Body-weight supported locomotor training (BWST) promotes recovery of load-bearing stepping in low... more Body-weight supported locomotor training (BWST) promotes recovery of load-bearing stepping in lower mammals, but its efficacy in individuals with a spinal cord injury (SCI) is limited and highly dependent on injury severity. While animal models with complete spinal transections recover stepping with step-training, motor complete SCI individuals do not, despite similarly intensive training. In this review, we examine the significant differences between humans and animal models that may explain this discrepancy in the results obtained with BWST. We also summarize the known effects of SCI and locomotor training on the muscular, motoneuronal, interneuronal, and supraspinal systems in human and non-human models of SCI and address the potential causes for failure to translate to the clinic. The evidence points to a deficiency in neuronal activation as the mechanism of failure, rather than muscular insufficiency. While motoneuronal and interneuronal systems cannot be directly probed in humans, the changes brought upon by step-training in SCI animal models suggest a beneficial re-organization of the systems' responsiveness to descending and afferent feedback that support locomotor recovery. The literature on partial lesions in humans and animal models clearly demonstrate a greater dependency on supraspinal input to the lumbar cord in humans than in non-human mammals for locomotion. Recent results with epidural stimulation that activates the lumbar interneuronal networks and/or increases the overall excitability of the locomotor centers suggest that these centers are much more dependent on the supraspinal tonic drive in humans. Sensory feedback shapes the locomotor output in animal models but does not appear to be sufficient to drive it in humans.
Page 1. 278 AMERICAN JOURNAL OF PUBLIC HEALTH Mar., 1945 in the study of the control of infectiou... more Page 1. 278 AMERICAN JOURNAL OF PUBLIC HEALTH Mar., 1945 in the study of the control of infectious diseases. The Penrose Memorial lec-ture on the international labor organi-zation completes an excellent sym-posium. REGINALD M. ATWATER ...
Apnea is a known response of concussive head injury. Hypoxic or ischemic brain injury has been do... more Apnea is a known response of concussive head injury. Hypoxic or ischemic brain injury has been documented in a high percentage of severe head injury deaths. The respiratory response after head injury remains poorly defined, however, and its contribution to hypoxic or ischemic mechanisms after severe head injury is unknown. Eighteen anesthetized but spontaneously breathing rats were subjected to fluid percussion head injury of varying severities. Respiratory rate and volume of air were recorded before and after injury with a Hans Rudolph/Varadyne pneumotach differential pressure transducer and graphically measured. Postmortem inspection of the brains was performed. Apnea and subsequent respiratory dysfunction are directly proportional to the magnitude of energy delivered to the brain. Higher energy results in a dysfunctional or absent respiratory response, probably attributable to failure or disorganized function of the medullary respiratory center. This study for the first time graphically depicts the respiratory response after head injury. Higher energy delivered to the brain directly correlates with a markedly abnormal respiratory response that probably contributes significantly to subsequent hypoxic or ischemic brain injury. The absence of the space-occupying hematoma or gross parenchymal disruption suggests that in the clinical setting many of these patients may otherwise have survivable head injury if rescued by early ventilatory assistance.
Lesions in either the habenula or its primary efferent pathway, the fasciculus retroflexus (FR), ... more Lesions in either the habenula or its primary efferent pathway, the fasciculus retroflexus (FR), impaired avoidance responding. However, lesions of only the FR provided a persistent elevation of locomotor activity. Immunocytochemical study of the interpeduncular nucleus (IPN) through injection of retrograde tracers into the IPN and the overlying ventral tegmental area indicated that habenular lesions spared both rostral habenula and forebrain projections to the caudal midbrain, but these projections were axotomized by FR lesions. Rostral sparing of the habenula resulted in normal peptidergic staining in the IPN, and normal cholinergic innervation was absent. Performance of individual rats in behavioral tests was consistent with variations in anatomical sparing. Such considerations may account for previous discrepancies in functional effects of habenular lesions.
In situ hybridization histochemistry was used to identify neurons in rat dorsal root ganglia that... more In situ hybridization histochemistry was used to identify neurons in rat dorsal root ganglia that contained mRNAs encoding {3-preprotachykinin and preprosomatostatin. The distribution of these neurons was compared with the distribution of neurons containing tachykinins or somatostatin, identified using immunocytochemical techniques. Neurons labelled for [3-preprotachykinin mRNA constituted 20% of the total neuronal population and belonged to the small cell class. Neurons labelled for preprosomatostatin mRNA with either RNA or DNA hybridization probes constituted approximately 10% of the total cells and comprised a small cell group that differed in average size from the [3-preprotachykinin labelled population. The distribution of cells containing tachykinin-or somatostatin-like immunoreactive material was identical to the distribution of cells containing the respective mRNAs and, in addition, individual somata in adjacent sections contained both the mRNA precursor and the peptide. These results suggest that for these neuropeptides the sensitivity of the two methods is equivalent and the respective mRNAs and peptides are co-localized in the same neurons.
Pharmacologic administration of sedatives is used routinely in the care of the critically ill to ... more Pharmacologic administration of sedatives is used routinely in the care of the critically ill to enhance patient comfort and optimize care. Long-term administration of NMB drugs is far less frequent but often occurs in patients with greater organ dysfunction. The experience of several authors using NMB drugs in the ICU is summarized in Table 5. Both classes of drugs have potential untoward effects. Some are readily predictable; others are not. NMB drugs enjoy a long record of safe, effective use during the perioperative period, but certain issues linger in defining appropriate administration to critically ill patients. Major concerns focus on the appropriate drug selection and delivery, monitoring, and neuromuscular recovery of patients who receive NMB drugs for longer than 24 hours. The development of myopathy and paresis has been increasingly recognized after prolonged use of NMB drugs in the ICU. Further investigation needs to fully characterize this process, identify those at risk, and outline a mechanism to prevent or limit the injury. Prolonged weakness may occur secondary to changes in the basic pharmacology and elimination of NMB drugs in ICU patients. Pathophysiologic changes in the nerve, muscle, or neuromuscular junction may also play a role in the development of some cases of prolonged weakness or myopathy after discontinuation of NMB drugs. Concerns about the potential for direct or indirect toxicity of NMB drugs to skeletal muscle and in the CNS remain. Resolution of these issues will improve the selection and optimal administration of sedative and NMB drugs in the ICU setting.
Purpose/Hypothesis: Cervical spinal cord injury results in specific deficits of limb function. In... more Purpose/Hypothesis: Cervical spinal cord injury results in specific deficits of limb function. In the rat, lesions to the rubrospinal tract impair forelimb function despite the presence of an intact corticospinal tract, making it a useful pathway to study. Both functional and anatomical recovery have been promoted by transplantation of neuronal and glial restricted precursors following thoracic injury and task-oriented practice is used clinically to maximize recovery of function. Terefore, we hypothesized that combination therapy will improve reach-to-grasp function to a greater extent than either treatment delivered separately. Number of Subjects: Twenty-two adult female Sprague-Dawley rats that demonstrate a preference to reach with their right forelimb for single pellets of food. Materials/Methods: All animals received a partial lesion to the right cervical spinal cord between the C3-4 dorsal roots. Ten animals received an injection of a liquid collagen matrix (Lesion Only) and 1...
Lesion-induced synaptogenesis was compared in the goldfish retinotectal system, which readily reg... more Lesion-induced synaptogenesis was compared in the goldfish retinotectal system, which readily regenerates after optic nerve crush, and in the cat spinal cord, in which collateral sprouting has been demonstrated after dorsal rhizotomy. Quantitative electron micro-scopic methods were used. Reinnervation of the tectum was complete, but was characterized by a prolonged time course. Reinnervation appeared to be achieved by retinal axons and not by sprouting from nonretinal axons. Reinnervation in the cat spinal cord was also virtually complete, but was very rapid and may be mediated by some axons that are similar to those destroyed and by other axons that are different.
We used behavioral assessment techniques to investigate the recovery of locomotion after spinal c... more We used behavioral assessment techniques to investigate the recovery of locomotion after spinal cord injury. Complete hemisec-tions were made at T13 and LI in the cat spinal cord. Observational and high-speed kinematic analyses of bipedal treadmill and overground locomotion were made from 1 to 5 weeks postoperatively. Both bipedal and overground locomotion showed partial recovery. The early stage of recovery was characterized by an increased range of joint movement in a proximal to distal progression. During later stages, hindlimb movements became more complex and interjoint coordination markedly improved. Overground locomotion recovered faster and to a greater extent than bipedal locomotion, as indicated by the time course of recovery, joint angular excursions and intralimb coordination. We propose that the recovery of bipedal locomotion may be more limited by reorganization of segmenta) sensory systems than overground locomotion, perhaps because alternate strategies for overground...
2003 IEEE 29th Annual Proceedings of Bioengineering Conference, 2003
We have optimized a method for producing strings of alginate bioconjugated with a laminin pentape... more We have optimized a method for producing strings of alginate bioconjugated with a laminin pentapeptide that aids in cell adhesion. These strings are 400-500 μm in thickness and could be bundled to act as a graft at the site of injury. In vitro studies have shown that rat (NB2a) and human (SHSY5Y) neuroblastoma cell lines adhere to, and differentiate on these modified alginate strings. The strings also have the capacity to hold genetically modified fibroblasts that release neurotrophins that would aid in neuronal regeneration. These strings are strong enough to be surgically transplanted to the spinal cord, and may ultimately help in bridging the gap at the injury site.
Proceedings of the IEEE 28th Annual Northeast Bioengineering Conference (IEEE Cat. No.02CH37342), 2002
Studies that have compared locomotion in the adult cat hindlimb before and after spinal transecti... more Studies that have compared locomotion in the adult cat hindlimb before and after spinal transection have found that "despite a few differences, the spinal cord and the hind limbs afferents are capable of generating very good locomotor patterns with almost normal kinematics" when the animals are submitted to a daily regimen of treadmill walking. We are trying to enhance motor
Severe spinal cord injury results in severe, persisting deficits with little hope for substantial... more Severe spinal cord injury results in severe, persisting deficits with little hope for substantial recovery. Recent developments in transplantation protocols, gene therapy, and methods of evaluation now offer hope of developing treatments that will lead to better prognoses. This review discusses the consequences of spinal injury, animal models used to study injury and recovery, types of cellular transplants, selection of behavioral and physiological tests of recovery, and ways to test the efficacy of the interventions and to improve transplant-mediated recovery.
Spinal cord injury in adult mammals causes atrophy or loss of axotomized neurons. We have previou... more Spinal cord injury in adult mammals causes atrophy or loss of axotomized neurons. We have previously found that the product of the antiapoptotic gene Bcl-2, delivered by intraspinal injection of a DNA plasmid, reduces atrophy and loss of axotomized Clarke's nucleus neurons in adult rats. Here we studied whether the same treatment protects axotomized red nucleus (RN) neurons. Two months after the right dorsolateral funiculus was ablated in adult Sprague-Dawley rats by C3/C4 subtotal hemisection, there was approximately 48% loss of RN neurons in the magnocellular portion of the RN contralateral to the lesion and atrophy of many surviving neurons. When a DNA plasmid encoding the human Bcl-2 gene and the bacterial reporter gene LacZ, complexed with cationic lipids, was injected just rostral to the subtotal hemisection site, 87% of RN neurons survived, and there was partial, but robust, protection from atrophy. These and our previous results indicated that intraspinal administration ...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1999
Adult mammalian CNS neurons do not normally regenerate their severed axons. This failure has been... more Adult mammalian CNS neurons do not normally regenerate their severed axons. This failure has been attributed to scar tissue and inhibitory molecules at the injury site that block the regenerating axons, a lack of trophic support for the axotomized neurons, and intrinsic neuronal changes that follow axotomy, including cell atrophy and death. We studied whether transplants of fibroblasts genetically engineered to produce brain-derived neurotrophic factor (BDNF) would promote rubrospinal tract (RST) regeneration in adult rats. Primary fibroblasts were modified by retroviral-mediated transfer of a DNA construct encoding the human BDNF gene, an internal ribosomal entry site, and a fusion gene of lacZ and neomycin resistance genes. The modified fibroblasts produce biologically active BDNF in vitro. These cells were grafted into a partial cervical hemisection cavity that completely interrupted one RST. One and two months after lesion and transplantation, RST regeneration was demonstrated w...
Abnormal apparent diffusion coefficient (ADC) values in injured spinal cord white matter and fibr... more Abnormal apparent diffusion coefficient (ADC) values in injured spinal cord white matter and fibroblast transplants have been shown to correspond with qualitative histologic findings of axonal loss or regeneration. We proposed that ADC values would correlate with quantitative axonal tracing in the transected rubrospinal tract (RST). Eleven rats received right-sided lateral funiculus lesions at C3-4 (disrupting the RST) and transplantation of fibroblasts that were unmodified or modified to secrete brain-derived neurotrophic factor (BDNF). Behavioral tests measured hindlimb function at 1, 2, 4, 6, 8, 10, and 12 weeks after injury. At 12 weeks after injury, the antegrade axon tracer biotinylated dextran amine was stereotactically injected into the red nucleus to label the injured RST axons. Animals were sacrificed 2 weeks later. Diffusion-weighted MR imaging of the excised, fixed spinal cord specimens was then performed at 9.4 T. In white matter surrounding transplants, ADC values tran...
Body-weight supported locomotor training (BWST) promotes recovery of load-bearing stepping in low... more Body-weight supported locomotor training (BWST) promotes recovery of load-bearing stepping in lower mammals, but its efficacy in individuals with a spinal cord injury (SCI) is limited and highly dependent on injury severity. While animal models with complete spinal transections recover stepping with step-training, motor complete SCI individuals do not, despite similarly intensive training. In this review, we examine the significant differences between humans and animal models that may explain this discrepancy in the results obtained with BWST. We also summarize the known effects of SCI and locomotor training on the muscular, motoneuronal, interneuronal, and supraspinal systems in human and non-human models of SCI and address the potential causes for failure to translate to the clinic. The evidence points to a deficiency in neuronal activation as the mechanism of failure, rather than muscular insufficiency. While motoneuronal and interneuronal systems cannot be directly probed in humans, the changes brought upon by step-training in SCI animal models suggest a beneficial re-organization of the systems' responsiveness to descending and afferent feedback that support locomotor recovery. The literature on partial lesions in humans and animal models clearly demonstrate a greater dependency on supraspinal input to the lumbar cord in humans than in non-human mammals for locomotion. Recent results with epidural stimulation that activates the lumbar interneuronal networks and/or increases the overall excitability of the locomotor centers suggest that these centers are much more dependent on the supraspinal tonic drive in humans. Sensory feedback shapes the locomotor output in animal models but does not appear to be sufficient to drive it in humans.
Page 1. 278 AMERICAN JOURNAL OF PUBLIC HEALTH Mar., 1945 in the study of the control of infectiou... more Page 1. 278 AMERICAN JOURNAL OF PUBLIC HEALTH Mar., 1945 in the study of the control of infectious diseases. The Penrose Memorial lec-ture on the international labor organi-zation completes an excellent sym-posium. REGINALD M. ATWATER ...
Apnea is a known response of concussive head injury. Hypoxic or ischemic brain injury has been do... more Apnea is a known response of concussive head injury. Hypoxic or ischemic brain injury has been documented in a high percentage of severe head injury deaths. The respiratory response after head injury remains poorly defined, however, and its contribution to hypoxic or ischemic mechanisms after severe head injury is unknown. Eighteen anesthetized but spontaneously breathing rats were subjected to fluid percussion head injury of varying severities. Respiratory rate and volume of air were recorded before and after injury with a Hans Rudolph/Varadyne pneumotach differential pressure transducer and graphically measured. Postmortem inspection of the brains was performed. Apnea and subsequent respiratory dysfunction are directly proportional to the magnitude of energy delivered to the brain. Higher energy results in a dysfunctional or absent respiratory response, probably attributable to failure or disorganized function of the medullary respiratory center. This study for the first time graphically depicts the respiratory response after head injury. Higher energy delivered to the brain directly correlates with a markedly abnormal respiratory response that probably contributes significantly to subsequent hypoxic or ischemic brain injury. The absence of the space-occupying hematoma or gross parenchymal disruption suggests that in the clinical setting many of these patients may otherwise have survivable head injury if rescued by early ventilatory assistance.
Lesions in either the habenula or its primary efferent pathway, the fasciculus retroflexus (FR), ... more Lesions in either the habenula or its primary efferent pathway, the fasciculus retroflexus (FR), impaired avoidance responding. However, lesions of only the FR provided a persistent elevation of locomotor activity. Immunocytochemical study of the interpeduncular nucleus (IPN) through injection of retrograde tracers into the IPN and the overlying ventral tegmental area indicated that habenular lesions spared both rostral habenula and forebrain projections to the caudal midbrain, but these projections were axotomized by FR lesions. Rostral sparing of the habenula resulted in normal peptidergic staining in the IPN, and normal cholinergic innervation was absent. Performance of individual rats in behavioral tests was consistent with variations in anatomical sparing. Such considerations may account for previous discrepancies in functional effects of habenular lesions.
In situ hybridization histochemistry was used to identify neurons in rat dorsal root ganglia that... more In situ hybridization histochemistry was used to identify neurons in rat dorsal root ganglia that contained mRNAs encoding {3-preprotachykinin and preprosomatostatin. The distribution of these neurons was compared with the distribution of neurons containing tachykinins or somatostatin, identified using immunocytochemical techniques. Neurons labelled for [3-preprotachykinin mRNA constituted 20% of the total neuronal population and belonged to the small cell class. Neurons labelled for preprosomatostatin mRNA with either RNA or DNA hybridization probes constituted approximately 10% of the total cells and comprised a small cell group that differed in average size from the [3-preprotachykinin labelled population. The distribution of cells containing tachykinin-or somatostatin-like immunoreactive material was identical to the distribution of cells containing the respective mRNAs and, in addition, individual somata in adjacent sections contained both the mRNA precursor and the peptide. These results suggest that for these neuropeptides the sensitivity of the two methods is equivalent and the respective mRNAs and peptides are co-localized in the same neurons.
Pharmacologic administration of sedatives is used routinely in the care of the critically ill to ... more Pharmacologic administration of sedatives is used routinely in the care of the critically ill to enhance patient comfort and optimize care. Long-term administration of NMB drugs is far less frequent but often occurs in patients with greater organ dysfunction. The experience of several authors using NMB drugs in the ICU is summarized in Table 5. Both classes of drugs have potential untoward effects. Some are readily predictable; others are not. NMB drugs enjoy a long record of safe, effective use during the perioperative period, but certain issues linger in defining appropriate administration to critically ill patients. Major concerns focus on the appropriate drug selection and delivery, monitoring, and neuromuscular recovery of patients who receive NMB drugs for longer than 24 hours. The development of myopathy and paresis has been increasingly recognized after prolonged use of NMB drugs in the ICU. Further investigation needs to fully characterize this process, identify those at risk, and outline a mechanism to prevent or limit the injury. Prolonged weakness may occur secondary to changes in the basic pharmacology and elimination of NMB drugs in ICU patients. Pathophysiologic changes in the nerve, muscle, or neuromuscular junction may also play a role in the development of some cases of prolonged weakness or myopathy after discontinuation of NMB drugs. Concerns about the potential for direct or indirect toxicity of NMB drugs to skeletal muscle and in the CNS remain. Resolution of these issues will improve the selection and optimal administration of sedative and NMB drugs in the ICU setting.
Purpose/Hypothesis: Cervical spinal cord injury results in specific deficits of limb function. In... more Purpose/Hypothesis: Cervical spinal cord injury results in specific deficits of limb function. In the rat, lesions to the rubrospinal tract impair forelimb function despite the presence of an intact corticospinal tract, making it a useful pathway to study. Both functional and anatomical recovery have been promoted by transplantation of neuronal and glial restricted precursors following thoracic injury and task-oriented practice is used clinically to maximize recovery of function. Terefore, we hypothesized that combination therapy will improve reach-to-grasp function to a greater extent than either treatment delivered separately. Number of Subjects: Twenty-two adult female Sprague-Dawley rats that demonstrate a preference to reach with their right forelimb for single pellets of food. Materials/Methods: All animals received a partial lesion to the right cervical spinal cord between the C3-4 dorsal roots. Ten animals received an injection of a liquid collagen matrix (Lesion Only) and 1...
Lesion-induced synaptogenesis was compared in the goldfish retinotectal system, which readily reg... more Lesion-induced synaptogenesis was compared in the goldfish retinotectal system, which readily regenerates after optic nerve crush, and in the cat spinal cord, in which collateral sprouting has been demonstrated after dorsal rhizotomy. Quantitative electron micro-scopic methods were used. Reinnervation of the tectum was complete, but was characterized by a prolonged time course. Reinnervation appeared to be achieved by retinal axons and not by sprouting from nonretinal axons. Reinnervation in the cat spinal cord was also virtually complete, but was very rapid and may be mediated by some axons that are similar to those destroyed and by other axons that are different.
We used behavioral assessment techniques to investigate the recovery of locomotion after spinal c... more We used behavioral assessment techniques to investigate the recovery of locomotion after spinal cord injury. Complete hemisec-tions were made at T13 and LI in the cat spinal cord. Observational and high-speed kinematic analyses of bipedal treadmill and overground locomotion were made from 1 to 5 weeks postoperatively. Both bipedal and overground locomotion showed partial recovery. The early stage of recovery was characterized by an increased range of joint movement in a proximal to distal progression. During later stages, hindlimb movements became more complex and interjoint coordination markedly improved. Overground locomotion recovered faster and to a greater extent than bipedal locomotion, as indicated by the time course of recovery, joint angular excursions and intralimb coordination. We propose that the recovery of bipedal locomotion may be more limited by reorganization of segmenta) sensory systems than overground locomotion, perhaps because alternate strategies for overground...
2003 IEEE 29th Annual Proceedings of Bioengineering Conference, 2003
We have optimized a method for producing strings of alginate bioconjugated with a laminin pentape... more We have optimized a method for producing strings of alginate bioconjugated with a laminin pentapeptide that aids in cell adhesion. These strings are 400-500 μm in thickness and could be bundled to act as a graft at the site of injury. In vitro studies have shown that rat (NB2a) and human (SHSY5Y) neuroblastoma cell lines adhere to, and differentiate on these modified alginate strings. The strings also have the capacity to hold genetically modified fibroblasts that release neurotrophins that would aid in neuronal regeneration. These strings are strong enough to be surgically transplanted to the spinal cord, and may ultimately help in bridging the gap at the injury site.
Proceedings of the IEEE 28th Annual Northeast Bioengineering Conference (IEEE Cat. No.02CH37342), 2002
Studies that have compared locomotion in the adult cat hindlimb before and after spinal transecti... more Studies that have compared locomotion in the adult cat hindlimb before and after spinal transection have found that "despite a few differences, the spinal cord and the hind limbs afferents are capable of generating very good locomotor patterns with almost normal kinematics" when the animals are submitted to a daily regimen of treadmill walking. We are trying to enhance motor
Severe spinal cord injury results in severe, persisting deficits with little hope for substantial... more Severe spinal cord injury results in severe, persisting deficits with little hope for substantial recovery. Recent developments in transplantation protocols, gene therapy, and methods of evaluation now offer hope of developing treatments that will lead to better prognoses. This review discusses the consequences of spinal injury, animal models used to study injury and recovery, types of cellular transplants, selection of behavioral and physiological tests of recovery, and ways to test the efficacy of the interventions and to improve transplant-mediated recovery.
Spinal cord injury in adult mammals causes atrophy or loss of axotomized neurons. We have previou... more Spinal cord injury in adult mammals causes atrophy or loss of axotomized neurons. We have previously found that the product of the antiapoptotic gene Bcl-2, delivered by intraspinal injection of a DNA plasmid, reduces atrophy and loss of axotomized Clarke's nucleus neurons in adult rats. Here we studied whether the same treatment protects axotomized red nucleus (RN) neurons. Two months after the right dorsolateral funiculus was ablated in adult Sprague-Dawley rats by C3/C4 subtotal hemisection, there was approximately 48% loss of RN neurons in the magnocellular portion of the RN contralateral to the lesion and atrophy of many surviving neurons. When a DNA plasmid encoding the human Bcl-2 gene and the bacterial reporter gene LacZ, complexed with cationic lipids, was injected just rostral to the subtotal hemisection site, 87% of RN neurons survived, and there was partial, but robust, protection from atrophy. These and our previous results indicated that intraspinal administration ...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1999
Adult mammalian CNS neurons do not normally regenerate their severed axons. This failure has been... more Adult mammalian CNS neurons do not normally regenerate their severed axons. This failure has been attributed to scar tissue and inhibitory molecules at the injury site that block the regenerating axons, a lack of trophic support for the axotomized neurons, and intrinsic neuronal changes that follow axotomy, including cell atrophy and death. We studied whether transplants of fibroblasts genetically engineered to produce brain-derived neurotrophic factor (BDNF) would promote rubrospinal tract (RST) regeneration in adult rats. Primary fibroblasts were modified by retroviral-mediated transfer of a DNA construct encoding the human BDNF gene, an internal ribosomal entry site, and a fusion gene of lacZ and neomycin resistance genes. The modified fibroblasts produce biologically active BDNF in vitro. These cells were grafted into a partial cervical hemisection cavity that completely interrupted one RST. One and two months after lesion and transplantation, RST regeneration was demonstrated w...
Abnormal apparent diffusion coefficient (ADC) values in injured spinal cord white matter and fibr... more Abnormal apparent diffusion coefficient (ADC) values in injured spinal cord white matter and fibroblast transplants have been shown to correspond with qualitative histologic findings of axonal loss or regeneration. We proposed that ADC values would correlate with quantitative axonal tracing in the transected rubrospinal tract (RST). Eleven rats received right-sided lateral funiculus lesions at C3-4 (disrupting the RST) and transplantation of fibroblasts that were unmodified or modified to secrete brain-derived neurotrophic factor (BDNF). Behavioral tests measured hindlimb function at 1, 2, 4, 6, 8, 10, and 12 weeks after injury. At 12 weeks after injury, the antegrade axon tracer biotinylated dextran amine was stereotactically injected into the red nucleus to label the injured RST axons. Animals were sacrificed 2 weeks later. Diffusion-weighted MR imaging of the excised, fixed spinal cord specimens was then performed at 9.4 T. In white matter surrounding transplants, ADC values tran...
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