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Marion Murray - One of the best experts on this subject based on the ideXlab platform.
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or FK506 Supports Survival of Transplanted Fibroblasts and Promotes Growth of Host Axons into the Transplant after Spinal Cord Injury
2013Co-Authors: Yoshikazu Hayashi, Jed S Shumsky, Alan Tessler, Theresa Connors, Takanobu Otsuka, Itzhak Fischer, Marion MurrayAbstract:Fibroblasts that have been genetically modified to secrete neurotrophins can stimulate axonal regeneration, rescue injured neurons, and improve function when grafted into a spinal cord injury site. These grafts are usually allografts that require immunosuppression to prevent rejection. In this study, we compared the effects of two immunophilin-ligands (cyclosporine A [CsA] and FK506) that are used clinically to prevent transplant rejection on protection of grafted fibroblasts. As there are risks associated with prolonged immunosuppression, we compared the effects of 2 or 8 weeks of administration of these drugs, in combination with our standard methylprednisolone protocol, in animals that survived for 8 weeks, to determine whether a shorter course of immunosuppression would be effective. Outcome measures included fibroblast survival, infiltration of activated macrophages and microglia into the graft, final lesion size, and growth of host axons into the graft. The graft consisted of a Vitrogen matrix into which fibroblasts were suspended; the graft was placed into a C3/C4 Lateral Funiculus lesion. The fibroblasts were isolated from a transgenic strain of Fischer rats that produce the marker alkaline phosphatase (Fb/AP). This enabled us to track the grafted fibroblasts and to evaluate the extent of their survival. The grafted matrix filled the lesion cavity. The density of fibroblast
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nogo 66 receptor antagonist peptide nep1 40 administration promotes functional recovery and axonal growth after Lateral Funiculus injury in the adult rat
Neurorehabilitation and Neural Repair, 2008Co-Authors: Yang Cao, Jed S Shumsky, M A Sabol, Robert Kushner, Stephen M Strittmatter, F P T Hamers, D H S Lee, S A Rabacchi, Marion MurrayAbstract:Objective. The myelin protein Nogo inhibits axon regeneration by binding to its receptor (NgR) on axons. Intrathecal delivery of an NgR antagonist (NEP1-40) promotes growth of injured corticospinal axons and recovery of motor function following a dorsal hemisection. The authors used a similar design to examine recovery and repair after a lesion that interrupts the rubrospinal tract (RST). Methods. Rats received a Lateral funiculotomy at C4 and NEP1-40 or vehicle was delivered to the cervical spinal cord for 4 weeks. Outcome measures included motor and sensory tests and immunohistochemistry. Results. Gait analysis showed recovery in the NEP1-40-treated group compared to operated controls, and a test of forelimb usage also showed a beneficial effect. The density of labeled RST axons increased ipsiLaterally in the NEP1-40 group in the Lateral Funiculus rostral to the lesion and contraLaterally in both gray and white matter. Thus, rubrospinal axons exhibited diminished dieback and/or growth up to the lesion site. This was accompanied by greater density of 5HT and calcitonin gene-related peptide axons adjacent to and into the lesion/matrix site in the NEP1-40 group. Conclusions. NgR blockade after RST injury is associated with axonal growth and/or diminished dieback of severed RST axons up to but not into or beyond the lesion/matrix site, and growth of serotonergic and dorsal root axons adjacent to and into the lesion/matrix site. NgR blockade also supported partial recovery of function. The authors' results indicate that severed rubrospinal axons respond to NEP1-40 treatment but less robustly than corticospinal, raphe-spinal, or dorsal root axons.
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nogo 66 receptor antagonist peptide nep1 40 administration promotes functional recovery and axonal growth after Lateral Funiculus injury in the adult rat
Neurorehabilitation and Neural Repair, 2008Co-Authors: Yang Cao, Jed S Shumsky, M A Sabol, Robert Kushner, Stephen M Strittmatter, F P T Hamers, D H S Lee, S A Rabacchi, Marion MurrayAbstract:Objective. The myelin protein Nogo inhibits axon regeneration by binding to its receptor (NgR) on axons. Intrathecal delivery of an NgR antagonist (NEP1-40) promotes growth of injured corticospinal...
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apparent diffusion coefficients in spinal cord transplants and surrounding white matter correlate with degree of axonal dieback after injury in rats
American Journal of Neuroradiology, 2005Co-Authors: Eric D. Schwartz, Jed S Shumsky, Marion Murray, Chih-liang Chin, Abbas F. Jawad, Kooper B. Brown, Suzanne Wehrli, Alan Tessler, David B. HackneyAbstract:BACKGROUND AND PURPOSE: 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). METHODS: 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. RESULTS: In white matter surrounding transplants, ADC values transverse to axons were elevated and ADC values longitudinal to axons were decreased. These ADC values were more abnormal closer to the transplant, and this correlated with decreases in numbers of labeled RST axons. ADC values in BDNF-expressing fibroblast transplants were significantly lower than those in unmodified fibroblast transplants, and these lower values correlated with decreased axonal dieback. Behaviorally, all animals showed partial recovery, but animals with BDNF-expressing fibroblast transplants had slightly improved hindlimb function compared to those with unmodified fibroblast transplants. CONCLUSION: ADC values may be able to evaluate graft function after spinal cord injury by demonstrating the degree of axonal dieback and preservation.
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Apparent Diffusion Coefficients in Spinal Cord Transplants and Surrounding White Matter Correlate with Degree of Axonal Dieback After Injury in Rats
2004Co-Authors: Eric D. Schwartz, Jed S Shumsky, Marion Murray, Chih-liang Chin, Abbas F. Jawad, Kooper B. Brown, Suzanne Wehrli, Alan Tessler, David B. HackneyAbstract:BACKGROUND AND PURPOSE: 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). METHODS: 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 brainderived 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. RESULTS: In white matter surrounding transplants, ADC values transverse to axons were elevated and ADC values longitudinal to axons were decreased. These ADC values were more abnormal closer to the transplant, and this correlated with decreases in numbers of labeled RST axons. ADC values in BDNF-expressing fibroblast transplants were significantly lowe
Alexandre Leite Rodrigues De Oliveira - One of the best experts on this subject based on the ideXlab platform.
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influence of delivery method on neuroprotection by bone marrow mononuclear cell therapy following ventral root reimplantation with fibrin sealant
PLOS ONE, 2014Co-Authors: Roberta Barbizan, Mateus Vidigal De Castro, Benedito Barraviera, Rui Seabra Ferreira, Alexandre Leite Rodrigues De OliveiraAbstract:The present work compared the local injection of mononuclear cells to the spinal cord Lateral Funiculus with the alternative approach of local delivery with fibrin sealant after ventral root avulsion (VRA) and reimplantation. For that, female adult Lewis rats were divided into the following groups: avulsion only, reimplantation with fibrin sealant; root repair with fibrin sealant associated with mononuclear cells; and repair with fibrin sealant and injected mononuclear cells. Cell therapy resulted in greater survival of spinal motoneurons up to four weeks post-surgery, especially when mononuclear cells were added to the fibrin glue. Injection of mononuclear cells to the Lateral Funiculus yield similar results to the reimplantation alone. Additionally, mononuclear cells added to the fibrin glue increased neurotrophic factor gene transcript levels in the spinal cord ventral horn. Regarding the motor recovery, evaluated by the functional peroneal index, as well as the paw print pressure, cell treated rats performed equally well as compared to reimplanted only animals, and significantly better than the avulsion only subjects. The results herein demonstrate that mononuclear cells therapy is neuroprotective by increasing levels of brain derived neurotrophic factor (BDNF) and glial derived neurotrophic factor (GDNF). Moreover, the use of fibrin sealant mononuclear cells delivery approach gave the best and more long lasting results.
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local injection of bdnf producing mesenchymal stem cells increases neuronal survival and synaptic stability following ventral root avulsion
Neurobiology of Disease, 2009Co-Authors: Rafaela C R Hell, Miriam Maria Silva Costa, Alfredo M Goes, Alexandre Leite Rodrigues De OliveiraAbstract:Abstract The present study proposed to graft mesenchymal stem cells (MSCs), which continuously produce BDNF, into the spinal cord ventral horn, after ventral root avulsion. Neurotrophin expression was naturally achieved by culturing MSCs in an undifferentiated state for at least 10 weeks. Lewis rats were subjected to uniLateral avulsion of lumbar ventral roots, receiving 3 × 105 cells injected through the Lateral Funiculus. Two weeks after surgery, the animals were sacrificed and neuronal survival, astroglial reaction and synaptic inputs within the motor nucleus analyzed. The results indicated that the MSCs treatment significantly rescued avulsed motoneurons. Such neuronal survival was related to in vivo mRNA up regulation as well as expression of BDNF and GDNF. Such increase was correlated to the preservation of synaptophysin- positive nerve terminals. Thus it was proposed that when maintained undifferentiated for a period of 10 weeks, MSCs may be used as a continuous source of BDNF, positively influencing neuronal survival and synaptic plasticity.
Jed S Shumsky - One of the best experts on this subject based on the ideXlab platform.
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or FK506 Supports Survival of Transplanted Fibroblasts and Promotes Growth of Host Axons into the Transplant after Spinal Cord Injury
2013Co-Authors: Yoshikazu Hayashi, Jed S Shumsky, Alan Tessler, Theresa Connors, Takanobu Otsuka, Itzhak Fischer, Marion MurrayAbstract:Fibroblasts that have been genetically modified to secrete neurotrophins can stimulate axonal regeneration, rescue injured neurons, and improve function when grafted into a spinal cord injury site. These grafts are usually allografts that require immunosuppression to prevent rejection. In this study, we compared the effects of two immunophilin-ligands (cyclosporine A [CsA] and FK506) that are used clinically to prevent transplant rejection on protection of grafted fibroblasts. As there are risks associated with prolonged immunosuppression, we compared the effects of 2 or 8 weeks of administration of these drugs, in combination with our standard methylprednisolone protocol, in animals that survived for 8 weeks, to determine whether a shorter course of immunosuppression would be effective. Outcome measures included fibroblast survival, infiltration of activated macrophages and microglia into the graft, final lesion size, and growth of host axons into the graft. The graft consisted of a Vitrogen matrix into which fibroblasts were suspended; the graft was placed into a C3/C4 Lateral Funiculus lesion. The fibroblasts were isolated from a transgenic strain of Fischer rats that produce the marker alkaline phosphatase (Fb/AP). This enabled us to track the grafted fibroblasts and to evaluate the extent of their survival. The grafted matrix filled the lesion cavity. The density of fibroblast
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nogo 66 receptor antagonist peptide nep1 40 administration promotes functional recovery and axonal growth after Lateral Funiculus injury in the adult rat
Neurorehabilitation and Neural Repair, 2008Co-Authors: Yang Cao, Jed S Shumsky, M A Sabol, Robert Kushner, Stephen M Strittmatter, F P T Hamers, D H S Lee, S A Rabacchi, Marion MurrayAbstract:Objective. The myelin protein Nogo inhibits axon regeneration by binding to its receptor (NgR) on axons. Intrathecal delivery of an NgR antagonist (NEP1-40) promotes growth of injured corticospinal axons and recovery of motor function following a dorsal hemisection. The authors used a similar design to examine recovery and repair after a lesion that interrupts the rubrospinal tract (RST). Methods. Rats received a Lateral funiculotomy at C4 and NEP1-40 or vehicle was delivered to the cervical spinal cord for 4 weeks. Outcome measures included motor and sensory tests and immunohistochemistry. Results. Gait analysis showed recovery in the NEP1-40-treated group compared to operated controls, and a test of forelimb usage also showed a beneficial effect. The density of labeled RST axons increased ipsiLaterally in the NEP1-40 group in the Lateral Funiculus rostral to the lesion and contraLaterally in both gray and white matter. Thus, rubrospinal axons exhibited diminished dieback and/or growth up to the lesion site. This was accompanied by greater density of 5HT and calcitonin gene-related peptide axons adjacent to and into the lesion/matrix site in the NEP1-40 group. Conclusions. NgR blockade after RST injury is associated with axonal growth and/or diminished dieback of severed RST axons up to but not into or beyond the lesion/matrix site, and growth of serotonergic and dorsal root axons adjacent to and into the lesion/matrix site. NgR blockade also supported partial recovery of function. The authors' results indicate that severed rubrospinal axons respond to NEP1-40 treatment but less robustly than corticospinal, raphe-spinal, or dorsal root axons.
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nogo 66 receptor antagonist peptide nep1 40 administration promotes functional recovery and axonal growth after Lateral Funiculus injury in the adult rat
Neurorehabilitation and Neural Repair, 2008Co-Authors: Yang Cao, Jed S Shumsky, M A Sabol, Robert Kushner, Stephen M Strittmatter, F P T Hamers, D H S Lee, S A Rabacchi, Marion MurrayAbstract:Objective. The myelin protein Nogo inhibits axon regeneration by binding to its receptor (NgR) on axons. Intrathecal delivery of an NgR antagonist (NEP1-40) promotes growth of injured corticospinal...
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apparent diffusion coefficients in spinal cord transplants and surrounding white matter correlate with degree of axonal dieback after injury in rats
American Journal of Neuroradiology, 2005Co-Authors: Eric D. Schwartz, Jed S Shumsky, Marion Murray, Chih-liang Chin, Abbas F. Jawad, Kooper B. Brown, Suzanne Wehrli, Alan Tessler, David B. HackneyAbstract:BACKGROUND AND PURPOSE: 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). METHODS: 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. RESULTS: In white matter surrounding transplants, ADC values transverse to axons were elevated and ADC values longitudinal to axons were decreased. These ADC values were more abnormal closer to the transplant, and this correlated with decreases in numbers of labeled RST axons. ADC values in BDNF-expressing fibroblast transplants were significantly lower than those in unmodified fibroblast transplants, and these lower values correlated with decreased axonal dieback. Behaviorally, all animals showed partial recovery, but animals with BDNF-expressing fibroblast transplants had slightly improved hindlimb function compared to those with unmodified fibroblast transplants. CONCLUSION: ADC values may be able to evaluate graft function after spinal cord injury by demonstrating the degree of axonal dieback and preservation.
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Apparent Diffusion Coefficients in Spinal Cord Transplants and Surrounding White Matter Correlate with Degree of Axonal Dieback After Injury in Rats
2004Co-Authors: Eric D. Schwartz, Jed S Shumsky, Marion Murray, Chih-liang Chin, Abbas F. Jawad, Kooper B. Brown, Suzanne Wehrli, Alan Tessler, David B. HackneyAbstract:BACKGROUND AND PURPOSE: 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). METHODS: 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 brainderived 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. RESULTS: In white matter surrounding transplants, ADC values transverse to axons were elevated and ADC values longitudinal to axons were decreased. These ADC values were more abnormal closer to the transplant, and this correlated with decreases in numbers of labeled RST axons. ADC values in BDNF-expressing fibroblast transplants were significantly lowe
Yang Cao - One of the best experts on this subject based on the ideXlab platform.
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nogo 66 receptor antagonist peptide nep1 40 administration promotes functional recovery and axonal growth after Lateral Funiculus injury in the adult rat
Neurorehabilitation and Neural Repair, 2008Co-Authors: Yang Cao, Jed S Shumsky, M A Sabol, Robert Kushner, Stephen M Strittmatter, F P T Hamers, D H S Lee, S A Rabacchi, Marion MurrayAbstract:Objective. The myelin protein Nogo inhibits axon regeneration by binding to its receptor (NgR) on axons. Intrathecal delivery of an NgR antagonist (NEP1-40) promotes growth of injured corticospinal axons and recovery of motor function following a dorsal hemisection. The authors used a similar design to examine recovery and repair after a lesion that interrupts the rubrospinal tract (RST). Methods. Rats received a Lateral funiculotomy at C4 and NEP1-40 or vehicle was delivered to the cervical spinal cord for 4 weeks. Outcome measures included motor and sensory tests and immunohistochemistry. Results. Gait analysis showed recovery in the NEP1-40-treated group compared to operated controls, and a test of forelimb usage also showed a beneficial effect. The density of labeled RST axons increased ipsiLaterally in the NEP1-40 group in the Lateral Funiculus rostral to the lesion and contraLaterally in both gray and white matter. Thus, rubrospinal axons exhibited diminished dieback and/or growth up to the lesion site. This was accompanied by greater density of 5HT and calcitonin gene-related peptide axons adjacent to and into the lesion/matrix site in the NEP1-40 group. Conclusions. NgR blockade after RST injury is associated with axonal growth and/or diminished dieback of severed RST axons up to but not into or beyond the lesion/matrix site, and growth of serotonergic and dorsal root axons adjacent to and into the lesion/matrix site. NgR blockade also supported partial recovery of function. The authors' results indicate that severed rubrospinal axons respond to NEP1-40 treatment but less robustly than corticospinal, raphe-spinal, or dorsal root axons.
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nogo 66 receptor antagonist peptide nep1 40 administration promotes functional recovery and axonal growth after Lateral Funiculus injury in the adult rat
Neurorehabilitation and Neural Repair, 2008Co-Authors: Yang Cao, Jed S Shumsky, M A Sabol, Robert Kushner, Stephen M Strittmatter, F P T Hamers, D H S Lee, S A Rabacchi, Marion MurrayAbstract:Objective. The myelin protein Nogo inhibits axon regeneration by binding to its receptor (NgR) on axons. Intrathecal delivery of an NgR antagonist (NEP1-40) promotes growth of injured corticospinal...
Glenn J Giesler - One of the best experts on this subject based on the ideXlab platform.
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locations of spinothalamic tract axons in cervical and thoracic spinal cord white matter in monkeys
Journal of Neurophysiology, 2000Co-Authors: Xijing Zhang, Heather N Wenk, Christopher N Honda, Glenn J GieslerAbstract:The spinothalamic tract (STT) is the primary pathway carrying nociceptive information from the spinal cord to the brain in humans. The aim of this study was to understand better the organization of STT axons within the spinal cord white matter of monkeys. The location of STT axons was determined using method of antidromic activation. Twenty-six lumbar STT cells were isolated. Nineteen were classified as wide dynamic range neurons and seven as high-threshold cells. Fifteen STT neurons were recorded in the deep dorsal horn (DDH) and 11 in superficial dorsal horn (SDH). The axons of 26 STT neurons were located at 73 low-threshold points (<30 μA) within the Lateral Funiculus from T9 to C6. STT neurons in the SDH were activated from 33 low-threshold points, neurons in the DDH from 40 low-threshold points. In lower thoracic segments, SDH neurons were antidromically activated from low-threshold points at the dorsal-ventral level of the denticulate ligament. Neurons in the DDH were activated from points located slightly ventral, within the ventral Lateral Funiculus. At higher segmental levels, axons from SDH neurons continued in a position dorsal to those of neurons in the DDH. However, axons from neurons in both areas of the gray matter were activated from points located in more ventral positions within the Lateral Funiculus. Unlike the suggestions in several previous reports, the present findings indicate that STT axons originating in the lumbar cord shift into increasingly ventral positions as they ascend the length of the spinal cord.
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spinothalamic and spinohypothalamic tract neurons in the cervical enlargement of rats iii locations of antidromically identified axons in the cervical cord white matter
Journal of Neurophysiology, 1994Co-Authors: Robert J Dado, James T Katter, Glenn J GieslerAbstract:1. Fifty-five neurons in the cervical enlargement (C6-C8) of urethan-anesthetized rats were antidromically activated from the contraLateral posterior diencephalon. In all cases, antidromic thresholds were < or = 30 microA. The locations of the axons of these neurons within the white matter of segments C2-C6 were determined by tracking systematically using a second antidromic stimulating electrode. 2. The recording locations of 51 neurons were marked and recovered. Twenty neurons were recorded in the superficial dorsal horn (SDH) and 31 were in the deep dorsal horn (DDH). Eighty-three lowest threshold points for antidromic activation within the white matter of segments C2-C6 were determined for these 51 neurons. The mean antidromic threshold at these points was 9.5 +/- 0.5 (SE) microA. For 26 neurons, the lowest threshold point for antidromic activation was determined at one segmental level. We also attempted to determine whether individual axons maintained their position as they ascended through the cervical cord white matter. In 25 cases, lowest threshold points were determined at two or more segmental levels. 3. In segments C5-C6, 88% (7/8) of the lowest threshold points of the examined axons were located in the contraLateral ventral Funiculus, indicating that the majority of examined axons crossed the midline within one or two segments. 4. In segments C3-C4, 32% (14/44) of all examined axons were found in the dorsal Lateral Funiculus (DLF) and 66% (29/44) were within the ventral quadrant [ventral Lateral Funiculus (VLF) and ventral Funiculus (VF)]. Sixty-nine percent (11/16) of the axons of neurons recorded in the SDH were located in the contraLateral DLF and 31% (5/16) were located in the ventral quadrant (VQ). In contrast, only 11% (3/28) of the axons of neurons recorded in the DDH were located in the contraLateral DLF and 86% (24/28) were located in the VQ. Therefore, in segments C3-C4, the locations of axons differed significantly. Those from neurons recorded in the SDH were located primarily in the DLF and those from neurons recorded in the DDH were located principally in the VQ. 5. In segment C2, 74% (23/31) of all examined axons were found in the DLF, 23% (7/31) were in the VQ, and 3% (1/31) were in the dorsal horn. Thus, the percentage of all examined axons in the DLF in C2 was approximately 2.5 times greater than it was in C3-C4.(ABSTRACT TRUNCATED AT 400 WORDS)
