Enabling hand function in chronic spinal cord injury patients with non-invasive transcutaneous stimulation and buspirone: A double-blinded, sham controlled pilot study

Spinal cord injury (SCI) is one of the leading causes of long term paralysis. For patients with a chronic SCI treatment options are limited. Physical therapy can help maintain general health but little to no functional improvement is expected after the first year of injury. Epidural electrical stimulation of the spinal cord via an implanted epidural electrode array can improve leg function, stabilize posture, and enable volitional movement. Epidural stimulation can result in functional improvement of the hand in quadriplegic patients. In this study, we sought to determine if transcutaneous electrical stimulation of the cervical spinal cord along with oral monoaminergic agonist could result in similar functional improvement of the hand. Twelve subjects were recruited that had been injured for at least a year. Of the recruited subjects, ten of the twelve subjects were motor complete (ASIA score of A or B). It has been reported that training with a handgrip alone did not result in significant improvement in these subjects after chronic testing (Hoffman et al. 2017). For this study, subjects received transcutaneous stimulation alone or in combination with the partial 5HT1A agonist buspirone while training with the handgrip device. Transcutaneous stimulation significantly improved hand function in seven of the twelve enrolled. While buspirone did not improve hand function, in some subjects it reduced spasm severity.

Authors: *L. MOORE1, S. ZDUNOWSKI1, E. MORIKAWA1, T. SIERRO1, D. SAYENKO1, P. GAD1, T. HOMSEY1, M. NUWER1, D. REINKENSMEYER2, M. SARRAFZADEH1, D. MCARTHUR1, Y. GERASIMENKO1,3, V. R. EDGERTON1, D. C. LU1;
1Univ. of California, Los Angeles, CA; 2Univ. of California, Irvine, CA; 3Pavlov Inst. of Physiol., St. Petersburg, Russian Federation
Disclosures: L. Moore: None. S. Zdunowski: None. E. Morikawa: None. T. Sierro: None. D. Sayenko: None. P. Gad: None. T. Homsey: None. M. Nuwer: None. D. Reinkensmeyer: E. Ownership Interest (stock, stock options, royalty, receipt of intellectual property rights/patent holder, excluding diversified mutual funds); Flint Rehabilitation Devices, Hocoma. F. Consulting Fees (e.g., advisory boards); Hocoma. M. Sarrafzadeh: E. Ownership Interest (stock, stock options, royalty, receipt of intellectual property rights/patent holder, excluding diversified mutual funds); MediSens handgrip. D. McArthur: None. Y. Gerasimenko: E. Ownership Interest (stock, stock options, royalty, receipt of intellectual property rights/patent holder, excluding diversified mutual funds); NeuroRecovery Technologies. V.R. Edgerton: E. Ownership Interest (stock, stock options, royalty, receipt of intellectual property rights/patent holder, excluding diversified mutual funds); NeuroRecovery Technologies. D.C. Lu: E. Ownership Interest (stock, stock options, royalty, receipt of intellectual property rights/patent holder, excluding diversified mutual funds); NeuroRecovery Technologies.

Grant Support
J. Yang & Family Foundation
NIH: EB15521 and R01EB007615 grants, funded by NIBIB, NINDS, and NICHD
UCLA Clinical and Translational Research Center (CTRC)

NIH/National Center for Advancing Translational Science (NCATS) UCLA CTSI Grant

Society for Neuroscience LINK

Los Angeles Magazine Article

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Linking axon transport to regeneration using in vitro laser axotomy

Bart Nieuwenhuis

Abstract: Spinal cord injury has devastating consequences because adult central nervous system (CNS) neurons do not regenerate their axons after injury. Two key reasons for axon regeneration failure are extrinsic inhibitory factors and a low intrinsic capacity for axon regrowth. Research has therefore focused on overcoming extrinsic growth inhibition, and enhancing intrinsic regeneration capacity. Both of these issues will need to be addressed to enable optimal repair of the injured spinal cord.

To re-establish motor function after spinal cord injury, descending corticospinal axons need to regenerate over long distances and past the site of injury before making meaningful connections (Tedeschi and Bradke, 2017). Current approaches to overcome inhibitory molecules stimulate sprouting and plasticity leading to some recovery of function, but do not enable long-range axon regrowth. Approaches to enhance the neurons intrinsic capacity for regeneration also stimulate short-range growth leading to limited functional recovery, however there are currently no interventions that stimulate the regeneration of descending motor axons over long distances through the adult spinal cord. Long-range regeneration is possible through the spinal cord, as has been recently demonstrated for sensory neurons regenerating their axons from the periphery towards the brain (Cheah et al., 2016). This was made possible by providing the dorsal root ganglia (DRG) with an activated integrin, which allows axon growth over the extracellular matrix (ECM) molecule tenascin-C (which is upregulated in the spinal cord after injury). Integrins are cell surface receptors for ECM molecules that mediate axon growth during CNS development and adult peripheral nervous system (PNS) regeneration after injury. Integrin α9β1 is one of the receptors for tenascin-C and had been shown to promote axon growth and regeneration. Expression of α9 integrin together with its activator kindlin-1 endows sensory axons with the ability to ignore inactivation by injury-induced molecules leading to vigorous effects on regeneration and functional recovery (Cheah et al., 2016). This method works for ascending sensory axons because PNS neurons efficiently transport integrins into their axons, allowing them to drive regeneration from the axon surface. The approach could be used to drive long-range regeneration of descending motor axons in the corticospinal tract (CST), however integrins are not transported into these axons. AAV mediated delivery of α9 integrin into CST neurons allows transport of integrins into dendrites but not into axons (Andrews et al., 2016). Endogenous integrins are similarly not transported into adult CNS axons but instead confined to dendrites. Examining the mechanisms controlling axonal integrin transport could identify ways of directing integrins into CNS axons. This would mean that the integrin method which drives long-range sensory regeneration could be applied to CST motor neurons. It might also help us to understand whether the CNS blockade of integrin axon transport contributes to regenerative failure.

Read the Full Article at Neural Regeneration Research

Spinal cord injury can lead to damage of the corticospinal tract and thereby result in paralysis. My PhD project aims to promote regeneration of corticospinal tract in vivo because this is the key event to restore motor function.

The research strategy is based on an integrin engineering protocol that has produced substantial regeneration of sensory axons in the spinal cord. This was achieved by expressing integrins and their activator kindlin in injured sensory neurons. However, that approach will not work for corticospinal neurons because integrins are selectively blocked at the axon initial segment. We therefore plan to overcome the transport block though demolition of the axon initial segment and co-transduce the neurons with alpha9 integrin and kindlin. The hypothesis is that this combinatorial intervention could lead to successful regeneration of the corticospinal tract after spinal cord injury.

The research is conducted at the University of Cambridge (United Kingdom) and the Netherlands Institute for Neuroscience.
BIO LINK

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Gene jumpstarts regeneration of damaged nerve cells

For Yale University by Bill Hathaway

Regeneration of axons can be seen in this image from the study, depicting a mouse’s optic nerve. Credit: Yale University

Searching the entire genome, a Yale research team has identified a gene that when eliminated can spur regeneration of axons in nerve cells severed by spinal cord injury.

For the first time, the limits on nerve fiber regeneration were studied in an unbiased way across nearly all genes,” said Stephen Strittmatter, the Vincent Coates Professor of Neurology and senior author of the study appearing April 10 in the journal Cell Reports. “We had no idea whether we knew a lot or a little about the mechanics of nerve cell regeneration.”

The Yale team found more than 580 different genes that may play a role in regeneration of axons in nerve cells, something that rarely occurs in adult mammals but is of vital interest to scientists hoping to repair injuries to the central nervous system. Intriguingly, said the researchers, about one in 10 of those came from a family of genes involved in transport of information within cells. The researchers also reported that eliminating one of those genes, Rab27, led to regeneration of axons in the optic nerve or spinal cord of mice.

We only looked at this one gene, and we have hundreds more to investigate,” Strittmatter said. “It is not hard to envision an approach where you can knock down two or three of these pathways and help spur regeneration further than achieved previously.”

The work was primarily funded by the National Institutes of Health.

Yale’s Yuichi Sekine is lead author of the paper.

Technology Networks Article

Reference: Sekine, Y., Lin-Moore, A., Chenette, D. M., Wang, X., Jiang, Z., Cafferty, W. B., … Strittmatter, S. M. (2018). Functional Genome-wide Screen Identifies Pathways Restricting Central Nervous System Axonal Regeneration. Cell Reports, 23(2), 415–428. https://doi.org/10.1016/j.celrep.2018.03.058

Posted in Chronic Spinal Cord Injury Research, Regenerative Medicine, Spinal Research, Stem Cell Research | Tagged , , | 1 Comment

UCLA researchers find a way to repair nerve damage with stem cells

UCLA researchers established a way to derive sensory interneurons, which are cells involved in reflexes and relaying sensory information to the brain, from stem cells. (Anthony Ismail/Daily Bruin)

UCLA researchers have developed a way to use stem cells to help potentially rebuild damaged spinal cords.

In a study published in January, researchers in the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research established a way to derive sensory interneurons, which are cells involved in reflexes and relaying sensory information to the brain, from stem cells. The researchers identified a specific signaling molecule that caused the stem cells to mature into sensory interneurons.

Stem cells are young cells that can differentiate, or mature, into specific cell types, such as blood cells or neurons, according to the National Institutes of Health. Learning how to differentiate stem cells into specific neuron types is important for some therapies for spinal cord injuries that replace old or damaged tissues with young and healthy cells, according to the study.

Spinal cord injuries cost $40 billion in health care annually in the United States, according to the study. Current therapies focus on protecting the spinal cord from further damage, while stem cell therapies have the potential to reverse and repair damage by replacing damaged cells with new ones.

Samantha Butler, a professor of neurobiology and senior author of the study, said sensory interneurons are involved in fast reflexes, like moving your hand away from heat. They process information and either react immediately or pass the information to the brain for further analysis, she added.

Butler said other researchers have already found ways to differentiate stem cells into other kinds of neurons, but had not yet found a way to differentiate stem cells into interneurons.

“Directing stem cells into spinal motor neurons was developed a while ago,” Butler said. “But how to differentiate stem cells into sensory interneurons was really an open question – a protocol needed to be developed.”

READ THE FULL STORY AT DAILY BRUIN

Stem Cell Reports Full Article:

Deriving Dorsal Spinal Sensory Interneurons from Human Pluripotent Stem Cells

 

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Closed-loop neuromodulation restores network connectivity and motor control after spinal cord injury

Dr. Patrick Ganzer, research fellow in the Texas Biomedical Device Center at UT Dallas, won a best paper award from the International Spinal Cord Repair group for his work that uses vagus nerve stimulation as a possible therapy for patients.

Abstract: Recovery from serious neurological injury requires substantial rewiring of neural circuits. Precisely-timed electrical stimulation could be used to restore corrective feedback mechanisms and promote adaptive plasticity after neurological insult, such as spinal cord injury (SCI) or stroke. This study provides the first evidence that closed-loop vagus nerve stimulation (CLV) based on the synaptic eligibility trace leads to dramatic recovery from the most common forms of SCI. The addition of CLV to rehabilitation promoted substantially more recovery of forelimb function compared to rehabilitation alone following chronic unilateral or bilateral cervical SCI in a rat model. Triggering stimulation on the most successful movements is critical to maximize recovery. CLV enhances recovery by strengthening synaptic connectivity from remaining motor networks to the grasping muscles in the forelimb. The benefits of CLV persist long after the end of stimulation because connectivity in critical neural circuits has been restored.

See the Full eLife Digest Article complete with Video in the Results Section

  1. Patrick D Ganzer Is a corresponding author  Michael J Darrow  Eric C Meyers
  2. Bleyda R Solorzano  Andrea D Ruiz  Nicole M Robertson
  3. Katherine S Adcock   Justin T James  Han S Jeong
  4. April M Becker  Mark P Goldberg   David T Pruitt
  5. Seth A Hays   Michael P Kilgard   Robert L Rennaker II Is a corresponding author  
  1. The University of Texas at Dallas, United States
  2. Texas Biomedical Device Center, United States
  3. University of Texas Southwestern Medical Center, United States
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Development of an intraneural peripheral stimulation paradigm for reversing hand paralysis in non-human primates

Regaining the capacity to grasp and manipulate objects is of crucial importance to people living with upper limb paralysis. Functional electrical stimulation of forearm muscles has been used to reanimate paralyzed muscles. However, complex setups requiring multiple muscles to be independently implanted and simultaneously controlled have so far hindered the functional restoration of hand and wrist movements beyond predetermined grasp types. Intraneural peripheral interfaces that present high spatial selectivity in the recruitment of muscles represent an alternative solution to overcome these limitations. Here we present the first steps towards the development of a neuroprosthesis based on intraneural stimulation for the restoration of precise hand movements in a non-human primate (NHP) model of transient paralysis. We investigated the fascicular topography and the branching patterns of the three main nerves involved in grasping (ulnar, median and radial nerves) to determine the optimal anatomical location of the intraneural interface. Using this morphological data, we built an anatomically realistic computational model of the nerves and their interactions with electrical stimulation. Simulations guided the design of an intraneural implant targeting the different fascicules of each nerve in order to maximize the selective recruitment of hand muscles. We are currently validating the functional properties of these intraneural electrodes experimentally. Our objective is to develop stimulation paradigms that evoke a repertoire of grasping movements in transitorily paralyzed NHP.

Authors: *M. BADI1, S. WURTH1, M. KAESER2, M. CAPOGROSSO2, S. DURAND3, W. RAFFOUL3, G. COURTINE4, E. ROUILLER2, S. MICERA1;
1Bertarelli Fndn. Chair in Translational Neural Engin., Swiss Federal Inst. of Technol. (EPFL), Geneva, Switzerland; 2Univ. of Fribourg, Fribourg, Switzerland; 3Ctr. Hospitalier Universitaire de Lausanne, Lausanne, Switzerland; 4CNP BMI EPFL, Geneva, Switzerland
Disclosures: M. Badi: None. S. Wurth: None. M. Kaeser: None. M. Capogrosso: None. S. Durand: None. W. Raffoul: None. G. Courtine: None. E. Rouiller: None. S. Micera: None.

Grant Support
FNS grant NeuGrasp [205321_170032]
Wyss Center for Bio and Neuroengineering
Bertarelli Foundation

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

Paraplegic rats walk again after therapy, now we know why

With the help of robot-assisted rehabilitation and electrochemical spinal cord stimulation, rats with clinically-relevant spinal cord injury regain control of their otherwise paralyzed limbs. But how do brain commands – about walking, swimming and stair-climbing – bypass the injury and still reach the spinal cord to execute these complex tasks? EPFL scientists have observed for the first time that the brain reroutes task-specific motor commands through alternative pathways originating in the brainstem and projecting to the spinal cord. The therapy triggers the growth of new connections from the motor cortex into the brainstem and from the brainstem into the spinal cord, thus reconnecting the brain with the spinal cord below the injury. The results are published in Nature Neuroscience March 19th.

READ THE FULL ARTICLE FROM EPFL at Mediacom

Abstract

Cortico–reticulo–spinal circuit reorganization enables functional recovery after severe spinal cord contusion

Severe spinal cord contusions interrupt nearly all brain projections to lumbar circuits producing leg movement. Failure of these projections to reorganize leads to permanent paralysis. Here we modeled these injuries in rodents. A severe contusion abolished all motor cortex projections below injury. However, the motor cortex immediately regained adaptive control over the paralyzed legs during electrochemical neuromodulation of lumbar circuits. Glutamatergic reticulospinal neurons with residual projections below the injury relayed the cortical command downstream. Gravity-assisted rehabilitation enabled by the neuromodulation therapy reinforced these reticulospinal projections, rerouting cortical information through this pathway. This circuit reorganization mediated a motor cortex–dependent recovery of natural walking and swimming without requiring neuromodulation. Cortico–reticulo–spinal circuit reorganization may also improve recovery in humans.

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

Chondroitinase improves anatomical and functional outcomes after primate spinal cord injury

Inhibitory chondroitin sulfate proteoglycans (CSPGs) in the extracellular matrix hinder axonal regeneration after spinal cord injury (SCI). In particular, CSPGs form ‘peri-neuronal nets’ that may limit axonal regrowth and synaptic plasticity. Moreover, CSPGs are newly synthesized at sites of central nervous system injury and directly block axon growth. Administration of the enzyme chondroitinase (Chase) degrades inhibitory portions of CSPGs and improves axonal sprouting and functional recovery after SCI in rodents. Here we show for the first time that Chase treatment is also effective in a non-human primate model of SCI. Adult rhesus monkeys received C7 spinal cord lateral hemisection lesions. Four weeks later, subjects received intraparenchymal spinal cord injections of 20 U/ml Chase (or saline) caudal to the lesion. Five µl of Chase / saline were injected at each of 10 sites (spaced 1.5 mm apart in the rostrocaudal axis) on the right side of the spinal cord from C7-T1. This effectively targets spinal cord circuits below the lesion that control hand function. Hand function and locomotion were assessed weekly in a large enriched environment and in a cage-based Brinkman task (retrieval of small food items from wells in a board). Corticospinal axons were labeled with dextran-conjugated tracer injections into right and left motor cortices 6 weeks before sacrifice.
Chase-treated monkeys recovered hand function (but not locomotion) better than control monkeys (Condition x Time, P<0.001, Linear Mixed Model [LMM]). The fact that the beneficial effect is specific to hand function is consistent with the hypothesis that Chase increases axonal sprouting in the treated region (segments C7-T1). Indeed, Chase increased corticospinal axon growth (P=0.036, LMM) and the number of corticospinal synapses (P=0.001, LMM) in gray matter caudal to the lesion. Thus, intraparenchymal Chase is an effective treatment in a primate model of SCI that recapitulates some aspects of traumatic human SCI. Chase treatment for SCI therefore warrants further research and translational development.

Authors: *E. S. ROSENZWEIG1, E. A. SALEGIO2, J. J. LIANG1, J. L. WEBER1, C. WEINHOLTZ1, J. H. BROCK1,3, R. MOSEANKO2, S. HAWBECKER2, R. PENDER2, J. F. IACI4, A. O. CAGGIANO4, A. R. BLIGHT4, B. HAENZI5, J. R. HUIE6, L. A. HAVTON7, Y. S. NOUT-LOMAS8, J. W. FAWCETT5, A. R. FERGUSON6, M. S. BEATTIE6, J. C. BRESNAHAN6, M. H. TUSZYNSKI1,3;
1Neurosciences, Univ. of California San Diego Dept. of Neurosciences, La Jolla, CA; 2California Natl. Primate Res. Ctr., Univ. of California, Davis, Davis, CA; 3VAMC, La Jolla, CA; 4Acorda Therapeutics, Inc., Ardsley, NY; 5Cambridge Univ., Cambridge, United Kingdom; 6Dept. of Neurolog. Surgery, Brain and Spinal Injury Ctr. (BASIC), UCSF, San Francisco, CA; 7Dept. of Neurol., UCLA, Los Angeles, CA; 8Col. of Vet. Med. and Biomed. Sci., Colorado State Univ., Fort Collins, CO
Disclosures: E.S. Rosenzweig: None. E.A. Salegio: None. J.J. Liang: None. J.L. Weber: None. C. Weinholtz: None. J.H. Brock: None. R. Moseanko: None. S. Hawbecker: None. R. Pender: None. J.F. Iaci: A. Employment/Salary (full or part-time):; Acorda Therapeutics, Inc. A.O. Caggiano: A. Employment/Salary (full or part-time):; Acorda Therapeutics, Inc. A.R. Blight: A. Employment/Salary (full or part-time):; Acorda Therapeutics, Inc.. B. Haenzi: None. J.R. Huie: None. L.A. Havton: None. Y.S. Nout-Lomas: None. J.W. Fawcett: F. Consulting Fees (e.g., advisory boards); Acorda Therapeutics, Inc.. A.R. Ferguson: None. M.S. Beattie: None. J.C. Bresnahan: None. M.H. Tuszynski: F. Consulting Fees (e.g., advisory boards); Acorda Therapeutics, Inc.

Grant Support
NIH NS042291
VA Gordon Mansfield Consortium
NIH NCRR P51 OD011107-56
Craig H. Neilsen Foundation
Spitzer Family Trust
Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
Christopher and Dana Reeve Foundation
Acorda Therapeutics
Medical Research Council

Society for Neuroscience LINK

Posted in Chronic Spinal Cord Injury Research, Neuroscience Abstracts, Regenerative Medicine, Spinal Research, Stem Cell Research | Tagged , ,

Spinal Cord Injury Research: Mayo Clinic Radio

Dr. Kristin Zhao, director of Mayo Clinic’s Assistive and Restorative Technology Laboratory, and Dr. Kendall Lee, director of Mayo Clinic’s Neural Engineering Laboratory, will discuss research that has successfully used intense physical therapy and electrical stimulation of the spinal cord to return voluntary movements to a previously paralyzed patient.

Dr. Peter Grahn, a Mayo Clinic neurobiology researcher, shares how a devastating injury inspired a career.

Recovery is now possible. Using a grant from the BEL13VE Foundation, in 2017 Mayo Clinic became the first medical center in the world to replicate and validate paralysis recovery results achieved using epidural stimulation.

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

Reducing Pericyte-Derived Scarring Promotes Recovery after Spinal Cord Injury

CNS injury often severs axons. Scar tissue that forms locally at the lesion site is thought to block axonal regeneration, resulting in permanent functional deficits. We report that inhibiting the generation of progeny by a subclass of pericytes led to decreased fibrosis and extracellular matrix deposition after spinal cord injury in mice. Regeneration of raphespinal and corticospinal tract axons was enhanced and sensorimotor function recovery improved following spinal cord injury in animals with attenuated pericyte-derived scarring. Using optogenetic stimulation, we demonstrate that regenerated corticospinal tract axons integrated into the local spinal cord circuitry below the lesion site. The number of regenerated axons correlated with improved sensorimotor function recovery. In conclusion, attenuation of pericyte-derived fibrosis represents a promising therapeutic approach to facilitate recovery following CNS injury.

Read the full article at Cell:

David Oliveira Dias, Hoseok Kim, Daniel Holl, Beata Werne Solnestam, Joakim Lundeberg, Marie Carlén, Christian Göritz5,6,’Correspondence information about the author Christian GöritzEmail the author Christian Göritz, Jonas Frisén5,’Correspondence information about the author Jonas Frisén.

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