Tissue-level thresholds for axonal damage in an experimental model of central nervous system white matter injury

In vivo, tissue-level, mechanical thresholds for axonal injury were determi ned by comparing morphological injury and electrophysiological impairment t o estimated tissue strain in an in vivo model of axonal injury. Axonal inju ry was produced by-dynamically stretching the right optic nerve of an adult male guinea pig to one of seven levels of ocular displacement (N-level=10; N-total=70). Morphological injury was detected with neurofilament immunohi stochemical staining (NF68, SM132). Simultaneously, functional injury was d etermined by the magnitude of the latency shift of the N-35 peak of the the visual evoked potentials (VEPs) recorded before and after stretch. A compa nion set of in situ experiments (N-level=5) was used to determine the empir ical relationship between the applied ocular displacement and the magnitude of optic nerve stretch. Logistic regression analysis, combined with sensit ivity and specificity measures and receiver operating characteristic (ROC) curves were used to predict strain thresholds for axonal injury. From this analysis, we determined three Lagrangian strain-based thresholds for morpho logical damage to white matter The liberal threshold, intended to minimize the detection of false positives, was a strain of 0.34, and the conservativ e threshold strain that minimized the false negative rate was 0.14. The opt imal threshold strain criterion that balanced the specificity and sensitivi ty measures was 0.21. Similar comparisons for electrophysiological impairme nt produced liberal, conservative; and optimal strain thresholds of 0.28 0. 13, and 0.18, respectively. With these threshold data, it is now possible t o predict more accurately the conditions that cause axonal injury in human white matter.