Decoding the brain state-dependent relationship between pupil dynamics and resting state fMRI signal fluctuation

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    Evaluation Summary:

    Pupil diameter is used as an index of the brain's arousal system, and has traditionally thought to be a non-invasive index of specific neuromodulatory activity. It is therefore been heavily used as a measure in neuroscience. More recent data suggests a more complex picture whereby a pupil dilation might track cocktail of different neuromodulators. This paper provides firm data supporting this view, and introduces the new view that the make-up of this cocktail changes significantly over time. Pupil dynamics are linked with different neuromodulatory centers over different intervals of time. This is clearly important data across a broad range of human and animal systems neuroscience.

    (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

Pupil dynamics serve as a physiological indicator of cognitive processes and arousal states of the brain across a diverse range of behavioral experiments. Pupil diameter changes reflect brain state fluctuations driven by neuromodulatory systems. Resting-state fMRI (rs-fMRI) has been used to identify global patterns of neuronal correlation with pupil diameter changes; however, the linkage between distinct brain state-dependent activation patterns of neuromodulatory nuclei with pupil dynamics remains to be explored. Here, we identified four clusters of trials with unique activity patterns related to pupil diameter changes in anesthetized rat brains. Going beyond the typical rs-fMRI correlation analysis with pupil dynamics, we decomposed spatiotemporal patterns of rs-fMRI with principal component analysis (PCA) and characterized the cluster-specific pupil–fMRI relationships by optimizing the PCA component weighting via decoding methods. This work shows that pupil dynamics are tightly coupled with different neuromodulatory centers in different trials, presenting a novel PCA-based decoding method to study the brain state-dependent pupil–fMRI relationship.

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  1. Author Response:

    Reviewer #1 (Public Review):

    [...] I do have a couple of concerns.

    Major issues:

    The BOLD hemodynamic response function is slower than the pupil impulse response function. It seems that the authors did not correct for the "lag" between the two (as in Yellin et al., 2015, for example). How much does this matter for the results?

    We thank the reviewer for highlighting the insufficient treatment of the potential “lag” between the two signals. In the initial submission we only compared linear regression prediction scores obtained after introducing shifts in the <-5; 5> s range between the signals and verified that prediction scores were the highest at 0 s lag (Figure 3–figure supplement 1B).

    In line with the reviewer’s suggestion, we followed the approach of Yellin et al. (2015) and convolved the pupil diameter size …

  2. Reviewer #2 (Public Review):

    In this work, Sobczak et al. suggest that correlations between fMRI and pupil diameter vary over time, and propose an approach to identify distinct clusters of such correlation patterns. The proposed methods are applied to data acquired from anesthetized rats. Based on the clusters obtained, the authors conclude that pupil dynamics are linked with different neuromodulatory centers over different intervals of time.

    Overall, I believe that the study is novel and uncovers potential new modes of coupling between neuromodulatory nuclei and pupil diameter. However, additional analysis may be needed to fully support the validity of the derived clusters, and the decoding methods may need some modification before the accuracy values can be properly interpreted. The mechanisms behind the time-varying fMRI-pupil …

  3. Reviewer #1 (Public Review):

    Human and animal work over the last couple of years established that fluctuations in pupil size track the activity of a number of neuromodulatory nuclei, including the noradrenergic locus coeruleus, cholinergic basal forebrain, serotonergic dorsal raphe and perhaps the dopaminergic midbrain. In other words, pupil size fluctuations might track a "cocktail" of neuromodulators. The current paper leverages sophisticated data driven analysis techniques to show that pupil size changes can indeed be modulated by different combinations of subcortical nuclei. Doing so, the paper helps laying a solid and nuanced neurophysiological foundation for the interpretation of results from cognitive pupillometry, an area of neuroscience and psychology that is rapidly expanding over the past years. I do have a couple of concerns.

  4. Evaluation Summary:

    Pupil diameter is used as an index of the brain's arousal system, and has traditionally thought to be a non-invasive index of specific neuromodulatory activity. It is therefore been heavily used as a measure in neuroscience. More recent data suggests a more complex picture whereby a pupil dilation might track cocktail of different neuromodulators. This paper provides firm data supporting this view, and introduces the new view that the make-up of this cocktail changes significantly over time. Pupil dynamics are linked with different neuromodulatory centers over different intervals of time. This is clearly important data across a broad range of human and animal systems neuroscience.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private …