Tissue-Level Thresholds for Axonal Damage in an Experimental Model of Central Nervous System White Matter Injury

[+] Author and Article Information
Allison C. Bain, David F. Meaney

Department of Bioengineering, 120 Hayden Hall, University of Pennsylvania, Philadelphia, PA 19104-6392

J Biomech Eng 122(6), 615-622 (Jul 24, 2000) (8 pages) doi:10.1115/1.1324667 History: Received November 05, 1998; Revised July 24, 2000
Copyright © 2000 by ASME
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Schematic of the guinea pig optic nerve stretch model. Elongation is triggered by a solenoid and is measured by a linear variable differential transformer (LVDT). The magnitude of the displacement is controlled by a micromanipulator. The force experienced by the nerve is measured by a strain gauge force transducer aligned in series with the optic nerve. The force transducer is also used in conjunction with a digital multimeter to apply a preload to the optic nerve prior to the experiment.
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(A) Schematic of the in situ experiments showing the placement of markers along the length of the nerve, the fixed reference point on the base of the skull, and the end point that is anatomically fixed to the base of the skull. (B) Schematic showing the gage length of the optic nerve (lin), and the measured displacement of the optic nerve after stretch. (C) Schematic of the right optic nerve demonstrating the three areas—retinal, middle, and chiasmatic—used to evaluate the strain uniformity in the nerve.
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Representation of the conservative (A) and liberal (B) thresholds calculated for morphological and functional injury. Below the conservative threshold, no nerves will be injured; therefore, there are no false negatives and the threshold achieves a sensitivity of 1.0. Above the liberal threshold, all nerves will exhibit injury and therefore there are no false positives, yielding a specificity of 1.0.
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Results of the in situ displacement-stretch experiments. The mean measured nerve displacements (dark circles) were plotted versus the applied ocular displacement. Linear regression was used to develop a relationship (R=0.99) between the applied displacement and resulting net displacement of the optic nerve; predicted nerve displacements fell within one standard deviation of measured for all but one level of ocular displacement.
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(A,B) Longitudinal optic nerve sections injured at 7 mm and stained with NF68, a marker for axonal pathology. Injured nerves exhibited clusters of retraction bulbs (black arrows) and axonal swellings (white arrows) near the retina and 1–2 mm from the chiasm. (C) Longitudinal section injured at 8 mm and stained with SMI32. At higher injury levels, degeneration fragments were observed. (D) Longitudinal section of an uninjured nerve stained with SMI32. Bar: (A) 40 μm, (B) 20 μm, (C,D) 40 μm.
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Logit analysis of morphological injury data. Nerves were labeled either injured (probability=1) or uninjured (probability=0) based on the presence or absence of morphological injury. Logit parameters were estimated with very high significance (likelihood ratio test, chi-squared, p<0.0001). The results of this analysis were used to define a conservative threshold (E11=0.14, 95 percent confidence limits (CL)=0.04, 0.18), a liberal threshold (E11=0.34, CL=0.16, 0.24), and the best, or optimal threshold (E11=0.21, CL=0.30, 0.42) for morphological injury.




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