Consecutive Transcutaneous and Epidural Spinal Cord Neuromodulation to Modify Clinical Complete Paralysis-the Proof of Concept.

Objective: To evaluate the effect of transcutaneous (tSCS) and epidural electrical spinal cord stimulation (EES) in facilitating volitional movements, balance, and nonmotor functions, in this observational study, tSCS and EES were consecutively tested in 2 participants with motor complete spinal cord injury (SCI). Participants and Methods: Two participants (a 48-year-old woman and a 28-year-old man), both classified as motor complete spinal injury, were enrolled in the study. Both participants went through a unified protocol, such as an initial electrophysiological assessment of neural connectivity, consecutive tSCS and EES combined with 8 wks of motor training with electromyography (EMG) and kinematic evaluation. The study was conducted from May 1, 2019, to December 31, 2021. Results: In both participants, tSCS reported a minimal improvement in voluntary movements still essential to start tSCS-enabled rehabilitation. Compared with tSCS, following EES showed immediate improvement in voluntary movements, whereas tSCS was more effective in improving balance and posture. Continuous improvement in nonmotor functions was found during tSCS-enabled and then during EES-enabled motor training. Conclusion: Results report a significant difference in the effect of tSCS and EES on the recovery of neurologic functions and support consecutive tSCS and EES applications as a potential therapy for SCI. The proposed approach may help in selecting patients with SCI responsive to neuromodulation. It would also help initiate neuromodulation and rehabilitation therapy early, particularly for motor complete SCI with minimal effect from conventional rehabilitation.

Evaluation of the Autologous Genetically Enriched Leucoconcentrate on the Lumbar Spinal Cord Morpho-Functional Recovery in a Mini Pig with Thoracic Spine Contusion Injury.

BACKGROUND: Pathological changes associated with spinal cord injury (SCI) can be observed distant, rostral, or caudal to the epicenter of injury. These remote areas represent important therapeutic targets for post-traumatic spinal cord repair. The present study aimed to investigate the following in relation to SCI: distant changes in the spinal cord, peripheral nerve, and muscles. METHODS: The changes in the spinal cord, the tibial nerve, and the hind limb muscles were evaluated in control SCI animals and after intravenous infusion of autologous leucoconcentrate enriched with genes encoding neuroprotective factors (VEGF, GDNF, and NCAM), which previously demonstrated a positive effect on post-traumatic restoration. RESULTS: Two months after thoracic contusion in the treated mini pigs, a positive remodeling of the macro- and microglial cells, expression of PSD95 and Chat in the lumbar spinal cord, and preservation of the number and morphological characteristics of the myelinated fibers in the tibial nerve were observed and were aligned with hind limb motor recovery and reduced soleus muscle atrophy. CONCLUSION: Here, we show the positive effect of autologous genetically enriched leucoconcentrate-producing recombinant neuroprotective factors on targets distant to the primary lesion site in mini pigs with SCI. These findings open new perspectives for the therapy of SCI.

Neurointerface with oscillator motifs for inhibitory effect over antagonist muscles.

The effect of inhibitory management is usually underestimated in artificial control systems, using biological analogy. According to our hypothesis, the muscle hypertonus could be effectively compensated via stimulation by bio-plausible patterns. We proposed an approach for the compensatory stimulation device as implementation of previously presented architecture of the neurointerface, where (1) the neuroport is implemented as a DAC and stimulator, (2) neuroterminal is used for neurosimulation of a set of oscillator motifs on one-board computer. In the set of experiments with five volunteers, we measured the efficacy of motor neuron inhibition via the antagonist muscle or nerve stimulation registering muscle force with and without antagonist stimulation. For the agonist activation, we used both voluntary activity and electrical stimulation. In the case of stimulation of both the agonist and the antagonist muscles and nerves, we experimented with delays between muscle stimulation in the range of 0-20 ms. We registered the subjective discomfort rate. We did not identify any significant difference between the antagonist muscle and nerve stimulation in both voluntary activity and electrical stimulation of cases showing agonist activity. We determined the most effective delay between the stimulation of the agonist and the antagonist muscles and nerves as 10-20 ms.

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.

Characterization and applications of evoked responses during epidural electrical stimulation.

BACKGROUND: Epidural electrical stimulation (EES) of the spinal cord has been FDA approved and used therapeutically for decades. However, there is still not a clear understanding of the local neural substrates and consequently the mechanism of action responsible for the therapeutic effects. METHOD: Epidural spinal recordings (ESR) are collected from the electrodes placed in the epidural space. ESR contains multi-modality signal components such as the evoked neural response (due to tonic or BurstDR™ waveforms), evoked muscle response, stimulation artifact, and cardiac response. The tonic stimulation evoked compound action potential (ECAP) is one of the components in ESR and has been proposed recently to measure the accumulative local potentials from large populations of neuronal fibers during EES. RESULT: Here, we first review and investigate the referencing strategies, as they apply to ECAP component in ESR in the domestic swine animal model. We then examine how ECAP component can be used to sense lead migration, an adverse outcome following lead placement that can reduce therapeutic efficacy. Lastly, we show and isolate concurrent activation of local back and leg muscles during EES, demonstrating that the ESR obtained from the recording contacts contain both ECAP and EMG components. CONCLUSION: These findings may further guide the implementation of recording and reference contacts in an implantable EES system and provide preliminary evidence for the utility of ECAP component in ESR to detect lead migration. We expect these results to facilitate future development of EES methodology and implementation of use of different components in ESR to improve EES therapy.

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 Effect of Non-invasive Spinal Cord Stimulation on Anorectal Function in Individuals With Spinal Cord Injury: A Case Series.

Spinal cord injury (SCI) is a devastating condition that impacts multiple organ systems. Neurogenic bowel dysfunction (NBD) frequently occurs after a SCI leading to reduced sensation of bowel fullness and bowel movement often leading to constipation or fecal incontinence. Spinal Neuromodulation has been proven to be a successful modality to improve sensorimotor and autonomic function in patients with spinal cord injuries. The pilot data presented here represents the first demonstration of using spinal neuromodulation to activate the anorectal regions of patients with spinal cord injuries and the acute and chronic effects of stimulation. We observed that spinal stimulation induces contractions as well as changes in sensation and pressure profiles along the length of the anorectal region. In addition, we present a case report of a patient with a SCI and the beneficial effect of spinal neuromodulation on the patient's bowel program.

New Therapy for Spinal Cord Injury: Autologous Genetically-Enriched Leucoconcentrate Integrated with Epidural Electrical Stimulation.

The contemporary strategy for spinal cord injury (SCI) therapy aims to combine multiple approaches to control pathogenic mechanisms of neurodegeneration and stimulate neuroregeneration. In this study, a novel regenerative approach using an autologous leucoconcentrate enriched with transgenes encoding vascular endothelial growth factor (VEGF), glial cell line-derived neurotrophic factor (GDNF), and neural cell adhesion molecule (NCAM) combined with supra- and sub-lesional epidural electrical stimulation (EES) was tested on mini-pigs similar in morpho-physiological scale to humans. The complex analysis of the spinal cord recovery after a moderate contusion injury in treated mini-pigs compared to control animals revealed: better performance in behavioural and joint kinematics, restoration of electromyography characteristics, and improvement in selected immunohistology features related to cell survivability, synaptic protein expression, and glial reorganization above and below the injury. These results for the first time demonstrate the positive effect of intravenous infusion of autologous genetically-enriched leucoconcentrate producing recombinant molecules stimulating neuroregeneration combined with neuromodulation by translesional multisite EES on the restoration of the post-traumatic spinal cord in mini-pigs and suggest the high translational potential of this novel regenerative therapy for SCI patients.

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.

Pre-motor versus motor cerebral cortex neuromodulation for chronic neuropathic pain.

Electrical stimulation of the cerebral cortex (ESCC) has been used to treat intractable neuropathic pain for nearly two decades, however, no standardized approach for this technique has been developed. In order to optimize targeting and validate the effect of ESCC before placing the permanent grid, we introduced initial assessment with trial stimulation, using a temporary grid of subdural electrodes. In this retrospective study we evaluate the role of electrode location on cerebral cortex in control of neuropathic pain and the role of trial stimulation in target-optimization for ESCC. Location of the temporary grid electrodes and location of permanent electrodes were evaluated in correlation with the long-term efficacy of ESCC. The results of this study demonstrate that the long-term effect of subdural pre-motor cortex stimulation is at least the same or higher compare to effect of subdural motor or combined pre-motor and motor cortex stimulation. These results also demonstrate that the initial trial stimulation helps to optimize permanent electrode positions in relation to the optimal functional target that is critical in cases when brain shift is expected. Proposed methodology and novel results open a new direction for development of neuromodulation techniques to control chronic neuropathic pain.

Spinal cord fMRI with MB-SWIFT for assessing epidural spinal cord stimulation in rats.

PURPOSE: Electrical epidural spinal cord stimulation (SCS) is used as a treatment for chronic pain as well as to partially restore motor function after a spinal cord injury. Monitoring the spinal cord activity during SCS with fMRI could provide important and objective measures of integrative responses to treatment. Unfortunately, spinal cord fMRI is severely challenged by motion and susceptibility artifacts induced by the implanted electrode and bones. This pilot study introduces multi-band sweep imaging with Fourier transformation (MB-SWIFT) technique for spinal cord fMRI during SCS in rats. Given the close to zero acquisition delay and high bandwidth in 3 dimensions, MB-SWIFT is demonstrated to be highly tolerant to motion and susceptibility-induced artifacts and thus holds promise for fMRI during SCS. METHODS: MB-SWIFT with 0.78 × 0.78 × 1.50 mm3 spatial resolution and 3-s temporal resolution was used at 9.4 Tesla in rats undergoing epidural SCS at different frequencies. Its performance was compared with spin echo EPI. The origin of the functional contrast was also explored using suppression bands. RESULTS: MB-SWIFT was tolerant to electrode-induced artifacts and respiratory motion, leading to substantially higher fMRI sensitivity than spin echo fMRI. Clear stimulation frequency-dependent responses to SCS were detected in the rat spinal cord close to the stimulation site. The origin of MB-SWIFT fMRI signals was consistent with dominant inflow effects. CONCLUSION: fMRI of the rat spinal cord during SCS can be consistently achieved with MB-SWIFT, thus providing a valuable experimental framework for assessing the effects of SCS on the central nervous system.

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.

Brain fMRI during orientation selective epidural spinal cord stimulation.

Epidural spinal cord stimulation (ESCS) is widely used for chronic pain treatment, and is also a promising tool for restoring motor function after spinal cord injury. Despite significant positive impact of ESCS, currently available protocols provide limited specificity and efficiency partially due to the limited number of contacts of the leads and to the limited flexibility to vary the spatial distribution of the stimulation field in respect to the spinal cord. Recently, we introduced Orientation Selective (OS) stimulation strategies for deep brain stimulation, and demonstrated their selectivity in rats using functional MRI (fMRI). The method achieves orientation selectivity by controlling the main direction of the electric field gradients using individually driven channels. Here, we introduced a similar OS approach for ESCS, and demonstrated orientation dependent brain activations as detected by brain fMRI. The fMRI activation patterns during spinal cord stimulation demonstrated the complexity of brain networks stimulated by OS-ESCS paradigms, involving brain areas responsible for the transmission of the motor and sensory information. The OS approach may allow targeting ESCS to spinal fibers of different orientations, ultimately making stimulation less dependent on the precision of the electrode implantation.