A Focal Traumatic Injury to the Neonatal Rodent Spinal Cord Causes an Immediate and Massive Spreading Depolarization Sustained by Chloride Ions, with Transient Network Dysfunction.

In clinics, physical injuries to the spinal cord cause a temporary motor areflexia below lesion, known as spinal shock. This topic is still underexplored due to the lack of preclinical spinal cord injury (SCI) models that do not use anesthesia, which would affect spinal excitability. Our innovative design considered a custom-made micro impactor that provides localized and calibrated strikes to the ventral surface of the thoracic spinal cord of the entire CNS isolated from neonatal rats.

Mapping lumbar efferent and afferent spinal circuitries via paddle array in a porcine model.

Background: Preclinical models are essential for identifying changes occurring after neurologic injury and assessing therapeutic interventions. Yucatan miniature pigs (minipigs) have brain and spinal cord dimensions like humans and are useful for laboratory-to-clinic studies. Yet, little work has been done to map spinal sensorimotor distributions and identify similarities and differences between the porcine and human spinal cords.

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.

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.

Passive limb training modulates respiratory rhythmic bursts.

Exercise modifies respiratory functions mainly through the afferent feedback provided by exercising limbs and the descending input from suprapontine areas, two contributions that are still underestimated in vitro. To better characterize the role of limb afferents in modulating respiration during physical activity, we designed a novel experimental in vitro platform. The whole central nervous system was isolated from neonatal rodents and kept with hindlimbs attached to an ad-hoc robot (Bipedal Induced Kinetic Exercise, BIKE) driving passive pedaling at calibrated speeds.

Suprapontine Structures Modulate Brainstem and Spinal Networks.

Several spinal motor output and essential rhythmic behaviors are controlled by supraspinal structures, although their contribution to neuronal networks for respiration and locomotion at birth still requires better characterization. As preparations of isolated brainstem and spinal networks only focus on local circuitry, we introduced the in vitro central nervous system (CNS) from neonatal rodents to simultaneously record a stable respiratory rhythm from both cervical and lumbar ventral roots (VRs).Electrical pulses supplied to multiple sites of brainstem evoked distinct VR responses with staggered onset in the rostro-caudal direction.

Stochastic spinal neuromodulation tunes the intrinsic logic of spinal neural networks.

The present review focuses on the physiological states of spinal networks, which are stochastically modulated by continuously changing ensembles of proprioceptive and supraspinal input resulting in highly redundant neural networks. Spinal epidural interfaces provide a platform for probing spinal network dynamics and connectivity among multiple motor pool-specific spinal networks post-injury under in vivo experimental conditions. Continuous epidural low-frequency pulses at low intensity can evoke motor responses of stochastically changing amplitudes and with an oscillatory pattern of modulation.

An epidural stimulating interface unveils the intrinsic modulation of electrically motor evoked potentials in behaving rats.

In intact and spinal-injured anesthetized animals, stimulation levels that did not induce any visible muscle twitches were used to elicit motor evoked potentials (MEPs) of varying amplitude, reflecting the temporal and amplitude dynamics of the background excitability of spinal networks. To characterize the physiological excitability states of neuronal networks driving movement, we designed five experiments in awake rats chronically implanted with an epidural stimulating interface, with and without a spinal cord injury (SCI). First, an uninjured rat at rest underwent a series of single electrical pulses at sub-motor threshold intensity, which generated responses that were continuously recorded from flexor and extensor hindlimb muscles, showing an intrinsic patterned modulation of MEPs.

A Biomimetic, SoC-Based Neural Stimulator for Novel Arbitrary-Waveform Stimulation Protocols.

Novel neural stimulation protocols mimicking biological signals and patterns have demonstrated significant advantages as compared to traditional protocols based on uniform periodic square pulses. At the same time, the treatments for neural disorders which employ such protocols require the stimulator to be integrated into miniaturized wearable devices or implantable neural prostheses. Unfortunately, most miniaturized stimulator designs show none or very limited ability to deliver biomimetic protocols due to the architecture of their control logic, which generates the waveform.

GABAergic Mechanisms Can Redress the Tilted Balance between Excitation and Inhibition in Damaged Spinal Networks.

Correct operation of neuronal networks depends on the interplay between synaptic excitation and inhibition processes leading to a dynamic state termed balanced network. In the spinal cord, balanced network activity is fundamental for the expression of locomotor patterns necessary for rhythmic activation of limb extensor and flexor muscles. After spinal cord lesion, paralysis ensues often followed by spasticity.

Selective Antagonism of A1 Adenosinergic Receptors Strengthens the Neuromodulation of the Sensorimotor Network During Epidural Spinal Stimulation.

Although epidural spinal stimulation (ESS) results in promising therapeutic effects in individuals with spinal cord injury (SCI), its potential to generate functional motor recovery varies between individuals and remains largely unclear. However, both preclinical and clinical studies indicate the capacity of electrical and pharmacological interventions to synergistically increase the engagement of spinal sensorimotor networks and regain motor function after SCI. This study explored whether selective pharmacological antagonism of the adenosine A1 receptor subtype synergizes with ESS, thereby increasing motor response.

Complications of epidural spinal stimulation: lessons from the past and alternatives for the future.

Study Design: Systematic review.

Objectives: Over the past decade, an increasing number of studies have demonstrated that epidural spinal cord stimulation (SCS) can successfully assist with neurorehabilitation following spinal cord injury (SCI). This approach is quickly garnering the attention of clinicians.

Histamine H Receptors Expressed in Ventral Horns Modulate Spinal Motor Output.

Motoneuron activity is modulated by histamine receptors. While H and H receptors have been widely explored, H histamine receptors (HRs) have not been sufficiently characterized. This paper targets the effects of the selective activation of HRs and their expression on the membranes of large ventral horn cells.

Acute neuromodulation restores spinally-induced motor responses after severe spinal cord injury.

Epidural electrical spinal stimulation can facilitate recovery of volitional motor control in individuals that have been completely paralyzed for more than a year. We recently reported a novel neuromodulation method named Dynamic Stimulation (DS), which short-lastingly increased spinal excitability and generated a robust modulation of locomotor networks in fully-anesthetized intact adult rats. In the present study, we applied repetitive DS patterns to four lumbosacral segments acutely after a contusive injury at lumbar level.

Using EMG to deliver lumbar dynamic electrical stimulation to facilitate cortico-spinal excitability.

Background: Potentiation of synaptic activity in spinal networks is reflected in the magnitude of modulation of motor responses evoked by spinal and cortical input. After spinal cord injury, motor evoked responses can be facilitated by pairing cortical and peripheral nerve stimuli.

Objective: To facilitate synaptic potentiation of cortico-spinal input with epidural electrical stimulation, we designed a novel neuromodulation method called dynamic stimulation (DS), using patterns derived from hind limb EMG signal during stepping.

A "noisy" electrical stimulation protocol favors muscle regeneration in vitro through release of endogenous ATP.

An in vitro system of electrical stimulation was used to explore whether an innovative "noisy" stimulation protocol derived from human electromyographic recordings (EMGstim) could promote muscle regeneration. EMGstim was delivered to cultured mouse myofibers isolated from Flexor Digitorum Brevis, preserving their satellite cells. In response to EMGstim, immunostaining for the myogenic regulatory factor myogenin, revealed an increased percentage of elongated myogenin-positive cells surrounding the myofibers.

Afferent Input Induced by Rhythmic Limb Movement Modulates Spinal Neuronal Circuits in an Innovative Robotic In Vitro Preparation.

Locomotor patterns are mainly modulated by afferent feedback, but its actual contribution to spinal network activity during continuous passive limb training is still unexplored. To unveil this issue, we devised a robotic in vitro setup (Bipedal Induced Kinetic Exercise, BIKE) to induce passive pedaling, while simultaneously recording low-noise ventral and dorsal root (VR and DR) potentials in isolated neonatal rat spinal cords with hindlimbs attached. As a result, BIKE evoked rhythmic afferent volleys from DRs, reminiscent of pedaling speed.

Histamine modulates spinal motoneurons and locomotor circuits.

Spinal motoneurons and locomotor networks are regulated by monoamines, among which, the contribution of histamine has yet to be fully addressed. The present study investigates histaminergic regulation of spinal activity, combining intra- and extracellular electrophysiological recordings from neonatal rat spinal cord in vitro preparations. Histamine dose-dependently and reversibly generated motoneuron depolarization and action potential firing.

And yet it moves: Recovery of volitional control after spinal cord injury.

Preclinical and clinical neurophysiological and neurorehabilitation research has generated rather surprising levels of recovery of volitional sensory-motor function in persons with chronic motor paralysis following a spinal cord injury. The key factor in this recovery is largely activity-dependent plasticity of spinal and supraspinal networks. This key factor can be triggered by neuromodulation of these networks with electrical and pharmacological interventions.

Multilevel Analysis of Locomotion in Immature Preparations Suggests Innovative Strategies to Reactivate Stepping after Spinal Cord Injury.

Locomotion is one of the most complex motor behaviors. Locomotor patterns change during early life, reflecting development of numerous peripheral and hierarchically organized central structures. Among them, the spinal cord is of particular interest since it houses the central pattern generator (CPG) for locomotion.

Neuromodulation of the neural circuits controlling the lower urinary tract.

The inability to control timely bladder emptying is one of the most serious challenges among the many functional deficits that occur after a spinal cord injury. We previously demonstrated that electrodes placed epidurally on the dorsum of the spinal cord can be used in animals and humans to recover postural and locomotor function after complete paralysis and can be used to enable voiding in spinal rats. In the present study, we examined the neuromodulation of lower urinary tract function associated with acute epidural spinal cord stimulation, locomotion, and peripheral nerve stimulation in adult rats.

A new model of nerve injury in the rat reveals a role of Regulator of G protein Signaling 4 in tactile hypersensitivity.

Tactile hypersensitivity is one of the most debilitating symptoms of neuropathic pain syndromes. Clinical studies have suggested that its presence at early postoperative stages may predict chronic (neuropathic) pain after surgery. Currently available animal models are typically associated with consistent tactile hypersensitivity and are therefore limited to distinguish between mechanisms that underlie tactile hypersensitivity as opposed to mechanisms that protect against it.

Two Distinct Stimulus Frequencies Delivered Simultaneously at Low Intensity Generate Robust Locomotor Patterns.

Objectives: Explore the primary characteristics of afferent noisy stimuli, which optimally activate locomotor patterns at low intensity.

Materials And Methods: Intracellular and extracellular electrophysiological traces were derived from single motoneurons and from ventral roots, respectively. From these recordings, we obtained noisy stimulating protocols, delivered to a dorsal root (DR) of an isolated neonatal rat spinal cord, while recording fictive locomotion (FL) from ventral roots.

Electrical Stimulation Able to Trigger Locomotor Spinal Circuits Also Induces Dorsal Horn Activity.

Objectives: Investigate whether electrical stimulation of the spinal cord adapted to trigger locomotor patterns additionally influences dorsal horn networks.

Materials And Methods: An in vitro model of isolated neonatal rat spinal cord was used to repetitively deliver electrical stimuli to lumbar dorsal roots and record from homolateral lumbar dorsal roots and ventral roots.

Results: Repetitive electrical lumbar dorsal root stimulation can affect both locomotor rhythms derived from ventral neuronal circuits and activity from dorsal neuronal circuits.

Extracellular stimulation with human "noisy" electromyographic patterns facilitates myotube activity.

Electrical stimulation (ES) of skeletal muscle partially mimics the benefits of physical activity. However, the stimulation protocols applied clinically to date, often cause unpleasant symptoms and muscle fatigue. Here, we compared the efficiency of a "noisy" stimulus waveform derived from human electromyographic (EMG) muscle patterns, with stereotyped 45 and 1 Hz electrical stimulations applied to mouse myotubes in vitro.