Optogenetic dissection of ictal propagation in the hippocampal–entorhinal cortex structures

Temporal lobe epilepsy (TLE) is one of the most common drug-resistant forms of epilepsy in adults and usually originates in the hippocampal formations. However, both the network mechanisms that support the seizure spread and the exact directions of ictal propagation remain largely unknown. Here we report the dissection of ictal propagation in the hippocampal–entorhinal cortex (HP–EC) structures using optogenetic methods in multiple brain regions of a kainic acid-induced model of TLE in VGAT-ChR2 transgenic mice. We perform highly temporally precise cross-area analyses of epileptic neuronal networks and find a feed-forward propagation pathway of ictal discharges from the dentate gyrus/hilus (DGH) to the medial entorhinal cortex, instead of a re-entrant loop. We also demonstrate that activating DGH GABAergic interneurons can significantly inhibit the spread of ictal seizures and largely rescue behavioural deficits in kainate-exposed animals. These findings may shed light on future therapeutic treatments of TLE

Seizure-onset mapping based on time-variant multivariate functional connectivity analysis of high-dimensional intracranial EEG : a Kalman filter approach

The visual interpretation of intracranial EEG (iEEG) is the standard method used in complex epilepsy surgery cases to map the regions of seizure onset targeted for resection. Still, visual iEEG analysis is labor-intensive and biased due to interpreter dependency. Multivariate parametric functional connectivity measures using adaptive autoregressive (AR) modeling of the iEEG signals based on the Kalman filter algorithm have been used successfully to localize the electrographic seizure onsets. Due to their high computational cost, these methods have been applied to a limited number of iEEG time-series (< 60). The aim of this study was to test two Kalman filter implementations, a well-known multivariate adaptive AR model (Arnold et al. 1998) and a simplified, computationally efficient derivation of it, for their potential application to connectivity analysis of high-dimensional (up to 192 channels) iEEG data. When used on simulated seizures together with a multivariate connectivity estimator, the partial directed coherence, the two AR models were compared for their ability to reconstitute the designed seizure signal connections from noisy data. Next, focal seizures from iEEG recordings (73-113 channels) in three patients rendered seizure-free after surgery were mapped with the outdegree, a graph-theory index of outward directed connectivity. Simulation results indicated high levels of mapping accuracy for the two models in the presence of low-to-moderate noise cross-correlation. Accordingly, both AR models correctly mapped the real seizure onset to the resection volume. This study supports the possibility of conducting fully data-driven multivariate connectivity estimations on high-dimensional iEEG datasets using the Kalman filter approach

Initiation and slow propagation of epileptiform activity from ventral to dorsal medial entorhinal cortex is constrained by an inhibitory gradient.

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.The medial entorhinal cortex (mEC) has an important role in the generation and propagation of seizure activity. The organisation of the mEC is such that a number of dorso-ventral relationships exist in neurophysiological properties of neurons. These range from intrinsic and synaptic properties to density of inhibitory connectivity. We examined the influence of these gradients on generation and propagation of epileptiform activity in the mEC. Using a 16-shank silicon probe array to record along the dorso-ventral axis of the mEC in vitro, we found 4-aminopyridine (4-AP) application produces ictal-like activity originating predominantly in ventral areas. This activity spreads to dorsal mEC at a surprisingly slow velocity (138 μm.s-1), while cross-site interictal-like activity appeared relatively synchronous. We propose that ictal propagation is constrained by differential levels of GABAergic control since increasing (diazepam) or decreasing (Ro19-4603) GABAAreceptor activation, respectively, reduced or increased the slope of ictal initiation. The observation that ictal activity is predominately generated in ventral mEC was replicated using a separate 0-Mg2+model of epileptiform activity in vitro. By using a distinct disinhibition model (co-application of kainate and picrotoxin) we show that additional physiological features (for example intrinsic properties of mEC neurons) still produce a prevalence for interictal-like initiation in ventral mEC. These findings suggest that the ventral mEC is more likely to initiate hyperexcitable discharges than dorsal, and that seizure propagation is highly dependent on levels of GABAergic expression across the mEC. This article is protected by copyright. All rights reserved.This work was supported by a University of Exeter and Eli Lilly studentship (T.R). P.M 513 was supported by an MRC Proximity to Discovery award in partnership with 514 AstraZeneca. K.G.P was an employee of Eli Lilly. A.D.R was part funded by a Royal 515 Society Industrial Fellowship. J.T.B was an Alzheimer’s Research UK Senior Research 516 Fellow (ARUK-SRF2012-6)

Speech Preservation during Language-dominant, Left Temporal Lobe Seizures: Report of a Rare, Potentially Misleading Finding

Purpose: To evaluate the prevalence and mechanism of ictal speech in patients with language-dominant, left temporal lobe seizures. Methods: We retrospectively reviewed the video-EEG telemetry records for the presence of ictal speech in 96 patients with surgically proven left temporal lobe epilepsy and studied the seizure-propagation patterns in three patients who required intracranial EEG recordings for seizure localization. Results: Ictal speech preservation was observed in five patients. One patient's seizures demonstrated rapid propagation of the ictal discharges to the contralateral temporal area where the seizure evolved, resembling a nondominant temporal lobe seizure. The other two patients had ictal discharges that remained confined to the inferomesial temporal areas, sparing language cortex. Conclusions: Preservation of speech in complex partial seizures of language-dominant, left temporal lobe origin is rare. Based on intracranial EEG recordings, the likely mechanism underlying this potentially misleading clinical finding is the preservation of language areas due to limited seizure-propagation patterns.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65559/1/j.1528-1167.2006.00606.x.pd

Neurocognitive and Seizure Outcomes of Selective Amygdalohippocampectomy versus Anterior Temporal Lobectomy for Mesial Temporal Lobe Epilepsy.

Objective. To report our institutional seizure and neuropsychological outcomes for a series of patients with mesial temporal lobe epilepsy (mTLE) undergoing anterior temporal lobectomy (ATL) or selective amygdalohippocampectomy (SelAH) between 2004 and 2011. Methods. A retrospective study of patients with mTLE was conducted. Seizure outcome was reported using time-to-event analysis. Cognitive outcome was reported using the change principal in component factor scores, one each, for intellectual abilities, visuospatial memory, and verbal memory. The Boston Naming Test was used for naming assessment. Language dominant and nondominant resections were compared separately. Student's t-test was used to assess statistical significance. Results. Ninety-six patients (75 ATL, 21 SelAH) were included; fifty-four had complete neuropsychological follow-up. Median follow-up was 40.5 months. There was no statistically significant difference in seizure freedom or any of the neuropsychological outcomes, although there was a trend toward greater postoperative decline in naming in the dominant hemisphere group following ATL. Conclusion. Seizure and neuropsychological outcomes did not differ for the two surgical approaches which is similar to most prior studies. Given the theoretical possibility of SelAH sparing language function in patients with epilepsy secondary to mesial temporal sclerosis and the limited high-quality evidence creating equipoise, a multicenter randomized clinical trial is warranted

Space-oriented segmentation and 3-dimensional source reconstruction of ictal EEG patterns

OBJECTIVES: Characterization of the EEG pattern during the early phase of a seizure is crucial for identifying the epileptic focus. The purpose of the present investigation was to evaluate a method that divides ictal EEG activity into segments of relatively constant surface voltage distribution, and to provide a 3-dimensional localization of the activity during the different segments. METHODS: For each timepoint the electrical voltage distribution on the scalp (the voltage map) was determined from the digitized EEG recording. Through a spatial cluster analysis time sequences where the maps did not change much (segments) were identified, and a 3-dimensional source reconstruction of the activity corresponding to the different mean maps was performed using a distributed linear inverse solution algorithm. RESULTS: Segments dominating early in seizure development were identified, and source reconstruction of the EEG activity corresponding to the maps of these segments yielded results which were consistent with the results from invasive recordings. In some cases a sequence of consecutive segments was obtained, which might reflect ictal propagation. CONCLUSIONS: Segmentation of ictal EEG with subsequent 3-dimensional source reconstruction is a useful method to non-invasively determine the initiation and perhaps also the spread of epileptiform activity in patients with epileptic seizures

The spatiotemporal dynamics of human focal seizures

Spontaneous human focal seizures can present with a plethora of behavioral manifestations that vary according to the affected cortical regions; however, several key features have been consistently observed. During my doctoral studies, I applied both theoretical and experimental methods to study mechanisms underpinning these consistently seen dynamics. I first analyzed human intracranial EEG recordings, describing statistical methods for measuring their electrophysiological signatures. I next proposed several neurophysiological hypotheses that could explain seizure dynamics and verified them in rodent seizure models. Finally, a computational model was developed, successfully explaining how the complex spatiotemporal evolution of focal seizures emerges from simple neurophysiological principles. In Chapter 1, the long-standing behavioral manifestations and the most up-to-date electrophysiology findings are reviewed. This section details the inspiration for the studies reported in the subsequent chapters. In Chapter 2, I describe several statistical methods for estimating traveling wave velocities. I show most ictal discharges can be described as traveling waves whose velocities contain rich information about the stages of seizure evolution. I compare performance of various statistical methods and propose a robust approach to boost the quality of each method’s estimation results. In Chapter 3, I show how inhibition modulates seizure propagation patterns. Surround inhibition spatially restrains focal seizures and masks excitatory projections of ictal activities. When compromised, two patterns of seizure propagation emerge according to the position of inhibition defects relative to the ictal focus. I show that two distant ictal foci can communicate via physiological connectivity without any chronic rewiring processes – confirming the existence of long-range propagation pathways that could lead to epileptic network formation. In Chapter 4, I show that thalamic inputs might be necessary for interictal epileptiform discharges (IEDs). The relative positions between IEDs and ictal foci indicate that surround inhibition, shown in the previous chapter, can be exhausted by repetitive exposure to ictal projections. In Chapter 5, I propose a neural network model that can explain both long-standing behavioral observations of seizures and account for the most up-to-date electrophysiological recordings of spontaneous human focal seizures. The model relies on few assumptions, all of which are proved or supported in earlier chapters of this thesis. The model explains phasic evolution of seizure dynamics – how the commonly observed patterns arise from simple neurophysiological principles, as well as seizure onset subtypes, traveling wave directions and speeds. The model also predicts how spontaneous seizures might arise from synaptic plasticity. The chapter ends with a discussion of the model’s implications and future work. The thesis is organized in a way that each chapter can be read independently, with Chapter 5 summarizing the central theory spanning the whole study. Each chapter is also tightly linked to a clinically relevant question. In sum, the dissertation’s goal is to provide an in-principle understanding of focal seizure dynamics. With rapid advancement of clinical and experimental tools, I believe this work provides a roadmap for future therapies for epilepsy patients

Role of Single Photon Emission Computed Tomography in Epilepsy

Molecular imaging with ictal single photon emission computed tomography (SPECT) is an established functional imaging modality for the presurgical evaluation of patients with refractory partial onset seizures. SPECT coregistered on to the MRI has greater sensitivity to identify the ictal onset zone. Ictal SPECT should always be interpreted in the context of other presurgical investigations. Ictal SPECT is sensitive method for the lateralization of TLE, but ictal SPECT is more sensitive when MRI is normal. Ictal SPECT and interictal PET are complementary to each other in lateralizing the side in patients with TLE and normal MRI. In extratemporal epilepsy, ictal SPECT will guide the placement of surface grid and depth electrodes

Napadaji posteriornog korteksa - izazovi u pedijatriji

Posterior cortex seizures have a complex semiologic presentation that is especially challenging in the pediatric population. Therefore, using clinical presentation in localizing ictal involvement is not sufficient in children, thus making this type of epilepsy quite under-recognized. As most of the ictal symptoms are subjective and could well be overshadowed by symptoms arising from adjacent cortices, primarily temporal and central ones, it is necessary not to overlook this large source of pharmacoresistant epilepsies. The parietal lobe as part of an extensive synaptic network is a great imitator, thus quite often producing inaccurate localization readings on scalp electroencephalography (EEG) due to very scattered interictal discharges and uninformative ictal recordings. Using direct cortical recordings in delineating the epileptogenic zone is helpful in some cases but even highly experienced epileptologists may erroneously interpret some features as arising from other localizations, especially the frontal lobe. Epilepsy surgery from the posterior quadrant is still quite rare and relatively unsuccessful, especially in non-lesional epilepsies due to elaborate mechanisms of connectivity, misleading semiology, and non-localizing EEG recordings, possibly due to insufficiency of parietal cortex synchronicity. Applying the aforementioned to the pediatric age makes it perhaps the most difficult challenge for a pediatric epileptologist.Napadaji posteriornog korteksa imaju složemu semiologiju koja je osobito izazovna u pedijatrijskoj populaciji. Upravo zato primjena kliničke prezentacije u lokalizaciji iktalnog ishodišta nije dovoljno u djece, čime je ova vrsta epilepsije slabo prepoznata. S obzirom na to da je većina iktalnih simptoma subjektivna i može biti skrivena simptomima susjednih korteksa, primarno temporalnim i centralnim, važno je ne preskočiti ovaj važan izvor farmakorezistentnih epilepsija. Uz semiologiju, parijetalni je režanj kao dio velike sinaptičke mreže veliki imitator i često stvara netočnu lokalizaciju na elektroencefalogramu (EEG) zbog velike distribucije interiktalnih izbijanja i neinformativnih iktalnih zapisa. Korištenje direktnih kortikalnih zapisa u definiciji epileptogene zone je korisno u nekim slučajevima, no čak i vrlo iskusni epileptolozi mogu pogrešno protumačiti neke značajke s ishodom iz drugih izvora, osobito frontalnog režnja. Operacije epilepsije posteriornog kvadranta su vrlo rijetke i prilično neuspješne, osobito u ne-lezionalnim epilepsijama zbog osebujnih mehanizama povezanosti, zavaravajuće semiologije i ne-lokalizirajućeg EEG zapisa moguće zbog nedovoljne sinkroniziranosti parijetalnog korteksa. Primjena navedenog na pedijatrijsku dob čini epilepsije ovog dijela korteksa možda najvećim izazovom za pedijatrijske epileptologe

If seizures left speechless: CA-P-S C-A-R-E, a proposal of a new ictal language evaluation protocol

Introduction: We aimed to create standardized protocol for language examination in patients who underwent video-EEG recording and assessed its efficacy in the characterization of ictal language impairment, its ability to differentiate this from impaired awareness, and interobserver reliability in clinical practice. Methods: From our database of video-EEG recordings, we selected a representative sample of 63 focal seizures with presumed language impairment. A multidisciplinary team of epileptologists, EEG technicians, and speech therapists analyzed the selected videos to highlight the critical issues of ordinary ictal language evaluation. We subsequently followed a multi-step process to develop the protocol and assess its interobserver reliability. Results: A protocol based on seven tests in hierarchical succession was created, summed up in the acronym CA-P-S C-A-R-E (Closed Answers, Pro-speak question, Simple orders, Common object denomination, Audio repetition, Reading, Evoke). Following its preliminary administration for 5 months, we assessed the inter-observer reliability of 16 healthcare professionals in distinguishing between language impairment and impaired awareness among a sample of 10 seizures, finding a substantial agreement (kappa 0.61). Conclusion: The proposed protocol, made of simple and easy to memorize tests, is an effective tool that evaluates multiple domains beyond language. Its use could help to recognize ictal aphasia effectively and differentiate it from impaired awareness, minimizing inter-examiner variability