Acute Effects of Strength and Skill Training on the Cortical and Spinal Circuits of Contralateral Limb.

Unilateral strength and skill training increase strength and performance in the contralateral untrained limb, a phenomenon known as cross-education. Recent evidence suggests that similar neural mechanisms might be responsible for the increase in strength and skill observed in the untrained hand after unimanual training. The aims of this study were to: investigate whether a single session of unimanual strength and skill (force-tracking) training increased strength and skill in the opposite hand; measure ipsilateral (untrained) brain (via transcranial magnetic stimulation, TMS) and spinal (via the monosynaptic reflex) changes in excitability occurring after training; measure ipsilateral (untrained) pathway-specific changes in neural excitability (via TMS-conditioning of the monosynaptic reflex) occurring after training. Participants (N = 13) completed a session of unimanual strength (ballistic isometric wrist flexions) and skill (force-tracking wrist flexions) training on two separate days. Strength increased after training in the untrained hand (p = 0.025) but not in the trained hand (p = 0.611). Force-tracking performance increased in both the trained (p = 0.007) and untrained (p = 0.010) hand. Corticospinal excitability increased after force-tracking and strength training (p = 0.027), while spinal excitability was not affected (p = 0.214). TMS-conditioned monosynaptic reflex increased after force-tracking (p = 0.001) but not strength training (p = 0.689), suggesting a possible role of polysynaptic pathways in the increase of cortical excitability observed after training. The results suggest that cross-education of strength and skill at the acute stage is supported by increased excitability of the untrained motor cortex.New & Noteworthy: A single session of isometric wrist flexion strength and skill straining increased strength and skill in the untrained limb. The excitability of the untrained motor cortex increased after strength and skill training. TMS-conditioned H-reflexes increased after skill but not strength training in the untrained hand, indicating that polysynaptic pathways in the increase of cortical excitability observed after skill training.

Dynamic electrical stimulation enhances the recruitment of spinal interneurons by corticospinal input.

Highly varying patterns of electrostimulation (Dynamic Stimulation, DS) delivered to the dorsal cord through an epidural array with 18 independent electrodes transiently facilitate corticospinal motor responses, even after spinal injury. To partly unravel how corticospinal input are affected by DS, we introduced a corticospinal platform that allows selective cortical stimulation during the multisite acquisition of cord dorsum potentials (CDPs) and the simultaneous supply of DS. Firstly, the epidural interface was validated by the acquisition of the classical multisite distribution of CDPs and their input-output profile elicited by pulses delivered to peripheral nerves. Apart from increased EMGs, DS selectively increased excitability of the spinal interneurons that first process corticospinal input, without changing the magnitude of commands descending from the motor cortex, suggesting a novel correlation between muscle recruitment and components of cortically-evoked CDPs. Finally, DS increases excitability of post-synaptic spinal interneurons at the stimulation site and their responsiveness to any residual supraspinal control, thus supporting the use of electrical neuromodulation whenever the motor output is jeopardized by a weak volitional input, due to a partial disconnection from supraspinal structures and/or neuronal brain dysfunctions.

Stretchable surface electromyography electrode array patch for tendon location and muscle injury prevention.

Surface electromyography (sEMG) can provide multiplexed information about muscle performance. If current sEMG electrodes are stretchable, arrayed, and able to be used multiple times, they would offer adequate high-quality data for continuous monitoring. The lack of these properties delays the widespread use of sEMG in clinics and in everyday life. Here, we address these constraints by design of an adhesive dry electrode using tannic acid, polyvinyl alcohol, and PEDOT:PSS (TPP). The TPP electrode offers superior stretchability (~200%) and adhesiveness (0.58 N/cm) compared to current electrodes, ensuring stable and long-term contact with the skin for recording (>20 dB; >5 days). In addition, we developed a metal-polymer electrode array patch (MEAP) comprising liquid metal (LM) circuits and TPP electrodes. The MEAP demonstrated better conformability than commercial arrays, resulting in higher signal-to-noise ratio and more stable recordings during muscle movements. Manufactured using scalable screen-printing, these MEAPs feature a completely stretchable material and array architecture, enabling real-time monitoring of muscle stress, fatigue, and tendon displacement. Their potential to reduce muscle and tendon injuries and enhance performance in daily exercise and professional sports holds great promise.

Spinal facilitation of descending motor input.

Highly varying patterns of electrostimulation (Dynamic Stimulation, DS) delivered to the dorsal cord through an epidural array with 18 independent electrodes transiently facilitate corticospinal motor responses, even after spinal injury. To partly unravel how corticospinal input are affected by DS, we introduced a corticospinal platform that allows selective cortical stimulation during the multisite acquisition of cord dorsum potentials (CDPs) and the simultaneous supply of DS. Firstly, the epidural interface was validated by the acquisition of the classical multisite distribution of CDPs on the dorsal cord and their input-output profile elicited by pulses delivered to peripheral nerves. Apart from increased EMGs, DS selectively increased excitability of the spinal interneurons that first process corticospinal input, without changing the magnitude of commands descending from the motor cortex, suggesting a novel correlation between muscle recruitment and components of cortically-evoked CDPs. Finally, DS increases excitability of post-synaptic spinal interneurons at the stimulation site and their responsiveness to any residual supraspinal control, thus supporting the use of electrical neuromodulation whenever the motor output is jeopardized by a weak volitional input, due to a partial disconnection from supraspinal structures and/or neuronal brain dysfunctions.

Simplified Markerless Stride Detection Pipeline (sMaSDP) for Surface EMG Segmentation.

To diagnose mobility impairments and select appropriate physiotherapy, gait assessment studies are often recommended. These studies are usually conducted in confined clinical settings, which may feel foreign to a subject and affect their motivation, coordination, and overall mobility. Conducting gait studies in unconstrained natural settings instead, such as the subject's Activities of Daily Life (ADL), could provide a more accurate assessment. To appropriately diagnose gait deficiencies, muscle activity should be recorded in parallel with typical kinematic studies. To achieve this, Electromyography (EMG) and kinematic are collected synchronously. Our protocol sMaSDP introduces a simplified markerless gait event detection pipeline for the segmentation of EMG signals via Inertial Measurement Unit (IMU) data, based on a publicly available dataset. This methodology intends to provide a simple, detailed sequence of processing steps for gait event detection via IMU and EMG, and serves as tutorial for beginners in unconstrained gait assessment studies. In an unconstrained gait experiment, 10 healthy subjects walk through a course designed to mimic everyday walking, with their kinematic and EMG data recorded, for a total of 20 trials. Five different walking modalities, such as level walking, ramp up/down, and staircase up/down are included. By segmenting and filtering the data, we generate an algorithm that detects heel-strike events, using a single IMU, and isolates EMG activity of gait cycles. Applicable to different datasets, sMaSDP was tested in healthy gait and gait data of Parkinson's Disease (PD) patients. Using sMaSDP, we extracted muscle activity in healthy walking and identified heel-strike events in PD patient data. The algorithm parameters, such as expected velocity and cadence, are adjustable and can further improve the detection accuracy, and our emphasis on the wearable technologies makes this solution ideal for ADL gait studies.

Evaluating Muscle Synergies With EMG Data and Physics Simulation in the Neurorobotics Platform.

Although we can measure muscle activity and analyze their activation patterns, we understand little about how individual muscles affect the joint torque generated. It is known that they are controlled by circuits in the spinal cord, a system much less well-understood than the cortex. Knowing the contribution of the muscles toward a joint torque would improve our understanding of human limb control. We present a novel framework to examine the control of biomechanics using physics simulations informed by electromyography (EMG) data. These signals drive a virtual musculoskeletal model in the Neurorobotics Platform (NRP), which we then use to evaluate resulting joint torques. We use our framework to analyze raw EMG data collected during an isometric knee extension study to identify synergies that drive a musculoskeletal lower limb model. The resulting knee torques are used as a reference for genetic algorithms (GA) to generate new simulated activation patterns. On the platform the GA finds solutions that generate torques matching those observed. Possible solutions include synergies that are similar to those extracted from the human study. In addition, the GA finds activation patterns that are different from the biological ones while still producing the same knee torque. The NRP forms a highly modular integrated simulation platform allowing these in silico experiments. We argue that our framework allows for research of the neurobiomechanical control of muscles during tasks, which would otherwise not be possible.

Caudal-Rostral Progression of Alpha Motoneuron Degeneration in the SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis.

Mice with transgenic expression of human SOD1G93A are a widely used model of ALS, with a caudal-rostral progression of motor impairment. Previous studies have quantified the progression of motoneuron (MN) degeneration based on size, even though alpha (α-) and gamma (γ-) MNs overlap in size. Therefore, using molecular markers and synaptic inputs, we quantified the survival of α-MNs and γ-MNs at the lumbar and cervical spinal segments of 3- and 4-month SOD1G93A mice, to investigate whether there is a caudal-rostral progression of MN death. By 3 months, in the cervical and lumbar spinal cord, there was α-MN degeneration with complete γ-MN sparing. At 3 months, the cervical spinal cord had more α-MNs per ventral horn than the lumbar spinal cord in SOD1G93A mice. A similar spatial trend of degeneration was observed in the corticospinal tract, which remained intact in the cervical spinal cord at 3- and 4- months of age. These findings agree with the corticofugal synaptopathy model that α-MNs and CST of the lumbar spinal cord are more susceptible to degeneration in SOD1G93A mice. Hence, there is a spatial and temporal caudal-rostral progression of α-MN and CST degeneration in SOD1G93A mice.

The effect of limb position on a static knee extension task can be explained with a simple spinal cord circuit model.

The influence of proprioceptive feedback on muscle activity during isometric tasks is the subject of conflicting studies. We performed an isometric knee extension task experiment based on two common clinical tests for mobility and flexibility. The task was carried out at four preset angles of the knee, and we recorded from five muscles for two different hip positions. We applied muscle synergy analysis using nonnegative matrix factorization on surface electromyograph recordings to identify patterns in the data that changed with internal knee angle, suggesting a link between proprioception and muscle activity. We hypothesized that such patterns arise from the way proprioceptive and cortical signals are integrated in neural circuits of the spinal cord. Using the MIIND neural simulation platform, we developed a computational model based on current understanding of spinal circuits with an adjustable afferent input. The model produces the same synergy trends as observed in the data, driven by changes in the afferent input. To match the activation patterns from each knee angle and position of the experiment, the model predicts the need for three distinct inputs: two to control a nonlinear bias toward the extensors and against the flexors, and a further input to control additional inhibition of rectus femoris. The results show that proprioception may be involved in modulating muscle synergies encoded in cortical or spinal neural circuits.NEW & NOTEWORTHY The role of sensory feedback in motor control when limbs are held in a fixed position is disputed. We performed a novel experiment involving fixed position tasks based on two common clinical tests. We identified patterns of muscle activity during the tasks that changed with different leg positions and then inferred how sensory feedback might influence the observations. We developed a computational model that required three distinct inputs to reproduce the activity patterns observed experimentally. The model provides a neural explanation for how the activity patterns can be changed by sensory feedback.

Heterogeneity in form and function of the rat extensor digitorum longus motor unit.

The motor unit comprises a variable number of muscle fibres that connect through myelinated nerve fibres to a motoneuron (MN), the central drivers of activity. At the simplest level of organisation there exist phenotypically distinct MNs that activate corresponding muscle fibre types, but within an individual motor pool there typically exists a mixed population of fast and slow firing MNs, innervating groups of Type II and Type I fibres, respectively. Characterising the heterogeneity across multiple levels of motor unit organisation is critical to understanding changes that occur in response to physiological and pathological perturbations. Through a comprehensive assessment of muscle histology and ex vivo function, mathematical modelling and neuronal tracing, we demonstrate regional heterogeneities at the level of the MN, muscle fibre type composition and oxygen delivery kinetics of the rat extensor digitorum longus (EDL) muscle. Specifically, the EDL contains two phenotypically distinct regions: a relatively oxidative medial and a more glycolytic lateral compartment. Smaller muscle fibres in the medial compartment, in combination with a greater local capillary density, preserve tissue O2 partial pressure (PO2 ) during modelled activity. Conversely, capillary supply to the lateral compartment is calculated to be insufficient to defend active muscle PO2 but is likely optimised to facilitate metabolite removal. Simulation of in vivo muscle length change and phasic activation suggest that both compartments are able to generate similar net power. However, retrograde tracing demonstrates (counter to previous observations) that a negative relationship between soma size and C-bouton density exists. Finally, we confirm a lack of specificity of SK3 expression to slow MNs. Together, these data provide a reference for heterogeneities across the rat EDL motor unit and re-emphasise the importance of sampling technique.

C-bouton components on rat extensor digitorum longus motoneurons are resistant to chronic functional overload.

Mammalian motor systems adapt to the demands of their environment. For example, muscle fibre types change in response to increased load or endurance demands. However, for adaptations to be effective, motoneurons must adapt such that their properties match those of the innervated muscle fibres. We used a rat model of chronic functional overload to assess adaptations to both motoneuron size and a key modulatory synapse responsible for amplification of motor output, C-boutons. Overload of extensor digitorum longus (EDL) muscles was induced by removal of their synergists, tibialis anterior muscles. Following 21 days survival, EDL muscles showed an increase in fatigue resistance and a decrease in force output, indicating a shift to a slower phenotype. These changes were reflected by a decrease in motoneuron size. However, C-bouton complexes remained largely unaffected by overload. The C-boutons themselves, quantified by expression of vesicular acetylcholine transporter, were similar in size and density in the control and overload conditions. Expression of the post-synaptic voltage-gated potassium channel (KV 2.1) was also unchanged. Small conductance calcium-activated potassium channels (SK3) were expressed in most EDL motoneurons, despite this being an almost exclusively fast motor pool. Overload induced a decrease in the proportion of SK3+ cells, however, there was no change in density or size of clusters. We propose that reductions in motoneuron size may promote early recruitment of EDL motoneurons, but that C-bouton plasticity is not necessary to increase the force output required in response to muscle overload.

The Effect of Sound and Stimulus Expectation on Transcranial Magnetic Stimulation-Elicited Motor Evoked Potentials.

The amplitude of motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) over the motor cortex is influenced by multiple factors. TMS delivery is accompanied by an abrupt clicking noise which can induce a startle response. This study investigated how masking/attenuating the sound produced by the TMS system discharging influences MEP amplitudes. In addition, the effects of increasing the time between consecutive stimuli and of making participants aware of the time at which they would be stimulated were studied. MEPs were recorded from the Flexor Carpi Radialis (FCR) muscle at rest by stimulation at motor threshold (MT), 120% MT and 140% MT intensity. Participants (N = 23) received stimulation under normal (NORMAL) conditions and while: wearing sound-attenuating earmuffs (EAR); listening to white noise (NOISE); the interval between stimuli were prolonged (LONG); stimulation timing was presented on a screen (READY). The results showed that masking (p = 0.020) and attenuating (p = 0.004) the incoming sound significantly reduced the amplitude of MEPs recorded across the intensities of stimulation. Increasing the interval between pulses had no effect on the recorded traces if a jitter was introduced (p = 1), but making participants aware of stimulation timing decreased MEP amplitudes (p = 0.049). These findings suggest that the sound produced by TMS at discharging increases MEP amplitudes and that MEP amplitudes are influenced by stimulus expectation. These confounding factors need to be considered when using TMS to assess corticospinal excitability.

Reliability of the TMS-conditioned monosynaptic reflex in the flexor carpi radialis muscle.

A subthreshold pulse of transcranial magnetic stimulation (TMS) on the motor cortex can modulate the amplitude of the monosynaptic reflex (H-reflex) elicited in the flexor carpi radialis (FCR) muscle, a method known as TMS-conditioning of the H-reflex. The purpose of this study was to establish the intersession reliability of this method over the course of three sessions. Eleven healthy participants received either peripheral nerve stimulation (PNS), TMS or a combination of the two. The intensity of the PNS stimuli was set to evoke a monosynaptic response (H-reflex) corresponding to 10 % of the maximum motor response (Mmax), HM10 %. The conditioning effect of TMS on the monosynaptic reflex was assessed by delivering subthreshold cortical pulses at different conditioning-test intervals (from -7 ms to 7 ms) from peripheral nerve stimulation. The first interval at which facilitation could be observed was deemed early facilitation (EF). Using intraclass correlation coefficients (ICCs), we found excellent reliability for Mmax amplitudes (ICC = 0.98), HM10 % amplitudes (ICC = 0.85) and TMS-conditioned H-reflexes recorded at the interval following EF (EF + 2 ms) (ICC = 0.87). Good reliability (ICCs ranging from 0.67 to 0.77) was found for the other conditioning-test intervals. We conclude that TMS-conditioned H-reflexes are reliable parameters to assess the excitability of corticospinal circuits.

Toward a Closed Loop, Integrated Biocompatible Biopolymer Wound Dressing Patch for Detection and Prevention of Chronic Wound Infections.

Chronic wound infections represent a significant burden to healthcare providers globally. Often, chronic wound healing is impeded by the presence of infection within the wound or wound bed. This can result in an increased healing time, healthcare cost and poor patient outcomes. Thus, there is a need for dressings that help the wound heal, in combination with early detection of wound infections to support prompt treatment. In this study, we demonstrate a novel, biocompatible wound dressing material, based on Polyhydroxyalkanoates, doped with graphene platelets, which can be used as an electrochemical sensing substrate for the detection of a common wound pathogen, Pseudomonas aeruginosa. Through the detection of the redox active secondary metabolite, pyocyanin, we demonstrate that a dressing can be produced that will detect the presence of pyocyanin across clinically relevant concentrations. Furthermore, we show that this sensor can be used to identify the presence of pyocyanin in a culture of P. aeruginosa. Overall, the sensor substrate presented in this paper represents the first step toward a new dressing with the capacity to promote wound healing, detect the presence of infection and release antimicrobial drugs, on demand, to optimized healing.

Simultaneous Assessment of Homonymous and Heteronymous Monosynaptic Reflex Excitability in the Adult Rat.

In order to successfully perform motor tasks such as locomotion, the central nervous system must coordinate contractions of antagonistic and synergistic muscles across multiple joints. This coordination is largely dependent upon the function of proprioceptive afferents (PAs), which make monosynaptic connections with homonymous motoneurons. Homonymous pathways have been well studied in both health and disease but their collateral fibers projecting to heteronymous, synergistic muscles receive relatively less attention. This is surprising given that PA collaterals have significant effects on the excitability of heteronymous motoneurons, and that their synaptic terminal density is activity dependent. It is likely that the relative lack of literature is due to the lack of a preparation which allows synergistic heteronymous pathways to be assessed in vivo. Here, we describe a method to simultaneously evoke homonymous and heteronymous (synergistic) monosynaptic reflexes (MSRs) and study their modulation by descending pathways in adult rats. Through stimulation of the medial plantar nerve, we were able to produce an H reflex in the intrinsic foot (IF) muscles of the hind paw with a latency of 10.52 ± 3.8 ms. Increasing the stimulus intensity evoked a robust signal with a monosynaptic latency (11.32 ± 0.35 ms), recorded in the ipsilateral gastrocnemius (Gs). Our subsequent analyses suggest that Gs motoneurons were activated via heteronymous afferent collaterals from the medial plantar nerve. These reflexes could be evoked bilaterally and were modulated by conditioning stimuli to the cortex (Cx) and reticular formation. Interestingly, cortical stimulation was equally efficient at modulating both ipsilateral and contralateral reflexes, indicating that cortical modulation of lumbar sensory afferents lacks the laterality demonstrated by studies of cortical muscle activation. This technique represents a novel, relatively simple way to assess heteronymous afferent pathways in normal motor control as well as in models of motor disorders where adaptive and maladaptive plasticity of PAs and descending systems affects functional outcomes.

Descending Systems Direct Development of Key Spinal Motor Circuits.

The formation of mature spinal motor circuits is dependent on both activity-dependent and independent mechanisms during postnatal development. During this time, reorganization and refinement of spinal sensorimotor circuits occurs as supraspinal projections are integrated. However, specific features of postnatal spinal circuit development remain poorly understood. This study provides the first detailed characterization of rat spinal sensorimotor circuit development in the presence and absence of descending systems. We show that the development of proprioceptive afferent input to motoneurons (MNs) and Renshaw cells (RCs) is disrupted by thoracic spinal cord transection at postnatal day 5 (P5TX). P5TX also led to malformation of GABApre neuron axo-axonic contacts on Ia afferents and of the recurrent inhibitory circuit between MNs and RCs. Using a novel in situ perfused preparation for studying motor control, we show that malformation of these spinal circuits leads to hyperexcitability of the monosynaptic reflex. Our results demonstrate that removing descending input severely disrupts the development of spinal circuits and identifies key mechanisms contributing to motor dysfunction in conditions such as cerebral palsy and spinal cord injury.SIGNIFICANCE STATEMENT Acquisition of mature behavior during postnatal development correlates with the arrival and maturation of supraspinal projections to the spinal cord. However, we know little about the role that descending systems play in the maturation of spinal circuits. Here, we characterize postnatal development of key spinal microcircuits in the presence and absence of descending systems. We show that formation of these circuits is abnormal after early (postnatal day 5) removal of descending systems, inducing hyperexcitability of the monosynaptic reflex. The study is a detailed characterization of spinal circuit development elucidating how these mechanisms contribute to motor dysfunction in conditions such as cerebral palsy and spinal cord injury. Understanding these circuits is crucial to developing new therapeutics and improving existing ones in such conditions.

Activity-Based Therapies for Repair of the Corticospinal System Injured during Development.

This review presents the mechanistic underpinnings of corticospinal tract (CST) development, derived from animal models, and applies what has been learned to inform neural activity-based strategies for CST repair. We first discuss that, in normal development, early bilateral CST projections are later refined into a dense crossed CST projection, with maintenance of sparse ipsilateral projections. Using a novel mouse genetic model, we show that promoting the ipsilateral CST projection produces mirror movements, common in hemiplegic cerebral palsy (CP), suggesting that ipsilateral CST projections become maladaptive when they become abnormally dense and strong. We next discuss how animal studies support a developmental "competition rule" whereby more active/used connections are more competitive and overtake less active/used connections. Based on this rule, after unilateral injury the damaged CST is less able to compete for spinal synaptic connections than the uninjured CST. This can lead to a progressive loss of the injured hemisphere's contralateral projection and a reactive gain of the undamaged hemisphere's ipsilateral CST. Knowledge of the pathophysiology of the developing CST after injury informs interventional strategies. In an animal model of hemiplegic CP, promoting injured system activity or decreasing the uninjured system's activity immediately after the period of a developmental injury both increase the synaptic competitiveness of the damaged system, contributing to significant CST repair and motor recovery. However, delayed intervention, despite significant CST repair, fails to restore skilled movements, stressing the need to consider repair strategies for other neural systems, including the rubrospinal and spinal interneuronal systems. Our interventional approaches harness neural activity-dependent processes and are highly effective in restoring function. These approaches are minimally invasive and are poised for translation to the human.

Pathophysiological mechanisms of impaired limb use and repair strategies for motor systems after unilateral injury of the developing brain.

The corticospinal tract (CST) is important for limb control. In humans, it begins developing prenatally but CST connections do not have a mature pattern until about 6 months of age and its capacity to evoke muscle contraction does not mature until mid-adolescence. An initially bilateral projection is subsequently refined, so that most ipsilateral CST connections are eliminated. Unilateral brain damage during refinement leads to bilateral developmental impairments. The damaged side develops sparse and weak contralateral spinal connections and the non-involved hemisphere maintains its ipsilateral projection to develop an aberrant bilateral spinal projection. In a kitten model of unilateral spastic cerebral palsy, we replicate key features of the CST circuit changes: robust bilateral CST projections from the non-involved hemisphere, sparse contralateral connections from the affected hemisphere, and motor impairments. We discuss the role of activity-dependent synaptic competition in development of bilateral CSTs and consider several experimental strategies for restoring a more normal pattern of CST connections from the damaged and non-involved sides. We highlight recent results stressing the importance of combined repair of CST axons, restoration of a more normal motor cortex motor representation, and key involvement of spinal cholinergic interneurons in restoring skilled motor function.

Selective corticospinal tract injury in the rat induces primary afferent fiber sprouting in the spinal cord and hyperreflexia.

The corticospinal tract (CST) has dense contralateral and sparse ipsilateral spinal cord projections that converge with proprioceptive afferents on common spinal targets. Previous studies in adult rats indicate that the loss of dense contralateral spinal CST connections after unilateral pyramidal tract section (PTx), which models CST loss after stroke or spinal cord injury, leads to outgrowth from the spared side into the affected, ipsilateral, spinal cord. The reaction of proprioceptive afferents after this CST injury, however, is not known. Knowledge of proprioceptive afferent responses after loss of the CST could inform mechanisms of maladaptive plasticity in spinal sensorimotor circuits after injury. Here, we hypothesize that the loss of the contralateral CST results in a reactive increase in muscle afferents from the impaired limb and enhancement of their physiological actions within the cervical spinal cord. We found that 10 d after PTx, proprioceptive afferents sprout into cervical gray matter regions denervated by the loss of CST terminations. Furthermore, VGlut1-positive boutons, indicative of group 1A afferent terminals, increased on motoneurons. PTx also produced an increase in microglial density within the gray matter regions where CST terminations were lost. These anatomical changes were paralleled by reduction in frequency-dependent depression of the H-reflex, suggesting hyperreflexia. Our data demonstrate for the first time that selective CST injury induces maladaptive afferent fiber plasticity remote from the lesion. Our findings suggest a novel structural reaction of proprioceptive afferents to the loss of CST terminations and provide insight into mechanisms underlying spasticity.

Using motor behavior during an early critical period to restore skilled limb movement after damage to the corticospinal system during development.

This study investigated the requirements for restoring motor function after corticospinal (CS) system damage during early postnatal development. Activity-dependent competition between the CS tracts (CSTs) of the two hemispheres is imperative for normal development. Blocking primary motor cortex (M1) activity unilaterally during a critical period [postnatal week 5 (PW5) to PW7] produces permanent contralateral motor skill impairments, loss of M1 motor map, aberrant CS terminations, and decreases in CST presynaptic sites and spinal cholinergic interneuron numbers. To repair these motor systems impairments and restore function, we manipulated motor experience in three groups of cats after this CST injury produced by inactivation. One group wore a jacket restraining the limb ipsilateral to inactivation, forcing use of the contralateral, impaired limb, for the month after M1 inactivation (PW8-PW13; "restraint alone"). A second group wore the restraint during PW8-PW13 and was also trained for 1 h/d in a reaching task with the contralateral forelimb ("early training"). To test the efficacy of intervention during adolescence, a third group wore the restraint and received reach training during PW20-PW24 ("delayed training"). Early training restored CST connections and the M1 motor map, increased cholinergic spinal interneurons numbers on the contralateral, relative to ipsilateral, side, and abrogated limb control impairments. Delayed training restored CST connectivity and the M1 motor map but not contralateral spinal cholinergic cell counts or motor performance. Restraint alone only restored CST connectivity. Our findings stress the need to reestablish the integrated functions of the CS system at multiple hierarchical levels in restoring skilled motor function after developmental injury.

Convection enhanced drug delivery of BDNF through a microcannula in a rodent model to strengthen connectivity of a peripheral motor nerve bridge model to bypass spinal cord injury.

Models employing peripheral nerve to bypass spinal cord injury (SCI), although highly promising, may benefit from improved nerve regeneration and motor bridge connectivity. Recent studies have demonstrated that neuronal growth factor-induced enhancement of endogenous neurorestoration may improve neuronal connectivity after severe neurologic injury, particularly if delivered intraparenchymally with zero-order kinetics. We sought to investigate the effect of convection-enhanced delivery of brain-derived neurotrophic factor (BDNF), a neuronal growth factor, on the connectivity of a peripheral motor-nerve bridge in a rodent model using electrophysiology and immunohistochemistry (IHC). Spinal cords of 29 female rats were hemisected at the L1 level. Ipsilateral T13 peripheral nerves were dissected from their muscular targets distally, while maintaining their connections with the spinal cord, and inserted caudal to the injury site to establish the nerve bridge. A microcannula attached to a six-week mini-osmotic pump was used to deliver either BDNF (n=12), saline (n=14), or fluorescein dye (n=3) directly into the spinal cord parenchyma between the site of nerve insertion and hemisection to a depth of 2mm into the area of the lateral motor pool. After four weeks, gastrocnemius muscle activation was assessed electromyographically in five animals from each group. Spinal cords were harvested and analyzed with IHC for cannula-associated injury, and nerve regeneration. Strength of motor bridge connection was illustrated by electrophysiology data. Intraspinal BDNF levels were measured using enzyme-linked immunosorbent assay. IHC revealed increased intraparenchymal BDNF concentration at the nerve bridge insertion site with evidence of minimal trauma from cannulation. BDNF infusion resulted in stronger connections between bridge nerves and spinal motor axons. Bridge nerve electrical stimulation in BDNF-treated rats evoked hind leg electromyogram responses of shorter latency and larger amplitudes than saline-infused controls. Thus, direct convection-assisted delivery provides reliable administration of potent growth factors directly into the spinal cord parenchyma. Delivery of BDNF at the peripheral nerve bridge site results in enhanced connectivity of the peripheral motor bridge in a rodent model of SCI.