Nerve growth At The Extremeties

Researchers have found a genetic signature located exclusively in the nerve cells that supply, or innervate, the muscles of an organism’s outermost extremities: the hands and feet. This signature, observed in both mice and chicks, involves the coordinated activity of multiple genes, and is fundamentally distinct from cells innervating nearby anatomical regions, such as more proximal muscles in the limb. The findings suggest that the evolution of the extremities may be related to the emergence of fine motor control, such as grasping — one of biology’s most essential adaptations.

The study, led by neuroscientists at Columbia University’s Mortimer B. Zuckerman Mind Brain Behavior Institute and New York University, was published in the journal Neuron.

“The emergence of hands, feet and digits — about 400 million years ago — represented a turning point in evolution; it helped the first land animals perform a variety of fine motor skills, like grasping, which eventually gave rise to the complex motor abilities that we humans use every day — from typing on a keyboard to painting a work of art,” said Thomas M. Jessell, PhD, the paper’s senior author and codirector of Columbia’s Zuckerman Institute. “But while fine motor control has proven critical for survival for hundreds of millions of years, little was known about how the nerve cells that extend to the tips of our fingers and toes make these skills possible.”

For this study, the researchers focused on motor neurons, the class of nerve cells that guide movement. Motor neurons achieve this by innervating specific muscles, and then relaying signals from the brain about how those muscles should move. The motor neurons that guide movement of the digits are called digit-innervating motor neurons.

“When we began this research, we were simply looking to compare key molecular features — namely gene activity — in motor neurons that supply different muscles in the leg,” said Alana Mendelsohn, an MD/PhD candidate at Columbia and the paper’s first author. “Instead, it soon became clear that the pattern of gene activity in the digit-innervating motor neurons in the foot was strikingly different compared to activity of motor neurons that innervate the more proximal muscles of the limb.”

Specifically, Mendelsohn observed that the motor neurons that supply both the hands and the feet did not produce a molecule called retinoic acid.

“One of the hallmark features of motor neurons is that they require retinoic acid for their growth and development,” said Mendelsohn. “But for some reason digit-innervating motor neurons weren’t producing it.”

Read the Full Article at Cell Science from Technology Networks LINK

Posted in Chronic Spinal Cord Injury Research, Gene Therapy, Regenerative Medicine, Spinal Research, Stem Cell Research

Noradrenergic pathways and epidural electrical stimulation synergistically modulate proprioceptive feedback circuits in order to restore locomotion after SCI

Several interventions exploiting chemical and electrical neuromodulation therapies have been designed to engage spinal sensorimotor circuits in order to facilitate the recovery of standing and walking after spinal cord injury. However, the mechanisms through which electrical and chemical stimulation modulate spinal circuits remain poorly understood. To study these mechanisms, we investigated the circuit-level interactions between noradrenergic receptor modulation and epidural electrical stimulation during standing and walking after a complete spinal cord injury. Previous work suggested that epidural electrical stimulation facilitates motor control through the modulation of proprioceptive feedback circuits. Using genetic deletion experiments and calcium imaging, we confirmed that epidural electrical stimulation promotes locomotion through the activation of proprioceptive feedback circuits. Anatomical experiments in genetically modified mice revealed that noradrenergic receptors are prominently expressed on these circuits. In turn, pharmacological testing in rats and genetic deletion in mice showed that the manipulation of noradrenergic pathways strongly modulated the gain in proprioceptive feedback circuits, which abolished or augmented the effects of epidural electrical stimulation. This electrochemical stimulation strategy restored robust locomotion in paralyzed animals. Our findings provide new insights into the mechanisms through which electrochemical neuromodulation therapies facilitate motor control after injury, and provide a framework to refine these interventions for clinical applications.

1EPFL, Lausanne, Switzerland; 2Pavlov Inst. of Physiol., Saint Petersburg, Russian Federation
K. Bartholdi: None. Q. Barraud: None. E. Formento: None. A. Rowald: None. P. Musienko: None. M. Capogrosso: None. G. Courtine: None.

LINK: Session 158 – Spinal Cord Injury and Plasticity

Technology Review LINK

Posted in Chronic Spinal Cord Injury Research, Neuroscience Abstracts, Rehabilitation, Spinal Research

Paul Knoepfler Stem Blog “The Niche” providing weekly Q & A.

The Niche LINK:

Segment 1.

Where is the stem cell field now and where the heck is it heading? There are hundreds of questions.

Readers often email me questions or leave them as comments. It’s not unusual to get questions about CRISPR as well.

As time permits, I’m hoping once or twice a month on Sundays to post a video answering some reader questions. Here’s today’s February 26th edition, focused on stem cells.

Posted in Regenerative Medicine, Spinal Research, Stem Cell Research, Uncategorized | Tagged

Electrical neuromodulation of the cervical spinal cord facilitates forelimb skilled function recovery in spinal cord injured rats

Abstract: Enabling motor control by epidural electrical stimulation of the spinal cord is a promising therapeutic technique for the recovery of motor function after a spinal cord injury (SCI). Although epidural electrical stimulation has resulted in improvement in hindlimb motor function, it is unknown whether it has any therapeutic benefit for improving forelimb fine motor function after a cervical SCI. We tested whether trains of pulses delivered at spinal cord segments C6 and C8 would facilitate the recovery of forelimb fine motor control after a cervical SCI in rats. Rats were trained to reach and grasp sugar pellets. Immediately after a dorsal funiculus crush at C4, the rats showed significant deficits in forelimb fine motor control. The rats were tested to reach and grasp with and without cervical epidural stimulation for 10 weeks post-injury. To determine the best stimulation parameters to activate the cervical spinal networks involved in forelimb motor function, monopolar and bipolar currents were delivered at varying frequencies (20, 40, and 60 Hz) concomitant with the reaching and grasping task. We found that cervical epidural stimulation increased reaching and grasping success rates compared to the no stimulation condition. Bipolar stimulation (C6– C8 + and C6 + C8–) produced the largest spinal motor-evoked potentials (sMEPs) and resulted in higher reaching and grasping success rates compared with monopolar stimulation (C6– Ref + and C8– Ref +). Forelimb performance was similar when tested at stimulation frequencies of 20, 40, and 60 Hz. We also found that the EMG activity in most forelimb muscles as well as the co-activation between flexor and extensor muscles increased post-injury. With epidural stimulation, however, this trend was reversed indicating that cervical epidural spinal cord stimulation has therapeutic potential for rehabilitation after a cervical SCI.

Monzurul Alama, 1, Guillermo Garcia-Aliasa, 1, Benita Jina, Jonathan Keyesa, Hui Zhonga, Roland R. Roya, b, Yury Gerasimenkoa, c, d, Daniel C. Lue, V. Reggie Edgertona, b, f, g, ,
a Department of Integrative Biology and Physiology, University of California, Los Angeles, CA 90095, United States
b Brain Research Institute, University of California, Los Angeles, CA 90095, United States
c Pavlov Institute of Physiology, St. Petersburg 199034, Russia
d Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420006, Russia
e Departments of Neurosurgery, University of California, Los Angeles, CA 90095, United States
f Departments of Neurobiology, University of California, Los Angeles, CA 90095, United States
g Departments of Neuroscience, University of California, Los Angeles, CA 90095, United States


Posted in Chronic Spinal Cord Injury Research, Spinal Research

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

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.

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
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

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

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.

Dept. of Neurolog. Surgery, The Miami Project to Cure Paralysis, Univ. of Miami, Miami, FL
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

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. NCT02978638

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

Dr. Creasey
Dr. Zhao
Dr. Latev
Dr. Ehsanian

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

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

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.

1Univ. of Louisville, Frazier Rehab Neurosci. Collaborative Ctr., Louisville, KY; 2Anatom. Sci. & Neurobiol., Univ. of Louisville, Louisville, KY
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

Parameters of multi muscle neuromuscular stimulation: Effect on Muscle Volume

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.

1Kessler Fndn. Res. Ctr., West Orange, NJ; 2Univ. of Lousiville, Louisville, KY; 3Kessler Fndn., West Orange, NJ
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

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

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.

Human Performance and Engin. Res., Kessler Fndn., West Orange, NJ
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