INDEX
A
Activities of daily living
outcomes by level of injury, 15–19
See also Functional outcomes
Acute care
clinical practice guidelines, 96
decompression of spinal cord, 98–99
during transport, 97–98
effectiveness, 97
goals, 23
immobilization, 97
informed consent issues, 160–161
at injury scene, 97
neuroprotective interventions, 99–100
research needs, 98
research prospects, 25
research recommendations, 5, 143
scope, 97
strategies, 122–125
targets of intervention, 122–123
Acute phase of injury, 36, 39–40
animal models, 68
research prospects, 25
Age at injury, 14
costs of injury and, 20–22
Alternative therapies, 275–277
Ambulation
outcomes by level of injury, 17, 19
See also Movement
American Association of Neurological Surgeons, 96, 192
American Paralysis Association, 192
American Paraplegia Society, 192
American Spinal Injury Association (ASIA), 32, 191–192
4-Aminopyridine, 133, 161, 174
Amyotrophic Lateral Sclerosis Functional Rating Scale, 171
assessment techniques, 74–76
generalizability, 70–73
primates, 73
recommendations for research, 88–89
research needs, 73–74
selection, 66–69
standardization, 70, 73–74, 88
training for research using, 74, 88
transgenic, 87
for validation of new therapies, 154–155
Apoptosis
biomarkers, 77–78
Assessment
biomarker applications, 77–79
of complications of spinal cord injury, 76
experimental models, 65
of functional outcomes of spinal cord injury, 74–76
imaging technologies, 83–88
injury classification, 32–36
injury outcomes, 260–267
pain, 53
recommendations for research, 89
standardization of outcome measures, 168–172, 178–179
technical development, 64
Astrocytes, 37
in glial scarring, 43
Atrophy, muscle, 112
Autonomic dysreflexia, 105
Autonomic nervous system
motor function and, 48
Axon anatomy and function, 31
embryonic development, 130
spinal cord pathophysiology, 43
Axonal regrowth, 3
animal models, 65–66, 70, 71–73
barriers to, strategies to remove, 127–129
cell transplantation to promote, 132, 135–136
combination therapies to promote, 140–141
environmental conditions for, 45–46, 129
gene therapies to improve, 130–132
glial scarring in inhibition of, 43–45, 127
guidance, 129–130
in vitro studies, 65
macrophage therapy to improve, 123
molecular processes, 65
muscle spasticity and, 52
neurotrophic factors to promote, 135
pain outcomes and, 101–102
research needs, 58
research recommendations, 4, 8, 143
restoration of impulse conduction, 133–134
spontaneous healing, 47
strategies for promoting, 129
synaptic connections, 129
tissue scaffolding to promote, 132
Axon anatomy and function, 31
embryonic development, 130
spinal cord pathophysiology, 43
B
Baclofen, 102
Basal ganglia, 48
Basso, Beattie, and Bresnahan (BBB) scale, 74–76, 260
Basso Mouse Scale (BMS), 74–76, 260–261
applications, 77–79
current technology, 77
future prospects for research, 81–83
in imaging technologies, 85–87
Bladder function, 105
anatomy, 55
outcomes by level of injury, 16, 18
therapeutic interventions, 103–104, 110–111
types of dysfunction, 103
Blood pressure, spinal cord injury and, 39
Body weight support training, 108–110
Bone disorders, 107
outcomes by level of injury, 16, 18
pathophysiology, 56–57
Brain-derived neurotrophic factor, 126
Brain stem, motor function, 48
Bryon Reisch Paralysis Foundation, 191
Buoniconti Fund to Cure Paralysis, 191
C
C fibers, 56
Calcium, intracellular, 126
in apoptosis, 42–43
in spinal cord injury pathophysiology, 41
Calpain, 125
Caspases, 125
CAT scan. See Computed tomography
Cauda equina, 55
Causes of spinal cord injury, 14–15
Cells
cell-based therapeutic interventions, 3, 123, 135–140
glial, 65
meningeal, 43
olfactory ensheathing, 136, 157
pathiophysiology of spinal cord injury, 36–39
Schwann, 37, 45, 65, 133, 135–136
T-lymphocytes, 38, 41, 42, 123
See also Apoptosis;
Neuron function;
Stem cell therapies
Center for International Blood and Marrow Transplant Research, 175
Centers for Disease Control and Prevention, 188–189
Central pattern generator, 50
Cerebellum, motor function, 48
Cerebral cortex
central pattern generator and, 50
motor control, 48
in pain experience, 55
Cervical spine, 32
Chondroitin sulfate, 65, 127–128
Chondroitinase ABC, 128
Christopher Reeve Clinical Trials Network, 171, 176, 192
Chronic phase of injury, 36, 43–45
clinical practice guidelines, 96
treatment strategies, 127–135
Circulatory system
acute response to spinal cord injury, 39–40
autonomic dysreflexia, 105
thromboembolism risk, 102–103
Classification
of injury, 32–36
of pain, 53
Clinical trials
challenges in spinal cord injury research, 160–162
clinician expertise, 164
collaborative multicenter studies, 164–167
coordination with care resources, 167–168
criteria for entering into, 154
future prospects, 159
historical review, 278–319
industry involvement, 172–174
informed consent issues, 160–161
interpretation of results, 172
patient recruitment, 161–162
phases, 153
purpose, 152–153
quality of past studies, 156–157
recommendations, 11, 12, 178–179, 239
research opportunities, 8–9
small population studies, 162–164, 179
spontaneous recovery in, 162
standardization of outcome measures, 168–172
Clip compression, 68
Collaborative research
centers of excellence for, 195, 196–197
clinical trials, 164–167
to develop imaging technology, 88
international efforts, 193–194
strategies for enhancing, 195–199, 230
Combination therapies, 3
challenges to development, 141
current state, 140–141
neurotrophic factors in, 127
research recommendations, 5, 8, 10, 141, 143
Communication abilities, spinal cord injury and, 17, 19
Completeness of injury, 20, 34–35
Compression injury
animal models, 68–70
decompression interventions, 98–99
Computed tomography, 84
Computed tomography (CT/CAT scan), 83
Congress of Neurological Surgeons, 96, 192
Consortium for Spinal Cord Medicine, 96, 193
Consortium of Multiple Sclerosis Centers, 175
Contusion injuries, 32
animal models, 68
Corticospinal tract, 48
Corticosteroid therapy, 166
Cost of research, 173
federal spending, 184–190
infrastructure construction, 213–214
state spending, 205, 206, 207, 208–209, 216
Costs of spinal cord injury, 20–23
Cyclosporin A, 123
Cytokines, 42
D
Data collection and management, 174–178, 190
Decompression of spinal cord, 98–99
Decubitus ulcers. See Pressure sores
Demographic characteristics of spinal cord injury victims, 14–15
Department of Education, U.S., 189–190
Department of Veterans Affairs, U.S., 6, 189
Depression
risk, 107–108
treatment, 108
Dermatomes, 33
Detrusor muscle, 55–56, 103–104
Dorsal horn, 32
Dysesthesia, 53
E
Early Detection Research Network, 82–83
Edema, 40
acute intervention, 122
spinal cord injury pathophysiology, 2–3
Education and training for research, 9
clinical trials expertise, 164
federal support, 186–187
rationale for expanding, 200–201
recommendations, 10, 11–12, 201
trends, 200
Ephrins, 130
Epilepsy, 184
Erectile dysfunction, 106
Erythropoietin, 126
Ethical issues, 156
Excitotoxicity, 39
F
F30 fellowships, 200
F31 fellowships, 200
Facilities of Research Excellence in Spinal Cord Injury, 155, 187
Fampridine, 102
Fas protein, 77–78
Feedback systems
movement control, 49–50
in muscle spasticity, 52
Fibroblast growth factor, 126
Fibroblasts, 70
See also Miami Project to Cure Paralysis
Food and Drug Administration, U.S., 153, 179, 223
Free radicals, 42
formation after injury, 40–41
intervention to prevent formation of, 123
Functional electrical stimulation
applications, 110
bladder dysfunction treatment, 110–111
with body weight support training, 109–110
clinical acceptance of, 112–113
future prospects, 113–114
lower-extremity, 111–112
to maintain muscle fitness, 112
mechanism of action, 110
upper-extremity, 111
Functional magnetic resonance imaging, 83–84
Functional outcomes
hypothermia treatment, 125
level of injury and, 15–20
neurobiology, 47–58
recommendations for research, 89
G
Gamma-aminobutyric acid (GABA), 102
Gene expression, 36
biomarkers of spinal cord injury progression, 77–79
research protocols, 83
Gene therapy
gene delivery techniques, 131
gene types in, 131
outcomes, 132
to promote neuronal repair, 130–132
rationale, 130–131
Genetics, generalizability of animal research, 70–71
Geoffrey Lance Foundation for Spinal Cord Injury Research and Support, 191
Glial cells, 65
Glial circuitry, 4
Glial-derived neurotrophic factor, 126
Glial scarring, 3
as barrier to axonal regrowth, 43–45, 127
therapeutic interventions, 127–128
Glucose metabolism, 86
Glutamate, 40
in apoptosis, 126
neuroprotective blocking of, 126
GM-1 ganglioside, 99
Gray matter, 32
acute response to spinal cord injury, 40
Growth cones, 65
Growth factors, 126
gene therapy to promote expression of, 131
in neuronal regeneration, 47
in spinal cord injury pathophysiology, 42
H
Hand control, 111
Health Insurance Portability and Accountability Act (HIPAA), 177
Heparin therapy, 103
Heterotopic ossification, 107
Home modification costs, 20
Hyperesthesia, 53
Hypothermia, therapeutic, 124–125, 161
I
Imaging technology
clinical applications, 87–88
functional magnetic resonance imaging, 83–84
future prospects, 85–87
magnetic resonance imaging, 83, 84, 85
modalities, 83–85
positron emission tomography, 83, 85, 86
recommendations for research, 89
Immune function
acute care interventions, 123–124
spinal cord injury pathophysiology, 41–42
Informed consent, 156–157, 160–161, 176–177
Injury prevention, 23
Inosine, 129
Institutional review boards, 165–167, 178
Interleukins, 77–78
International Campaign for Cures of Spinal Cord Injury Paralysis, 193–194
International Collaboration on Repair Discoveries, 170, 194
International Spinal Research Trust, 159, 168, 171, 194
Ion channel function, 39, 43, 133
in apoptosis, 126
in pain pathophysiology, 55
response to axon demyelination, 133
in sensory neuron hyperexcitability, 102
therapeutic interventions targeting, 133–134
Ischemia, 40
acute intervention, 122
K
Kentucky Spinal Cord Injury Research Center, 6, 191, 217–219
L
Laceration injuries, 32
Length of hospital stay, 20
sensory and motor levels, 32–34
Limbic system, 57
Lumbar spine, 32
M
Macrophage therapy, 123
Magnetic resonance imaging (MRI), 83, 84, 85.
See also Functional magnetic resonance imaging
MAP kinase, 102
Medical industry. See Pharmaceutical and medical device industry
Medications
apoptosis inhibitors, 125
biomarkers to study effectiveness of, 86
bladder dysfunction treatment, 104
combination therapies, 140–141
costs, 20
immunosuppressant drugs, 123–124
to improve nerve conduction, 133
incentives for research, 173–174
neuropathic pain treatment, 100–101
research and development process, 152–154, 173
sodium channel regulators, 133–134
spasticity treatment, 102
thromboembolism prevention, 103
Meningeal cells, 43
N-Methyl-D-aspartate, 86
Methylprednisolone, 99, 159, 269–272
Miami Project to Cure Paralysis, 6, 155, 191, 213, 220–223
Microglia, 38
spinal cord injury pathophysiology, 41–42
Minocycline, 125
Mitochondria, 40
Model Spinal Cord Injury Care System, 6, 20, 167–168, 176, 190, 197
acute intervention to prevent infiltration of, 124
Motor function
assessment, 74–76
central pattern generator role, 50
cortical control, 48
feedback control of movement, 49–50
functional electrical stimulation, 110–114
injury classification, 32–34
neurophysiology, 48–50
prognostic factors, 20
therapeutic interventions, 108–114
zone of partial preservation, 35–36
See also Motor neurons
Motor neurons, 48
in muscle spasticity, 52
Motor vehicle accidents, 14, 207
injury prevention strategies, 23
Movement
body weight support training, 108–110
feedback control, 49–50
lower-extremity functional electrical stimulation, 112
proprioception in, 134–135
MRI. See Magnetic resonance imaging
mRNA, 81–82
Muscle
atrophy, 112
feedback control of movement, 49–50
functional electrical stimulation, 110
motor function, 48
strength assessment, 35
See also Spasticity
Musculoskeletal pain, 53
Myelin, 31
in impulse conduction, 133
natural remyelination after injury, 46–47
olfactory ensheathing cells, 136, 157
oligodendrocytes, 37, 43, 44, 46–47, 65, 85–86
replacement, 3
Schwann cells, 37, 46, 65, 133, 135–136
spinal cord injury pathophysiology, 43
therapeutic remyelination, 133, 136
N
National Acute Spinal Cord Injury Study (NASCIS), 159, 268–271
National Cancer Institute, 82, 88, 175
National Center for Medical Rehabilitation Research, 188
National Institute of Child Health and Human Development, 195
National Institute of Neurological Disorders and Stroke, 155
biomarker research, 82–83
recommendations for, 5, 10, 11, 141, 143
research program, 5, 141, 143, 187–188
National Institute on Disability and Rehabilitation Research, 189–190
National Institutes of Health, 6, 195, 197, 236
recommendations for, 4, 6, 7, 10, 11, 12, 143, 179, 201
research funding, 184–187, 201, 213–214
National Spinal Cord Injury Research Network, 7, 11, 197–199, 201
Necrosis
acute response to spinal cord injury, 39
intervention to prevent, 123
spinal cord injury pathophysiology, 2–3, 42
NEP1-40 peptide, 128
Netrins, 130
Neurobiology of spinal cord
acute effects of spinal cord injury, 39, 122–125
animal models, 65–74
basic research, 194–195
bladder function and dysfunction, 55–56
body weight support training effects, 109
bowel dysfunction, 56–57
causes of muscle spasticity, 52
central pattern generator role, 50
chronic phase of spinal cord injury, 43–45
current understanding of injury and repair, 1, 25, 26, 58, 121
imaging technologies, 83–84, 86–87
in vitro research, 65
injury pathophysiology, 2–3
macrophages in, 123
motor function, 48–50
pain pathophysiology, 53–55, 100, 101–102
phases of spinal cord injury, 36–39
remyelination, natural and therapeutic, 46–47, 133, 136
research recommendations, 4, 8, 10, 201
Schwann cells in, 37, 45, 65, 133, 135–136
secondary phase of injury, 40–43, 125–127
sexual function, 57–58
spontaneous healing, 45–47
trophic factors in, 126–127
types and levels of injury, 15–20, 32–34, 66–69
See also Axonal regrowth;
Neuron function
Neurological level, 33–34
Neuron function, 37
animal research, 68
in vitro studies, 65
See also Motor neurons
Neuropathic pain, 53–54, 100–101
Neuroprostheses
research needs, 143
See also Functional electrical stimulation
Neuroprotection
definition, 125
effectiveness, 99–100
glutamate receptor blockers, 126
goals, 125
immunosuppressant drugs for, 123–124
protease inhibition, 125
research recommendations, 4, 143
Neurotransmitters
acute response to spinal cord injury, 39
in pain pathophysiology, 54
Neurotrophic factor-3, 126, 135
Neurotrophic factors, 3, 126–127
gene therapy to promote expression of, 131
Neutrophils, 38
acute intervention to prevent infiltration of, 124
spinal cord injury pathophysiology, 41
New York State Spinal Cord Injury Research Board, 1, 7, 12, 26, 190–191, 229–230
benefits to state, 211–212, 215
CART awards, 230
challenges, 232–234
future prospects, 238–239
IDEA awards, 230
motivation, 210
number of researchers, 232–233, 239
origin, 227–228
performance evaluations, 228–229, 240
private sector linkages, 237–238
program strengths, 228, 235–238
proposal review process, 228, 229
recommendations for, 239–240
research areas, 230–231
resources, 236–237
significance of, 205–206
Nitric oxide, 56
Nogo receptor blockade, 128–129
Nonprofit organizations
research role, 4, 5, 11, 191–194
O
Olfactory ensheathing cells, 136, 157
radiolabeled, 85–86
spinal cord injury pathophysiology, 43, 44
in spontaneous healing, 46–47
Opioid therapy, 101
Orphan Drug Act, 173–174
Outcomes, 25
biomarker expression data, 79
challenges to improving, 26
data collection and management, 174–178, 198
decompression interventions, 98–99
depression, 107–108
emergency response, 97–98
ensheathing cell therapies, 136
gene therapy, 132
historical development, 13–14, 95
individual differences, 15
macrophage therapy, 123
neuroprotective therapies, 99–100
pain prevention interventions, 100–101
research needs, 8
sensory function therapy, 135
spasticity interventions, 102, 133
standardization of measures, 168–172, 178–179
stem cell therapies, 137
therapeutic hypothermia, 124–125
See also Functional outcomes
P
P01 grants, 188
P30 grants, 188
P50 grants, 188
Pain
definition and classification, 52–53, 100
hypersensitivity, 53–54
neurophysiology, 53–55, 100, 101–102
risk of, in spinal cord injury, 52, 53
therapeutic interventions, 100–102
Paralysis Project of America, 191
Paralyzed Veterans of America, 193
Paraplegia, 15–20
prognosis, 20
Parkinson’s disease, 21, 184, 187
acute phase, 39–40
bladder dysfunction, 55–56, 103
bowel dysfunction, 56–57
cellular processes, 36–39
chronic phase of injury, 43–45
pressure ulcers, 105
secondary phase of spinal cord injury, 40–43
spontaneous healing, 45–47
Peripheral nerve transplantation, 132
Personal assistance
costs, 20
requirements by level of injury, 17, 19
PET scan. See Positron emission tomography
Pharmaceutical and medical device industry
collaboration in state-sponsored research, 237
incentives for spinal cord injury research, 173–174
obstacles to spinal cord injury research, 172–173
recommendations for, 4, 143, 179
Phases of injury, 36–39.
See also Acute phase of injury;
Chronic phase of injury;
Secondary phase of injury
Plasticity, nervous system, 45, 56, 195
Pons, 55
Positron emission tomography (PET scan), 83, 85, 86
Potassium metabolism, 126, 133
Pressure sores, 52
classification, 105
pathophysiology, 105
prevention and treatment, 105–106
risk, 105
Preventive interventions, 23, 192
Primary motor cortex, 48
Privacy issues, 177
Private sector
collaboration in state-sponsored research, 237–238
research role, 11
See also Pharmaceutical and medical device industry
Prognostic factors, 20
duration of spinal cord compression, 98
Proprioception, 49–50, 134–135
Proteases, 125
Protein expression
clinical significance, 77–78
future prospects for research, 81–82
in spinal cord injury, 79–81
Protein kinase C inhibition, 127–128
Proteoglycans, 44–45, 65, 127–128
Pulmonary embolism, 103
Q
prognosis, 20
R
Recreational sports, 14
Reeve-Irvine Research Center, 6, 155, 224
Rehabilitation
length of stay, 20
research funding, 188, 189–190
research recommendations, 5
Replication studies, 154–155
Reproductive health, 57, 106, 107.
See also Sexual functioning
Research
basic, 194–195
biochemical, 58
biomarker development, 81–83
clinical priorities, 3–5, 8, 10, 141–143
combination therapies, 5, 8, 10, 141
costs, 173
current state of, 9, 25–26, 184
data collection and management, 174–178
development of new therapies, 152–154
funding, 4, 5, 7, 12, 143, 183, 184–194, 201
imaging technology development, 85–88
in vitro techniques, 65
industry incentives, 172–174, 179
infrastructure requirements, 5–9, 11–12, 183, 195, 213
patient safety concerns, 156–157
performance monitoring, 12
prospects, 25–26
publishing, 155
recommendations, 201
requirements for progress in, 5, 8–9, 183
strategies for accelerating, 194–201
validation of new therapies, 154–157
See also Animal models;
Clinical trials;
Collaborative research;
Translational research
Research personnel
goals for research infrastructure, 5, 9, 239
supply, 232–233
See also Education and training for research
Respiratory function
functional electrical stimulation, 111–112
Rho-asssociated kinase, 128–129
Rick Hansen Spinal Cord Injury Network, 198
Robert Packard Center for ALS Research, 197–198
Roman Reed Research Grants Program, 224–226
S
Sacral spine, 32
Safety, patient, 142, 152, 153, 154, 156–157
to promote axonal regrowth, 135–136
remyelination with, 133
Secondary phase of injury, 36, 40–43
treatment strategies, 125–127
Sensory function
anatomy, 31–32
in control of movement, 49–50, 134
injury classification, 32–34
prognostic factors, 20
reflex reactions, 50
therapeutic interventions to restore, 134–135
zone of partial preservation, 35–36
Sensory neurons
C fibers, 56
hyperexcitability, 102
Severity of injury, 35
Sexual functioning
neurophysiology, 57–58
therapeutic interventions, 106–107
See also Reproductive health
Shock, 39
Sodium, intracellular, 133–134
Solid cord injury, 32
Spasticity
complications, 50–52
definition, 52
neurophysiology, 52
risk, 52
therapeutic interventions, 102, 133
Sphincter muscle, 55, 56, 103–104
Spinal cord anatomy, 31–32
areas of control, 32
Spinal Cord Injury Research Centers of Excellence, 5
collaborative research relationships, 196–197
infrastructure, 196
recommendation for, 6, 11, 201
Spinal Cord Society, 191
Spontaneous healing, 45–47, 162
Standards of care, 95–97
State-sponsored research, 320–322
advantages, 212–214
allocation of resources, 191, 209–210
data management, 176
funding sources, 7, 190–191, 207–208, 209–210, 213, 214, 217–220, 226
infrastructure for, 213
model programs, 205–206, 214–227
returns to states, 211–212
spending, 7, 190, 205, 206, 207, 208–209, 216, 220, 224, 225
trends, 205, 206–207, 208, 210–211
See also New York State Spinal Cord Injury Research Board
Stem cell therapies, 135, 136–140, 226–227
Synaptic connections
in axonal regrowth, 129
research recommendations, 4, 8, 143
T
Tendon transfer surgery, 111
Tetraplegia. See Quadriplegia
Therapeutic interventions
alternative therapies, 275–277
autonomic dysreflexia, 105
biomarker analysis in, 78–79
bladder dysfunction, 103–104
bone disorders, 107
bowel dysfunction, 104
cell-based, 135–140
chronic phase, 127–135
costs, 20
criteria for validating, 154–157
depression, 108
functional electrical stimulation, 110–114
generalizability of animal research, 70–73
historical and technical development, 1, 3, 13–14
imaging markers to monitor effectiveness of, 86–87
informed consent issues, 156–157, 160–161
motor dysfunction, 108–114
outcomes assessment, 74–76, 168–172
pain prevention and management, 53, 100–102
patient safety concerns, 142, 152, 153, 154, 156–157, 160
pressure ulcers, 105–106
research and development process, 152–154
research priorities, 3–5, 8, 10, 141–143
research recommendations, 178–179
secondary phase, 125–127
sexual dysfunction, 106–107
for spasticity, 102
standards of care, 95–97
strategic focus for development of new, 121
thromboembolism prevention, 102–103
using spontaneous healing, 45–47
See also Acute care;
Axonal regrowth;
Combination therapies
Think First National Injury Prevention Foundation, 192
Thoracic spine, 32
Thromboembolism, 102–103
Thyrotropin-releasing hormone, 100
Tissue engineering, 132
T-lymphocytes, 38
spinal cord injury pathophysiology, 41, 42
therapeutic application, 123
Transection injuries, 68–70
Transgenic animals, 87
Translational research
biomarker development, 82–83
current state, 183
ethical considerations, 156–157
imaging technologies, 87–88
recommendations, 6, 11, 197, 201
research networks to facilitate, 8–9, 197–198
state-sponsored programs, 230, 231
Transplantation
in combination therapies, 140–141
tissue, 132
Trauma Care Systems Planning and Development Act, 176
Trophic factors, 126–127
U
Unified Parkinson’s Disease Rating Scale, 171
United Spinal Association, 193
V
Vasospasm, 40
VCAM-1 antibodies, 124
Vehicle modification costs, 20
Veterans Administration. See Department of Veterans Affairs, U.S.
Violence, 14
Visceral pain, 53
Voiding reflex, 55
W
White matter, 31
Work-related injury, 14
Z
Zone of partial preservation, 35–36