A geometric approach to quantifying the neuromodulatory effects of persistent inward currents on individual motor unit discharge patterns.

Objective.All motor commands flow through motoneurons, which entrain control of their innervated muscle fibers, forming a motor unit (MU). Owing to the high fidelity of action potentials within MUs, their discharge profiles detail the organization of ionotropic excitatory/inhibitory as well as metabotropic neuromodulatory commands to motoneurons. Neuromodulatory inputs (e.g. norepinephrine, serotonin) enhance motoneuron excitability and facilitate persistent inward currents (PICs). PICs introduce quantifiable properties in MU discharge profiles by augmenting depolarizing currents upon activation (i.e. PIC amplification) and facilitating discharge at lower levels of excitatory input than required for recruitment (i.e. PIC prolongation).Approach. Here, we introduce a novel geometric approach to estimate neuromodulatory and inhibitory contributions to MU discharge by exploiting discharge non-linearities introduced by PIC amplification during time-varying linear tasks. In specific, we quantify the deviation from linear discharge ('brace height') and the rate of change in discharge (i.e. acceleration slope, attenuation slope, angle). We further characterize these metrics on a simulated motoneuron pool with known excitatory, inhibitory, and neuromodulatory inputs and on human MUs (number of MUs; Tibialis Anterior: 1448, Medial Gastrocnemius: 2100, Soleus: 1062, First Dorsal Interosseus: 2296).Main results. In the simulated motor pool, we found brace height and attenuation slope to consistently indicate changes in neuromodulation and the pattern of inhibition (excitation-inhibition coupling), respectively, whereas the paired MU analysis (ΔF) was dependent on both neuromodulation and inhibition pattern. Furthermore, we provide estimates of these metrics in human MUs and show comparable variability in ΔFand brace height measures for MUs matched across multiple trials.Significance. Spanning both datasets, we found brace height quantification to provide an intuitive method for achieving graded estimates of neuromodulatory and inhibitory drive to individual MUs. This complements common techniques and provides an avenue for decoupling changes in the level of neuromodulatory and pattern of inhibitory motor commands.

Multimodal parameter spaces of a complex multi-channel neuron model.

One of the most common types of models that helps us to understand neuron behavior is based on the Hodgkin-Huxley ion channel formulation (HH model). A major challenge with inferring parameters in HH models is non-uniqueness: many different sets of ion channel parameter values produce similar outputs for the same input stimulus. Such phenomena result in an objective function that exhibits multiple modes (i.e., multiple local minima). This non-uniqueness of local optimality poses challenges for parameter estimation with many algorithmic optimization techniques. HH models additionally have severe non-linearities resulting in further challenges for inferring parameters in an algorithmic fashion. To address these challenges with a tractable method in high-dimensional parameter spaces, we propose using a particular Markov chain Monte Carlo (MCMC) algorithm, which has the advantage of inferring parameters in a Bayesian framework. The Bayesian approach is designed to be suitable for multimodal solutions to inverse problems. We introduce and demonstrate the method using a three-channel HH model. We then focus on the inference of nine parameters in an eight-channel HH model, which we analyze in detail. We explore how the MCMC algorithm can uncover complex relationships between inferred parameters using five injected current levels. The MCMC method provides as a result a nine-dimensional posterior distribution, which we analyze visually with solution maps or landscapes of the possible parameter sets. The visualized solution maps show new complex structures of the multimodal posteriors, and they allow for selection of locally and globally optimal value sets, and they visually expose parameter sensitivities and regions of higher model robustness. We envision these solution maps as enabling experimentalists to improve the design of future experiments, increase scientific productivity and improve on model structure and ideation when the MCMC algorithm is applied to experimental data.

The Cellular Basis for the Generation of Firing Patterns in Human Motor Units.

Motor units, which comprise a motoneuron and the set of muscle fibers it innervates, are the fundamental neuromuscular transducers for all motor commands. The one to one relationship between a motoneuron and its innervated muscle fibers allow motoneuron firing patterns to be readily measured in humans. In this chapter, we summarize the current understanding of the cellular basis for the generation of firing patterns in human motor units. We provide a brief review of landmark insights from classic studies and then proceed to consider the features of motor unit firing patterns that are most likely to be sensitive estimators of motoneuron inputs and properties. In addition, we discuss recent advances in technology for recording human motor unit firing patterns and highly realistic computer simulations of motoneurons. The final section presents our recent efforts to use the power of supercomputers for implementation of the motoneuron models, with a goal of achieving a true "reverse engineering" approach that maximizes the insights from motor unit firing patterns into the synaptic structure of motor commands.

In-Vivo Study of Passive Musculotendon Mechanics in Chronic Hemispheric Stroke Survivors.

We characterized the passive mechanical properties of the affected and contralateral musculotendon units in 9 chronic stroke survivors as well as in 6 neurologically-intact controls. Using a position-controlled motor, we precisely indented the distal tendon of the biceps brachii to a 20 mm depth from skin, recording both its sagittal motion using ultrasound movies and the compression force at the tip of the indenter. Length changes of 8 equally-spaced features along the aponeurosis axis were quantified using a pixel-tracking protocol. We report that, on the aggregate and with respect to contralateral and control, respectively, the affected side initiates feature motion at a shorter indentation distance by 61% and 50%, travels further by 15% and 9%, at a lower rate of 28% and 15%, and is stiffer by 40% and 57%. In an extended analysis including the spatial location of the 8 designated features, we report that in contrast to the contralateral and control muscles, the affected musculotendon unit does not strain measurably within the imaging window. These results confirm that chronic stroke-induced spasticity changes musculotendon unit passive mechanics, causing it to not strain under stretch. The mechanisms responsible for altered passive mechanics may lie within extracellular matrix fibrosis.

Stretch reflex excitability in contralateral limbs of stroke survivors is higher than in matched controls.

BACKGROUND: Spasticity, characterized by hyperreflexia, is a motor impairment that can arise following a hemispheric stroke. While the neural mechanisms underlying spasticity in chronic stroke survivors are unknown, one probable cause of hyperreflexia is increased motoneuron (MN) excitability. Potential sources of increased spinal MN excitability after a stroke include increased vestibulospinal (VS) and/or reticulospinal (RS) drive. Spasticity, as clinically assessed in stroke survivors, is highly lateralized, thus RS contributions to stroke-induced spasticity are more difficult to reconcile, as RS nuclei routinely project bilaterally to the spinal cord. Yet studies in stroke survivors suggest that there may also be changes in neuromodulation at the spinal level, indicative of RS tract influence. We hypothesize that after hemispheric stroke, alterations in the excitability of the RS nuclei affect both sides of the spinal cord, and thereby contribute to increased MN excitability on both paretic/spastic and contralateral sides of stroke survivors, as compared to neurologically intact subjects. METHODS: We estimated stretch reflex thresholds of the biceps brachii (BB) muscle using a position-feedback controlled linear motor to progressively indent the BB distal tendon in both spastic and contralateral limbs of hemispheric stroke survivors and in age-matched intact subjects. RESULTS: Our previously reported results show a significant difference between reflex thresholds of spastic and contralateral limbs of stroke survivors recorded from BB-medial (p < 0.005) and BB-lateral (p < 0.001). For this study, we report that there is also a significant difference between the reflex thresholds in the contralateral limb of stroke subjects and the dominant arm of intact subjects, again measured from both BB-medial (p < 0.05) and BB-lateral (p < 0.05). CONCLUSION: The reduction in stretch reflex thresholds in the contralateral limb of stroke survivors, based here on comparisons with thresholds of intact subjects, suggests an increased MN excitability on contralateral sides of stroke survivors as compared to intact subjects. This in turn supports our contention that RS tract activation, which has bilateral descending influences, is at least partially responsible for increased stretch reflex excitability, post-stroke, as both contralateral and affected sides show increased MN excitability as compared to intact subjects. Still, spasticity, presently diagnosed only on the affected side, with increased MN excitability on the affected side as compared to the contralateral side (our previous study), may be due to a different strongly lateralized pathway, such as the VS tract, which has not been directly tested here. Currently available clinical methods of spasticity assessment, such as the Modified Ashworth Scale, lack the resolution to quantify this phenomenon of a bilateral increase in MN excitability.

Scaling of Motor Output, From Mouse to Humans.

Appropriate scaling of motor output from mouse to humans is essential. The motoneurons that generate all motor output are, however, very different in rodents compared with humans, being smaller and much more excitable. In contrast, feline motoneurons are more similar to those in humans. These scaling differences need to be taken into account for the use of rodents for translational studies of motor output.

Spinal dura mater: biophysical characteristics relevant to medical device development.

Understanding the relevant biophysical properties of the spinal dura mater is essential to the design of medical devices that will directly interact with this membrane or influence the contents of the intradural space. We searched the literature and reviewed the pertinent characteristics for the design, construction, testing, and imaging of novel devices intended to perforate, integrate, adhere or reside within or outside of the spinal dura mater. The spinal dura mater is a thin tubular membrane composed of collagen and elastin fibres that varies in circumference along its length. Its mechanical properties have been well-described, with the longitudinal tensile strength exceeding the transverse strength. Data on the bioelectric, biomagnetic, optical and thermal characteristics of the spinal dura are limited and sometimes taken to be similar to those of water. While various modalities are available to visualise the spinal dura, magnetic resonance remains the best modality to segment its structure. The reaction of the spinal dura to imposition of a foreign body or other manipulations of it may compromise its biomechanical and immune-protective benefits. Therefore, dural sealants and replacements are of particular clinical, research and commercial interest. In conclusion, existing devices that are in clinical use for spinal cord stimulation, intrathecal access or intradural implantation largely adhere to traditional designs and their attendant limitations. However, if future devices are built with an understanding of the dura's properties incorporated more fully into the designs, there is potential for improved performance.

Spinal Cord Stimulation for Spasticity: Historical Approaches, Current Status, and Future Directions.

INTRODUCTION: Millions of people worldwide suffer with spasticity related to irreversible damage to the brain or spinal cord. Typical antecedent events include stroke, traumatic brain injury, and spinal cord injury, although insidious onset is also common. Regardless of the cause, the resulting spasticity leads to years of disability and reduced quality of life. Many treatments are available to manage spasticity; yet each is fraught with drawbacks including incomplete response, high cost, limited duration, dose-limiting side effects, and periodic maintenance. Spinal cord stimulation (SCS), a once promising therapy for spasticity, has largely been relegated to permanent experimental status. METHODS: In this review, our goal is to document and critique the history and assess the development of SCS as a treatment of lower limb spasticity. By incorporating recent discoveries with the insights gained from the early pioneers in this field, we intend to lay the groundwork needed to propose testable hypotheses for future studies. RESULTS: SCS has been tested in over 25 different conditions since a potentially beneficial effect was first reported in 1973. However, the lack of a fully formed understanding of the pathophysiology of spasticity, archaic study methodology, and the early technological limitations of implantable hardware limit the validity of many studies. SCS offers a measure of control for spasticity that cannot be duplicated with other interventions. CONCLUSIONS: With improved energy-source miniaturization, tailored control algorithms, novel implant design, and a clearer picture of the pathophysiology of spasticity, we are poised to reintroduce and test SCS in this population.

Estimation of musculotendon kinematics under controlled tendon indentation.

The effects of tendon indentation on musculotendon unit mechanics have been left largely unexplored. Tendon indentation is however routinely used in the tendon reflex exam to diagnose the state of reflex pathways. Because muscle mechanoreceptors are sensitive to mechanical changes of the musculotendon unit, this gap in knowledge could potentially impact our understanding of these neurological exams. Accordingly, we have used ultrasound (US) imaging to compare the effects of tendon indentation with the effects angular rotation of the elbow in six neurologically intact individuals. We used sagittal ultrasound movies of the biceps brachii to compare length changes induced by each of these perturbations. Length changes were quantified using a pixel-tracking protocol. Our results show that a 20mm indentation of the distal tendon is broadly equivalent to a 15° elbow rotation. We also show that within the imaging window the strain differences between the two stretching protocols are statistically insignificant. Finally, we show that there exists a significant linear relationship between the two stretching techniques and that this relationship spans a large rotational angle to indentation depth. We have used a novel tendon probe to administer controlled tendon indentations as a way to characterize musculotendon kinematics. Using this probe, we confirm that tendon indentation can be physiologically equated with joint rotation, and can thus be used as an input for muscle stretching protocols. Furthermore, this is potentially a simpler and more practical alternative to externally imposed angular joint motion.

Contributions of motoneuron hyperexcitability to clinical spasticity in hemispheric stroke survivors.

OBJECTIVE: Muscle spasticity is one of the major impairments that limits recovery in hemispheric stroke survivors. One potential contributing mechanism is hyperexcitability of motoneurons. Previously, the response latency of the surface electromyogram (EMG) record evoked by joint rotation has been used to characterize motoneuron excitability. Given the limitations of this method, the objective of the current study was to reexamine the excitability of motoneurons in chronic stroke survivors by estimating reflex latency using single motor unit discharge. METHODS: We quantified the excitability of spastic motoneurons using the response latency of a single motor unit discharge elicited by a position controlled tap on the biceps brachii tendon. We applied tendon taps of different amplitudes on the biceps tendons of both arms of the stroke survivors. Unitary reflex responses were recorded using intramuscular EMG recordings. RESULTS: Our results showed that the latency of unitary discharge was systematically shorter in the spastic muscle compared with the contralateral muscle, and this effect was consistent across multiple tap amplitudes. CONCLUSIONS: This method allowed us to quantify latencies more accurately, potentially enabling a more rigorous analysis of contributing mechanisms. SIGNIFICANCE: The findings provide evidence supporting a contribution of hyperexcitable motoneurons to muscle spasticity.

Quantifying the deep tendon reflex using varying tendon indentation depths: applications to spasticity.

The deep tendon reflex (DTR) is often utilized to characterize the neuromuscular health of individuals because it is cheap, quick to implement, and requires limited equipment. However, DTR assessment is unreliable and assessor-dependent improve the reliability of the DTR assessment, we devised a novel standardization procedure. Our approach is based on the hypothesis that the neuromuscular state of a muscle changes systematically with respect to the indentation depth of its tendon. We tested the hypothesis by progressively indenting the biceps tendons on each side of nine hemiplegic stroke survivors to different depths, and then superimposing a series of brief controlled taps at each indentation depth to elicit a reflex response. Our results show that there exists a unique indentation depth at which reflex responses are consistently recorded (termed the Reflex Threshold) with increasing amplitude along increasing indentation depth. We further show that the reflex threshold depth is systematically smaller on the affected side of stroke survivors and that it is negatively correlated with the Modified Ashworth Score (VAF 70%). Our procedure also enables measurement of passive mechanical properties at the indentation location. In conclusion, our study shows that controlling for the indentation depth of the tendon of a muscle alters its reflex response predictably. Our novel device and method could be used to estimate neuromuscular changes in muscle (e.g., spasticity). Although some refinement is needed, this method opens the door to more reliable quantification of the DTR.

An evaluation of passive properties of spastic muscles in hemiparetic stroke survivors.

We have reported earlier [1] a new method for estimating reflex threshold in spastic muscles of stroke survivors, using controlled amplitude taps superimposed on progressive and controlled muscle indentation of the bicipital tendon in the bicipital fossa. This muscle indentation is done with a linear actuator positioned over the biceps muscle tendon at the elbow. In the course of testing for increased stretch reflex responses, (a cardinal feature of spasticity), we have also observed that the intrinsic or passive stiffness of the muscle is often increased. This assessment is derived from recordings of the force generated by the tendon during progressive loading, and by the instantaneous force response to the tendon tap. Thus, it appears that passive properties of muscle are often also changed in parallel with the reflex abnormalities. While some of these mechanical features have been described in earlier studies of torque-angle relations of spastic joints, it appears that these features can also be recognized readily using a small actuator that loads the tendon progressively. These findings may help clinicians recognize early changes in muscle mechanical properties, and may help them prevent large-scale adverse changes in muscle function.

A new method for reflex threshold estimation in spastic muscles.

Many clinical measures of spasticity, such as Ashworth tests and tendon tap responses, are linked to stretch reflex thresholds but these methods are relatively imprecise and unreliable. To address this deficit, we examined the utility of a system that relies on a small position controlled actuator to better estimate this threshold. We compared the reflex threshold estimates in the passive spastic and contralateral elbow flexor muscles of 4 hemiparetic spastic stroke survivors. We propose that the use of controlled indentation of the tendon may be a practical and accurate method of estimating stretch reflex threshold as well as passive muscle properties.