Igor A. Lavrov

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

Abstract 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.

Spinal Epidural Stimulation Strategies: Clinical Implications of Locomotor Studies in Spinal Rats:

Significant advancements in spinal epidural stimulation (ES) strategies to enable volitional motor control in persons with a complete spinal cord injury (SCI) have generated much excitement in the field of neurorehabilitation. Still, an obvious gap lies in the ability of ES to effectively generate a robust locomotor stepping response after a complete SCI in rodents, but not in humans. In order to reveal potential discrepancies between rodent and human studies that account for this void, in this review, we summarize the findings of studies that have utilized ES strategies to enable successful hindlimb stepping in spinal rats. Recent clinical and preclinical evidence indicates that motor training with ES plays a crucial role in tuning spinal neural circuitry to generate meaningful motor output. Concurrently administered pharmacology can also facilitate the circuitry to provide near optimal motor performance in SCI rats. However, as of today, the evidence for pharmacological agents to enhance motor function in persons with complete SCI is insignificant. These and other recent findings discussed in this review provide insight into addressing the translational gap, guide the design of relevant preclinical experiments, and facilitate development of new approaches for motor recovery in patients with complete SCIs.

A pilot study of cell-mediated gene therapy for spinal cord injury in mini pigs

Currently, in clinical practice there is no efficient way to overcome the sequences of neurodegeneration after spinal cord traumatic injury. Using a new experimental model of spinal cord contusion injury on miniature pigs, we proposed to deliver therapeutic genes encoding vascular endothelial growth factor (VEGF), glial cell line-derived neurotrophic factor (GDNF) and neural cell adhesion molecule (NCAM) to the damaged area, using umbilical cord blood mononuclear cells (UCBC). In this study, genetically engineered UCBC (2×106 cells in 200 ml of saline) were injected intrathecally to mini-pigs 10days after SCI. Control and experimental mini pigs were observed for 60days after surgery. Histological, electrophysiological, and clinical evaluation demonstrated significant improvement in animal treated with genetically engineered UCBCs. Difference in recovery of the somatosensory evoked potentials and in histological findings in control and treated animals support the positive effect of the gene-cell constriction for recovery after spinal cord injury. Results of this study suggest that transplantation of UCBCs simultaneously transduced with three recombinant adenoviruses Ad5-VEGF, Ad5-GDNF and Ad5-NCAM represent a novel potentially successful approach for treatment of spinal cord injury.

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.In a human subject with chronic paraplegia, a combination of epidural electrical stimulation and long-term rehabilitative training have culminated in the first report of unassisted, voluntary independent stepping in a paralyzed individual.

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.

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.

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.

Evaluation of direct and cell-mediated triple-gene therapy in spinal cord injury in rats

Current treatment options for spinal cord injury (SCI) are scarce. One of the most promising innovative approaches include gene-therapy, however no single gene has so far been shown to be of clinical relevance. This study investigates the efficacy of various combinations of vascular endothelial growth factor (VEGF), glial cell-derived neurotrophic factor (GDNF), angiogenin (ANG) and neuronal cell adhesion molecule (NCAM) in rats. Multiple therapeutic genes were administered intrathecally either via adenoviral vectors or by using genetically modified human umbilical cord blood mononuclear cells (hUCBMCs). Following the induction of SCI, serial assessment of cord regeneration was performed, including morphometric analysis of gray and white matters, electrophysiology and behavioral test. The therapeutic gene combinations VEGF+GDNF+NCAM and VEGF+ANG+NCAM had positive outcomes on spinal cord regeneration, with enhanced recovery seen by the cell-based approach when compared to direct gene therapy. The efficacy of the genes and the delivery methods are discussed in this paper, recommending their potential use in 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.