Cognitive control networks in human and macaque

  1. Valentina Mione
  2. Freja Holm Prins
  3. Moataz Assem
  4. Urs Schüffelgen
  5. Søren Kyllingsbæk
  6. Mark J Buckley
  7. Daniel J Mitchell
  8. John Duncan

  • Curated by eLife

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    eLife Assessment

    This study presents a valuable contribution to comparative cognitive neuroscience by directly mapping functional homologues of the human multiple-demand network in macaques using a matched spatial maze task. It provides solid evidence for functional correspondence between human and macaque cognitive control networks in dorsomedial frontal cortex and insula. However, given only two animals and no cross-animal convergence in parietal or ventrolateral prefrontal regions, claims that these regions form part of a macaque MD network should be read as provisional. The work will be of interest to researchers studying the evolution of cognitive control and cross-species neuroimaging.

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Abstract

A much-replicated finding in human brain imaging is a distributed “multiple-demand” or MD system, increasing in activity for many kinds of cognitive demand, and centrally involved in cognitive control. MD regions are proposed to encode a distributed mental model of critical task events, bound together in the roles and relationships needed to direct action selection. Though previous data hint at a corresponding network in the macaque, there has been no direct comparison to human data. Here we used functional magnetic resonance imaging to measure whole brain activation in a multi-step saccadic maze task, compared to a control requiring similar moves but without goal-based decisions. Human data were a close match to the canonical MD network, extended to include adjacent regions and in particular much of the canonical dorsal attention network. Data from two monkeys suggested correspondences in dorsomedial frontal, insula/orbitofrontal and posterior temporal cortex. In lateral frontal cortex there was just a single, largely dorsal activation patch, in contrast to multiple distinct human patches. In one animal, as in human, there was accompanying activation of dorsal and medial parietal cortex. In macaque as in human, together with previous data, our findings suggest an extended and strongly interconnected brain network recruited by increased cognitive challenge.

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  1. eLife

    eLife Assessment

    This study presents a valuable contribution to comparative cognitive neuroscience by directly mapping functional homologues of the human multiple-demand network in macaques using a matched spatial maze task. It provides solid evidence for functional correspondence between human and macaque cognitive control networks in dorsomedial frontal cortex and insula. However, given only two animals and no cross-animal convergence in parietal or ventrolateral prefrontal regions, claims that these regions form part of a macaque MD network should be read as provisional. The work will be of interest to researchers studying the evolution of cognitive control and cross-species neuroimaging.

  2. eLife

    Reviewer #2 (Public review):

    Summary:

    Mione et al. aim to resolve a long-standing question in comparative neuroscience: whether the macaque brain contains a functional analogue to the distributed human multiple-demand (MD) network. To address this, they employ a direct cross-species fMRI comparison using a multi-step saccadic maze task in humans and a simplified two-step version in macaques. By contrasting goal-directed navigation against a control condition that requires similar motor responses but no strategic planning, the study isolates the neural signatures of cognitive control across species.

    Strengths:

    The most compelling aspect of this work is its methodological alignment. Previous attempts to compare these systems often relied on comparisons of human BOLD signals and macaque single-unit recordings. By running parallel fMRI protocols, the authors establish a shared measurement basis that allows for a more direct comparison. The resulting activation maps demonstrate conserved network topology in dorsolateral and dorsomedial frontal cortex and insula. Individual-level data are presented alongside a conjunction map across the two animals, with the threshold used to define common activations stated explicitly, and supplementary analyses restricted to correctly completed trials or using a smaller smoothing kernel leave the main features intact. This strengthens confidence in the frontal correspondences that appear robust.

    Weaknesses:

    A design asymmetry between the human and monkey tasks remains. In humans, 2-, 4- and 6-step problems were intermixed within blocks, whereas macaques solved only two-step trials. Because participants never know when a harder problem will occur, they may stay in a state of proactive cognitive control (Braver, 2012) throughout the block, which could inflate MD activation even during simpler trials and complicate direct comparison with the monkey data. The authors acknowledge this limitation but do not quantify or correct for the effect.

    Individual-level consistency for some claimed MD regions is limited. The two monkeys differ considerably in parietal cortex, and a conjunction analysis shows no common activation there even at a permissive threshold of t > 1.5. Strong dorsal/medial parietal and ventrolateral prefrontal activations were each seen in only one animal, and the abstract presents them accordingly. This is an honest presentation, but it leaves the evidence for these regions resting on one subject, so whether they can be regarded as part of a macaque MD network remains uncertain.

    In the Discussion, the authors conclude that results from single animals "tell against" genuine species differences in these regions. The implied reasoning appears to be that if macaques truly lacked parietal and ventrolateral prefrontal nodes, neither animal would have shown activation there. Since one monkey did show it, they take this as evidence that the regions are not genuinely different between species, attributing the other animal's absence to limited power or insufficient task demands. This inference is difficult to justify with only two animals and no common activation across them at any meaningful threshold. A single positive result does not establish that a region reliably belongs to the macaque MD network.

    Overall, this manuscript provides solid evidence for functional correspondence between human and macaque cognitive control networks in dorsomedial frontal cortex and insula. Individual-level data are presented transparently, with conjunction thresholds stated explicitly and limitations acknowledged throughout. What remains is largely interpretive. Given only two animals and no cross-animal convergence in parietal or ventrolateral prefrontal regions, claims that these form part of a macaque MD network should be read as provisional.

  3. eLife

    Author response:

    The following is the authors’ response to the previous reviews.

    Public Reviews:

    Reviewer #1 (Public review):

    Summary:

    The "multiple-demand" (MD) system is a well-known finding of human brain imaging and is thought to play a central role in cognitive control. To directly compare the MD system in humans and monkeys, Mione et al. used functional magnetic resonance imaging to measure whole brain activation in a multi-step saccadic maze task. In humans, the authors found a distributed pattern of brain activity close match to the canonical MD network and extending to adjacent regions of dorsal attention and other networks. While there was good correspondence between monkey and human data, differences were also notable in lateral frontal cortex, dorsal parietal cortex, and sensorimotor cortex.

    Strengths:

    Though previous data hint at a corresponding network in the macaque, there has been no direct comparison to human data. This study provides a direct cross-species comparison with whole-brain data of fMRI, and the findings suggest an extended and strongly interconnected brain network recruited by increased cognitive challenge.

    Weaknesses:

    In previous human imaging, the MD system is defined by overlapping activation for many kinds of cognitive demand. In the present work, however, the authors used just a single task. Although there is some overlap between putative monkey MD network and canonical MD network identified in human imaging, it should be cautious to link current findings to MD system based on limited task events.

    We agree that present conclusions are limited by data from a single task. As we note, however, our human data show that this contrast works well for identifying the usual components of the MD network, suggesting it is a suitable candidate for use in the monkey.

    Reviewer #2 (Public review):

    Summary:

    Mione et al. aim to resolve a long-standing question in comparative neuroscience: whether the macaque brain contains a functional analogue to the distributed human multiple-demand (MD) network. To address this, the authors employ a direct cross-species fMRI comparison using a multi-step saccadic maze task in humans and a simplified two-step version in macaques. By contrasting goal-directed navigation against a control condition that requires similar motor responses but no strategic planning, the study isolates the neural signatures of cognitive control across species.

    Strengths:

    The most compelling aspect of this work is its methodological alignment. Previous attempts to compare these systems often relied on comparisons of human BOLD signals and macaque single-unit recordings. By running parallel fMRI protocols, the authors establish a shared measurement basis that allows for a more direct comparison. The resulting activation maps demonstrate conserved network topology in dorsolateral and dorsomedial frontal cortex and insula.

    Weaknesses:

    However, there is concerning inter-individual variability in the macaque data, along with a notable design asymmetry between the human and monkey tasks. In the human experiment, 2-, 4-, and 6-step trials were mixed within the same blocks, whereas macaques performed only 2-step problems. This design difference likely places human participants in a state of sustained proactive cognitive control (Braver, 2012), as they must remain prepared for more demanding trials at any moment. This elevated baseline arousal may potentially inflate MD network activation even during the simpler 2-step trials in humans, making direct comparisons with the macaque data difficult.

    The authors acknowledge this concern and note that similarities between species survive despite this procedural difference. However, their own individual-level data raise doubts about how robust these "similarities" really are. A defining feature of the MD system is consistent recruitment across individuals performing the same task. In this study, however, the two monkeys show markedly different activation maps in parietal cortex. The conjunction map (Supplementary Figure 6) does not support the claim that lateral and medial parietal regions are commonly activated across both animals at any meaningful statistical threshold, even when using a permissive threshold of |t| > 1.5, corresponding to approximately p ≈ 0.13 - 0.14 (two-tailed).

    This suggests that the group-level parietal activations are largely driven by a single animal, raising questions about whether these regions can reliably be considered as part of the monkey MD network. Notably, in Premereur et al. (2018), the only other direct macaque fMRI study of a cognitively demanding task, their conjunction map between the two animals also failed to show common parietal activation during task switching. Taken together, these findings suggest that either the monkey MD network is not as similar to its human counterpart as claimed, or the monkey version of the maze task was simply not sufficiently challenging to fully engage parietal MD nodes.

    Because of the design asymmetry described above, it remains difficult to determine which of these possibilities is correct (a genuine species difference versus insufficient task demands in macaques). The authors' current claims treat the group-level activations, which appear largely driven by one animal, as reliable evidence for homology, but without consistent individual-level support, such conclusions remain tentative.

    In summary, the authors demonstrate functional correspondence between human and macaque cognitive control networks in dorsolateral and dorsomedial frontal regions. However, assertions that this extends to lateral and medial parietal cortex are not consistently supported at the individual level. While the overall conclusions are plausible, they would be significantly strengthened by demonstrating consistent activation across both animals in all claimed MD regions, ideally with a properly thresholded conjunction map.

    These are all good points, and in the revision, we have placed greater emphasis on differences as well as similarities between animals. We have also pointed out the limitations of the conjunction map. In particular, two strong components of the human MD network (vlPFC and parietal cortex) are each seen in only one of the two animals. As we note, limited task difficulty, long training, and limited statistical power may all contribute to negative results. For these regions we agree that between-animal differences limit conclusions, though provisionally, results for single animals tell against genuine species differences.

    Recommendations for the authors:

    Reviewer #1 (Recommendations for the authors):

    (1) Although the whole-brain data obtained by fMRI can provide a direct comparison between species, a single cognitive task might be insufficient to link the findings with MD system. A cognitively challenging task likely activates multiple regions of the MD system; however, it may also recruit some task-specific regions, which do not belong to the canonical MD network.

    Though this is a very reasonable concern, the results suggest little influence on the present findings. In the human, strong MD activation was accompanied by activation of the DA network, perhaps reflecting the spatial content of the task. In the monkey, however, there was little evidence of DA activation, likely reflecting limited statistical power.

    (2) Based on the current work, the title seems to be too general.

    For the above reason, we think the title is reasonable – acknowledging limitations of data from single animals (see below), the cortical and subcortical distribution of monkey activations indeed suggests correspondence to the human MD network.

    Reviewer #2 (Recommendations for the authors):

    (1) Please clearly state the statistical threshold used for your conjunction analysis in Supplementary Figure 6. The current display appears to rely on |t| > 0, which is not a meaningful criterion: it effectively includes any voxel with positive activation regardless of significance. Even at a more permissive but still unjustified threshold of t = 1.5 (corresponding to roughly p ≈ 0.13-0.14, two-tailed), lateral and posterior medial parietal regions do not appear in the conjunction map. Without a properly justified threshold, it is difficult to accept the claim that these regions are commonly activated across both animals.

    The threshold and limitations of the conjunction map are now described (p. 13), and differences between animals given stronger emphasis.

    (2) Given that lateral and medial parietal activations do not survive even a low uncorrected threshold in the conjunction analysis and are therefore largely driven by one animal at the individual level, I recommend explicitly acknowledging this limitation in the Discussion rather than treating these regions as reliable components of the macaque MD network. Alternatively, acquiring data from a third monkey would help determine whether this reflects limited statistical power or genuine inter-individual variability.

    We have reworded our conclusions concerning parietal activation throughout (beginning with Abstract), emphasising their dependence on data from a single animal.

    (3) The design asymmetry between humans and monkeys makes it difficult to interpret cross-species differences in activation. For parietal and ventral prefrontal regions specifically, the monkey version of the task may simply have been insufficiently demanding to fully engage these MD nodes, which might require higher cognitive load before they are reliably recruited. Alternatively, this could reflect a genuine species difference. I recommend discussing this possibility explicitly when interpreting missing or inconsistent activations in these regions.

    These possibilities are now considered in a new paragraph of the Discussion (p. 18).

    (4) Please specify exactly how Figure 7 was thresholded and state whether FDR correction was applied separately for cortical and subcortical analyses. The colorbar suggests t > 0 as a starting point, but large empty regions within the slices imply that some higher masking or threshold was applied.

    See revised figure legend.

  4. Version published to 10.7554/elife.111502.3 on eLife
  5. Version published to 10.7554/elife.111502 on eLife
  6. eLife

    eLife Assessment

    This study presents a valuable contribution to comparative cognitive neuroscience by directly mapping functional homologues of the human multiple-demand network in macaques using a matched spatial maze task. However, the evidence is incomplete due to methodological asymmetries in the task design that appear to affect the results in ways that are not fully analyzed and discussed. The work will be of interest to researchers studying the evolution of cognitive control and cross-species neuroimaging.

  7. eLife

    Reviewer #1 (Public review):

    Summary:

    The "multiple-demand" (MD) system is a well-known finding of human brain imaging and is thought to play a central role in cognitive control. To directly compare the MD system in humans and monkeys, Mione et al. used functional magnetic resonance imaging to measure whole brain activation in a multi-step saccadic maze task. In humans, the authors found a distributed pattern of brain activity close match to the canonical MD network and extending to adjacent regions of dorsal attention and other networks. While there was good correspondence between monkey and human data, differences were also notable in lateral frontal cortex, dorsal parietal cortex, and sensorimotor cortex.

    Strengths:

    Though previous data hint at a corresponding network in the macaque, there has been no direct comparison to human data. This study provides a direct cross-species comparison with whole-brain data of fMRI, and the findings suggest an extended and strongly interconnected brain network recruited by increased cognitive challenge.

    Weaknesses:

    In previous human imaging, the MD system is defined by overlapping activation for many kinds of cognitive demand. In the present work, however, the authors used just a single task. Although there is some overlap between putative monkey MD network and canonical MD network identified in human imaging, it should be cautious to link current findings to MD system based on limited task events.

  8. eLife

    Reviewer #2 (Public review):

    Summary:

    Mione et al. aim to resolve a long-standing question in comparative neuroscience: whether the macaque brain contains a functional analogue to the distributed human multiple-demand (MD) network. To address this, the authors employ a direct cross-species fMRI comparison using a multi-step saccadic maze task in humans and a simplified two-step version in macaques. By contrasting goal-directed navigation against a control condition that requires similar motor responses but no strategic planning, the study isolates the neural signatures of cognitive control across species.

    Strengths:

    The most compelling aspect of this work is its methodological alignment. Previous attempts to compare these systems often relied on comparisons of human BOLD signals and macaque single-unit recordings. By running parallel fMRI protocols, the authors establish a shared measurement basis that allows for a more direct comparison. The resulting activation maps demonstrate conserved network topology in dorsolateral and dorsomedial frontal cortex and insula.

    Weaknesses:

    However, there is concerning inter-individual variability in the macaque data, along with a notable design asymmetry between the human and monkey tasks. In the human experiment, 2-, 4-, and 6-step trials were mixed within the same blocks, whereas macaques performed only 2-step problems. This design difference likely places human participants in a state of sustained proactive cognitive control (Braver, 2012), as they must remain prepared for more demanding trials at any moment. This elevated baseline arousal may potentially inflate MD network activation even during the simpler 2-step trials in humans, making direct comparisons with the macaque data difficult.

    The authors acknowledge this concern and note that similarities between species survive despite this procedural difference. However, their own individual-level data raise doubts about how robust these "similarities" really are. A defining feature of the MD system is consistent recruitment across individuals performing the same task. In this study, however, the two monkeys show markedly different activation maps in parietal cortex. The conjunction map (Supplementary Figure 6) does not support the claim that lateral and medial parietal regions are commonly activated across both animals at any meaningful statistical threshold, even when using a permissive threshold of |t| > 1.5, corresponding to approximately p ≈ 0.13 - 0.14 (two-tailed).

    This suggests that the group-level parietal activations are largely driven by a single animal, raising questions about whether these regions can reliably be considered as part of the monkey MD network. Notably, in Premereur et al. (2018), the only other direct macaque fMRI study of a cognitively demanding task, their conjunction map between the two animals also failed to show common parietal activation during task switching. Taken together, these findings suggest that either the monkey MD network is not as similar to its human counterpart as claimed, or the monkey version of the maze task was simply not sufficiently challenging to fully engage parietal MD nodes.

    Because of the design asymmetry described above, it remains difficult to determine which of these possibilities is correct (a genuine species difference versus insufficient task demands in macaques). The authors' current claims treat the group-level activations, which appear largely driven by one animal, as reliable evidence for homology, but without consistent individual-level support, such conclusions remain tentative.

    In summary, the authors demonstrate functional correspondence between human and macaque cognitive control networks in dorsolateral and dorsomedial frontal regions. However, assertions that this extends to lateral and medial parietal cortex are not consistently supported at the individual level. While the overall conclusions are plausible, they would be significantly strengthened by demonstrating consistent activation across both animals in all claimed MD regions, ideally with a properly thresholded conjunction map.

  9. eLife

    Author response:

    The following is the authors’ response to the original reviews.

    Reviewer #1 (Public review):

    Summary:

    The "multiple-demand" (MD) system is a well-known finding of human brain imaging and is thought to play a central role in cognitive control. To directly compare the MD system in humans and monkeys, Mione et al. used functional magnetic resonance imaging to measure whole-brain activation in a multi-step saccadic maze task. In humans, the authors found a distributed pattern of brain activity close match to the canonical MD network and extends to adjacent regions of dorsal attention and other networks. While there was good correspondence between monkey and human data, differences were also notable in the lateral frontal cortex, the dorsal parietal cortex, and the sensorimotor cortex.

    Strengths:

    Though previous data hint at a corresponding network in the macaque, there has been no direct comparison to human data. This study provides a direct cross-species comparison with whole-brain data from fMRI, and the findings suggest an extended and strongly interconnected brain network recruited by increased cognitive challenge.

    Weaknesses:

    In previous human imaging, the MD system is defined by overlapping activation for many kinds of cognitive demands. In the present work, however, the authors used just a single task. Although there is some overlap between the putative monkey MD network and the canonical MD network identified in human imaging, there should be caution in linking current findings to the MD system based on limited task events.

    In the Discussion, we acknowledge the limitation of using a single task. With this one task, however, the canonical MD network is clearly shown in our human data. Accompanying activation, especially of the canonical dorsal attention network, likely reflects the specific spatial demands of the maze task. In the monkey data, much of this dorsal attention activity is not seen (e.g. superior and medial parietal), likely reflecting limited power. Instead, there is distributed overlap with the previous limited monkey studies than have contrasted higher with lower cognitive demand. Though we agree that task-specific activations may contribute to our results, these arguments suggest that, in large part, our method does successfully identify a distributed set of multiple-demand regions. At the same time we acknowledge the desirability of further work to examine a wider range of task demands.

    Reviewer #1 (Recommendations for the authors):

    (1) Though the whole-brain data obtained by fMRI can provide a direct comparison between species, a single cognitive task might be insufficient to link the findings with the MD system. A cognitively challenging task likely activates multiple regions of the MD system; however, it may also recruit some task-specific regions, which do not belong to the canonical MD network. Furthermore, this is probably the reason that the dorsal attention network showed the strongest activation rather than the core MD for the current visuospatial maze task.

    In the Discussion, we acknowledge the limitation of using a single task (p. 15-16), and the likely contribution of task-specific activations to our data, especially involving the dorsal attention network (p. 15).

    (2) Ideally, a meta-analysis recruiting more fMRI studies on humans and monkeys when they perform various similar cognitive tasks may strengthen the evidence that there is a comparable MD system between species.

    Many human meta-analyses, of course, show the common MD system. For monkeys, however, at least to our knowledge, there are insufficient studies for a similar meta-analysis. Instead we discuss overlaps between the current activation findings and two previous studies of respectively antisaccades and task switching (p. 15), suggesting that, in monkey as in human, there is convergence for different kinds of demand.

    (3) Different from human subjects, monkeys usually require substantial training before fMRI scanning. More details about the training of the two monkeys should be given. In addition, training may reshape cognitive task activations. This potential impact should also be discussed.

    We now address this point in the Discussion (p. 18). As we note, similar results for the two species apparently survive even large differences in protocol. A training summary has been added to Methods (p. 27).

    (4) According to the description in the text, the two monkeys have obvious differences in cognitive task activations. It is necessary to show individual-level brain activations as well.

    Individual results and a conjunction map are shown in Supplementary Figure 6 (see accompanying text on p. 13). As expected, the conjunction map had substantial similarity to the findings from the two animals combined. Similarities and differences between animals are addressed in the Discussion (p. 17).

    (5) Based on the current research content, the title seems to be too general.

    For the reasons given above (see point 2), we think our title is reasonable.

    Reviewer #2 (Public review):

    Summary:

    Mione et al. aim to resolve a long-standing question in comparative neuroscience: whether the macaque brain contains a functional analogue to the distributed human multiple demand (MD) network. To address this, the authors employ a direct cross-species fMRI comparison using a multi-step saccadic maze task in humans and a simplified two-step version in macaques. By contrasting goal-directed navigation against a control condition that requires similar motor responses but no strategic planning, the study isolates the neural signatures of cognitive control across species.

    Strengths:

    The most compelling aspect of this work is its methodological alignment. Previous attempts to compare these systems often relied on comparisons of human BOLD signals and macaque single-unit recordings. By running parallel fMRI protocols, the authors establish a shared measurement basis that allows for a more direct comparison. The resulting activation maps clearly demonstrate conserved network topology across dorsomedial frontal, lateral, and medial parietal, and insula cortices. Combining these results with recent research on functional and structural connectivity further supports the idea that these networks evolved across species and provides a helpful starting point for future comparative studies. The findings will be highly useful for researchers investigating the evolutionary origins of domain-general cognitive control, as well as for neuroimaging methodologists developing cross-species alignment pipelines.

    Weaknesses:

    However, there are several differences in how the two groups were studied that make it harder to compare the results precisely. The human task mixed 2-, 4-, and 6-step trials within the same experimental blocks, whereas macaques performed only 2-step trials. This design difference likely places human participants in a state of sustained proactive cognitive control (Braver, 2012), as they must remain prepared for highly demanding trials at any moment. This elevated baseline arousal may artificially inflate MD network activation during the simpler 2-step trials in humans, making direct magnitude comparisons with the macaque data difficult.

    This is a reasonable concern, which we note in the Discussion. Crucially, as we point out, similarities between species appear to survive this and other differences in procedure.

    Additionally, the general linear model combined correct and error trials into a single regressor. Given that macaques exhibited substantially higher error rates, this approach risks diluting task-specific planning signals with activity related to error monitoring and reward prediction errors. The preprocessing pipeline also applied a 4 mm full-width half-maximum smoothing kernel to macaque data acquired at 1.5 mm resolution. Relative to the smaller size of the macaque brain, this kernel is quite large and likely blurs fine-grained topographical distinctions. This may partly explain why the macaque lateral frontal cortex shows a single dorsal activation patch rather than multiple discrete patches seen in humans.

    These are also reasonable concerns. To address them, we have added supplementary analyses using (a) only correct trials, and (b) a smaller smoothing kernel (see Supplementary Figure 3 and 4). In both cases, there is some loss of power, but otherwise similar results.

    Furthermore, there is concerning inter-individual variability in the macaque data. Normally, a functional network like the MD system is identified by consistent activation across all individuals. In this study, however, the two monkeys show substantially different activation maps and behavioral patterns. This lack of consistency renders the group-level results questionable, as it is unclear whether the group-level map represents a unified biological system or merely an average of disparate individual maps.

    Results for individual animals have now been supplemented with a conjunction map (Supplementary Figure 6). As expected, the conjunction map is similar to the map obtained by pooling data from the two animals.

    Finally, the subcortical activations shown in Figure 7 require more precise anatomical localization to confidently distinguish cerebellar nodes from adjacent brainstem structures.

    The slices shown in Figure 7 have been amended to better show the detail of activation outside cerebral cortex, in particular in cerebellum.

    The authors demonstrate a broad functional correspondence between human and macaque cognitive control networks, moving the field beyond speculative homology. The data suggest that an extended, interconnected network is recruited by cognitive challenge in both species; however, the strength of this claim is limited by the inter-individual variability and methodological constraints noted above. Assertions of precise topological equivalence should therefore be tempered. The absence of ventrolateral prefrontal and strong dorsal parietal activations in the macaque group analysis may reflect genuine biological differences, but could also stem from limited statistical power, excessive smoothing, or task design asymmetries. While the overall conclusions are plausible, they would be significantly strengthened by a more explicit discussion of these limitations and additional analytical clarifications regarding individual-level consistency.

    Indeed, as we note in the Discussion, there is a strong possibility that ventrolateral frontal and dorsal parietal activation are missing in our monkey data because of limited statistical power. Further work would be needed to address these possible limitations.

    Reviewer #2 (Recommendations for the authors):

    (1) Please discuss how the mixed-difficulty block design in humans may induce a state of proactive cognitive control that elevates baseline MD activation compared to the fixed 2step macaque condition. A supplementary analysis comparing early versus late block 2-step trials in humans would help clarify whether activation magnitudes reflect sustained task-set maintenance or transient trial demands.

    We now note the potential importance of this in the Discussion (p. 18), and point out that similarities between species appear to survive this difference in procedure.

    (2) Please clarify the rationale for combining correct and error trials in a single regressor.

    Given the higher macaque error rates, please provide a supplementary GLM restricted to correct trials only for the monkey data. This will demonstrate whether the core activation topography remains consistent when error-related signals are excluded.

    A new analysis addresses this point (Supplementary Figure 3). As we note, restricting analysis to correctly-completed problems somewhat reduces power but leaves major features of the results intact.

    (3) Please justify the use of a 4 mm FWHM smoothing kernel for macaque data, given cortical thickness and brain size differences. If feasible, re-run the analysis with a smaller kernel or surface-based smoothing to assess whether finer topographical distinctions emerge in lateral frontal and parietal cortices.

    This new analysis has also been run (Supplementary Figure 4), again with reduced power but major features of the results intact. We also refer to previous work indicating choice of either 3 mm or 4 mm smoothing for macaque fMRI (p. 13), approximately matching the smoothing needed to align electrophysiological and fMRI maps (Issa et al., 2013, J.Neurosci.).

    (4) Please detail how the human '2-step problems only' analysis in Supplementary Figure 1 was specified in the GLM. Explicitly state whether 4- and 6-step trials were modeled as separate regressors of no interest to prevent hemodynamic bleed-over from contaminating the 2-step beta weights.

    Indeed, 4- and 6-step trials were removed using regressors of no interest, as now specified in Methods (p. 24).

    (5) Please provide higher-resolution slices or probabilistic atlas overlays for the cerebellar and subcortical activations in Figure 7. This will help clearly distinguish cerebellar hemispheres from adjacent brainstem structures and ensure anatomical labeling is accurate.

    To address this question, additional slices have been added to a revised Figure 7, in particular adding detail to cerebellar activation.

    (6) Please address the substantial inter-individual variability in the macaque data, particularly regarding Monkey B's performance. Even after excluding five poor-performing sessions, Monkey B only reached about 65% accuracy on the first step of the maze task. This suggests that the animal was largely guessing rather than following a strategic, goal directed plan. The notably higher accuracy on step 2 (>80%) could simply be a selection bias artifact, as the task terminates immediately following step 1 errors, meaning step 2 trials only occur when step 1 was already correct. Including an animal that likely did not fully grasp the overarching task rule in a cohort of N=2 raises serious concerns about signal dilution and the reliability of the group-level maps. Please explicitly justify why Monkey B's data were retained despite these performance concerns, or consider excluding this animal and acquiring data from a third, behaviorally reliable subject. At minimum, report a conjunction map showing regions strictly active in both animals alongside the combined analysis, and present individual subject maps more prominently to improve transparency.

    Though we appreciate this concern, we do not think the data indicate that monkey B failed to use the maze goal to constrain choices. As shown in Figure 3, the great majority of errors were timing errors (mostly not waiting for go signal). Excluding these, for step 1, of choices directed to one of the two available alternatives, 88% were correct (Figure 4, compare “correct” with “wrong open location”).

    As noted above, we have added a conjunction map (Supplementary Figure 6) to our previous presentation of individual data. We note (p. 13) that, as expected, this map strongly resembles results from the combined-animal analysis.

  10. Version published to 10.7554/elife.111502.2 on eLife
  11. Version published to 10.64898/2026.02.24.707621v5 on bioRxiv
  12. Mentioned by @rridrobot.bsky.social on Bluesky

    Authors published a paper in Biorxiv, they used FreeSurfer in the study. Including #RRIDs will make this less ambiguous. SciScore made a table with this resource, see “Automated Services” module (download as csv, xml or #jats) #STMpublishing #RRID

  13. Version published to 10.64898/2026.02.24.707621v4 on bioRxiv
  14. Version published to 10.7554/elife.111502.1 on eLife
  15. eLife

    eLife Assessment

    This study presents a valuable contribution to comparative cognitive neuroscience by directly mapping functional homologues of the human multiple-demand network in macaques using a matched spatial maze task. However, the evidence is incomplete due to methodological asymmetries in task design and preprocessing parameters that warrant careful consideration. The work will be of interest to researchers studying the evolution of cognitive control and cross-species neuroimaging.

  16. eLife

    Reviewer #1 (Public review):

    Summary:

    The "multiple-demand" (MD) system is a well-known finding of human brain imaging and is thought to play a central role in cognitive control. To directly compare the MD system in humans and monkeys, Mione et al. used functional magnetic resonance imaging to measure whole-brain activation in a multi-step saccadic maze task. In humans, the authors found a distributed pattern of brain activity close match to the canonical MD network and extends to adjacent regions of dorsal attention and other networks. While there was good correspondence between monkey and human data, differences were also notable in the lateral frontal cortex, the dorsal parietal cortex, and the sensorimotor cortex.

    Strengths:

    Though previous data hint at a corresponding network in the macaque, there has been no direct comparison to human data. This study provides a direct cross-species comparison with whole-brain data from fMRI, and the findings suggest an extended and strongly interconnected brain network recruited by increased cognitive challenge.

    Weaknesses:

    In previous human imaging, the MD system is defined by overlapping activation for many kinds of cognitive demands. In the present work, however, the authors used just a single task. Although there is some overlap between the putative monkey MD network and the canonical MD network identified in human imaging, there should be caution in linking current findings to the MD system based on limited task events.

  17. eLife

    Reviewer #2 (Public review):

    Summary:

    Mione et al. aim to resolve a long-standing question in comparative neuroscience: whether the macaque brain contains a functional analogue to the distributed human multiple-demand (MD) network. To address this, the authors employ a direct cross-species fMRI comparison using a multi-step saccadic maze task in humans and a simplified two-step version in macaques. By contrasting goal-directed navigation against a control condition that requires similar motor responses but no strategic planning, the study isolates the neural signatures of cognitive control across species.

    Strengths:

    The most compelling aspect of this work is its methodological alignment. Previous attempts to compare these systems often relied on comparisons of human BOLD signals and macaque single-unit recordings. By running parallel fMRI protocols, the authors establish a shared measurement basis that allows for a more direct comparison. The resulting activation maps clearly demonstrate conserved network topology across dorsomedial frontal, lateral, and medial parietal, and insula cortices. Combining these results with recent research on functional and structural connectivity further supports the idea that these networks evolved across species and provides a helpful starting point for future comparative studies. The findings will be highly useful for researchers investigating the evolutionary origins of domain-general cognitive control, as well as for neuroimaging methodologists developing cross-species alignment pipelines.

    Weaknesses:

    However, there are several differences in how the two groups were studied that make it harder to compare the results precisely. The human task mixed 2-, 4-, and 6-step trials within the same experimental blocks, whereas macaques performed only 2-step trials. This design difference likely places human participants in a state of sustained proactive cognitive control (Braver, 2012), as they must remain prepared for highly demanding trials at any moment. This elevated baseline arousal may artificially inflate MD network activation during the simpler 2-step trials in humans, making direct magnitude comparisons with the macaque data difficult. Additionally, the general linear model combined correct and error trials into a single regressor. Given that macaques exhibited substantially higher error rates, this approach risks diluting task-specific planning signals with activity related to error monitoring and reward prediction errors. The preprocessing pipeline also applied a 4 mm full-width half-maximum smoothing kernel to macaque data acquired at 1.5 mm resolution. Relative to the smaller size of the macaque brain, this kernel is quite large and likely blurs fine-grained topographical distinctions. This may partly explain why the macaque lateral frontal cortex shows a single dorsal activation patch rather than multiple discrete patches seen in humans. Furthermore, there is concerning inter-individual variability in the macaque data. Normally, a functional network like the MD system is identified by consistent activation across all individuals. In this study, however, the two monkeys show substantially different activation maps and behavioral patterns. This lack of consistency renders the group-level results questionable, as it is unclear whether the group-level map represents a unified biological system or merely an average of disparate individual maps. Finally, the subcortical activations shown in Figure 7 require more precise anatomical localization to confidently distinguish cerebellar nodes from adjacent brainstem structures.

    The authors demonstrate a broad functional correspondence between human and macaque cognitive control networks, moving the field beyond speculative homology. The data suggest that an extended, interconnected network is recruited by cognitive challenge in both species; however, the strength of this claim is limited by the inter-individual variability and methodological constraints noted above. Assertions of precise topological equivalence should therefore be tempered. The absence of ventrolateral prefrontal and strong dorsal parietal activations in the macaque group analysis may reflect genuine biological differences, but could also stem from limited statistical power, excessive smoothing, or task-design asymmetries. While the overall conclusions are plausible, they would be significantly strengthened by a more explicit discussion of these limitations and additional analytical clarifications regarding individual-level consistency.

  18. Version published to 10.64898/2026.02.24.707621v3 on bioRxiv
  19. Version published to 10.64898/2026.02.24.707621v2 on bioRxiv
  20. Mentioned by @earlkmiller.bsky.social on Bluesky

    Cognitive control networks in human and macaque doi.org/10.64898/202... #neuroscience

  21. Mentioned by @jeremyhogeveen.bsky.social on Bluesky

    "Multiple demand" network cognitive control interrogation across humans and macaques. Lateral PFC more functionally heterogeneous in humans than NHPs. Very cool translational work from @markboxf.bsky.social and colleagues! doi.org/10.64898/202...

  22. Mentioned by @biorxivpreprint.bsky.social on Bluesky

    Cognitive control networks in human and macaque https://www.biorxiv.org/content/10.64898/2026.02.24.707621v1

  23. Mentioned by @biorxiv-neursci.bsky.social on Bluesky

    Cognitive control networks in human and macaque https://www.biorxiv.org/content/10.64898/2026.02.24.707621v1

  24. Version published to 10.64898/2026.02.24.707621v1 on bioRxiv