Translating promising strategies for bowel and bladder management in spinal cord injury

Loss of control over voiding following spinal cord injury (SCI) impacts autonomy, participation and dignity, and can cause life-threatening complications. The importance of SCI bowel and bladder dysfunction warrants significantly more attention from researchers in the field. To address this gap, key SCI clinicians, researchers, government and private funding organizations met to share knowledge and examine emerging approaches. This report reviews recommendations from this effort to identify and prioritize near-term treatment, investigational and translational approaches to addressing the pressing needs of people with SCI.

Authors: Tracey L.Wheeler Bowel and Bladder Workshop Participants William deGroat Kymberly Eisner Anton Emmanuel Jennifer French Warren Grille Michael J.Kennelly Andrei Krassioukov Bruno Gallo Santa cruz Fin Biering-Sørenseni Naomi Kleitman

Read the Full Publication Here:

Posted in Chronic Spinal Cord Injury Research, Spinal Research

Task specific spinal cord epidural stimulation enables independent step cycles during BWST stepping in motor complete humans

Various studies in the animal model have shown recovery of stepping with spinal cord epidural stimulation following a spinal cord injury. Our group had shown that epidural stimulation of lumbosacral spinal cord, combined with activity based training, enabled four motor complete paraplegics to progressively regain full weight bearing standing and achieve voluntary movement of their lower extremities.
The objective of this study is to determine whether task-specific epidural stimulation in combination with intense step training can recover independent stepping on a treadmill with partial weight bearing in subjects with a motor complete injury.
Three individuals with a motor complete injury (2 AIS-B and 1 AIS-A) implanted with an epidural electrode array over the L1-S1 segments of the spinal cord participated in this study. Individuals received intense step training with step scES and stand training with stand-scES for 160 sessions. EMG, kinematics and ground reaction forces were recorded during stepping on a treadmill with body weight support.
All three individuals were able to independently generate a full step cycle (stance and swing) with optimized subject specific stimulation parameters for stepping following 20-60 training sessions. The maximum number of consecutive steps generated by the three subjects were 94, 319 and 381 steps. Intention to step with a specific leg (left or right) was needed for independent stepping of that same leg to occur. Although both left and right legs of a given subject could generate independent stepping cycles, neither of the subjects could step bilaterally, simultaneously. These results have important implications with respect to identifying strategies that are likely to be most efficacious in enabling improved motor function for stepping after motor complete paralysis. This study provides evidence that the combination of intense step training with task-specific Step-scES promotes significant plasticity in the spinal circuitry leading to improvements in stepping performance.

1Frazier Rehab Inst., Louisville, KY; 3Dept Neurol Surgery, 2Univ. of Louisville, Louisville, KY; 4Univ. of California Los Angeles, Los Angeles, CA; 5Pavloc Inst., St Petersburg, Russian Federation
Disclosures: C.A. Angeli: None. Y. Gerasimenko: None. V. Edgerton: None. S.J. Harkema: None.

Grant Support
NININ Grant R011EB007615
MS P30 GM103507
Christopher and Dana Reeve Foundation
Kessler Foundation
Leona M and Harry B Helmsley Charitable Trust
Kentucky Spinal Cord Injury Research Center
University of Louisville Foundation
Medtronic Inc

LINK: Society for Neuroscience

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

Neurons Survive Long-Term in Pigs with Spinal Cord Injuries

A major hurdle to using neural stem cells derived from genetically different donors to replace damaged or destroyed tissues, such as in a spinal cord injury, has been the persistent rejection of the introduced material (cells), necessitating the use of complex drugs and techniques to suppress the host’s immune response.

In a new paper, publishing May 9 in Science Translational Medicine, an international team led by scientists at University of California San Diego School of Medicine describe successfully grafting induced pluripotent stem cell (iPSC)-derived neural precursor cells back into the spinal cords of genetically identical adult pigs with no immunosuppression efforts. The grafted cells survived long-term, displayed differentiated functionality and caused no tumors.

The researchers also demonstrated that the same cells showed similar long-term survival in adult pigs with different genetic backgrounds after only short course use of immunosuppressive treatment once injected into injured spinal cord.

“The promise of iPSCs is huge, but so too have been the challenges. In this study, we’ve demonstrated an alternate approach,” said senior author Martin Marsala, MD, professor in the Department of Anesthesiology at UC San Diego School of Medicine and a member of the Sanford Consortium for Regenerative Medicine.

Read the full story by Scott LaFee, University of California San Diego Health

Survival of syngeneic and allogeneic iPSC-derived neural precursors after spinal grafting in minipigs

May 9 in Science Translational Medicine
Abstract: The use of autologous (or syngeneic) cells derived from induced pluripotent stem cells (iPSCs) holds great promise for future clinical use in a wide range of diseases and injuries. It is expected that cell replacement therapies using autologous cells would forego the need for immunosuppression, otherwise required in allogeneic transplantations. However, recent studies have shown the unexpected immune rejection of undifferentiated autologous mouse iPSCs after transplantation. Whether similar immunogenic properties are maintained in iPSC-derived lineage-committed cells (such as neural precursors) is relatively unknown. We demonstrate that syngeneic porcine iPSC-derived neural precursor cell (NPC) transplantation to the spinal cord in the absence of immunosuppression is associated with long-term survival and neuronal and glial differentiation. No tumor formation was noted. Similar cell engraftment and differentiation were shown in spinally injured transiently immunosuppressed swine leukocyte antigen (SLA)-mismatched allogeneic pigs. These data demonstrate that iPSC-NPCs can be grafted into syngeneic recipients in the absence of immunosuppression and that temporary immunosuppression is sufficient to induce long-term immune tolerance after NPC engraftment into spinally injured allogeneic recipients. Collectively, our results show that iPSC-NPCs represent an alternative source of transplantable NPCs for the treatment of a variety of disorders affecting the spinal cord, including trauma, ischemia, or amyotrophic lateral sclerosis.

Authors: Strnadel J1,2, Carromeu C3, Bardy C4,5, Navarro M1, Platoshyn O1, Glud AN1, Marsala S1, Kafka J1, Miyanohara A1,6, Kato T Jr7, Tadokoro T1, Hefferan MP1, Kamizato K1, Yoshizumi T1, Juhas S8, Juhasova J8, Ho CS9, Kheradmand T9, Chen P1, Bohaciakova D1,10, Hruska-Plochan M1,11, Todd AJ12, Driscoll SP13, Glenn TD13, Pfaff SL13, Klima J8, Ciacci J14, Curtis E14, Gage FH4, Bui J15, Yamada K16, Muotri AR3, Marsala M17,18.

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

Advantages of soft subdural implants for the delivery of electrochemical neuromodulation therapies to the spinal cord.

e-Dura implant developed by EPFL scientists

Journal of Neural Engineering
We recently developed soft neural interfaces enabling the delivery of electrical and chemical stimulation to the spinal cord. These stimulations restored locomotion in animal models of paralysis. Soft interfaces can be placed either below or above the dura mater. Theoretically, the subdural location combines many advantages, including increased selectivity of electrical stimulation, lower stimulation thresholds, and targeted chemical stimulation through local drug delivery. However, these advantages have not been documented, nor have their functional impact been studied in silico or in a relevant animal model of neurological disorders using a multimodal neural interface.

We characterized the recruitment properties of subdural interfaces using a realistic computational model of the rat spinal cord that included explicit representation of the spinal roots. We then validated and complemented computer simulations with electrophysiological experiments in rats. We additionally performed behavioral experiments in rats that received a lateral spinal cord hemisection and were implanted with a soft interface.

In silico and in vivo experiments showed that the subdural location decreased stimulation thresholds compared to the epidural location while retaining high specificity. This feature reduces power consumption and risks of long-term damage in the tissues, thus increasing the clinical safety profile of this approach. The hemisection induced a transient paralysis of the leg ipsilateral to the injury. During this period, the delivery of electrical stimulation restricted to the injured side combined with local chemical modulation enabled coordinated locomotor movements of the paralyzed leg without affecting the non-impaired leg in all tested rats. Electrode properties remained stable over time, while anatomical examinations revealed excellent bio-integration properties.

Soft neural interfaces inserted subdurally provide the opportunity to deliver electrical and chemical neuromodulation therapies using a single, bio-compatible and mechanically compliant device that effectively alleviates locomotor deficits after spinal cord injury.

Capogrosso M1, Gandar J, Greiner N, Moraud EM, Wenger N, Shkorbatova P, Musienko P, Minev I, Lacour S, Courtine G. Author information 1 Center for Neuroprosthetics and Brain Mind Institute, School of Life Sciences, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland. Department of Medicine, Platform of Translational Neuroscience, University of Fribourg, Fribourg, Switzerland.

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

Synaptic connectivity between host and neural progenitor cell-derived neurons after spinal cord injury

Neural stem cells (NSCs) grafted into sites of spinal cord injury (SCI) may act as new electrophysiological relays between host neurons above and below the lesion. Host axons regenerate robustly into NSC grafts and form synapses; in turn, graft axons extend long distances into host white and gray matter caudal to the injury and form synapses. To investigate potential functionality of these new synaptic pathways, we performed calcium imaging and whole-cell patch clamp recordings in mice with NSC grafts after SCI. We placed T12 dorsal column lesions and acutely grafted embryonic day thirteen (E13)-derived spinal cord neural progenitor cells (NPCs) expressing the calcium indicator GCaMP6f into the lesion site. From 6 to 8 weeks later, we imaged the activity of populations of neurons within NPC grafts in acute spinal cord slices, anesthetized, or awake behaving animals.
In acute spinal cord slices, grafted neurons exhibited spontaneous activity. Moreover, dorsal column stimulation evoked responses in grafted cells. In vivo imaging revealed spontaneous activity in both neurons and glia, as well as hindpaw pinch- and cold air puff-evoked responses. Activity patterns included both large-scale events and independent, single-neuron activity. We are currently optimizing methods for interrogating host-to-graft inputs through optogenetic techniques. We are also planning to probe the host response to graft output by stimulating graft axons and imaging host cells in the areas that they innervate. Additionally, using cell type-specific transgenic Cre lines to drive GCaMP expression in grafts, we will assess the activities of different graft cell types.

1Biomed. Sci., 2Neurosciences, Univ. of California – San Diego, La Jolla, CA; 3Waitt Advanced Biophotonics Ctr., Salk Inst. for Biol. Studies, La Jolla, CA
Disclosures: S.L. Ceto: None. K.J. Sekiguchi: None. A. Nimmerjahn: None. M.H. Tuszynski: None.

Grant Support
The Veterans Administration
Wings for Life
Nakajima Foundation

Society for Neuroscience LINK

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

The Role of Cortical Plasticity in Spinal Cord Injury Recovery – David Gimbel, MD

“The Role of Cortical Plasticity in Spinal Cord Injury Recovery”

David Gimbel, MD
Clinical Instructor
University of Cincinnati College of Medicine

Posted in Chronic Spinal Cord Injury Research, Regenerative Medicine, Spinal Research | Tagged

Alliance for Regenerative Medicine (ARM) Neuralstem Presentation

Alliance for Regenerative Medicine (ARM) Neuralstem Presentation
April 17, 2018
Neuralstem is a clinical-stage biopharmaceutical company developing novel treatments for nervous system diseases of high unmet medical need. The company’s lead asset and stem cell therapy candidate, NSI-566, is a spinal cord-derived neural stem cell line being tested in Amyotrophic Lateral Sclerosis (ALS), chronic spinal cord injury (cSCI) and ischemic stroke. Additionally, NSI-189, is a chemical entity in development for major depressive disorder (MDD) and for Angelman syndrome, irradiation-induced cognitive impairment, neuropathy associated with Type 1 and Type 2 diabetes and stroke. These product candidates are based on the company’s proprietary neural stem cell technology.

Karl Johe, Ph.D., Chief Scientific Officer
Germantown, MD

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

A computational model of epidural electrical stimulation of the cervical spinal cord in non-human primates

Abstract: Cervical spinal cord injury alters the communication between the brain and the spinal circuits controlling movement, often leading to tetraplegia. Epidural Electrical Stimulation (EES) of the lumbar spinal cord has shown promising results to restore leg motor control after paralysis. EES modulates the activity of proprioceptive afferent circuits, enabling the spinal cord to elaborate coordinated movements of previously paralyzed limbs. Similar proprioceptive afferent circuits contribute to upper-limb motor control, suggesting that EES may also improve the recovery of upper-limb movements after injury. The ability to engage individual or small groups of muscles is essential to facilitate motor control with EES. At this stage, however, this ability remains largely unexplored.
To address this question, we developed a realistic Finite Element/axon-cable biophysical model of EES applied to the non-human primate cervical spinal cord. Our objective was to evaluate and optimize the specificity of tailored, dura mater-like electrode implants placed dorsally over the spinal cord. The anatomically realistic model was derived from CT-scan acquisitions that supported 3D-reconstruction of the cervical vertebrae. We inserted physical compartments for the electrode silicone paddle and for the spinal roots, and used curvilinear coordinates to represent the white matter and spinal roots conductivity anisotropy.
We used the model to quantify the recruitment of Group I and Group II afferent fibers in the dorsal roots, motor axons in the ventral roots, and large myelinated fibers in the dorsal columns. To validate our model, we estimated the muscle responses to single pulses of EES using a realistic connectivity model between Ia-afferents and motoneurons innervating upper-limb muscles. We then compared our results to experimental recordings performed in two macaque monkeys under anesthesia.
We found a high correlation between the responses derived from simulations and obtained in vivo. However, the anatomical features exerted a non-negligible impact on the predicted recruitments. These results emphasize the importance of including realistic anatomical features to derive implant specificity from computer simulations.

Finally, we found that lateralized epidural stimulation of the cervical spinal cord recruits individual dorsal roots at significantly lower thresholds than other neighboring structures, suggesting that targeted EES could selectively modulate upper-limb motor pools. Taken together, these results establish the framework for the design of targeted cervical implants to facilitate upper-limb movements after spinal cord injury.

1Ctr. for Neuroprosthetics, Brain Mind Inst., EPFL, Geneve, Switzerland; 2Domain of Neurophysiology, Dept. of Med., Univ. of Fribourg, Fribourg, Switzerland; 3Ctr. Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
N. Greiner: None. B. Barra: None. S. Borgognon: None. G. Schiavone: None. S. Lacour: None. J. Bloch: None. E.M. Rouiller: None. G. Courtine: None. M. Capogrosso: None.

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

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

Abstract: 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.

Four Video Supplements LINK

Authors: Leonie Asboth, Lucia Friedli, Janine Beauparlant, Cristina Martinez-Gonzalez, Selin Anil, Elodie Rey, Laetitia Baud, Galyna Pidpruzhnykova, Mark A. Anderson, Polina Shkorbatova, Laura Batti, Stephane Pagès, Julie Kreider, Bernard L. Schneider, Quentin Barraud & Gregoire Courtine

Nature Neuroscience LINK

Paraplegic Rat Walks Again After Therapy, and Now We Know Why

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

Serotonin receptor and dendritic plasticity in the spinal cord mediated by chronic serotonergic pharmacotherapy combined with exercise following complete SCI in the adult rat

Patrick Ganzer

Abstract: Severe spinal cord injury (SCI) damages descending motor and serotonin (5-HT) fiber projections leading to paralysis and serotonin depletion. 5-HT receptors (5-HTRs) subsequently upregulate following 5-HT fiber degeneration, and dendritic density decreases indicative of atrophy. 5-HT pharmacotherapy or exercise can improve locomotor behavior after SCI. One might expect that 5-HT pharmacotherapy acts on upregulated spinal 5-HTRs to enhance function, and that exercise alone can influence dendritic atrophy. In the current study, we assessed locomotor recovery and spinal proteins influenced by SCI and therapy. 5-HT, 5-HT2AR, 5-HT1AR, and dendritic densities were quantified both early (1 week) and late (9 weeks) after SCI, and also following therapeutic interventions (5-HT pharmacotherapy, bike therapy, or a combination). Interestingly, chronic 5-HT pharmacotherapy largely normalized spinal 5-HTR upregulation following injury. Improvement in locomotor behavior was not correlated to 5-HTR density. These results support the hypothesis that chronic 5-HT pharmacotherapy can mediate recovery following SCI, despite acting on largely normal spinal 5-HTR levels. We next assessed spinal dendritic plasticity and its potential role in locomotor recovery. Single therapies did not normalize the loss of dendritic density after SCI. Groups displaying significantly atrophied dendritic processes were rarely able to achieve weight supported open-field locomotion.

Only a combination of 5-HT pharmacotherapy and bike therapy enabled significant open-field weigh-supported stepping, mediated in part by restoring spinal dendritic density. These results support the use of combined therapies to synergistically impact multiple markers of spinal plasticity and improve motor recovery.

Patrick D.Ganzera    Carl R.Beringera    Jed S.Shumskyb   ChiemelaNwaobasia  

Karen A.Moxonab

School of Biomedical Engineering, Science and Health Systems, Drexel University, 3141 Chestnut St., Philadelphia, PA 19104, United States
Department of Neurobiology and Anatomy, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129, United States

Experimental Neurology LINK

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