Spatiotemporal Dissociation of Human Amygdala Response to Negative Affect

Reviewer #1 (Public review):

Summary:

The authors aimed to re-analyse two fMRI datasets of studies investigating the effect of cognitive emotional regulation on amygdala response during the viewing of negative images, in order to assess whether such effects might have been missed in previous reports of the results of these studies. In order to accommodate potential non-typical response profiles in the amygdala, they used a modelling approach that is agnostic about the shape of the BOLD response (finite impulse response modelling). Furthermore, the authors sought to differentiate between amygdala subregions using i) two previously published probabilistic atlases of amygdala subnuclei; and ii) a data-driven analysis focusing on temporal response profiles, which identified four clusters that mostly overlapped with anatomical parcellations. The analyses confirmed their previous results insofar as they did not find any impact of emotional regulation on the amygdala response in any subregion. However, their approach revealed differences in temporal response profiles between amygdala subregions: the centromedial amygdala showed sustained activation extending into the post-stimulus rating period, whereas laterobasal and superficial subregions peaked earlier during stimulus presentation. Overall, this study helps to clarify whether cognitive emotional regulation during negative image viewing alters amygdala response, and demonstrates the value of flexible response modelling to differentiate between functional subregions of an important brain structure.

Strengths:

The strengths of this study lie in the amount of data used (a combined N of 358 participants is rather high), the flexibility of the modelling approach (FIR), the exploratory nature of the data-driven clustering based on temporal response profiles, and clarity of the text and of the findings. One weakness would be the fact that no fMRI data acquired at higher field strengths were used for the aim of differentiating responses of amygdala subunits.

In my opinion, the authors achieved their aims of re-analysing these datasets with complementary methods, and helped to discover new aspects of the BOLD response in the amygdala during emotional regulation. The results support their conclusions.

This work is likely to stimulate discussion of the response of amygdala subnuclei during emotional regulation, and might encourage researchers to resort to more flexible analysis methods by demonstrating the information gain achieved with the FIR approach.

Weaknesses:

There are 7T studies of the amygdala response that have looked at differences in BOLD response across subnuclei. While I don't know of any that have investigated emotional regulation, I think these studies should nevertheless be mentioned and discussed in the Discussion, at least to compare the differences observed across subnuclei.

Reviewer #2 (Public review):

Summary:

In this paper, Bo et al. study the spatiotemporal organization of BOLD responses in the amygdala. They apply FIR modelling to a large sample (two cohorts tested at the same site and scanner, totalling >350 individuals) who completed a negative/neutral picture viewing and cognitive reappraisal task. Averaging voxelwise BOLD responses across two distinct probabilistic atlases of the amygdala, the authors found that a corresponding centromedial region showed sustained activation to negative stimuli beyond the stimulus period. Laterobasal and superficial subregions peaked earlier, within the stimulus presentation period. In all cases, reappraisal did not change these profiles. Lateralization effects (left-side dominance) were found in the CM region at later time points, and to a lesser extent in the superficial nucleus area at earlier time points. Data-driven clustering of voxelwise time courses could partly recover findings from probabilistic atlases, but nonetheless showed partial decoupling of anatomical and functional boundaries in the amygdala.

Strengths:

This is a well-written paper with a clear objective addressed by sound methods. The authors set out to address two main questions: (1) "do amygdala subregions exhibit distinct temporal dynamics in response to negative emotional stimuli?" and (2) "does cognitive reappraisal differentially modulate these temporal profiles across subregions?" Regarding question 1, FIR modelling results indicate strong differentiation of the centromedial region of the amygdala from other subdivisions, with strong and late responses to presented negative stimuli. On question 2, cognitive reappraisal does not seem to play a major role here, although I raise a question on this in the next section. Overall, all presented conclusions are supported by study findings. I would add that lateralization effects are not mentioned in the main objectives/questions of the paper, but this analysis represents a large section of the results that may warrant mention in the introduction as well.

Weaknesses:

(1) An important concern when looking at mesiotemporal regions such as the amygdala is signal-to-noise. Yet, this challenge in analyzing data from the amygdala was not addressed here but represents a potential confound if SNR varies within the amygdala along its major subdivisions.

(2) The authors analyze BOLD evoked response time courses, but I did not find a GLM analysis showing that the task reliably engaged the amygdala, either when analyzed with a canonical HRF or with the FIR model used here. We can see from Figure 2 that the task may not engage the entire amygdala (e.g. LB/LA subregions seem to show lower amplitude evoked-responses), yet the authors focus equally on time courses of subregions engaged and not engaged in the task. As such, differences observed between subregions may reflect different underlying processes (e.g. different processes of engagement in the task, or high/low engagement).

(3) The study uses two different probabilistic atlases to parse BOLD response time courses in the amygdala. However, methodological details on the processing of the atlas data are missing from the text. For example, it is unclear if the subregions were thresholded or overlap in any way, which would affect the strength of detected effects if there is substantial overlap between areas.

(4) The authors found no effect of reappraisal on BOLD response time courses. However, if I understand correctly, not all participants showed successful reappraisal according to their behavioural ratings (lines 125-126: "Eighty-one percent of participants showed a regulation effect in the same direction as the group-level effect"). Were these participants excluded from the reappraisal analysis on evoked response time courses? This is currently unclear, but holds significance in reliably answering question 2.