Recruitment Of Motoneurons Research Articles

Estimation of self-sustained activity produced by persistent inward currents using firing rate profiles of multiple motor units in humans.

Persistent inward calcium and sodium currents (IP) activated during motoneuron recruitment help synaptic inputs maintain self-sustained firing until derecruitment. Here, we estimate the contribution of the IP to self-sustained firing in human motoneurons of varying recruitment threshold by measuring the difference in synaptic input needed to maintain minimal firing once the IP is fully activated compared with the larger synaptic input required to initiate firing before full IP activation. Synaptic input to ≈20 dorsiflexor motoneurons simultaneously recorded during ramp contractions was estimated from firing profiles of motor units decomposed from high-density surface electromyography (EMG). To avoid errors introduced when using high-threshold units firing in their nonlinear range, we developed methods where the lowest threshold units firing linearly with force were used to construct a composite (control) unit firing rate profile to estimate synaptic input to higher threshold (test) units. The difference in the composite firing rate (synaptic input) at the time of test unit recruitment and derecruitment (ΔF = Frecruit - Fderecruit) was used to measure IP amplitude that sustained firing. Test units with recruitment thresholds 1-30% of maximum had similar ΔF values, which likely included both slow and fast motor units activated by small and large motoneurons, respectively. This suggests that the portion of the IP that sustains firing is similar across a wide range of motoneuron sizes.NEW & NOTEWORTHY A new method of estimating synaptic drive to multiple, simultaneously recorded motor units provides evidence that the portion of the depolarizing drive from persistent inward currents that contributes to self-sustained firing is similar across motoneurons of different sizes.

Interrogating interneurone function using threshold tracking of the H reflex in healthy subjects and patients with motor neurone disease

ObjectiveThe excitability of the lower motoneurone pool is traditionally tested using the H reflex and a constant-stimulus paradigm, which measures changes in the amplitude of the reflex response. This technique has limitations because reflex responses of different size must involve the recruitment or inhibition of different motoneurones. The threshold-tracking technique ensures that the changes in excitability occur for an identical population of motoneurones. We aimed to assess this technique and then apply it in patients with motor neurone disease (MND). MethodsThe threshold-tracking approach was assessed in 17 healthy subjects and 11 patients with MND. The soleus H reflex was conditioned by deep peroneal nerve stimulation producing reciprocal Ia and so-called D1 and D2 inhibitions, which are believed to reflect presynaptic inhibition of soleus Ia afferents. ResultsThreshold tracking was quicker than the constant-stimulus technique and reliable, properties that may be advantageous for clinical studies. D1 inhibition was significantly reduced in patients with MND. ConclusionsThreshold tracking is useful and may be preferable under some conditions for studying the excitability of the motoneurone pool. The decreased D1 inhibition in the patients suggests that presynaptic inhibition may be reduced in MND. SignificanceReduced presynaptic inhibition could be evidence of an interneuronopathy in MND. It is possible that the hyperreflexia is a spinal pre-motoneuronal disorder, and not definitive evidence of corticospinal involvement in MND.

Lactate stimulates central respiratory motor output in bullfrogs, Lithobates catesbeianus

Ventilation must constantly change to meet varying metabolic and acid‐base regulation needs of the organism. Although O2 and CO2/pH sensors have received much attention for the chemical control of breathing, metabolites such as lactate and ATP have recently been shown to play important roles in both the hypoxic and hypercapnic ventilatory responses of vertebrates. In mammals and fish, lactate anions increase ventilation through peripheral mechanisms, but the actions of lactate in the central respiratory network of any vertebrate species remain unclear. Anuran amphibians (frogs and toads) accumulate large amounts of lactate in the brain during periods of high respiratory drive, suggesting that lactate may act at central sites to stimulate breathing. For example, hypoxia increases brain lactate which may contribute to elevated ventilation following physiological hypoxia caused by breath‐holding. Furthermore, anurans perform mainly anaerobic exercise, leading to large lactate loads in the blood that may get delivered to the brain through transporters present in the blood‐brain barrier. Thus, we tested the hypothesis that lactate stimulates output from the central respiratory network in amphibians. To test this hypothesis, we measured respiratory‐related cranial nerve X (CNX) and hypoglossal nerve (SNII) activity in isolated brainstem‐spinal cord preparations from the American bullfrog, Lithobates catesbeianus, in response to sodium lactate (lac−; n=8). The brainstem‐spinal cord preparation is advantageous because we can assess the actions of lac− on rhythm generating and motor functions of the respiratory network independent of peripheral feedback. Lac− failed to increase frequency of the respiratory rhythm and amplitude of CNX output. However, we identified a striking dose‐dependent increase in amplitude of respiratory‐related SNII output in each preparation, indicating enhanced motor neuron firing and/or recruitment by lac− (P=0.008; Friedman test; 0.5 mM= 33±11, 2 mM= 56±19, 4 mM= 89±29 % increase above baseline). To control for slight increases in [Na+], osmolality, extracellular pH, and time during exposure to sodium lactate, we superfused a separate group of preparations with 0.5, 2, and 4 mM sodium bicarbonate (HCO3−; n=4). HCO3− did not increase the motor amplitude of either SNII or CNX (P>0.9; Friedman test). Thus, lactate anions lead to increased respiratory motor output of SNII, which may enhance activation of buccal floor musculature during periods of high respiratory demand such as hypoxia and exercise. Overall, this work directly implicates lactate anions in the control of central motor networks that regulate breathing in vertebrates.Support or Funding InformationThis work was funded by start‐up funds provided by UNC‐Greensboro to JS.

Neuromodulatory Selection of Motor Neuron Recruitment Patterns in a Visuomotor Behavior Increases Speed.

Animals generate locomotion at different speeds to suit their behavioral needs. Spinal circuits generate locomotion at these varying speeds by sequential activation of different spinal interneurons and motor neurons. Larval zebrafish can generate slow swims for prey capture and exploration by activation of secondary motor neurons and much faster and vigorous swims during escape and struggle via additional activation of primary motor neurons. Neuromodulators are known to alter the motor output of spinal circuits, but their precise role in speed regulation is not wellunderstood. Here, in the context of optomotor response (OMR), an innate evoked locomotor behavior, we show that dopamine (DA) provides an additional layer to regulation of swim speed in larval zebrafish. Activation of D1-like receptors increases swim speed during OMR in free-swimming larvae. By analyzing tail bend kinematics in head-restrained larvae, we show that the increase in speed is actuated by larger tail bends. Whole-cell patch-clamp recordings from motor neurons reveal that, during OMR, typically only secondary motor neurons are active, whereas primary motor neurons are quiescent. Activation of D1-like receptors increases intrinsic excitability and excitatory synaptic drive in primary and secondary motor neurons. These actions result in greater recruitment of motor neurons during OMR. Our findings provide an example of neuromodulatory reconfiguration of spinal motor neuron speed modules where members are selectively recruited and motor drive is increased to effect changes in locomotor speed. VIDEO ABSTRACT.

Glutamatergic input varies with phrenic motor neuron size.

Like all skeletal muscles, the diaphragm muscle accomplishes a range of motor behaviors by recruiting different motor unit types in an orderly fashion. Recruitment of phrenic motor neurons (PhMNs) is generally assumed to be based primarily on the intrinsic properties of PhMNs with an equal distribution of descending excitatory inputs to all PhMNs. However, differences in presynaptic excitatory input across PhMNs of varying sizes could also contribute to the orderly recruitment pattern. In the spinal cord of Sprague-Dawley rats, we retrogradely labeled PhMNs using cholera toxin B (CTB) and validated a robust confocal imaging-based technique that utilizes semiautomated processing to identify presynaptic glutamatergic (Glu) terminals within a defined distance around the somal membrane of PhMNs of varying size. Our results revealed an ~10% higher density of Glu terminals at PhMNs in the lower tertile of somal surface area. These smaller PhMNs are likely recruited first to accomplish lower force ventilatory behaviors of the diaphragm as compared with larger PhMNs in the upper tertile that are recruited to accomplish higher force expulsive behaviors. These results suggest that differences in excitatory synaptic input to PhMNs may also contribute to the orderly recruitment of diaphragm motor units.NEW & NOTEWORTHY The distribution of excitatory glutamatergic synaptic input to phrenic motor neurons differs across motor neurons of varying size. These findings support the size principle of motor unit recruitment that underlies graded force generation in a muscle, which is based on intrinsic electrophysiological properties of motor neurons resulting from differences in somal surface area. A higher density of glutamatergic inputs at smaller, more excitable motor neurons substantiates the earlier and more frequent recruitment of these units.

Investigation of Low-Current Direct Stimulation for Rehabilitation Treatment Related to Muscle Function Loss Using Self-Powered TENG System.

Muscle function loss is characterized as abnormal or completely lost muscle capabilities, and it can result from neurological disorders or nerve injuries. The currently available clinical treatment is to electrically stimulate the diseased muscles. Here, a self‐powered system of a stacked‐layer triboelectric nanogenerator (TENG) and a multiple‐channel epimysial electrode to directly stimulate muscles is demonstrated. Then, the two challenges regarding direct TENG muscle stimulation are further investigated. For the first challenge of improving low‐current TENG stimulation efficiency, it is found that the optimum stimulation efficiency can be achieved by conducting a systematic mapping with a multiple‐channel epimysial electrode. The second challenge is TENG stimulation stability. It is found that the force output generated by TENGs is more stable than using the conventional square wave stimulation and enveloped high frequency stimulation. With modelling and in vivo measurements, it is confirmed that the two factors that account for the stable stimulation using TENGs are the long pulse duration and low current amplitude. The current waveform of TENGs can effectively avoid synchronous motoneuron recruitment at the two stimulation electrodes to reduce force fluctuation. Here, after investigating these two challenges, it is believed that TENG direct muscle stimulation could be used for rehabilitative and therapeutic purpose of muscle function loss treatment.

Targeted Vagus Nerve Stimulation for Rehabilitation After Stroke.

Stroke is a leading cause of disability worldwide, and in approximately 60% of individuals, upper limb deficits persist 6 months after stroke. These deficits adversely affect the functional use of the upper limb and restrict participation in day to day activities. An important goal of stroke rehabilitation is to improve the quality of life by enhancing functional independence and participation in activities. Since upper limb deficits are one of the best predictors of quality of life after stroke, effective interventions targeting these deficits may represent a means to improve quality of life. An increased understanding of the neurobiological processes underlying stroke recovery has led to the development of targeted approaches to improve motor deficits. One such targeted strategy uses brief bursts of Vagus Nerve Stimulation (VNS) paired with rehabilitation to enhance plasticity and support recovery of upper limb function after chronic stroke. Stimulation of the vagus nerve triggers release of plasticity promoting neuromodulators, such as acetylcholine and norepinephrine, throughout the cortex. Timed engagement of neuromodulators concurrent with motor training drives task-specific plasticity in the motor cortex to improve function and provides the basis for paired VNS therapy. A number of studies in preclinical models of ischemic stroke demonstrated that VNS paired with rehabilitative training significantly improved the recovery of forelimb motor function compared to rehabilitative training without VNS. The improvements were associated with synaptic reorganization of cortical motor networks and recruitment of residual motor neurons controlling the impaired forelimb, demonstrating the putative neurobiological mechanisms underlying recovery of motor function. These preclinical studies provided the basis for conducting two multi-site, randomized controlled pilot trials in individuals with moderate to severe upper limb weakness after chronic ischemic stroke. In both studies, VNS paired with rehabilitation improved motor deficits compared to rehabilitation alone. The trials provided support for a 120-patient pivotal study designed to evaluate the efficacy of paired VNS therapy in individuals with chronic ischemic stroke. This manuscript will discuss the neurobiological rationale for VNS therapy, provide an in-depth discussion of both animal and human studies of VNS therapy for stroke, and outline the challenges and opportunities for the future use of VNS therapy.

You are as fast as your motor neurons: speed of recruitment and maximal discharge of motor neurons determine the maximal rate of force development in humans.

We propose and validate a method for accurately identifying the activity of populations of motor neurons during contractions at maximal rate of force development in humans. The behaviour of the motor neuron pool during rapid voluntary contractions in humans is presented. We show with this approach that the motor neuron recruitment speed and maximal motor unit discharge rate largely explains the individual ability in generating rapid force contractions. The results also indicate that the synaptic inputs received by the motor neurons before force is generated dictate human potential to generate force rapidly. This is the first characterization of the discharge behaviour of a representative sample of human motor neurons during rapid contractions. During rapid contractions, motor neurons are recruited in a short burst and begin to discharge at high frequencies (up to >200Hz). In the present study, we investigated the behaviour of relatively large populations of motor neurons during rapid (explosive) contractions in humans, applying a new approach to accurately identify motor neuron activity simultaneous to measuring the rate of force development. The activity of spinal motor neurons was assessed by high-density electromyographic decomposition from the tibialis anterior muscle of 20 men during isometric explosive contractions. The speed of motor neuron recruitment and the instantaneous motor unit discharge rate were analysed as a function of the impulse (the time-force integral) and the maximal rate of force development. The peak of motor unit discharge rate occurred before force generation and discharge rates decreased thereafter. The maximal motor unit discharge rate was associated with the explosive force variables, at the whole population level (r2 =0.71±0.12; P<0.001). Moreover, the peak motor unit discharge and maximal rate of force variables were correlated with an estimate of the supraspinal drive, which was measured as the speed of motor unit recruitment before the generation of afferent feedback (P<0.05). We show for the first time the full association between the effective neural drive to the muscle and human maximal rate of force development. The results obtained in the present study indicate that the variability in the maximal contractile explosive force of the human tibialis anterior muscle is determined by the neural activation preceding force generation.

Hyperexcitability and plasticity induced by sustained hypoxia on rectus abdominis motoneurons.

Acute hypoxia induces active expiration in rectus abdominis (RA) muscles in conscious freely moving rats, although its overall contribution is smaller than in internal oblique (IO) muscles. Tonically active and silent RA motoneurons were identified in invitro preparations of rat spinal cords. Sustained hypoxia (SH) increased the synaptic strength and induced morphological changes in tonically active RA motoneurons. Expiratory RA motoneurons were recorded in the insitu preparation and SH enhanced both the excitability and the synaptic transmission in those firing during the stage 2 expiration. The present study contributes to a better understanding of the mechanisms involved in SH recruitment of RA motoneurons to induce active expiration in rats. Rectus abdominis (RA) motoneurons translate the complex respiratory brainstem inputs into effective muscle contractions. Despite their fundamental role in respiration, their functional and morphological properties are not fully understood. In the present study, we investigated for the first time the contribution of RA muscle to active expiration and characterized RA motoneurons regarding their electrical, molecular and morphological profiles in control rats and in rats submitted to sustained hypoxia (SH), which induces chronic recruitment of abdominal muscles. Electromyographic experiments in conscious freely moving control rats and SH rats showed that RA contributes to active expiration induced by acute hypoxia, although its contribution is smaller than in internal oblique muscles. invitro whole-cell patch clamp recordings from RA motoneurons revealed two populations of cells: tonically active and silent. SH induced hyperexcitability in the tonically active cells by changing their action potential properties, and EPSCs. Three-dimensional morphological reconstructions of these cells showed that SH increased the dendritic complexity, stimulated the appearance of dendrite spines, and increased the somatic area and volume. Physiologically identified RA motoneurons, firing in two distinct phases of expiration, were recorded in the brainstem-spinal cord in situ preparation of rats. SH increased the firing frequency and EPSCs of neurons firing during stage 2 expiration. Taken together, our results show that RA motoneurons reconfigure their biophysical properties, morphology and synaptic strength to produce an appropriate expiratory drive in response to SH in rats.

The Subprimary Range of Firing Is Present in Both Cat and Mouse Spinal Motoneurons and Its Relationship to Force Development Is Similar for the Two Species.

In the motor system, force gradation is achieved by recruitment of motoneurons and rate modulation of their firing frequency. Classical experiments investigating the relationship between injected current to the soma during intracellular recording and the firing frequency (the I-f relation) in cat spinal motoneurons identified two clear ranges: a primary range and a secondary range. Recent work in mice, however, has identified an additional range proposed to be exclusive to rodents, the subprimary range (SPR), due to the presence of mixed mode oscillations of the membrane potential. Surprisingly, fully summated tetanic contractions occurred in mice during SPR frequencies. With the mouse now one of the most popular models to investigate motor control, it is crucial that such discrepancies between observations in mice and basic principles that have been widely accepted in larger animals are resolved. To do this, we have reinvestigated the I-f relation using ramp current injections in spinal motoneurons in both barbiturate-anesthetized and decerebrate (nonanesthetized) cats and mice. We demonstrate the presence of the SPR and mixed mode oscillations in both species and show that the SPR is enhanced by barbiturate anesthetics. Our measurements of the I-f relation in both cats and mice support the classical opinion that firing frequencies in the higher end of the primary range are necessary to obtain a full summation. By systematically varying the leg oil pool temperature (from 37°C to room temperature), we found that only at lower temperatures can maximal summation occur at SPR frequencies due to prolongation of individual muscle twitches.SIGNIFICANCE STATEMENT This work investigates recent revelations that mouse motoneurons behave in a fundamentally different way from motoneurons of larger animals with respect to the importance of rate modulation of motoneuron firing for force gradation. The current study systematically addresses the proposed discrepancies between mice and larger species (cats) and demonstrates that mouse motoneurons, in fact, use rate modulation as a mechanism of force modulation in a similar manner to the classical descriptions in larger animals.

Selective Recruitment of Arm Motoneurons in Nonhuman Primates Using Epidural Electrical Stimulation of the Cervical Spinal Cord.

Recovery of reaching and grasping ability is the priority for people with cervical spinal cord injury (SCI). Epidural electrical stimulation (EES) has shown promising results in improving motor control after SCI in various animal models and in humans. Notably, the application of stimulation bursts with spatiotemporal sequences that reproduce the natural activation of motoneurons restored skilled leg movements in rodent and nonhuman primate models of SCI. Here, we studied whether this conceptual framework could be transferred to the design of cervical EES protocols for the recovery of reaching and grasping in nonhuman primates. We recorded muscle activity during a reaching and grasping task in a macaque monkey and found that this task involves a stereotypical spatiotemporal map of motoneuron activation. We then characterized the specificity of a spinal implant for the delivery of EES to cervical spinal segments in the same animal. Finally, we combined these results to design a simple stimulation protocol that may reproduce natural motoneuron activation and thus facilitate upper limb movements after injury.

Volume EM Reconstruction of Spinal Cord Reveals Wiring Specificity in Speed-Related Motor Circuits

Spinal interneurons coordinate the activity of motoneurons to generate the spatiotemporal patterns of muscle contractions required for vertebrate locomotion. It is controversial to what degree the orderly, gradual recruitment of motoneurons is determined by biophysical differences among them rather than by specific connections from presynaptic interneurons to subsets of motoneurons. To answer this question, we mapped all connections from two types of interneurons onto all motoneurons in a larval zebrafish spinal cord hemisegment, using serial block-face electron microscopy (SBEM). We found specific synaptic connectivity from dorsal but not from ventral excitatory ipsilateral interneurons, with large motoneurons, active only when strong force is required, receiving specific inputs from dorsally located interneurons, active only during fast swims. By contrast, the connectivity between inhibitory commissural interneurons and motoneurons lacks any discernible pattern. The wiring pattern is consistent with a recruitment mechanism that depends to a considerable extent on specific connectivity.

The effects of model composition design choices on high-fidelity simulations of motoneuron recruitment and firing behaviors

Objective. Computational models often require tradeoffs, such as balancing detail with efficiency; yet optimal balance should incorporate sound design features that do not bias the results of the specific scientific question under investigation. The present study examines how model design choices impact simulation results. Approach. We developed a rigorously-validated high-fidelity computational model of the spinal motoneuron pool to study three long-standing model design practices which have yet to be examined for their impact on motoneuron recruitment, firing rate, and force simulations. The practices examined were the use of: (1) generic cell models to simulate different motoneuron types, (2) discrete property ranges for different motoneuron types, and (3) biological homogeneity of cell properties within motoneuron types. Main results. Our results show that each of these practices accentuates conditions of motoneuron recruitment based on the size principle, and minimizes conditions of mixed and reversed recruitment orders, which have been observed in animal and human recordings. Specifically, strict motoneuron orderly size recruitment occurs, but in a compressed range, after which mixed and reverse motoneuron recruitment occurs due to the overlap in electrical properties of different motoneuron types. Additionally, these practices underestimate the motoneuron firing rates and force data simulated by existing models. Significance. Our results indicate that current modeling practices increase conditions of motoneuron recruitment based on the size principle, and decrease conditions of mixed and reversed recruitment order, which, in turn, impacts the predictions made by existing models on motoneuron recruitment, firing rate, and force. Additionally, mixed and reverse motoneuron recruitment generated higher muscle force than orderly size motoneuron recruitment in these simulations and represents one potential scheme to increase muscle efficiency. The examined model design practices, as well as the present results, are applicable to neuronal modeling throughout the nervous system.

Effects of microgravity on characteristics of the accuracy control of movements

Effects of microgravity on characteristics of the accuracy control of movements

Neurturin is a PGC-1α1-controlled myokine that promotes motor neuron recruitment and neuromuscular junction formation

ObjectiveWe examined whether skeletal muscle overexpression of PGC-1α1 or PGC-1α4 affected myokine secretion and neuromuscular junction (NMJ) formation. MethodsA microfluidic device was used to model endocrine signaling and NMJ formation between primary mouse myoblast-derived myotubes and embryonic stem cell-derived motor neurons. Differences in hydrostatic pressure allowed for fluidic isolation of either cell type or unidirectional signaling in the fluid phase. Myotubes were transduced to overexpress PGC-1α1 or PGC-1α4, and myokine secretion was quantified using a proximity extension assay. Morphological and functional changes in NMJs were measured by fluorescent microscopy and by monitoring muscle contraction upon motor neuron stimulation. ResultsSkeletal muscle transduction with PGC-1α1, but not PGC-1α4, increased NMJ formation and size. PGC-1α1 increased muscle secretion of neurturin, which was sufficient and necessary for the effects of muscle PGC-1α1 on NMJ formation. ConclusionsOur findings indicate that neurturin is a mediator of PGC-1α1-dependent retrograde signaling from muscle to motor neurons.

Neural and non-neural related properties in the spastic wrist flexors: An optimization study

Quantifying neural and non-neural contributions to increased joint resistance in spasticity is essential for a better understanding of its pathophysiological mechanisms and evaluating different intervention strategies. However, direct measurement of spasticity-related manifestations, e.g., motoneuron and biophysical properties in humans, is extremely challenging. In this vein, we developed a forward neuromusculoskeletal model that accounts for dynamics of muscle spindles, motoneuron pools, muscle activation and musculotendon of wrist flexors and relies on the joint angle and resistant torque as the only input measurement variables. By modeling the stretch reflex pathway, neural and non-neural related properties of the spastic wrist flexors were estimated during the wrist extension test. Joint angle and resistant torque were collected from 17 persons with chronic stroke and healthy controls using NeuroFlexor, a motorized force measurement device during the passive wrist extension test. The model was optimized by tuning the passive and stretch reflex-related parameters to fit the measured torque in each participant. We found that persons with moderate and severe spasticity had significantly higher stiffness than controls. Among subgroups of stroke survivors, the increased neural component was mainly due to a lower muscle spindle rate at 50% of the motoneuron recruitment. The motoneuron pool threshold was highly correlated to the motoneuron pool gain in all subgroups. The model can describe the overall resistant behavior of the wrist joint during the test. Compared to controls, increased resistance was predominantly due to higher elasticity and neural components. We concluded that in combination with the NeuroFlexor measurement, the proposed neuromusculoskeletal model and optimization scheme served as suitable tools for investigating potential parameter changes along the stretch-reflex pathway in persons with spasticity.

Inefficient skeletal muscle oxidative function flanks impaired motor neuron recruitment in Amyotrophic Lateral Sclerosis during exercise

This study aimed to evaluate muscle oxidative function during exercise in amyotrophic lateral sclerosis patients (pALS) with non-invasive methods in order to assess if determinants of reduced exercise tolerance might match ALS clinical heterogeneity. 17 pALS, who were followed for 4 months, were compared with 13 healthy controls (CTRL). Exercise tolerance was assessed by an incremental exercise test on cycle ergometer measuring peak O2 uptake (dot{{rm{V}}}O2peak), vastus lateralis oxidative function by near infrared spectroscopy (NIRS) and breathing pattern (dot{{rm{V}}}E peak). pALS displayed: (1) 44% lower dot{{rm{V}}}O2peakvs. CTRL (p < 0.0001), paralleled by a 43% decreased peak skeletal muscle oxidative function (p < 0.01), with a linear regression between these two variables (r2 = 0.64, p < 0.0001); (2) 46% reduced dot{{rm{V}}}Epeakvs. CTRL (p < 0.0001), achieved by using an inefficient breathing pattern (increasing respiratory frequency) from the onset until the end of exercise. Inefficient skeletal muscle O2 function, when flanking the impaired motor units recruitment, is a major determinant of pALS clinical heterogeneity and working capacity exercise tolerance. CPET and NIRS are useful tools for detecting early stages of oxidative deficiency in skeletal muscles, disclosing individual impairments in the O2 transport and utilization chain.

A novel cortical target to enhance hand motor output in humans with spinal cord injury.

A main goal of rehabilitation strategies in humans with spinal cord injury is to strengthen transmission in spared neural networks. Although neuromodulatory strategies have targeted different sites within the central nervous system to restore motor function following spinal cord injury, the role of cortical targets remain poorly understood. Here, we use 180 pairs of transcranial magnetic stimulation for ∼30 min over the hand representation of the motor cortex at an interstimulus interval mimicking the rhythmicity of descending late indirect (I) waves in corticospinal neurons (4.3 ms; I-wave protocol) or at an interstimulus interval in-between I-waves (3.5 ms; control protocol) on separate days in a randomized order. Late I-waves are thought to arise from trans-synaptic cortical inputs and have a crucial role in the recruitment of spinal motor neurons following spinal cord injury. Motor evoked potentials elicited by transcranial magnetic stimulation, paired-pulse intracortical inhibition, spinal motor neuron excitability (F-waves), index finger abduction force and electromyographic activity as well as a hand dexterity task were measured before and after both protocols in 15 individuals with chronic incomplete cervical spinal cord injury and 17 uninjured participants. We found that motor evoked potentials size increased in spinal cord injury and uninjured participants after the I-wave but not the control protocol for ∼30 to 60 min after the stimulation. Intracortical inhibition decreased and F-wave amplitude and persistence increased after the I-wave but not the control protocol, suggesting that cortical and subcortical networks contributed to changes in corticospinal excitability. Importantly, hand motor output and hand dexterity increased in individuals with spinal cord injury after the I-wave protocol. These results provide the first evidence that late synaptic input to corticospinal neurons may represent a novel therapeutic target for improving motor function in humans with paralysis due to spinal cord injury.

Dynamic cortical participation during bilateral, cyclical ankle movements: effects of aging

The precise role of the human primary motor cortex in walking is unknown. Our previous study showed that the primary motor cortex may contribute to specific requirements of walking (i.e., maintaining a constant movement frequency and bilaterally coordinating the feet). Because aging can impair (i) the ability to fulfill the aforementioned requirements and (ii) corticomuscular communication, we hypothesized that aging would impair the motoneuronal recruitment by the primary motor cortex during bilateral cyclical movements. Here, we used corticomuscular coherence (i.e., coherence between the primary motor cortex and the active muscles) to examine whether corticomuscular communication is affected in older individuals during cyclical movements that shared some functional requirements with walking. Fifteen young men and 9 older men performed cyclical, anti-phasic dorsiflexion and plantarflexion of the feet while seated. Coherence between the midline primary motor cortex and contracting leg muscles cyclically increased in both age groups. However, the coherence of older participants was characterized by (i) lower magnitude and (ii) mediolaterally broader and more rostrally centered cortical distributions. These characteristics suggest that aging changes how the primary motor cortex participates in the cyclical movements, and such change may extend to walking.

A Gradient in Synaptic Strength and Plasticity among Motoneurons Provides a Peripheral Mechanism for Locomotor Control

The recruitment of motoneurons during force generation follows a general pattern that has been confirmed across diverse species [1-3]. Motoneurons are recruited systematically according to synaptic inputs and intrinsic cellular properties and corresponding to movements of different intensities. However, much less is known about the output properties of individual motoneurons and how they affect the translation of motoneuron recruitment to the strength of muscle contractions. In larval zebrafish, spinal motoneurons are recruited in a topographic gradient according to their input resistance (Rin) at different swimming strengths and speeds. Whereas dorsal, lower-Rin primary motoneurons (PMns) are only activated during behaviors that involve strong and fast body bends, more ventral, higher-Rin secondary motoneurons (SMns) are recruited during weaker and slower movements [4-6]. Here we perform invivo paired recordings between identified spinal motoneurons and skeletal muscle cells in larval zebrafish. We characterize individual motoneuron outputs to single muscle cells and show that the strength and reliability of motoneuron outputs are inversely correlated with motoneuron Rin. During repetitive high-frequency motoneuron drive, PMn synapses undergo depression, whereas SMn synapses potentiate. We monitor muscle cell contractions elicited by single motoneurons and show that the pattern of motoneuron output strength and plasticity observed in electrophysiological recordings is reflected in muscle shortening. Our findings indicate a link between the recruitment pattern and output properties of spinal motoneurons that can together generate appropriate intensities for muscle contractions. We demonstrate that motoneuron output properties provide an additional peripheral mechanism for graded locomotor control at the neuromuscular junction.