Hierarchical cortical plasticity in congenital sight impairment

Reviewer #1 (Public review):

Summary:

This paper examines plasticity in early cortical (V1-V3) areas in an impressively large number of rod monochromats (individuals with achromatopia). The paper examines three things:

(1) Cortical thickness. It is now well established that early complete blindness leads to increases in cortical thickness. This paper shows increased thickness confined to the foveal projection zone within achromats. This paper replicates the work by Molz (2022) and Lowndes (2021), but the detailed mapping of cortical thickness as a function of eccentricity and the inclusion of higher visual areas is particularly elegant.

(2) Failure to show largescale reorganization of early visual areas using retinotopic mapping. This is a replication of a very recent study by Molz et al. but I believe, given anatomical variability (and the very large n in this study) and how susceptible pRF findings are to small changes in procedure, this replication is also of interest.

(3) Connective field modelling, examining the connections between V3-V1. The paper finds changes in the pattern of connections, and smaller connective fields in individuals with achromatopsia than normally sighted controls, and suggests that these reflect compensatory plasticity, with V3 compensating for the lower resolution V1 signal in individuals with achromatopsia.

Strengths:

This is a carefully done study (both in terms of data collection and analysis) that is an impressive amount of work. I have a number of methodological comments but I hope they will be considered as constructive engagement - this work is highly technical with a large number of factors to consider.

Weaknesses:

(1) Effects of eye-movements

I have some concerns with how the effects of eye-movements are being examined. There are two main reasons the authors give for excluding eye-movements as a factor in their results. Both explanations have limitations.

a) The first is that R2 values are similar across groups in the foveal confluence. This is fine as far as it goes, but R2 values are going to be low in that region. So this shows that eye-movements don't affect coverage (the number of voxels that generate a reliable pRF), but doesn't show that eye-movements aren't impacting their other measures.

b) The authors don't see a clear relationship between coverage and fixation stability. This seems to rest on a few ad hoc examples. (What happens if one plots mean fixation deviation vs. coverage (and sets the individuals who could not be calibrated as the highest value of calibrated fixation deviation. Does a relationship then emerge?).

In any case, I wouldn't expect coverage to be particularly susceptible to eye-movements. If a voxel in the cortex entirely projects to the scotoma then it should be robustly silent. The effects of eye-movements will be to distort the size and eccentricity estimates of voxels that are not entirely silent.

There are many places in the paper where eye-movements might be playing an important role.

Examples include the larger pRF sizes observed in achromats. Are those related to fixation instability? Given that fixation instability is expected to increase pRF size by a fixed amount, that would explain why ratios are close to 1 in V3 (Figure 4).

(2) Topography

The claim of no change in topography is a little confusing given that you do see a change in eccentricity mapping in achromats.

Either this result is real, in which case there *is* a change in topography, albeit subtle, or it's an artifact.

Perhaps these results need a little bit of additional scrutiny.

One reason for concern is that you see different functions relating eccentricity to V1 segments depending on the stimulus. That almost certainly reflects biases in the modelling, not reorganization - the curves of Figure 2D are exactly what Binda et al. predict.

Another reason for concern is that I'm very surprised that you see so little effect of including/not including the scotoma - the differences seem more like what I'd expect from simply repeating the same code twice. (The quickest sanity check is just to increase the size of the estimated scotoma to be even bigger?).

I'd also look at voxels that pass an R2>0.2 threshold for both the non-selective and selective stimulus. Are the pRF sizes the same for both stimuli? Are the eccentricity estimates? If not, that's another clear warning sign.

(3) Connective field modelling

Let's imagine a voxel on the edge of the scotoma. It will tend to have a connective field that borders the scotoma, and will be reduced in size (since it will likely exclude the cortical region of V1 that is solely driven by resting state activity). This predicts your rod monochromat data. The interesting question is why this doesn't happen for controls. One possibility is that there is top-down 'predictive' activity that smooths out the border of the scotoma (there's some hint of that in the data), e.g., Masuda and Wandell.

One thing that concerns me is that the smaller connective fields don't make sense intuitively. When there is a visual stimulus, connective fields are predominantly driven by the visual signal. In achromats, there is a large swath of cortex (between 1-2.5 degrees) which shows relatively flat tuning as regards eccentricity. The curves for controls are much steeper, See Figure 2b. This predicts that visually driven connective fields should be larger for achromats. So, what's going on? The beta parameter is not described (and I believe it can alter connective field sizes). Similarly, it's possible to get very small connective fields, but there wasn't a minimum size described in the thresholding. I might be missing something obvious, but I'm just deeply confused as to how the visual maps and the connectome maps can provide contradictory results given that the connectome maps are predominantly determined by the visual signal. Some intuition would be helpful.

Some analyses might also help provide the reader with insight. For example, doing analyses separately on V3 voxels that project entirely to scotoma regions, project entirely to stimulus-driven regions, and V3 voxels that project to 'mixed' regions.

The finding that pRF sizes are larger in achromats by a constant factor as a function of eccentricity is what differences in eye-movements would predict. It would be worth examining the relationship between pRF sizes and fixation stability.

Reviewer #2 (Public review):

Summary:

The authors inspect the stability and compensatory plasticity in the retinotopic mapping in patients with congenital achromatopsia. They report an increased cortical thickness in central (eccentricities 0-2 deg) in V1 and the expansion of this effect to V2 (trend) and V3 in a cohort with an average age of adolescents.

In analyzing the receptive fields, they show that V1 had increased receptive field sizes in achromats, but there were no clear signs of reorganization filling in the rod-free area.
In contrast, V3 showed an altered readout of V1 receptive fields. V3 of achromats oversampled the receptive fields bordering the rod-free zone, presumably to compensate and arrive at similar receptive fields as in the controls.

These findings support a retention of peripheral-V1 connectivity, but a reorganization of later hierarchical stages of the visual system to compensate for the loss, highlighting a balance between stability and compensation in different stages of the visual hierarchy.

Strengths:

The experiment is carefully analyzed, and the data convey a clear and interesting message about the capacities of plasticity.

Weaknesses:

The existence of unstable fixation and nystagmus in the patient group is alluded to, but not quantified or modeled out in the analyses. The authors may want to address this possible confound with a quantitative approach.

Author response:

We would like to thank the reviewers for their positive evaluation of our work, and their comments inspiring useful discussion. We will provide an in-depth response once one of the key authors has returned from parental leave (in some months), but below we share initial thoughts:

Both reviewers asked to see more gaze data to understand how eye movements in patients with achromatopsia might drive our results. We will expand our analyses of eye tracking data and discuss the implications in more depth, but would like to note that our key findings (no change in signal coverage in the foveal rod-scotoma projection zone in achromats, and changes in connective fields) are both robust to eye movement, and unlikely to be driven by gaze differences. Where this is less clear (i.e., population Receptive Field eccentricities are shifted outwards and increased in size), we have highlighted this and avoided drawing strong conclusions.

Reviewer 1 questioned why smaller connective fields (CFs) were observed in achromats, suggesting that their flatter V1 eccentricity tuning should predict larger CFs. It’s not straightforward to predict how V1's population receptive field (pRF) tuning profile shapes V3's sampling extent, as CFs are driven, but not dictated by V1 - they combine and integrate V1 signals. As we’re dealing with an atypically developed visual system, assumptions about expected relationships are complicated further. We believe that the most relevant aspect of pRF data to the interpretability of V3 CF extent, is the ratio between V1 and V3 pRF sizes. Our outcomes show that pRF sizes in achromats, while larger in V1, are more normalized in V3, predicting more local V3 sampling from V1. This is what our quantifications of CF size show across two independent measures with different stimuli. We will provide further data to address reviewer 1's various queries about the potential causes of the pRF eccentricity shifts in achromats, the relationship between pRFs and CFs, and methodological details of CF fits.

We thank the reviewers again for their insightful comments and look forward to providing more comprehensive responses to their queries substantiated with data as soon as possible.