Comprehensive translational assessment of human-induced pluripotent stem cell derived cardiomyocytes for evaluating drug-induced arrhythmias

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

Muscle synergies for directional control of center of mass in various postural strategies

Our long-term goal is to better understand how the nervous system controls muscles to generate movement. Our overall hypothesis is that the nervous system coordinates muscles by flexibly recruiting muscle synergies, defined here as groups of muscles simultaneously activated in fixed ratios, in order to map high-level task goals into motor actions. Here we studied muscle coordination in the context of balance control - a task that requires multisensory integration and coordination of multiple muscles, yet has a clear goal of controlling the center of mass (CoM), which can be achieved by using different strategies. If muscle synergies are a common mechanism used by the nervous system for balance control, we would expect to see the same muscle synergies used in a variety of strategies. Therefore we investigated the robustness of the muscle synergies in a variety of human postural strategies, such as standing, stepping and walking, to determine whether muscle synergies are a consistent underlying mechanism used by the nervous system. We hypothesized that muscle synergies are recruited to control a task-level variable (e.g. CoM direction) that is not specific to a particular postural strategy. We demonstrated that similar muscle synergies are used in reactive responses to standing balance perturbations, in reactive stepping responses, in walking, and in reactive postural responses during walking, suggesting a common neural mechanism not only for balance control in various contexts, but for movement in general. The differences in the timing and spatial organization of muscle activity in standing, stepping, and walking postural responses were largely explained by altering the recruitment of a common set of muscle synergies, with the addition of only a single muscle synergy specific to each behavior. We demonstrated the functionality of muscle synergies by showing that each muscle synergy was correlated with a particular force produced at the ground and component of CoM acceleration both in stepping and in non-stepping postural responses. These results suggest that muscle synergies reflect the neural organization of the motor system, representing motor modules recruited to achieve a common biomechanical function across different postural behaviors. Additionally, muscle synergies used during walking were recruited during atypical phases of the gait cycle in response to an unexpected perturbation, in order to maintain balance and continue walking, suggesting a common neural mechanism for different balance requirements during walking. The compositions of muscle synergies used during walking were similar to those used during walking perturbations as well as standing balance perturbations, suggesting that muscle synergies represent common neural mechanisms for CoM movement control under different dynamic conditions. These results are of interest to a variety of fields such as rehabilitation science, prosthetics, and robotics.PhDCommittee Chair: Ting, Lena; Committee Member: Chang, Young-Hui; Committee Member: Lee, Robert; Committee Member: Nichols, T. Richard; Committee Member: Wolf, Steve

Common muscle synergies for balance and walking

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 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 versus 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 versus 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

Neuromuscular constraints on muscle coordination during overground walking in persons with chronic incomplete spinal cord injury

h i g h l i g h t s Persons with chronic incomplete spinal cord injury (iSCI) exhibit significant reduced muscle coordination during overground walking as compared to age-matched adults. Neuromuscular constraints following iSCI contribute to person-specific deficits in overground walking. Neuromuscular mechanisms underlying gait deficits may provide guidance for targeted SCI rehabilitation. a b s t r a c t Objective: Incomplete spinal cord injury (iSCI) disrupts motor control and limits the ability to coordinate muscles for overground walking. Inappropriate muscle activity has been proposed as a source of clinically observed walking deficits after iSCI. We hypothesized that persons with iSCI exhibit lower locomotor complexity compared to able-body (AB) controls as reflected by fewer motor modules, as well as, altered module composition and activation. Methods: Eight persons with iSCI and eight age-matched AB controls walked overground at prescribed cadences. Electromyograms of fourteen single leg muscles were recorded. Non-negative matrix factorization was used to identify the composition and activation of motor modules, which represent groups of consistently co-activated muscles that accounted for 90% of variability in muscle activity. Results: Motor module number, composition, and activation were significantly altered in persons with iSCI as compared to AB controls during overground walking at self-selected cadences. However, there was no significant difference in module number between persons with iSCI and AB controls when cadence and assistive device were matched. Conclusions: Muscle coordination during overground walking is impaired after chronic iSCI. Significance: Our results are indicative of neuromuscular constraints on muscle coordination after iSCI. Altered muscle coordination contributes to person-specific gait deficits during overground walking