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

Komoltsev, Ilia; Синкин, М. В.; Volkova, A. A.; Смирнова, Е. А.; Новикова, М. Р.; Kordonskaya, O. O.; Talypov, Aleksandr; Guekht, Alla; Krylov, Vladimir; Gulyaeva, N. V.

doi:10.3390/brainsci10090570

Cited by 12 publications

(5 citation statements)

References 58 publications

(65 reference statements)

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“…These findings suggest that CI-1040 could be used acutely to prevent or reduce cytoarchitectonic changes in other spike-associated pathologies, such as those that occur after a TBI. 64 , 65 …”

Section: Discussionmentioning

confidence: 99%

Spike-induced cytoarchitectonic changes in epileptic human cortex are reduced via MAP2K inhibition

Smith,

Mir,

Butler

et al. 2024

Brain Communications

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Interictal spikes are electroencephalographic discharges that occur at or near brain regions that produce epileptic seizures. While their role in generating seizures is not well understood, spikes have profound effects on cognition and behavior, depending on where and when they occur. We previously demonstrated that spiking areas of human neocortex show sustained MAPK activation in superficial cortical layers I-III and are associated with microlesions in deeper cortical areas characterized by reduced neuronal nuclear protein (NeuN) staining and increased microglial infiltration. Based on these findings, we chose to investigate additional neuronal populations within microlesions, specifically inhibitory interneurons. Additionally, we hypothesized that spiking would be sufficient to induce similar cytoarchitectonic changes within the rat cortex, and that inhibition of MAPK signaling, using a MAP2K inhibitor, would not only inhibit spike formation but also reduce these cytoarchitectonic changes and improve behavioral outcomes. To test these hypotheses, we analyzed tissue samples from 16 patients with intractable epilepsy who required cortical resections. We also utilized a tetanus toxin-induced animal model of interictal spiking, designed to produce spikes without seizures in male Sprague-Dawley rats. Rats were fitted with epidural electrodes, to permit EEG recording for the duration of the study, and automated algorithms were implemented to quantify spikes. After 6 months, animals were sacrificed to assess the effects of chronic spiking on cortical cytoarchitecture. Here, we show that microlesions may promote excitability due to a significant reduction of inhibitory neurons that could be responsible for promoting interictal spikes in superficial layers. Similarly, we found that the induction of epileptic spikes in the rat model produced analogous changes, including reduced NeuN, calbindin, and parvalbumin-positive neurons and increased microglia, suggesting that spikes are sufficient for inducing these cytoarchitectonic changes in humans. Finally, we implicated MAPK signaling as a driving force producing these pathological changes. Using CI-1040 to inhibit MAP2K, both acutely and after spikes developed, resulted in fewer interictal spikes, reduced microglial activation, and less inhibitory neuron loss. Treated animals had significantly fewer high-amplitude, short-duration spikes, which correlated with improved spatial memory performance on the Barnes maze. Together, our results provide evidence for a cytoarchitectonic pathogenesis underlying epileptic cortex, which can be ameliorated through both early and delayed MAP2K inhibition. These findings highlight the potential role for CI-1040 as a pharmacological treatment that could prevent the development of epileptic activity and reduce cognitive impairment in both patients with epilepsy and those with non-epileptic spike-associated neurobehavioral disorders.

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Section: Discussionmentioning

confidence: 99%

Spike-induced cytoarchitectonic changes in epileptic human cortex are reduced via MAP2K inhibition

Smith,

Mir,

Butler

et al. 2024

Brain Communications

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“…Neuronal loss in the hippocampal DG is accompanied by and correlated with an increase of hippocampal neurons excitability after perforant path stimulation one week after TBI [ 34 ]. In our previous study, we reported that spontaneously generated high-amplitude epileptiform hippocampal spike occurrence correlates with increase of microglial cell density and neuronal loss in the hippocampal DG 7 days after TBI [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

Neuroinflammation and Neuronal Loss in the Hippocampus Are Associated with Immediate Posttraumatic Seizures and Corticosterone Elevation in Rats

Komoltsev

Frankevich

Shirobokova

et al. 2021

IJMS

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Hippocampal damage after traumatic brain injury (TBI) is associated with late posttraumatic conditions, such as depression, cognitive decline and epilepsy. Mechanisms of selective hippocampal damage after TBI are not well understood. In this study, using rat TBI model (lateral fluid percussion cortical injury), we assessed potential association of immediate posttraumatic seizures and changes in corticosterone (CS) levels with neuroinflammation and neuronal cell loss in the hippocampus. Indices of distant hippocampal damage (neurodegeneration and neuroinflammation) were assessed using histological analysis (Nissl staining, Iba-1 immunohistochemical staining) and ELISA (IL-1β and CS) 1, 3, 7 and 14 days after TBI or sham operation in male Wistar rats (n = 146). IL-1β was elevated only in the ipsilateral hippocampus on day 1 after trauma. CS peak was detected on day 3 in blood, the ipsilateral and contralateral hippocampus. Neuronal cell loss in the hippocampus was demonstrated bilaterally; in the ipsilateral hippocampus it started earlier than in the contralateral. Microglial activation was evident in the hippocampus bilaterally on day 7 after TBI. The duration of immediate seizures correlated with CS elevation, levels of IL-1β and neuronal loss in the hippocampus. The data suggest potential association of immediate post-traumatic seizures with CS-dependent neuroinflammation-mediated distant hippocampal damage.

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“…Based on the corresponding clinical literature highlighting e.g. Komoltsev et al (2020), Kural et al (2020) spike salience is another important parameter used by human experts when detecting epileptogenic activity. The extent to which a spike stands out of the local background can be easily computed, for example, as the ratio of the absolute peak value, h p (t) = c 4 (t), to the standard deviation of the background activity within the time window preceding and succeeding the considered spike time interval.…”

Section: Verbal Description Of a Criterion Expression In Terms Of Spl...mentioning

confidence: 99%

Fast parametric curve matching (FPCM) for automatic spike detection

et al. 2022

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Epilepsy is a widely spread neurological disease, whose treatment often requires resection of the pathological cortical tissue. Interictal spike analysis observed in the non-invasively collected EEG or MEG data offers a way to localize epileptogenic cortical structures for surgery planning purposes. While a plethora of automatic spike detection techniques have been developed each with its own assumptions and limitations, non of them is ideal and the best results are achieved when the output of several automatic spike detectors are combined. This is especially true in the low signal-to-noise ratio conditions. To this end we propose a novel biomimetic approach for automatic spike detection based on a constrained mixed spline machinery that we dub as fast parametric curve matching (FPCM). Using the peak-wave shape parametrization, the constrained parametric morphological model is constructed and convolved with the observed multichannel data to very efficiently determine mixed spline parameters corresponding to each time-point in the dataset. Then the logical predicates that directly map to the expected interictal event morphology allow us to accomplish the spike detection task. The results of simulations mimicking typical low SNR scenario show the robustness and high ROC AUC values of the FPCM method as compared to the spike detection performed by the means of more conventional approaches such as wavelet decomposition, template matching or simple amplitude thresholding. Applied to the real MEG and EEG data from the human patients and to ECoG data from the rat, the FPCM technique demonstrates reliable detection of the interictal events and localization of epileptogenic zones concordant with independent conclusions made by the epileptologist. Since the FPCM is computationally light, tolerant to high amplitude artifacts and flexible to accommodate verbalized descriptions of the arbitrary target morphology, it may complement the existing arsenal of means for analysis of noisy interictal datasets.

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

Cited by 12 publications

References 58 publications

Spike-induced cytoarchitectonic changes in epileptic human cortex are reduced via MAP2K inhibition

Spike-induced cytoarchitectonic changes in epileptic human cortex are reduced via MAP2K inhibition

Neuroinflammation and Neuronal Loss in the Hippocampus Are Associated with Immediate Posttraumatic Seizures and Corticosterone Elevation in Rats

Fast parametric curve matching (FPCM) for automatic spike detection

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