LIBЯARY

New manuscript “Case report: Combined transcutaneous spinal cord stimulation and physical therapy on recovery of neurological function after spinal cord infarction”

To evaluate the effect of transcutaneous (tSCS) and epidural electric. The case of a 37-year-old woman who suffered from spinal cord infarction (SI), resulting in a complete spinal cord injury (AIS A, neurological level T10), and autonomic dysfunction is presented. This study aimed to assess the effect of transcutaneous Spinal Cord Electrical Stimulation (tSCS) on improving motor, sensory, and autonomic function after SI. During the first 8 months, tSCS was applied alone, then, physical therapy (PT) was included in the sessions (tSCS+PT), until completion of 20 months. Compared to baseline, at 20 months, an increase in ISNCSCI motor (50 vs. 57) and sensory scores (light touch, 72 vs. 82; pinprick, 71 vs. 92) were observed. Neurogenic Bladder Symptoms Score (NBSS) changed from 27 at baseline to 17 at 20 months. ISAFSCI scores in sacral autonomic function improved from 0 pts (absent function) to 1 pt. (altered function) indicating better sphincter control. As this is the first report on the use of tSCS in the case of SI, future studies in a case series are warranted.

Our new manuscript “Selective Activation of the Spinal Cord with Epidural Electrical Stimulation”.

In this study, we exploited different ESS paradigms, designed as either Spatial-Selective Stimulation (SSES) or Orientation-Selective Epidural Stimulation (OSES), and compared them to Conventional Monopolar Epidural Stimulation (CMES). SSES, OSES, and CMES. The results demonstrate that the amplitudes of SEMPs in hindlimb muscles depend on the orientation of the electrical field and vary between stimulation modalities. These findings show that the electric field applied with SSES or OSES provides more selective control of amplitudes of the SEMPs as compared to CMES. Spinal cord epidural stimulation applied with SSES or OSES paradigms in the rodent model could be tailored to the functional spinal cord neuroanatomy.

New manuscript “Consecutive Transcutaneous and Epidural Spinal Cord Neuromodulation to Modify Clinical Complete Paralysis—the Proof of Concept”.

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 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. 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. 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. 

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

Pathological changes associated with spinal cord injury can be observed distant, rostral, or caudal to the epicenter of injury. The present study aimed to investigate the following in relation to SCI: distant changes in the spinal cord, peripheral nerve, and muscles. 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

New manuscript “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.

New study “Neurointerface with Oscillator Motifs for inhibitory
effect over antagonist muscles for compensation of
spastical syndrome”.

The inhibitory management effect 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 the approach for the compensatory
stimulation device in development of previously presented architecture of neurointerface, where neuroport is implemented as DAC and stimulator, neuroterminal – as neurosimulation
of a set of oscillator motifs on one-board computer.

In the set of experiments with 5 volunteers we measured the efficacy of motor neuron inhibition via 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 agonist and antagonist muscles and nerves, we experimented with delays between muscles stimulation starts in the range 0…20 ms. We registered the subjective discomfort rate. We didn’t identify a significant difference between antagonist
muscle and nerve stimulation in both voluntary and stimulation of agonist activity. We determined the most effective delay between stimulation of agonist and antagonist muscle/nerve as 10–20 ms.

Our new manuscript “Epidural electrical spinal cord stimulation of the thoracic segments (T2-T5) facilitates respiratory function in patients with complete spinal cord injury” is out in Resp. Physiology & Neurobiology.

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. 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 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.

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.

Our new manuscript “Implementing Principles of Neuroontogenesis and Neuroplasticity for Spinal Cord Injury Therapy“

Starting with the works of Santiago Ramon y Cajal, the problem of neuroregeneration remains one of the most important in neurobiology with still resonating the prophetic statement of Cajal: “…once development was ended, the founts of growth and regeneration of the axons and dendrites dried up irrevocably. In adult centres the nerve paths are something fixed, ended, immutable. Everything may die, nothing may be regenerated. It is for the science of the future to change, if possible, this harsh decree”

Our manuscript “The Translesional Spinal Network and Its Reorganization after Spinal Cord Injury” is out in ‘The Neuroscientist’.

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.

New study “The Effect of Non-invasive Spinal Cord Stimulation on Anorectal Function in Individuals With Spinal Cord Injury: A Case Series” is out in Frontiers in Neuroscience. 

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. 

These pilot data 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.

Our new manuscript “New Therapy for Spinal Cord Injury: Autologous Genetically-Enriched Leucoconcentrate Integrated with Epidural Electrical Stimulation”  is out in Cells.

In this study, a novel regenerative approach using an autologous leucoconcentrate enriched with transgenes encoding VEGF, GDNF, and NCAM combined with supra- and sub-lesional epidural electrical stimulation was tested on mini-pigs. The analysis of the spinal cord recovery after a moderate contusion injury in treated mini-pigs compared to control animals revealed better performance in behavioral 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 epidural stimulation 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. 

This work is a part of exciting long-term collaboration with Professor Islamov and his team.

Our new study “Newly regenerated axons via scaffolds promote sub-lesional reorganization and motor recovery with epidural electrical stimulation” is out in NPJ Regenerative Medicine. This project was possible because of amazing efforts of Ahad and Riaz, fantastic collaboration with Dr. Windebank and Dr. Yaszemski, and hard work of all colleagues involved in this study!

In this study a combination of regenerative scaffold technology with spinal cord neuromodulation was validated and tested after complete spinal transection. Our results demonstrate that newly regenerated axons through the cell-containing scaffold with epidural electrical stimulation can reorganize sub-lesional circuitry and improve motor performance. 

The results of this work for the first time demonstrate that neuroregenerative therapy and neuromodulation cumulatively enhancing motor function after anatomically complete spinal cord injury, providing a platform for synergistic testing and translation of regenerative and neuromodulatory therapies to maximize functional restoration after severe spinal cord injury.

Our new study “Pre-motor vs. motor cerebral cortex neuromodulation for chronic neuropathic pain”  is out in ‘Scientific Reports’. 

In this 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 the effect of subdural cerebral cortex stimulation. Locations of the temporary grid electrodes and permanent electrodes were evaluated in correlation with the long‑term efficacy of cortical stimulation in nine subjects with chronic neuropathic pain.

Results demonstrate that the long‑term effect of subdural pre‑motor cortex stimulation is at least the same or higher compare to effect of motor or combined pre‑motor and motor cortex stimulation. These results also show that the initial trial stimulation helps to optimize permanent electrode positions in relation to the optimal functional target.

Proposed methodology and novel results open a new potential for development of neuromodulation techniques to control chronic neuropathic pain.

Understanding of the spinal cord functional neuroanatomy is essential for diagnosis and treatment of multiple disorders including, chronic pain, movement disorders, and spinal cord injury. Although the role of the main spinal cord structures in neuromodulation therapy was broadly discussed, till now, there is no solid information on segment-specific distribution of the spinal roots and other spinal structures in humans. Previously we demonstrated the role of the spinal cord neuroanatomy иn effect of epidural stimulation to evoke motor responses. Positioning the electrode close to the dorsal roots produced a significantly higher motor response than shift of the electrode from segment to segment. These results couldn’t be collected on small models, like rats, due to different anatomy and we used a swine model to further translate these findings to human:

https://www.frontiersin.org/articles/10.3389/fnana.2017.00082/full

The multiple aspects of the spinal cord anatomy are still unknown for humans. In our study published in Mayo Clinic Proceedings we collected neuroanatomical measurements of the spinal roots across the spinal cord segments, together with spinal cord and vertebral bones measurements on cadavers. A spatial orientation of the dorsal and ventral roots and spinal structures was correlated to selected bone landmarks. These results demonstrate less variability in rostral root angles compared to the caudal angles across all segments and different orientation of the dorsal and ventral rootlets at the cervical, thoracic, and lumbar segments. Additional information on segment-specific variation in number of rootlets and other spinal measurements was provided. We also demonstrate the strongest correlation between the length of intervertebral foramen to rostral rootlet and vertebral bone length.

https://www.sciencedirect.com/science/article/abs/pii/S0025619620310570

As spinal cord neuromodulation strategies continue to evolve and novel spinal interfaces translated to clinical practice, the results of these studies will be important to precisely locate spinal roots and spinal cord structures for stimulation or surgical procedures. These results will help to improve stereotactic surgical procedures and electrode positioning for therapy of chronic pain, spinal cord injury and other conditions.

Our new study “Comparison of systemic and localized carrier-mediated delivery of methylprednisolone succinate for treatment of acute spinal cord injury” published in Experimental Brain Research. This work is based on early described the proof of principle of carrier-mediated administration for spinal cord injury.

In new study we evaluate 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 spinal cord injury. Following local vs. systemic application, functional improvement was observed with MPS+TBS compared with either local or systemic MPS administration alone. The use of TBC carrier increased the active substance content in treated tissues by more than four times compare to either local or systemic MPS administration.

These findings suggest that the local treatment of acute SCI could be enhanced with mixed micelles with TBC, increasing local drug accumulation, improving therapeutic outcome, and reducing side effects.

Our new manuscript “Epidural Stimulation Combined with Triple Gene Therapy for Spinal Cord Injury Treatment” has been published in IJMS and now is online.

Here we report functional restoration and morphological reorganization after spinal contusion in mini pigs, following a combined treatment of locomotor training facilitated with epidural electrical stimulation (EES) and cell-mediated triple gene therapy with umbilical cord blood mononuclear cells overexpressing recombinant vascular endothelial growth factor, glial-derived neurotrophic factor, and neural cell adhesion molecule. Results demonstrate positive effect of combined EES-facilitated motor training and cell-mediated triple gene therapy after spinal contusion in large animals, informing a background for further studies and clinical translation. This work is a product of long-term collaboration with Professor Islamov and his team.

A new manuscript “Combined Supra- and Sub-Lesional Epidural Electrical Stimulation for Restoration of the Motor Functions after Spinal Cord Injury in Mini Pigs” is out in ‘Brain Sciences’.

In this study we evaluated the effect of epidural electrical stimulation applied at the cervical (C5) and lumbar (L2) segments on functional restoration following spinal cord contusion that could be related with facilitation of the spinal circuitry at both levels and activation of complex multisegmental coordination across supra-lesional and sub-lesional spinal networks. These findings suggest that locomotor training enabled with combined electrical stimulation may improve the functional restoration through the reorganization of translesional spinal network. Tested approach can be potentially taken as a basis for the future development of new therapeutic protocols for neuromodulation and neurorehabilitation in patients with severe spinal cord injury.

Our new work “Translesional Spinal Network and its Reorganization After Spinal Cord Injury” is out in ‘The Neuroscientist’. Special congrats to Petr Krupa who did fantastic job on this manuscript!

In this prospective manuscript we evaluate available evidence that sub- and supralesional spinal circuitries could form a ‘translesional spinal network’. We discuss the supralesional changes, particularly cortical and brain stem reorganization after spinal cord injury, as well as the newly formed detour pathways in the spinal cord that are responsible for mediating supraspinal signaling to sublesional network and the potential role of the major spinal pathways in transmitting signals via residual connections that span the injury. Furthermore, we evaluate available evidence which demonstrates supra- and sublesional changes in the spinal cord circuitry and present new evidence supporting the concept of translesional and sublesional reorganization, which can be facilitated by emerging therapies, such as spinal cord stimulation with dynamic rehabilitation to recover functions in humans with paralysis.

on ResearchGate

Finally, we discuss the potential of neuromodulation technologies to engage various components that comprise the translesional network and the implications of the concept of translesional network on development of future neuromodulation, rehabilitation, and neuroprosthetics technologies.

A new manuscript ‘Changes in spinal cord hemodynamics reflect modulation of spinal network with different parameters of epidural stimulation’ is out in ‘NeuroImage’. This exciting work is a product of fantastic collaboration with Dr. Chen (Mayo Clinic) and Dr. Song (UIUC)

In this study we show that the transient hemodynamic changes in the spinal cord during electrical epidural stimulation respond to the changes in parameters of stimulation that likely reflect modulation of the spinal cord circuitry and neurovascular coupling. The results of this work open a new direction for quantitative evaluation of the spinal cord hemodynamic, understanding a new level of spinal cord functional organization, and real-time mechanisms of neuromodulation.

A new manuscript titled ‘Supraspinal and Afferent Signaling Facilitate Spinal Sensorimotor Network Excitability After Discomplete Spinal Cord Injury‘: A Case Report’ is out Frontiers in Neuroscience.

The results of this work demonstrate that the afferent flow can provide necessary excitation of spinal cord circuitry, helping in identification of neural connections, which can be further enhanced with rehabilitation and neuromodulation therapy. We show that combination of electrophysiological techniques with positional and reinforcement maneuvers can help in diagnostics of discomplete SCI. Thus, integration of supraspinal and afferent flow on sub-lesional circuitry plays a critical role in facilitation of spinal network after SCI.

A new manuscript on Multifactorial behavioral assessment that integrates electrophysiological and biomechanical properties with behavioral aspects of motor task performance now is out in Sci Reports

Multifactorial Behavioral Assessment (MfBA) integrates simultaneously records of limb kinematics, multi-directional forces and electrophysiological metrics. The latest one represents the key and integrative part of this approach, providing information about intramuscular motor evoked responses synchronized in time to spinal stimulation during different motor tasks in order to characterize different components of spinal cord functional motor evoked potentials (fMEPs).

Multifactorial Behavioral Assessment (MfBA) integrates simultaneously records of limb kinematics, multi-directional forces and electrophysiological metrics. The latest one represents the key and integrative part of this approach, providing information about intramuscular motor evoked responses synchronized in time to spinal stimulation during different motor tasks in order to characterize different components of spinal cord functional motor evoked potentials (fMEPs). The results presented in new manuscript demonstrate the this approach is capable of integrating multiple metrics of motor activity in order to characterize relationships between stimulation and sensory inputs that modulate mono- and polysynaptic outputs from spinal circuitry.

MfBA combined with fMEP analysis is effective tool for at dissecting therapeutically-enabled characteristics of motor performance and at targeting of different components of locomotor circuitry related with variations in motor behavior. This approach and designed for this purpose BWS system provide a platform for future investigations of the interactions between CNS inputs and outputs while manipulating external perturbations, and therapeutic administration in order to better understand how the CNS coordinates and executes complex motor tasks in healthy animals and in animals with neurologic deficit at different CNS levels.

Effect of spinal cord electrical stimulation to modulate local hemodynamic evaluated with functional ultrasound (fUS): “Functional Ultrasound Imaging of Spinal Cord Hemodynamic Responses to Epidural Electrical Stimulation: A Feasibility Study”. This is collaborative work with Dr. Song (UIUC) and Dr. Chen  and Dr. Tang (Mayo Clinic).

It represents the first implementation of fUS to explore functional organization of the spinal cord hemodynamics and provides results on correlations between SCS induced neural activities and local hemodynamics changes. The fUS measurements indicate temporal and spatial resolutions not achievable by other in vivo electrophysiological methods. 

Electrical epidural stimulation (EES) has been successfully applied to control chronic refractory pain and was evolved to alleviate motor impairment after spinal cord injury, in Parkinson’s disease, and other neurological conditions. The mechanisms underlying the EES remain unclear, and current methods for monitoring EES are limited in sensitivity and spatiotemporal resolutions to evaluate functional changes in response to EES. We tested the hypothesis that the transient hemodynamic response of the spinal cord to EES could reflect modulation of the spinal cord circuitry and accordingly respond to the changes in parameters of EES. The proposed methodology opens a new direction for quantitative evaluation of the spinal cord hemodynamic in understanding the mechanisms of spinal cord functional organization and effect of neuromodulation.