NICHD’s ongoing research, as well as its support for research on spinal cord injury (SCI), focuses on investigations in the neurosciences, particularly as they affect developing systems and rehabilitation. NICHD supports the full spectrum of basic, clinical, and translational research in the arenas of biomedical and behavioral neuroscience. In addition to NICHD-sponsored initiatives and investigator-initiated projects, the agency supports neuroscience research through the pooling of its resources and expertise with 15 other NIH institutes and centers. NICHD also conducts research on how to prevent SCI through the education of young drivers.
NICHD research related to SCI is focused on increasing the health, productivity, independence, well-being, and recovery of all people living with SCI. The intent is to develop social, physical, and behavioral rehabilitation treatments for people with spinal-injury disabilities while also performing and supporting basic research in such fields as neurology, neurophysiology, osteology, biochemistry, motor control, and neuromechanics as a foundation for these developments.
NICHD's research efforts on SCI include a range of overlapping areas:
- Understanding of the biochemistry of the normal, wounded, and healing spinal cord
- Developing new tools that can scan and provide images of living tissue to diagnose the extent of SCI
- Understanding the mechanisms of bladder and bowel infections and how to prevent them
- Understanding the mechanisms and means of prevention of other secondary complications of SCI, such as pressure sores, blood clots, pneumonia, spasticity, sexual dysfunction, and neuropathic pain
- Investigating the biochemistry of nerve regeneration
- Improving the quality of life of individuals with SCI (e.g., improved accessibility for activities of daily living [ADLs]; improved upper limb function or functional mobility)
- Helping people with SCI adapt their behavior to the loss of sensory, motor, and organ-control function
- Assessing the efficacy and outcomes of medical rehabilitation therapies and practices in spine-injured people
- Developing improved assistive technologies for the SCI population
- Understanding whole-body−system responses of spine-injured people to physical impairments and functional changes
- Developing more precise methods of measuring impairments, disabilities, and both societal and functional limitations
- Training research scientists in the field of rehabilitation
Through its intramural and extramural organizational units, NICHD supports and conducts a range of research on spinal cord injury (SCI), especially in the area of rehabilitation. Short descriptions of some of this research are included below.
Several NICHD and organizational units support research and other activities related to SCIs and spinal cord development.
- NICHD's National Center for Medical Rehabilitation Research (NCMRR) is the primary NICHD entity that supports research to advance the understanding of treatments and devices to assist movement in patients with SCIs.
- NICHD's Pregnancy and Perinatology Branch (PPB) supports studies to understand and treat birth defects that affect the spinal cord, such as spina bifida.
- NICHD's Division of Population Health Research (DiPHR) supports and conducts research relevant to human development and spinal cord health through studies of nutrients in the prevention of birth defects. For example, studies are investigating the importance of folic acid in preventing neural tube defects.
- Researchers in NICHD's Division of Intramural Research (DIR) are developing methods for improved imaging of the central nervous system. These methods will assist not only in studying normal patterns of development, but also in evaluating and studying SCIs and spinal cord diseases.
Some recent findings related to SCIs are described below.
Folate Found to Encourage Healing in SCIs
The B vitamin folate seems to stimulate healing in the damaged spinal cord tissue of rats by touching off a change in DNA, according to a laboratory study funded by NICHD's NCMRR and three other NIH Institutes. The greater the doses of folate the researchers administered (up to a maximum of 80 micrograms of the B vitamin per kilogram of body weight), the more regrowth of axons occurred. The scientists found that folate fueled an intracellular process in which DNA is superficially altered by the attachment of chemical compounds known as methyl groups. This natural biochemical process is called DNA methylation. The regrowth of axons in rats suggests that more research on folate metabolism and DNA methylation could open new paths to healing damaged spinal cords—not to mention the healing of other forms of trauma to nerve tissue, as in the brain. The research represents an advance in the new field of epigenetics, in which changes are made to DNA to alter its function without changing the structure of genes, a seemingly counterintuitive exercise given the long-established notion that the only way DNA's function can be changed is to alter its composition through mutation.
The researchers went a step further and investigated how folate repairs damaged nerve tissue. Traumatized axons, they found, start to produce surface receptors for folate. Folate is attracted to the receptors and fits into them like a hand in a glove and then is absorbed into the axon. After absorbing folate, the nerve cells begin producing enzymes that fasten methyl groups to DNA. When the scientists chemically blocked folate from binding to the nerve cells, or blocked the methylation enzymes, they found that the nerve-healing process tapered off.1
Brain Control of Wheelchairs, Prostheses, and Computers
Researchers funded by a grant from the NCMRR, which is part of NICHD, demonstrated that a tiny microelectrode array implanted in the brain cortex can help a person with tetraplegia achieve repeatable and accurate point-and-click control of a computer interface nearly 3 years after implantation of the device. The goal of these researchers, who were working in a human clinical trial at Massachusetts General Hospital in Boston, was to make progress in developing a system called BrainGate2 that can help those with SCIs and other nervous system injuries to turn brain impulses into electrical signals that can control external devices such as computers, wheelchairs, and prostheses or robotic appendages. For 5 days, the scientists tested a 4×4 mm array of 100 microelectrodes that had been implanted 1,000 days previously in the motor cortex of a patient with longtime tetraplegia from a brainstem stroke. Across the 5 days, spiking signals were obtained from 41 of 96 electrodes and were successfully decoded to provide neural cursor point-and-click control with a mean task performance of 91.3% ± 0.1% (mean ± standard deviation) correct target acquisition.
The ultimate aim of BrainGate2 is to help people with SCI, stroke, muscular dystrophy, amyotrophic lateral sclerosis, limb loss, or other serious conditions to restore their mobility and independence. In addition to the brain-implanted sensor that records signals directly related to imagined limb movement, the system consists of a decoder, which includes a set of computers and embedded software that turns the brain signals into a useful command for an external device, which could be a standard computer desktop or other communication device, a powered wheelchair, or a prosthetic or robotic limb.
Working together, the system components can turn thought into action. For example, the user thinks about moving a cursor on a computer, and the brain emits a signal that is captured by the implanted sensor. The sensor signals the decoder, which translates it into a command for the computer to move the cursor.2
Strengthening SCI Patients' Leg Muscles Through Electrical Stimulation
The mass, strength, and endurance of the thigh muscles of people with tetraplegia and paraplegia can be significantly increased through the electrical stimulation of the area's nerves and muscles combined with resistance training, according to a small longitudinal study, conducted at the Department of Cell Biology at the Emory University School of Medicine in Atlanta, which was supported by NICHD. During the study, the experimenters also measured the femoral artery's diameter and blood flow.
In the study, five male patients, ages 31 to 41, who had chronic complete paralysis below the level of injury (C5 vertebra to the T10) completed 18 weeks of home-based neuromuscular electrical stimulation (NMES) resistance training. While seated, the participants trained their quadriceps muscle group twice a week with four sets of 10 dynamic knee extensions against resistance. All measurements were made before training and after 8, 12, and 18 weeks of training. Ultrasound was used to measure the femoral artery diameter and blood flow. Blood flow was measured before and after 5 and 10 minutes of occluding blood circulation with a cuff and during a 4-minute isometric electrical stimulation fatigue protocol.
The training led to substantial increases in muscle mass and ability to lift weight, as well as a 60% reduction in muscle fatigue. However, training did not increase the diameter of the femoral artery and the volume of blood flow—both of which typically diminish with SCI.
In summary, NMES resistance training improved muscle size and reduced fatigue without a corresponding increase in the blood supply. This suggests that the effects of SCI on artery size and blood flow are not linked directly with muscle mass and resistance to fatigue. It also shows that muscle fatigue in SCI patients can be improved without increases in arterial diameter or in blood flow capacity.3
Training a Key Researcher to Study the SCI Population in High-Risk Communities
A 5-year NICHD award is connecting registered nurses with Ph.D. degrees to the scholarly training, mentorship, and support necessary to become a skilled independent researcher in SCI, while also providing help to those living SCI. At the completion of training, candidates are expected to create and oversee a large randomized controlled trial (RCT) focusing on people with SCI who are living in a local community whose residents are at high risk for this injury. It is anticipated that this research project will provide empirical data to develop programs that will improve the health and quality of life of this vulnerable population.
The training will take place at the Medical University of South Carolina in Charleston, a facility that features senior experts in the areas of community-based participatory research (CBPR), research in health disparities, and applied SCI research. The trainee is connected with mentors who have complementary expertise in the measurement and interpretation of health and social outcomes after SCI and in the development and implementation of RCTs of community-based health promotion interventions with vulnerable populations using a CBPR approach. The mentoring team will be responsible for monitoring the trainee's progress during the 5-year program.
The planned research project, to be conducted in partnership with a local center for independent living, as well as the Medical University of South Carolina, includes strategies to identify and address obstacles in the physical and social environment that affect health after SCI. The overall goals are to reduce rehospitalizations and the development of secondary conditions, to improve community participation in the program, and to increase satisfaction with life after SCI. The study is employing the novel approach of having community-based peer navigators who have SCI. These navigators will proactively mitigate barriers and facilitate access to health care and other community-based services for other people in the community with SCI. (NIH/NICHD K23. Project Dates: 2/01/2010 to 3/31/2015. Susan Newman, Ph.D., RN, CRRN. Grant/Project No. 5K23HD062637-03)
Microimaging of Living Nerve Tissue
NICHD scientists in the DIR Section on Biophysics and Biomimetics invented a breakthrough living-tissue imaging technique known as diffusion tensor magnetic resonance imaging (DTI). This technique allows researchers to better understand the function and organization of the central nervous system in its normal, diseased, and injured states, and thus it contributes to improving the diagnosis of neurological and developmental disorders. DTI measures how water diffuses along gradients in three directions. Water takes the path of least resistance, even as it travels through biological structures such as cell membranes. By imaging the path and rate of flow of biosystem water in tiny three-dimensional sectors called voxels, a highly detailed image of normal and abnormal nerve microstructures can be constructed. The resulting "picture" looks like tissue "stains" on a lab slide, but these pictures are "developed" without chemical contrast agents or dyes.
DTI is the most successful imaging technique to date for identifying ischemic regions in the brain during acute stroke. It is also used to follow changes in normally and abnormally developing white matter, including demyelination, the loss of axons' myelin sheath that often happens in SCI. NICHD researchers also pioneered the use of DTI-derived color maps to encode the orientation of nerve fibers. One example of this type of work, published in 2006 in the American Journal of Neuroradiology, can be found at: http://www.ajnr.org/content/27/4/786.full?ref=starshemale.com
More recently, NICHD scientists invented and have been developing several advanced live-tissue magnetic resonance methods to measure fine microstructural features of nerve fascicles, which are bundles or tracts of nerve cells or fibers. Previously, these fascicles could be measured only by optical microscopy, and then only by using laborious dead-tissue histological methods. The scientists also recently developed a DTI method to measure the distribution of axon diameters within large white-matter fascicles, dubbing this method AxCaliber MRI. After careful validation studies, the researchers recently reported the first in vivo measurement of the distribution of axon diameters within the corpus callosum in the rodent brain. This measurement is important neurophysiologically and developmentally because the axon diameter determines the velocity of nerve conduction and thus the rate of information transfer along nerve pathways. See the article at: https://science.nichd.nih.gov/confluence/download/attachments/117212440/barazanybasserassaf_brain09.pdf (PDF 902 KB).
Understanding Spinal Cord Injury and Bone Loss
People who experience spinal cord injury often have the added problem of osteoporosis and bone loss. As a result, patients with spinal cord injury are more prone to bone fractures and other serious medical complications such as increased pain, amputation, and prolonged hospitalization for treatment. Unfortunately, a lack of understanding of what causes spinal cord injury-related osteoporosis makes it difficult to diagnose, treat, and prevent. In short-term animal studies, bone loss was associated with increases in a specific protein called sclerostin. To assess whether these research results could lead to new ways to help humans with spinal cord injury, scientists studied this same protein in a group of men who had suffered spinal cord injury at least two years previously.
The results from the earlier animal studies suggested that researchers may find high levels of the sclerostin protein in patients with complete spinal cord injury who could not walk. However, what scientists discovered was the opposite—the amount of the protein was significantly lower in the men who were wheelchair bound, compared with those who could walk. Additionally, the researchers found that men with spinal cord injury but who could walk had very similar sclerostin levels to men without any spinal cord injury. Scientists theorized that sclerostin may increase shortly after spinal cord injury, while bone loss is occurring rapidly, and then fall to low levels once most of the damage is already done. Additional research is needed to determine whether sclerostin is simply a marker of osteoporosis or whether blocking the effects of the protein soon after an injury could help prevent or reduce long-term bone loss.4
To achieve its goals for research on SCI, NICHD supports a variety of other activities. Some of these activities are managed through the Institute's components; others are part of NIH-wide or collaborative efforts in which NICHD participates. Some of these activities are listed below.
- The Medical Rehabilitation Research Resource Network (MR3 Network), funded through the NCMRR, the National Institute of Neurological Disorders and Stroke, and the National Institute of Biomedical Imaging and Bioengineering, builds research infrastructure in medical rehabilitation. The Network provides investigators with access to expertise, courses and workshops, technologies, and other collaborative opportunities from allied disciplines such as neuroscience, engineering, applied behavior, and the social sciences. The Network provides rehabilitation researchers access to resources to study a wide range of conditions, including SCI, stroke and traumatic brain injury, musculoskeletal and joint disorders, developmental disorders, and degenerative disorders.
- Among its many activities, the NCMRR supports research on SCIs and musculoskeletal disorders, as well as assistive devices. A large portion of this program's activities focus on developing and supporting the application of devices to improve the human-environment interface and to restore or enhance an individual's capacity to function in his or her environment. This type of applied research and rehabilitation technology includes, but is not limited to, prosthetics, wheelchairs, biomechanical modeling, and other topics that aim to enhance mobility, communication, cognition, and environmental control.
- The Paul D. Wellstone Muscular Dystrophy Specialized Research Centers (MDSRCs) is supported by the NICHD's IDDB and several other NIH Institutes. The Centers promote basic, translational, and clinical research and provide important resources that can be used by the national muscle biology and neuromuscular research communities, including those conducting research on SCIs and spinal cord health.
- NICHD held a 2-day workshop on Personal Motion Technologies for Healthy Independent Living to discuss the clinical needs of older and/or disabled persons and how sensor technologies can be used to monitor personal motion in their everyday lives. The Workshop provided critical information and discussion on how such devices could be used to monitor patients with SCIs.
- NICHD also sponsored the 2-day workshop on Pregnancy in Women with Disabilities to review the current body of evidence on the management of pregnancy in women with physical disabilities. The Workshop identified key gaps in knowledge and recommendations for priority avenues for future research.
- Iskandar, B. J., Rizk, E., Meier, B., Hariharan, N., Bottiglieri, T., Finnell, R. H., et al. (2010). Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation. Journal of Clinical Investigation, 120, 1603-1616. PMID: 20424322
- Simeral, J. D., Kim, S. P., Black, M. J., Donoghue, J. P., & Hochberg, L. R. (2011). Neural control of cursor trajectory and click by a human with tetraplegia 1000 days after implant of an intracortical microelectrode array. Journal of Neural Engineering, 8, 025027. PMID: 21436513
- Sabatier, M. J., Stoner, L., Mahoney, E. T., Black, C., Elder, C., Dudley, G. A., et al. (2006). Electrically stimulated resistance training in SCI individuals increases muscle fatigue resistance but not femoral artery size or blood flow. Spinal Cord, 44, 227-233. PMID: 16158074
- Morse, L. R., Sudhakar, S., Danilack, V., Tun, C., Lazzari, L., Gagnon, D. R., et al. (2012). Association between sclerostin and bone density in chronic spinal cord injury. Journal of Bone and Mineral Research, 27(2), 352-359. PMID: 22006831