Pathologic electrographic changes after experimental traumatic brain injury

Abstract

Objective: To investigate possible electroencephalography (EEG) correlates of epileptogenesis after traumatic brain injury (TBI) using the fluid percussion model.

Methods: Experiments were conducted on adult 2- to 4-month-old male Sprague-Dawley rats. Two groups of animals were studied: (1) the TBI group with depth and screw electrodes implanted immediately after the fluid percussion injury (FPI) procedure, and (2) a naive age-matched control group with the same electrode implantation montage. Pairs of tungsten microelectrodes (50 μm outer diameter) and screw electrodes were implanted in neocortex inside the TBI core, areas adjacent to TBI, and remote areas. EEG activity, recorded on the day of FPI, and continuously for 2 weeks, was analyzed for possible electrographic biomarkers of epileptogenesis. Video-EEG monitoring was also performed continuously in the TBI group to capture electrographic and behavioral seizures until the caps came off (28-189 days), and for 1 week, at 2, 3, and 6 months of age, in the control group.

Results: Pathologic high-frequency oscillations (pHFOs) with a central frequency between 100 and 600 Hz, were recorded from microelectrodes, beginning during the first two post-FPI weeks, in 7 of 12 animals in the TBI group (58%) and never in the controls. pHFOs only occurred in cortical areas within or adjacent to the TBI core. These were associated with synchronous multiunit discharges and popSpikes, duration 15-40 msec. Repetitive pHFOs and EEG spikes (rHFOSs) formed paroxysmal activity, with a unique arcuate pattern, in the frequency band 10-16 Hz in the same areas as isolated pHFOs, and these events were also recorded by screw electrodes. Although loss of caps prevented long-term recordings from all rats, pHFOs and rHFOSs occurred during the first 2 weeks in all four animals that later developed seizures, and none of the rats without these events developed late seizures.

Significance: pHFOs, similar to those associated with epileptogenesis in the status rat model of epilepsy, may also reflect epileptogenesis after FPI. rHFOSs could be noninvasive biomarkers of epileptogenesis.

Keywords: Electroencephalography; Epileptogenesis; Pathologic high frequency oscillations; Repetitive HFOs and spikes; Seizure; Spindles; Traumatic brain injury.

Figure 1

(A) Pathologic high frequency oscillations (pHFOs) in the neocortex 3 days after FPI. (A) Five individual examples (black lines) and time frequency plots (below). (Right) time frequency plots of 45 pHFOs. (B) An example of pHFOs associated with a local slowwave. (C) HFO (dashed box) followed by rHFOS (bracket) containing popSpikes. Epilepsia © ILAE

Figure 2

(A) Local generation of pHFOs in the area adjacent to the traumatic brain injury on the 10th day after the injury. pHFOs appeared in the perilesional area anterior to the TBI core, but not in other areas of neocortex. Black lines are raw data recorded within a frequency band of 0.1 Hz–10 kHz, and red band pass (100–600 Hz). (B) Power spectrum density graph illustrating that the area generating pHFOs has higher power of electrical activity in the frequency band 60–300 Hz. (C) Examples of pHFOs, which have different patterns of evolution: descending, ascending, and mixed. LFC and RFC, left and right frontal cortex; ATBI, LTBI, and PTBI, areas adjacent to the TBI core from anterior and lateral and posterior sites sites; TBI, center of traumatic brain injury; CTBI, area homotopical to the TBI in the contralateral hemisphere. Epilepsia © ILAE

Figure 3

An example of pHFO propagation in rat TBI-4. The pHFO is generated in the TBI area and propagates to adjacent areas but not distant areas. Dashed boxes outline the channels involved in the generation of pHFO. Black lines are raw data recorded within a frequency band 0.1 Hz–10 kHz, blue and red: band pass filtered at 100–600 Hz. Calibration scale is 0.5 mV for raw records, 0.1 mV for band pass filtered. Dashed boxes outline the number of recording sites where pHFOs were detected. Arrows indicate propagation of pHFOs. LFC, left frontal cortex; LTBI, neocortex lateral to the TBI core; ATBI, neocortex anterior to the TBI core; TBI, TBI core; PTBI, neocortex posterior to the TBI core; CTBI, neocortex in the homotopical point in the contralateral hemisphere. Epilepsia © ILAE

Figure 4

(A) An example of rHFOS recorded 10 days after TBI in the area anterior to TBI (ATBI) and normal spindle that coincidently occurred in the area contralateral to the TBI core (CTBI). (B) Fifty-five superimposed single waves from normal spindles (black) and rHFOSs. White and red thick lines are normalized averages of correspondingly normal and pathologic events. Epilepsia © ILAE

Figure 5

(A) rHFOS recorded with a band pass 0.1 Hz–10 kHz. A1, black line: an expanded popSpike indicated by the dashed box. Blue line high passed (500 Hz) multiunit activity from the same electrode, indicating increased neuronal discharges during the spike of the rHFOS. (B) Red line: an average of 88 rHFOSs; black: peri-event histogram of multiunit activity triggered by the peak of the largest spike of the rHFOS. Epilepsia © ILAE

Figure 6

(A) An example of spontaneous seizure on day 2 after TBI. (B) An example of seizure 167 days after FPI. LFC, and RFC: left and right frontal cortex; TBI, TBI core, place of application of FPI; ATBI, LTBI, PTBI and CTBI, correspond respectfully to areas of neocortex anterior, lateral, posterior, and contralateral to the TBI core. Epilepsia © ILAE