Electrocorticographic Dynamics as a Novel Biomarker in Five Models of Epileptogenesis.
Postinjury epilepsy (PIE) is a devastating sequela of various brain insults. While recent studies offer novel insights into the mechanisms underlying epileptogenesis and discover potential preventive treatments, the lack of PIE biomarkers hinders the clinical implementation of such treatments. Here we explored the biomarker potential of different electrographic features in five models of PIE. Electrocorticographic or intrahippocampal recordings of epileptogenesis (from the insult to the first spontaneous seizure) from two laboratories were analyzed in three mouse and two rat PIE models. Time, frequency, and fractal and nonlinear properties of the signals were examined, in addition to the daily rate of epileptiform spikes, the relative power of five frequency bands (theta, alpha, beta, low gamma, and high gamma) and the dynamics of these features over time. During the latent pre-seizure period, epileptiform spikes were more frequent in epileptic compared with nonepileptic rodents; however, this feature showed limited predictive power due to high inter- and intra-animal variability. While nondynamic rhythmic representation failed to predict epilepsy, the dynamics of the theta band were found to predict PIE with a sensitivity and specificity of >90%. Moreover, theta dynamics were found to be inversely correlated with the latency period (and thus predict the onset of seizures) and with the power change of the high-gamma rhythm. In addition, changes in theta band power during epileptogenesis were associated with altered locomotor activity and distorted circadian rhythm. These results suggest that changes in theta band during the epileptogenic period may serve as a diagnostic biomarker for epileptogenesis, able to predict the future onset of spontaneous seizures.SIGNIFICANCE STATEMENTPostinjury epilepsy is an unpreventable and devastating disorder that develops following brain injuries, such as traumatic brain injury and stroke, and is often associated with neuropsychiatric comorbidities. As PIE affects as many as 20% of brain-injured patients, reliable biomarkers are imperative before any preclinical therapeutics can find clinical translation. We demonstrate the capacity to predict the epileptic outcome in five different models of PIE, highlighting theta rhythm dynamics as a promising biomarker for epilepsy. Our findings prompt the exploration of theta dynamics (using repeated electroencephalographic recordings) as an epilepsy biomarker in brain injury patients.
Departments of Physiology and Cell Biology, Cognitive and Brain Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
Dan Z
DZ
Milikovsky
Departments of Physiology and Cell Biology, Cognitive and Brain Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
Itai
I
Weissberg
Departments of Physiology and Cell Biology, Cognitive and Brain Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.|Department of Medical Neuroscience, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.
Lyn
L
Kamintsky
Institute of Neurophysiology, Charité-University of Medicine Berlin, 10117 Berlin, Germany, and.
Kristina
K
Lippmann
Departments of Physiology and Cell Biology, Cognitive and Brain Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
Osnat
0000-0002-7225-8225
O
Schefenbauer
Department of Neuroscience, Experimental Neurology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", 20156 Milan, Italy.
Federica
F
Frigerio
Department of Neuroscience, Experimental Neurology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", 20156 Milan, Italy.
Massimo
0000-0002-5477-2263
M
Rizzi
Departments of Physiology and Cell Biology, Cognitive and Brain Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
Liron
L
Sheintuch
Departments of Physiology and Cell Biology, Cognitive and Brain Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
Daniel
0000-0001-5500-4007
D
Zelig
Departments of Physiology and Cell Biology, Cognitive and Brain Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
Jonathan
0000-0003-4866-0828
J
Ofer
Department of Neuroscience, Experimental Neurology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", 20156 Milan, Italy.
Annamaria
A
Vezzani
Departments of Physiology and Cell Biology, Cognitive and Brain Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel, alon.friedman@dal.ca.|Department of Medical Neuroscience, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.
Alon
A
Friedman
D000818:Animals; D015415:Biomarkers; D001930:Brain Injuries / Q000150:complications; D002940:Circadian Rhythm; D003292:Convulsants / Q000008:administration & dosage; D000069280:Electrocorticography; D004827:Epilepsy / Q000139:chemically induced / Q000503:physiopathology*; D006624:Hippocampus / Q000503:physiopathology; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008959:Models, Neurological; D009043:Motor Activity; D051381:Rats; D012640:Seizures / Q000503:physiopathology
D015415:Biomarkers; D003292:Convulsants
EEG; biomarker; epilepsy; epileptogenesis; stroke; traumatic brain injury