Electrical implant reduces ‘invisible’ symptoms of man’s spinal cord injury

An experimental treatment that sends electrical currents through the spinal cord has improved ‘invisible’ yet debilitating side effects for a Canadian man with a spinal cord injury.

A diving accident six years ago left Isaac Darrel, of Langley, British Columbia, with a spinal cord injury. Side effects of the injury include dizziness, fluctuations in blood pressure and changes in bladder and bowel function.

Darrel made the decision to have electrodes surgically implanted over his spinal cord in 2016 to test out a treatment known as epidural stimulation in the hopes of improving some of the side effects. A case study about his experiences was published today in JAMA Neurology.

Full Article at Science Daily News

Association of Epidural Stimulation With Cardiovascular Function in an Individual With Spinal Cord Injury
Christopher R. West et al. Association of Epidural Stimulation With Cardiovascular Function in an Individual With Spinal Cord Injury. JAMA Neurology, 2018 DOI: 10.1001/jamaneurol.2017.5055

ICORD LINK

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

American Disabilities Act (ADA) gutted in the HR 620 passage today

Seventeen members of ADAPT have been charged with Disruption of Congress. For many of these folks, this was the second arrest THIS WEEK in defending the Americans with Disabilities Act. The ADAPT Community honors their hard work and sacrifice. Watch what happened in the House of Representatives today and reported on NBC in the tape below…

Activists from the disability rights organization ADAPT were a big part of getting the landmark civil rights legislation the Americans with Disabilities Act (ADA) passed in 1990. ADAPT members are in the House Rules Committee Hearing protesting the weakening of ADA protections in HR620, the ADA Education and Reform Act (HR620). HR620 is ill-informed legislation that would require people with disabilities to jump through numerous procedural hoops before they can secure their rights for equal access and full participation in public life, and removes any reason for businesses to proactively comply with the ADA. This bill would be a devastating blow to the ADA.

“Businesses have had over 27 years to come into compliance with the ADA,” said Anita Cameron, an organizer with ADAPT who was at the Capitol Crawl protest in 1990 that led to the ADA’s passage. “The civil and human rights of disabled people are being trampled upon. We demand access to public spaces to live our lives just like everyone else.”

Instead of ensuring that people with disabilities have access, as the ADA requires, HR620 incentivizes businesses to wait until a customer confronts an obstruction and has completed the detailed notification process. Even then, the only action the business is required to make is “substantial progress” in removing the barrier described in the notice. A business could wait years without actually removing barriers and face no penalty. There would be no incentive for a business to learn about ADA compliance and take steps prior to notification.

“One in five Americans have a disability, making Disabled Americans the largest voting minority. We want our rights expanded through legislation like the Disability Integration Act-DIA HR2472/S910, not ripped away with HR 620,” said Laura Halvorson of Virginia who is an organizer with DC Metro ADAPT. “Support for DIA and opposition to HR620 are quickly developing into a litmus test for Congressional candidates; if they won’t use their vote to support us, they won’t get our vote!”

ADAPT has worked for decades to secure and advance the civil rights guaranteed to disabled Americans under the ADA. ADAPT’s history, the issues it is fighting for, and its activities can be found at http://www.adapt.org, the NationalADAPT Facebook page and on Twitter under the hashtags #ADAPTandRESIST, #StopHR620, and #HandsOffMyADA.

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Online learning of stimuli parameters for standing in spinally stimulated paraplegia

Authors: *Y. SUI1, J. W. BURDICK2;
1CMS, California Institute of Technology, Pasadena, CA; 2Caltech, Pasadena, CA

Yanan Sui, Graduate Student at Caltech

Previous research has shown that spinal stimulation via electrode arrays implanted in the epidural space over the lumbosacral area enables paralyzed patients to achieve full weight-bearing standing, improvements in stepping, and partial recovery of lost autonomic functions. The optimal stimulus varies significantly across patients. And even for the same patient, the outcome of the same stimulus varies from trial to trial. Thus, clinicians must determine the optimal stimulus for each patient, under noisy conditions, from a large decision space. Currently, the search for the optimal stimulating parameters is a laborious approach that consumes valuable clinician and patient time, and does not guarantee an optimal outcome.

We developed and tested a Correlated Dueling Bandit algorithm to automatically plot the large decision space of possible stimuli. This algorithms selects and improves the spinal stimulation parameters for standing ability in epidurally stimulated paraplegics, and optimizes them over time. In practice, the algorithm chooses a stimuli, whose effect on the subject is tested and ranked by observing clinicians. The algorithm then balances the exploration for more optimal stimuli while also exploiting currently known good ones to provide effective therapy. The algorithm also seeks to maximize total performance during the limited clinical period within which we can search for the optimal solution.

The standing skill of two paraplegic subjects implanted with 16-electrode epidural implants was tested in response to 90 and 117 different stimuli respectively over two non-consecutive weeks. The algorithm chose stimuli that enable the subjects to achieve full weight-bearing standing, consistently improved standing performance over the evaluation period. Moreover, the optimal stimuli sets found by the algorithm included the same stimulating parameters that were selected for each subject by clinical staff using an intuitive search process, validating the effectiveness of the approach.

Disclosures: Y. Sui: None. J.W. Burdick: None.

Grant Support
NIH U01 EB007615-08
NIH U01 EB015521-05

Society for Neuroscience LINK

Yanan Sui Homepage LINK

SCRIR&A: By utilizing an algorithm program, scientists can detect the “sweet spot” to increase efficacy of the movement they are attempting to create with the implanted stimulator. The parameters are being validated by the staff observations in real time. The amount of stimulation needed can be different for each patient and each training session, so by utilizing a computer program, it can help make the decision changes faster and more precise.

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

Interleaving stand-step training with spinal cord epidural stimulation effectively improved standing in individuals with chronic complete spinal cord injury

Dr. Enrico Rejc University of Louisville

We have recently shown that approximately 80 sessions of stand training with spinal cord epidural stimulation (scES) optimized for standing promoted standing ability improvements in four individuals with chronic complete spinal cord injury (SCI). In particular, two individuals were able to stand without any external assistance, while other two individuals needed assistance for hip extension. Also, all individuals assisted balance with their upper limbs. Interestingly, 80 sessions of step training performed after stand training remarkably impaired standing in three of these four participants. These findings led us to investigate whether standing and stepping can be concurrently trained without limiting the recovery of standing in individuals with chronic complete SCI using scES. In particular, this study examined the effects of an interleaving stand-step training with scES on motor function for standing in three individuals with chronic complete SCI. Stand training and step training alternated every session, and the total number of training sessions remained the same as in the previous protocol (N=160). During this training paradigm we also were more focused on increasing the volitional involvement of the participant, and allowed longer seated rest (up to 30 minutes per session).After approximately 80 sessions of stand-step training, the ability to stand without external assistance was observed in all 3 individuals, for up to 11.4 minutes within a 60-minute standing session. After 160 sessions of stand-step training, standing time without external assistance further increased in all participants (up to 60 minutes within a 60-minute session). Throughout training, participants were also able to stand using less stable upper limb supports (from a standing frame to a walker as well as holding the hands of a trainer). Standing ability improvements were accompanied by adaptations in muscle activation pattern. For example, training promoted less variable electromyographic patterns during standing, and generally increased the evoked potentials amplitude modulation induced by the sit-to-stand transition.

In conclusion, the interleaving stand-step training with scES performed in this study promoted significant recovery of standing ability in three chronic complete SCI individuals, and seemed more effective than the previous paradigm in which stand training was completed prior to step training. This indicates that the human spinal circuitry can learn standing while also stepping, as long as standing is practiced. These findings also underline the importance of task-specificity in driving training-induced plasticity of spinal neural networks.

Authors: *E. REJC, C. ANGELI, S. HARKEMA; Univ. of Louisville, Louisville, KY
Disclosures: E. Rejc: None. C. Angeli: None. S. Harkema: None.
Grant Support
NIH (NIBIB)R01EB007615
The Christopher & Dana Reeve Foundation
Leona M. and Harry B. Helmsley Charitable Trust
Kessler Foundation
Medtronic Inc
LINK: Society for Neuroscience

LAB LINK and PUBLICATIONS

Nature Article

New Update on scES study: Kate WilletteSpinal cord stimulation (scES) involves planting an array of electrodes into the epidural space in the lumbar area of the cord. By way of a wireless control, those electrodes allow a researcher to send a pulse on command into the lower spine. The idea of scES isn’t to stimulate a muscle or two, but to activate whole networks of neurons that injury to the spinal cord has left without useful input.”

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

Injured adult motor and sensory axons regenerate into appropriate organotypic domains of neural progenitor grafts

Jennifer Dulin, Postdoctoral Research, UC San Diego, Neurosciences

Neural progenitor cell (NPC) transplantation has high therapeutic potential in neurological disorders. Functional restoration may depend on the formation of reciprocal connections between host and graft. While it has been reported that axons extending out of neural grafts in the brain form contacts onto phenotypically appropriate host target regions, it is not known whether adult, injured host axons regenerating into NPC grafts also form appropriate connections. We report that spinal cord NPCs grafted into the injured adult rat spinal cord self-assemble organotypic, dorsal horn-like domains. These clusters are extensively innervated by regenerating adult host sensory axons and are avoided by corticospinal axons. Moreover, host axon regeneration into grafts increases significantly after enrichment with appropriate neuronal targets. Together, these findings demonstrate that injured adult axons retain the ability to recognize appropriate targets and avoid inappropriate targets within neural progenitor grafts, suggesting that restoration of complex circuitry after SCI may be achievable.

Jennifer N. Dulin,1 Andrew F. Adler,1 Hiromi Kumamaru,1 Gunnar H. D. Poplawski,1 Corinne Lee-Kubli,1 Hans Strobl,1Daniel Gibbs,1 Ken Kadoya,1,2 James W. Fawcett,3 Paul Lu,1,4 and Mark H. Tuszynskicorresponding author1,4

Full Publication at Nature Communications

This work was supported by the Craig H. Neilsen Foundation, the US Veterans Administration Gordon Mansfield Spinal Cord Injury Consortium, the National Institutes of Health (NS042291), and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.

Identifying appropriate neural stem cell grafts to stimulate regeneration of the corticospinal axons after injury (in an animal model) could most closely predict human benefit to this vitally important motor system. This is a collaborative endeavor between six research groups working closely together to accelerate understanding and discovery of therapies for SCI.

Bridging the injured spinal cord with neural stem cells: Jennifer N. Dulin and Paul Lu.

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

Combined Gene Therapy and Stem Cell Transplantation for SCI

Dr. Murray Blackmore W2W 2017 Miami

Research in the Blackmore Lab

Neurons depend on long axons to communicate with target cells. Neurons in the brain and spinal cord have almost no ability to regenerate axons that are disrupted by injury or disease, resulting in a devastating and permanent loss of function. On the other hand, many other types of neurons, including peripheral neurons, neurons in lower vertebrates, and embryonic neurons, can regenerate their axons robustly. What mechanisms allow regeneration in some types of neurons but prevent it in others? The goals of my research program are to 1) identify genes that explain differences in regenerative ability between different types of neurons and 2) manipulate gene expression in neurons to promote regenerative ability. To do so we compare gene expression in regenerating versus non-regenerating neurons, and then test the activity of differentially expressed genes in culture assays of axon outgrowth. Then, using viral-mediated gene delivery in a rodent model of spinal cord injury, we test the strongest candidate genes for the ability to promote axon growth in living animals. Ultimately we aim to develop gene therapies to promote the regrowth of axons in the injured spinal cord and brain.

Posted in Chronic Spinal Cord Injury Research, Gene Therapy, Regenerative Medicine, Spinal Research, Unite 2 Fight Paralysis, Working 2 Walk Science & Advocacy Symposium | Tagged | 3 Comments

Spinal cord epidural stimulation effects on urogenital and bowel outcomes

Authors: *A. N. HERRITY1,4, C. A. ANGELI1,2,4, E. REJC1,2, S. J. HARKEMA1,2,4, C. H. HUBSCHER1,3;
1Kentucky Spinal Cord Injury Res. Ctr., 2Dept. of Neurolog. Surgery, 3Dept. of Anatom. Sci. and Neurobio., Univ. of Louisville, Louisville, KY; 4Frazier Rehab Inst., Louisville, KY

Spinal cord injury (SCI) results in profound changes to sensorimotor as well as autonomic systems. Deficits in urogenital and bowel function after spinal cord injury profoundly impact quality of life and are ranked as top priority issues in the SCI population. Bladder dysfunction 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. Urinary retention and an inability of the bladder to store urine under appropriately low pressures can lead to infection and ultimately impact renal health. Bowel issues such as frequent constipation can trigger blood pressure increases associated with autonomic dysreflexia. The impact of injury on sexual function includes impairments in genital responses in both male and females. While standard pharmacological therapy aims to manage the prevalent urogenital and bowel issues, therapies addressing recovery of function are still needed. Thus, the objective of this study is to describe the effects of spinal cord epidural stimulation as an alternative approach to improve bladder, bowel and sexual function after SCI. This study included AIS grade A and B subjects (n=8) receiving spinal cord epidural stimulation at L1-S1 spinal levels in combination with activity-based therapy: locomotor and/or stand training, cardiovascular and voluntary motor training by our research team. Urodynamic assessments, with and without the use of spinal cord epidural stimulation, at pre- and post-training time-points and the Spinal Cord Injury Data Set questionnaires for bladder, bowel and sexual function management accompanied each urodynamic procedure. We identified specific configurations and stimulation parameters optimal for continence and micturition in several subjects during filling cystometry. While activity-based therapies have resulted in improvements in bladder capacity and voiding efficiency, this study provides evidence that the use of spinal cord epidural stimulation can further enhance these parameters and in a frequency-dependent manner. Importantly, as capacity increased in these participants, bladder pressures continued to remain low, indicating better compliance. Several participants reported reductions in the time required for defecation post-training as well as enhanced ejaculatory ability. Spinal cord epidural stimulation, along with activity-based training, may help provide an appropriate level of excitation to the spinal cord, targeting the neural circuitry involved in urogenital and bowel function.

Disclosures
A.N. Herrity: None. C.A. Angeli: None. E. Rejc: None. S.J. Harkema: None. C.H. Hubscher: None.

Grant Support
R01HD080205
1R01EB007615-01A1
OICB140483

LINK: Society for Neuroscience

Science News Article LINK

PLOS One Article LINK

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

Rapid and robust recovery of breathing 1.5 years after cervical spinal cord injury

Dr. Pippa Warren

Methods to restore respiratory function following chronic cervical spinal cord injury (SCI) have not been extensively studied. This represents a major gap in our current understanding as the primary cause of morbidity and mortality following cervical SCI is respiratory motor dysfunction. The loss of this activity after SCI is caused by disruption to supraspinal control of motor pathways. We have previously shown that formation of the chondroitin sulphate proteoglycan (CSPG) rich perineuronal net is the major impediment to sprouting and reawakening of the residual cross-phrenic pathway that can lead to restoration of respiratory motor function. Indeed, our data demonstrate that robust and rapid recovery of respiratory motor function is possible up to 1.5 years following severe cervical spinal cord hemisection injury through a combination of enzymatic degradation of perineuronal net associated proteoglycans and rehabilitative conditioning. We now provide evidence that this recovery is essentially permanent, lasting up to six months following the cessation of treatment. Our combination treatment strategy mitigates these effects through CSPG breakdown by intraspinal injection of chrondroitinase ABC (ChABC) and intermittent hypoxia (IH) training to increase respiratory drive and synaptic strength. Following conclusion of our treatment strategy, immunohistochemistry has revealed that the extracellular matrix does not reform normally, perhaps suggestive of on-going plasticity. Further, we provide evidence that our combination treatment strategy allows for re-innervation of diaphragm neuromuscular junctions (NMJs) previously denervated due to paralysis induced atrophy. In addition, we provide data describing the ventilatory response of our animals throughout treatment detailing how our recovered animals respond to environmental challenge. Collectively, these data demonstrate the significant restoration of diaphragm function and nerve activity at chronic points following cervical SCI due to matrix modification, induction of plasticity and facilitation of drive. Indeed, our results indicate that essentially complete recovery of motor function in this model of spinal cord trauma may not be limited by time after injury.

Authors: *P. M. WARREN1,2, S. C. STEIGER3, T. E. DICK4, P. M. MACFARLANE5, W. J. ALILAIN6,2, J. SILVER2;
1Sch. of Biomed. Sci., Univ. of Leeds, Leeds, United Kingdom; 2Dept. of Neurosciences, 3Sch. of Biomed. Sci., Case Western Reserve Univ., Cleveland, OH; 4Dept. of Med., Case Western Res. Univ., Cleveland, OH; 5Pediatrics, RB&C, CWRU, Cleveland, OH; 6Anat. and Neurobio., Univ. of Kentucky, Lexington, KY
Disclosures: P.M. Warren: None. S.C. Steiger: None. T.E. Dick: None. P.M. MacFarlane: None. W.J. Alilain: None. J. Silver: None.

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

Dimensions matter: Why do the spinal cords of humans and rodents respond differently to epidural electrical stimulation

Authors: *E. FORMENTO1, M. CAPOGROSSO2, K. MINASSIAN1, F. B. WAGNER1, J.-B. MIGNARDOT1, C. G. M. LE GOFF1, T. MILEKOVIC3, E. BEZARD4,5,6, J. BLOCH7, S. MICERA1, G. COURTINE1;
1École Polytechnique Fédérale De Lausanne, Geneve, Switzerland; 2Dept. of Med., Univ. of Fribourg, Fribourg, Switzerland; 3Fac. of Medicine, Dept. of Basic Neurosci., Univ. of Geneva, Geneva, Switzerland; 4Inst. des Maladies Neurodégénératives, CNRS, Bordeaux, France; 5Inst. des Maladies Neurodégénératives, Univ. of Bordeaux, Bordeaux, France; 6Inst. of Lab. Animal Sciences, China Acad. of Med. Sci., Beijing, China; 7Ctr. Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland

Electrical neuromodulation of the spinal cord reversed leg paralysis in rodent and primate models of spinal cord injury (SCI), but has not mediated similar effects in people with paraplegia. Here, we combined computational modelling and experimental procedures in rodents, nonhuman primates and humans to decipher species-specific effects of epidural electrical stimulation (EES) on the production of leg movements. Computer simulations showed that EES interacts with proprioceptive feedback circuits that are naturally modulated during movement and critically contribute to motor pattern formation, both in rodents and humans. However, anatomical differences between rodents and humans dramatically alter these interactions. We found that the probability of antidromic collisions between EES-induced activity and movement-related information augments with the increase in afferent fibers length. Consequently, continuous EES disrupted the modulation of proprioceptive feedback circuits in humans, which strongly diminished the facilitation of movements with EES. We validated these results in rodents and humans with incomplete SCI. While continuous EES enabled robust locomotion in rats, the limited range of functional EES parameters prevented a similar facilitation of gait in humans. Simulations identified two stimulation strategies that effectively limited the cancellation of proprioceptive information. These strategies involved high-frequency low amplitude stimulation, and EES protocols encoding the natural proprioceptive information in the temporal and spatial structure of stimulation. We validated both strategies in nonhuman primates, whose anatomical properties are comparable to humans. While continuous EES induced co-activation of leg muscles, spatiotemporal EES enabled alternating extension and flexion movements of a paralyzed leg. These findings establish a mechanistic framework to design neuromodulation therapies that enable motor control in humans.

Disclosures
E. Formento: None. M. Capogrosso: None. K. Minassian: None. F.B. Wagner: None. J. Mignardot: None. C.G.M. Le Goff: None. T. Milekovic: None. E. Bezard: None. J. Bloch: E. Ownership Interest (stock, stock options, royalty, receipt of intellectual property rights/patent holder, excluding diversified mutual funds); founder and shareholder of G-Therapeutics SA. S. Micera: E. Ownership Interest (stock, stock options, royalty, receipt of intellectual property rights/patent holder, excluding diversified mutual funds); founder and shareholder of G-Therapeutics SA. G. Courtine: E. Ownership Interest (stock, stock options, royalty, receipt of intellectual property rights/patent holder, excluding diversified mutual funds); founder and shareholder of G-Therapeutics SA.

Grant Support
International Foundation for Research in Paraplegia Chair in Spinal Cord Repair
Grant Support
Bertarelli Foundation Chair in Translational Neuroengineering

LINK: Society for Neuroscience

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

Hybrid peripheral-spinal neuromodulation therapies enable refined locomotion after paralysis by combining global and local control of leg movements

Electrical spatiotemporal neuromodulation of the lumbar spinal cord enabled controlling extension and flexion of paralyzed legs after spinal cord injury, both in animal models and humans. However, this stimulation protocol is not selective enough to modulate the distal musculature independently and efficiently, impeding a refined movement execution. Peripheral nerve stimulation selectively activates passing axons, which allowed precise control over agonist and antagonist muscles of the ankle in animal models. These results suggest that combined electrical stimulation of both spinal cord and peripheral nerves may provide a global and local control over leg movements, respectively. To evaluate this complementarity, we developed a hybrid neuroprosthetic system that targeted the spinal cord with epidural electrical stimulation and both sciatic nerves with intraneural electrodes in rat models of leg paralysis. Real-time control of peripheral nerve stimulation allowed the selective and graded tuning of distal leg movements, which was not possible with electrical spinal cord stimulation. This local stimulation enabled paralyzed rats to walk over ground and to climb a staircase. Preliminary results in humans suggested similar synergies between spatiotemporal neuromodulation of the lumbar spinal cord and peripheral nerve stimulation. These findings open promising perspectives for the development of hybrid neuroprosthetic systems to restore functional leg movements after spinal cord injury, and potentially other neurological disorders.

Authors
*S. M. WURTH1,2, J. GANDAR2, M. CAPOGROSSO2,3, A. CUTRONE4, S. RASPOPOVIC1,4, N. PAVLOVA2,5, P. SHKORBATOVA2,5, L. BAUD2, E. D’ANNA1, Q. BARRAUD2, K. MINASSIAN2, F. WAGNER2, S. MICERA1,4, G. COURTINE2;

1Bertarelli Fndn. Chair in Translational Neuroengineering, EPFL – Campus Biotech B3.04, Geneve, Switzerland; 2EPFL Ctr. for Neuroprosthetics and Brain Mind Inst., Geneva, Switzerland; 3Med., Fribourg Univ., Fribourg, Switzerland; 4The Biorobotics Institute, Scuola Superiore Sant’Anna, Pisa, Italy; 5Pavlov Inst. of Physiol., St Petersbourg, Russian Federation
Disclosures
S.M. Wurth: None. J. Gandar: None. M. Capogrosso: None. A. Cutrone: None. S. Raspopovic: None. N. Pavlova: None. P. Shkorbatova: None. L. Baud: None. E. D’Anna: None. Q. Barraud: None. K. Minassian: None. F. Wagner: None. S. Micera: None. G. Courtine: None.

Grant Support
FNS grant Dynamo [315230_149902]
Grant Support
FNS grant NeuGrasp [205321_170032]
Grant Support
ERC
Grant Support
Wyss Center for Bio and Neuroengineering
Grant Support
Bertarelli Foundation

LINK: Society for Neuroscience

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