Assessment of the combined effects of chondroitinase and autologous Schwann cells on hand function after cervical SCI in primates

Abstract
Introduction: Chondroitinase ABC and Schwann cells have been shown independently to promote functional recovery in rodents after contusive injury. Autologous human Schwann cells ahSC are being tested in Phase 1 clinical trials for sub-acute and chronic SCI. Recognizing the necessity of combination strategies, we are exploring the acute injection of a lentiviral transfer vector carrying a mammalian compatible engineered chABC gene (LV-chABC), with or without sub-acute aSC transplantation, in primates following unilateral C3/4 SCI. Here, we present the preliminary evaluation of the hand and arm recovery up to six months post-injury and treatment. Methods: Seven young adult male primates (Macaca fascicularis) received a right-sided hemi-contusion using the Miami Large Animal Impactor. They were randomized into: Injury only controls (n=2), Injury + 2 hours post-injury perilesional injection of LV-chABC (n=3), and Injury + LV-chABC injection + aSC transplant 14 days post-SCI (n=2). Animals were acclimatized to be comfortable within a primate chair and also provided with cage objects to promote grasp practice. They were trained to retrieve food pellets from a modified Brinkman board consisting of 20 cross-shaped slots suited to the monkeys’ fingers. The board was presented in the horizontal and vertical planes (relative to the floor) to test arm and shoulder strength, wrist rotation and thenar opposition. Both hands were exposed to the tasks equally during the pre and post injury phases.
Results: Significant differences in retrieval time and retrieval quality were found between the left (control) and right (injured) hand in each animal and between the 3 groups as of 6 months post-injury. LV-chABC injected animals showed the most rapid recovery. Additionally observed differences include the rate to reach hand function plateau and the variety of strategies developed to perform the task.
Conclusions: Animals continue to survive. The tests discriminate recovery of fine dexterity of finger movements from adaptation strategies. Deficits and recovery of combined upper and lower extremity gait coupling are assessed with treadmill kinematics.

Authors
*A. Y. FLORES1, A. J. SANTAMARIA1, R. DE NEGRI1, F. D. BENAVIDES1, N. D. JAMES4, Y. NUNEZ-GOMEZ2, J. P. SOLANO2, J. VERHAAGEN5,6, E. J. BRADBURY4, J. D. GUEST1,3;
1Miami Project to Cure Paralysis, 2Pediatric Critical Care, 3Neurolog. Surgery, Univ. of Miami, Miller Sch. of Med., Miami, FL; 4The Wolfson Ctr. for Age-Related Dis., King’s Col., London, United Kingdom; 5Lab. for Neuroregeneration, Netherlands Inst. for Neurosci., Amsterdam, Netherlands; 6Ctr. for Neurogenomics and Cognition research, Vrije Univ. Amsterdam, Amsterdam, Netherlands
Disclosures
A.Y. Flores: None. A.J. Santamaria: None. R. de Negri: None. F.D. Benavides: None. N.D. James: None. Y. Nunez-Gomez: None. J.P. Solano: None. J. Verhaagen: None. E.J. Bradbury: None. J.D. Guest: None.

LINK: Session 158 – Spinal Cord Injury and Plasticity

Posted in Chronic Spinal Cord Injury Research, Neuroscience Abstracts, Regenerative Medicine, Rehabilitation, Spinal Research, Stem Cell Research | Leave a comment

Selective late I-wave stimulation enhances voluntary motor output after SCI

Abstract
Targeted stimulation of the corticospinal tract has been shown to improve voluntary motor output in humans with spinal cord injury (SCI; Bunday and Perez, 2012). Here, we used a novel protocol that targeted late synaptic inputs into corticospinal neurons in humans with and without incomplete cervical chronic SCI. We used 180 paired transcranial magnetic stimulation (TMS) pulses over the hand representation of the primary motor cortex at interstimulus intervals of 4.3 ms (targeting I3-wave circuits; iTMS protocol) and 3.5 ms (targeting no I-wave interval; control protocol) at 0.1 Hz for a total of 30 min. Motor evoked potentials (MEPs) in an intrinsic finger muscle where measured at rest before, immediately after, and up to 30 min after the stimulation with the coil oriented to induce currents in the brain in the posterior-anterior (PA) and anterior-posterior (AP) direction to preferentially activate early and late synaptic inputs to corticospinal neurons, respectively. We found that MEPs size increased in the AP but not in the PA direction after the iTMS protocol for up to 30 min after the stimulation in control (by ~175%) and SCI (by ~142%) participants. No changes in MEP size were observed after the control protocol when tested with the coil either in the PA or AP direction in both groups. Notably, EMG and force outcomes during index finger abduction increased after the iTMS protocol in control (EMG by ~135%; force by ~129%) and SCI (EMG by ~130%; force by ~127%) participants. No changes were observed after the control protocol. SCI subjects needed ~15% less time to complete the nine-hold-peg-test after the iTMS protocol compared to baseline. Thus, we propose that targeting late synaptic inputs into corticospinal neurons might represent a novel strategy for enhancing corticospinal drive and voluntary motor output after human SCI.

Authors
J. LONG, P. FEDERICO, *S. LEHMANN, M. A. PEREZ;
Dept. of Neurolog. Surgery, The Miami Project to Cure Paralysis, Univ. of Miami, Miami, FL
Disclosures
J. Long: None. P. Federico: None. S. Lehmann: None. M.A. Perez: None.

LINK: Session 158 – Spinal Cord Injury and Plasticity

Posted in Chronic Spinal Cord Injury Research, Neuroscience Abstracts, Rehabilitation, Spinal Research | 1 Comment

Restoring Bladder, Bowel and Sexual Function after SCI – Berkeley Spinal Network

Presenter: Graham Creasey, MD, Professor of Spinal Cord Injury Medicine, Stanford University

Dr. Creasey discusses a pacemaker developed in Britain that is capable of producing an erection as well as emptying the bladder and bowel, reducing infection and the use of catheters by men and women with SCI. Dr. Creasey is developing this solution further for people with SCI in the US. The presentation describes the advances made and future directions in the control of bladder function.

ClinicalTrials.gov: NCT02978638

If you are interested in the clinical trial, you may contact one of the following:

Dr. Creasey gcreasey@stanford.edu
Dr. Zhao shenru.zhao@va.gov
Dr. Latev zoia.latev@va.gov
Dr. Ehsanian rezaehsanian@gmail.com

Posted in Chronic Spinal Cord Injury Research, Rehabilitation, Spinal Research | Tagged | 1 Comment

Improvements in bladder, bowel and sexual outcomes following task specific training in human SCI

Abstract
The loss of urogenital and bowel functions are some of the most important sequalae as a result of spinal cord injury (SCI). In an upper motor neuron (UMN) injury, a neurogenic bladder may manifest as a failure to store, characterized by uninhibited bladder contractions and an areflexic outlet or as a failure to empty with an areflexic bladder and a sphincter that is unable to relax. An UMN injury also results in increased colonic and anal tone and as a result, constipation and fecal retention are prevalent. Depending on the degree of preserved neurologic function, in men with SCI, reflexogenic erections may be achieved but not necessarily maintained and most often ejaculation is impaired. In females with SCI, impairments in genital responses and sexual arousal are common, while the impact of injury on fertility is not as severe as it is in men. While standard pharmacological therapy aims to manage the prevalent urogenital and bowel issues, therapies addressing recovery of function are still needed. Locomotor training (LT) is one such tool which has been shown to be effective for improving post-SCI motor outcomes, but has also been shown to have a beneficial impact on responses from autonomic systems, such as with cardiovascular and respiratory. Given the overlap of neural networks controlling the pelvic viscera and locomotor function in the lumbosacral cord, we hypothesized that a viscerosomatic relationship is influenced by LT resulting in improved bladder, bowel and sexual function. In this study, eight subjects who sustained a SCI received 80 daily 1-hr sessions of LT on a treadmill, using body-weight support, or 1-hr of LT and stand training (on alternate days). Urodynamic assessments were performed at pre-and post-training time points, revealing significant increases in bladder capacity, voiding efficiency and detrusor contraction time as well as a significant decrease in voiding pressure post-training. Questionnaires were used to assess bowel and sexual function management and it was found that post-training there was a significant decrease in the time required for defecation as well as a significant increase in sexual desire. These results suggest there is an appropriate level of sensory information provided to the spinal cord, generated through task-specific stepping and/or loading, which appears to influence the neural circuitry involved urogenital and bowel control.

Authors
*A. N. HERRITY1, C. HUBSCHER2, L. MONTGOMERY2, A. WILLHITE1, C. ANGELI1, S. HARKEMA1;
1Univ. of Louisville, Frazier Rehab Neurosci. Collaborative Ctr., Louisville, KY; 2Anatom. Sci. & Neurobiol., Univ. of Louisville, Louisville, KY
Disclosures
A.N. Herrity: None. C. Hubscher: None. L. Montgomery: None. A. Willhite: None. C. Angeli: None. S. Harkema: None.

LINK: Session 158 – Spinal Cord Injury and Plasticity

Posted in Chronic Spinal Cord Injury Research, Neuroscience Abstracts, Rehabilitation, Spinal Research | Leave a comment

Parameters of multi muscle neuromuscular stimulation: Effect on Muscle Volume

Abstract
Acute spinal cord injury often leads to rapid muscle atrophy in the paralyzed limbs. Recently, we have shown that an intense novel form of standardized multi-muscle neuromuscular electrical stimulation (NMES) combined with dynamic standing retraining tasks may potentially restore muscle structure and function after a sub acute to chronic, motor-complete spinal cord injury. Specifically, we have presented data for a large number of standardized repetitive task specific training sessions of multi muscle NMES of the lower limbs combined with mechanical loading to demonstrate an increase in bilateral muscle volume in conjunction with a significant increase in flexor and extensor muscle activation amplitude during continuous stepping. However, reported data has been for a small sample. We will present data for a much larger cohort to show the effect of NMES (35 Hz, 300usec) training on muscle cross sectional area/muscle volume of the left and right lower limb. Data for longitudinal training effect of NMES training combined with loading compared to the “no loading” or the “no NMES” group shows a significant increase in average muscle volume for each of anterior, posterior and total lower limb muscle groups. Furthermore, for the multi-muscle “NMES loaded” group there was an increase in cross sectional area throughout slices within the limb. The “NMES alone” group (unloaded) compared to “no NMES” group shows a significant increase in average muscle volume in the lower limbs particularly in the posterior lower limb.

Authors
*G. F. FORREST1, E. REJC2, E. GARBARIN3, A. RAMANUJAM3, J. AUGUSTINE3, S. J. HARKEMA2;
1Kessler Fndn. Res. Ctr., West Orange, NJ; 2Univ. of Lousiville, Louisville, KY; 3Kessler Fndn., West Orange, NJ
Disclosures
G.F. Forrest: B. Contracted Research/Research Grant (principal investigator for a drug study, collaborator or consultant and pending and current grants). If you are a PI for a drug study, report that research relationship even if those funds come to an institution.; New Jersey on Spinal Cord Research. E. Rejc: None. E. Garbarin: None. A. Ramanujam: None. J. Augustine: None. S.J. Harkema: None.

LINK: Session 158 – Spinal Cord Injury and Plasticity

Posted in Chronic Spinal Cord Injury Research, Rehabilitation, Spinal Research | Leave a comment

Lower limb electrical stimulation alters trunk stability in individuals with spinal cord injury

Abstract
Loss of movement ability below the level of injury is often a consequence of spinal cord injury (SCI). Subsequently, the associated rapid muscle atrophy after the injury may negatively affect overall functional recovery. Previously, our data have shown that a novel form of multi-muscle electrical stimulation (ES) combined with dynamic stand retraining task (SRT) can increase the amplitude of muscle activation in the lower limbs during continuous step training. Our early preliminary data also demonstrated that this dynamic clinical intervention could also potentially improve trunk stability during stepping and standing. The purpose of the present study was to further examine trunk stability in persons with motor-complete SCI during the first minute of a 10-minute stepping bout on a treadmill, using an overhead body-weight support system, before and after the SRT+ES clinical intervention. Sixty sessions of electrical stimulation was applied 4-5 times per week, for 60 minutes each. Symmetrical, biphasic pulses of 300 µs at 35 Hz were delivered to four lower limb muscles over a duty cycle of 11 seconds on and 60 seconds off. During treadmill stepping, trunk stability was measured by examining 2-dimensional spatial and temporal profiles of Center of Mass (CoM), as well as the underlying neuromuscular changes that precipitate the alterations in postural mechanics.Our results demonstrated that the training, which combines the SRT and ES, improves trunk stability by showing a decrease in the anterior-posterior excursions of the CoM. Greater anterior-posterior excursions before the training might be due to a deliberate activation of the trunk muscles during treadmill stepping in order to maintain stability and postural form. However, after the training, it could be argued that the major contribution to the movement is not from the trunk, but the pelvis during treadmill stepping. Furthermore, overall consistency of the CoM excursions across multiple gait cycles improved after the SRT+ES training.

Authors
*K. MOMENI, S. CANTON, A. RAMANUJAM, E. GARBARINI, G. F. FORREST;
Human Performance and Engin. Res., Kessler Fndn., West Orange, NJ
Disclosures
K. Momeni: None. S. Canton: None. A. Ramanujam: None. E. Garbarini: None. G.F. Forrest: None.
LINK: Session 158 – Spinal Cord Injury and Plasticity

Posted in Chronic Spinal Cord Injury Research, Rehabilitation, Spinal Research | Leave a comment

Comparative transcriptomic analysis of sprouting and regenerating corticospinal neurons

Abstract
The corticospinal tract (CST) is a critical motor system in humans for voluntary movement. The inability of adult corticospinal axons to spontaneously regenerate after spinal cord injury (SCI) may be attributable in part to incomplete activation of neuronal growth programs after injury. Recently we reported that robust corticospinal regeneration can be elicited in neural stem cell (NSC) grafts implanted into sites of injury (Kadoya et al., Nat Med 2016). To gain insight into intrinsic corticospinal neuronal mechanisms associated with successful regeneration, we performed transcriptomic analysis of regenerating corticospinal neurons. In a second study, we performed complimentary transcriptomic analysis on CST neurons in which compensatory regenerative sprouting was triggered by a unilateral pyramidotomy. Bioinformatic data mining and gene regulatory network analysis of both datasets revealed several master regulatory hub genes that are converging in both models. We are now testing several of these potential master regulators of regeneration in in vitro and in vivo models of spinal cord injury.

Authors
*G. H. POPLAWSKI1, K. KHOO1, N. MEHTA1, R. KAWAGUCHI2, E. ROSENZWEIG1, K. KADOYA1, P. LU1, G. COPPOLA2, M. TUSZYNSKI1;
1Neurosci., Univ. of California San Diego, La Jolla, CA; 2Departments of Psychiatry & Neurol., UC Los Angeles, Los Angeles, CA
Disclosures
G.H. Poplawski: None. K. Khoo: None. N. Mehta: None. R. Kawaguchi: None. E. Rosenzweig: None. K. Kadoya: None. P. Lu: None. G. Coppola: None. M. Tuszynski: None.

LINK: Session 142 – Mechanisms in Spinal Cord Injury

Posted in Chronic Spinal Cord Injury Research, Neuroscience Abstracts, Regenerative Medicine, Spinal Research

Working 2 Walk Panel Discussion with Carrie Shogren and Nick Terrafranca

The Working 2 Walk audience asks questions about the presentations given by Ms. Shogren and Dr. Terrafranca.

Carrie Shogren OTR/L Courage Kenny Rehabilitation Institute Outpatient, Independent Living Services, Transitional Rehab Program and now the ABLE program. NeuroRecovery Network (NRN) Community Fitness and Wellness Facility supervisor

Carrie Shogren OTR/L
Courage Kenny Rehabilitation Institute Outpatient, Independent Living Services, Transitional Rehab Program and now the ABLE program. NeuroRecovery Network (NRN) Community Fitness and Wellness Facility supervisor

Nick Terrafranca, CEO NeuroRecovery Technologies Inc

Nick Terrafranca, CEO NeuroRecovery Technologies Inc

Posted in Chronic Spinal Cord Injury Research, Rehabilitation, Spinal Research, Unite 2 Fight Paralysis, Working 2 Walk Science & Advocacy Symposium | Tagged ,

LPA pathway modulates intrinsic axon growth of intact CNS neurons after spinal cord injury

Abstract
Neurons in the adult central nervous system (CNS) are unable to regenerate after spinal cord injury (SCI) due to an inhibitory environment and a decreased intrinsic growth capacity. Modulating environmental inhibitors and their neuronal receptors such as Nogo Receptor 1 (NgR1) results in increased regeneration and sprouting of intact neurons spared by injury, which correlates with enhanced functional recovery. Cell intrinsic factors also increase regeneration and sprouting, but side effects and limited functional improvements suggest these factors do not activate endogenous sprouting mechanisms. We sought to identify the mechanisms underlying spontaneous sprouting of intact neurons after incomplete SCI. We completed a unilateral corticospinal tract (CST) lesion (pyramidotomy, PyX) in transgenic wild type (n=6) and NgR1 knockout mice (ngr1-/-, n=6) expressing GFP under the µ-crystallin (crym) promoter (crym-GFP) for intrinsic corticospinal tract (CST) labeling. Two weeks post-lesion, mice received infusion of the retrograde tracer fast blue (FB) into the denervated spinal cord to label sprouting CST neurons. Two weeks later, we used laser capture microdissection to isolate CST neurons in a quiescent (GFP+FB-) or active (GFP+FB+) growth state. With enhanced sprouting in ngr1-/- mice, an abundance of FB+ sprouting neurons allowed us to complete RNAseq and conduct a transcriptomic analysis. 1174 genes were significantly differentially expressed (SDE) between sprouting and quiescent neurons, with lysophosphatidic acid (LPA) receptor 1 (lpar1) the most downregulated gene in sprouting neurons. Lpar1 interactors, including a negative regulator of Lpar1, lipid phosphate phosphatase related protein 1 (lppr1), were also SDE in sprouting neurons, suggesting a role for the LPA pathway in regulating intrinsic CNS axon growth. Overexpressing Lppr1 in cortical neurons in vitro resulted in an increase in neurite outgrowth and an increase in growth in an in vitro injury model. Next we sought to determine if modulating the LPA pathway in vivo would enhance functional sprouting. Adult wild type mice received PyX or sham lesion and either cortical infusion of AAV-Lppr1 (n=21), oral treatment with an Lpar1 antagonist AM095 (n=15), or vehicle control (n=19). Lppr1-expressing and AM095-treated mice had significantly enhanced sprouting of CST neurons into the denervated ventral horn and AM095-treated mice recovered greater fore and hind limb function in a grid walking task. With these data, we have demonstrated that bidirectional modulation of the LPA pathway is beneficial for axon growth with therapeutic potential for restoring function after SCI.

Authors
*K. FINK, S. STRITTMATTER, W. CAFFERTY;
Yale Univ., New Haven, CT
Disclosures
K. Fink: None. S. Strittmatter: None. W. Cafferty: None.

LINK: Session 142 – Mechanisms in Spinal Cord Injury

Posted in Neuroscience Abstracts, Spinal Research | 1 Comment

Neuromuscular Electrical Stimulation and Optimizing Functional Recovery – Carrie Shogren

Ms. Shogren’s Working 2 Walk 2016 video presentation focuses on the clinical application of epidural stimulation, and how it drives neuro recovery when combined with activity based therapies.

Carrie Shogren OTR/L

Carrie Shogren OTR/L

Carrie Shogren, OTR/L, has worked at Courage Kenny Rehabilitation Institute since 2001 in outpatient, Independent Living Services, Transitional Rehab Program and now the ABLE program where she is the NeuroRecovery Network (NRN) Community Fitness and Wellness Facility supervisor. She also is a member of the NRN leadership team and co-director of the NRN. Her role includes being part of the workgroup that developed the ABLE program. As an OT and co-director in NRN she is leading a national group working on integration of OT into the clinical NRN sites. Carrie is also the staff supervisor for the adapted yoga program at Courage Kenny Rehabilitation Institute. She was recently published as co-author of “Assessment of functional improvement without compensation for human spinal cord injury: extending the Neuromuscular Recovery Scale to the upper extremities” in the Journal of Neurotrauma.

Posted in Chronic Spinal Cord Injury Research, Rehabilitation, Unite 2 Fight Paralysis, Working 2 Walk Science & Advocacy Symposium | Tagged