Differential expression analysis in single-cell transcriptomics enables the dissection of cell-type-specific responses to perturbations such as disease, trauma, or experimental manipulations. While many statistical methods are available to identify differentially expressed genes, the principles that distinguish these methods and their performance remain unclear. Here, we show that the relative performance of these methods is contingent on their ability to account for variation between biological replicates. Methods that ignore this inevitable variation are biased and prone to false discoveries. Indeed, the most widely used methods can discover hundreds of differentially expressed genes in the absence of biological differences. To exemplify these principles, we exposed true and false discoveries of differentially expressed genes in the injured mouse spinal cord.

Differential expression analysis in single-cell transcriptomics enables the dissection of cell-type-specific responses to perturbations such as disease, trauma, or experimental manipulation. While many statistical methods are available to identify differentially expressed genes, the principles that distinguish these methods and their performance remain unclear. Here, we show that the relative performance of these methods is contingent on their ability to account for variation between biological replicates. Methods that ignore this inevitable variation are biased and prone to false discoveries. Indeed, the most widely used methods can discover hundreds of differentially expressed genes in the absence of biological differences. Our results suggest an urgent need for a paradigm shift in the methods used to perform differential expression analysis in single-cell data.

Sensorimotor integration is essential for controlling movement and acquiring new motor tasks in humans. The aim of this project was to understand how lower limb proprioceptive sense contributes to the acquisition of a skilled walking task. We assessed lower limb joint position and movement detection sense in healthy human subjects using the Lokomat robotic exoskeleton. Subjects walked on a treadmill to practice a skilled motor task (200 trials) requiring them to match their foot height during the swing phase to the height of a virtual obstacle displayed on a monitor in front of them. Subjects were given visual feedback on their error relative to the obstacle height after it was crossed. Lower limb joint position sense was related to the final performance error, but not the learning rate of the skilled walking task. The findings from this study support the role of lower limb proprioceptive sense on locomotor skill performance in healthy adult subjects.

Many people with motor-incomplete spinal cord injury (m-iSCI) experience difficulty navigating obstacles, such as curbs and stairs. The ability to relearn walking skills may be limited by proprioceptive deficits. The purpose of this study was to determine the capacity of participants to acquire a precision walking skill, and to evaluate the influence of proprioceptive deficits on the skill acquisition in individuals with m-iSCI. Sixteen individuals with m-iSCI and eight controls performed a precision walking task that required matching their foot height to a target during the swing phase. Proprioceptive deficits were quantified at the hip and knee for joint position and movement detection sense. Participants completed 600 steps of training with visual feedback. Pretraining and posttraining tests were conducted without visual feedback, along with a transfer test with an ankle weight. Posttraining and transfer tests were repeated 1 day later. Participants returned to the laboratory 1 wk later to repeat the training. Performance was calculated as the vertical distance between the target and actual foot height for each step. The posttraining and transfer performances were similar between groups. However, participants with m-iSCI had a slower rate of acquisition to achieve a similar performance level compared with controls. Acquisition rate and posttraining performance of the precision walking task were related to lower limb joint position sense among SCI participants. Although they can achieve a similar level of performance in a precision walking task, proprioceptive deficits impair the rate of learning among individuals with m-iSCI compared with able-bodied controls. NEW & NOTEWORTHY People with motor-incomplete spinal cord injuries are able to achieve the same level of performance accuracy on a precision walking task as able-bodied controls; however, the rate of learning is slower, indicating that more practice is required to stabilize performance. Our findings also show a relationship between impaired sensory function and reduced accuracy when performing a precision walking task after spinal cord injury.

Proprioception is critical for movement control. After a spinal cord injury (SCI), individuals not only experience paralysis but may also experience proprioceptive deficits, further confounding motor recovery. The objective of this study was to test the effects of a robotic-based proprioception training protocol on lower limb proprioceptive sense in people with incomplete SCI. A secondary objective was to assess whether the effects of training transferred to a precision stepping task in people with motor-incomplete SCI. Participants with chronic incomplete SCI and able-bodied controls underwent a 2-day proprioceptive training protocol using the Lokomat robotic exoskeleton. The training involved positioning the test leg to various positions and participants were asked to report whether they felt their heel position (end-point position) was higher or lower compared with a reference position. Feedback was provided after each trial to help participants learn strategies that could help them discern different positions of their foot. Changes in end-point position as well as knee joint position sense were assessed pre- and posttraining. We also assessed the effects of proprioception training on the performance of a precision stepping task in people with motor-incomplete SCI. Following training, there were significant improvements in end-point and knee joint position sense in both groups. The magnitude of improvement was related to pretraining (baseline) proprioceptive sense, indicating that those who initially had better lower limb position sense showed greater changes. Participants also showed improvements in performance of a precision stepping task. NEW & NOTEWORTHY We show that it is possible to alter proprioceptive sense in people with incomplete SCI using a passive proprioception training protocol combined with feedback. Improvements in proprioceptive sense transferred from end-point to joint position sense and also to an untrained precision stepping task.

Abstract-People are required to adapt their basic walking pattern to turn and change directions safely for activities of daily living. This case study describes the changes in neuromuscular control among individuals with stroke on walking paths of different curvatures. Two men with hemiparetic stroke and one control subject walked along a straight, wide curved, and tight curved pathway while muscle activation of the medial and lateral gastrocnemius was recorded, along with the trajectory of the center of pressure (COP) during the single support phase. Balance, sensorimotor control, and functional ambulation were also evaluated. The subject with greater lower-limb sensorimotor impairment displayed a larger difference in the anterior-posterior COP displacement between limbs, which exacerbated as the path curvature increased. In addition, while the control subject demonstrated a lateral shift in the mediallateral COP position, this person was unable to adapt the COP position on the nonparetic side. The second participant with a stroke demonstrated better balance and lateral shifting of the COP position. Modulation of the COP trajectory is required to safely perform curved walking. Further study is required to confirm the role of stroke-related gait deficits in the ability to adapt to curved walking.

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