Separating the control of moving and holding still in post-stroke arm paresis

Reviewer #1 (Public Review):

This study extends the previous interesting work of this group to address the potentially differential control of movement and posture. Their earlier work explored a broad range of data to make the case for a downstream neural integrator hypothesized to convert descending velocity movement commands into postural holding commands. Included in that data were observations from people with hemiparesis due to stroke. The current study uses similar data but pushes into a different, but closely related direction, suggesting that these data may address the independence of these two fundamental components of motor control. I find the logic laid out in the second sentence of the abstract ("The paretic arm after stroke is notable for abnormalities both at rest and during movement, thus it provides an opportunity to address the relationships between control of reaching, stopping, and stabilizing") less than compelling, but the study does make some interesting observations. Foremost among them, is the relation between the resting force postural bias and the effect of force perturbations during the target hold periods, but not during movement. While this interesting observation is consistent with the central mechanism the authors suggest, it seems hard to me to rule out other mechanisms, including peripheral ones.

On the other hand, the relation between force bias and the well-recognized flexor synergy seems rather self-evident, and I don't see that these results add much to that story. I am also struck by what seems to be a contradiction between the conclusions of the current and former studies: "These findings in stroke suggest that moving and holding still are functionally separable modes of control" and "the commands that hold the arm and finger at a target location depend on the mathematical integration of the commands that moved the limb to that location." The former study is mentioned here only in passing, in a single phrase in the discussion, with no consideration of the relation between the two studies. This is odd and should be addressed.

A minor wording concern I had is that the term "holding still" is frequently hard to parse. A couple of examples: "These findings in stroke suggest that moving and holding still are functionally separable modes of control." This example is easily read, "moving and holding [continue to be] functionally separable". Another: "...active reaching and holding still in the same workspace, " could be "...active reaching and holding [are] still in the same workspace." Simply "holding", "posture" or "posture maintenance" would all be better options.

Reviewer #2 (Public Review):

Summary:
Here the authors address the idea that postural and movement control are differentially impacted with stroke. Specifically, they examined whether resting postural forces influenced several metrics of sensorimotor control (e.g., initial reach angle, maximum lateral hand deviation following a perturbation, etc.) during movement or posture. The authors found that resting postural forces influenced control only following the posture perturbation for the paretic arm of stroke patients, but not during movement. They also found that resting postural forces were greater when the arm was unsupported, which correlated with abnormal synergies (as assessed by the Fugl-Meyer). The authors suggest that these findings can be explained by the idea that the neural circuitry associated with posture is relatively more impacted by stroke than the neural circuitry associated with movement. They also propose a conceptual model that differentially weights the reticulospinal tract (RST) and corticospinal tract (CST) to explain greater relative impairments with posture control relative to movement control, due to abnormal synergies, in those with stroke.

Strengths:
The strength of the paper is that they clearly demonstrate with the posture task (i.e., active holding against a load) that the resting postural forces influence subsequent control (i.e., the path to stabilize, time to stabilize, max. deviation) following a sudden perturbation (i.e., suddenly removal of the load). Further, they can explain their findings with a conceptual model, which is depicted in Figure 9.

Weaknesses:
Current weaknesses and potential concerns relate to i) not displaying or reporting the results of healthy controls and non-paretic arm in Experiment 2 and ii) large differences in force perturbation waveforms between movement (sudden onset) and posture (sudden release), which could potentially influence the results and or interpretation.

Larger concerns
1. Additional analyses to further support the interpretation. In Experiment 1 the authors present the results for the paretic arm, non-paretic arm, and controls. However, in Experiment 2 for several key analyses, they only report summary statistics for the paretic arm (Figure 5D-I; Figure 6D-E; Figure 7F). It is understood that the controls have much smaller resting postural force biases, but they are still present (Figure 3B). It would strengthen the position of the paper to show that controls and the non-paretic arm are not influenced by resting postural force biases during movement and particularly during posture, while acknowledging the caveat that the resting positional forces are smaller in these groups. It is recommended that the authors report and display the results shown in Figure 5D-I; Figure 6D-E; Figure 7F for the controls and non-paretic arm. If these results are all null, the authors could alternatively place these results in an additional supplementary.

Further, the results could be further boosted by reporting/displaying additional analyses. In Figure 6D the authors performed a correlation analysis. Can they also display the same analysis for initial deviation and endpoint deviation for the data shown in Figure 5D-F & 5G-I, as well for 7F for the path to stabilization, time to stabilization, and max deviation? This will also create consistency in the analyses performed for each dependent variable across the paper.

2. Inconsistency in perturbations that would differentially impact muscle and limb states during movement and posture. It is well known that differences in muscle state (activation / preloaded, muscle fiber length and velocity) and limb state (position and velocity) impact sensorimotor control (Pruszynski, J. A., & Scott, S. H. (2012). Experimental brain research, 218, 341-359.). Of course, it is appreciated that it is not possible to completely control all states when comparing movement and posture (i.e., muscle and limb velocity). However, using different perturbations differentially impacts muscle and limb states. Within this paper, the authors used very different force waveforms for movement perturbations (i.e., 12 N peak, bell-shaped, 0.7ms duration -> sudden force onset to push the limb; Figure 6A) and posture perturbations (i.e., 6N, 2s ramp up -> 3s hold -> sudden force release that resulted in limb movement; Figure 4) that would differentially impact muscle (and limb) states. Preloaded muscle (as in the posture perturbation) has a very different response compared to muscle that has little preload (as in the movement perturbations, where muscles that would resist a sudden lateral perturbation would likely be less activated since they are not contributing to the forward movement). Would the results hold if the same perturbation had been used for both posture and movement (e.g., 12 N pulse for both experiments)? It is recommended that the authors comment and discuss in the paper why they chose different perturbations and how that might impact the results.

Relatedly, an alternative interpretation of the results is that preloading muscle for stroke patients, whether by supporting the weight of one's arm (experiment 1) or statically resisting a load prior to force release (experiment 2), leads to a greater postural force bias that can subsequently influence control. It is recommended that the authors comment on this.

Reviewer #3 (Public Review):

The authors attempt to dissociate differences in resting vs active vs perturbed movement biases in people with motor deficits resulting from stroke. The analysis of movement utilizes techniques that are similar to previous motor control in both humans and non-human primates, to assess impairments related to sensorimotor injuries. In this regard, the authors provide additional support to the extensive literature describing movement abnormalities in patients with hemiparesis both at rest and during active movement. The authors describe their intention to separate out the contribution of holding still at a position vs active movement as a demonstration that these two aspects of motor control are controlled by two separate control regimes.

Strengths:
1. The authors utilize a device that is the same or similar to devices previously used to investigate motor control of movement in normal and impaired conditions in humans and non-human primates. This allows comparisons to existing motor control studies.
2. Experiment 1 demonstrates resting flexion biases both in supported and unsupported forelimb conditions. These biases show a correlated relationship with FM-UE scores, suggesting that the degree of motor impairment and the degree of resting bias are related.
3. The stroke patient participant population had a wide range of both levels of impairment and time since stroke, including both sub-acute and chronic cases allowing the results to be compared across impairment levels.

The authors describe several results from their study: 1. Postural biases were systematically toward the body (flexion) and increased with distance from the body (when the arm was more extended) and were stronger when the arm was unsupported. 2. These postural biases were correlated with FM-UE score. 3. They found no evidence of postural biases impacting movement, even when that movement was perturbed. 4. When holding a position at the end of a movement, if the position was perturbed opposite of the direction of bias, movement back to the target was improved compared to the perturbation in the direction of bias. Taken together, the authors suggest that there are at least two separate motor controls for tasks at rest versus with motion. Further, the authors propose that these results indicate that there is an imbalance between cortical control of movement (through the corticospinal tracts) and postural control (through the reticulospinal tract). There are several weaknesses related to the interpretation of the results:

In Experiment 1, the participants are instructed to keep their limbs in a passive position after being moved. The authors show that, in the impaired limb, these resting biases are significantly higher when the limb is unsupported and increase when the arm is moved to a more extended position.

When supported by the air sled, the arm is in a purely passive position, not requiring the same anti-gravity response so will have less RST but also less CST involvement. While the unsupported task invokes more involvement of the reticulospinal tract (RST), it likely also has significantly higher CST involvement due to the increased difficulty and novelty of the task.

If there were an imbalance in CST regulating RST as proposed by the authors, the bias should be higher in the supported condition as there should be relatively less CST activation/involvement/modulation leading to less moderating input onto the RST and introducing postural biases. In the unsupported condition, there is likely more CST involvement, potentially leading to an increased modulatory effect on RST. If the proportion of CST involvement significantly outweighs the RST activation in the unsupported task, then it isn't obvious that there is a clear differentiation of motor control. As the degree of resting force bias and FM-UE score are correlated, an argument could be made that they are both measuring the impairment of the CST unrelated to any RST output. If it is purely the balance of CST integrity compared to RST, then the degree of bias should have been the same in both conditions. In this idea of controller vs modulator, it is unclear when this switch occurs or how to weigh individual contributions of CST vs. extrapyramidal tracts. Further, it isn't clear why less modulation on the RST would lead only to abnormal flexion.

This resting bias could be explained by an imbalance in the activation of flexors vs extensors which follows the results that this bias is larger as the arm is extended further, and/or in a disconnect in sensory integration that is overcome during active movement. Neither would necessitate separate motor control for holding vs active movement.

In Experiment 2, the participants are actively moving to and holding at targets for all trials while being supported by the air sled. Even with the support, the paretic participants all showed start- and end-point force biases around the movement despite not showing systematic deviations in force direction during active movement start or stop. There could be several factors that limit systematic deviations in force direction. The most obvious is that the measured biases are significantly higher when the limb is unsupported and by testing with a supported limb the authors are artificially limiting any effect of the bias. It is also possible that significant adaptation or plasticity with the CST or rubrospinal tracts could give rise to motor output that already accounts for any intrinsic resting bias. In any case, the results from the reaching phase of Experiment 2 do not definitively show that directional biases are not present during active reaching, just that the authors were unable to detect them with their design. The authors do acknowledge the limitations in this design (a 2D constrained task) in explaining motor impairment in 3D unconstrained tasks.

It would have been useful, in Experiment 2, to use FM-UE scores (and time from injury) as a factor to determine the relationship between movement and rest biases. Using a GLMM would have allowed a similar comparison to Experiment 1 of how impairment level is related to static perturbation responses. While not a surrogate for imaging tractography data showing a degree of CST involvement in stroke, FM-UE may serve as an appropriate proxy so that this perturbation at hold responses may be put into context relative to impairment.

It is not clear that even in the static perturbation trials that the hold (and subsequent move from perturbation) is being driven by reticulospinal projections. Given a task where ~20% of the trials are going to be perturbed, there is likely a significant amount of anticipatory or preparatory signaling from the CST. How does this balance with any proposed contribution that the RST may have with increased grip?

In general, the weakness of the interpretation of the results with respect to the CST/RST framework is that it is necessary to ascribe relative contributions of different tracts to different phases of movement and hold using limited or indirect measures. Barring any quantification of this data during these tasks, different investigators are likely to assess these contributions in different ways and proportions limiting the framework's utility.