Tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) are focal malformations of cortical development (FMCDs) that are highly associated with intractable epilepsy. TSC and FCD are ...mTORopathies caused by a spectrum of pathogenic variants in the mechanistic target of rapamycin (mTOR) pathway genes leading to differential activation of mTOR signaling. However, whether the degree of mTOR hyperactivity influences disease severity remains unclear. Here, we examined the effects of differential mTOR hyperactivity levels on epilepsy and associated neuropathology in a mouse model of TSC and FCD. Constitutively active Rheb (Rheb
), the canonical activator of mTOR complex 1 (mTORC1), was expressed in mouse embryos of either sex via
electroporation at low, intermediate, and high concentrations to induce different mTORC1 activity levels in developing cortical neurons. We found that Rheb
expression induced mTORC1 hyperactivation and increased neuronal soma size and misplacement in a dose-dependent manner. No seizures were detected in the low Rheb
mice, whereas the intermediate and high Rheb
mice displayed spontaneous, recurrent seizures that significantly increased with higher Rheb
concentrations. Seizures were associated with a global increase in microglial activation that was notably higher in the regions containing Rheb
-expressing neurons. These data demonstrate that neuronal mTOR hyperactivity levels influence the severity of epilepsy and associated neuropathology in experimental TSC and FCD. Overall, these findings highlight the importance of evaluating the outcome of individual variants on mTOR activity levels and support personalized medicine strategies based on patient variants and mTOR activity level for TSC, FCD, and potentially other mTORopathies.
Tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) are epileptogenic cortical malformations caused by pathogenic variants in mechanistic target of rapamycin (mTOR) pathway genes leading to differential mTOR hyperactivation. Here, we present novel findings that neuronal mTOR hyperactivity levels correlate with the severity of epilepsy and associated neuropathology in a mouse model of TSC and FCD. Our findings suggest the need to evaluate the outcome of individual variants on mTOR activity levels in clinical assessments and support personalized medicine strategies based on patient variants and mTOR activity level. Additionally, we present useful modifications to a previously described mouse model of TSC and FCD that allows for titration of seizure frequency and generation of a mild to severe epilepsy phenotype as applicable for preclinical drug testing and mechanistic studies.
Neuromechanical principles define the properties and problems that shape neural solutions for movement. Although the theoretical and experimental evidence is debated, we present arguments for ...consistent structures in motor patterns, i.e., motor modules, that are neuromechanical solutions for movement particular to an individual and shaped by evolutionary, developmental, and learning processes. As a consequence, motor modules may be useful in assessing sensorimotor deficits specific to an individual and define targets for the rational development of novel rehabilitation therapies that enhance neural plasticity and sculpt motor recovery. We propose that motor module organization is disrupted and may be improved by therapy in spinal cord injury, stroke, and Parkinson’s disease. Recent studies provide insights into the yet-unknown underlying neural mechanisms of motor modules, motor impairment, and motor learning and may lead to better understanding of the causal nature of modularity and its underlying neural substrates.
Ting et al. discuss neuromechanical principles supporting the hypothesis that modular motor solutions underlie individual-specific behaviors. Studying motor modularity in neurological motor deficits may drive rational development of targeted rehabilitation therapies as well as basic motor science.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The musculoskeletal redundancy of the body provides multiple solutions for performing motor tasks. We have proposed that the nervous system solves this unconstrained problem through the recruitment ...of motor modules or functional muscle synergies that map motor intention to action. Consistent with this hypothesis, we showed that trial-by-trial variations in muscle activation for multidirectional balance control in humans were constrained by a small set of muscle synergies. However, apparent muscle synergy structures could arise from characteristic patterns of sensory input resulting from perturbations or from low-dimensional optimal motor solutions. Here we studied electromyographic (EMG) responses for balance control across a range of biomechanical contexts, which alter not only the sensory inflow generated by postural perturbations, but also the muscle activation patterns used to restore balance. Support-surface translations in 12 directions were delivered to subjects standing in six different postural configurations: one-leg, narrow, wide, very wide, crouched, and normal stance. Muscle synergies were extracted from each condition using nonnegative matrix factorization. In addition, muscle synergies from the normal stance condition were used to reconstruct muscle activation patterns across all stance conditions. A consistent set of muscle synergies were recruited by each subject across conditions. When balance demands were extremely different from the normal stance (e.g., one-legged or crouched stance), task-specific muscle synergies were recruited in addition to the preexisting ones, rather generating de novo muscle synergies. Taken together, our results suggest that muscle synergies represent consistent motor modules that map intention to action, regardless of the biomechanical context of the task.
The Wallace H. Coulter Department of Biomedical Engineering, at Georgia Tech and Emory University, Atlanta, Georgia
Submitted 28 December 2006;
accepted in final form 18 July 2007
Postural control is ...a natural behavior that requires the spatial and temporal coordination of multiple muscles. Complex muscle activation patterns characterizing postural responses suggest the need for independent muscle control. However, our previous work shows that postural responses in cats can be robustly reproduced by the activation of a few muscle synergies. We now investigate whether a similar neural strategy is used for human postural control. We hypothesized that a few muscle synergies could account for the intertrial variability in automatic postural responses from different perturbation directions, as well as different postural strategies. Postural responses to multidirectional support-surface translations in 16 muscles of the lower back and leg were analyzed in nine healthy subjects. Six or fewer muscle synergies were required to reproduce the postural responses of each subject. The composition and temporal activation of several muscle synergies identified across all subjects were consistent with the previously identified "ankle" and "hip" strategies in human postural responses. Moreover, intertrial variability in muscle activation patterns was successfully reproduced by modulating the activity of the various muscle synergies. This suggests that trial-to-trial variations in the activation of individual muscles are correlated and, moreover, represent variations in the amplitude of descending neural commands that activate individual muscle synergies. Finally, composition and temporal activation of most of the muscle synergies were similar across subjects. These results suggest that muscle synergies represent a general neural strategy underlying muscle coordination in postural tasks.
Address for reprint requests and other correspondence: L. H. Ting, The Wallace H. Coulter Department of Biomedical Engineering, at Georgia Tech and Emory University, 313 Ferst Drive, Atlanta, GA 30322-0535 (E-mail: lting{at}emory.edu )
Balance control must be rapidly modified to provide stability in the face of environmental challenges. Although changes in reactive balance over repeated perturbations have been observed previously, ...only anticipatory postural adjustments preceding voluntary movements have been studied in the framework of motor adaptation and learning theory. Here, we hypothesized that adaptation occurs in task-level balance control during responses to perturbations due to central changes in the control of both anticipatory and reactive components of balance. Our adaptation paradigm consisted of a Training set of forward support-surface perturbations, a Reversal set of novel countermanding perturbations that reversed direction, and a Washout set identical to the Training set. Adaptation was characterized by a change in a motor variable from the beginning to the end of each set, the presence of aftereffects at the beginning of the Washout set when the novel perturbations were removed, and a return of the variable at the end of the Washout to a level comparable to the end of the Training set. Task-level balance performance was characterized by peak center of mass (CoM) excursion and velocity, which showed adaptive changes with repetitive trials. Only small changes in anticipatory postural control, characterized by body lean and background muscle activity were observed. Adaptation was found in the evoked long-latency muscular response, and also in the sensorimotor transformation mediating that response. Finally, in each set, temporal patterns of muscle activity converged towards an optimum predicted by a trade-off between maximizing motor performance and minimizing muscle activity. Our results suggest that adaptation in balance, as well as other motor tasks, is mediated by altering central sensitivity to perturbations and may be driven by energetic considerations.
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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 before 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.
How does long-term training affect the neural control of movements? Here we tested the hypothesis that long-term training leading to skilled motor performance alters muscle coordination during ...challenging, as well as nominal everyday motor behaviors. Using motor module (a.k.a., muscle synergy) analyses, we identified differences in muscle coordination patterns between professionally trained ballet dancers (experts) and untrained novices that accompanied differences in walking balance proficiency assessed using a challenging beam-walking test. During beam walking, we found that experts recruited more motor modules than novices, suggesting an increase in motor repertoire size. Motor modules in experts had less muscle coactivity and were more consistent than in novices, reflecting greater efficiency in muscle output. Moreover, the pool of motor modules shared between beam and overground walking was larger in experts compared with novices, suggesting greater generalization of motor module function across multiple behaviors. These differences in motor output between experts and novices could not be explained by differences in kinematics, suggesting that they likely reflect differences in the neural control of movement following years of training rather than biomechanical constraints imposed by the activity or musculoskeletal structure and function. Our results suggest that to learn challenging new behaviors, we may take advantage of existing motor modules used for related behaviors and sculpt them to meet the demands of a new behavior.
System identification techniques have been applied to model human sensorimotor systems for research and diagnostic purposes. Accurate human modeling via system identification requires informative ...experimental data, which further require informative perturbations applied to the human. Previously, designing ideal perturbations for system identification has been extensively studied. On the other hand, the physical realization of perturbations often produces distorted perturbations, resulting in less accurate system identification and incorrect conclusions about the target dynamic system. However, such issues associated with an uncompensated physical realization process have not been fully resolved in the literature. A notable application is the design and use of the pseudorandom sequence (PRS). This article considers the physical realization of PRS perturbations. The impact of zero-order-hold (ZOH) on perturbation quality in terms of the previously proposed band-limited spectral flatness measure (SFM) is identified. To compensate for the spectral flatness degradation due to ZOH, a reference prefilter designed by the Parks-McClellan algorithm is incorporated into the motion control design. A relationship between the prefilter performance and band-limited SFM is established, based on which a prefilter design procedure that guarantees an SFM lower bound of the physically realized perturbations is proposed. Experimental results demonstrated that the proposed prefilter design method effectively improves the SFM of the physical perturbations.
Muscle spindle proprioceptive receptors play a primary role in encoding the effects of external mechanical perturbations to the body. During externally-imposed stretches of passive, i.e. ...electrically-quiescent, muscles, the instantaneous firing rates (IFRs) of muscle spindles are associated with characteristics of stretch such as length and velocity. However, even in passive muscle, there are history-dependent transients of muscle spindle firing that are not uniquely related to muscle length and velocity, nor reproduced by current muscle spindle models. These include acceleration-dependent initial bursts, increased dynamic response to stretch velocity if a muscle has been isometric, and rate relaxation, i.e., a decrease in tonic IFR when a muscle is held at a constant length after being stretched. We collected muscle spindle spike trains across a variety of muscle stretch kinematic conditions, including systematic changes in peak length, velocity, and acceleration. We demonstrate that muscle spindle primary afferents in passive muscle fire in direct relationship to muscle force-related variables, rather than length-related variables. Linear combinations of whole muscle-tendon force and the first time derivative of force (dF/dt) predict the entire time course of transient IFRs in muscle spindle Ia afferents during stretch (i.e., lengthening) of passive muscle, including the initial burst, the dynamic response to lengthening, and rate relaxation following lengthening. Similar to acceleration scaling found previously in postural responses to perturbations, initial burst amplitude scaled equally well to initial stretch acceleration or dF/dt, though later transients were only described by dF/dt. The transient increase in dF/dt at the onset of lengthening reflects muscle short-range stiffness due to cross-bridge dynamics. Our work demonstrates a critical role of muscle cross-bridge dynamics in history-dependent muscle spindle IFRs in passive muscle lengthening conditions relevant to the detection and sensorimotor response to mechanical perturbations to the body, and to previously-described history-dependence in perception of limb position.
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