Imaging of epileptic activity using EEG-correlated functional MRI.

This thesis describes the method of EEG-correlated fMRI and its application to patients with epilepsy. First, an introduction on MRI and functional imaging methods in the field of epilepsy is provided. Then, the present and future role of EEG-correlated fMRI in the investigation of the epilepsies is discussed. The fourth chapter reviews the important practicalities of EEG-correlated fMRI that were addressed in this project. These included patient safety, EEG quality and MRI artifacts during EEG-correlated fMRI. Technical solutions to enable safe, good quality EEG recordings inside the MR scanner are presented, including optimisation of the EEG recording techniques and algorithms for the on-line subtraction of pulse and image artifact. In chapter five, a study applying spike-triggered fMRI to patients with focal epilepsy (n = 24) is presented. Using statistical parametric mapping (SPM), cortical Blood Oxygen Level-Dependent (BOLD) activations corresponding to the presumed generators of the interictal epileptiform discharges (IED) were identified in twelve patients. The results were reproducible in repeated experiments in eight patients. In the remaining patients no significant activation (n = 10) was present or the activation did not correspond to the presumed epileptic focus (n = 2). The clinical implications of this finding are discussed. In a second study it was demonstrated that in selected patients, individual (as opposed to averaged) IED could also be associated with hemodynamic changes detectable with fMRI. Chapter six gives examples of combination of EEG-correlated fMRI with other modalities to obtain complementary information on interictal epileptiform activity and epileptic foci. One study compared spike-triggered fMRI activation maps with EEG source analysis based on 64-channel scalp EEG recordings of interictal spikes using co-registration of both modalities. In all but one patient, source analysis solutions were anatomically concordant with the BOLD activation. Further, the combination of spike- triggered fMRI with diffusion tensor and chemical shift imaging is demonstrated in a patient with localisation-related epilepsy. In chapter seven, applications of EEG-correlated fMRI in different areas of neuroscience are discussed. Finally, the initial imaging findings with the novel technique for the simultaneous and continuous acquisition of fMRI and EEG data are presented as an outlook to future applications of EEG-correlated fMRI. In conclusion, the technical problems of both EEG-triggered fMRI and simultaneous EEG-correlated fMRI are now largely solved. The method has proved useful to provide new insights into the generation of epileptiform activity and other pathological and physiological brain activity. Currently, its utility in clinical epileptology remains unknown

Epileptic Seizures and the EEG

A study of epilepsy from an engineering perspective, this volume begins by summarizing the physiology and the fundamental ideas behind the measurement, analysis and modeling of the epileptic brain. It introduces the EEG and provides an explanation of the type of brain activity likely to register in EEG measurements, offering an overview of how these EEG records are and have been analyzed in the past. The book focuses on the problem of seizure detection and surveys the physiologically based dynamic models of brain activity. Finally, it addresses the fundamental question: can seizures be predicted? Based on the authors' extensive research, the book concludes by exploring a range of future possibilities in seizure prediction

Non-invasive measurements of ictal and interictal epileptiform activity using optically pumped magnetometers

Magneto- and electroencephalography (MEG/EEG) are important techniques for the diagnosis and pre-surgical evaluation of epilepsy. Yet, in current cryogen-based MEG systems the sensors are offset from the scalp, which limits the signal-to-noise ratio (SNR) and thereby the sensitivity to activity from deep structures such as the hippocampus. This effect is amplified in children, for whom adult-sized fixed-helmet systems are typically too big. Moreover, ictal recordings with fixed-helmet systems are problematic because of limited movement tolerance and/or logistical considerations. Optically Pumped Magnetometers (OPMs) can be placed directly on the scalp, thereby improving SNR and enabling recordings during seizures. We aimed to demonstrate the performance of OPMs in a clinical population. Seven patients with challenging cases of epilepsy underwent MEG recordings using a 12-channel OPM-system and a 306-channel cryogen-based whole-head system: three adults with known deep or weak (low SNR) sources of interictal epileptiform discharges (IEDs), along with three children with focal epilepsy and one adult with frequent seizures. The consistency of the recorded IEDs across the two systems was assessed. In one patient the OPMs detected IEDs that were not found with the SQUID-system, and in two patients no IEDs were found with either system. For the other patients the OPM data were remarkably consistent with the data from the cryogenic system, noting that these were recorded in different sessions, with comparable SNRs and IED-yields overall. Importantly, the wearability of OPMs enabled the recording of seizure activity in a patient with hyperkinetic movements during the seizure. The observed ictal onset and semiology were in agreement with previous video- and stereo-EEG recordings. The relatively affordable technology, in combination with reduced running and maintenance costs, means that OPM-based MEG could be used more widely than current MEG systems, and may become an affordable alternative to scalp EEG, with the potential benefits of increased spatial accuracy, reduced sensitivity to volume conduction/field spread, and increased sensitivity to deep sources. Wearable MEG thus provides an unprecedented opportunity for epilepsy, and given its patient-friendliness, we envisage that it will not only be used for presurgical evaluation of epilepsy patients, but also for diagnosis after a first seizure

Epileptic Seizures and the EEG

A study of epilepsy from an engineering perspective, this volume begins by summarizing the physiology and the fundamental ideas behind the measurement, analysis and modeling of the epileptic brain. It introduces the EEG and provides an explanation of the type of brain activity likely to register in EEG measurements, offering an overview of how these EEG records are and have been analyzed in the past. The book focuses on the problem of seizure detection and surveys the physiologically based dynamic models of brain activity. Finally, it addresses the fundamental question: can seizures be predicted? Based on the authors' extensive research, the book concludes by exploring a range of future possibilities in seizure prediction

Electrophysiological correlates of the BOLD signal for EEG-informed fMRI

EEG and fMRI are important tools in cognitive and clinical neuroscience. Combined EEGfMRI has been shown to help to characterise brain networks involved in epileptic activity, as well as in different sensory, motor and cognitive functions. A good understanding of the electrophysiological correlates of the blood oxygen level dependent (BOLD) signal is necessary to interpret fMRI maps, particularly when obtained in combination with EEG. We review the current understanding of electrophysiological-haemodynamic correlates, during different types of brain activity. We start by describing the basic mechanisms underlying EEG and BOLD signals, and proceed by reviewing EEG-informed fMRI studies using fMRI to map specific EEG phenomena over the entire brain (“EEG-fMRI mapping”), or exploring a range of EEGderived quantities to determine which best explain co-localised BOLD fluctuations (“local EEG-fMRI coupling”). While reviewing studies of different forms of brain activity (epileptic and non-epileptic spontaneous activity; cognitive, sensory and motor functions), a significant attention is given to epilepsy because the investigation of its haemodynamic correlates is the most common application of EEG-informed fMRI. Our review is focused on EEG-informed fMRI, an asymmetric approach of data integration. We give special attention to the invasiveness of electrophysiological measurements and the simultaneity of multimodal acquisitions because these methodological aspects determine the nature of the conclusions that can be drawn from EEG-informed fMRI studies. We emphasise the advantages of, and need for, simultaneous intracranial EEG-fMRI studies in humans, which recently became available and hold great potential to improve our understanding of the electrophysiological correlates of BOLD fluctuations

In Vivo characterization of Epileptic Tissue with Optical Spectroscopy

For children with intractable seizures, surgical removal of epileptic foci, if identifiable and feasible, can be an effective way to reduce or eliminate seizures. The success of this type of surgery strongly hinges upon the ability to identify and demarcate those epileptic foci. The ultimate goal of this research project is to develop an effective technology for detection of unique in vivo pathophysiological characteristics of epileptic cortex and, subsequently, to use this technology to guide epilepsy surgery intraoperatively. In this PhD dissertation the feasibility of using optical spectroscopy to identify unique in vivo pathophysiological characteristics of epileptic cortex was evaluated and proven using the data collected from children undergoing epilepsy surgery. In this first in vivo human study, static diffuse reflectance and fluorescence spectra were measured from the epileptic cortex, defined by intraoperative ECoG, and its surrounding tissue from pediatric patients undergoing epilepsy surgery. When feasible, biopsy samples were taken from the investigated sites for the subsequent histological analysis. Using the histological data as the gold standard, spectral data was analyzed with statistical tools. The results of the analysis show that static diffuse reflectance spectroscopy and its combination with static fluorescence spectroscopy can be used to effectively differentiate between epileptic cortex with histopathological abnormalities and normal cortex in vivo with a high degree of accuracy. To maximize the efficiency of optical spectroscopy in detecting and localizing epileptic cortex intraoperatively, the static system was upgraded to investigate histopathological abnormalities deep within the epileptic cortex, as well as to detect unique temporal pathophysiological characteristics of epileptic cortex. Detection of deep abnormalities within the epileptic cortex prompted a redesign of the fiberoptic probe. A mechanical probe holder was also designed and constructed to maintain the probe contact pressure and contact point during the time dependent measurements. The dynamic diffuse reflectance spectroscopy system was used to characterize in vivo pediatric epileptic cortex. The results of the study show that some unique wavelength dependent temporal characteristics (e.g., multiple horizontal bands in the correlation coefficient map g(λref = 800 nm, λcomp,t)) can be found in the time dependent recordings of diffuse reflectance spectra from epileptic cortex defined by ECoG

Methodological and clinical aspects of ictal and interictal MEG

During the last years magnetoencephalography (MEG), has become an important part of the pre-surgical epilepsy workup. Interictal activity is usually recorded. Nevertheless, the technological advances now enable ictal MEG recordings as well. The records of 26 pharmaco-resistant focal epilepsy patients, who underwent ictal MEG and epilepsy surgery, were reviewed. In 12 patients prediction of ictal onset zone (IOZ) localization by ictal and interictal MEG was compared with ictal intracranial EEG (icEEG). On the lobar surface level the sensitivity of ictal MEG in IOZ location was 0.71 and the specificity 0.73. The sensitivity of the interictal MEG was 0.40 and specificity 0.77. The records of 34 operated epilepsy patients with focal cortical dysplasia (FCD) were retrospectively evaluated. The resected proportion of the source cluster related to interictal MEG was evaluated in respect to postoperative seizure outcome. 17 out of 34 patients with FCD (50%) achieved seizure freedom. The seizure outcome was similar in patients with MR-invisible and MR-visible FCD. With MEG source clusters and favorable seizure outcome (Engel class I and II) the proportion of the cluster volume resection was 49% - significantly higher (p=0.02) than with MEG clusters but unfavorable outcome (5.5% of cluster volume resection). Median nerve somatosensory evoked MEG responses were processed by movement compensation based on signal space separation (MC-SSS) and on spatio-temporal signal space separation (MC-tSSS). MEG was recorded in standard and deviant head positions. With up to 5 cm head displacement, MC-SSS decreased the mean localization error from 3.97 to 2.13 cm, but increased noise of planar gradiometers from 3.4 to 5.3 fT/cm. MC-tSSS reduced noise from 3.4 to 2.8 fT/cm and reduced the mean localization error from 3.91 to 0.89 cm. The MEG data containing speech-related artifacts and data containing alpha rhythm were processed by tSSS with different correlation limits. The speech artifact was progressively suppressed with the decreasing tSSS correlation limit. The optimal artifact suppression was achieved at correlation of 0.8. The randomly distributed source current (RDCS), and auditory and somatosensory evoked fields (AEFs and SEFs) were simulated. The information was calculated employing Shannon's theory of communication for a standard 306-sensor MEG device and for a virtual MEG helmet (VMH), which was constructed based on simulated MEG measurements in different head positions. With the simulation of 360 recorded events using RDCS model the maximum Shannon's number was 989 for single head position in standard MEG array and 1272 in VMH (28.6% additional information). With AEFs the additional contribution of VMH was 12.6% and with SEFs only 1.1%. To conclude, ictal MEG predicts IOZ location with higher sensitivity than interictal MEG. Resection of larger proportion of the MEG source cluster in patients with FCD is associated with a better seizure outcome, however, complete resection of MEG source cluster is often not required for achievement of favorable seizure outcome. The seizure outcome is similar in patients having MR-positive and MR-negative FCD. MC-tSSS decreases the source localization error to less than 1 cm, when the head is displaced up to 5 cm; however, it is reasonable to limit use of movement compensation for no more than 3-cm head displacement to keep the head inside sensor helmet. The optimization of the tSSS correlation limit to about 0.8 can improve the artifact suppression in MEG without substantial change of brain signals. MEG recording of the same brain activity in different head positions with subsequent construction of VMH can improve the information content of the data.Magnetoenkefalografia (MEG) on menetelmä, jolla mitataan aivojen tuottamia heikkoja magneettikenttiä. Yksi menetelmän tärkeimmistä kliinisistä käyttö-tarkoituksista on paikantaa epilepsiapesäkkeitä aivoissa. Tämä on tärkeää epilepsiakirurgian suunnittelussa. Potilaan liikkeet mittauksen aikana ovat aiheuttaneet epätarkkuutta pesäkkeiden paikannukseen ja häiriösignaaleja mittauksiin. Ongelma on ollut erityisen korostunut lasten mittauksissa ja epileptisten kohtausten rekisteröinneissä. Useimmissa potilaissa MEG-paikannus onkin perustunut kohtausten välisten epileptiformisten aivosähköilmiöiden paikannukseen. Pitkät MEG-rekisteröinnit ovat myös olleet haastavia koska yhteistyökykyisten potilaidenkin on vaikea olla liikkumatta pitkiä aikoja. Viime vuosien tekninen kehitys on mahdollistanut MEG-mittaukset myös pään liikkeiden aikana. Myös aivosignaalien ja kehossa olevien magneettisten materiaalien (esim hammaspaikat, sydämen tahdistimet tai aivostimulaattorit) aiheuttamien magneettisten häiriöiden erottaminen on nykyisin toteutettavissa. Tämä kehitys on mahdollistanut MEG-mittaukset potilailla, joilla aiemmin ei ollut mahdollisuutta hyötyä MEG-paikannuksista ja myös MEG-mittaukset epileptisten kohtausten aikana. Tärkeä osa väitöskirjaa on epilepsiakohtausten aikaisten MEG-mittausten kliinisen hyödyn arviointi. Tulokset osoittavat, että kohtauksenaikaiset MEG-mittaukset paikantavat herkemmin epilepsiakohtauksen lähdealueen aivoissa kuin kohtausten välisten epilepsiailmiöiden lähdepaikannus. Lähdealueiden paikannus on yhtä tarkka sekä aivokuoren pinnalla että 4 cm syvyydessä aivouurteissa. Pää ei kuitenkaan saisi liikkua 3 cm enempää MEG-mittauksen aikana, ja menetelmän herkkyys paranee oilennaisesti magneettikenttien matemaattiseen mallinnukseen perustuvalla magneettisten liikehäiriöiden poistolla. Väitöskirja tutkii lisäksi aivokuoren rakennemuutosten (paikallinen aivokuoridysplasia) aiheuttaman epilepsian kohtausten välisiä MEG-mittauksia. Päinvastoin kuin aiemmin on väitetty, ei aina ole tarpeen poistaa koko epileptisia lähdealueita sisältävää aivojen aluetta hyvän leikkaustuloksen saamiseksi. Väitöskirja esittelee myös laskennallisen MEG-anturiston määritysmenetelmän , joka lisää MEG-mittausten informaatiosisältöä huomioimalla pään liikkeet tulosten analyysissä

Development of simultaneous electroencephalography and near-infrared optical topography for applications to neurovascular coupling and neonatal seizures

This thesis describes the development and preliminary application of methods for performing simultaneous electroencephalography (EEG) and near-infrared (NIR) imaging of the brain. The simultaneous application of EEG and NIR imaging has many benefits because of the complementary nature of the two modalities, and has significant potential in the study of the relationship between neuronal activity and cerebral haemodynamics. This work goes beyond previous experiments which have combined EEG and limited-channel near-infrared spectroscopy by designing and implementing an arrangement which allows dense near-infrared optical topography and EEG to be performed over the same cortical area, with as simple an application method as possible. These application methods are described in detail, as is their extensive testing using novel dual-modality phantoms and an in-vivo EEG-NIR imaging experiment in a healthy adult. These methods are subsequently applied to the study of neonates in the clinical environment. An intricate EEG-NIR imaging experiment is designed and implemented in an investigation of functional activation in the healthy neonatal visual cortex. This series of experiments also acts as a further test of the suitability of our EEG-NIR imaging methods for clinical application. The results of these experiments are presented. The EEG-NIR imaging arrangement is then applied to four neurologically damaged infants in the neonatal intensive care unit, each of whom had been diagnosed with seizures. The results of these studies are presented, and a potentially significant haemodynamic feature, which is not present in agematched controls, is identified. The importance and physiological implications of our findings are discussed, as is the suitability of a combined EEG and NIR imaging approach to the study and monitoring of neonatal brain injury

Magnetoencephalography

This is a practical book on MEG that covers a wide range of topics. The book begins with a series of reviews on the use of MEG for clinical applications, the study of cognitive functions in various diseases, and one chapter focusing specifically on studies of memory with MEG. There are sections with chapters that describe source localization issues, the use of beamformers and dipole source methods, as well as phase-based analyses, and a step-by-step guide to using dipoles for epilepsy spike analyses. The book ends with a section describing new innovations in MEG systems, namely an on-line real-time MEG data acquisition system, novel applications for MEG research, and a proposal for a helium re-circulation system. With such breadth of topics, there will be a chapter that is of interest to every MEG researcher or clinician