Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) hold promise for assessment of drug-induced arrhythmias and are being considered for use under the comprehensive in vitro proarrhythmia assay (CiPA). We studied the effects of 26 drugs and 3 drug combinations on 2 commercially available iPSC-CM types using high-throughput voltage-sensitive dye and microelectrode-array assays being studied for the CiPA initiative and compared the results with clinical QT prolongation and torsade de pointes (TdP) risk. Concentration-dependent analysis comparing iPSC-CMs to clinical trial results demonstrated good correlation between drug-induced rate-corrected action potential duration and field potential duration (APDc and FPDc) prolongation and clinical trial QTc prolongation. Of 20 drugs studied that exhibit clinical QTc prolongation, 17 caused APDc prolongation (16 in Cor.4U and 13 in iCell cardiomyocytes) and 16 caused FPDc prolongation (16 in Cor.4U and 10 in iCell cardiomyocytes). Of 14 drugs that cause TdP, arrhythmias occurred with 10 drugs. Lack of arrhythmic beating in iPSC-CMs for the four remaining drugs could be due to differences in relative levels of expression of individual ion channels. iPSC-CMs responded consistently to human ether-a-go-go potassium channel blocking drugs (APD prolongation and arrhythmias) and calcium channel blocking drugs (APD shortening and prevention of arrhythmias), with a more variable response to late sodium current blocking drugs. Current results confirm the potential of iPSC-CMs for proarrhythmia prediction under CiPA, where iPSC-CM results would serve as a check to ion channel and in silico modeling prediction of proarrhythmic risk. A multi-site validation study is warranted.

Little is known about the integration of neural mechanisms for balance and locomotion. Muscle synergies have been studied independently in standing balance and walking, but not compared. Here, we hypothesized that reactive balance and walking are mediated by a common set of lower-limb muscle synergies. In humans, we examined muscle activity during multidirectional support-surface perturbations during standing and walking, as well as unperturbed walking at two speeds. We show that most muscle synergies used in perturbations responses during standing were also used in perturbation responses during walking, suggesting common neural mechanisms for reactive balance across different contexts. We also show that most muscle synergies using in reactive balance were also used during unperturbed walking, suggesting that neural circuits mediating locomotion and reactive balance recruit a common set of muscle synergies to achieve task-level goals. Differences in muscle synergies across conditions reflected differences in the biomechanical demands of the tasks. For example, muscle synergies specific to walking perturbations may reflect biomechanical challenges associated with single limb stance, and muscle synergies used during sagittal balance recovery in standing but not walking were consistent with maintaining the different desired center of mass motions in standing vs. walking. Thus, muscle synergies specifying spatial organization of muscle activation patterns may define a repertoire of biomechanical subtasks available to different neural circuits governing walking and reactive balance and may be recruited based on task-level goals. Muscle synergy analysis may aid in dissociating deficits in spatial vs. temporal organization of muscle activity in motor deficits. Muscle synergy analysis may also provide a more generalizable assessment of motor function by identifying whether common modular mechanisms are impaired across the performance of multiple motor tasks.

The modular control of muscles in groups, often referred to as muscle synergies, has been proposed to provide a motor repertoire of actions for the robust control of movement. However it is not clear whether muscle synergies identified in one task are also recruited by different neural pathways subserving other motor behaviors. We tested the hypothesis that voluntary and reactive modifications to walking in humans result from the recruitment of locomotor muscle synergies. We recorded the activity of 16 muscles in the right leg as subjects walked a 7.5 m path at two different speeds. To elicit a second motor behavior, midway through the path we imposed ramp and hold translation perturbations of the support surface in each of four cardinal directions. Variations in the temporal recruitment of locomotor muscle synergies could account for cycle-by-cycle variations in muscle activity across strides. Locomotor muscle synergies were also recruited in atypical phases of gait, accounting for both anticipatory gait modifications prior to perturbations and reactive feedback responses to perturbations. Our findings are consistent with the idea that a common pool of spatially-fixed locomotor muscle synergies can be recruited by different neural pathways, including the central pattern generator for walking, brainstem pathways for balance control, and cortical pathways mediating voluntary gait modifications. Together with electrophysiological studies, our work suggests that muscle synergies may provide a library of motor subtasks that can be flexibly recruited by parallel descending pathways to generate a variety of complex natural movements in the upper and lower limbs.

We investigated muscle activity, ground reaction forces, and center of mass (CoM) acceleration in two different postural behaviors for standing balance control in humans to determine whether common neural mechanisms are used in different postural tasks. We compared nonstepping responses, where the base of support is stationary and balance is recovered by returning CoM back to its initial position, with stepping responses, where the base of support is enlarged and balance is recovered by pushing the CoM away from the initial position. In response to perturbations of the same direction, these two postural behaviors resulted in different muscle activity and ground reaction forces. We hypothesized that a common pool of muscle synergies producing consistent task-level biomechanical functions is used to generate different postural behaviors. Two sets of support-surface translations in 12 horizontal-plane directions were presented, first to evoke stepping responses and then to evoke nonstepping responses. Electromyographs in 16 lower back and leg muscles of the stance leg were measured. Initially (∼100-ms latency), electromyographs, CoM acceleration, and forces were similar in nonstepping and stepping responses, but these diverged in later time periods (∼200 ms), when stepping occurred. We identified muscle synergies using non-negative matrix factorization and functional muscle synergies that quantified correlations between muscle synergy recruitment levels and biomechanical outputs. Functional muscle synergies that produce forces to restore CoM position in nonstepping responses were also used to displace the CoM during stepping responses. These results suggest that muscle synergies represent common neural mechanisms for CoM movement control under different dynamic conditions: stepping and nonstepping postural responses.

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