Distinct higher-order representations of natural sounds in human and ferret auditory cortex
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Evaluation Summary:
Landemard et al. compare the response properties of primary vs. non-primary auditory cortex in ferrets with respect to natural and model-matched sounds, using functional ultrasound imaging. They find that responses do not differentiate between natural and model-matched sounds across ferret auditory cortex; in contrast, by drawing on previously published data in humans, the authors suggest that this is a defining distinction between human and non-human auditory cortex.
This was found to be a very nice study and with interesting results that are applicable to the general neuroscience community. The analyses are conducted well and a wealth of results are included, including findings for individual subjects and hemispheres (in supplementary figures). Concerns involved the size of the data set (only 2 animals), and some more explanation was needed with respect to data analysis choices.
(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 and Reviewer #2 agreed to share their names with the authors.)
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Abstract
Little is known about how neural representations of natural sounds differ across species. For example, speech and music play a unique role in human hearing, yet it is unclear how auditory representations of speech and music differ between humans and other animals. Using functional ultrasound imaging, we measured responses in ferrets to a set of natural and spectrotemporally matched synthetic sounds previously tested in humans. Ferrets showed similar lower-level frequency and modulation tuning to that observed in humans. But while humans showed substantially larger responses to natural vs. synthetic speech and music in non-primary regions, ferret responses to natural and synthetic sounds were closely matched throughout primary and non-primary auditory cortex, even when tested with ferret vocalizations. This finding reveals that auditory representations in humans and ferrets diverge sharply at late stages of cortical processing, potentially driven by higher-order processing demands in speech and music.
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Author Response:
Reviewer #1:
The submitted manuscript 'Distinct higher-order representations of natural sounds in human and ferret auditory cortex' by Landemard and colleagues seeks to investigate the neural representations of sound in the ferret auditory cortex. Specifically, they examine the stages of processing via manipulating the complexity and sound structure of stimuli. The authors create synthetic auditory stimuli that are statistically equivalent to natural sounds in their cochlear representation, temporal modulation structure, spectral modulation structure, and spectro-temporal modulation structure. The authors use functional ultrasound imaging (fUS) which allowed for the measurement of the hemodynamic signal at much finer spatial scales than fMRI, making it particularly suitable for the ferret. The authors then compare …
Author Response:
Reviewer #1:
The submitted manuscript 'Distinct higher-order representations of natural sounds in human and ferret auditory cortex' by Landemard and colleagues seeks to investigate the neural representations of sound in the ferret auditory cortex. Specifically, they examine the stages of processing via manipulating the complexity and sound structure of stimuli. The authors create synthetic auditory stimuli that are statistically equivalent to natural sounds in their cochlear representation, temporal modulation structure, spectral modulation structure, and spectro-temporal modulation structure. The authors use functional ultrasound imaging (fUS) which allowed for the measurement of the hemodynamic signal at much finer spatial scales than fMRI, making it particularly suitable for the ferret. The authors then compare their results to work done in humans that has previously been published (e.g. Norman-Haignere and McDermott, 2018) and find that: 1. While human non-primary auditory cortex demonstrates a significant difference between natural speech/music sounds and their synthetic counterparts, the ferret non-primary auditory cortex does not. 2. For each sound manipulation in humans, the dissimilarity increases as the distance from the primary auditory cortex increases, whereas for ferrets it does not. 3. While ferrets behaviorally respond to con-specific vocalizations, the ferret auditory cortex does not demonstrate the same hierarchical processing stream as humans do.
Overall, I find the approach (especially the sound manipulations) excellent and the overall finding quite intriguing. My only concern, is that it is essentially a null-result. While this result will be useful to the literature, there is always the concern that a lack of finding could also be due to other factors.
Thank you for taking the time to carefully read our manuscript. We have done our best to address all of your questions and concerns, which has improved the paper.
We note that our finding differs from a typical null result in two ways. First, our key finding is that responses to natural and synthetic sounds are closely matched throughout primary and non-primary auditory cortex. Unlike a typical null result, this finding cannot be due to a noisy measure, since if our data were noisy, we would not have observed any correspondence between natural and synthetic sounds. Second, we have a clear prediction from humans as to what we should observe if the organization were similar: matched responses in primary auditory cortex and divergent responses in non-primary auditory cortex. Our data clearly demonstrate that this prediction is wrong, for all of the reasons noted in our general response above. In essence, what we are showing is that there is a region by species interaction in the similarity of responses to natural vs. synthetic sounds (as reflected by a significant difference in slopes between species, see our response above). We have investigated and ruled out all of the alternative explanations we can think of for this interaction (e.g. differences in SNR or spatial resolution) and are left with the conclusion that there is a meaningful difference in functional organization between humans and ferrets. If there are any additional concerns you have, we would be happy to address them.
Major points:
- What if the stages in the ferret are wrong? The authors use 4 different manipulations thought to reflect key elements of sound structure and/or the relevant hierarchy of the processing stages of the auditory cortex, but it's possible that the dimensions in the ferret auditory cortex are along a different axis than spectro/temporal modulations. While I do not expect the authors to attempt every possible axis, it would be beneficial to discuss.
Thank you for raising this question. We now directly address this question in the Discussion (page 11):
"Our findings show that a prominent signature of hierarchical functional organization present in humans – preferential responses for natural vs. spectrotemporal structure – is largely absent in ferret auditory cortex. But this finding does not imply that there is no functional differentiation between primary and non-primary regions in ferrets. For example, ferret non-primary regions show longer latencies, greater spectral integration bandwidths, and stronger task-modulated responses compared with primary regions (Elgueda et al., 2019). The fact that we did not observe differences between primary and non-primary regions is not because the acoustic features manipulated are irrelevant to ferret auditory cortex, since our analysis shows that matching frequency and modulation statistics is sufficient to match the ferret cortical response, at least as measured by ultrasound. Indeed, if anything, it appears that modulation features are more relevant to the ferret auditory cortex since these features appear to drive responses throughout primary and non-primary regions, unlike human auditory cortex where we only observed strong, matched responses in primary regions."
- For the ferret vocalizations, it is possible that a greater N would allow for a clearer picture of whether or not the activation is greater than speech/music? While it is clear that any difference would be subtle and probably require a group analysis, this would help settle this result/issue (at least at the group level).
Below we plot the distribution of NSE values for ferret vocalizations, speech, and music, averaged across all of auditory cortex and plotted separately for each ferret tested (panel A). As is evident, we observe larger NSE values for ferret vocalizations in one animal (p < 0.01, Wilcoxon test), but no difference in the other two (p > 0.55). When we perform a group analysis, averaging across all three animals, we do not observe any significant difference between the categories (panel B) (p = 0.27). Moreover, even for ferret vocalizations, NSE values were similar throughout primary and non-primary regions, and this was true in all three animals tested (panel C). Given these data, we do not believe our study provides evidence for a difference between ferret vocalizations and other categories. Panel A is plotted in the revised Figure 4 - figure supplement 1E. The distance-to-PAC curves (panel C) and the corresponding slopes are plotted in Figure 4D-E.
Individual and group analyses of the difference between natural and spectrotemporally matched synthetic sounds, broken down by sound category. A, The NSE between natural and synthetic sounds plotted separately for each animal and sound category. NSE values have been averaged across all of auditory cortex. Each circle represents a single pair of natural/synthetic sounds. We find that the NSE values are larger for ferret vocalizations in Ferret A, but this effect is not present in Ferret T or C (** indicates p < 0.005, Wilcoxon test). B, NSE values averaged across animals. C, NSEs for ferret vocalizations, plotted as a function of distance to primary auditory cortex (PAC). Figure shows both individual subject (thin pink lines) and group-averaged data (thick pink line).
Below, we have reproduced the relevant paragraph of the results where we discuss these and other related findings (page 6):
"To directly test if ferrets showed preferential responses to natural vs. synthetic ferret vocalizations, we computed maps plotting the average difference between natural vs. synthetic sounds for different categories, using data from both Experiments I and II (Figure 4C). We also separately measured the NSE for sounds from different categories, again plotting NSE values as a function of distance to PAC (Figure 4D-E). The differences that we observed between natural and synthetic sounds were small and scattered throughout primary and non-primary auditory cortex, even for ferret vocalizations. In one animal, we observed significantly larger NSE values for ferret vocalizations compared with speech and music (Ferret A, Mdvoc = 0.137 vs MdSpM = 0.042, Wilcoxon rank-sum test: T = 1138, z = 3.29, p < 0.01). But this difference was not present in the other two ferrets tested (p > 0.55) and was also not present when we averaged NSE values across animals (Mdvoc = 0.053 vs MdSpM = 0.033, Wilcoxon rank- sum test: T = 1016, z = 1.49, p = 0.27). Moreover, the slope of the NSE vs. distance-to- PAC curve was near 0 for all animals and sound categories, even for ferret vocalizations, and was substantially lower than the slopes measured in all 12 human subjects (Figure 4F) (vocalizations in ferrets vs. speech in humans: p < 0.001 via a sign test; speech in ferrets vs. speech in humans: p < 0.001). In contrast, human cortical responses were substantially larger for natural vs. synthetic speech and music, and these response enhancements were concentrated in distinct non-primary regions (lateral for speech and anterior/posterior for music) and clearly different from those for other natural sounds (Figure 4C). Thus, ferrets do not show any of the neural signatures of higher-order sensitivity that we previously identified in humans (large effect size, spatially clustered responses, and a clear non-primary bias), even for con- specific vocalizations."
- Relatedly, did the magnitude of this effect increase outside the auditory cortex?
We did not record outside of auditory cortex. Unlike fMRI, it is not easy to get whole-brain coverage using current fUS probes. Since our goal was to test if ferret auditory cortex showed similar organization as human auditory cortex, we focused our data collection on auditory regions. We have clarified this point in the Methods (page 13):
"fUS data are collected as a series of 2D images or ‘slices’. Slices were collected in the coronal plane and were spaced 0.4 mm apart. The slice plane was varied across sessions in order to cover the region-of-interest which included both primary and non- primary regions of auditory cortex. We did not collect data from non-auditory regions due to limited time/coverage."
- It would be useful to have a measure of the noise floor for each plot and/or species for NSE analyses. This would make it easier to distinguish whether, for instance, in 2A-D, an NSE of 0.1 (human primary) vs. an NSE of 0.042 (ferret primary) should be interpreted as a bit more than double, or both close to the noise floor (which is what I presume).
All of our NSE measures are noise-corrected such that the effective floor is zero (noise- correction provides an estimate of what the NSE value would be given perfectly reliable measurements). The only exception are cases where we plot the NSE values for example voxels/ROIs (Figure 2A-D, Figure 2 - figure supplement 1), in which case we plot both the raw NSE values along with the noise floor, which is given by the test-retest NSE of the measurements. To address your comment, we have included a supplemental plot (Figure 2 - figure supplement 3) that shows the median uncorrected NSE as a function of distance to primary auditory cortex, along with the noise floor given by the reliability of the measurements. The figure is reproduced below.
Figure 2 - figure supplement 3. Uncorrected NSE values. This figure plots the uncorrected NSE between natural and synthetic sounds as a function of distance to primary auditory cortex (PAC). The test-retest NSE value, which provides a noise floor for the natural vs. synthetic NSE, is plotted below each set of curves using dashed lines. Each thin line corresponds to a single ferret (gray) or a single human subject (gold). Thick lines show the average across all subjects. Format is the same as Figure 2F.
We have clarified this important detail in the Results (page 4):
"We used the test-retest reliability of the responses to noise-correct the measured NSE values such that the effective noise floor given the reliability of the measurements is zero."
Reviewer #2:
Landemard et al. compare the response properties of primary vs. non-primary auditory cortex in ferrets with respect to natural and model-matched sounds, using functional ultrasound imaging. They find that responses do not differentiate between natural and model-matched sounds across ferret auditory cortex; in contrast, by drawing on previously published data in humans where Norman-Haignere & McDermott (2018) showed that non-primary (but not primary) auditory cortex differentiates between natural and model-matched sounds, the authors suggest that this is a defining distinction between human and non-human auditory cortex. The analyses are conducted well and I appreciate the authors including a wealth of results, also split up for individual subjects and hemispheres in supplementary figures, which helps the reader get a better idea of the underlying data.
Overall, I think the authors have completed a very nice study and present interesting results that are applicable to the general neuroscience community. I think the manuscript could be improved by using different terminology ('sensitivity' as opposed to 'selectivity'), a larger subject pool (only 2 animals), and some more explanation with respect to data analysis choices.
Many thanks for your thoughtful critiques and comments. We have attempted to address all of them, which has improved the manuscript.
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Reviewer #2 (Public Review):
Landemard et al. compare the response properties of primary vs. non-primary auditory cortex in ferrets with respect to natural and model-matched sounds, using functional ultrasound imaging. They find that responses do not differentiate between natural and model-matched sounds across ferret auditory cortex; in contrast, by drawing on previously published data in humans where Norman-Haignere & McDermott (2018) showed that non-primary (but not primary) auditory cortex differentiates between natural and model-matched sounds, the authors suggest that this is a defining distinction between human and non-human auditory cortex. The analyses are conducted well and I appreciate the authors including a wealth of results, also split up for individual subjects and hemispheres in supplementary figures, which helps the …
Reviewer #2 (Public Review):
Landemard et al. compare the response properties of primary vs. non-primary auditory cortex in ferrets with respect to natural and model-matched sounds, using functional ultrasound imaging. They find that responses do not differentiate between natural and model-matched sounds across ferret auditory cortex; in contrast, by drawing on previously published data in humans where Norman-Haignere & McDermott (2018) showed that non-primary (but not primary) auditory cortex differentiates between natural and model-matched sounds, the authors suggest that this is a defining distinction between human and non-human auditory cortex. The analyses are conducted well and I appreciate the authors including a wealth of results, also split up for individual subjects and hemispheres in supplementary figures, which helps the reader get a better idea of the underlying data.
Overall, I think the authors have completed a very nice study and present interesting results that are applicable to the general neuroscience community. I think the manuscript could be improved by using different terminology ('sensitivity' as opposed to 'selectivity'), a larger subject pool (only 2 animals), and some more explanation with respect to data analysis choices.
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Reviewer #1 (Public Review):
The submitted manuscript 'Distinct higher-order representations of natural sounds in human and ferret auditory cortex' by Landemard and colleagues seeks to investigate the neural representations of sound in the ferret auditory cortex. Specifically, they examine the stages of processing via manipulating the complexity and sound structure of stimuli. The authors create synthetic auditory stimuli that are statistically equivalent to natural sounds in their cochlear representation, temporal modulation structure, spectral modulation structure, and spectro-temporal modulation structure. The authors use functional ultrasound imaging (fUS) which allowed for the measurement of the hemodynamic signal at much finer spatial scales than fMRI, making it particularly suitable for the ferret. The authors then compare their …
Reviewer #1 (Public Review):
The submitted manuscript 'Distinct higher-order representations of natural sounds in human and ferret auditory cortex' by Landemard and colleagues seeks to investigate the neural representations of sound in the ferret auditory cortex. Specifically, they examine the stages of processing via manipulating the complexity and sound structure of stimuli. The authors create synthetic auditory stimuli that are statistically equivalent to natural sounds in their cochlear representation, temporal modulation structure, spectral modulation structure, and spectro-temporal modulation structure. The authors use functional ultrasound imaging (fUS) which allowed for the measurement of the hemodynamic signal at much finer spatial scales than fMRI, making it particularly suitable for the ferret. The authors then compare their results to work done in humans that has previously been published (e.g. Norman-Haignere and McDermott, 2018) and find that: 1. While human non-primary auditory cortex demonstrates a significant difference between natural speech/music sounds and their synthetic counterparts, the ferret non-primary auditory cortex does not. 2. For each sound manipulation in humans, the dissimilarity increases as the distance from the primary auditory cortex increases, whereas for ferrets it does not. 3. While ferrets behaviorally respond to con-specific vocalizations, the ferret auditory cortex does not demonstrate the same hierarchical processing stream as humans do.
Overall, I find the approach (especially the sound manipulations) excellent and the overall finding quite intriguing. My only concern, is that it is essentially a null-result. While this result will be useful to the literature, there is always the concern that a lack of finding could also be due to other factors.
Major points:
What if the stages in the ferret are wrong? The authors use 4 different manipulations thought to reflect key elements of sound structure and/or the relevant hierarchy of the processing stages of the auditory cortex, but it's possible that the dimensions in the ferret auditory cortex are along a different axis than spectro/temporal modulations. While I do not expect the authors to attempt every possible axis, it would be beneficial to discuss.
For the ferret vocalizations, it is possible that a greater N would allow for a clearer picture of whether or not the activation is greater than speech/music? While it is clear that any difference would be subtle and probably require a group analysis, this would help settle this result/issue (at least at the group level).
Relatedly, did the magnitude of this effect increase outside the auditory cortex?
It would be useful to have a measure of the noise floor for each plot and/or species for NSE analyses. This would make it easier to distinguish whether, for instance, in 2A-D, an NSE of 0.1 (human primary) vs. an NSE of 0.042 (ferret primary) should be interpreted as a bit more than double, or both close to the noise floor (which is what I presume).
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Evaluation Summary:
Landemard et al. compare the response properties of primary vs. non-primary auditory cortex in ferrets with respect to natural and model-matched sounds, using functional ultrasound imaging. They find that responses do not differentiate between natural and model-matched sounds across ferret auditory cortex; in contrast, by drawing on previously published data in humans, the authors suggest that this is a defining distinction between human and non-human auditory cortex.
This was found to be a very nice study and with interesting results that are applicable to the general neuroscience community. The analyses are conducted well and a wealth of results are included, including findings for individual subjects and hemispheres (in supplementary figures). Concerns involved the size of the data set (only 2 animals), and some …
Evaluation Summary:
Landemard et al. compare the response properties of primary vs. non-primary auditory cortex in ferrets with respect to natural and model-matched sounds, using functional ultrasound imaging. They find that responses do not differentiate between natural and model-matched sounds across ferret auditory cortex; in contrast, by drawing on previously published data in humans, the authors suggest that this is a defining distinction between human and non-human auditory cortex.
This was found to be a very nice study and with interesting results that are applicable to the general neuroscience community. The analyses are conducted well and a wealth of results are included, including findings for individual subjects and hemispheres (in supplementary figures). Concerns involved the size of the data set (only 2 animals), and some more explanation was needed with respect to data analysis choices.
(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 and Reviewer #2 agreed to share their names with the authors.)
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