A Translational Study on Acute Traumatic Brain Injury: High Incidence of Epileptiform Activity on Human and Rat Electrocorticograms and Histological Correlates in Rats

Abstract

Background: In humans, early pathological activity on invasive electrocorticograms (ECoGs) and its putative association with pathomorphology in the early period of traumatic brain injury (TBI) remains obscure.

Methods: We assessed pathological activity on scalp electroencephalograms (EEGs) and ECoGs in patients with acute TBI, early electrophysiological changes after lateral fluid percussion brain injury (FPI), and electrophysiological correlates of hippocampal damage (microgliosis and neuronal loss), a week after TBI in rats.

Results: Epileptiform activity on ECoGs was evident in 86% of patients during the acute period of TBI, ECoGs being more sensitive to epileptiform and periodic discharges. A "brush-like" ECoG pattern superimposed over rhythmic delta activity and periodic discharge was described for the first time in acute TBI. In rats, FPI increased high-amplitude spike incidence in the neocortex and, most expressed, in the ipsilateral hippocampus, induced hippocampal microgliosis and neuronal loss, ipsilateral dentate gyrus being most vulnerable, a week after TBI. Epileptiform spike incidence correlated with microglial cell density and neuronal loss in the ipsilateral hippocampus.

Conclusion: Epileptiform activity is frequent in the acute period of TBI period and is associated with distant hippocampal damage on a microscopic level. This damage is probably involved in late consequences of TBI. The FPI model is suitable for exploring pathogenetic mechanisms of post-traumatic disorders.

Keywords: electrocorticograms; epileptiform discharges; hippocampus; local field potentials; microglia; neocortex; neurodegeneration; post-traumatic epilepsy; traumatic brain injury.

Figure 1

Study design flowchart. The study includes clinical and experimental parts. Direct translational links between them are provided through clinical and behavioral data concerning the severity of trauma and electrical activity recorded from the surface of the cerebral cortex (electrocorticograms (ECoGs)). Sz, immediate seizures.

Figure 2

Interictal spikes in a patient 1 day after TBI. High-amplitude spikes are evident on ECoGs (L3–L4 electrodes on the strip) but not in scalp EEG. A typical example, patient #7.

Figure 3

Distinctions in the pathological activities detected in scalp EEGs and ECoGs. The analysis of discordance between scalp EEG (sEEGs) and ECoGs was performed. Each dot denotes a patient with (or without) different pathological activity (left to right: ED, epileptiform discharge; RDA, rhythmic delta activity; PD, periodic discharges; ES, electrographic seizures). Concordance or discordance between sEEG and ECoG is shown on different lines. A discordance was identified if the activity was present either on sEEG or ECoG, or if differences in ED index changes were significant (for ED). The concordance was stated if the activity was presented or absent in both scalp and invasive electrodes. The ECoG was more sensitive with respect to ED and PD, and, in some patient, RDA and ES could be detected only with invasive electrodes, n = 21.

Figure 4

(A) Periodic discharges with the “brushes” on day 3 after TBI in patient #9. Periodic discharges with frequency 0.5 (complexes/sec) accompanied by fast (30–33 Hz) activity are evident on invasive ECoG (electrode L4); (B) The brushes from L4 electrodes; (C) Midline shift on CT correlates with subdural hematoma (SDH) volume (p < 0.005), the brushes appear in patients with low grade midline shift and SDH volume (p < 0.05, see text), n = 21.

Figure 5

High-amplitude spikes before and after TBI in rats. (A) High-amplitude spikes 7 days after TBI. The spikes are evident on ECoG (LF, RF), but maximum amplitude was recorded in the ipsilateral hippocampal DG (HLFP); (B) Spike occurrence increased after TBI as compared with either background or sham-operated animals; (C) Spike occurrence in individual animals before and after TBI. n = 7 (TBI), n = 5 (Sham). * p < 0.05, Sham vs. TBI, Mann–Whitney test; # p < 0.05, background vs. craniotomy, Wilcoxon test; LF, left frontal cortex; RF, right frontal cortex; LO, left occipital cortex; RO, right occipital cortex; LDG, left dorsal hippocampus; RDG, right dorsal hippocampus; Acc, accelerometer.

Figure 6

Histological alterations in the hippocampus 7 days after TBI. (A) Microglial activation in the dentate gyrus (DG) as compared with the contralateral hemisphere; (B) Iba-staining; (C) Loss of neurons in the polymorph layer of the DG as compared with the contralateral hemisphere; (D) Nissl staining.

Figure 7

Distant damage to the hippocampus and spike occurrence. (A) Microglial cell density in the hippocampus (Iba-staining); (B) Neuronal cell density in the hippocampus (Nissl staining); (C) Neuronal cell loss correlates with microglial cell density in the ipsilateral dentate gyrus (DG) (red dots, rats with TBI and black dots, sham-operated animals, p = 0.001); (D) Microglial cell density in the hippocampal CA1 and CA3 fields and the DG. (E) Correlation between microglial cell density and spike occurrence on day 7 after TBI (p = 0.001); (F) Neuronal cell density in the hippocampal CA1 and CA3 fields, and the DG; (G) Correlation between neuronal cell density and spike occurrence on day 7 after TBI (p = 0.009). n = 7 (TBI) and n = 5 (Sham). * p < 0.05, Sham vs. TBI, Mann–Whitney test; # p < 0.05, ipsilateral vs. contralateral hemisphere, Wilcoxon test.

Figure 8

Putative interconnections among EDs and key mechanisms of remote hippocampal damage. Understanding the mechanisms of distant hippocampal damage is essential for the development of pathogenetically justified new treatment strategies to predict and prevent long-term consequences of TBI.