Injured Nervous System Research Articles

Neuroprotective effects of testosterone metabolites and dependency on receptor action on the morphology of somatic motoneurons following the death of neighboring motoneurons.

Partial depletion of spinal motoneuron populations induces dendritic atrophy in neighboring motoneurons, and treatment with testosterone is neuroprotective, attenuating induced dendritic atrophy. In this study we examined whether the protective effects of testosterone could be mediated via its androgenic or estrogenic metabolites. Furthermore, to assess whether these neuroprotective effects were mediated through steroid hormone receptors, we used receptor antagonists to attempt to prevent the neuroprotective effects of hormones after partial motoneuron depletion. Motoneurons innervating the vastus medialis muscles of adult male rats were selectively killed by intramuscular injection of cholera toxin-conjugated saporin. Simultaneously, some saporin-injected rats were treated with either dihydrotestosterone or estradiol, alone or in combination with their respective receptor antagonists, or left untreated. Four weeks later, motoneurons innervating the ipsilateral vastus lateralis muscle were labeled with cholera toxin-conjugated horseradish peroxidase, and dendritic arbors were reconstructed in three dimensions. Compared with intact normal animals, partial motoneuron depletion resulted in decreased dendritic length in remaining quadriceps motoneurons. Dendritic atrophy was attenuated with both dihydrotestosterone and estradiol treatment to a degree similar to that seen with testosterone, and attenuation of atrophy was prevented by receptor blockade. Together, these findings suggest that neuroprotective effects on motoneurons can be mediated by either androgenic or estrogenic hormones and require action via steroid hormone receptors, further supporting a role for hormones as neurotherapeutic agents in the injured nervous system. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 691-707, 2017.

Monoclonal antibody Py recognizes neurofilament heavy chain and is a selective marker for large diameter neurons in the brain.

Almost 30years ago, the monoclonal antibody Py was developed to detect pyramidal neurons in the CA3 region of the rat hippocampus. The utility of this antibody quickly expanded when several groups discovered that it could be used to identify very specific populations of neurons in the normal, developing, and diseased or injured central nervous system. Despite this body of literature, the identity of the antigen that the Py antibody recognizes remained elusive. Here, immunoprecipitation experiments from the adult rat cortex identified the Py antigen as neurofilament heavy chain (NF-H). Double immunolabeling of sections through the rat brain using Py and NF-H antibodies confirmed the identity of the Py antigen, and reveal that Py/NF-H+ neurons appear to share the feature of being particularly large in diameter. These include the neurons of the gigantocellular reticular formation, pyramidal neurons of layers II/III and V of the cortex, cerebellar Purkinje neurons as well as CA3 pyramidal neurons. Taken together, this finding gives clarity to past work using the monoclonal Py antibody, and immediately expands our understanding of the importance of NF-H in neural development, functioning, and disease.

Increased TNFR1 expression and signaling in injured peripheral nerves of mice with reduced BACE1 activity

Hematogenous macrophages remove myelin debris from injured peripheral nerves to provide a micro-environment conducive to axonal regeneration. Previously, we observed that injured peripheral nerves from Beta–site APP Cleaving Enzyme 1 (BACE1) knockout (KO) mice displayed earlier influx of and enhanced phagocytosis by macrophages when compared to wild-type (WT) mice. These observations suggest that BACE1 might regulate macrophage influx into distal stumps of injured nerves. To determine through which pathway BACE1 influences macrophage influx, we used a mouse inflammation antibody array to assay the expression of inflammation-related proteins in injured nerves of BACE1 KO and WT mice. The most significant change was in expression of tumor necrosis factor receptor 1 (TNFR1) in the distal stump of injured BACE1 KO nerves. Western blotting of protein extracts confirmed increased expression of TNFR1 and its downstream transcriptional factor NFκB in the BACE1 KO distal stumps. Additionally, treatment of WT mice with a BACE1 inhibitor resulted in increased TNFR1 expression and signaling in the distal stump of injured nerves. Exogenous TNFα increased nuclear translocation of p65 NFκB in BACE1 KO tissue and cultured fibroblasts compared with control WT. BACE1 regulates TNFR1 expression at the level of gene expression and not through proteolytic processing. The accelerated macrophage influx in injured nerves of BACE1 KO mice correlates with increased expression and signaling via TNFR1, indicating a link between BACE1 activity and TNFR1 expression/signaling that might contribute to repair of the injured nervous system.

Sciatic nerve regeneration in KLF7-transfected acellular nerve allografts

Objective: Krüppel-like Factor 7 (KLF7) is a transcription factor that promotes axon regeneration in the central nervous system. Here, we assessed whether KLF7 stimulates regeneration after peripheral nerve injury.Methods: C57BL/6 mice received an acellular nerve allograft (ANA) injected with either adeno-associated virus 2 (AAV2) vector or AAV2-KLF7 for sciatic nerve gap repair. After 4 weeks, KLF7 was detected by RT-PCR, western blot and immunohistochemistry in regenerated nerves. Axonal regeneration and functional recovery were examined by immunohistochemistry, Fluorogold (FG) and cholera toxin B (CTB) retrograde neural tracing, sciatic function index (SFI), angle of ankle, Hargreaves test and electrophysiological analysis.Results: With AAV2-KLF7 injection, KLF7 expression increased in regenerated nerves, and amplitude, score of SFI, angle of ankle and FG-labelled spinal cord neurons were increased. We observed elevated CTB-labelled neurons in dorsal root ganglia (DRG), neurofilaments, P0 (peripheral myelin) and S100 and decreased latency period and withdrawal latencies in the Hargreaves test. The SFI was significantly correlated with amplitude and regenerated axon number. Tyrosine kinase A (TrkA) and B (TrkB) receptors were also increased in the DRG.Conclusions: Our findings suggest that KLF7 promoted peripheral nerve axonal regeneration, further supporting a role for KLF7 as a growth-promoting transcription factor in the injured nervous system.

Causal Link between the Cortico-Rubral Pathway and Functional Recovery through Forced Impaired Limb Use in Rats with Stroke.

The research aimed at determining the causal linkage between reorganization of the motor pathway induced by intensive rehabilitative training and recovery after stroke. We clarified the expansion of the forelimb representation area of the ipsilesional motor cortex by forced impaired forelimb use (FLU) after lesioning the internal capsule with intracerebral hemorrhaging (ICH) in rats. Anterograde tracing showed robust axonal sprouting from the forelimb area to the red nucleus in response to FLU. Selective blockade of the cortico-rubral pathway by the novel double-viral vector technique clearly revealed that the increased cortico-rubral axonal projections had causal linkage to the recovery of reaching movements induced by FLU. Our data demonstrate that the cortico-rubral pathway is responsible for the effect of intensive limb use.

Neural Stem and Progenitor Cells in Nervous System Function and Therapy.

Neural Stem and Progenitor Cells in Nervous System Function and Therapy.

Anti-tumor and repairing nerve injuries: A drug-loaded monosialoganliosides micelles delivered to brain for glioblastoma

Event Abstract Back to Event Anti-tumor and repairing nerve injuries: A drug-loaded monosialoganliosides micelles delivered to brain for glioblastoma Dan Zou1, Yazhou Wang1, Zong Li1, Wei Wang1, Tieying Yin1, Bochu Wang1 and Guixue Wang1 1 College of Bioengineering, Chongqing University, Key Laboratory of Biorheological Science and Technology, Ministry of Education, China Introduction: Compared with clinical remission and extending life, quality of life in patients with glioblastoma have not been given enough attention in clinical treatment. Nerve injuries directly or indirectly effect on life of patients with glioblastoma. And the treatment of brain cancers remains great challenges because most of the therapeutic drugs can’t be delivered to the tumors in the brain directly for the existence of blood-brain barrier (BBB)[1]. Therefore, we applied monosialoganglioside GM1 as drug-loaded nanosized carrier, which is amphiphilic molecules that spontaneously self-assemble into micelles. Moreover, GM1 is a kind of drug that can cross the BBB and treat neurological disease, exogenously administered GM1 have been proved to provoke regeneration and neurite outgrowth in the injured nervous system[2]-[4]. The anti-tumor drugs can be encapsulated in self-assembled micelles of GM1 and are delivered to brain. Therefore, this drug delivery system has the capabilities of overcoming BBB, repairing nerve injuries, and eliminating tumor cells. Materials and Methods: Stock solution of DOX were prepared by dissolving the drug in dimethylsulfoxide (DMSO). Stock solution of purified monosialogangliosides GM1 were prepared by dissolving the gangliosides in tri-distilled water, and the solution were maintained at 4℃, they should be centrifuged and filtered prior to use. Stock solutions of DOX were slowly added to the solution of GM1micelles. Then the mixed micelles were incubated at 4℃ for 24h and dialyzed for 24h. The structure and morphology were characterized by TEM, and the mean diameter and its distribution were measured by means of Zetasizer. The method of DIR-loaded micelles is consistent with the preparation of mixed micelles of GM1 and DOX. Fluorescent micelles were injected intravenously in the caudal vein. Discussion and Conclusion: The morphology of micelles was detected using a JEM 1200EX transmission electron microscope. Fig A showed micelles GM1/DOX mixed micelles with about 20nm of mean diameter tends to evenly distributed. A normal mouse was injected with GM1/DIR micelles, distribution and intensity of DIR were monitored by In-Vivo FX PRO for small animal imaging. It revealed that GM1 can cross blood-brain barrier and target to brain because DIR were concentrated mainly in the brain tissue. (Fig.B). Figure A. Electron microscopy of GM1 and DOX mixed micelles. Scale bar: 200nm.B. Experimental group (A) was injected with GM1/Dir micelles after 5 hours. National Natural Science Foundation of China (31200713); National Key Basic Research Project (“973” Project) （2014CB541600）; Fundamental Research Funds for the Central Universities(106112015CDJZR235514)

Low-density Lipoprotein Receptor-related Proteins in a Novel Mechanism of Axon Guidance and Peripheral Nerve Regeneration

The low-density lipoprotein receptor-related protein receptors 1 and 2 (LRP1 and LRP2) are emerging as important cell signaling mediators in modulating neuronal growth and repair. We examined whether LRP1 and LRP2 are able to mediate a specific aspect of neuronal growth: axon guidance. We sought to identify LRP1 and LRP2 ligands that could induce axonal chemoattraction, which might have therapeutic potential. Using embryonic sensory neurons (rat dorsal root ganglia) in a growth cone turning assay, we tested a range of LRP1 and LRP2 ligands for the ability to guide growth cone navigation. Three ligands were chemorepulsive: α-2-macroglobulin, tissue plasminogen activator, and metallothionein III. Conversely, only one LRP ligand, metallothionein II, was found to be chemoattractive. Chemoattraction toward a gradient of metallothionein II was calcium-dependent, required the expression of both LRP1 and LRP2, and likely involves further co-receptors such as the tropomyosin-related kinase A (TrkA) receptor. The potential for LRP-mediated chemoattraction to mediate axonal regeneration was examined in vivo in a model of chemical denervation in adult rats. In these in vivo studies, metallothionein II was shown to enhance epidermal nerve fiber regeneration so that it was complete within 7 days compared with 14 days in saline-treated animals. Our data demonstrate that both LRP1 and LRP2 are necessary for metallothionein II-mediated chemotactic signal transduction and that they may form part of a signaling complex. Furthermore, the data suggest that LRP-mediated chemoattraction represents a novel, non-classical signaling system that has therapeutic potential as a disease-modifying agent for the injured peripheral nervous system.

Transcriptomic Approaches to Neural Repair

Understanding why adult CNS neurons fail to regenerate their axons following injury remains a central challenge of neuroscience research. A more complete appreciation of the biological mechanisms shaping the injured nervous system is a crucial prerequisite for the development of robust therapies to promote neural repair. Historically, the identification of regeneration associated signaling pathways has been impeded by the limitations of available genetic and molecular tools. As we progress into an era in which the high-throughput interrogation of gene expression is commonplace and our knowledge base of interactome data is rapidly expanding, we can now begin to assemble a more comprehensive view of the complex biology governing axon regeneration. Here, we highlight current and ongoing work featuring transcriptomic approaches toward the discovery of novel molecular mechanisms that can be manipulated to promote neural repair. Transcriptional profiling is a powerful technique with broad applications in the field of neuroscience. Recent advances such as single-cell transcriptomics, CNS cell type-specific and developmental stage-specific expression libraries are rapidly enhancing the power of transcriptomics for neuroscience applications. However, extracting biologically meaningful information from large transcriptomic datasets remains a formidable challenge. This mini-symposium will highlight current work using transcriptomic approaches to identify regulatory networks in the injured nervous system. We will discuss analytical strategies for transcriptomics data, the significance of noncoding RNA networks, and the utility of multiomic data integration. Though the studies featured here specifically focus on neural repair, the approaches highlighted in this mini-symposium will be of broad interest and utility to neuroscientists working in diverse areas of the field.

Cortical control of intraspinal microstimulation: Toward a new approach for restoration of function after spinal cord injury.

Approximately 6 million people in the United States are currently living with paralysis in which 23% of the cases are related to spinal cord injury (SCI). Miniaturized closed-loop neural interfaces have the potential for restoring function and mobility lost to debilitating neural injuries such as SCI by leveraging recent advancements in bioelectronics and a better understanding of the processes that underlie functional and anatomical reorganization in an injured nervous system. This paper describes our current progress toward developing a miniaturized brain-machine-spinal cord interface (BMSI) that converts in real time the neural command signals recorded from the cortical motor regions to electrical stimuli delivered to the spinal cord below the injury level. Using a combination of custom integrated circuit (IC) technology for corticospinal interfacing and field-programmable gate array (FPGA)-based technology for embedded signal processing, we demonstrate proof-of-concept of distinct muscle pattern activation via intraspinal microstimulation (ISMS) controlled in real time by intracortical neural spikes in an anesthetized laboratory rat.

Improved poly(d,l-lactide-co-1,3-trimethylene carbonate)6 copolymer microparticle vehicles for sustained and controlled delivery of bioactive basic fibroblast growth factor

A novel, biocompatible and biodegradable six-arm branched copolymer poly(d,l-lactide)-co-(1,3-trimethylene carbonate)6 has been synthesized and fabricated as a porous microparticle with an oil-in-water single emulsion method. Poly(d,l-lactide-co-1,3-trimethylene carbonate)6 microparticles were further conjugated with heparin by 1-ethyl-3-3-dimethylamino-propylcarbodiimide/ N-hydroxysuccinimide chemistry and characterized using 1H-nuclear magnetic resonance and scanning electron microscopy. The heparin-loading capacity of poly(d,l-lactide-co-1,3-trimethylene carbonate)6 microparticles was identified as 213 ± 6 pmol/mg-particle determined with toluidine blue method. The resultant binding efficiency and release profile of basic fibroblast growth factor which is bound on heparin–poly(d,l-lactide-co-1,3-trimethylene carbonate)6 microparticles were quantitatively analyzed by enzyme-linked immunosorbent assay. Thus, the developed poly(d,l-lactide-co-1,3-trimethylene carbonate)6 porous microparticles presented superior capacity of growth factor cargo as 1965 ± 117 pg basic fibroblast growth factor per mg-microparticles and displayed a sustained release profile over 4 weeks with quite low initial burst. Additionally, the viability of dissociated basic fibroblast growth factor was confirmed with methylthiazolyltetrazolium quantitative assay along with in vitro culturing model of rodent neural stem cell. Collectively, our results demonstrate that heparin–poly(d,l-lactide-co-1,3-trimethylene carbonate)6 microparticles attained controllable and sustained delivery of bioactive basic fibroblast growth factor for 4 weeks with significantly reduced burst release. The present heparin–poly(d,l-lactide-co-1,3-trimethylene carbonate)6 porous microparticulate system could be potentially developed to foster a novel bioengineering platform for repair and regeneration of injured nervous system.

Enhanced neurite outgrowth of human model (NT2) neurons by small-molecule inhibitors of Rho/ROCK signaling.

Axonal injury in the adult human central nervous system often results in loss of sensation and motor functions. Promoting regeneration of severed axons requires the inactivation of growth inhibitory influences from the tissue environment and stimulation of the neuron intrinsic growth potential. Especially glial cell derived factors, such as chondroitin sulfate proteoglycans, Nogo-A, myelin-associated glycoprotein, and myelin in general, prevent axon regeneration. Most of the glial growth inhibiting factors converge onto the Rho/ROCK signaling pathway in neurons. Although conditions in the injured nervous system are clearly different from those during neurite outgrowth in vitro, here we use a chemical approach to manipulate Rho/ROCK signalling with small-molecule agents to encourage neurite outgrowth in cell culture. The development of therapeutic treatments requires drug testing not only on neurons of experimental animals, but also on human neurons. Using human NT2 model neurons, we demonstrate that the pain reliever Ibuprofen decreases RhoA (Ras homolog gene family, member A GTPase) activation and promotes neurite growth. Inhibition of the downstream effector Rho kinase by the drug Y-27632 results in a strong increase in neurite outgrowth. Conversely, activation of the Rho pathway by lysophosphatidic acid results in growth cone collapse and eventually to neurite retraction. Finally, we show that blocking of Rho kinase, but not RhoA results in an increase in neurons bearing neurites. Due to its anti-inflammatory and neurite growth promoting action, the use of a pharmacological treatment of damaged neural tissue with Ibuprofen should be explored.

Stem Cell Strategy for the Treatment of Motor Neuron Diseases

Motor Neuron disease is a neurodegenerative disease of central nervous system leading to death of motor neurons from CNS and spinal cord. Due to the lack of effective treatment modalities, recently, many scientists have considered stem cells as a potential strategy for the treatment of this disease. Amongst the different types of stem cells, MSCs have been thought as a promising source of stem cells in regenerative medicine applications. These cells can be transplanted into the injured nervous system as a new therapeutic strategy. Although many challenges and concerns still remain, and the exact mechanism by which stem cells act is still unknown, the positive effect of stem cells following transplantation has encouraged many researchers to consider this as a treatment option in the future. There has been a lot of research ongoing on the derivation of motor neurons from stem cells in vitro and many scientists are attempting to bring these cells into clinical applications by conducting a number of clinical trials. Here, in this review, we discuss the current progress in pre-clinical studies and the status of clinical trials using stem cells in motor neuron diseases. We also discuss the hurdles which need to be overcome while moving from bench to bedside. Based on current information available, stem cell derived motor neurons can pave the way as a new treatment option for patients with the disease which seems to be highly promising.

Recombinant self‐assembling 16‐residue peptide nanofiber scaffolds for neuronal axonal outgrowth

Self‐assembling peptides are considered a good biological scaffold for the repair of injured nervous system. In order to set up a stable system to produce the peptides at low cost, we used a gene recombinant expression method. The sequence of the peptide was devised to facilitate neural cell attachment and growth. The nucleotide sequence of the self‐assembling peptide was designed, artificially synthesized, and inserted into the fusion protein vector pTYB2. After being transformed and expressed in Escherichia coli BL‐21 (DE3) by means of the fusion protein, the soluble 16‐residue peptide (named RAE16) was obtained by one‐step chitin affinity chromatography. During cell culture, bone marrow stromal cells were fully embedded in the 3D environment of the peptide scaffolds. The MTT (3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5‐diphenyl‐2‐H‐tetrazolium bromide) test indicated that bone marrow stromal cells cultured in RAE16 had the highest survival rate with the absorbance value of 0.7 at 7 days. Moreover, the cortical neural axons in the RAE16 group were longer (118.36 ± 7.04 μm) than in the other groups (p < 0.01). The recombinant peptide nanofiber scaffolds we designed provide a promising cell culture system for general molecular and cell biology studies and are useful as well for neural regeneration studies.

An in vitro assay to study induction of the regenerative state in sensory neurons

After injury, peripheral neurons activate a pro-regenerative program that facilitates axon regeneration. While many regeneration-associated genes have been identified, the mechanism by which injury activates this program is less well understood. Furthermore, identifying pharmacological methods to induce a pro-regenerative state could lead to novel treatments to repair the injured nervous system. Therefore, we have developed an in vitro assay to study induction of the pro-regenerative state following injury or pharmacological treatment. First, we took advantage of the observation that dissociating and culturing sensory neurons from dorsal root ganglia activates a pro-regenerative program. We show that cultured neurons activate transcription factors and upregulate regeneration-associated genes common to the pro-regenerative program within the first hours after dissection. In a paradigm similar to pre-conditioning, neurons injured by dissociation display enhanced neurite outgrowth when replated as early as 12h after being removed from the animal. Furthermore, stimulation of the pro-regenerative state improves growth on inhibitory substrates and requires DLK/JNK signaling, both hallmarks of the pro-regeneration response in vivo. Finally, we modified this assay in order to identify new methods to activate the pro-regenerative state in an effort to mimic the pre-conditioning effect. We report that after several days in culture, neurons down-regulate many molecular hallmarks of injury and no longer display enhanced neurite outgrowth after replating. Hence, these neurons are functionally naïve and are a useful tool for identifying methods to induce the pro-regenerative state. We show that both injury and pre-treatment with forskolin reactivate the pro-regenerative state in this paradigm. Hence, this assay is useful for identifying pharmacological agents that induce the pro-regenerative state in the absence of injury.

Biocompatibility of a coacervate-based controlled release system for protein delivery to the injured spinal cord

The efficacy of protein-based therapies for treating injured nervous tissue is limited by the short half-life of free proteins in the body. Affinity-based biomaterial delivery systems provide sustained release of proteins, thereby extending the efficacy of such therapies. Here, we investigated the biocompatibility of a novel coacervate delivery system based on poly(ethylene argininylaspartate diglyceride) (PEAD) and heparin in the damaged spinal cord. We found that the presence of the [PEAD:heparin] coacervate did not affect the macrophage response, glial scarring or nervous tissue loss, which are hallmarks of spinal cord injury. Moreover, the density of axons, including serotonergic axons, at the injury site and the recovery of motor and sensorimotor function were comparable in rats with and without the coacervate. These results revealed the biocompatibility of our delivery system and supported its potential to deliver therapeutic proteins to the injured nervous system.

Aucubin promotes neurite outgrowth in neural stem cells and axonal regeneration in sciatic nerves.

Aucubin is an iridoid glycoside with a wide range of biological activities, including anti-inflammatory, anti-microbial, anti-algesic as well as anti-tumor activities. Recently, it has been shown that aucubin prevents neuronal death in the hippocampal CA1 region in rats with diabetic encephalopathy. In addition, it has protective effects on H2O2-induced apoptosis in PC12 cells. We have shown here that aucubin promotes neuronal differentiation and neurite outgrowth in neural stem cells cultured primarily from the rat embryonic hippocampus. We also investigated whether aucubin facilitates axonal elongation in the injured peripheral nervous system. Aucubin promoted lengthening and thickness of axons and re-myelination at 3 weeks after sciatic nerve injury. These results indicate that administration of aucubin improved nerve regeneration in the rat model of sciatic nerve injury, suggesting that aucubin may be a useful therapeutic compound for the human peripheral nervous system after various nerve injuries.

Locomotor training alters the behavior of flexor reflexes during walking in human spinal cord injury.

In humans, a chronic spinal cord injury (SCI) impairs the excitability of pathways mediating early flexor reflexes and increases the excitability of late, long-lasting flexor reflexes. We hypothesized that in individuals with SCI, locomotor training will alter the behavior of these spinally mediated reflexes. Nine individuals who had either chronic clinically motor complete or incomplete SCI received an average of 44 locomotor training sessions. Flexor reflexes, elicited via sural nerve stimulation of the right or left leg, were recorded from the ipsilateral tibialis anterior (TA) muscle before and after body weight support (BWS)-assisted treadmill training. The modulation pattern of the ipsilateral TA responses following innocuous stimulation of the right foot was also recorded in 10 healthy subjects while they stepped at 25% BWS to investigate whether body unloading during walking affects the behavior of these responses. Healthy subjects did not receive treadmill training. We observed a phase-dependent modulation of early TA flexor reflexes in healthy subjects with reduced body weight during walking. The early TA flexor reflexes were increased at heel contact, progressively decreased during the stance phase, and then increased throughout the swing phase. In individuals with SCI, locomotor training induced the reappearance of early TA flexor reflexes and changed the amplitude of late TA flexor reflexes during walking. Both early and late TA flexor reflexes were modulated in a phase-dependent pattern after training. These new findings support the adaptive capability of the injured nervous system to return to a prelesion excitability and integration state.

News from the NIH: Diversity, disparities, and disabilities research.

The National Institutes of Health continues to evolve in its efforts to recognize and ameliorate negative health consequences associated with issues of diversity, disparities, and disabilities. This includes the creation of the National Institute of Child Health and Human Development (NICHD) in 1962 to investigate human development across the lifespan and to focus on understanding developmental disabilities. Although the NICHD was later renamed the Eunice Kennedy Shriver National Institute of Child Health and Human Development, its continuing mission is to ensure that every person is born healthy and wanted, that women suffer no harmful effects from reproductive processes, and that all children have the chance to achieve their full potential for healthy and productive lives, free from disability, and to ensure the health, productivity, independence, and well-being of all people through optimal rehabilitation (http://www.nichd.nih.gov/Pages/index.aspx). To accomplish its broad mission, the NICHD conducts and supports laboratory research, descriptive studies, clinical trials, and epidemiological studies that explore health processes, the impact of diseases, diversity, disparities, and disabilities on the lives of individuals. Translational research is encouraged to disseminate effective preventive interventions and treatments designed to improve the lives of those experiencing disease, disability, or health disparity. The National Center for Medical Rehabilitation Research (NCMRR) http://www.nichd.nih.gov/about/org/ncmrr/Pages/overview.aspx, logistically situated within the NICHD, functions to foster development of scientific knowledge necessary to enhance the health, productivity, and quality of life of people with physical disabilities. The NCMRR has research interests in numerous topics related to rehabilitation including the following: pathophysiology and management of chronically injured nervous and musculoskeletal systems; repair and recovery of motor and cognitive function; rehabilitative interventions and strategies; secondary conditions associated with chronic disabilities; improved diagnosis, assessment, and outcome measures; and development of assistive technologies and devices. This focus on research involving physical disabilities complements the NICHD’s interests in identifying and promoting the prerequisites of optimal physical, mental, and behavioral growth and development through infancy, childhood, and adolescence, and in preventing and treating intellectual and developmental disabilities.

Towards a miniaturized brain-machine-spinal cord interface (BMSI) for restoration of function after spinal cord injury.

Nearly 6 million people in the United States are currently living with paralysis in which 23% of the cases are related to spinal cord injury (SCI). Miniaturized closed-loop neural interfaces have the potential for restoring function and mobility lost to debilitating neural injuries such as SCI by leveraging recent advancements in bioelectronics and a better understanding of the processes that underlie functional and anatomical reorganization in an injured nervous system. This paper describes our current progress towards developing a miniaturized brain-machine-spinal cord interface (BMSI) that is envisioned to convert in real time the neural command signals recorded from the brain to electrical stimuli delivered to the spinal cord below the injury level. Specifically, the paper reports on a corticospinal interface integrated circuit (IC) as a core building block for such a BMSI that is capable of low-noise recording of extracellular neural spikes from the cerebral cortex as well as muscle activation using intraspinal microstimulation (ISMS) in a rat with contusion injury to the thoracic spinal cord. The paper further presents results from a neurobiological study conducted in both normal and SCI rats to investigate the effect of various ISMS parameters on movement thresholds in the rat hindlimb. Coupled with proper signal-processing algorithms in the future for the transformation between the cortically recorded data and ISMS parameters, such a BMSI has the potential to facilitate functional recovery after an SCI by re-establishing corticospinal communication channels lost due to the injury.