MRI biomarkers for post-traumatic epileptogenesis

Abstract

The present study tested a hypothesis that early identification of injury severity with quantitative magnetic resonance imaging (MRI) provides biomarkers for predicting increased seizure susceptibility and epileptogenesis after traumatic brain injury (TBI). TBI was induced by lateral fluid percussion injury (FPI) in adult rats. Quantitative T2, T1ρ, and diffusion were assessed with MRI at 9 days, 23 days, or 2 months post-TBI in the perilesional cortex, thalamus, and hippocampus. Seizure susceptibility was assessed at 12 months after TBI using the pentylenetetrazol seizure-susceptibility test. At 9 and 23 days post-TBI, a change in T1ρ of the perilesional cortex showed the greatest predictive value for increased seizure susceptibility at 12 months post-TBI [area under the curve (AUC), 0.929 and 0.952, respectively; p<0.01]. At 2 months post-TBI, Dav in the thalamus was the best of the biomarkers analyzed (AUC, 0.988; p<0.05). The highest predictive value of all biomarkers was achieved by combining the measurement of Dav in the perilesional cortex and the thalamus at 2 months post-TBI (AUC, 1.000; p<0.01). Our results provide proof-of-concept evidence that clinically relevant MRI biomarkers predict increased seizure susceptibility after experimental TBI.

FIG. 1.

Coronal slice from the center of the brain after lateral fluid-percussion–induced traumatic brain injury (TBI), imaged at 23 days post-TBI. (A) A T2-weighted image is shown. Dashed outlines show the regions of interest: (1) somatosensory cortex (S1); (2) dorsal perilesional cortex; (3) ventral perilesional cortex; and (4) perirhinal cortex (PRh). Scale bar=1 mm. (B) T1ρ, (C) T2, and (D) Dav maps from the same location (slice thickness, 1.5 mm) displaying increased relaxation and diffusion values in the perilesional cortex as well as abnormal values within the thalamus ipsilateral to the injury. (E) Results of the pentylenetetrazol (PTZ) seizure-susceptibility test at 12 months post-TBI. As outcomes, we assessed (1) the number of spikes (left panel) and (2) the number of epileptiform discharges (middle panel) during the first 60 min after PTZ injection, as well as (3) the latency to the first epileptiform spike after PTZ injection (right panel). From these, the number of spikes/60 min was chosen to divide animals into increased (iSS) or unchanged (uSS) seizure-susceptibility groups in the ROC analysis because it showed the lowest variation among control animals. Consequently, rats with a spike number higher than the mean+1 standard deviation in controls (>77 spikes/60 min) were considered as animals with iSS (epileptogenic) and those with <77 spikes/60 min as rats with uSS (nonepileptogenic). The number of spikes and number of epileptiform discharges were higher in the TBI group, as compared to controls (*p<0.05). Color image is available online at www.liebertpub.com/neu

FIG. 2.

Summary of receiver operating characteristic (ROC) for parameters assessed at 9 days, 23 days, or 2 months postinjury, which predicted increased seizure susceptibility (iSS) at 12 months post-TBI (traumatic brain injury). A diagonal line represents 50% probability for correct prognosis. Area under the curve (AUC) and sensitivity at 100% or 90% specificity are shown in Supplementary Table 1 (see online supplementary material at http://www.liebertpub.com).