A direct spinal cord-computer interface enables the control of the paralysed hand in spinal cord injury.

The paralysis of the muscles controlling the hand dramatically limits the quality of life of individuals living with spinal cord injury (SCI). Here, with a non-invasive neural interface, we demonstrate that eight motor complete SCI individuals (C5-C6) are still able to task-modulate in real-time the activity of populations of spinal motor neurons with residual neural pathways. In all SCI participants tested, we identified groups of motor units under voluntary control that encoded various hand movements. The motor unit discharges were mapped into more than 10 degrees of freedom, ranging from grasping to individual hand-digit flexion and extension. We then mapped the neural dynamics into a real-time controlled virtual hand. The SCI participants were able to match the cue hand posture by proportionally controlling four degrees of freedom (opening and closing the hand and index flexion/extension). These results demonstrate that wearable muscle sensors provide access to spared motor neurons that are fully under voluntary control in complete cervical SCI individuals. This non-invasive neural interface allows the investigation of motor neuron changes after the injury and has the potential to promote movement restoration when integrated with assistive devices.

The Forces Generated by Agonist Muscles during Isometric Contractions Arise from Motor Unit Synergies.

The purpose of our study was to identify the low-dimensional latent components, defined hereafter as motor unit modes, underlying the discharge rates of the motor units in two knee extensors (vastus medialis and lateralis, eight men) and two hand muscles (first dorsal interossei and thenars, seven men and one woman) during submaximal isometric contractions. Factor analysis identified two independent motor unit modes that captured most of the covariance of the motor unit discharge rates. We found divergent distributions of the motor unit modes for the hand and vastii muscles. On average, 75% of the motor units for the thenar muscles and first dorsal interosseus were strongly correlated with the module for the muscle in which they resided. In contrast, we found a continuous distribution of motor unit modes spanning the two vastii muscle modules. The proportion of the muscle-specific motor unit modes was 60% for vastus medialis and 45% for vastus lateralis. The other motor units were either correlated with both muscle modules (shared inputs) or belonged to the module for the other muscle (15% for vastus lateralis). Moreover, coherence of the discharge rates between motor unit pools was explained by the presence of shared synaptic inputs. In simulations with 480 integrate-and-fire neurons, we demonstrate that factor analysis identifies the motor unit modes with high levels of accuracy. Our results indicate that correlated discharge rates of motor units that comprise motor unit modes arise from at least two independent sources of common input among the motor neurons innervating synergistic muscles.SIGNIFICANCE STATEMENT It has been suggested that the nervous system controls synergistic muscles by projecting common synaptic inputs to the engaged motor neurons. In our study, we reduced the dimensionality of the output produced by pools of synergistic motor neurons innervating the hand and thigh muscles during isometric contractions. We found two neural modules, each representing a different common input, that were each specific for one of the muscles. In the vastii muscles, we found a continuous distribution of motor unit modes spanning the two synergistic muscles. Some of the motor units from the homonymous vastii muscle were controlled by the dominant neural module of the other synergistic muscle. In contrast, we found two distinct neural modules for the hand muscles.

Specificity of early motor unit adaptations with resistive exercise training.

After exposure of the human body to resistive exercise, the force-generation capacity of the trained muscles increases significantly. Despite decades of research, the neural and muscular stimuli that initiate these changes in muscle force are not yet fully understood. The study of these adaptations is further complicated by the fact that the changes may be partly specific to the training task. For example, short-term strength training does not always influence the neural drive to muscles during the early phase (<100 ms) of force development in rapid isometric contractions. Here we discuss some of the studies that have investigated neuromuscular adaptations underlying changes in maximal force and rate of force development produced by different strength training interventions, with a focus on changes observed at the level of spinal motor neurons. We discuss the different motor unit adjustments needed to increase force or speed, and the specificity of some of the adaptations elicited by differences in the training tasks.

Motor unit modes in the calf muscles during a submaximal isometric contraction are changed by brief stretches.

The purpose of our study was to investigate the influence of a stretch intervention on the common modulation of discharge rate among motor units in the calf muscles during a submaximal isometric contraction. The current report comprises a computational analysis of a motor unit dataset that we published previously (Mazzo et al., 2021). Motor unit activity was recorded from the three main plantar flexor muscles while participants performed an isometric contraction at 10% of the maximal voluntary contraction force before and after each of two interventions. The interventions were a control task (standing balance) and static stretching of the plantar flexor muscles. A factorization analysis on the smoothed discharge rates of the motor units from all three muscles yielded three modes that were independent of the individual muscles. The composition of the modes was not changed by the standing-balance task, whereas the stretching exercise reduced the average correlation in the second mode and increased it in the third mode. A centroid analysis on the correlation values showed that most motor units were associated with two or three modes, which were presumed to indicate shared synaptic inputs. The percentage of motor units adjacent to the seven centroids changed after both interventions: Control intervention, mode 1 decreased and the shared mode 1 + 2 increased; stretch intervention, shared modes either decreased (1 + 2) or increased (1 + 3). These findings indicate that the neuromuscular adjustments during both interventions were sufficient to change the motor unit modes when the same task was performed after each intervention. KEY POINTS: Based on covariation of the discharge rates of motor units in the calf muscles during a submaximal isometric contraction, factor analysis was used to assign the correlated discharge trains to three motor unit modes. The motor unit modes were determined from the combined set of all identified motor units across the three muscles before and after each participant performed a control and a stretch intervention. The composition of the motor unit modes changed after the stretching exercise, but not after the control task (standing balance). A centroid analysis on the distribution of correlation values found that most motor units were associated with a shared centroid and this distribution, presumably reflecting shared synaptic input, changed after both interventions. Our results demonstrate how the distribution of multiple common synaptic inputs to the motor neurons innervating the plantar flexor muscles changes after a brief series of stretches.

Antagonism of 5-HT2 receptors attenuates self-sustained firing of human motor units.

5-HT2 receptors on motoneurones play a critical role in facilitating persistent inward currents (PICs). Although facilitation of PICs can enhance self-sustained firing after periods of excitation, the relationship between 5-HT2 receptor activity and self-sustained firing in human motor units (MUs) has not been resolved. MU activity was assessed from the tibialis anterior of 10 healthy adults (24.9 ± 2.8 years) during two contraction protocols. Both protocols featured steady-state isometric contractions with constant descending drive to the motoneurone pool. However, one protocol also included an additional phase of superimposed descending drive. Adding and then removing descending drive in the middle of steady-state contractions altered MU firing behaviour across the motor pool, where newly recruited units in the superimposed phase were unable to switch off (P = 0.0002), and units recruited prior to additional descending drive reduced their discharge rates (P < 0.0001, difference in estimated marginal means (∆) = 2.24 pulses/s). The 5-HT2 receptor antagonist, cyproheptadine, was then administered to determine whether changes in MU firing were mediated by serotonergic mechanisms. 5-HT2 receptor antagonism caused reductions in MU discharge rate (P < 0.001, ∆ = 1.65 pulses/s), recruitment threshold (P = 0.00112, ∆ = 1.09% maximal voluntary contraction) and self-sustained firing duration (P < 0.0001, ∆ = 1.77s) after the additional descending drive was removed in the middle of the steady-state contraction. These findings indicate that serotonergic neuromodulation plays a key role in facilitating discharge and self-sustained firing of human motoneurones, where adaptive changes in MU recruitment must occur to meet the demands of the contraction. KEY POINTS: Animal and cellular preparations indicate that somato-dendritic 5-HT2 receptors regulate the intrinsic excitability of motoneurones. 5-HT2 receptor antagonism reduces estimates of persistent inward currents in motoneurones, which contribute to self-sustained firing when synaptic inputs are reduced or removed. This human study employed a contraction task that slowly increased (and then removed) the additional descending drive in the middle of a steady-state contraction where marked self-sustained firing occurred when the descending drive was removed. 5-HT2 receptor antagonism caused widespread reductions in motor unit (MU) discharge rates during contractions, which was accompanied by reduced recruitment threshold and attenuation of self-sustained firing duration after the removal of the additional descending drive to motoneurones. These findings support the role that serotonergic neuromodulation is a key facilitator of MU discharge and self-sustained firing of human motoneurones, where adaptative changes in MU recruitment must occur to meet the demands of the contraction.

Reading and Modulating Cortical ß Bursts from Motor Unit Spiking Activity.

ß Oscillations (13-30 Hz) are ubiquitous in the human motor nervous system. Yet, their origins and roles are unknown. Traditionally, ß activity has been treated as a stationary signal. However, recent studies observed that cortical ß occurs in "bursting events," which are transmitted to muscles. This short-lived nature of ß events makes it possible to study the main mechanism of ß activity found in the muscles in relation to cortical ß. Here, we assessed whether muscle ß activity mainly results from cortical projections. We ran two experiments in healthy humans of both sexes (N = 15 and N = 13, respectively) to characterize ß activity at the cortical and motor unit (MU) levels during isometric contractions of the tibialis anterior muscle. We found that ß rhythms observed at the cortical and MU levels are indeed in bursts. These bursts appeared to be time-locked and had comparable average durations (40-80 ms) and rates (approximately three to four bursts per second). To further confirm that cortical and MU ß have the same source, we used a novel operant conditioning framework to allow subjects to volitionally modulate MU ß. We showed that volitional modulation of ß activity at the MU level was possible with minimal subject learning and was paralleled by similar changes in cortical ß activity. These results support the hypothesis that MU ß mainly results from cortical projections. Moreover, they demonstrate the possibility to decode cortical ß activity from MU recordings, with a potential translation to future neural interfaces that use peripheral information to identify and modulate activity in the central nervous system.SIGNIFICANCE STATEMENT We show for the first time that ß activity in motor unit (MU) populations occurs in bursting events. These bursts observed in the output of the spinal cord appear to be time-locked and share similar characteristics of ß activity at the cortical level, such as the duration and rate at which they occur. Moreover, when subjects were exposed to a novel operant conditioning paradigm and modulated MU ß activity, cortical ß activity changed in a similar way as peripheral ß. These results provide evidence for a strong correspondence between cortical and peripheral ß activity, demonstrating the cortical origin of peripheral ß and opening the pathway for a new generation of neural interfaces.

Interfacing Motor Units in Non-Human Primates Identifies a Principal Neural Component for Force Control Constrained by the Size Principle.

Motor units convert the last neural code of movement into muscle forces. The classic view of motor unit control is that the central nervous system sends common synaptic inputs to motoneuron pools and that motoneurons respond in an orderly fashion dictated by the size principle. This view however is in contrast with the large number of dimensions observed in motor cortex which may allow individual and flexible control of motor units. Evidence for flexible control of motor units may be obtained by tracking motor units longitudinally during tasks with some level of behavioural variability. Here we identified and tracked populations of motor units in the brachioradialis muscle of two macaque monkeys during ten sessions spanning over one month with a broad range of rate of force development (1.8 - 38.6 N·m·s-1). We found a very stable recruitment order and discharge characteristics of the motor units over sessions and contraction trials. The small deviations from orderly recruitment were fully predicted by the motor unit recruitment intervals, so that small shifts in recruitment thresholds happened only during contractions at high rate of force development. Moreover, we also found that one component explained more than ∼50% of the motor unit discharge rate variance, and that the remaining components represented a time-shifted version of the first. In conclusion, our results show that motoneurons recruitment is determined by the interplay of the size principle and common input and that this recruitment scheme is not violated over time nor by the speed of the contractions.SIGNIFICANCE STATEMENT:With a new non-invasive high-density electromyographic framework we show the activity of motor unit ensembles in macaques during voluntary contractions. The discharge characteristics of brachioradialis motor units revealed a relatively fixed recruitment order and discharge characteristics across days and rate of force developments. These results were further confirmed through invasive axonal stimulation and recordings of intramuscular electromyographic activity from 16 arm muscles. The study shows for the first time the feasibility of longitudinal non-invasive motor unit interfacing and tracking of the same motor units in non-human primates.

Correlation networks of spinal motor neurons that innervate lower limb muscles during a multi-joint isometric task.

Movements are reportedly controlled through the combination of synergies that generate specific motor outputs by imposing an activation pattern on a group of muscles. To date, the smallest unit of analysis of these synergies has been the muscle through the measurement of its activation. However, the muscle is not the lowest neural level of movement control. In this human study (n = 10), we used a purely data-driven method grounded on graph theory to extract networks of motor neurons based on their correlated activity during an isometric multi-joint task. Specifically, high-density surface electromyography recordings from six lower limb muscles were decomposed into motor neurons spiking activity. We analysed these activities by identifying their common low-frequency components, from which networks of correlated activity to the motor neurons were derived and interpreted as networks of common synaptic inputs. The vast majority of the identified motor neurons shared common inputs with other motor neuron(s). In addition, groups of motor neurons were partly decoupled from their innervated muscle, such that motor neurons innervating the same muscle did not necessarily receive common inputs. Conversely, some motor neurons from different muscles-including distant muscles-received common inputs. The study supports the theory that movements are produced through the control of small numbers of groups of motor neurons via common inputs and that there is a partial mismatch between these groups of motor neurons and muscle anatomy. We provide a new neural framework for a deeper understanding of the structure of common inputs to motor neurons. KEY POINTS: A central and unresolved question is how spinal motor neurons are controlled to generate movement. We decoded the spiking activities of dozens of spinal motor neurons innervating six muscles during a multi-joint task, and we used a purely data-driven method grounded on graph theory to extract networks of motor neurons based on their correlated activity (considered as common input). The vast majority of the identified motor neurons shared common inputs with other motor neuron(s). Groups of motor neurons were partly decoupled from their innervated muscle, such that motor neurons innervating the same muscle did not necessarily receive common inputs. Conversely, some motor neurons from different muscles, including distant muscles, received common inputs. The study supports the theory that movement is produced through the control of groups of motor neurons via common inputs and that there is a partial mismatch between these groups of motor neurons and muscle anatomy.

Blockade of 5-HT2 receptors suppresses motor unit firing and estimates of persistent inward currents during voluntary muscle contraction in humans.

Serotonergic neuromodulation contributes to enhanced voluntary muscle activation. However, it is not known how the likely motoneurone receptor candidate (5-HT2 ) influences the firing rate and activation threshold of motor units (MUs) in humans. The purpose of this study was to determine whether 5-HT2 receptor activity contributes to human MU behaviour during voluntary ramped contractions of differing intensity. High-density surface EMG (HDsEMG) of the tibialis anterior was assessed during ramped isometric dorsiflexions at 10, 30, 50 and 70% of maximal voluntary contraction (MVC). MU characteristics were successfully extracted from HDsEMG of 11 young adults (four female) pre- and post-ingestion of 8 mg cyproheptadine or a placebo. Antagonism of 5-HT2 receptors caused a reduction in MU discharge rate during steady-state muscle activation that was independent of the level of contraction intensity [P < 0.001; estimated mean difference (∆) = 1.06 pulses/s], in addition to an increase in MU derecruitment threshold (P < 0.013, ∆ = 1.23% MVC), without a change in force during MVC (P = 0.652). A reduction in estimates of persistent inward current amplitude was observed at 10% MVC (P < 0.001, ∆ = 0.99 Hz) and 30% MVC (P = 0.003, ∆ = 0.75 Hz) that aligned with 5-HT changes in MU firing behaviour attributable to 5-HT2 antagonism. Overall, these findings indicate that 5-HT2 receptor activity has a role in regulating the discharge rate in populations of spinal motoneurones when performing voluntary contractions. This study provides evidence of a direct link between MU discharge properties, persistent inward current activity and 5-HT2 receptor activity in humans. KEY POINTS: Activation of 5-HT receptors on the soma and dendrites of motoneurones regulates their excitability. Previous work using chlorpromazine and cyproheptadine has demonstrated that the 5-HT2 receptor regulates motoneurone activity in humans with chronic spinal cord injury and non-injured control subjects. It is not known how the 5-HT2 receptor directly influences motor unit (MU) discharge and MU recruitment in larger populations of human motoneurones during voluntary contractions of differing intensity. Despite the absence of change in force during maximal voluntary dorsiflexions, 5-HT2 receptor antagonism caused a reduction in MU discharge rate during submaximal steady-state muscle contraction, in addition to an increase in MU derecruitment threshold, irrespective of the submaximal contraction intensity. Reductions in estimates of persistent inward currents after 5-HT2 receptor antagonism support the viewpoint that the 5-HT2 receptor plays a crucial role in regulating motor activity, whereby a persistent inward current-based mechanism is involved in regulating the excitability of human motoneurones.

Standard intensities of transcranial alternating current stimulation over the motor cortex do not entrain corticospinal inputs to motor neurons.

Transcranial alternating current stimulation (TACS) is commonly used to synchronize a cortical area and its outputs to the stimulus waveform, but gathering evidence for this based on brain recordings in humans is challenging. The corticospinal tract transmits beta oscillations (∼21 Hz) from the motor cortex to tonically contracted limb muscles linearly. Therefore, muscle activity may be used to measure the level of beta entrainment in the corticospinal tract due to TACS over the motor cortex. Here, we assessed whether TACS is able to modulate the neural inputs to muscles, which would provide indirect evidence for TACS-driven neural entrainment. In the first part of the study, we ran simulations of motor neuron (MN) pools receiving inputs from corticospinal neurons with different levels of beta entrainment. Results suggest that MNs are highly sensitive to changes in corticospinal beta activity. Then, we ran experiments on healthy human subjects (N = 10) in which TACS (at 1 mA) was delivered over the motor cortex at 21 Hz (beta stimulation), or at 7 Hz or 40 Hz (control conditions) while the abductor digiti minimi or the tibialis anterior muscle were tonically contracted. Muscle activity was measured using high-density electromyography, which allowed us to decompose the activity of pools of motor units innervating the muscles. By analysing motor unit pool activity, we observed that none of the TACS conditions could consistently alter the spectral contents of the common neural inputs received by the muscles. These results suggest that 1 mA TACS over the motor cortex given at beta frequencies does not entrain corticospinal activity. KEY POINTS: Transcranial alternating current stimulation (TACS) is commonly used to entrain the communication between brain regions. It is challenging to find direct evidence supporting TACS-driven neural entrainment due to the technical difficulties in recording brain activity during stimulation. Computational simulations of motor neuron pools receiving common inputs in the beta (∼21 Hz) band indicate that motor neurons are highly sensitive to corticospinal beta entrainment. Motor unit activity from human muscles does not support TACS-driven corticospinal entrainment.

Adaptations in motor unit properties underlying changes in recruitment, rate coding, and maximum force.

Changes in the discharge characteristics of motor units as well as in the maximum force-producing capacity of the muscle are observed following training, aging, and fatiguability. The ability to measure the adaptations in the neuromuscular properties underlying these changes experimentally, however, is limited. In this study we used a computational model to systematically investigate the effects of various neural and muscular adaptations on motor unit recruitment thresholds, average motor unit discharge rates in submaximal contractions, and maximum force. The primary focus was to identify candidate adaptations that can explain experimentally observed changes in motor unit discharge characteristics after 4 wk of strength training (Del Vecchio A, Casolo A, Negro F, Scorcelletti M, Bazzucchi I, Enoka R, Felici F, Farina D. J Physiol 597: 1873-1887, 2019). The simulation results indicated that multiple combinations of adaptations, likely involving an increase in maximum discharge rate across motor units, may occur after such training. On a more general level, we found that the magnitude of the adaptations scales linearly with the change in recruitment thresholds, discharge rates, and maximum force. In addition, the combination of multiple adaptations can be predicted as the linear sum of their individual effects. Together, this implies that the outcomes of the simulations can be generalized to predict the effect of any combination of neural and muscular adaptations. In this way, the study provides a tool for estimating potential underlying adaptations in neural and muscular properties to explain any change in commonly used measures of rate coding, recruitment, and maximum force.NEW & NOTEWORTHY Our ability to measure adaptations in neuromuscular properties in vivo is limited. Using a computational model, we quantify the effect of multiple neuromuscular adaptations on common measures of motor unit recruitment, rate coding, and force-producing capacity. Scaling and combining adaptations had a near-linear effect on these measures, indicating that the results can explain and predict neuromuscular adaptations in a wide range of conditions, including, but not limited to, strength training.

Neuromechanics of the Rate of Force Development.

The rate at which an individual can develop force during rapid voluntary contractions can be influenced by both the neural drive to a muscle and its intrinsic musculotendinous properties. We hypothesize that the maximal rate of force development across human individuals is mainly attributable to the rate of motor unit recruitment.

Is Smaller Better? Cu2+/Cu+ Coordination Chemistry and Copper-64 Radiochemical Investigation of a 1,4,7-Triazacyclononane-Based Sulfur-Rich Chelator.

The biologically triggered reduction of Cu2+ to Cu+ has been postulated as a possible in vivo decomplexation pathway in 64/67Cu-based radiopharmaceuticals. In an attempt to hinder this phenomenon, we have previously developed a family of S-containing polyazamacrocycles based on 12-, 13-, or 14-membered tetraaza rings able to stabilize both oxidation states. However, despite the high thermodynamic stability of the resulting Cu2+/+ complexes, a marked [64Cu]Cu2+ release was detected in human serum, likely as a result of the partially saturated coordination sphere around the copper center. In the present work, a new hexadentate macrocyclic ligand, 1,4,7-tris[2-(methylsulfanyl)ethyl)]-1,4,7-triazacyclononane (NO3S), was synthesized by hypothesizing that a smaller macrocyclic backbone could thwart the observed demetalation by fully encapsulating the copper ion. To unveil the role of the S donors in the metal binding, the corresponding alkyl analogue 1,4,7-tris-n-butyl-1,4,7-triazacyclononane (TACN-n-Bu) was considered as comparison. The acid-base properties of the free ligands and the kinetic, thermodynamic, and structural properties of their Cu2+ and Cu+ complexes were investigated in solution and solid (crystal) states through a combination of spectroscopic and electrochemical techniques. The formation of two stable mononuclear species was detected in aqueous solution for both ligands. The pCu2+ value for NO3S at physiological pH was 6 orders of magnitude higher than that computed for TACN-n-Bu, pointing out the significant stabilizing contribution arising from the Cu2+-S interactions. In both the solid state and solution, Cu2+ was fully embedded in the ligand cleft in a hexacoordinated N3S3 environment. Furthermore, NO3S exhibited a remarkable ability to form a stable complex with Cu+ through the involvement of all of the donors in the coordination sphere. Radiolabeling studies evidenced an excellent affinity of NO3S toward [64Cu]Cu2+, as quantitative incorporation was achieved at high apparent molar activity (∼10 MBq/nmol) and under mild conditions (ambient temperature, neutral pH, 10 min reaction time). Human serum stability assays revealed an increased stability of [64Cu][Cu(NO3S)]2+ when compared to the corresponding complexes formed by 12-, 13-, or 14-membered tetraaza rings.

Mental fatigue impairs physical performance but not the neural drive to the muscle: a preliminary analysis.

Mental fatigue (MF) does not only affect cognitive but also physical performance. This study aimed to explore the effects of MF on muscle endurance, rate of perceived exertion (RPE), and motor units' activity. Ten healthy males participated in a randomised crossover study. The subjects attended two identical experimental sessions separated by 3 days with the only difference of a cognitive task (incongruent Stroop task [ST]) and a control condition (watching a documentary). Perceived MF and motivation were measured for each session at baseline and after each cognitive task. Four contractions at 20% of maximal voluntary contraction (MVIC) were performed at baseline, after each cognitive and after muscle endurance task while measuring motor units by high-density surface electromyography. Muscle endurance until failure at 50% of MVIC was measured after each cognitive task and the RPE was measured right after failure. ST significantly increased MF (p = 0.001) reduced the motivation (p = 0.008) for the subsequent physical task and also impaired physical performance (p = 0.044). However, estimates of common synaptic inputs and motor unit discharge rates as well as RPE were not affected by MF (p > 0.11). In conclusion, MF impairs muscle endurance and motivation for the physical task but not the neural drive to the muscle at any frequency bands. Although it is physiologically possible for mentally fatigued subjects to generate an optimal neuromuscular function, the altered motivation seems to limit physical performance. Preliminarily, our results suggest that the corticospinal pathways are not affected by MF.

Startling stimuli increase maximal motor unit discharge rate and rate of force development in humans.

Maximal rate of force development in adult humans is determined by the maximal motor unit discharge rate, however, the origin of the underlying synaptic inputs remains unclear. Here, we tested a hypothesis that the maximal motor unit discharge rate will increase in response to a startling cue, a stimulus that purportedly activates the pontomedullary reticular formation neurons that make mono- and disynaptic connections to motoneurons via fast-conducting axons. Twenty-two men were required to produce isometric knee extensor forces "as fast and as hard" as possible from rest to 75% of maximal voluntary force, in response to visual (VC), visual-auditory (VAC; 80 dB), or visual-startling cue (VSC; 110 dB). Motoneuron activity was estimated via decomposition of high-density surface electromyogram recordings over the vastus lateralis and medialis muscles. Reaction time was significantly shorter in response to VSC compared with VAC and VC. The VSC further elicited faster neuromechanical responses including a greater number of discharges per motor unit per second and greater maximal rate of force development, with no differences between VAC and VC. We provide evidence, for the first time, that the synaptic input to motoneurons increases in response to a startling cue, suggesting a contribution of subcortical pathways to maximal motoneuron output in humans.NEW & NOTEWORTHY Motor unit discharge characteristics are a key determinant of rate of force development in humans, but the neural substrate(s) underpinning such output remains unknown. Using decomposition of high-density electromyogram, we show greater number of discharges per motor unit per second and greater rate of force development after a startling auditory stimulus. These observations suggest a possible subcortical contribution to maximal in vivo motor unit discharge rate in adult humans.

The role of the neural stimulus in regulating skeletal muscle hypertrophy.

Resistance training is frequently performed with the goal of stimulating muscle hypertrophy. Due to the key roles motor unit recruitment and mechanical tension play to induce muscle growth, when programming, the manipulation of the training variables is oriented to provoke the correct stimulus. Although it is known that the nervous system is responsible for the control of motor units and active muscle force, muscle hypertrophy researchers and trainers tend to only focus on the adaptations of the musculotendinous unit and not in the nervous system behaviour. To better guide resistance exercise prescription for muscle hypertrophy and aiming to delve into the mechanisms that maximize this goal, this review provides evidence-based considerations for possible effects of neural behaviour on muscle growth when programming resistance training, and future neurophysiological measurement that should be tested when training to increase muscle mass. Combined information from the neural and muscular structures will allow to understand the exact adaptations of the muscle in response to a given input (neural drive to the muscle). Changes at different levels of the nervous system will affect the control of motor units and mechanical forces during resistance training, thus impacting the potential hypertrophic adaptations. Additionally, this article addresses how neural adaptations and fatigue accumulation that occur when resistance training may influence the hypertrophic response and propose neurophysiological assessments that may improve our understanding of resistance training variables that impact on muscular adaptations.

Deficit in knee extension strength following anterior cruciate ligament reconstruction is explained by a reduced neural drive to the vasti muscles.

The persistence of quadriceps weakness represents a major concern following anterior cruciate ligament reconstruction (ACLR). The underlying adaptations occurring in the activity of spinal motoneurons are still unexplored. This study examined the discharge patterns of large populations of motor units (MUs) in the vastus lateralis (VL) and vastus medialis muscles following ACLR. Nine ACLR individuals and 10 controls performed unilateral trapezoidal contractions of the knee extensor muscles at 35%, 50% and 70% of the maximal voluntary isometric force (MVIF). High-density surface electromyography (HDsEMG) was used to record the myoelectrical activity of the vasti muscles in both limbs. HDsEMG signals were decomposed with a convolutive blind source separation method and MU properties were extracted and compared between sides and groups. The ACLR group showed a lower MVIF on the reconstructed side compared to the contralateral side (28.1%; P < 0.001). This force deficit was accompanied by reduced MU discharge rates (∼21%; P < 0.05), lower absolute MU recruitment and derecruitment thresholds (∼22% and ∼22.5%, respectively; P < 0.05) and lower input-output gain of motoneurons (27.3%; P = 0.009). Deficits in MU discharge rates of the VL and in absolute recruitment and derecruitment thresholds of both vasti MUs were associated with deficits in MVIF (P < 0.05). A strong between-side correlation was found for MU discharge rates of the VL of ACLR individuals (P < 0.01). There were no significant between-group differences (P > 0.05). These results indicate that mid- to long-term strength deficits following ACLR may be attributable to a reduced neural drive to vasti muscles, with potential changes in excitatory and inhibitory synaptic inputs. KEY POINTS: Impaired expression and control of knee extension forces is common after anterior cruciate ligament reconstruction and is related to high risk of a second injury. To provide novel insights into the neural basis of this impairment, the discharge patterns of motor units in the vastus lateralis and vastus medialis were investigated during voluntary force contractions. There was lower knee extensor strength on the reconstructed side with respect to the contralateral side, which was explained by deficits in motor unit discharge rate and an altered motoneuronal input-output gain. Insufficient excitatory inputs to motoneurons and increased inhibitory afferent signals potentially contributed to these alterations. These results further our understanding of the neural underpinnings of quadriceps weakness following anterior cruciate ligament reconstruction and can help to develop effective rehabilitation protocols to regain muscle strength and reduce the risk of a second injury.

Sensing and decoding the neural drive to paralyzed muscles during attempted movements of a person with tetraplegia using a sleeve array.

Motor neurons convey information about motor intent that can be extracted and interpreted to control assistive devices. However, most methods for measuring the firing activity of single neurons rely on implanted microelectrodes. Although intracortical brain-computer interfaces (BCIs) have been shown to be safe and effective, the requirement for surgery poses a barrier to widespread use that can be mitigated by instead using noninvasive interfaces. The objective of this study was to evaluate the feasibility of deriving motor control signals from a wearable sensor that can detect residual motor unit activity in paralyzed muscles after chronic cervical spinal cord injury (SCI). Despite generating no observable hand movement, volitional recruitment of motor units below the level of injury was observed across attempted movements of individual fingers and overt wrist and elbow movements. Subgroups of motor units were coactive during flexion or extension phases of the task. Single digit movement intentions were classified offline from the electromyogram (EMG) power [root-mean-square (RMS)] or motor unit firing rates with median classification accuracies >75% in both cases. Simulated online control of a virtual hand was performed with a binary classifier to test feasibility of real-time extraction and decoding of motor units. The online decomposition algorithm extracted motor units in 1.2 ms, and the firing rates predicted the correct digit motion 88 ± 24% of the time. This study provides the first demonstration of a wearable interface for recording and decoding firing rates of motor units below the level of injury in a person with motor complete SCI.NEW & NOTEWORTHY A wearable electrode array and machine learning methods were used to record and decode myoelectric signals and motor unit firing in paralyzed muscles of a person with motor complete tetraplegia. The myoelectric activity and motor unit firing rates were task specific, even in the absence of visible motion, enabling accurate classification of attempted single-digit movements. This wearable system has the potential to enable people with tetraplegia to control assistive devices through movement intent.

The knowns and unknowns of neural adaptations to resistance training.

The initial increases in force production with resistance training are thought to be primarily underpinned by neural adaptations. This notion is firmly supported by evidence displaying motor unit adaptations following resistance training; however, the precise locus of neural adaptation remains elusive. The purpose of this review is to clarify and critically discuss the literature concerning the site(s) of putative neural adaptations to short-term resistance training. The proliferation of studies employing non-invasive stimulation techniques to investigate evoked responses have yielded variable results, but generally support the notion that resistance training alters intracortical inhibition. Nevertheless, methodological inconsistencies and the limitations of techniques, e.g. limited relation to behavioural outcomes and the inability to measure volitional muscle activity, preclude firm conclusions. Much of the literature has focused on the corticospinal tract; however, preliminary research in non-human primates suggests reticulospinal tract is a potential substrate for neural adaptations to resistance training, though human data is lacking due to methodological constraints. Recent advances in technology have provided substantial evidence of adaptations within a large motor unit population following resistance training. However, their activity represents the transformation of afferent and efferent inputs, making it challenging to establish the source of adaptation. Whilst much has been learned about the nature of neural adaptations to resistance training, the puzzle remains to be solved. Additional analyses of motoneuron firing during different training regimes or coupling with other methodologies (e.g., electroencephalography) may facilitate the estimation of the site(s) of neural adaptations to resistance training in the future.

Neural and muscular determinants of maximal rate of force development.

The ability to produce rapid forces requires quick motor unit recruitment, high motor unit discharge rates, and fast motor unit force twitches. The relative importance of these parameters for maximum rate of force development (RFD), however, is poorly understood. In this study, we systematically investigated these relationships using a computational model of motor unit pool activity and force. Across simulations, neural and muscular properties were systematically varied in experimentally observed ranges. Motor units were recruited over an interval starting from contraction onset (range: 22-233 ms). Upon recruitment, discharge rates declined from an initial rate (range: 89-212 pulses per second), with varying likelihood of doublet (interspike interval of 3 ms; range: 0-50%). Finally, muscular adaptations were modeled by changing average twitch contraction time (range: 42-78 ms). Spectral analysis showed that the effective neural drive to the simulated muscle had smaller bandwidths than the average motor unit twitch, indicating that the bandwidth of the motor output, and thus the capacity for explosive force, was limited mainly by neural properties. The simulated RFD increased by 1,050 ± 281% maximal voluntary contraction force per second from the longest to the shortest recruitment interval. This effect was more than fourfold higher than the effect of increasing the initial discharge rate, more than fivefold higher than the effect of increasing the chance of doublets, and more than sixfold higher than the effect of decreasing twitch contraction times. The simulated results suggest that the physiological variation of the rate by which motor units are recruited during ballistic contractions is the main determinant for the variability in RFD across individuals.NEW & NOTEWORTHY An important limitation of human performance is the ability to generate explosive movements by means of rapid development of muscle force. The physiological determinants of this ability, however, are poorly understood. In this study, we show using extensive simulations that the rate by which motor units are recruited is the main limiting factor for maximum rate of force development.