have chosen this unusual procedure.

Also, the introduction mentions that little is known about potential cerebral differences between expectations of high vs. low pain expectations. I think the fear conditioning literature could be cited here. Activations in ACC, SMA, Ins, parahippocampal gyrus, PAG, etc. are often associated with upcoming threat, whereas activations vmPFC/default mode network are associated with safety.

The fact that the authors didn't observe a clearer distinction between high and low expectations here could be related to their specific instructions that imply that the stimulus is the same and that it is the subjective perception that is expected to change. In any case, this is a relatively minor issue that is easy to address.

Towards the end of the introduction, the authors present the aims of the study in mainly exploratory terms:
(1) What are the differences between anticipation and perception?
(2) What regions display a difference between high and low expectations (high > low or low < high) vs. an effect of expectation regardless of the direction (high and low different than neutral)?
I think these are good questions, but the authors should provide more justification, or framework, for these questions. More specifically, what will they be able to conclude based on their observations?

For instance (note that this is just an example to illustrate my point. I encourage the authors to come up with their own framework/predictions) :

(1) Possibility #1: A certain region encodes expectations in a directed fashion (high > low) and that same region also responds to perception in the same direction (high > low). This region would therefore modulate pain by assimilating perception towards expectations.
(2) Possibility # 2: different regions are involved in expectation and perception. Perhaps this could mean that certain regions influence pain processing through descending facilitation for instance...

Regarding analyses, I think that examining the transition from expectations to perception is a strong angle of the manuscript given the EGG-fMRI nature of the study. However, I feel that more could have been done here. One problem is that the sequence of analyses starts by identifying an fMRI signal of interest and then attempts to find its EEG correlates. The problem is that the low temporal resolution of fMRI makes it difficult to differentiate expectation from perception, which doesn't make this analysis a good starting point in my opinion. Why not start by identifying an EEG signal that differentiates perception vs expectation, and then look for its fMRI correlates?

Finally, I found the hypotheses on "valenced" vs. "absolute" effects a little bit more difficult to follow. This is because "neutral" is not really neutral: it falls in between low and high. If I follow correctly, participants know that the temperature is always the same. Therefore, if they are told that the machine cannot predict whether their perception is going to be low or high, then it must be because it is likely to be in between. Ratings of expectation and pain ratings confirm that. The neutral condition is not "devoid" of expectations as the authors suggest. Therefore, it would make sense to look at regions with the following pattern low > neutral > high, or vice-versa, low < neutral < high. Low & high being different than neutral is more difficult to interpret. I don't think that you can say that it reflects "absolute" expectations because neutral is also the expectation of a medium temperature. Perhaps it reflects "certainty/uncertainty" or something like that, but it is not clear that it reflects "expectations".