Neural Correlates and Reinstatement of Recent and Remote Memory: A Comparison Between Children and Young Adults

Reviewer #1 (Public Review):

Summary:
This paper by Schommartz and colleagues investigates the neural basis of memory reinstatement as a function of both how recently the memory was formed (recent, remote) and its development (children, young adults). The core question is whether memory consolidation processes as well as the specificity of memory reinstatement differ with development. A number of brain regions showed a greater activation difference for recent vs. remote memories at the long versus shorter delay specifically in adults (cerebellum, parahippocampal gyrus, LOC). A different set showed decreases in the same comparison, but only in children (precuneus, RSC). The authors also used neural pattern similarity analysis to characterize reinstatement, though I have substantive concerns about how this analysis was performed and as such will not summarize the results. Broadly, the behavioural and univariate findings are consistent with the idea that memory consolidation differs between children and adults in important ways, and takes a step towards characterizing how.

Strengths:
The topic and goals of this paper are very interesting. As the authors note, there is little work on memory consolidation over development, and as such this will be an important data point in helping us begin to understand these important differences. The sample size is great, particularly given this is an onerous, multi-day experiment; the authors are to be commended for that. The task design is also generally well controlled, for example as the authors include new recently learned pairs during each session.

Weaknesses:
As noted above, the pattern similarity analysis for both item and category-level reinstatement was performed in a way that is not interpretable given concerns about temporal autocorrelation within the scanning run. Below, I focus my review on this analytic issue, though I also outline additional concerns.

1. The pattern similarity analyses were not done correctly, rendering the results uninterpretable (assuming my understanding of the authors' approach is correct).

a. First, the scene-specific reinstatement index: The authors have correlated a neural pattern during a fixation cross (delay period) with a neural pattern associated with viewing a scene as their measure of reinstatement. The main issue with this is that these events always occurred back-to-back in time. As such, the two patterns will be similar due simply to the temporal autocorrelation in the BOLD signal. Because of the issues with temporal autocorrelation within the scanning run, it is always recommended to perform such correlations only across different runs. In this case, the authors always correlated patterns extracted from the same run, which moreover have temporal lags that are perfectly confounded with their comparison of interest (i.e., from Fig 4A, the "scene-specific" comparisons will always be back-to-back, having a very short temporal lag; "set-based" comparisons will be dispersed across the run, and therefore have a much higher lag). The authors' within-run correlation approach also yields correlation values that are extremely high - much higher than would be expected if this analysis was done appropriately. The way to fix this would be to restrict the analysis to only cross-run comparisons, but I don't believe this is possible unfortunately given the authors' design; I believe the target (presumably reinstated) scene only appears once during scanning, so there is no separate neural pattern during the presentation of this picture that they can use. For these reasons, any evidence for "significant scene-specific reinstatement" and the like is completely uninterpretable and would need to be removed from the paper.

b. From a theoretical standpoint, I believe the way this analysis was performed considering the fixation and the immediately following scene also means that the differences between recent and remote could have to do with either the reactivation (processes happening during the fixation, presumably) or differences in the processing of the stimulus itself (happening during the scene presentation). For example, people might be more engaged with the more novel scenes (recent) and therefore process those scenes more; such a difference would be interpreted in this analysis as having to do with reinstatement, but in fact could be just related to the differential scene processing/recognition, etc. It would be important when comparing scene-specific neural patterns as templates for reinstatement across conditions that, at the time of scene presentation itself, the two conditions are equal (e.g., no difference in familiarity and so on); otherwise, we do not know which trial period (and therefore which underlying process) is driving the differences.

c. For the category-based neural reinstatement: (1) This suffers from the same issue of correlations being performed within the run. Again, to correct this the authors would need to restrict comparisons to only across runs (i.e., patterns from run 1 correlated with patterns for run 2 and so on). With this restriction, it may or may not be possible to perform this analysis, depending upon how the same-category scenes are distributed across runs. However, there are other issues with this analysis, as well. (2) This analysis uses a different approach of comparing fixations to one another, rather than fixations to scenes. The authors do not motivate the reason for this switch. Please provide reasoning as to why fixation-fixation is more appropriate than fixation-scene similarity for category-level reinstatement, particularly given the opposite was used for item-level reinstatement. Even if the analyses were done properly, it would remain hard to compare them given this difference in approach. (3) I believe the fixation cross with itself is included in the "within category" score. Is this not a single neural pattern correlated with itself, which will yield maximal similarity (pearson r=1) or minimal dissimilarity (1-pearson r=0)? Including these comparisons in the averages for the within-category score will inflate the difference between the "within-category" and "between-category" comparisons. These (e.g., forest1-forest1) should not be included in the within-category comparisons considered; rather, they should be excluded, so the fixations are always different but sometimes the comparisons are two retrievals of the same scene type (forest1-forest2), and other times different scene types (forest1-field1). (4) It is troubling that the results from the category reinstatement metric do not seem to conceptually align with past work; for example, a lot of work has shown category-level reinstatement in adults. Here the authors do not show any category-level reinstatement in adults (yet they do in children), which generally seems extremely unexpected given past work and I would guess has to do with the operationalization of the metric.

2. I did not see any compelling statistical evidence for the claim of less robust consolidation in children. Specifically in terms of the behavioural results of retention of the remote items at 1 vs 14 days, shown in Figure 2B, the authors conclude that memory consolidation is less robust in children (line 246). Yet they do not report statistical evidence for this point, as there was no interaction of this effect with the age group. Children had worse memory than adults overall (in terms of a main effect - i.e. across recent and remote items). If it were consolidation-specific, one would expect that the age differences are bigger for the remote items, and perhaps even most exaggerated for the 14-day-old memories. Yet this does not appear to be the case based on the data the authors report. Therefore, the behavioural differences in retention do not seem to be consolidation specific, and therefore might have more to do with differences in encoding fidelity or retrieval processes more generally across the groups. This should be taken into account when interpreting the findings.

3. Please clarify which analyses were restricted to correct retrievals only. The univariate analyses states that correct and incorrect trials were modelled separately, but does not say which were considered in the main contrast (I assume correct only?). The item specific reinstatement analysis states that only correct trials were considered, but the category-level reinstatement analysis does not say. Please include this detail.

4. To what extent could performance differences be impacting the differences observed across age groups? I think (see prior comment) that the analyses were probably limited to correct trials, which is helpful, but still yields pretty big differences across groups in terms of the amount of data going into each analysis. In general, children showed more attenuated neural effects (e.g., recent/remote or session effects); could this be explained by their weaker memory? Specifically, if only correct trials are considered that means that fewer trials would be going into the analysis for kids, especially for the 14-day remote memories, and perhaps pushing the remove > recent difference for this condition towards 0. The authors might be able to address this analytically; for example, does the remote > recent difference in the univariate data at day 14 correlate with day 14 memory?

5. Some of the univariate results reporting is a bit strange, as they are relying upon differences between retrieval of 1- vs. 14-day memories in terms of the recent vs. report difference, and yet don't report whether the regions are differently active for recent and remote retrieval. For example in Figure 3A, neither anterior nor posterior hippocampus seem to be differentially active for recent vs. remote memories for either age group (i.e., all data is around 0). This difference from zero or lack thereof seems important to the message - is that correct? If so, can the authors incorporate descriptions of these findings?

6. Please provide more details about the choices available for locations in the 3AFC task. (1) Were they different each time, or always the same? If they are always the same, could this be a motor or stimulus/response learning task? (2) Do the options in the 3AFC always come from the same area - in which case the participant is given a clue as to the gist of the location/memory? Or are they sometimes randomly scattered across the image (in which case gist memory, like at a delay, would be sufficient for picking the right option)? Please clarify these points and discuss the logic/impact of these choices on the interpretation of the results.

7. Often p values are provided but test statistics, effect sizes, etc. are not - please include this information. It is at times hard to tell whether the authors are reporting main effects, interactions, pairwise comparisons, etc.

8. There are not enough methodological details in the main paper to make sense of the results. For example, it is not clear from reading the text that there are new object-location pairs learned each day.

9. The retrieval task does not seem to require retrieval of the scene itself, and as such it would be helpful for the authors to both explain their reasoning for this task to measure reinstatement. Strictly speaking, participants could just remember the location of the object on the screen. Was it verified that children and adults were recalling the actual scene rather than just the location (e.g. via self-report)? It's possible that there may be developmental differences in the tendency to reinstate the scene depending on e.g., their strategy.

10. In general I found the Introduction a bit difficult to follow. Below are a few specific questions I had.

a. At points findings are presented but the broader picture or take-home point is not expressed directly. For example, lines 112-127, these findings can all be conceptualized within many theories of consolidation, and yet those overarching frameworks are not directly discussed (e.g., that memory traces go from being more reliant on the hippocampus to more on the neocortex). Making these connections directly would likely be helpful for many readers.

b. Lines 143-153 - The comparison of the Tompary & Davachi (2017) paper with the Oedekoven et al. (2017) reads like the two analyses are directly comparable, but the authors were looking at different things. The Tompary paper is looking at organization (not reinstatement); while the Oedekoven et al. paper is measuring reinstatement (not organization). The authors should clarify how to reconcile these findings.

c. Line 195-6: I was confused by the prediction of "stable involvement of HC over time" given the work reviewed in the Introduction that HC contribution to memory tends to decrease with consolidation. Please clarify or rephrase.

d. Lines 200-202: I was a bit confused about this prediction. Firstly, please clarify whether immediate reinstatement has been characterized in this way for kids versus adults. Secondly, don't adults retain gist more over long delays (with specific information getting lost), at least behaviourally? This prediction seems to go against that; please clarify.

Reviewer #2 (Public Review):

Schommartz et al. present a manuscript characterizing neural signatures of reinstatement during cued retrieval of middle-aged children compared to adults. The authors utilize a paradigm where participants learn the spatial location of semantically related item-scene memoranda which they retrieve after short or long delays. The paradigm is especially strong as the authors include novel memoranda at each delayed time point to make comparisons across new and old learning. In brief, the authors find that children show more forgetting than adults, and adults show greater engagement of cortical networks after longer delays as well as stronger item-specific reinstatement. Interestingly, children show more category-based reinstatement, however, evidence supports that this marker may be maladaptive for retrieving episodic details. The question is extremely timely both given the boom in neurocognitive research on the neural development of memory, and the dearth of research on consolidation in this age group. Also, the results provide novel insights into why consolidation processes may be disrupted in children. Despite these strengths, there are quite a few important design and analytical choices that derail my enthusiasm for the paper. If the authors could address these concerns, this manuscript would provide a solid foundation to better understand memory consolidation in children.

Reviewer #3 (Public Review):

Summary:
This study aimed to understand the neural correlates of memory recall over short (1-day) and long (14-days) intervals in children (5-7 years old) relative to young adults. The results show that children recall less than young adults and that this is accompanied by less activation (relative to young adults) in brain networks associated with memory retrieval.

Strengths:
This paper is one of few investigating long-term memory (multiple days) in a developmental population, an important gap in the field. Also, the authors apply a representational similarity analysis to understand how specific memories evolve over time. This analysis shows how the specificity of memories decreases over time in children relative to adults. This is an interesting finding.

Weaknesses:
Overall, these results are consistent with what we already know: recall is worse in children relative to adults (e.g., Cycowicz et al., 2001) and children activate memory retrieval networks to a lesser extent than adults (Bauer et al, 2017).

It seems that the reduced activation in memory recall networks is likely associated with less depth of memory encoding in children due to inattentiveness, reduced motivation, and documented differences in memory strategies. In regards to this, there was consideration of IQ, sex, and handedness but these were not included as covariates as they were not significant although I note p<.16 suggests there was some level of association nonetheless. Also, IQ is measured differently for the children and adults so it's not clear these can be directly contrasted. The authors suggest the instructed elaborative encoding strategy is effective for children and adults but the reference in support of this (Craik & Tulving, 1975) does not seem to support this point.