Memristive circuit-based model of central pattern generator to reproduce spinal neuronal activity in walking pattern.

Existing methods of neurorehabilitation include invasive or non-invasive stimulators that are usually simple digital generators with manually set parameters like pulse width, period, burst duration, and frequency of stimulation series. An obvious lack of adaptation capability of stimulators, as well as poor biocompatibility and high power consumption of prosthetic devices, highlights the need for medical usage of neuromorphic systems including memristive devices. The latter are electrical devices providing a wide range of complex synaptic functionality within a single element. In this study, we propose the memristive schematic capable of self-learning according to bio-plausible spike-timing-dependant plasticity to organize the electrical activity of the walking pattern generated by the central pattern generator.

Oligo (Poly (Ethylene Glycol) Fumarate)-Based Multicomponent Cryogels for Neural Tissue Replacement.

Synthetic hydrogels provide a promising platform to produce neural tissue analogs with improved control over structural, physical, and chemical properties. In this study, oligo (poly (ethylene glycol) fumarate) (OPF)-based macroporous cryogels were developed as a potential next-generation alternative to a non-porous OPF hydrogel previously proposed as an advanced biodegradable scaffold for spinal cord repair. A series of OPF cryogel conduits in combination with PEG diacrylate and 2-(methacryloyloxy) ethyl-trimethylammonium chloride (MAETAC) cationic monomers were synthesized and characterized. The contribution of each component to viscoelastic and hydration behaviors and porous structure was identified, and concentration relationships for these properties were revealed. The rheological properties of the materials corresponded to those of neural tissues and scaffolds, according to the reviewed data. A comparative assessment of adhesion, migration, and proliferation of neuronal cells in multicomponent cryogels was carried out to optimize cell-supporting characteristics. The results show that OPF-based cryogels can be used as a tunable synthetic scaffold for neural tissue repair with advantages over their hydrogel counterparts.

Epidural electrical spinal cord stimulation of the thoracic segments (T2-T5) facilitates respiratory function in patients with complete spinal cord injury.

INTRODUCTION: Patients with high cervical Spinal Cord Injury (SCI) usually require mechanical ventilation support. Phrenic Nerve Stimulation (PNS) both direct and indirect is the main alternative for these patients to wean off ventilator although PNS has several limitations and phrenic nerve could be also damaged after cervical spinal cord injury. OBJECTIVE: In this study, we assessed if the spinal cord Epidural Electrical Stimulation (EES) at the segments T2-T5, related to intercostal muscles, can facilitate respiratory function and particularly inspired tidal volume during mechanic ventilation. METHODS: Two patients with a high cervical injury were selected for this study with ethical committee permission and under review board supervision. A phrenic nerve conduction study with diaphragm electromyography (DEMG) was performed before and after trial of EES. RESULTS: Results demonstrate that EES at T2-T5 substantially increase the inspired volume. The results of this study also demonstrate that EES at spinal segments T2-T5 can bring patients dependent from mechanical ventilation to pressure support (on CPAP), preventing Baro-trauma and other complications related to mechanical ventilation. CONCLUSION: These findings suggest that tested approach applied alone or in combination with the phrenic nerve stimulation could help to reduce time on mechanical ventilation and related complications.

The Translesional Spinal Network and Its Reorganization after Spinal Cord Injury.

Evidence from preclinical and clinical research suggest that neuromodulation technologies can facilitate the sublesional spinal networks, isolated from supraspinal commands after spinal cord injury (SCI), by reestablishing the levels of excitability and enabling descending motor signals via residual connections. Herein, we evaluate available evidence that sublesional and supralesional spinal circuits could form a translesional spinal network after SCI. We further discuss evidence of translesional network reorganization after SCI in the presence of sensory inputs during motor training. In this review, we evaluate potential mechanisms that underlie translesional circuitry reorganization during neuromodulation and rehabilitation in order to enable motor functions after SCI. We discuss the potential of neuromodulation technologies to engage various components that comprise the translesional network, their functional recovery after SCI, and the implications of the concept of translesional network in development of future neuromodulation, rehabilitation, and neuroprosthetics technologies.

Voluntary Modulation of Evoked Responses Generated by Epidural and Transcutaneous Spinal Stimulation in Humans with Spinal Cord Injury.

Transcutaneous (TSS) and epidural spinal stimulation (ESS) are electrophysiological techniques that have been used to investigate the interactions between exogenous electrical stimuli and spinal sensorimotor networks that integrate descending motor signals with afferent inputs from the periphery during motor tasks such as standing and stepping. Recently, pilot-phase clinical trials using ESS and TSS have demonstrated restoration of motor functions that were previously lost due to spinal cord injury (SCI). However, the spinal network interactions that occur in response to TSS or ESS pulses with spared descending connections across the site of SCI have yet to be characterized. Therefore, we examined the effects of delivering TSS or ESS pulses to the lumbosacral spinal cord in nine individuals with chronic SCI. During low-frequency stimulation, participants were instructed to relax or attempt maximum voluntary contraction to perform full leg flexion while supine. We observed similar lower-extremity neuromusculature activation during TSS and ESS when performed in the same participants while instructed to relax. Interestingly, when participants were instructed to attempt lower-extremity muscle contractions, both TSS- and ESS-evoked motor responses were significantly inhibited across all muscles. Participants with clinically complete SCI tested with ESS and participants with clinically incomplete SCI tested with TSS demonstrated greater ability to modulate evoked responses than participants with motor complete SCI tested with TSS, although this was not statistically significant due to a low number of subjects in each subgroup. These results suggest that descending commands combined with spinal stimulation may increase activity of inhibitory interneuronal circuitry within spinal sensorimotor networks in individuals with SCI, which may be relevant in the context of regaining functional motor outcomes.

Newly regenerated axons via scaffolds promote sub-lesional reorganization and motor recovery with epidural electrical stimulation.

Here, we report the effect of newly regenerated axons via scaffolds on reorganization of spinal circuitry and restoration of motor functions with epidural electrical stimulation (EES). Motor recovery was evaluated for 7 weeks after spinal transection and following implantation with scaffolds seeded with neurotrophin producing Schwann cell and with rapamycin microspheres. Combined treatment with scaffolds and EES-enabled stepping led to functional improvement compared to groups with scaffold or EES, although, the number of axons across scaffolds was not different between groups. Re-transection through the scaffold at week 6 reduced EES-enabled stepping, still demonstrating better performance compared to the other groups. Greater synaptic reorganization in the presence of regenerated axons was found in group with combined therapy. These findings suggest that newly regenerated axons through cell-containing scaffolds with EES-enabled motor training reorganize the sub-lesional circuitry improving motor recovery, demonstrating that neuroregenerative and neuromodulatory therapies cumulatively enhancing motor function after complete SCI.

Segment-Specific Orientation of the Dorsal and Ventral Roots for Precise Therapeutic Targeting of Human Spinal Cord.

OBJECTIVE: To provide precise description of the dorsal and ventral roots orientation along with the main spinal cord anatomical measurements and their segment-specific variations. PATIENTS AND METHODS: We collected and analyzed the measurements of the spines, spinal cords, and dorsal and ventral roots (C2-L5) of nine adult cadavers (five males and four females). RESULTS: This study for the first time provides analysis of the dorsal and ventral roots orientation along with spinal cord anatomical measurements and their segment-specific distribution. The results of this study showed less variability in rostral root angles compared with the caudal. Dorsal and ventral rootlets were oriented mostly perpendicular to the spinal cord at the cervical level and had more parallel orientation to the spinal cord at the thoracic and lumbar segments. The number of rootlets per root was greatest at dorsal cervical and lumbar segments. Spinal cord transverse diameter and width of the dorsal columns were largest at cervical segments. The strongest correlation between the spinal cord and vertebrae structures was found between the length of intervertebral foramen to rostral rootlet distance and vertebral bone length. CONCLUSION: These results demonstrate consistent variation in spinal cord anatomical features across all tested subjects. The results of this study can be used to locate spinal roots and main spinal cord landmarks based on bone marks on computed tomography or X-rays. These results could improve stereotactic surgical procedures and electrode positioning for neuromodulation procedures.

Comparison of systemic and localized carrier-mediated delivery of methylprednisolone succinate for treatment of acute spinal cord injury.

Localized carrier-mediated administration of drugs is a promising approach to treatment of acute phase of spinal cord injury (SCI) as it allows enhanced and/or sustained drug delivery to damaged tissues along with minimization of systemic side effects. We studied the effect of locally applied self-assembling micellar formulation of methylprednisolone succinate (MPS) with trifunctional block copolymer of ethylene oxide and propylene oxide (TBC) on functional recovery and tissue drug content after SCI in rats in comparison with local and systemic administration of MPS alone. Variations in the amplitude of motor evoked responses in the hindlimb muscles induced by epidural stimulation during acute phase of SCI and restoration of movements during chronic period after local vs. systemic application of MPS were evaluated in this study. Results demonstrate that local delivery of MPS in combination with TBC facilitates spinal cord sensorimotor circuitry, increasing the excitability. In addition, this formulation was found to be more effective in improvement of locomotion after SCI compared to systemic administration. LC-MS/MS data shows that the use of TBC carrier increases the glucocorticoid content in treated spinal cord by more than four times over other modes of treatment. The results of this study demonstrate that the local treatment of acute SCI with MPS in the form of mixed micelles with TBC can provide improved therapeutic outcome by promoting drug accumulation and functional restoration of the spinal cord.

Changes in spinal cord hemodynamics reflect modulation of spinal network with different parameters of epidural stimulation.

In this study functional ultrasound (fUS) imaging has been implemented to explore the local hemodynamics response induced by electrical epidural stimulation and to study real-time in vivo functional changes of the spinal cord, taking advantage of the superior spatiotemporal resolution provided by fUS. By quantifying the hemodynamics and electromyographic response features, we tested the hypothesis that the temporal hemodynamics response of the spinal cord to electrical epidural stimulation could reflect modulation of the spinal circuitry and accordingly respond to the changes in parameters of electrical stimulation. The results of this study for the first time demonstrate that the hemodynamics response to electrical stimulation could reflect a neural-vascular coupling of the spinal cord. Response in the dorsal areas to epidural stimulation was significantly higher and faster compared to the response in ventral spinal cord. Positive relation between the hemodynamics and the EMG responses was observed at the lower frequencies of epidural stimulation (20 and 40 Hz), which according to our previous findings can facilitate spinal circuitry after spinal cord injury, compared to higher frequencies (200 and 500 Hz). These findings suggest that different mechanisms could be involved in spinal cord hemodynamics changes during different parameters of electrical stimulation and for the first time provide the evidence that neural-vascular coupling of the spinal cord circuitry could be related to specific organization of spinal cord vasculature and hemodynamics.

Alterations of Spinal Epidural Stimulation-Enabled Stepping by Descending Intentional Motor Commands and Proprioceptive Inputs in Humans With Spinal Cord Injury.

Background: Regaining control of movement following a spinal cord injury (SCI) requires utilization and/or functional reorganization of residual descending, and likely ascending, supraspinal sensorimotor pathways, which may be facilitated via task-specific training through body weight supported treadmill (BWST) training. Recently, epidural electrical stimulation (ES) combined with task-specific training demonstrated independence of standing and stepping functions in individuals with clinically complete SCI. The restoration of these functions may be dependent upon variables such as manipulation of proprioceptive input, ES parameter adjustments, and participant intent during step training. However, the impact of each variable on the degree of independence achieved during BWST stepping remains unknown. Objective: To describe the effects of descending intentional commands and proprioceptive inputs, specifically body weight support (BWS), on lower extremity motor activity and vertical ground reaction forces (vGRF) during ES-enabled BWST stepping in humans with chronic sensorimotor complete SCI. Furthermore, we describe perceived changes in the level of assistance provided by clinicians when intent and BWS are modified. Methods: Two individuals with chronic, mid thoracic, clinically complete SCI, enrolled in an IRB and FDA (IDE G150167) approved clinical trial. A 16-contact electrode array was implanted in the epidural space between the T11-L1 vertebral regions. Lower extremity motor output and vertical ground reaction forces were obtained during clinician-assisted ES-enabled treadmill stepping with BWS. Consecutive steps were achieved during various experimentally-controlled conditions, including intentional participation and varied BWS (60% and 20%) while ES parameters remain unchanged. Results: During ES-enabled BWST stepping, the knee extensors exhibited an increase in motor activation during trials in which stepping was passive compared to active or during trials in which 60% BWS was provided compared to 20% BWS. As a result of this increased motor activation, perceived clinician assistance increased during the transition from stance to swing. Intentional participation and 20% BWS resulted in timely and purposeful activation of the lower extremities muscles, which improved independence and decreased clinician assistance. Conclusion: Maximizing participant intention and optimizing proprioceptive inputs through BWS during ES-enabled BWST stepping may facilitate greater independence during BWST stepping for individuals with clinically complete SCI. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT02592668.

Functional Ultrasound Imaging of Spinal Cord Hemodynamic Responses to Epidural Electrical Stimulation: A Feasibility Study.

This study presents the first implementation of functional ultrasound (fUS) imaging of the spinal cord to monitor local hemodynamic response to epidural electrical spinal cord stimulation (SCS) on two small and large animal models. SCS has been successfully applied to control chronic refractory pain and recently was evolved to alleviate motor impairment in Parkinson's disease and after spinal cord injury. At present, however, the mechanisms underlying SCS remain unclear, and current methods for monitoring SCS are limited in their capacity to provide the required sensitivity and spatiotemporal resolutions to evaluate functional changes in response to SCS. fUS is an emerging technology that has recently shown promising results in monitoring a variety of neural activities associated with the brain. Here we demonstrated the feasibility of performing fUS on two animal models during SCS. We showed in vivo spinal cord hemodynamic responses measured by fUS evoked by different SCS parameters. We also demonstrated that fUS has a higher sensitivity in monitoring spinal cord response than electromyography. The high spatial and temporal resolutions of fUS were demonstrated by localized measurements of hemodynamic responses at different spinal cord segments, and by reliable tracking of spinal cord responses to patterned electrical stimulations, respectively. Finally, we proposed optimized fUS imaging and post-processing methods for spinal cord. These results support feasibility of fUS imaging of the spinal cord and could pave the way for future systematic studies to investigate spinal cord functional organization and the mechanisms of spinal cord neuromodulation in vivo.

Chronic subdural cortical stimulation for phantom limb pain: report of a series of two cases.

Phantom limb pain is a complex, incompletely understood pain syndrome that is characterized by chronic painful paresthesias in a previous amputated body part. Limited treatment modalities exist that provide meaningful relief, including pharmacological treatments and spinal cord stimulation that are rarely successful for refractory cases. Here, we describe our two-patient cohort with recalcitrant upper extremity phantom limb pain treated with chronic subdural cortical stimulation. The patient with evidence of cortical reorganization and almost 60 years of debilitating phantom limb pain experienced sustained analgesic relief at a follow-up period of 6 months. The second patient became tolerant to the stimulation and his pain returned to baseline at a 1-month follow-up. Our unique case series report adds to the growing body of literature suggesting critical appraisal before widespread implementation of cortical stimulation for phantom limb pain can be considered.

Electrophysiological Guidance of Epidural Electrode Array Implantation over the Human Lumbosacral Spinal Cord to Enable Motor Function after Chronic Paralysis.

Epidural electrical stimulation (EES) of the spinal cord has been shown to restore function after spinal cord injury (SCI). Characterization of EES-evoked motor responses has provided a basic understanding of spinal sensorimotor network activity related to EES-enabled motor activity of the lower extremities. However, the use of EES-evoked motor responses to guide EES system implantation over the spinal cord and their relation to post-operative EES-enabled function in humans with chronic paralysis attributed to SCI has yet to be described. Herein, we describe the surgical and intraoperative electrophysiological approach used, followed by initial EES-enabled results observed in 2 human subjects with motor complete paralysis who were enrolled in a clinical trial investigating the use of EES to enable motor functions after SCI. The 16-contact electrode array was initially positioned under fluoroscopic guidance. Then, EES-evoked motor responses were recorded from select leg muscles and displayed in real time to determine electrode array proximity to spinal cord regions associated with motor activity of the lower extremities. Acceptable array positioning was determined based on achievement of selective proximal or distal leg muscle activity, as well as bilateral muscle activation. Motor response latencies were not significantly different between intraoperative recordings and post-operative recordings, indicating that array positioning remained stable. Additionally, EES enabled intentional control of step-like activity in both subjects within the first 5 days of testing. These results suggest that the use of EES-evoked motor responses may guide intraoperative positioning of epidural electrodes to target spinal cord circuitry to enable motor functions after SCI.

Publisher Correction: Neuromodulation of lumbosacral spinal networks enables independent stepping after complete paraplegia.

In the version of this article originally published, Dimitry G. Sayenko's affiliations were not correct. The following affiliation for this author was missing: Department of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, USA. This affiliation has been added for the author, and the rest of the affiliations have been renumbered accordingly. The error has been corrected in the HTML and PDF versions of this article.

Neuromodulation of lumbosacral spinal networks enables independent stepping after complete paraplegia.

Spinal sensorimotor networks that are functionally disconnected from the brain because of spinal cord injury (SCI) can be facilitated via epidural electrical stimulation (EES) to restore robust, coordinated motor activity in humans with paralysis1-3. Previously, we reported a clinical case of complete sensorimotor paralysis of the lower extremities in which EES restored the ability to stand and the ability to control step-like activity while side-lying or suspended vertically in a body-weight support system (BWS)4. Since then, dynamic task-specific training in the presence of EES, termed multimodal rehabilitation (MMR), was performed for 43 weeks and resulted in bilateral stepping on a treadmill, independent from trainer assistance or BWS. Additionally, MMR enabled independent stepping over ground while using a front-wheeled walker with trainer assistance at the hips to maintain balance. Furthermore, MMR engaged sensorimotor networks to achieve dynamic performance of standing and stepping. To our knowledge, this is the first report of independent stepping enabled by task-specific training in the presence of EES by a human with complete loss of lower extremity sensorimotor function due to SCI.

Spinal Cord Molecular and Cellular Changes Induced by Adenoviral Vector- and Cell-Mediated Triple Gene Therapy after Severe Contusion.

The gene therapy has been successful in treatment of spinal cord injury (SCI) in several animal models, although it still remains unavailable for clinical practice. Surprisingly, regardless the fact that multiple reports showed motor recovery with gene therapy, little is known about molecular and cellular changes in the post-traumatic spinal cord following viral vector- or cell-mediated gene therapy. In this study we evaluated the therapeutic efficacy and changes in spinal cord after treatment with the genes encoding vascular endothelial growth factor (VEGF), glial cell-derived neurotrophic factor (GDNF), angiogenin (ANG), and neuronal cell adhesion molecule (NCAM) applied using both approaches. Therapeutic genes were used for viral vector- and cell-mediated gene therapy in two combinations: (1) VEGF+GDNF+NCAM and (2) VEGF+ANG+NCAM. For direct gene therapy adenoviral vectors based on serotype 5 (Ad5) were injected intrathecally and for cell-mediated gene delivery human umbilical cord blood mononuclear cells (UCB-MC) were simultaneously transduced with three Ad5 vectors and injected intrathecally 4 h after the SCI. The efficacy of both treatments was confirmed by improvement in behavioral (BBB) test. Molecular and cellular changes following post-traumatic recovery were evaluated with immunofluorescent staining using antibodies against the functional markers of motorneurons (Hsp27, synaptophysin, PSD95), astrocytes (GFAP, vimentin), oligodendrocytes (Olig2, NG2, Cx47) and microglial cells (Iba1). Our results suggest that both approaches with intrathecal delivery of therapeutic genes may support functional recovery of post-traumatic spinal cord via lowering the stress (down regulation of Hsp25) and enhancing the synaptic plasticity (up regulation of PSD95 and synaptophysin), supporting oligodendrocyte proliferation (up regulation of NG2) and myelination (up regulation of Olig2 and Cx47), modulating astrogliosis by reducing number of astrocytes (down regulation of GFAP and vimetin) and microglial cells (down regulation of Iba1).

The Role of Functional Neuroanatomy of the Lumbar Spinal Cord in Effect of Epidural Stimulation.

In this study, the neuroanatomy of the swine lumbar spinal cord, particularly the spatial orientation of dorsal roots was correlated to the anatomical landmarks of the lumbar spine and to the magnitude of motor evoked potentials during epidural electrical stimulation (EES). We found that the proximity of the stimulating electrode to the dorsal roots entry zone across spinal segments was a critical factor to evoke higher peak-to-peak motor responses. Positioning the electrode close to the dorsal roots produced a significantly higher impact on motor evoked responses than rostro-caudal shift of electrode from segment to segment. Based on anatomical measurements of the lumbar spine and spinal cord, significant differences were found between L1-L4 to L5-L6 segments in terms of spinal cord gross anatomy, dorsal roots and spine landmarks. Linear regression analysis between intersegmental landmarks was performed and L2 intervertebral spinous process length was selected as the anatomical reference in order to correlate vertebral landmarks and the spinal cord structures. These findings present for the first time, the influence of spinal cord anatomy on the effects of epidural stimulation and the role of specific orientation of electrodes on the dorsal surface of the dura mater in relation to the dorsal roots. These results are critical to consider as spinal cord neuromodulation strategies continue to evolve and novel spinal interfaces translate into clinical practice.

Electrical Neuromodulation of the Respiratory System After Spinal Cord Injury.

Spinal cord injury (SCI) is a complex and devastating condition characterized by disruption of descending, ascending, and intrinsic spinal circuitry resulting in chronic neurologic deficits. In addition to limb and trunk sensorimotor deficits, SCI can impair autonomic neurocircuitry such as the motor networks that support respiration and cough. High cervical SCI can cause complete respiratory paralysis, and even lower cervical or thoracic lesions commonly result in partial respiratory impairment. Although electrophrenic respiration can restore ventilator-independent breathing in select candidates, only a small subset of affected individuals can benefit from this technology at this moment. Over the past decades, spinal cord stimulation has shown promise for augmentation and recovery of neurologic function including motor control, cough, and breathing. The present review discusses the challenges and potentials of spinal cord stimulation for restoring respiratory function by overcoming some of the limitations of conventional respiratory functional electrical stimulation systems.

Review of Epidural Spinal Cord Stimulation for Augmenting Cough after Spinal Cord Injury.

Spinal cord injury (SCI) remains a debilitating condition for which there is no cure. In addition to loss of somatic sensorimotor functions, SCI is also commonly associated with impairment of autonomic function. Importantly, cough dysfunction due to paralysis of expiratory muscles in combination with respiratory insufficiency can render affected individuals vulnerable to respiratory morbidity. Failure to clear sputum can aggravate both risk for and severity of respiratory infections, accounting for frequent hospitalizations and even mortality. Recently, epidural stimulation of the lower thoracic spinal cord has been investigated as novel means for restoring cough by evoking expiratory muscle contraction to generate large positive airway pressures and expulsive air flow. This review article discusses available preclinical and clinical evidence, current challenges and clinical potential of lower thoracic spinal cord stimulation (SCS) for restoring cough in individuals with SCI.

Enabling Task-Specific Volitional Motor Functions via Spinal Cord Neuromodulation in a Human With Paraplegia.

We report a case of chronic traumatic paraplegia in which epidural electrical stimulation (EES) of the lumbosacral spinal cord enabled (1) volitional control of task-specific muscle activity, (2) volitional control of rhythmic muscle activity to produce steplike movements while side-lying, (3) independent standing, and (4) while in a vertical position with body weight partially supported, voluntary control of steplike movements and rhythmic muscle activity. This is the first time that the application of EES enabled all of these tasks in the same patient within the first 2 weeks (8 stimulation sessions total) of EES therapy.