The spatio-temporal mapping of epileptic networks: Combination of EEG–fMRI and EEG source imaging

Simultaneous EEG–fMRI acquisitions in patients with epilepsy often reveal distributed patterns of Blood Oxygen Level Dependant (BOLD) change correlated with epileptiform discharges. We investigated if electrical source imaging (ESI) performed on the interictal epileptiform discharges (IED) acquired during fMRI acquisition could be used to study the dynamics of the networks identified by the BOLD effect, thereby avoiding the limitations of combining results from separate recordings. Nine selected patients (13 IED types identified) with focal epilepsy underwent EEG–fMRI. Statistical analysis was performed using SPM5 to create BOLD maps. ESI was performed on the IED recorded during fMRI acquisition using a realistic head model (SMAC) and a distributed linear inverse solution (LAURA). ESI could not be performed in one case. In 10/12 remaining studies, ESI at IED onset (ESIo) was anatomically close to one BOLD cluster. Interestingly, ESIo was closest to the positive BOLD cluster with maximal statistical significance in only 4/12 cases and closest to negative BOLD responses in 4/12 cases. Very small BOLD clusters could also have clinical relevance in some cases. ESI at later time frame (ESIp) showed propagation to remote sources co-localised with other BOLD clusters in half of cases. In concordant cases, the distance between maxima of ESI and the closest EEG–fMRI cluster was less than 33 mm, in agreement with previous studies. We conclude that simultaneous ESI and EEG–fMRI analysis may be able to distinguish areas of BOLD response related to initiation of IED from propagation areas. This combination provides new opportunities for investigating epileptic networks

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

Localizing Epileptic Foci Using Simultaneous EEG-fMRI Recording: Template Component Cross-Correlation

Conventional EEG-fMRI methods have been proven to be of limited use in the sense that they cannot reveal the information existing in between the spikes. To resolve this issue, the current study obtains the epileptic components time series detected on EEG and uses them to fit the Generalized Linear Model (GLM), as a substitution for classical regressors. This approach allows for a more precise localization, and equally importantly, the prediction of the future behavior of the epileptic generators. The proposed method approaches the localization process in the component domain, rather than the electrode domain (EEG), and localizes the generators through investigating the spatial correlation between the candidate components and the spike template, as well as the medical records of the patient. To evaluate the contribution of EEG-fMRI and concordance between fMRI and EEG, this method was applied on the data of 30 patients with refractory epilepsy. The results demonstrated the significant numbers of 29 and 24 for concordance and contribution, respectively, which mark improvement as compared to the existing literature. This study also shows that while conventional methods often fail to properly localize the epileptogenic zones in deep brain structures, the proposed method can be of particular use. For further evaluation, the concordance level between IED-related BOLD clusters and Seizure Onset Zone (SOZ) has been quantitatively investigated by measuring the distance between IED/SOZ locations and the BOLD clusters in all patients. The results showed the superiority of the proposed method in delineating the spike-generating network compared to conventional EEG-fMRI approaches. In all, the proposed method goes beyond the conventional methods by breaking the dependency on spikes and using the outside-the-scanner spike templates and the selected components, achieving an accuracy of 97%. Doing so, this method contributes to improving the yield of EEG-fMRI and creates a more realistic perception of the neural behavior of epileptic generators which is almost without precedent in the literature

Bayesian multi-modal model comparison: a case study on the generators of the spike and the wave in generalized spike–wave complexes

We present a novel approach to assess the networks involved in the generation of spontaneous pathological brain activity based on multi-modal imaging data. We propose to use probabilistic fMRI-constrained EEG source reconstruction as a complement to EEG-correlated fMRI analysis to disambiguate between networks that co-occur at the fMRI time resolution. The method is based on Bayesian model comparison, where the different models correspond to different combinations of fMRI-activated (or deactivated) cortical clusters. By computing the model evidence (or marginal likelihood) of each and every candidate source space partition, we can infer the most probable set of fMRI regions that has generated a given EEG scalp data window. We illustrate the method using EEG-correlated fMRI data acquired in a patient with ictal generalized spike–wave (GSW) discharges, to examine whether different networks are involved in the generation of the spike and the wave components, respectively. To this effect, we compared a family of 128 EEG source models, based on the combinations of seven regions haemodynamically involved (deactivated) during a prolonged ictal GSW discharge, namely: bilateral precuneus, bilateral medial frontal gyrus, bilateral middle temporal gyrus, and right cuneus. Bayesian model comparison has revealed the most likely model associated with the spike component to consist of a prefrontal region and bilateral temporal–parietal regions and the most likely model associated with the wave component to comprise the same temporal–parietal regions only. The result supports the hypothesis of different neurophysiological mechanisms underlying the generation of the spike versus wave components of GSW discharges

Imaging haemodynamic changes related to seizures: comparison of EEG-based general linear model, independent component analysis of fMRI and intracranial EEG

Background: Simultaneous EEG-fMRI can reveal haemodynamic changes associated with epileptic activity which may contribute to understanding seizure onset and propagation. Methods: Nine of 83 patients with focal epilepsy undergoing pre-surgical evaluation had seizures during EEG-fMRI and analysed using three approaches, two based on the general linear model (GLM) and one using independent component analysis (ICA): 1. EEGs were divided into up to three phases: early ictal EEG change, clinical seizure onset and late ictal EEG change and convolved with a canonical haemodynamic response function (HRF) (canonical GLM analysis). 2. Seizures lasting three scans or longer were additionally modelled using a Fourier basis set across the entire event (Fourier GLM analysis). 3. Independent component analysis (ICA) was applied to the fMRI data to identify ictal BOLD patterns without EEG. The results were compared with intracranial EEG. Results: The canonical GLM analysis revealed significant BOLD signal changes associated with seizures on EEG in 7/9 patients, concordant with the seizure onset zone in 4/7. The Fourier GLM analysis revealed changes in BOLD signal corresponding with the results of the canonical analysis in two patients. ICA revealed components spatially concordant with the seizure onset zone in all patients (8/9 confirmed by intracranial EEG). Conclusion: Ictal EEG-fMRI visualises plausible seizure related haemodynamic changes. The GLM approach to analysing EEG-fMRI data reveals localised BOLD changes concordant with the ictal onset zone when scalp EEG reflects seizure onset. ICA provides additional information when scalp EEG does not accurately reflect seizures and may give insight into ictal haemodynamics

Functional connectivity of the irritative zone identified by electrical source imaging, and EEG-correlated fMRI analyses.

OBJECTIVE: The irritative zone - the area generating epileptic spikes - can be studied non-invasively during the interictal period using Electrical Source Imaging (ESI) and simultaneous electroencephalography-functional magnetic resonance imaging (EEG-fMRI). Although the techniques yield results which may overlap spatially, differences in spatial localization of the irritative zone within the same patient are consistently observed. To investigate this discrepancy, we used Blood Oxygenation Level Dependent (BOLD) functional connectivity measures to examine the underlying relationship between ESI and EEG-fMRI findings. METHODS: Fifteen patients (age 20-54), who underwent presurgical epilepsy investigation, were scanned using a single-session resting-state EEG-fMRI protocol. Structural MRI was used to obtain the electrode localisation of a high-density 64-channel EEG cap. Electrical generators of interictal epileptiform discharges were obtained using a distributed local autoregressive average (LAURA) algorithm as implemented in Cartool EEG software. BOLD activations were obtained using both spike-related and voltage-map EEG-fMRI analysis. The global maxima of each method were used to investigate the temporal relationship of BOLD time courses and to assess the spatial similarity using the Dice similarity index between functional connectivity maps. RESULTS: ESI, voltage-map and spike-related EEG-fMRI methods identified peaks in 15 (100%), 13 (67%) and 8 (53%) of the 15 patients, respectively. For all methods, maxima were localised within the same lobe, but differed in sub-lobar localisation, with a median distance of 22.8 mm between the highest peak for each method. The functional connectivity analysis showed that the temporal correlation between maxima only explained 38% of the variance between the time course of the BOLD response at the maxima. The mean Dice similarity index between seed-voxel functional connectivity maps showed poor spatial agreement. SIGNIFICANCE: Non-invasive methods for the localisation of the irritative zone have distinct spatial and temporal sensitivity to different aspects of the local cortical network involved in the generation of interictal epileptiform discharges

Independent component analysis of interictal fMRI in focal epilepsy: comparison with general linear model-based EEG-correlated fMRI

The general linear model (GLM) has been used to analyze simultaneous EEG–fMRI to reveal BOLD changes linked to interictal epileptic discharges (IED) identified on scalp EEG. This approach is ineffective when IED are not evident in the EEG. Data-driven fMRI analysis techniques that do not require an EEG derived model may offer a solution in these circumstances. We compared the findings of independent components analysis (ICA) and EEG-based GLM analyses of fMRI data from eight patients with focal epilepsy. Spatial ICA was used to extract independent components (IC) which were automatically classified as either BOLD-related, motion artefacts, EPI-susceptibility artefacts, large blood vessels, noise at high spatial or temporal frequency. The classifier reduced the number of candidate IC by 78%, with an average of 16 BOLD-related IC. Concordance between the ICA and GLM-derived results was assessed based on spatio-temporal criteria. In each patient, one of the IC satisfied the criteria to correspond to IED-based GLM result. The remaining IC were consistent with BOLD patterns of spontaneous brain activity and may include epileptic activity that was not evident on the scalp EEG. In conclusion, ICA of fMRI is capable of revealing areas of epileptic activity in patients with focal epilepsy and may be useful for the analysis of EEG–fMRI data in which abnormalities are not apparent on scalp EEG

Network perspectives on epilepsy using EEG/MEG source connectivity

The evolution of EEG/MEG source connectivity is both, a promising, and controversial advance in the characterization of epileptic brain activity. In this narrative review we elucidate the potential of this technology to provide an intuitive view of the epileptic network at its origin, the different brain regions involved in the epilepsy, without the limitation of electrodes at the scalp level. Several studies have confirmed the added value of using source connectivity to localize the seizure onset zone and irritative zone or to quantify the propagation of epileptic activity over time. It has been shown in pilot studies that source connectivity has the potential to obtain prognostic correlates, to assist in the diagnosis of the epilepsy type even in the absence of visually noticeable epileptic activity in the EEG/MEG, and to predict treatment outcome. Nevertheless, prospective validation studies in large and heterogeneous patient cohorts are still lacking and are needed to bring these techniques into clinical use. Moreover, the methodological approach is challenging, with several poorly examined parameters that most likely impact the resulting network patterns. These fundamental challenges affect all potential applications of EEG/MEG source connectivity analysis, be it in a resting, spiking, or ictal state, and also its application to cognitive activation of the eloquent area in presurgical evaluation. However, such method can allow unique insights into physiological and pathological brain functions and have great potential in (clinical) neuroscience

Mapping Epileptic Networks Using Simultaneous Intracranial EEG-fMRI

Background: Potentially curative epilepsy surgery can be offered if a single, discrete epileptogenic zone (EZ) can be identified. For individuals in whom there is no clear concordance between clinical localization, scalp EEG, and imaging data, intracranial EEG (icEEG) may be needed to confirm a predefined hypothesis regarding irritative zone (IZ), seizure onset zone (SOZ), and EZ prior to surgery. However, icEEG has limited spatial sampling and may fail to reveal the full extent of epileptogenic network if predefined hypothesis is not correct. Simultaneous icEEG-fMRI has been safely acquired in humans and allows exploration of neuronal activity at the whole-brain level related to interictal epileptiform discharges (IED) captured intracranially. Methods: We report icEEG-fMRI in eight patients with refractory focal epilepsy who had resective surgery and good postsurgical outcome. Surgical resection volume in seizure-free patients post-surgically reflects confirmed identification of the EZ. IEDs on icEEG were classified according to their topographic distribution and localization (Focal, Regional, Widespread, and Non-contiguous). We also divided IEDs by their location within the surgical resection volume [primary IZ (IZ1) IED] or outside [secondary IZ (IZ2) IED]. The distribution of fMRI blood oxygen level-dependent (BOLD) changes associated with individual IED classes were assessed over the whole brain using a general linear model. The concordance of resulting BOLD map was evaluated by comparing localization of BOLD clusters with surgical resection volume. Additionally, we compared the concordance of BOLD maps and presence of BOLD clusters in remote brain areas: precuneus, cuneus, cingulate, medial frontal, and thalamus for different IED classes. Results: A total of 38 different topographic IED classes were identified across the 8 patients: Focal (22) and non-focal (16, Regional = 9, Widespread = 2, Non-contiguous = 5). Twenty-nine IEDs originated from IZ1 and 9 from IZ2. All IED classes were associated with BOLD changes. BOLD maps were concordant with the surgical resection volume for 27/38 (71%) IED classes, showing statistical global maximum BOLD cluster or another cluster in the surgical resection volume. The concordance of BOLD maps with surgical resection volume was greater (p < 0.05) for non-focal (87.5%, 14/16) as compared to Focal (59%, 13/22) IED classes. Additionally, BOLD clusters in remote cortical and deep brain areas were present in 84% (32/38) of BOLD maps, more commonly (15/16; 93%) for non-focal IED-related BOLD maps. Conclusions: Simultaneous icEEG-fMRI can reveal BOLD changes at the whole-brain level for a wide range of IEDs on icEEG. BOLD clusters within surgical resection volume and remote brain areas were more commonly seen for non-focal IED classes, suggesting that a wider hemodynamic network is at play

Dynamic imaging of coherent sources reveals different network connectivity underlying the generation and perpetuation of epileptic seizures

The concept of focal epilepsies includes a seizure origin in brain regions with hyper synchronous activity (epileptogenic zone and seizure onset zone) and a complex epileptic network of different brain areas involved in the generation, propagation, and modulation of seizures. The purpose of this work was to study functional and effective connectivity between regions involved in networks of epileptic seizures. The beginning and middle part of focal seizures from ictal surface EEG data were analyzed using dynamic imaging of coherent sources (DICS), an inverse solution in the frequency domain which describes neuronal networks and coherences of oscillatory brain activities. The information flow (effective connectivity) between coherent sources was investigated using the renormalized partial directed coherence (RPDC) method. In 8/11 patients, the first and second source of epileptic activity as found by DICS were concordant with the operative resection site; these patients became seizure free after epilepsy surgery. In the remaining 3 patients, the results of DICS / RPDC calculations and the resection site were discordant; these patients had a poorer post-operative outcome. The first sources as found by DICS were located predominantly in cortical structures; subsequent sources included some subcortical structures: thalamus, Nucl. Subthalamicus and cerebellum. DICS seems to be a powerful tool to define the seizure onset zone and the epileptic networks involved. Seizure generation seems to be related to the propagation of epileptic activity from the primary source in the seizure onset zone, and maintenance of seizures is attributed to the perpetuation of epileptic activity between nodes in the epileptic network. Despite of these promising results, this proof of principle study needs further confirmation prior to the use of the described methods in the clinical praxis