Understanding Epileptiform After-Discharges as Rhythmic Oscillatory Transients

Electro-cortical activity in patients with epilepsy may show abnormal rhythmic transients in response to stimulation. Even when using the same stimulation parameters in the same patient, wide variability in the duration of transient response has been reported. These transients have long been considered important for the mapping of the excitability levels in the epileptic brain but their dynamic mechanism is still not well understood. To understand the occurrence of abnormal transients dynamically, we use a thalamo-cortical neural population model of epileptic spike-wave activity and study the interaction between slow and fast subsystems. In a reduced version of the thalamo-cortical model, slow wave oscillations arise from a fold of cycles (FoC) bifurcation. This marks the onset of a region of bistability between a high amplitude oscillatory rhythm and the background state. In vicinity of the bistability in parameter space, the model has excitable dynamics, showing prolonged rhythmic transients in response to suprathreshold pulse stimulation. We analyse the state space geometry of the bistable and excitable states, and find that the rhythmic transient arises when the impending FoC bifurcation deforms the state space and creates an area of locally reduced attraction to the fixed point. This area essentially allows trajectories to dwell there before escaping to the stable steady state, thus creating rhythmic transients. In the full thalamo-cortical model, we find a similar FoC bifurcation structure. Based on the analysis, we propose an explanation of why stimulation induced epileptiform activity may vary between trials, and predict how the variability could be related to ongoing oscillatory background activity.Comment: http://journal.frontiersin.org/article/10.3389/fncom.2017.00025/ful

Involvement of fast-spiking cells in ictal sequences during spontaneous seizures in rats with chronic temporal lobe epilepsy

Epileptic seizures represent altered neuronal network dynamics, but the temporal evolution and cellular substrates of the neuronal activity patterns associated with spontaneous seizures are not fully understood. We used simultaneous recordings from multiple neurons in the hippocampus and neocortex of rats with chronic temporal lobe epilepsy to demonstrate that subsets of cells discharge in a highly stereotypical sequential pattern during ictal events, and that these stereotypical patterns were reproducible across consecutive seizures. In contrast to the canonical view that principal cell discharges dominate ictal events, the ictal sequences were predominantly composed of fast-spiking, putative inhibitory neurons, which displayed unusually strong coupling to local field potential even before seizures. The temporal evolution of activity was characterized by unique dynamics where the most correlated neuronal pairs before seizure onset displayed the largest increases in correlation strength during the seizures. These results demonstrate the selective involvement of fast spiking interneurons in structured temporal sequences during spontaneous ictal events in hippocampal and neocortical circuits in experimental models of chronic temporal lobe epilepsy

Simultaneous intracranial EEG and fMRI of interictal epileptic discharges in humans

Simultaneous scalp EEG–fMRI measurements allow the study of epileptic networks and more generally, of the coupling between neuronal activity and haemodynamic changes in the brain. Intracranial EEG (icEEG) has greater sensitivity and spatial specificity than scalp EEG but limited spatial sampling. We performed simultaneous icEEG and functional MRI recordings in epileptic patients to study the haemodynamic correlates of intracranial interictal epileptic discharges (IED). Two patients undergoing icEEG with subdural and depth electrodes as part of the presurgical assessment of their pharmaco-resistant epilepsy participated in the study. They were scanned on a 1.5 T MR scanner following a strict safety protocol. Simultaneous recordings of fMRI and icEEG were obtained at rest. IED were subsequently visually identified on icEEG and their fMRI correlates were mapped using a general linear model (GLM). On scalp EEG–fMRI recordings performed prior to the implantation, no IED were detected. icEEG–fMRI was well tolerated and no adverse health effect was observed. intra-MR icEEG was comparable to that obtained outside the scanner. In both cases, significant haemodynamic changes were revealed in relation to IED, both close to the most active electrode contacts and at distant sites. In one case, results showed an epileptic network including regions that could not be sampled by icEEG, in agreement with findings from magneto-encephalography, offering some explanation for the persistence of seizures after surgery. Hence, icEEG–fMRI allows the study of whole-brain human epileptic networks with unprecedented sensitivity and specificity. This could help improve our understanding of epileptic networks with possible implications for epilepsy surgery

Imaging fast neural activity in the brain during epilepsy with electrical impedance tomography

Electrical impedance tomography (EIT) is a medical imaging technique which reconstructs images of the internal conductivity of an object using boundary measurements obtained by applying current through pairs of non-penetrating surface electrodes. EIT is able to image impedance changes which arise during neural activity at a high spatiotemporal resolution through the rat cerebral cortex and therefore represents a novel method for understanding neuronal network dynamics in epilepsy. Additionally, it holds therapeutic potential for improving the presurgical localisation of epileptogenic foci in individuals with drug-resistant epilepsy. This thesis was aimed at developing EIT for imaging epileptiform activity in vivo and assessing its potential for clinical use. Chapter 1 is a review of existing functional neuroimaging modalities, the principles of EIT and previous studies that have used EIT for imaging epileptic events. In Chapter 2, the safety of continuous current application to the rat cortical surface at 10-100 μA and 1725 Hz, parameters that are representative of fast neural EIT protocols, was verified by histological evaluation. Chapter 3 details the development of two acute rat models of focal epilepsy, the cortical and hippocampal epileptic afterdischarges models, for assessing the feasibility of imaging epileptiform activity with fast neural EIT using epicortical electrode arrays. In Chapter 4, EIT was used to image the propagation of ictal spike-and-wave activity through the cerebral cortex at a resolution of 2 ms and ≤300 µm. In order to enable imaging of epileptiform discharges in deeper subcortical structures, the optimal carrier frequency for current application was determined in Chapter 5. Results demonstrated that the maximal signal-to-noise ratio of fast neural impedance changes during ictal discharges is obtained at 1355 Hz. Finally, in Chapter 6, epileptiform activity in the hippocampus was imaged, with a localisation accuracy of ≤400 µm, using epicortical impedance measurements obtained at this optimised carrier frequency

Ictal epileptic headache. an old story with courses and appeals

The term "ictal epileptic headache" has been recently proposed to classify the clinical picture in which headache is the isolated ictal symptom of a seizure. There is emerging evidence from both basic and clinical neurosciences that cortical spreading depression and an epileptic focus may facilitate each other, although with a different degree of efficiency. This review address the long history which lead to the 'migralepsy' concept to the new emerging pathophysiological aspects, and clinical and electroencephalography evidences of ictal epileptic headache. Here, we review and discuss the common physiopathology mechanisms and the historical aspects underlying the link between headache and epilepsy. Either experimental or clinical measures are required to better understand this latter relationship: the development of animal models, molecular studies defining more precise genotype/phenotype correlations as well as multicenter clinical studies with revision of clinical criteria for headache-/epilepsy-related disorders represent the start of future research. Therefore, the definition of ictal epileptic headache should be used to classify the rare events in which headache is the only manifestation of a seizure. Finally, using our recently published criteria, we will be able to clarify if ictal epileptic headache represents an underestimated phenomenon or not

Diminished presynaptic GABA(B) receptor function in the neocortex of a genetic model of absence epilepsy

Changes in GABA(B) receptor subunit expression have been recently reported in the neocortexof epileptic WAG/Rij rats that are genetically prone to experience absence seizures.These alterations may lead to hyperexcitability by downregulating the function of presynapticGABA(B) receptors in neocortical networks as suggested by a reduction in paired-pulsedepression. Here, we tested further this hypothesis by analyzing the effects induced by theGABA(B) receptor agonist baclofen (0.1-10 μM) on the inhibitory events recorded in vitro fromneocortical slices obtained from epileptic (>180 day-old) WAG/Rij and age-matched, nonepilepticcontrol (NEC) rats. We found that higher doses of baclofen were required todepress pharmacologically isolated, stimulus-induced IPSPs generated by WAG/Rij neuronsas compared to NEC. We also obtained similar evidence by comparing the effects ofbaclofen on the rate of occurrence of synchronous GABAergic events recorded by WAG/Rijand NEC neocortical slices treated with 4-aminopyridine+glutamatergic receptor antagonists.In conclusion, these data highlight a decreased function of presynaptic GABA(B) receptorsin the WAG/Rij rat neocortex. We propose that this alteration may contribute toneocortical hyperexcitability and thus to absence seizures

A computational study of stimulus driven epileptic seizure abatement

This is the final version of the article. Available from Public Library of Science via the DOI in this record.Active brain stimulation to abate epileptic seizures has shown mixed success. In spike-wave (SW) seizures, where the seizure and background state were proposed to coexist, single-pulse stimulations have been suggested to be able to terminate the seizure prematurely. However, several factors can impact success in such a bistable setting. The factors contributing to this have not been fully investigated on a theoretical and mechanistic basis. Our aim is to elucidate mechanisms that influence the success of single-pulse stimulation in noise-induced SW seizures. In this work, we study a neural population model of SW seizures that allows the reconstruction of the basin of attraction of the background activity as a four dimensional geometric object. For the deterministic (noise-free) case, we show how the success of response to stimuli depends on the amplitude and phase of the SW cycle, in addition to the direction of the stimulus in state space. In the case of spontaneous noise-induced seizures, the basin becomes probabilistic introducing some degree of uncertainty to the stimulation outcome while maintaining qualitative features of the noise-free case. Additionally, due to the different time scales involved in SW generation, there is substantial variation between SW cycles, implying that there may not be a fixed set of optimal stimulation parameters for SW seizures. In contrast, the model suggests an adaptive approach to find optimal stimulation parameters patient-specifically, based on real-time estimation of the position in state space. We discuss how the modelling work can be exploited to rationally design a successful stimulation protocol for the abatement of SW seizures using real-time SW detection.This work was supported by the EPSRC (EP/K026992/1), the BBSRC, the DTC for Systems Biology (University of Manchester), and the Nanyang Technological University Singapore. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript