Investigating working memory updating processes of the human subcortex using 7 Tesla fMRI

Reviewer #1 (Public Review):

Summary:

Trutti and colleagues used 7T fMRI to identify brain regions involved in subprocesses of updating the content of working memory. Contrary to past theoretical and empirical claims that the striatum serves a gating function when new information is to be entered into working memory, the relevant contrast during a reference-back task did not reveal significant subcortical activation. Instead, the experiment provided support for the role of subcortical (and cortical) regions in other subprocesses.

Strengths:

The use of high-field imaging optimized for subcortical regions in conjunction with the theory-driven experimental design mapped well to the focus on a hypothetical striatal gating mechanism.

Consideration of multiple subprocesses and the transparent way of identifying these, summarized in a table, will make it easy for future studies to replicate and extend the present experiment.

Weaknesses:

The reference-back paradigm seems to only require holding a single letter in working memory (X or O; Figure 1). It remains unclear how such low demand on working memory influences associated fMRI updating responses. It is also not clear whether reference-switch trials with 'same' response truly tax working-memory updating (and gate opening), as the working-memory content/representation does not need to be updated in this case. These potential design issues, together with the rather low number of experimental trials, raise concerns about the demonstrated absence of evidence for striatal gate opening.

The authors provide a motivation for their multi-step approach to fMRI analyses. Still, the three subsections of fMRI results (3.2.1; 3.2.2; 3.3.3) for 4 subprocesses each (gate opening, gate closing, substitution, updating mode) made the Results section complex and it was not always easy to understand why some but not other approaches revealed significant effects (as the midbrain in gate opening).

The many references to the role of dopamine are interesting, but the discussion of dopaminergic pathways and signals remains speculative and must be confirmed in future studies (e.g., with PET imaging).

Reviewer #2 (Public Review):

Summary:

The study reported by Trutti et al. uses high-field fMRI to test the hypothesized involvement of subcortical structure, particularly striatum, in WM updating. Specifically, participants were scanned while performing the Reference Back task (e.g., Rac-Lubashevsky and Kessler, 2016), which tests constructs like working memory gate opening and closing and substitution. While striatal activation was involved in substitution, it was not observed in gate opening. This observation is cited as a challenge to cortico-striatal models of WM gating, like PBWM (Frank and O'Reilly, 2005).

Strengths:

While there have been prior fMRI studies of the reference back task (Nir-Cohen et al., 2020), the present study overcomes limitations in prior work, particularly with regard to subcortical structures, by applying high-field imaging with a more precise definition of ROIs. And, the fMRI methods are careful and rigorous, overall. Thus, the empirical observations here are useful and will be of interest to specialists interested in working memory gating or the reference back task specifically.

Weaknesses:

I am less persuaded by the more provocative points regarding the challenge it presents to models like PBWM, made in several places by the paper. As detailed below, issues with conceptual clarity of the main constructs and their connection to models, like PBWM, along with some incomplete aspects of the results, make this stronger conclusion less compelling.

(1) The relationship of the Nir-Cohen et al. (2020) task analysis of the reference back task, with its contrasts like gate opening and closing, and the predictions of PBWM is far from clear to me for several reasons.

First, contrasts like gate opening and gate closing make strong finite state assumptions. As far as I know, this is not an assumption of PBWM, certainly not for gate opening. At a minimum, PBWM is default closed because of the tonic inhibition of cortico-thalamic dynamics by the globus pallidus. Indeed, this was even noted in the discussion of this paper, which seems to acknowledge this discrepancy, but then goes on to conclude that they have challenged the PBWM model anyway.

Second, as far as I know, PBWM emphasizes go/no-go processes around constructs of input- and output-gating, rather than state shifts between gate opening and closing. While this relationship is less clear in reference back, substituting task-relevant items into working memory does appear to be an example of input gating, as modeled by PBWM. Thus, it is not clear to me why the substitution contrast would not be more of a test of input gating than the gate opening contrast, which requires assumptions that are not clear are required by the model, as noted above.

Third, PBWM relies on striatal mechanisms to solve the problem of selective gating, inputting, or outputting items in memory while also holding on to others. Selective gating contrasts with global gating, in which everything in memory is gated or nothing. The reference back task is a test of global gating. It is an important distinction because non-striatal mechanisms that can solve global gating, cannot solve selective gating. Indeed, this limitation of non-striatal mechanisms was the rationale for PBWM adding striatum. The connectivity of the striatum with the cortex permits this selectivity. It is not clear that the reference back task tests these selective demands in the first place. That limitation in this task was the rationale behind the recent Rac-Lubashevsky and Frank (2022) paper using the reference back 2 procedure that modifies the original reference back for selective gating.

So, if the primary contribution of the paper is to test PBWM, as suggested by the first line of the abstract, then it is not clear that the reference back task in general, or the gate opening contrast in particular, is the best test of these predictions. Other contrasts (substitution), or indeed, tasks (reference back 2) would have been better suited.

(2) In general, observations of univariate activity in the striatum have been notoriously variable in the context of WM. Indeed, Chatham et al. (2014) who tested working memory output gating - notably in a direct test of the predictions of PBWM - noted this variability. They too did not observe univariate activation in the striatum associated with selective output gating. Rather they found evidence of increased connectivity between the striatum and cortex during selective output gating. They argued that one account of this difference is that striatal gating dynamics emerge from the balance between the firing of both Go and NoGo cell populations that decide whether to gate or not. It is not always clear how this balance should relate to univariate activation in the striatum. Thus, the present study might also test cortico-striatal connectivity, rather than relying exclusively on univariate activation, in their test of striatal involvement in these WM constructs.

(3) It is concerning that there was no behavioral cost for comparison switch vs. repeat trials. This differs from with prior observations from the reference back (e.g., Nir-Cohen et al., 2020), and in general, is odd given the task switch/cue interpretation component. This failure to observe a basic behavioral effect raises a concern about how participants approached this task and how that might differ from prior reports of the reference back. If they were taking an unusual strategy, it further complicates the interpretation of these results and the implications they hold for theory.

In summary, the present observations are useful, particularly for those interested in the reference back task. For example, they might call into question verbal theories and task analyses of the reference back task that tie constructs like gate-opening to striatal mechanisms. However, given the ambiguities noted above, the broader implications for models like PBWM, or indeed, other models of working memory gating, are less clear.