Hyperreactivity to uncertainty is a key feature of subjective cognitive impairment
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Evaluation Summary:
This paper tests the hypothesis that subjective cognitive impairment (SCI) is linked to hyperreactivity to uncertainty. Using an information-gathering task, the authors demonstrate that individuals with subjective cognitive impairment sample more than controls under uncertainty. Despite the clear strengths of the experimental design and the novel insights into SCI, some of the findings rely on problematic between-subject correlation analyses that should be corrected. Furthermore, alternative accounts of the main findings are consistent with the data.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Abstract
With an increasingly ageing global population, more people are presenting with concerns about their cognitive function, but not all have an underlying neurodegenerative diagnosis. Subjective cognitive impairment (SCI) is a common condition describing self-reported deficits in cognition without objective evidence of cognitive impairment. Many individuals with SCI suffer from depression and anxiety, which have been hypothesised to account for their cognitive complaints. Despite this association between SCI and affective features, the cognitive and brain mechanisms underlying SCI are poorly understood. Here, we show that people with SCI are hyperreactive to uncertainty and that this might be a key mechanism accounting for their affective burden. Twenty-seven individuals with SCI performed an information sampling task, where they could actively gather information prior to decisions. Across different conditions, SCI participants sampled faster and obtained more information than matched controls to resolve uncertainty. Remarkably, despite their ‘urgent’ sampling behaviour, SCI participants were able to maintain their efficiency. Hyperreactivity to uncertainty indexed by this sampling behaviour correlated with the severity of affective burden including depression and anxiety. Analysis of MRI resting functional connectivity revealed that SCI participants had stronger insular-hippocampal connectivity compared to controls, which also correlated with faster sampling. These results suggest that altered uncertainty processing is a key mechanism underlying the psycho-cognitive manifestations in SCI and implicate a specific brain network target for future treatment.
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Evaluation Summary:
This paper tests the hypothesis that subjective cognitive impairment (SCI) is linked to hyperreactivity to uncertainty. Using an information-gathering task, the authors demonstrate that individuals with subjective cognitive impairment sample more than controls under uncertainty. Despite the clear strengths of the experimental design and the novel insights into SCI, some of the findings rely on problematic between-subject correlation analyses that should be corrected. Furthermore, alternative accounts of the main findings are consistent with the data.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
Attaallah et al. report a detailed study about uncertainty processing in patients with subjective cognitive impairment (SCI). The task paradigm they developed recently (Petitet et al., 2021, Nature Human Behaviour) allowed a rigorous computational analysis of how SCI participants and matched controls differed in active sampling behaviour aimed at reducing uncertainty. The results show that to resolve uncertainty SCI participants sampled faster and obtained more information than matched controls. Importantly, in spite of this urgent sampling behaviour the SCI participants were equally efficient in reducing uncertainty as controls. In contrast, findings from a 'passive' task condition where participants estimated and valued uncertainty but were not able to actively reduce uncertainty, showed no group …
Reviewer #1 (Public Review):
Attaallah et al. report a detailed study about uncertainty processing in patients with subjective cognitive impairment (SCI). The task paradigm they developed recently (Petitet et al., 2021, Nature Human Behaviour) allowed a rigorous computational analysis of how SCI participants and matched controls differed in active sampling behaviour aimed at reducing uncertainty. The results show that to resolve uncertainty SCI participants sampled faster and obtained more information than matched controls. Importantly, in spite of this urgent sampling behaviour the SCI participants were equally efficient in reducing uncertainty as controls. In contrast, findings from a 'passive' task condition where participants estimated and valued uncertainty but were not able to actively reduce uncertainty, showed no group differences. This emphasizes the importance of agency over uncertainty in characterizing SCI participants.
So far I found the findings were highly robust and convincing. I was less enthusiastic about the authors' choice to summarize these findings as adults with SCI being 'hypersensitive' to uncertainty. If the SCI group was hypersensitive to uncertainty, then why did the SCI group not differ from controls in how they estimated and valued uncertainty in the 'passive' condition? In other places of the manuscript, the authors summarize the same key findings as the SCI group being 'hyperreactive' to uncertainty. Given the importance of agency and active sampling, I believe the term 'hyperreactivity' is far more appropriate in this context than 'hypersensitivity'. So I encourage the authors to adjust their terminology, also in the title of the paper.
In the second half of the results section, we first learn from fMRI data that the SCI group and control group differ in resting-state functional connectivity, specifically between bilateral insula and bilateral hippocampal/parahippocampal regions - a finding that may have interesting theoretical repercussions. Finally, the authors report cross-subject correlations between a number of variables that were found to differ between the two groups: (i) measures of hyperreactivity to uncertainty, (ii) affective burden and (iii) insular-hippocampal connectivity (Figure 5C and Figure 7). Here the authors make a critical methodological mistake. The mistake is that they draw conclusions from correlation analyses in which all study participants (SCI and control) were included. If you take two variables that both significantly differ between groups and then correlate the two variables across all study participants, you are almost bound to find a significant correlation, even when within each group there is no significant correlation. This problem is illustrated by the classic statistical textbook example of a spurious correlation between two random point clouds that are separated from each other along both axes. These correlations (grey numbers in Figures 5C and 7) should not be reported because they probably reflect little more than the significant main effects of the group on the two variables that were already reported in earlier parts of the results section.
The authors are 'lucky' because the correlations between measures of hyperreactivity and affective burden (purple numbers in Fig 5C) are also significant when only the SCI participants are included. The same is true for the correlation between hyperreactivity and insular-hippocampal connectivity (purple numbers in Fig 7). The problem is with the correlation between affective burden and insular-hippocampal connectivity (Fig 7): this correlation is significant when all participants are included but is clearly not present when only the SCI participants (or only the controls) are considered. This means that it cannot be concluded that these measures are related to each other and I am afraid that the same argument also invalidates the mediation analysis that includes all three variables (and corresponding conclusions). If the authors want to report a mediation analysis, they should base it only on the SCI participants.
Note that on page 16 the authors acknowledge that "Caution should be exercised when interpreting these [correlation] results as these models were performed with data from both groups included. This was done to take advantage of the larger sample size for this type of analysis, while also trying to explore inter-individual differences regardless of group assignment." While this may be true, the authors overlook the statistical problem associated with these correlation analyses. I would suggest that the authors remove these analyses including all participants and adjust the results/discussion sections accordingly. In my view, there are plenty of remaining (i.e. valid) results that are interesting and novel, and that together with the rigorous methods and appropriate discussion form a very strong paper.
I believe this paper could have a major impact on the community of SCI researchers but it also presents a showcase of how one can rigorously examine active sampling behaviours and sensitivity to uncertainty in other clinical populations.
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Reviewer #2 (Public Review):
In this paper, the authors set out to clarify potential mechanisms underpinning subjective cognitive impairment (SCI) in the absence of objective impairment. Noting that individuals with (SCI) often present with high levels of depression and anxiety, which are linked to altered processing of uncertainty, the paper proposes that hypersensitivity to uncertainty may be a mechanism in SCI. Using an information-gathering task, the authors demonstrate that individuals with SCI sample more than controls before committing to a decision and sample faster, although this is not linked to subjective reports of uncertainty, suggesting is it not necessarily an adaptive response to exaggerated uncertainty estimation. Faster sampling was linked to symptoms of anxiety and depression, and to insular-hippocampal connectivity.
S…
Reviewer #2 (Public Review):
In this paper, the authors set out to clarify potential mechanisms underpinning subjective cognitive impairment (SCI) in the absence of objective impairment. Noting that individuals with (SCI) often present with high levels of depression and anxiety, which are linked to altered processing of uncertainty, the paper proposes that hypersensitivity to uncertainty may be a mechanism in SCI. Using an information-gathering task, the authors demonstrate that individuals with SCI sample more than controls before committing to a decision and sample faster, although this is not linked to subjective reports of uncertainty, suggesting is it not necessarily an adaptive response to exaggerated uncertainty estimation. Faster sampling was linked to symptoms of anxiety and depression, and to insular-hippocampal connectivity.
Strengths:
- The task used provides an effective measure of information gathering.
- The sample of individuals with SCI is well characterised and this study represents a rare and valuable attempt to understand the condition's cognitive mechanisms.
- The resting-state fMRI provides some indication that exaggerated information gathering may be linked to altered function in a specific brain network.
Weaknesses:
- The subjective reports of uncertainty in the passive task may not necessarily tap into the actual uncertainty used to guide decision-making in the active task.
- While the claim that hypersensitivity to uncertainty is a reasonable interpretation of the results, this hypothesis isn't tested directly and so it remains a relatively speculative conclusion.
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