Top-down processing alone activates the early somatosensory nuclei

Reviewer #1 (Public review):

Summary:

The authors investigated somatosensory processing along the afferent somatosensory pathway (cuneate nucleus, thalamus, S1) in a group of spinal cord injury patients and a group of controls. They propose that reduced motor function in SCI patients would reduce bottom-up activity; thus, recorded activity in SCI patients would reflect top-down modulation of overt or attempted movements.

Strengths:

(1) Strong methods.

(2) Experimental and control groups.

(3) Strong writing.

(4) Results well presented.

(5) Appropriate statistics.

Weaknesses:

Some results (or lack of) cast doubt about the ability of the used technique (3T fMRI) to detect the desired effects (bottom-up vs top-down activity).

Reviewer #2 (Public review):

Summary:

This study addresses a question that has been essentially inaccessible in humans: whether the early somatosensory relay nuclei are engaged by anything other than peripheral drive. Using functional and quantitative MRI in individuals with chronic cervical spinal cord injury, the authors show that the cuneate nucleus and VPL are robustly engaged during overt or attempted hand movement, and that this engagement persists in a participant with complete hand paralysis and no detectable muscle activity. They further report structural degeneration of the cuneate nucleus that is unrelated to the preserved task-evoked activity, and interpret the residual activity as reflecting top-down corticocuneate signalling.

Strengths:

The work is well conceived and clearly written, and the demonstration that the cuneate nucleus and VPL are robustly engaged during (attempted) hand movement after chronic cervical spinal cord injury is, to my knowledge, novel at this level of anatomical resolution. The finding is convincing. The dissociation between preserved task-evoked activity and marked structural degeneration of the cuneate nucleus is a highly interesting result with clear implications for rehabilitation. The manuscript is straightforward to follow, and the imaging protocol is carefully executed.

Weaknesses:

My main reservation concerns the inferential step from "not peripheral" to "corticocuneate". The data establish the former convincingly; the latter may not.

(1) Attribution of the observed activity to corticocuneate projections.

The central claim rests on an argument by elimination: because bottom-up drive is excluded in PT01, the residual activity must be top-down and, by extension, corticocuneate. Two distinct gaps should be addressed. First, "top-down" is not equivalent to "direct corticocuneate". Descending influence could reach the cuneate nucleus through multiple indirect pathways. Second, the activity observed at the three levels (cuneate, VPL, S1) need not be serially propagated, since layer 6 corticothalamic projections, for example, could drive VPL independently of any cuneate contribution. I would ask the authors to either provide evidence bearing on the routing, or to consistently use a route-neutral term (e.g. "descending" or "top-down") and reserve "corticocuneate" for the discussion of candidate mechanisms.

(2) Afferent input arising above the lesion level.

The EMG control in PT01 was restricted to hand and forearm muscles. Musculature innervated above C4 (cervical paraspinals, trapezius, and to a variable extent the shoulder girdle) remained available to this participant, and attempted hand movement is frequently accompanied by increased proximal co-contraction, postural stabilization, and altered respiratory effort. Afferent to the upper cervical cord is known to project to the ipsilateral cuneate nucleus, and its activity would produce lateralized, ipsilaterally dominant cuneate input - that is, precisely the pattern reported. This alternative is not excluded by the present control and should be addressed directly, ideally with proximal EMG in PT01 (and, if possible, in the other participants), or at minimum with an explicit discussion. Relatedly, the authors recorded respiratory and cardiac signals: please report whether respiratory volume or heart rate differed between movement and rest blocks, and between groups, since the dorsal medulla lies adjacent to cardiorespiratory nuclei.

(3) Functional significance of the preserved top-down signal.

The discussion establishes that top-down input persists but says relatively little about why it should. If the principal role of descending input to the cuneate nucleus is the gating of incoming afferent traffic, then in the absence of afferents there is nothing left to gate, and one might have expected the signal to be lost. Its persistence is the most interesting aspect of the finding and deserves fuller discussion. Candidate accounts the authors may wish to consider include: an efference copy or predictive signal delivered to a comparator that no longer receives its input, in the framework the authors already invoke (references 27, 28); engagement of the non-lemniscal outputs of the dorsal column nuclei (e.g., cuneocerebellar, cuneo-olivary projections); attempted movement engages motor imagery and attention, in which case the relevant question becomes what distinguishes these from movement-related gating. A related interpretational point: in behaving primates, movement-related modulation of cuneate transmission is bidirectional and includes prominent suppression (refs. 7/12). Note also that BOLD increases are compatible with increased inhibition, so they do not indicate facilitated throughput.

Author response:

Reviewer #1:

Some results (or lack of) cast doubt about the ability of the used technique (3T fMRI) to detect the desired effects (bottom-up vs top-down activity). 

As the reviewer notes, 3 T MRI alone cannot partition the relative contributions of bottom-up and top-down signals, since both are present during movement in an intact system. This reflects the premise of our study design but is also an important caveat when interpreting the group-level results, which characterise the net task-related response. Our central inference therefore focuses on the persistence of activation in PT01, in whom hand movement was absent. PT01 therefore lacks bottom-up signals, and any observed activity must be driven by top-down processes. In the revised manuscript, we provide measures of signal quality and activation magnitude to better characterise the sensitivity of these measurements and will draw on existing evidence that our approach resolves task-specific responses within these nuclei.

Reviewer #2:

(1) Attribution of the observed activity to corticocuneate projections: My main reservation concerns the inferential step from "not peripheral" to "corticocuneate". The data establish the former convincingly; the latter may not. The central claim rests on an argument by elimination: because bottom-up drive is excluded in PT01, the residual activity must be top-down and, by extension, corticocuneate. Two distinct gaps should be addressed. First, "top-down" is not equivalent to "direct corticocuneate". Descending influence could reach the cuneate nucleus through multiple indirect pathways. Second, the activity observed at the three levels (cuneate, VPL, S1) need not be serially propagated, since layer 6 corticothalamic projections, for example, could drive VPL independently of any cuneate contribution. I would ask the authors to either provide evidence bearing on the routing, or to consistently use a route-neutral term (e.g. "descending" or "top-down") and reserve "corticocuneate" for the discussion of candidate mechanisms. 

We agree with the reviewer that our previous attribution of the observed brainstem effects to corticocuneate processing was speculative and should have been presented as such. Our findings support a non-peripheral, top-down contribution but do not allow us to attribute this descending influence to a specific anatomical route. We have therefore revised the manuscript throughout to use “top-down” processing as a more route-neutral term, reserving the corticocuneate pathway for discussion of possible candidate mechanisms. We have also clarified in the revised discussion that activity observed across the cuneate nucleus, VPL, and S1 does not necessarily imply serial propagation through these structures.

(2) Afferent input arising above the lesion level: The EMG control in PT01 was restricted to hand and forearm muscles. Musculature innervated above C4 (cervical paraspinals, trapezius, and to a variable extent the shoulder girdle) remained available to this participant, and attempted hand movement is frequently accompanied by increased proximal co-contraction, postural stabilization, and altered respiratory effort. Afferent to the upper cervical cord is known to project to the ipsilateral cuneate nucleus, and its activity would produce lateralized, ipsilaterally dominant cuneate input - that is, precisely the pattern reported. This alternative is not excluded by the present control and should be addressed directly, ideally with proximal EMG in PT01 (and, if possible, in the other participants), or at minimum with an explicit discussion. Relatedly, the authors recorded respiratory and cardiac signals: please report whether respiratory volume or heart rate differed between movement and rest blocks, and between groups, since the dorsal medulla lies adjacent to cardiorespiratory nuclei.

The reviewer raises an important point. To test whether proximal muscle activity could account for the cuneate response in PT01, we collected additional EMG data during attempted hand movements, focusing on muscles innervated above the lesion level. These included the anterior (AD) and middle deltoid (MD), upper (UT) and middle trapezius (MT), and cervical paraspinals (CP), along with two of the original distal recordings (thenar eminence, TE; extensor digitorum, ED). Nonetheless, we found no significant difference in EMG activity in any recorded muscle during attempted left- or right-hand movement versus rest (Supplementary Figure 3A and 3B). To confirm that the chosen electrode montage could detect proximal muscle activity, we further instructed the participant to perform left or right shoulder shrugs during the same session. This produced a clear increase in activity during movement across the trapezius, cervical paraspinal and middle deltoid recordings (Supplementary Figure 3C and 3D).

In addition, we analysed the cardiac and respiratory recordings acquired during fMRI to determine whether movement-related physiological changes could explain the observed brainstem activity. Importantly, any physiological change in heart rate during movement is global and therefore cannot explain the hand-dependent lateralisation of the cuneate response. Furthermore, cardiac and respiratory nuisance regressors were included in all first-level models. Heart rate showed a small but significant increase during movement compared with rest (controls: +0.31 bpm; SCI: +0.69 bpm; main effect of condition F(1,33) = 10.22, p = 0.003, η²p = 0.24, BF₁₀ = 8.44), whereas respiratory volume per time (RVT) did not differ between conditions (F(1,33) = 0.35, p = 0.56, η²p = 0.01, BF₁₀ = 0.24). Given the autonomic consequences of cervical injury, we also tested whether these changes differed between groups. Neither measure showed a Group × Condition interaction (heart rate: F(1,33) = 1.41, p = 0.24, BF₁₀ = 0.56; RVT: F(1,33) = 1.60, p = 0.22, BF₁₀ = 0.61), suggesting that they cannot account for the group differences we report.

We have added the additional EMG control and the cardiorespiratory analyses to the Supplementary Material of the revised manuscript. Together, these controls suggest that neither proximal muscular nor cardiorespiratory factors explain our findings.

(3) Functional significance of the preserved top-down signal: The discussion establishes that top-down input persists but says relatively little about why it should. If the principal role of descending input to the cuneate nucleus is the gating of incoming afferent traffic, then in the absence of afferents there is nothing left to gate, and one might have expected the signal to be lost. Its persistence is the most interesting aspect of the finding and deserves fuller discussion. Candidate accounts the authors may wish to consider include: an efference copy or predictive signal delivered to a comparator that no longer receives its input, in the framework the authors already invoke (references 27, 28); engagement of the non-lemniscal outputs of the dorsal column nuclei (e.g., cuneocerebellar, cuneo-olivary projections); attempted movement engages motor imagery and attention, in which case the relevant question becomes what distinguishes these from movement-related gating. A related interpretational point: in behaving primates, movement-related modulation of cuneate transmission is bidirectional and includes prominent suppression (refs. 7/12). Note also that BOLD increases are compatible with increased inhibition, so they do not indicate facilitated throughput. 

We thank the reviewer for their comment and agree that the persistence of this descending signal despite profound loss of peripheral input is a very interesting aspect of the findings, and that our manuscript will benefit from a more extended discussion of this result. We will expand on this and the candidate accounts raised in the revised discussion. We will also clarify that movement-related modulation of cuneate processing may include both facilitation and suppression, and that our finding of increased BOLD activity does not necessarily imply facilitated sensory throughput.