The Pathology of Human Spinal Cord Injury: Defining the Problems

Norenberg, Michael D.; Smith, Jon; Marcillo, Alexander

doi:10.1089/089771504323004575

Cited by 561 publications

(454 citation statements)

References 43 publications

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“…19 The improvement in CMAP responses that we have observed in the current study might also be linked to the resolution of hemorrhage and edema in the spinal cord and/or ventral root, which is observed in the initial days following human SCI. 4 Restoration of the blood-brain barrier and extracellular ion and neurotransmitter homeostasis may also play important roles. However, in our rat cervical contusion model, we previously showed that CMAPs remain chronically reduced for at least 6 weeks, suggesting that these early events only account for partial CMAP loss.…”

Section: Discussionmentioning

confidence: 99%

“…1 We previously described a model of midcervical (C4) contusion in the adult rat. 2 We demonstrated that this paradigm models a number of the histopathological and functional features seen in human patients, 3,4 including extensive PhMN loss, phrenic nerve axonal degeneration, diaphragm atrophy, and chronically persistent unilateral diaphragm deficits, such as decreased diaphragm compound muscle action potential (CMAP) amplitudes following phrenic nerve stimulation, making it a clinically relevant model of respiratory compromise following midcervical contusion SCI. Nevertheless, experimental data are lacking regarding the timing of early PhMN loss and the consequent role of gray matter sparing on global breathing function during the initial stages following midcervical spinal contusion.…”

Section: Introductionmentioning

confidence: 99%

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Early Phrenic Motor Neuron Loss and Transient Respiratory Abnormalities after Unilateral Cervical Spinal Cord Contusion

Nicaise

Frank

Hala

et al. 2013

Journal of Neurotrauma

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Contusion-type cervical spinal cord injury (SCI) is one of the most common forms of SCI observed in patients. In particular, injuries targeting the C3-C5 region affect the pool of phrenic motor neurons (PhMNs) that innervates the diaphragm, resulting in significant and often chronic respiratory dysfunction. Using a previously described rat model of unilateral midcervical C4 contusion with the Infinite Horizon Impactor, we have characterized the early time course of PhMN degeneration and consequent respiratory deficits following injury, as this knowledge is important for designing relevant treatment strategies targeting protection and plasticity of PhMN circuitry. PhMN loss (48% of the ipsilateral pool) occurred almost entirely during the first 24 h post-injury, resulting in persistent phrenic nerve axonal degeneration and denervation at the diaphragm neuromuscular junction (NMJ). Reduced diaphragm compound muscle action potential amplitudes following phrenic nerve stimulation were observed as early as the first day post-injury (30% of pre-injury maximum amplitude), with slow functional improvement over time that was associated with partial reinnervation at the diaphragm NMJ. Consistent with ipsilateral diaphragmatic compromise, the injury resulted in rapid, yet only transient, changes in overall ventilatory parameters measured via whole-body plethysmography, including increased respiratory rate, decreased tidal volume, and decreased peak inspiratory flow. Despite significant ipsilateral PhMN loss, the respiratory system has the capacity to quickly compensate for partially impaired hemidiaphragm function, suggesting that C4 hemicontusion in rats is a model of SCI that manifests subacute respiratory abnormalities. Collectively, these findings demonstrate significant and persistent diaphragm compromise in a clinically relevant model of midcervical contusion SCI; however, the therapeutic window for PhMN protection is restricted to early time points post-injury. On the contrary, preventing loss of innervation by PhMNs and/or inducing plasticity in spared PhMN axons at the diaphragm NMJ are relevant long-term targets.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Early Phrenic Motor Neuron Loss and Transient Respiratory Abnormalities after Unilateral Cervical Spinal Cord Contusion

Nicaise

Frank

Hala

et al. 2013

Journal of Neurotrauma

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“…Damage to the adult human cervical spinal cord dorsal columns leads to sensory dysfunctions of the upper limbs as evidenced by transient exaggeration or abolishment of the cutaneous sensations of fine touch, vibration, and proprioception (for a review, see York, 1985;Nathan et al, 1986). Similarly (Metz et al, 2000;Norenberg et al, 2004), transient and persistent upper limb cutaneous sensation dysfunctions occur in adult rats with damage to their cervical spinal cord dorsal columns (Schrimsher and Reier, 1993;McKenna and Whishaw, 1999;Ballerman et al, 2001a,b;Onifer et al, 2005;Kanagal and Muir, 2007). Abolished upper limb somatosensory evoked potentials (SSEPs) also can recover spontaneously in persons with incomplete cervical SCI (Curt and Dietz, 1996).…”

Section: Introductionmentioning

confidence: 99%

Loss and spontaneous recovery of forelimb evoked potentials in both the adult rat cuneate nucleus and somatosensory cortex following contusive cervical spinal cord injury

Onifer

Nunn

Decker

et al. 2007

Experimental Neurology

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Varying degrees of neurologic function spontaneously recovers in humans and animals during the days and months after spinal cord injury (SCI). For example, abolished upper limb somatosensory potentials (SSEPS) and cutaneous sensations can recover in persons post-contusive cervical SCI. To maximize recovery and the development/evaluation of repair strategies, a better understanding of the anatomical locations and physiological processes underlying spontaneous recovery after SCI is needed. As an initial step, the present study examined whether recovery of upper limb SSEPs after contusive cervical SCI was due to the integrity of some spared dorsal column primary afferents that terminate within the cuneate nucleus and not one of several alternate routes. C5-C6 contusions were performed on male adult rats. Electrophysiological techniques were used in the same rat to determine forelimb evoked neuronal responses in both cortex (SSEPS) and the cuneate nucleus (terminal extracellular recordings). SSEPs were not evoked 2 days post-SCI but were found at 7 days and beyond, with an observed change in latencies between 7 and 14 days (suggestive of spared axon remyelination). Forelimb evoked activity in the cuneate nucleus at 15 but not 3 days post-injury occurred despite dorsal column damage throughout the cervical injury (as seen histologically). Neuroanatomical tracing (using 1% unconjugated cholera toxin B subunit) confirmed that upper limb primary afferent terminals remained within the cuneate nuclei. Taken together, these results indicate Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access

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“…Staining of sections taken from areas considered positive for schwannosis in PPD-stained plastic sections were negative for the presence of Schwann cells. We speculate that instead these structures are primarily composed of fibroblasts (i.e., mesenchymal-derived), similar to the mesenchymal scar described in human spinal cord injury patients, primarily after a laceratingtype of injury (Berry et al, 1983;Norenberg et al, 2004).…”

Section: Figmentioning

confidence: 66%

“…The presence of hypertrophic astrocytes, but the lack of astrocytic scar formation, in minipigs is similar if not identical to what has been described in human spinal cord specimens taken from patients at chronic stages of spinal cord injury. In these studies the presence of hypertrophic astrocytes was described; however, no typical astrocyte scar was identified (Norenberg et al, 2004). These authors' characterization included ''.…”

Section: Figmentioning

confidence: 99%

Chronic Spinal Compression Model in Minipigs: A Systematic Behavioral, Qualitative, and Quantitative Neuropathological Study

Navarro

Juhás²,

Keshavarzi³

et al. 2012

Journal of Neurotrauma

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The goal of the present study was to develop a porcine spinal cord injury (SCI) model, and to describe the neurological outcome and characterize the corresponding quantitative and qualitative histological changes at 4-9 months after injury. Adult Gottingen-Minnesota minipigs were anesthetized and placed in a spine immobilization frame. The exposed T12 spinal segment was compressed in a dorso-ventral direction using a 5-mmdiameter circular bar with a progressively increasing peak force (1.5, 2.0, or 2.5 kg) at a velocity of 3 cm/sec. During recovery, motor and sensory function were periodically monitored. After survival, the animals were perfusion fixed and the extent of local SCI was analyzed by (1) post-mortem MRI analysis of dissected spinal cords, (2) qualitative and quantitative analysis of axonal survival at the epicenter of injury, and (3) defining the presence of local inflammatory changes, astrocytosis, and schwannosis. Following 2.5-kg spinal cord compression the animals demonstrated a near complete loss of motor and sensory function with no recovery over the next 4-9 months. Those that underwent spinal cord compression with 2 kg force developed an incomplete injury with progressive partial neurological recovery characterized by a restricted ability to stand and walk. Animals injured with a spinal compression force of 1.5 kg showed near normal ambulation 10 days after injury. In fully paralyzed animals (2.5 kg), MRI analysis demonstrated a loss of spinal white matter integrity and extensive septal cavitations. A significant correlation between the magnitude of loss of small and medium-sized myelinated axons in the ventral funiculus and neurological deficits was identified. These data, demonstrating stable neurological deficits in severely injured animals, similarities of spinal pathology to humans, and relatively good post-injury tolerance of this strain of minipigs to spinal trauma, suggest that this model can successfully be used to study therapeutic interventions targeting both acute and chronic stages of SCI.

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The Pathology of Human Spinal Cord Injury: Defining the Problems

Cited by 561 publications

References 43 publications

Early Phrenic Motor Neuron Loss and Transient Respiratory Abnormalities after Unilateral Cervical Spinal Cord Contusion

Early Phrenic Motor Neuron Loss and Transient Respiratory Abnormalities after Unilateral Cervical Spinal Cord Contusion

Loss and spontaneous recovery of forelimb evoked potentials in both the adult rat cuneate nucleus and somatosensory cortex following contusive cervical spinal cord injury

Chronic Spinal Compression Model in Minipigs: A Systematic Behavioral, Qualitative, and Quantitative Neuropathological Study

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