Circumscribing laser cuts attenuate seizure propagation in a mouse model of focal epilepsy

In partial onset epilepsy, seizures arise focally in the brain and often propagate, causing acute behavior changes, chronic cognitive decline, and increased mortality. Patients frequently become refractory to medical management, leaving neurosurgical resection of the seizure focus as a primary treatment, which can cause neurologic deficits. In the cortex, focal seizures are thought to spread through horizontal connections in layers II/III, suggesting that selectively severing these connections could block seizure propagation while preserving normal columnar circuitry and function. We induced focal neocortical epilepsy in mice and used tightly-focused femtosecond-duration laser pulses to create a sub-surface, open-cylinder cut surrounding the seizure focus and severing cortical layers II-IV. We monitored seizure propagation using electrophysiological recordings at the seizure focus and at distant electrodes for 3-8 months. With laser cuts, only 5% of seizures propagated to the distant electrodes, compared to 85% in control animals. Laser cuts also decreased the number of seizures that were initiated, so that the average number of propagated seizures per day decreased from 42 in control mice to 1.5 with laser cuts. Physiologically, these cuts produced a modest decrease in cortical blood flow that recovered within days and, at one month, left a ~20-μm wide scar with increased gliosis and localized inflammatory cell infiltration but minimal collateral damage. When placed over motor cortex, cuts did not cause notable deficits in a skilled reaching task. Femtosecond laser produced sub-surface cuts hold promise as a novel neurosurgical approach for intractable focal cortical epilepsy, as might develop following traumatic brain injury.

Lateralized phenotypic differences in females in the intrahippocampal kainic acid mouse model of temporal lobe epilepsy

Clinical evidence indicates that patients with temporal lobe epilepsy (TLE) often show differential outcomes of comorbid conditions dependent on the lateralization of the seizure focus. However, whether a left or right seizure focus produces differential effects on comorbid outcomes has not been investigated in a rodent model of chronic recurrent seizures. Here, we used the intrahippocampal kainic acid (IHKA) mouse model of TLE to determine whether targeting of left or right dorsal hippocampus for injection produces different outcomes in hippocampal sclerosis, body weight gain, and multiple measures of reproductive endocrine dysfunction in female mice. At one, two, and four months after injection, in vivo measurements of estrous cycles and weight were followed by ex vivo examination of hippocampal sclerosis, circulating ovarian hormone and corticosterone levels, ovarian morphology, and pituitary gene expression. IHKA mice with right-targeted injection (IHKA-R) showed greater granule cell dispersion and pituitary Fshb expression compared to mice with left-targeted injection (IHKA-L). By contrast, pituitary expression of Lhb and Gnrhr were higher in IHKA-L mice compared to IHKA-R, but these values were not different from respective saline-injected controls. IHKA-L mice also showed an increased rate of weight gain compared to IHKA-R mice. Disruptions to estrous cyclicity, however, were similar in both IHKA-L and IHKA-R mice. These findings indicate that although major reproductive endocrine dysfunction phenotypes present similarly after targeting left or right dorsal hippocampus in the IHKA model of TLE, distinct latent mechanisms based on lateralization of seizure focus may contribute to produce similar emergent reproductive endocrine outcomes.Significance StatementPeople with epilepsy often develop comorbidities dependent on the side of the brain in which the seizures originate. However, the mechanisms linking laterality of seizure initiation side to different comorbidities are unknown. Here, we examined whether injection of kainic acid in the left or right hippocampus, a model of temporal lobe epilepsy, produces differential effects on hippocampal damage, weight gain, and measurements of female reproductive endocrine function in female mice. We found that hippocampal sclerosis, pituitary gene expression, and weight gain are influenced by the side of injection. These results are the first demonstration of changes in pituitary gene expression in a model of epilepsy and indicate that the hemisphere targeted in the intrahippocampal kainic acid model impacts phenotypic outcomes.

Network-Related Changes in Neurotransmitters and Seizure Propagation During Rodent Epileptogenesis

Objective:To test the hypothesis that glutamate and GABA are linked to the formation of epilepsy networks and the triggering of spontaneous seizures, we examined seizure initiation/propagation characteristics and neurotransmitter levels during epileptogenesis in a translationally relevant rodent model of mesial temporal lobe epilepsy.Methods:The glutamine synthetase (GS) inhibitor methionine sulfoximine was infused into one of the hippocampi in laboratory rats to create a seizure focus. Long-term video-intracranial EEG recordings and brain microdialysis combined with mass spectrometry were used to examine seizure initiation, seizure propagation, and extracellular brain levels of glutamate and GABA.Results:All seizures (n = 78 seizures, n = 3 rats) appeared first in the GS-inhibited hippocampus of all animals, followed by propagation to the contralateral hippocampus. Propagation time decreased significantly from 11.65 seconds early in epileptogenesis (weeks 1-2) to 6.82 seconds late in epileptogenesis (weeks 3 – 4, paired t-test, p = 0.025). Baseline extracellular glutamate levels were 11.6-fold higher in the hippocampus of seizure propagation (7.3 µM) vs. the hippocampus of seizure onset (0.63 µM, ANOVA/Fisher’s LSD, p = 0.01), even though the concentrations of the major glutamate transporter proteins EAAT1, EAAT2 and xCT were unchanged between the brain regions. Finally, extracellular GABA in the seizure focus decreased significantly from baseline several hours before a spontaneous seizure (paired t-test/FDR).Conclusion:The changes in glutamate and GABA suggest novel and potentially important roles of the amino acids in epilepsy network formation and in the initiation and propagation of spontaneous seizures.

Clinically Localized Seizure Focus Maybe Not Exactly the Position of Abating Seizures: A Computational Evidence

Seizure focus localization is the key to control seizures. However, in this paper, we show that the clinically localized seizure focus may be not exactly the positions to abate seizures. Firstly, the reliability of a previously proposed methodology employed to estimate the synchronicity and directionality of information flows over time between EEG signals, is numerically assessed with a coupled mass neural model. Then 10 channels' EEG signals from a patient with focal epilepsy are used to reconstruct the dynamical complex network of pathological seizure. This may facilitate to identify the evolution paths of information flows and localize the potential seizure foci. What's more, based on the controllability and observability principles of complex systems, we can focus on the key nodes which is effective to control the network seizure behaviors and the key ones that can allow us to estimate the state of all other variables. Results show that to fully control the epileptic network may not just be related to the focus zone, it may also involves in other non-focus nodes. In addition, we use the spatiotemporal neural network model connected by our modeled dynamical adjacent matrix to successfully reproduce the original EEG signals which can be effectively abated by applying the normal distribution noise stimulation with cathodic phase pulses (cNDNs) on the identified key nodes or resecting them. Our results enrich the clinical results and provide new insights into the seizure resection and electronic stimulation therapies.

How to Inject Ictal SPECT? From Manual to Automated Injection

BackgroundSuccessful surgery depends on the accurate localization of epileptogenic zone before surgery. Ictal SPECT is the only imaging modality that allows identification of the ictal onset zone by measuring the regional cerebral blood flow at the time of injection. The main limitations of ictal SPECT in epilepsy are the complex methodology of the tracer injection during a seizure. To overcome these limitations, we present the main features of the first automated injector for ictal SPECT (epijet, LemerPax; La Chapelle -sur-Erdre; France). In this study we compared traditional manual injection with automated injection for ictal SPECT in122 patients with drug-resistant epilepsy. MethodsThe study included 55 consecutive prospective patients with drug-resistant epilepsy undergoing injection with the automated injector. The control group was our retrospective database of a historic pool of 67 patients, injected manually from 2014-2016. Calculated annual exposure/radioactive dose for operators was measured. Injection time, seizure focus localization with ictal SPECT, as well as repeated hospitalizations related to fails injections were compared in these two groups of patients. ResultsThere were no differences in the average injection time with epijet (13 s) compared with the traditional manual injection (14s). The seizure focus was successfully localized with ictal SPECT with epijet in 44/55 (80%) patients and with manual injection in 46/67 (68%) patients (p=0.694). Repeated studies were required in 16/67 (23%) patients in the manual injection group compared to 4 patients (7%) in the epijet group (p=0.022). Calculated annual exposure/dose for operators of 0.39 mSv/year and administered dose error inferior to 5% are other advantages of epijet. ConclusionThe first results using epijet are promising in adjustment of the injection dose, reducing the rate of radiation exposure for patients and nurses, maintaining the same injection time and allowing high SPECT accuracy. These preliminary results support the use of an automated injection system to inject radioactive ictal SPECT doses in epilepsy units.

An exploratory study into the influence of laterality and location of hippocampal sclerosis on seizure prognosis and global cortical thinning

In mesial temporal lobe epilepsy (mTLE), the correlation between disease duration, seizure laterality, and rostro-caudal location of hippocampal sclerosis has not been examined in the context of seizure severity and global cortical thinning. In this retrospective study, we analyzed structural 3 T MRI from 35 mTLE subjects. Regions of FLAIR hyperintensity (as an indicator of sclerosis)—based on 2D coronal FLAIR sequences—in the hippocampus were manually segmented, independently and in duplicate; degree of segmentation agreement was confirmed using the DICE index. Segmented lesions were used for separate analyses. First, the correlation of cortical thickness with disease duration and seizure focus laterality was explored using linear model regression. Then, the relationship between the rostro-caudal location of the FLAIR hyperintense signal and seizure severity, based on the Cleveland Clinic seizure freedom score (ccSFS), was explored using probabilistic voxel-wise mapping and functional connectivity analysis from normative data. The mean DICE Index was 0.71 (range 0.60–0.81). A significant correlation between duration of epilepsy and decreased mean whole brain cortical thickness was identified, regardless of seizure laterality (p < 0.05). The slope of cortical volume loss over time, however, was greater in subjects with right seizure focus. Based on probabilistic voxel-wise mapping, FLAIR hyperintensity in the posterior hippocampus was significantly associated with lower ccSFS scores (greater seizure severity). Finally, the right hippocampus was found to have greater brain-wide connectivity, compared to the left side, based on normative connectomic data. We have demonstrated a significant correlation between duration of epilepsy and right-sided seizure focus with global cortical thinning, potentially due to greater brain-wide connectivity. Sclerosis along the posterior hippocampus was associated with greater seizure severity, potentially serving as an important biomarker of seizure outcome after surgery.

MRI network progression in mesial temporal lobe epilepsy related to healthy brain architecture

We measured MRI network progression in mesial temporal lobe epilepsy (mTLE) patients as a function of healthy brain architecture. Resting-state functional MRI and diffusion-weighted MRI were acquired in 40 unilateral mTLE patients and 70 healthy controls. Data were used to construct region-to-region functional connectivity, structural connectivity, and streamline length connectomes per subject. Three models of distance from the presumed seizure focus in the anterior hippocampus in the healthy brain were computed using the average connectome across controls. A fourth model was defined using regions of transmodal (higher cognitive function) to unimodal (perceptual) networks across a published functional gradient in the healthy brain. These models were used to test whether network progression in patients increased when distance from the anterior hippocampus or along a functional gradient in the healthy brain decreases. Results showed that alterations of structural and functional networks in mTLE occur in greater magnitude in regions of the brain closer to the seizure focus based on healthy brain topology, and decrease as distance from the focus increases over duration of disease. Overall, this work provides evidence that changes across the brain in focal epilepsy occur along healthy brain architecture.