PROJƎCTS

Restoration of voluntary control of movements and posture after spinal cord injury in human.

Our recent clinical efforts with spinal cord neuromodulation went beyond expectations to show that epidural stimulation promotes voluntary movement, independent standing, and step-like activity. To further enhance volitional motor functionality in human with SCI, we are currently studying the effects of early-introduced noninvasive transcutaneous stimulation and epidural stimulation applied with temporary electrodes for initial assessment and pre-selection. Our following steps to extend this clinical research will include development of highly sensitive neurophysiological assessment to select the most responsive subjects to neuromodulation therapy and further improve optimization of neurostimulation protocols for recovery after spinal cord injury, using closed-loop control system and biofeedback.

Targeting spinal cord circuitry with segment-specific stimulation.

By relying on new results of spinal cord segments specific orientation of target structures for achieving selective electrical stimulation and advanced electrophysiological assessment established by our group, we are currently advancing the efficiency and specificity of spinal cord stimulation. The results of this ongoing work show that electrical stimulation applied based on segments-specific approach can target fibers with different orientation that could be utilized to activate spinal circuitry at lower thresholds stimulation and to guide multidirectional regeneration across the injury. To extend practical application of this technique we are also developing conceptually new stimulating electrode, designed to cover individual variation in neuroanatomy and a new navigational system for spinal surgery and for electrodes placement based on the first generation of human spinal cord mapping.

Spinal cord vascular changes evoked by spinal cord electrical stimulation tested with functional ultrasound (fUS)

Functional ultrasound (fUS) technique has recently been demonstrated to be able to robustly measure hemodynamic responses to stimulation in the brain through neurovascular coupling effect. fUS has superior spatial and temporal resolution compare to fMRI, and is directly correlated with blood flow volume change to stimulation. Recently, in collaboration with Dr. Song (UIUC) and Dr. Chen (Mayo Clinic), we have successfully validated capacity of fUS to assess changes in the spinal cord during epidural stimulation. Our results demonstrate that fUS has adequate spatial and temporal resolutions to investigate microvascular hemodynamics response to stimulation post SCI. In this ongoing collaboration we are planning to further evaluate the effect of different parameters of electrical stimulation on spinal cord hemodynamic response and functional reorganization of spinal cord microvascular system after SCI

Spinal cord sensory-motor network prosthesis

Although the whole domain of artificial neural networks was inspired by neuronal functions, up to now there is no successful artificial/electronic implementation of any functional unit of a nervous system. Using a novel electrophysiological assessment, we aim to re-implement a part of spinal cord circuitry responsible for motor pattern via synthetic neural circuit. Proposed neuromorphic prosthesis with self-learning and self-adaptation functions is radically different from direct or biofeedback based devices and implements functions of neuronal circuits including proposed topology of central pattern generator (CPG). This ‘synthetic spinal cord circuitry’ would closely replicate mammalian dynamics and functions and will be integrated via adapter/interface into biological nervous system. In this ongoing collaboration with Dr. Talanov (KFU), we are implementing the basic level of spinal cord reflexes and planning to extend it to the pattern formation level.

Using knowledge about spinal cord circuitry organization, we propose to further restore functions and dynamics of spinal cord circuitry using artificial networks implemented in electronic schematic topology that will be inherently self-learning and self-adaptive and thus flexible enough for the replication of basic functionality of the neuronal circuit. This can be envisioned as prosthesis or a part of a spinal cord, working together with machine-to-brain and brain-to-machine interfaces technologies to help synchronize multiple devices commonly used in neurorehabilitation and neurostimulation.

Mechanisms of engaging hind limb central pattern generators via lumbosacral epidural stimulation

The initiation of locomotor activity involves activation driven by spinal circuits commonly termed central pattern generator (CPG). The basic definition of CPG involves rhythmic motor activation even in the absence of supraspinal control or afferent feedback. In spite of the extensive literature describing different features of CPG, the majority of these studies in mammals have been done in acute experiments in paralyzed animals or in in vitro preparations. Moreover, studies providing additional information of the CPG during actual stepping in animals are still missing. Evidence of CPG activation during electrical epidural stimulation enabling motor activation in spinal rats and in humans after spinal cord injury supports the notion of the importance of afferent feedback as a determinant contribution to produce rhythmic motor output. Our current results support feasibility of collecting multiple modalities coming from sensory feedback for evaluation of motor performance facilitated by epidural stimulation in control and injured animals. With this approach we are able to target modulation of different parts of spinal circuitry based on analysis of spinal cord functional motor evoked responses during different tasks. The characterization of spinal cord circuitry will eventually lead to clinical translation of novel therapies and will aid in understanding the links between neurologic impairment and subsequent loss of locomotion.

The role of translesional network in restoration of motor functions with electrical stimulation.

In clinical trials with EES, subjects were diagnosed with motor complete injury, although, evidence suggests spared neural connections remain across the injury site. This injury profile has been defined as ‘discomplete’. Currently, there is no animal model that adequately represents the complex injury profile of discomplete SCI, and only few reports used neuromodulation to improve or guide neural tissue regeneration across the injury. Our new results demonstrate axonal regeneration across hydrogel scaffolds loaded with Schwann cells that expressed glial derived growth factor (GDNF) transplanted after spinal transection and behavioral recovery when spinal cord stimulation applied below the injury. Currently we are evaluating the role of sub- and supra-lesional networks in effect of EES with limited reconnection across implanted scaffold. We expect that findings of this study will facilitate development of novel algorithms for spinal cord stimulation with combined approach of stimulation at sub- and supra-lesional levels.

Prevention of neuropathic pain after SCI with locomotor training enabled by spinal cord electrical stimulation.

Neuropathic pain is a common complication of SCI. In most cases of neuropathic pain, available treatment options are not effective. It was reported that motor rehabilitation can improve and even prevent SCI-associated neuropathic pain when introduced before pain development. The therapeutic use of motor rehabilitation could be further strengthened with EES-enabled motor training to alleviate neuropathic pain and improve motor recovery after SCI. This is particularly important in cases of severe SCI causing paraplegia with limited motor control without electrical stimulation. In this collaboration with Dr. Chang (Mayo Clinic), using sophisticated electrophysiological recording and analysis, we will for the first time investigate the therapeutic effect of EES-enabled motor training on prevention and treatment of SCI-associated neuropathic pain and recovery of motor functions after severe SCI.

Combined neuromodulation therapy.

Progress of these ongoing projects will result in novel neuromodulation strategies for treatment of neural injury, enhancement of axonal growth, assessment of the spinal cord networks and their reorganization following injury. With the goal to cover the key principles of neuromodulation and neuronal repair, the results of this research will lead to the development of new neuromodulation and neurorehabilitation paradigms for prevention and treatment of chronic neuropathic pain, for improvement of motor performance after severe spinal cord injury and other neurological conditions.