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PubMed1998

Disruption of MAP-2 immunostaining in rat hippocampus after traumatic brain injury.

The effects of diffuse brain injury on dendritic morphology in rat hippocampus and cortex were examined in this study using the recently described impact acceleration model of traumatic brain injury (Marmarou et al., 1994). Dendritic structure was visualized using immunostaining of microtubule associated protein-2 (MAP-2). Brains were studied 24, 48, and 72 h after brain injury. Results from immunohistochemistry and light microscopy indicated a time-dependent disruption of dendritic cytoarchitecture in the CA1 subregion and in the hilus of the hippocampus but not in the dentate gyrus or CA3 subregion. Similar disruption was observed in the cortical mantle overlying the hippocampus. Although disruption of dendritic structure was observed at 24 h, the most severe damage was at 48 h after injury with evidence of at least partial recovery of MAP-2 immunostaining by 72 h. In the most severe damage, dendrites appeared to be fragmented, scattered, and unaligned, consisting of irregularly spaced and darkly stained swollen segments. A mixed pattern of immunostaining was observed in somata of hilar cells, with some appearing normal while others stained only faintly, appearing to have lost their typical polygonal shape. Semiquantitative rankings confirmed these qualitative findings. Immediate post-injury behavioral evaluations of injury severity were compared to the degree of disruption of MAP-2 immunostaining. The results of this study indicate that diffuse brain injury is associated not only with axonal damage but also with injury to dendrites.

Animals↗
PubMed2002

Mitochondrial encephalomyopathy: comparison of conventional MR imaging with diffusion-weighted and diffusion tensor imaging: case report.

SUMMARY: Conventional MR imaging, MR spectroscopy, diffusion-weighted imaging, and diffusion tensor imaging were performed in a 5-month-old male patient with mitochondrial encephalomyopathy. On conventional T2-weighted MR images, symmetric, confluent high signal intensity was found in the temporoparietal white matter. A large lactate peak and decreased N-acetylaspartate were found in this region on proton MR spectroscopic images. Diffusion-weighted imaging showed increased apparent diffusion coefficient, representing vasogenic edema. Diffusion tensor imaging revealed decreased anisotropy, consistent with injury to the oligodendro-axonal unit. A muscle biopsy specimen revealed an isolated complex III enzyme respiratory chain deficiency. Diffusion-weighted and diffusion tensor imaging are valuable techniques for the characterization of hyperintense lesions on T2-weighted MR images in cases of mitochondrial encephalomyopathy.

Anisotropy↗
PubMedDate not supplied

Trauma to the corpus callosum: MR features.

The frequency, distribution, and appearance of corpus callosum injuries were evaluated with MR and CT in a prospective study of 78 patients with acute (n = 63) and chronic (n = 15) head injuries. Traumatic lesions of the corpus callosum were detected in 47% of patients. MR was significantly (p less than .001) more sensitive than CT in the detection of callosal injuries. MR and CT visualized 100% and 27%, respectively, of the traumatic callosal lesions that were detected in the study population. The majority of lesions were located in the splenium but a few were also found in the body and genu. Patients with callosal injuries had a significantly higher incidence of primary brainstem injury (p less than .02) as well as a greater number of subcortical gray-matter (p less than .05) and diffuse axonal "shear" (p less than .001) lesions. In addition, patients with callosal injuries had a significantly higher incidence of traumatic lesions of the septum pellucidum (p less than .007) and fornix (p less than .001). Intraventricular hemorrhage occurred significantly more often (p less than .002) in patients with callosal injuries, especially if traumatic lesions of the fornix or septum pellucidum were also present. Patients with callosal injuries had significantly lower initial Glasgow Coma Scale scores (mean, 6.6) than those without injuries (mean, 10.7) (p less than .001). Injury to the corpus callosum occurs much more often with nonfatal head injuries than had been believed previously.

Adolescent↗
PubMed2006

Principles of diffusion tensor imaging and its applications to basic neuroscience research.

The brain contains more than 100 billion neurons that communicate with each other via axons for the formation of complex neural networks. The structural mapping of such networks during health and disease states is essential for understanding brain function. However, our understanding of brain structural connectivity is surprisingly limited, due in part to the lack of noninvasive methodologies to study axonal anatomy. Diffusion tensor imaging (DTI) is a recently developed MRI technique that can measure macroscopic axonal organization in nervous system tissues. In this article, the principles of DTI methodologies are explained, and several applications introduced, including visualization of axonal tracts in myelin and axonal injuries as well as human brain and mouse embryonic development. The strengths and limitations of DTI and key areas for future research and development are also discussed.

Animals↗
PubMed2006

Diffusion tensor imaging of time-dependent axonal and myelin degradation after corpus callosotomy in epilepsy patients.

Axonal degeneration of white matter fibers is a key consequence of neuronal or axonal injury. It is characterized by a series of time-related events with initial axonal membrane collapse followed by myelin degradation being its major hallmarks. Standard imaging cannot differentiate these phenomena, which would be useful for clinical investigations of degeneration, regeneration and plasticity. Animal models suggest that diffusion tensor magnetic resonance imaging (DTI) is capable of making such distinction. The applicability of this technique in humans would permit inferences on white matter microanatomy using a non-invasive technique. The surgical bisection of the anterior 2/3 of the corpus callosum for the palliative treatment of certain types of epilepsy serves as a unique opportunity to assess this method in humans. DTI was performed on three epilepsy patients before corpus callosotomy and at two time points (1 week and 2-4 months) after surgery. Tractography was used to define voxels of interest for analysis of mean diffusivity, fractional anisotropy and eigenvalues. Diffusion anisotropy was reduced in a spatially dependent manner in the genu and body of the corpus callosum at 1 week and remained low 2-4 months after the surgery. Decreased anisotropy at 1 week was due to a reduction in parallel diffusivity (consistent with axonal fragmentation), whereas at 2-4 months, it was due to an increase in perpendicular diffusivity (consistent with myelin degradation). DTI is capable of non-invasively detecting, staging and following the microstructural degradation of white matter following axonal injury.

Adult↗
PubMed2001

The role of basic fibroblast growth factor in peripheral nerve regeneration.

In the peripheral nervous system regeneration and gradual functional restoration occur following peripheral nerve injury. Growth of regenerating axons depends on the presence of diffusible neurotrophic factors, in addition to the substratum. Neurotrophic factors that are involved in peripheral nerve regeneration include nerve growth factor, brain-derived neurotrophic factor, ciliary neurotrophic factor, glial cell line-derived neurotrophic factor, and interleukin-6. Recent functional and expression studies of basic fibroblast growth factor and its receptors have emphasized a physiological role of these molecules in the peripheral nervous system. Basic fibroblast growth factor and its receptors are constitutively expressed in dorsal root ganglia and the peripheral nerve. These molecules display an upregulation in dorsal root ganglia and in the proximal and distal nerve stumps following peripheral nerve injury. In the ganglia these molecules show a mainly neuronal expression, whereas at the lesion site of the nerve, Schwann cells and invading macrophages represent the main cellular sources of basic fibroblast growth factor and the receptors 1-3. Exogenously applied basic fibroblast growth factor mediates rescue effects on injured sensory neurons and supports neurite outgrowth of transectioned nerves. Regarding the expression patterm and the effects after exogenous administration of basic fibroblast growth factor, this molecule seems to play a physiological role during nerve regeneration. Thus, basic fibroblast growth factor could be a promising candidate to contribute to the development of new therapeutic strategies for the treatment of peripheral nerve injuries.

Animals↗
PubMed2006

Spatiotemporal distribution of spectrin breakdown products induced by anoxia in adult rat optic nerve in vitro.

Hypoxic/ischemic and traumatic injury to central nervous system myelinated axons is heavily dependent on accumulation of Ca ions in the axoplasm, itself promoted by Na influx from the extracellular space. Given the high density of nodal Na channels, we hypothesized that nodes of Ranvier might be particularly vulnerable to Ca overload and subsequent damage, as this is the expected locus of maximal Na influx. Adult rat optic nerves were exposed to in vitro anoxia and analyzed immunohistochemically for the presence of spectrin breakdown. Cleavage of spectrin became detectable between 15 and 30 mins of anoxia, and increased homogeneously along the lengths of fibers; localized breakdown was not observed at nodes of Ranvier at any time point analyzed. Spectrin breakdown was also found in glial processes surrounding axons. Confocal imaging of axoplasmic Ca also revealed a gradual and nonlocalized increase as anoxia progressed, without evidence of Ca 'hot-spots' anywhere along the axons at any time between 0 and 30 mins of anoxic exposure in vitro. Calculations of Ca diffusion rates indicated that even if Ca entered or was released focally in axons, this ion would diffuse rapidly into the internodes and likely produce diffuse injury by activating Ca-dependent proteases. Western blot analysis for voltage-gated Na channel protein revealed that key functional proteins such as these are also degraded by anoxia/ischemia. Thus, proteolysis of structural and functional proteins will conspire to irreversibly injure central axons and render them nonfunctional, eventually leading to transection, degradation, and Wallerian degeneration.

Animals↗
PubMed1989

Traumatic brain stem injury: MR imaging.

Eighty-seven patients with acute (n = 70) or chronic (n = 17) head injuries were prospectively studied with magnetic resonance (MR) imaging and computed tomography (CT) to characterize the frequency and nature of traumatic brain stem injury (BSI). Forty-eight traumatic lesions were identified in 36 patients. Of 36 patients, 35 had neurologic findings that corroborated the radiographic impression of BSI. T1- and T2-weighted MR images demonstrated a significantly higher number of lesions than did CT. Patients with BSI had a significantly higher frequency of corpus callosum and diffuse axonal "shear" lesions. The number of cortical contusions and extraaxial hematomas was similar in both groups. The mean Glasgow Coma Scale (GCS) scores at admission were significantly lower in patients with evidence of BSI on MR images. Patients with primary BSI had lower initial GCS scores, a longer duration of coma, more diffuse axonal "shear" lesions, and a higher frequency of corpus callosum injury than patients with secondary BSI. The location of primary and secondary lesions was significantly different. Overall, MR imaging was more helpful than CT in detecting, localizing, and characterizing BSI.

Acute Disease↗
PubMed2004

Conditioning lesions enhance axonal regeneration of descending brain neurons in spinal-cord-transected larval lamprey.

In larval lamprey, with increasing recovery times after a transection of the rostral spinal cord, there is a gradual recovery of locomotor behavior, and descending brain neurons regenerate their axons for progressively greater distances below the transection site. In the present study, spinal cord "conditioning lesions" (i.e., transections) were performed in the spinal cord at 30% body length (BL; normalized distance from the head) or 50% BL. After various "lesion delay times" (D), a more proximal spinal cord "test lesion" (i.e., transection) was performed at 10% BL, and then, after various recovery times (R), horseradish peroxidase was applied to the spinal cord at 20% BL to determine the extent of axonal regeneration of descending brain neurons. Conditioning lesions at 30% BL, lesion delay times of 2 weeks, and recovery times of 4 weeks (D-R = 2-4 group) resulted in a significant enhancement of axonal regeneration for the total numbers of descending brain neurons as well as neurons in certain brain cell groups compared to control animals without conditioning lesions. Experiments with hemiconditioning lesions, which reduce interanimal variability, confirmed that conditioning lesions do significantly enhance axonal regeneration and indicate that axotomy rather than diffusible factors released at the injury site is primarily involved in this enhancement. Results from the present study suggest that conditioning lesions "prime" descending brain neurons via cell body responses and enhance subsequent axonal regeneration, probably by reducing the initial delay and/or increasing the initial rate of axonal outgrowth.

Animals↗
PubMed2005

Inflammatory demyelination is not central to the pathogenesis of multiple sclerosis.

Multiple sclerosis is a disease of the central nervous system that destroys myelin, oligodendrocytes, neurons and axons. Historically considered to be caused by an autoimmune process mainly affecting myelin and oligodendrocytes in the white matter, recent data provide evidence that a generalized, diffuse neurodegenerative process plays an important role in the pathogenesis of MS. There is a high density of axonal transections in active demyelinating lesions, but also persistent low-level axonal damage in inactive plaques and diffuse axonal and neuronal loss throughout the nervous system. Initial axonal injury appears to be closely related to inflammation, but is not restricted to the lesions themselves. Damage may be propagated throughout the nervous system by anterograde Wallerian, retrograde or transynaptic degeneration. Cumulative tissue loss in the grey and white matter, especially of axons, is important and probably the principal determinant of accumulation of irreversible neurological disability and of conversion to a progressive disease course.

Axons↗
PubMed2004

Traumatic injury in the developing brain--effects of hypothermia.

Little is known about the underlying mechanisms of head trauma in the developing brains, despite considerable social and economic impact following such injuries. Age has been shown to substantially influence morbidity and mortality. Children younger than 4 years of age had worse cognitive, motor, and brain atrophy outcomes than children 6 years of age and older. Younger children tend to more frequently suffer from diffuse cerebral swelling compared to adults. Typical autoptic findings also include axonal injury and ischemic neurodegeneration. These differences impact not only the primary response of the brain to injury but the secondary response as well. The complexity of damaging mechanisms in traumatic brain injury contributes to the problem of determining effective therapy. As an alternative/ adjunct to pharmacological approaches, hypothermia has been shown to be cerebroprotective in traumatized adult brains. Although a large number of animal studies have shown protective effects of hypothermia in a variety of damaging mechanisms after TBI, little data exist for young, developing brains. The injury mechanisms of TBI in the immature, effects of hypothermia following resuscitation on adult and immature traumatized brains, and some possible mechanisms of action of hypothermia in the immature traumatized brain are discussed in this review.

Age Factors↗
PubMed2005

Quantification of cervical cord pathology in primary progressive MS using diffusion tensor MRI.

OBJECTIVE: To investigate the extent and severity of cervical cord damage using diffusion tensor MRI (DT-MRI) and histogram analysis in patients with primary progressive MS (PPMS). METHODS: Diffusion-weighted sensitivity-encoded (SENSE) echoplanar images of the cervical cord and brain dual-echo and diffusion-weighted scans were acquired from 24 patients with PPMS and 13 healthy controls. Cord and brain mean diffusivity and fractional anisotropy histograms were produced. An analysis of variance model, adjusting for cord volume, was used to compare cord DT-MRI parameters from controls and patients. RESULTS: Compared to healthy controls, PPMS patients had reduced cervical cord cross-sectional area and average cord fractional anisotropy (p = 0.007), and increased cord mean diffusivity (p = 0.024). No correlations were found between DT-MRI metrics of the cord and quantities obtained from conventional and DT-MRI of the brain. CONCLUSIONS: DT-MRI of the cervical cord can quantify the extent of diffuse cord pathology in patients with PPMS. Such cord diffusivity changes in patients with PPMS are likely to reflect irreversible axonal injury and reactive gliosis and seem to be independent of brain damage.

Adult↗
PubMed1999

Neural tissue formation within porous hydrogels implanted in brain and spinal cord lesions: ultrastructural, immunohistochemical, and diffusion studies.

A biocompatible heterogeneous hydrogel of poly [N-(2-hydroxypropyl) methacrylamide] (PHPMA), was evaluated for its ability to promote tissue repair and enhance axonal regrowth across lesion cavities in the brain and spinal cord in adult and juvenile (P17 P21) rats. Incorporation of PHPMA hydrogels into surrounding host tissue was examined at the ultrastructural level and using immunohistochemical techniques. In addition, and in parallel to these studies, diffusion parameters (volume fraction and tortuosity of the gel network) of the PHPMA hydrogels were evaluated pre- to postimplantation using an in vivo real-time iontophoretic method. The polymer hydrogels were able to bridge tissue defects created in the brain or spinal cord, and supported cellular ingrowth, angiogenesis, and axonogenesis within the structure of the polymer network. As a result, a reparative tissue grew within the porous structure of the gel, composed of glial cells, blood vessels, axons and dendrites, and extracellular biological matrices, such as laminin and/or collagen. Consistent with matrix deposition and tissue formation within the porous structure of the PHPMA hydrogels, there were measurable changes in the diffusion characteristics of the polymers. Extracellular space volume decreased and tortuosity increased within implanted hydrogels, attaining values similar to that seen in developing neural tissue. PHPMA polymer hydrogel matrices thus show neuroinductive and neuroconductive properties. They have the potential to repair tissue defects in the central nervous system by replacing lost tissue and by promoting the formation of a histotypic tissue matrix that facilitates and supports regenerative axonal growth. () ()

Animals↗
PubMed1997

Immunohistochemical study of calpain-mediated breakdown products to alpha-spectrin following controlled cortical impact injury in the rat.

This study examined the effect of unilateral controlled cortical impact on the appearance of calpain-mediated alpha-spectrin breakdown products (BDPs) in the rat cortex and hippocampus at various times following injury. Coronal sections were taken from animals at 15 min, 1 h, 3 h, 6 h, and 24 h after injury and immunolabeled with an antibody that recognizes calpain-mediated BDPs to alpha-spectrin (Roberts-Lewis et al., 1994). Sections from a separate group of rats were also taken at the same times and stained with hematoxylin and eosin. Analyses of early time points (15 min, 1 h, 3 h, and 6 h following injury) revealed alpha-spectrin BDPs in structurally intact neuronal soma and dendrites in cortex ipsilateral to site of injury that was not present in tissue from sham-injured control rats. By 24 h after injury labeling was not restricted to clearly defined neuronal structures in ipsilateral cortex, although there was an increased extent of diffuse labeling. BDPs to alpha-spectrin in axons were not detected until 24 h after injury, in contrast to the more rapid accumulation of BDPs observed in neuronal soma and dendrites. The presence of BDPs to alpha-spectrin in the cortex at the site of impact, and in the rostral and contralateral cortex, coincided with morphopathology detected by hematoxylin and eosin. alpha-Spectrin BDPs were also observed in the hippocampus ipsilateral to the injury in the absence of overt cell death. This investigation provides further evidence that calpain is activated after controlled cortical impact and could contribute to necrosis at the site of injury. The appearance of calpain-mediated BDPs at sites distal to the contusion site and in the hippocampus also suggests that calpain activation may precede and/or occur in the absence of extensive morphopathological changes.

Animals↗
PubMed2003

An image-based finite difference model for simulating restricted diffusion.

Water diffusion in tissues is generally restricted and often anisotropic. Neural tissue is of particular interest, since it is well known that injury alters diffusion in a characteristic manner. Both Monte Carlo simulations and approximate analytical models have previously been reported in attempts to predict water diffusion behavior in the central nervous system. These methods have relied on axonal models, which assume simple geometries (e.g., ellipsoids, cylinders, and square prisms) and ignore the thickness of the myelin sheath. The current work describes a method for generating models using synthetic images. The computations are based on a 3D finite difference (FD) approximation of the diffusion equation. The method was validated with known analytic solutions for diffusion in a cylindrical pore and in a hexagonal array of cylinders. Therefore, it is envisioned that, by exploiting histologic images of neuronal tissues as input model, current method allows investigating the water diffusion behavior inside biological tissues and potentially assessing the status of neural injury and regeneration.

Axons↗
PubMed2003

Co-localization of sodium channel Nav1.6 and the sodium-calcium exchanger at sites of axonal injury in the spinal cord in EAE.

Axonal degeneration contributes to the development of non-remitting neurological deficits and disability in multiple sclerosis, but the molecular mechanisms that underlie axonal loss in multiple sclerosis are not clearly understood. Studies of white matter axonal injury have demonstrated that voltage-gated sodium channels can provide a route for sodium influx into axons that triggers reverse operation of the Na(+)/Ca(2+) exchanger (NCX) and subsequent influx of damaging levels of intra-axonal calcium. The molecular identities of the involved sodium channels have, however, not been determined. We have previously demonstrated extensive regions of diffuse expression of Na(v)1.6 and Na(v)1.2 sodium channels along demyelinated axons in experimental allergic encephalomyelitis (EAE). Based on the hypothesis that the co-localization of Na(v)1.6 and NCX along extensive regions of demyelinated axons may predispose these axons to injury, we examined the expression of myelin basic protein, Na(v)1.2, Na(v)1.6, NCX and beta-amyloid precursor protein (beta-APP), a marker of axonal injury, in the spinal cord dorsal columns of mice with EAE. We demonstrate a significant increase in the number of demyelinated axons demonstrating diffuse Na(v)1.6 and Na(v)1.2 sodium channel immunoreactivity in EAE (92.2 +/- 2.1% of beta-APP positive axons were Na(v)1.6-positive). Only 38.0 +/- 2.9% of beta-APP positive axons were Na(v)1.2 positive, and 95% of these co-expressed Na(v)1.6 together with Na(v)1.2. Using triple-labelled fluorescent immunohistochemistry, we demonstrate that 73.5 +/- 4.3% of beta-APP positive axons co-express Na(v)1.6 and NCX, compared with 4.4 +/- 1.0% in beta-APP negative axons. Our results indicate that co-expression of Na(v)1.6 and NCX is associated with axonal injury in the spinal cord in EAE.

Amyloid beta-Protein Precursor↗
PubMed1974

An outflow of acetylcholine from normal and regenerating ventral roots of the cat.

1. An outflow of acetylcholine (ACh) has been measured from cat ventral roots in situ and in vitro, using standard bio-assay techniques. The ACh was collected in chambers, filled with physiological solution containing anticholinesterase, which surrounded the root.2. The outflow fell rapidly at first and then progressively more slowly, taking several hours to fall to a level near the assay threshold. The outflow of ACh resulted from cutting a root or from such conventional manipulations as stretching the root or teasing apart root filaments. The outflow could occur either from the end of a root (following cutting) or from along the length of the root (following stretching or teasing). The outflow was only detected in the presence of an anticholinesterase.3. ACh was resynthesized by roots at a rate which was usually rapid enough to maintain their ACh content at its original level in spite of a considerable ACh outflow. In roots subjected to a minimum of interference their ACh content built up to about twice the initial content after 5-7 hr soaking in eserinized Krebs solution although the total ACh outflow was equivalent to the original ACh content.Roots which were cut or stretched several times within a few hours put out a large amount of ACh and showed a fall in their ACh content below the initial level.4. The time course of sealing of the damaged ends of axons following crushing was assessed by measuring the injury potential for 1-2 hr after crushing at room temperature; in normal roots the half-time for decline of the injury potential was 91 +/- 10 min. This was slower than the rate of decline of the ACh outflow.5. An explanation for the observed outflow of ACh is discussed in terms of diffusion of ACh and sealing of axon ends. It is concluded that much of the ACh in normal ventral root axons is present in a readily diffusible form.6. Similar experiments on roots regenerating 9-10 days after crushing showed that the ACh outflow from regenerating roots was much smaller than from normal axons, although their ACh content was similar. This could have been due to more rapid sealing of the cut regenerating axons since the half-time for the decline of the injury potential following crushing of the regenerating axons was less than half that in control roots. The alternative possibility is considered that a high proportion of the ACh might be much less diffusible than in normal axons.7. The subcellular distribution of ACh in normal and regenerating peripheral axons is discussed.

Acetylcholine↗
PubMed1997

Calpain activity promotes the sealing of severed giant axons.

A barrier (seal) must form at the cut ends of a severed axon if a neuron is to survive and eventually regenerate. Following severance of crayfish medial giant axons in physiological saline, vesicles accumulate at the cut end and form a barrier (seal) to ion and dye diffusion. In contrast, squid giant axons do not seal, even though injury-induced vesicles form after axonal transection and accumulate at cut axonal ends. Neither axon seals in Ca2+-free salines. The addition of calpain to the bath saline induces the sealing of squid giant axons, whereas the addition of inhibitors of calpain activity inhibits the sealing of crayfish medial giant axons. These complementary effects involving calpain in two different axons suggest that endogenous calpain activity promotes plasmalemmal repair by vesicles or other membranes which form a plug or a continuous membrane barrier to seal cut axonal ends.

Animals↗