Dynamics of sensorimotor cortex activation during absence and myoclonic seizures in a mouse model of juvenile myoclonic epilepsy

Abstract

Objective Generalized epilepsy syndromes often confer multiple types of seizures, but it is not known if these seizures activate separate or overlapping brain networks. Recently, we reported that mice with a juvenile myoclonic epilepsy mutation [Gabra1(A322D)] exhibited both absence and myoclonic generalized seizures. Here, we determined the time course of sensorimotor cortex activation and the spatial distribution of spike voltage during these two seizures. Methods We implanted Gabra1+/A322D mice with multiple EEG electrodes over bilateral somatosensory cortex barrel fields (S1) and anterior (aM1) and posterior (pM1) motor cortices and recorded absence seizures / spike-wave discharges (SWDs) and myoclonic seizures. We used nonlinear-association analyses and cross-correlation calculations to determine the strength, leading regions, and time delays of cortical coupling from the preictal to ictal states and within the spike and interspike periods. The distribution of spike voltage was also measured in SWDs and myoclonic seizures. Results EEG connectivity among all electrode pairs increased at the onset of both SWDs and myoclonic seizures. Surprisingly, during spikes of both seizure types, S1 led M1 with similar delay times. Myoclonic seizure spikes started more focally than SWD spikes with a significant majority appearing first only in S1 electrodes while a substantial fraction of SWD spikes were detected first in S1 and at least one M1 electrode. The absolute voltage of myoclonic seizure spikes was significantly higher than that of SWD spikes and there was a greater relative voltage over M1 during myoclonic seizure spikes than in the first one to two SWD spikes. Significance The leading sites in S1 and similar delay times suggest both SWDs and myoclonic seizures activate overlapping networks in sensorimotor cortex and thus, therapeutically targeting this network could potentially treat both seizures. Spike focality, absolute voltage and voltage distribution provide insight into neuronal activation during these two seizure types.

Cortical activation in generalized seizures

“…Based on the results of the prior studies of rodent SWDs, it was surprising that the area exhibiting the largest t 0 voltage and pre‐spike activity was in the motor, and not somatosensory cortex. It should be emphasized that increased voltage/spectral density does not necessarily imply a leading role of that region.…”

“…All protocols were approved by the Vanderbilt University Institutional Animal Care and Use Committee. We previously described Gabra1 +/A322D mouse creation and that, unlike their wild‐type littermates, Gabra1 +/− and Gabra1 +/A322D mice have frequent ethosuximide‐sensitive SWDs with behavior arrest and electromyography (EMG) attenuation and MS with generalized spikes . We used six adult (mean age ± standard deviation [SD] 21 ± 3 weeks, range 19‐26 weeks) Gabra1 +/A322 D mice of both sexes.…”

“…We previously demonstrated that Gabra1 +/− and Gabra1 +/A322D mice had substantially more‐frequent epileptiform events than their wild‐type littermates, and we described the EEG and behavioral properties of SWDs (characteristic 6‐8 Hz complexes with behavior arrest) and MS (spikes with head or body jerks) . The HdEEG record was visually inspected to identify these epileptiform discharges (Figure C).…”

“…We previously described Gabra1 +/A322D mouse creation 20 and that, unlike their wild-type littermates, Gabra1 +/− and Gabra1 +/A322D mice have frequent ethosuximide-sensitive SWDs with behavior arrest and electromyography (EMG) attenuation and MS with generalized spikes. 20,21 We used six adult (mean age ± standard deviation [SD] 21 ± 3 weeks, range 19-26 weeks) Gabra1 +/A322D mice of both sexes. The mice were housed in a facility with a temperature-and humidity-controlled environment and a 12-hour lights-on/lights-off cycle and were provided unlimited access to food and water.…”

Abnormal Brain Network in Epilepsy and Associated Comorbidites

“…Functional network abnormalities and underlying mechanisms of JME were investigated with the development of functional connectivity techniques. A study of animal model of myoclonic seizures [48] showed that EEG connectivity among all electrode pairs increased at the onset of seizures. In an EEG study on spike-and-wave discharge (SWD) in JME [49] used graph theoretical measures, including nodal degree, characteristic path length, clustering coefficient, and smallworld index to evaluate the characteristics of epileptic networks in JME.…”