Impaired axonal transport and altered axolemmal permeability occur in distinct populations of damaged axons following traumatic brain injury

Stone, James L.; Okonkwo, David O.; Dialo, Alfa O.; Rubin, David G.; Mutlu, Leman; Povlishock, John T.; Helm, Gregory A.

doi:10.1016/j.expneurol.2004.05.022

Cited by 128 publications

(88 citation statements)

References 25 publications

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“…However, NF200 is primarily expressed in large diameter neurons not small, nociceptive afferents. Stone et al (2004) suggest that impairment of axonal transport following mechanical tissue strain is variable across different sized fiber subpopulations and that such impairment is preferentially more severe in larger axons. That report implies that an assessment of NF200 transport impairment may overestimate the damage that is produced in small, unmyelinated fibers because those fibers are less susceptible to damage following tissue strain.…”

Section: Discussionmentioning

confidence: 97%

Dorsal root compression produces myelinated axonal degeneration near the biomechanical thresholds for mechanical behavioral hypersensitivity

Hubbard¹,

Winkelstein²

2008

Experimental Neurology

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Increased sensitivity to mechanical stimuli produced by transient cervical nerve root compression is dependent on the severity of applied load. In addition, trauma in the nervous system induces local inflammation, Wallerian degeneration, and a host of other degenerative processes leading to axonal dysfunction. Here, axonal degeneration and inflammation were assessed following transient dorsal root compression to establish a relationship between conditions for dorsal root axonal changes and those previously established for the onset and maintenance of mechanical behavioral hypersensitivity (26.3mN and 38.2mN, respectively). Compression loads were applied over a range (0-110mN) known to produce sustained behavioral hypersensitivity. CD68-and NF200-immunoreactivity, as well as axonal pathological changes, were assessed in the dorsal root to investigate the load thresholds requisite for inducing macrophage infiltration and axonal degeneration relative to those thresholds for producing the onset and persistence of behavioral hypersensitivity. Neurofilament accumulation and the depletion of NF200-immunoreactivity in the region of compressed tissue were produced for loads that produce mechanical behavioral hypersensitivity. A 50 th -percentile load threshold was determined (31.6mN) governing the onset of NF200 depletion. However, CD68-immunoreactivity was increased for nearly all loads, suggesting that macrophage recruitment may not be directly related to nerve root-mediated behavioral hypersensitivity. This study provides new evidence for thresholdmediated degenerative changes in the context of behavioral hypersensitivity following nerve root compression.

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Section: Discussionmentioning

confidence: 97%

Dorsal root compression produces myelinated axonal degeneration near the biomechanical thresholds for mechanical behavioral hypersensitivity

Hubbard¹,

Winkelstein²

2008

Experimental Neurology

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“…3). We performed IHC analysis in serial coronal and sagittal sections using an antibody targeting the C terminus of the APP (Stone et al, 2000;Stone et al, 2004). We found very high number of APP-labeled injured axons in this area as early as 30 min following TBI (Fig.…”

Section: Analysis Of Axonal Degeneration In White Matter Tracts Aftermentioning

confidence: 99%

Mild traumatic brain injury to the infant mouse causes robust white matter axonal degeneration which precedes apoptotic death of cortical and thalamic neurons

Dikranian

Cohen

Donald

et al. 2008

Experimental Neurology

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The immature brain in the first several years of childhood is very vulnerable to trauma. Traumatic brain injury (TBI) during this critical period often leads to neuropathological and cognitive impairment. Previous experimental studies in rodent models of infant TBI were mostly concentrated on neuronal degeneration, while axonal injury and its relationship to cell death have attracted much less attention. To address this, we developed a closed controlled head injury model in infant (P7) mice and characterized the temporospatial pattern of axonal degeneration and neuronal cell death in the brain following mild injury. Using amyloid precursor protein (APP) as marker of axonal injury we found that mild head trauma causes robust axonal degeneration in the cingulum/external capsule as early as 30 min post-impact. These levels of axonal injury persisted throughout a 24 hr period, but significantly declined by 48 hrs. During the first 24 hrs injured axons underwent significant and rapid pathomorphological changes. Initial small axonal swellings evolved into larger spheroids and clublike swellings indicating the early disconnection of axons. Ultrastructural analysis revealed compaction of organelles, axolemmal and cytoskeletal defects. Axonal degeneration was followed by profound apoptotic cell death in the posterior cingulate and retrosplenial cortex and anterior thalamus which peaked between 16 and 24 hrs post-injury. At early stages post-injury no evidence of excitotoxic neuronal death at the impact site was found. At 48 hrs apoptotic cell death was reduced and paralleled with the reduction in the number of APP-labeled axonal profiles. Our data suggest that early degenerative response to injury in axons of the cingulum and external capsule may cause disconnection between cortical and thalamic neurons, and lead to their delayed apoptotic death.

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“…[98][99][100] In rats, neuronal disconnection appears to occur due to breakdown of the subaxolemmal cytoskeletal network. 101,102 Diffuse injury causes axonal degeneration near the neuron cell body leading to neuronal atrophy rather than apoptosis. 103,104 Such atrophy has been quantified by structural imaging in human TBI; 105 the brain appears to melt away while cranial fluid-filled spaces enlarge on serial scans in the severely injured patient.…”

Section: Traumatic Brain Injury (Tbi) and Impaired Consciousnessmentioning

confidence: 99%

Vagus nerve stimulation to augment recovery from severe traumatic brain injury impeding consciousness: a prospective pilot clinical trial

Chen

Flanagan

Samadani

2013

Neurological Research

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Objectives-Traumatic brain injury has a high morbidity and mortality in both civilian and military populations. Blast and other mechanisms of traumatic brain injury damage the brain by causing neurons to disconnect and atrophy. Such traumatic axonal injury can lead to persistently vegetative and minimally conscious states, for which limited treatment options exist, including physical, occupational, speech and cognitive therapies.More than 60,000 patients have received vagus nerve stimulation for epilepsy and depression. In addition to decreased seizure frequency and severity, patients report enhanced mood, reduced daytime sleepiness independent of seizure control, increased slow wave sleep, and improved cognition, memory, and quality of life.Early stimulation of the vagus nerve accelerates the rate and extent of behavioral and cognitive recovery after fluid percussion brain injury in rats.Methods-We recently obtained FDA approval for a pilot prospective randomized crossover trial to demonstrate objective improvement in clinical outcome by placement of a vagus nerve stimulator in patients who are recovering from severe traumatic brain injury. Our hypothesis is that stimulation of the vagus nerve results in increased cerebral blood flow and metabolism in the forebrain, thalamus and reticular formation, which promotes arousal and improved consciousness, thereby improving outcome after traumatic brain injury resulting in minimally conscious or persistent vegetative states.Discussion-If this study demonstrates that vagus nerve stimulation can safely and positively impact outcome, then a larger randomized prospective crossover trial will be proposed.

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Impaired axonal transport and altered axolemmal permeability occur in distinct populations of damaged axons following traumatic brain injury

Cited by 128 publications

References 25 publications

Dorsal root compression produces myelinated axonal degeneration near the biomechanical thresholds for mechanical behavioral hypersensitivity

Dorsal root compression produces myelinated axonal degeneration near the biomechanical thresholds for mechanical behavioral hypersensitivity

Mild traumatic brain injury to the infant mouse causes robust white matter axonal degeneration which precedes apoptotic death of cortical and thalamic neurons

Vagus nerve stimulation to augment recovery from severe traumatic brain injury impeding consciousness: a prospective pilot clinical trial

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