Acute thalamic damage as a prognostic biomarker for post‐traumatic epileptogenesis

Abstract

Objective To identify magnetic resonance imaging (MRI) biomarkers for post‐traumatic epilepsy. Methods The EPITARGET (Targets and biomarkers for antiepileptogenesis, epitarget.eu) animal cohort completing T2 relaxation and diffusion tensor MRI follow‐up and 1‐month‐long video‐electroencephalography monitoring included 98 male Sprague‐Dawley rats with traumatic brain injury and 18 controls. T2 imaging was performed on day (D) 2, D7, and D21 and diffusion tensor imaging (DTI) on D7 and D21 using a 7‐Tesla Bruker PharmaScan MRI scanner. The mean and standard deviation (SD) of the T2 relaxation rate, multiple diffusivity measures, and diffusion anisotropy at each time‐point within the ventroposterolateral and ventroposteromedial thalamus were used as predictor variables in multi‐variable logistic regression models to distinguish rats with and without epilepsy. Results Twenty‐nine percent (28/98) of the rats with traumatic brain injury (TBI) developed epilepsy. The best‐performing logistic regression model utilized the D2 and D7 T2 relaxation time as well as the D7 diffusion tensor data. The model distinguished rats with and without epilepsy (Bonferroni‐corrected p‐value < .001) with a cross‐validated concordance statistic of 0.74 (95% confidence interval [CI] 0.60–0.84). In a cross‐validated classification test, the model exhibited 54% sensitivity and 91% specificity, enriching the epilepsy rate within the study population from the expected 29% to 71%. A model using the D2 T2 data only resulted in a 73% enriched epilepsy rate (regression p‐value .007, cross‐validated concordance 0.70, 95% CI 0.56–0.80, sensitivity 29%, specificity 96%). Significance An MRI parameter set reporting on acute and subacute neuropathologic changes common to experimental and human TBI presents a diagnostic biomarker for post‐traumatic epileptogenesis. Significant enrichment of the study population was achieved even when using a single time‐point measurement, producing an expected epilepsy rate of 73%.

Hippocampal position and orientation as prognostic biomarkers for posttraumatic epileptogenesis: An experimental study in a rat lateral fluid percussion model

“…Our present findings agree with previous studies showing that hippocampal changes assessed at 6–9 months after TBI differentiate between epileptogenic and nonepileptogenic animals, even though no statistics for differentiation accuracy were provided by earlier reports 10,19,20 . Interestingly, in the EPITARGET cohort analyzed here, we recently showed that thalamic diffusion changes differentiated epileptogenic from nonepileptogenic animals already during the first postinjury weeks 38 . Instead, the severity of cortical damage or its progression were without prognostic value 26 .…”

“…10,19,20 Interestingly, in the EPITARGET cohort analyzed here, we recently showed that thalamic diffusion changes differentiated epileptogenic from nonepileptogenic animals already during the first postinjury weeks. 38 Instead, the severity of cortical damage or its progression were without prognostic value. 26 These data suggest that whole-brain multimodal MRI analysis could prove highly valuable in the study of epileptogenesis and its biomarkers.…”

Secondary thalamic neuroinflammation after focal cortical stroke and traumatic injury mirrors corticothalamic functional connectivity

“…Despite being insulated from the primary site of cortical injury, the ipsilateral thalamus exhibits intensifying secondary neuroinflammation even while the cortical inflammatory response associated with the primary injury abates. This phenomenon has been observed in both rodent models and human patients and has been associated with secondary thalamic neurodegeneration and neuroinflammation after TBI (Holden et al., 2021; Manninen et al., 2021; Ramlackhansingh et al., 2011; Scott et al., 2010), and after stroke (Cao et al., 2020; Kuchcinski et al., 2017; Langen et al., 2007; Pappata et al., 2000; Paz et al., 2010; Paz et al., 2013; Weishaupt et al., 2016).…”

“…Indeed, the thalamus has been implicated in a variety of secondary poststroke and TBI impairments in both rodent models and human patients, including cognitive dysfunction, sleep disruption, and sensory‐perceptual errors (Cao et al., 2020; Grossman & Inglese, 2016; Grossman et al., 2012; Kuchcinski et al., 2017; Sandsmark et al., 2017). In particular, while moderate neuroinflammation may serve a neuroprotective function (Fraser et al., 2010), thalamic inflammation after TBI has been associated with sleep‐wake disruptions (Hazra et al., 2014) as well as abnormal sleep spindles and epileptic activity (Manninen et al., 2021; Holden et al., 2021). Moreover, the degree of preservation of thalamic circuitry after cortical ischemia is a predictor of motor performance after TBI in humans (Binkofski et al., 1996).…”

MRI-Guided Electrode Implantation for Chronic Intracerebral Recordings in a Rat Model of Post−Traumatic Epilepsy—Challenges and Gains

“…Like in humans with PTE, progressive brain damage involves epileptogenic regions, including the cerebral cortex and hippocampus [ 7 , 19 , 20 ]. The progression of cortical and hippocampal atrophy and spatial distortion, however, varies significantly between animals over time [ 7 , 21 , 22 , 23 ].…”