Recruitment order of motor neurons promoted by epidural stimulation in individuals with spinal cord injury.

Spinal cord epidural stimulation (scES) combined with activity-based training can promote motor function recovery in individuals with motor complete spinal cord injury (SCI). The characteristics of motor neuron recruitment, which influence different aspects of motor control, are still unknown when motor function is promoted by scES. Here, we enrolled five individuals with chronic motor complete SCI implanted with an scES unit to study the recruitment order of motor neurons during standing enabled by scES. We recorded high-density electromyography (HD-EMG) signals on the vastus lateralis muscle and inferred the order of recruitment of motor neurons from the relation between amplitude and conduction velocity of the scES-evoked EMG responses along the muscle fibers. Conduction velocity of scES-evoked responses was modulated over time, whereas stimulation parameters and standing condition remained constant, with average values ranging between 3.0 ± 0.1 and 4.4 ± 0.3 m/s. We found that the human spinal circuitry receiving epidural stimulation can promote both orderly (according to motor neuron size) and inverse trends of motor neuron recruitment, and that the engagement of spinal networks promoting rhythmic activity may favor orderly recruitment trends. Conversely, the different recruitment trends did not appear to be related with time since injury or scES implant, nor to the ability to achieve independent knees extension, nor to the conduction velocity values. The proposed approach can be implemented to investigate the effects of stimulation parameters and training-induced neural plasticity on the characteristics of motor neuron recruitment order, contributing to improve mechanistic understanding and effectiveness of epidural stimulation-promoted motor recovery after SCI.NEW & NOTEWORTHY After motor complete spinal cord injury, the human spinal cord receiving epidural stimulation can promote both orderly and inverse trends of motor neuron recruitment. The engagement of spinal networks involved in the generation of rhythmic activity seems to favor orderly recruitment trends

Spinal cord stimulation in chronic pain: evidence and theory for mechanisms of action.

Well-established in the field of bioelectronic medicine, Spinal Cord Stimulation (SCS) offers an implantable, non-pharmacologic treatment for patients with intractable chronic pain conditions. Chronic pain is a widely heterogenous syndrome with regard to both pathophysiology and the resultant phenotype. Despite advances in our understanding of SCS-mediated antinociception, there still exists limited evidence clarifying the pathways recruited when patterned electric pulses are applied to the epidural space. The rapid clinical implementation of novel SCS methods including burst, high frequency and dorsal root ganglion SCS has provided the clinician with multiple options to treat refractory chronic pain. While compelling evidence for safety and efficacy exists in support of these novel paradigms, our understanding of their mechanisms of action (MOA) dramatically lags behind clinical data. In this review, we reconstruct the available basic science and clinical literature that offers support for mechanisms of both paresthesia spinal cord stimulation (P-SCS) and paresthesia-free spinal cord stimulation (PF-SCS). While P-SCS has been heavily examined since its inception, PF-SCS paradigms have recently been clinically approved with the support of limited preclinical research. Thus, wide knowledge gaps exist between their clinical efficacy and MOA. To close this gap, many rich investigative avenues for both P-SCS and PF-SCS are underway, which will further open the door for paradigm optimization, adjunctive therapies and new indications for SCS. As our understanding of these mechanisms evolves, clinicians will be empowered with the possibility of improving patient care using SCS to selectively target specific pathophysiological processes in chronic pain

Neural bases of hand synergies

abstract: The human hand has so many degrees of freedom that it may seem impossible to control. A potential solution to this problem is “synergy control” which combines dimensionality reduction with great flexibility. With applicability to a wide range of tasks, this has become a very popular concept. In this review, we describe the evolution of the modern concept using studies of kinematic and force synergies in human hand control, neurophysiology of cortical and spinal neurons, and electromyographic (EMG) activity of hand muscles. We go beyond the often purely descriptive usage of synergy by reviewing the organization of the underlying neuronal circuitry in order to propose mechanistic explanations for various observed synergy phenomena. Finally, we propose a theoretical framework to reconcile important and still debated concepts such as the definitions of “fixed” vs. “flexible” synergies and mechanisms underlying the combination of synergies for hand control.View the article as published at http://journal.frontiersin.org/article/10.3389/fncom.2013.00023/ful

Neural Control of Interlimb Oscillations II. Biped and Quadruped Gaits and Bifurications

Behavioral data concerning animal and human gaits and gait transitions are simulated as emergent properties of a central pattern generator (CPG) model. The CPG model is a version of the Ellias-Grossberg oscillator. Its neurons obey Hodgkin-Huxley type equations whose excitatory signals operate on a faster time scale than their inhibitory signals in a recurrent on-center off-surround anatomy. A descending command or GO signal activates the gaits and triggers gait transitions as its amplitude increases. A single model CPG can generate both in-phase and anti-phase oscillations at different GO amplitudes. Phase transition from either in-phase to anti-phase oscillations, or from anti-phase to in-phase oscillations, can occur in different parameter ranges, as the GO signal increases. Quadruped vertebrate gaits, including the amble, the walk, all three pairwise gaits (trot, pace, and gallop), and the pronk are simulated using this property. Rapid gait transitions are simulated in the order walk, trot, pace, and gallop that occurs in the cat, along with the observed increase in oscillation frequency. Precise control of quadruped gait switching uses GO-dependent. modulation of inhibitory interactions, which generates a different functional anatomy at different arousal levels. The primary human gaits (the walk and the run) and elephant gaits (the amble and the walk) are simulated, without modulation, by oscillations with the same phase relationships but different waveform shapes at different GO signal levels, much as the duty cycles of the feet are longer in the walk than in the run. Relevant neural data from spinal cord, globus palliclus, and motor cortex, among other structures, are discussedArmy Research Office (DAAL03-88-K-0088); Advanced Research Projects Agency (90-0083); National Science Foundation (IRI-90-24877); Office of Naval Research (N00014-92-J-1309); Air Force Office of Scientific Research (F49620-92-J-0499, F49620-92-J-0225, 90-0128

Neural bases of hand synergies

The human hand has so many degrees of freedom that it may seem impossible to control. A potential solution to this problem is "synergy control" which combines dimensionality reduction with great flexibility. With applicability to a wide range of tasks, this has become a very popular concept. In this review, we describe the evolution of the modern concept using studies of kinematic and force synergies in human hand control, neurophysiology of cortical and spinal neurons, and electromyographic (EMG) activity of hand muscles. We go beyond the often purely descriptive usage of synergy by reviewing the organization of the underlying neuronal circuitry in order to propose mechanistic explanations for various observed synergy phenomena. Finally, we propose a theoretical framework to reconcile important and still debated concepts such as the definitions of "fixed" vs. "flexible" synergies and mechanisms underlying the combination of synergies for hand control

Description of motor control using inverse models

Humans can perform complicated movements like writing or running without giving them much thought. The scientific understanding of principles guiding the generation of these movements is incomplete. How the nervous system ensures stability or compensates for injury and constraints – are among the unanswered questions today. Furthermore, only through movement can a human impose their will and interact with the world around them. Damage to a part of the motor control system can lower a person’s quality of life. Understanding how the central nervous system (CNS) forms control signals and executes them helps with the construction of devices and rehabilitation techniques. This allows the user, at least in part, to bypass the damaged area or replace its function, thereby improving their quality of life. CNS forms motor commands, for example a locomotor velocity or another movement task. These commands are thought to be processed through an internal model of the body to produce patterns of motor unit activity. An example of one such network in the spinal cord is a central pattern generator (CPG) that controls the rhythmic activation of synergistic muscle groups for overground locomotion. The descending drive from the brainstem and sensory feedback pathways initiate and modify the activity of the CPG. The interactions between its inputs and internal dynamics are still under debate in experimental and modelling studies. Even more complex neuromechanical mechanisms are responsible for some non-periodic voluntary movements. Most of the complexity stems from internalization of the body musculoskeletal (MS) system, which is comprised of hundreds of joints and muscles wrapping around each other in a sophisticated manner. Understanding their control signals requires a deep understanding of their dynamics and principles, both of which remain open problems. This dissertation is organized into three research chapters with a bottom-up investigation of motor control, plus an introduction and a discussion chapter. Each of the three research chapters are organized as stand-alone articles either published or in preparation for submission to peer-reviewed journals. Chapter two introduces a description of the MS kinematic variables of a human hand. In an effort to simulate human hand motor control, an algorithm was defined that approximated the moment arms and lengths of 33 musculotendon actuators spanning 18 degrees of freedom. The resulting model could be evaluated within 10 microseconds and required less than 100 KB of memory. The structure of the approximating functions embedded anatomical and functional features of the modelled muscles, providing a meaningful description of the system. The third chapter used the developments in musculotendon modelling to obtain muscle activity profiles controlling hand movements and postures. The agonist-antagonist coactivation mechanism was responsible for producing joint stability for most degrees of freedom, similar to experimental observations. Computed muscle excitations were used in an offline control of a myoelectric prosthesis for a single subject. To investigate the higher-order generation of control signals, the fourth chapter describes an analytical model of CPG. Its parameter space was investigated to produce forward locomotion when controlled with a desired speed. The model parameters were varied to produce asymmetric locomotion, and several control strategies were identified. Throughout the dissertation the balance between analytical, simulation, and phenomenological modelling for the description of simple and complex behavior is a recurrent theme of discussion

Afferent information modulates spinal network activity in vitro and in preclinical animal models

Primary afferents are responsible for the transmission of peripheral sensory information to the spinal cord. Spinal circuits involved in sensory processing and in motor activity are directly modulated by incoming input conveyed by afferent fibres. Current neurorehabilitation exploits primary afferent information to induce plastic changes within lesioned spinal circuitries. Plasticity and neuromodulation promoted by activity-based interventions are suggested to support both the functional recovery of locomotion and pain relief in subjects with sensorimotor disorders. The present study was aimed at assessing spinal modifications mediated by afferent information. At the beginning of my PhD project, I adopted a simplified in vitro model of isolated spinal cord from the newborn rat. In this preparation, dorsal root (DR) fibres were repetitively activated by delivering trains of electrical stimuli. Responses of dorsal sensory-related and ventral motor-related circuits were assessed by extracellular recordings. I demonstrated that electrostimulation protocols able to activate the spinal CPG for locomotion, induced primary afferent hyperexcitability, as well. Thus, evidence of incoming signals in modulating spinal circuits was provided. Furthermore, a robust sensorimotor interplay was reported to take place within the spinal cord. I further investigated hyperexcitability conditions in a new in vivo model of peripheral neuropathic pain. Adult rats underwent a surgical procedure where the common peroneal nerve was crushed using a calibrated nerve clamp (modified spared nerve injury, mSNI). Thus, primary afferents of the common peroneal nerve were activated through the application of a noxious compression, which presumably elicited ectopic activity constitutively generated in the periphery. One week after surgery, animals were classified into two groups, with (mSNI+) and without (mSNI-) tactile hypersensitivity, based on behavioral tests assessing paw withdrawal threshold. Interestingly, the efficiency of the mSNI in inducing tactile hypersensitivity was halved with respect to the classical SNI model. Moreover, mSNI animals with tactile hypersensitivity (mSNI+) showed an extensive neuroinflammation within the dorsal horn, with activated microglia and astrocytes being significantly increased with respect to mSNI animals without tactile hypersensitivity (mSNI-) and to sham-operated animals. Lastly, RGS4 (regulator of G protein signaling 4) was reported to be enhanced in lumbar dorsal root ganglia (DRGs) and dorsal horn ipsilaterally to the lesion in mSNI+ animals. Thus, a new molecular marker was demonstrated to be involved in tactile hypersensitivity in our preclinical model of mSNI. Lastly, we developed a novel in vitro model of newborn rat, where hindlimbs were functionally connected to a partially dissected spinal cord and passively-driven by a robotic device (Bipedal Induced Kinetic Exercise, BIKE). I aimed at studying whether spinal activity was influenced by afferent signals evoked during passive cycling. I first demonstrated that BIKE could actually evoke an afferent feedback from the periphery. Then, I determined that spinal circuitries were differentially affected by training sessions of different duration. On one side, a short exercise session could not directly activate the locomotor CPG, but was able to transiently facilitate an electrically-induced locomotor-like activity. Moreover, no changes in reflex or spontaneous activity of dorsal and ventral networks were promoted by a short training. On the other side, a long BIKE session caused a loss in facilitation of spinal locomotor networks and a depression in the area of motor reflexes. Furthermore, activity in dorsal circuits was long-term enhanced, with a significant increase in both electrically-evoked and spontaneous antidromic discharges. Thus, the persistence of training-mediated effects was different, with spinal locomotor circuits being only transiently modulated, whereas dorsal activity being strongly and stably enhanced. Motoneurons were also affected by a prolonged training, showing a reduction in membrane resistance and an increase in the frequency of post-synaptic currents (PSCs), with both fast- and slow-decaying synaptic inputs being augmented. Changes in synaptic transmission onto the motoneuron were suggested to be responsible for network effects mediated by passive training. In conclusion, I demonstrated that afferent information might induce changes within the spinal cord, involving both neuronal and glial cells. In particular, spinal networks are affected by incoming peripheral signals, which mediate synaptic, cellular and molecular modifications. Moreover, a strong interplay between dorsal and ventral spinal circuits was also reported. A full comprehension of basic mechanisms underlying sensory-mediated spinal plasticity and bidirectional interactions between functionally different spinal networks might lead to the development of neurorehabilitation strategies which simultaneously promote locomotor recovery and pain relief

Neurophysiological markers predicting recovery of standing in humans with chronic motor complete spinal cord injury

The appropriate selection of individual-specific spinal cord epidural stimulation (scES) parameters is crucial to re-enable independent standing with self-assistance for balance in individuals with chronic, motor complete spinal cord injury, which is a key achievement toward the recovery of functional mobility. To date, there are no available algorithms that contribute to the selection of scES parameters for facilitating standing in this population. Here, we introduce a novel framework for EMG data processing that implements spectral analysis by continuous wavelet transform and machine learning methods for characterizing epidural stimulation-promoted EMG activity resulting in independent standing. Analysis of standing data collected from eleven motor complete research participants revealed that independent standing was promoted by EMG activity characterized by lower median frequency, lower variability of median frequency, lower variability of activation pattern, lower variability of instantaneous maximum power, and higher total power. Additionally, the high classification accuracy of assisted and independent standing allowed the development of a prediction algorithm that can provide feedback on the effectiveness of muscle-specific activation for standing promoted by the tested scES parameters. This framework can support researchers and clinicians during the process of selection of epidural stimulation parameters for standing motor rehabilitation

Evolutionary robotics and neuroscience

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