Late-onset temporal lobe epilepsy: insights from brain atrophy and Alzheimer's disease biomarkers.

Considering the growing age of the world population, the incidence of epilepsy in older adults is expected to increase significantly. It has been suggested that late-onset temporal lobe epilepsy (LO-TLE) may be neurodegenerative in origin and overlap with Alzheimer's Disease (AD). Herein, we aimed to characterize the pattern of cortical atrophy and cerebrospinal fluid (CSF) biomarkers of AD (total and phosphorylated tau, and ß-amyloid) in a selected population of LO-TLE of unknown origin. We prospectively enrolled individuals with temporal lobe epilepsy onset after the age of 50 and no cognitive impairment. They underwent a structural MRI scan and CSF biomarkers measurement. Imaging and biomarkers data were compared to three retrospectively collected groups: (i) age-sex-matched healthy controls, (ii) patients with Mild Cognitive Impairment (MCI) and abnormal CSF AD biomarkers (MCI-AD), and (iii) patients with MCI and normal CSF AD biomarkers (MCI-noAD). From a pool of 52 patients, twenty consecutive eligible LO-TLE patients with a mean disease duration of 1.8 years were recruited. As control populations, 25 patients with MCI-AD, 25 patients with MCI-noAD, and 25 healthy controls were enrolled. CSF biomarkers returned normal values in LO-TLE, significantly different from patients with MCI due to AD. There were no differences in cortico-subcortical atrophy between epilepsy patients and healthy controls, while patients with MCI demonstrated widespread injuries of cortico-subcortical structures. Individuals with a late-onset form of temporal lobe epilepsy, characterized by short disease duration and normal CSF ß-amyloid and tau protein levels, showed patterns of cortical thickness and subcortical volumes not significantly different from healthy controls, but highly different from patients with MCI, either due to Alzheimer's Disease or not.

Safety of intracranial electroencephalography during functional electromagnetic resonance imaging in humans at 1.5 tesla using a head transmit RF coil: Histopathological and heat-shock immunohistochemistry observations.

OBJECTIVES: Simultaneous intracranial EEG and functional MRI (icEEG-fMRI) recordings in humans, whereby EEG is recorded from electrodes implanted inside the cranium during fMRI scanning, were made possible following safety studies on test phantoms and our specification of a rigorous data acquisition protocol. In parallel with this work, other investigations in our laboratory revealed the damage caused by the EEG electrode implantation procedure at the cellular level. The purpose of this report is to further explore the safety of performing MRI, including simultaneous icEEG-fMRI data acquisitions, in the presence of implanted intra-cranial EEG electrodes, by presenting some histopathological and heat-shock immunopositive labeling observations in surgical tissue samples from patients who underwent the scanning procedure. METHODS: We performed histopathology and heat shock protein expression analyses on surgical tissue samples from nine patients who had been implanted with icEEG electrodes. Three patients underwent icEEG-fMRI and structural MRI (sMRI); three underwent sMRI only, all at similar time points after icEEG implantation; and three who did not undergo functional or sMRI with icEEG electrodes. RESULTS: The histopathological findings from the three patients who underwent icEEG-fMRI were similar to those who did not, in that they showed no evidence of additional damage in the vicinity of the electrodes, compared to cases who had no MRI with implanted icEEG electrodes. This finding was similar to our observations in patients who only underwent sMRI with implanted icEEG electrodes. CONCLUSION: This work provides unique evidence on the safety of functional MRI in the presence of implanted EEG electrodes. In the cases studied, icEEG-fMRI performed in accordance with our protocol based on low-SAR (≤0.1 W/kg) sequences at 1.5T using a head-transmit RF coil, did not result in measurable additional damage to the brain tissue in the vicinity of implanted electrodes. Furthermore, while one cannot generalize the results of this study beyond the specific electrode implantation and scanning conditions described herein, we submit that our approach is a useful framework for the post-hoc safety assessment of MR scanning with brain implants.

Peri-ictal hypoxia is related to extent of regional brain volume loss accompanying generalized tonic-clonic seizures.

OBJECTIVES: Hypoxia, or abnormally low blood-oxygen levels, often accompanies seizures and may elicit brain structural changes in people with epilepsy which contribute to central processes underlying sudden unexpected death in epilepsy (SUDEP). The extent to which hypoxia may be related to brain structural alterations in this patient group remains unexplored. METHODS: We analyzed high-resolution T1-weighted magnetic resonance imaging (MRI) to determine brain morphometric and volumetric alterations in people with generalized tonic-clonic seizures (GTCS) recorded during long-term video-electroencephalography (VEEG), recruited from two sites (n = 22), together with data from age- and sex-matched healthy controls (n = 43). Subjects were sub-divided into those with mild/moderate (GTCS-hypox-mild/moderate, n = 12) and severe (GTCS-hypox-severe, n = 10) hypoxia, measured by peripheral oxygen saturation (SpO2 ) during VEEG. Whole-brain voxel-based morphometry (VBM) and regional volumetry were used to assess group comparisons and correlations between brain structural measurements as well as the duration and extent of hypoxia during GTCS. RESULTS: Morphometric and volumetric alterations appeared in association with peri-GTCS hypoxia, including volume loss in the periaqueductal gray (PAG), thalamus, hypothalamus, vermis, cerebellum, parabrachial pons, and medulla. Thalamic and PAG volume was significantly reduced in GTCS patients with severe hypoxia compared with GTCS patients with mild/moderate hypoxia. Brainstem volume loss appeared in both hypoxia groups, although it was more extensive in those with severe hypoxia. Significant negative partial correlations emerged between thalamic and hippocampal volume and extent of hypoxia, whereas vermis and accumbens volumes declined with increasing hypoxia duration. SIGNIFICANCE: Brain structural alterations in patients with GTCS are related to the extent of hypoxia in brain sites that serve vital functions. Although the changes are associative only, they provide evidence of injury to regulatory brain sites related to respiratory manifestations of seizures.

BOLD mapping of human epileptic spikes recorded during simultaneous intracranial EEG-fMRI: The impact of automated spike classification.

OBJECTIVES: Simultaneous intracranial EEG and functional MRI (icEEG-fMRI) can be used to map the haemodynamic (BOLD) changes associated with the generation of IEDs. Unlike scalp EEG-fMRI, in most patients who undergo icEEG-fMRI, IEDs recorded intracranially are numerous and show variability in terms of field amplitude and morphology. Therefore, visual marking can be highly subjective and time consuming. In this study, we applied an automated spike classification algorithm, Wave_clus (WC), to IEDs marked visually on icEEG data acquired during simultaneous fMRI acquisition. The motivation of this work is to determine whether using a potentially more consistent and unbiased automated approach can produce more biologically meaningful BOLD patterns compared to the BOLD patterns obtained based on the conventional, visual classification. METHODS: We analysed simultaneous icEEG-fMRI data from eight patients with severe drug resistant epilepsy, and who subsequently underwent resective surgery that resulted in a good outcome: confirmed epileptogenic zone (EZ). For each patient two fMRI analyses were performed: one based on the conventional visual IED classification and the other based on the automated classification. We used the concordance of the IED-related BOLD maps with the confirmed EZ as an indication of their biological meaning, which we compared for the automated and visual classifications for all IED originating in the EZ. RESULTS: Across the group, the visual and automated classifications resulted in 32 and 24 EZ IED classes respectively, for which 75% vs 83% of the corresponding BOLD maps were concordant. At the single-subject level, the BOLD maps for the automated approach had greater concordance in four patients, and less concordance in one patient, compared to those obtained using the conventional visual classification, and equal concordance for three remaining patients. These differences did not reach statistical significance. CONCLUSION: We found automated IED classification on icEEG data recorded during fMRI to be feasible and to result in IED-related BOLD maps that may contain similar or greater biological meaning compared to the conventional approach in the majority of the cases studied. We anticipate that this approach will help to gain significant new insights into the brain networks associated with IEDs and in relation to postsurgical outcome.

Combined electroencephalography-functional magnetic resonance imaging and electrical source imaging improves localization of pediatric focal epilepsy.

OBJECTIVE: Surgical treatment in epilepsy is effective if the epileptogenic zone (EZ) can be correctly localized and characterized. Here we use simultaneous electroencephalography-functional magnetic resonance imaging (EEG-fMRI) data to derive EEG-fMRI and electrical source imaging (ESI) maps. Their yield and their individual and combined ability to (1) localize the EZ and (2) predict seizure outcome were then evaluated. METHODS: Fifty-three children with drug-resistant epilepsy underwent EEG-fMRI. Interictal discharges were mapped using both EEG-fMRI hemodynamic responses and ESI. A single localization was derived from each individual test (EEG-fMRI global maxima [GM]/ESI maximum) and from the combination of both maps (EEG-fMRI/ESI spatial intersection). To determine the localization accuracy and its predictive performance, the individual and combined test localizations were compared to the presumed EZ and to the postsurgical outcome. RESULTS: Fifty-two of 53 patients had significant maps: 47 of 53 for EEG-fMRI, 44 of 53 for ESI, and 34 of 53 for both. The EZ was well characterized in 29 patients; 26 had an EEG-fMRI GM localization that was correct in 11, 22 patients had ESI localization that was correct in 17, and 12 patients had combined EEG-fMRI and ESI that was correct in 11. Seizure outcome following resection was correctly predicted by EEG-fMRI GM in 8 of 20 patients, and by the ESI maximum in 13 of 16. The combined EEG-fMRI/ESI region entirely predicted outcome in 9 of 9 patients, including 3 with no lesion visible on MRI. INTERPRETATION: EEG-fMRI combined with ESI provides a simple unbiased localization that may predict surgery better than each individual test, including in MRI-negative patients. Ann Neurol 2017;82:278-287.

ICN_Atlas: Automated description and quantification of functional MRI activation patterns in the framework of intrinsic connectivity networks.

Generally, the interpretation of functional MRI (fMRI) activation maps continues to rely on assessing their relationship to anatomical structures, mostly in a qualitative and often subjective way. Recently, the existence of persistent and stable brain networks of functional nature has been revealed; in particular these so-called intrinsic connectivity networks (ICNs) appear to link patterns of resting state and task-related state connectivity. These networks provide an opportunity of functionally-derived description and interpretation of fMRI maps, that may be especially important in cases where the maps are predominantly task-unrelated, such as studies of spontaneous brain activity e.g. in the case of seizure-related fMRI maps in epilepsy patients or sleep states. Here we present a new toolbox (ICN_Atlas) aimed at facilitating the interpretation of fMRI data in the context of ICN. More specifically, the new methodology was designed to describe fMRI maps in function-oriented, objective and quantitative way using a set of 15 metrics conceived to quantify the degree of 'engagement' of ICNs for any given fMRI-derived statistical map of interest. We demonstrate that the proposed framework provides a highly reliable quantification of fMRI activation maps using a publicly available longitudinal (test-retest) resting-state fMRI dataset. The utility of the ICN_Atlas is also illustrated on a parametric task-modulation fMRI dataset, and on a dataset of a patient who had repeated seizures during resting-state fMRI, confirmed on simultaneously recorded EEG. The proposed ICN_Atlas toolbox is freely available for download at http://icnatlas.com and at http://www.nitrc.org for researchers to use in their fMRI investigations.

Simultaneous Intracranial EEG-fMRI Shows Inter-Modality Correlation in Time-Resolved Connectivity Within Normal Areas but Not Within Epileptic Regions.

For the first time in research in humans, we used simultaneous icEEG-fMRI to examine the link between connectivity in haemodynamic signals during the resting-state (rs) and connectivity derived from electrophysiological activity in terms of the inter-modal connectivity correlation (IMCC). We quantified IMCC in nine patients with drug-resistant epilepsy (i) within brain networks in 'healthy' non-involved cortical zones (NIZ) and (ii) within brain networks involved in generating seizures and interictal spikes (IZ1) or solely spikes (IZ2). Functional connectivity (h 2 ) estimates for 10 min of resting-state data were obtained between each pair of electrodes within each clinical zone for both icEEG and fMRI. A sliding window approach allowed us to quantify the variability over time of h 2 (vh 2) as an indicator of connectivity dynamics. We observe significant positive IMCC for h 2 and vh 2, for multiple bands in the NIZ only, with the strongest effect in the lower icEEG frequencies. Similarly, intra-modal h 2 and vh 2 were found to be differently modified as a function of different epileptic processes: compared to NIZ, [Formula: see text] was higher in IZ1, but lower in IZ2, while [Formula: see text] showed the inverse pattern. This corroborates previous observations of inter-modal connectivity discrepancies in pathological cortices, while providing the first direct invasive and simultaneous comparison in humans. We also studied time-resolved FC variability multimodally for the first time, finding that IZ1 shows both elevated internal [Formula: see text] and less rich dynamical variability, suggesting that its chronic role in epileptogenesis may be linked to greater homogeneity in self-sustaining pathological oscillatory states.

Towards motion insensitive EEG-fMRI: Correcting motion-induced voltages and gradient artefact instability in EEG using an fMRI prospective motion correction (PMC) system.

The simultaneous acquisition of electroencephalography and functional magnetic resonance imaging (EEG-fMRI) is a multimodal technique extensively applied for mapping the human brain. However, the quality of EEG data obtained within the MRI environment is strongly affected by subject motion due to the induction of voltages in addition to artefacts caused by the scanning gradients and the heartbeat. This has limited its application in populations such as paediatric patients or to study epileptic seizure onset. Recent work has used a Moiré-phase grating and a MR-compatible camera to prospectively update image acquisition and improve fMRI quality (prospective motion correction: PMC). In this study, we use this technology to retrospectively reduce the spurious voltages induced by motion in the EEG data acquired inside the MRI scanner, with and without fMRI acquisitions. This was achieved by modelling induced voltages from the tracking system motion parameters; position and angles, their first derivative (velocities) and the velocity squared. This model was used to remove the voltages related to the detected motion via a linear regression. Since EEG quality during fMRI relies on a temporally stable gradient artefact (GA) template (calculated from averaging EEG epochs matched to scan volume or slice acquisition), this was evaluated in sessions both with and without motion contamination, and with and without PMC. We demonstrate that our approach is capable of significantly reducing motion-related artefact with a magnitude of up to 10mm of translation, 6° of rotation and velocities of 50mm/s, while preserving physiological information. We also demonstrate that the EEG-GA variance is not increased by the gradient direction changes associated with PMC. Provided a scan slice-based GA template is used (rather than a scan volume GA template) we demonstrate that EEG variance during motion can be supressed towards levels found when subjects are still. In summary, we show that PMC can be used to dramatically improve EEG quality during large amplitude movements, while benefiting from previously reported improvements in fMRI quality, and does not affect EEG data quality in the absence of large amplitude movements.

EEG-fMRI in the presurgical evaluation of temporal lobe epilepsy.

OBJECTIVE: Drug-resistant temporal lobe epilepsy (TLE) often requires thorough investigation to define the epileptogenic zone for surgical treatment. We used simultaneous interictal scalp EEG-fMRI to evaluate its value for predicting long-term postsurgical outcome. METHODS: 30 patients undergoing presurgical evaluation and proceeding to temporal lobe (TL) resection were studied. Interictal epileptiform discharges (IEDs) were identified on intra-MRI EEG and used to build a model of haemodynamic changes. In addition, topographic electroencephalographic correlation maps were calculated between the average IED during video-EEG and intra-MRI EEG, and used as a condition. This allowed the analysis of all data irrespective of the presence of IED on intra-MRI EEG. Mean follow-up after surgery was 46 months. International League Against Epilepsy (ILAE) outcomes 1 and 2 were considered good, and 3-6 poor, surgical outcome. Haemodynamic maps were classified according to the presence (Concordant) or absence (Discordant) of Blood Oxygen Level-Dependent (BOLD) change in the TL overlapping with the surgical resection. RESULTS: The proportion of patients with good surgical outcome was significantly higher (13/16; 81%) in the Concordant than in the Discordant group (3/14; 21%) (χ(2) test, Yates correction, p=0.003) and multivariate analysis showed that Concordant BOLD maps were independently related to good surgical outcome (p=0.007). Sensitivity and specificity of EEG-fMRI results to identify patients with good surgical outcome were 81% and 79%, respectively, and positive and negative predictive values were 81% and 79%, respectively. INTERPRETATION: The presence of significant BOLD changes in the area of resection on interictal EEG-fMRI in patients with TLE retrospectively confirmed the epileptogenic zone. Surgical resection including regions of haemodynamic changes in the TL may lead to better postoperative outcome.

Tracking slow modulations in synaptic gain using dynamic causal modelling: validation in epilepsy.

In this work we propose a proof of principle that dynamic causal modelling can identify plausible mechanisms at the synaptic level underlying brain state changes over a timescale of seconds. As a benchmark example for validation we used intracranial electroencephalographic signals in a human subject. These data were used to infer the (effective connectivity) architecture of synaptic connections among neural populations assumed to generate seizure activity. Dynamic causal modelling allowed us to quantify empirical changes in spectral activity in terms of a trajectory in parameter space - identifying key synaptic parameters or connections that cause observed signals. Using recordings from three seizures in one patient, we considered a network of two sources (within and just outside the putative ictal zone). Bayesian model selection was used to identify the intrinsic (within-source) and extrinsic (between-source) connectivity. Having established the underlying architecture, we were able to track the evolution of key connectivity parameters (e.g., inhibitory connections to superficial pyramidal cells) and test specific hypotheses about the synaptic mechanisms involved in ictogenesis. Our key finding was that intrinsic synaptic changes were sufficient to explain seizure onset, where these changes showed dissociable time courses over several seconds. Crucially, these changes spoke to an increase in the sensitivity of principal cells to intrinsic inhibitory afferents and a transient loss of excitatory-inhibitory balance.

Electrophysiological correlates of the BOLD signal for EEG-informed fMRI.

Electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) are important tools in cognitive and clinical neuroscience. Combined EEG-fMRI 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 EEG-derived quantities to determine which best explain colocalised BOLD fluctuations (local EEG-fMRI coupling). While reviewing studies of different forms of brain activity (epileptic and nonepileptic 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.

Characterisation and reduction of the EEG artefact caused by the helium cooling pump in the MR environment: validation in epilepsy patient data.

The EEG acquired simultaneously with fMRI is distorted by a number of artefacts related to the presence of strong magnetic fields, which must be reduced in order to allow for a useful interpretation and quantification of the EEG data. For the two most prominent artefacts, associated with magnetic field gradient switching and the heart beat, reduction methods have been developed and applied successfully. However, a number of artefacts related to the MR-environment can be found to distort the EEG data acquired even without ongoing fMRI acquisition. In this paper, we investigate the most prominent of those artefacts, caused by the Helium cooling pump, and propose a method for its reduction and respective validation in data collected from epilepsy patients. Since the Helium cooling pump artefact was found to be repetitive, an average template subtraction method was developed for its reduction with appropriate adjustments for minimizing the degradation of the physiological part of the signal. The new methodology was validated in a group of 15 EEG-fMRI datasets collected from six consecutive epilepsy patients, where it successfully reduced the amplitude of the artefact spectral peaks by 95 ± 2 % while the background spectral amplitude within those peaks was reduced by only -5 ± 4 %. Although the Helium cooling pump should ideally be switched off during simultaneous EEG-fMRI acquisitions, we have shown here that in cases where this is not possible the associated artefact can be effectively reduced in post processing.

Generalized spike and waves: effect of discharge duration on brain networks as revealed by BOLD fMRI.

In the past decade, the possibility of combining recordings of EEG and functional MRI (EEG-fMRI), has brought a new insight into the brain network underlying generalized spike wave discharges (GSWD). Nevertheless, how GSWD duration influences this network is not fully understood. In this study we aim to investigate whether GSWD duration had a threshold (non-linear) and/or a linear effect on the amplitude of the associated BOLD changes in any brain regions. This could help in elucidating if there is an hemodynamic background supporting the differentiation between interictal and ictal events. We studied a population of 42 patients with idiopathic generalized epilepsies (IGE) who underwent resting-state EEG-fMRI recordings in three centres (London, UK; Modena, Italy; Rome, Italy), applying a parametric analysis of the GSWD duration. Patients were classified as having Childhood Absence epilepsy, Juvenile Absence Epilepsy, or Juvenile Myoclonic Epilepsy. At the population level linear GSWD duration-related BOLD signal changes were found in a network of brain regions: mainly BOLD increase in thalami and cerebral ventricles, and BOLD decrease in posterior cingulate, precuneus and bilateral parietal regions. No region of significant BOLD change was found in the group analysis for the non-linear effect of GSWD duration. To explore the possible effect of both the different IGE sub-syndromes and the different protocols and scanning equipment used in the study, a full-factorial ANOVA design was performed revealing no significant differences. These findings support the idea that the amplitude of the BOLD changes is linearly related to the GSWD duration with no universal threshold effect of spike and wave duration on the brain network supporting this activity.

The influence of wakefulness fluctuations on brain networks involved in centrotemporal spike occurrence.

OBJECTIVE: Drowsiness has been implicated in the modulation of centro-temporal spikes (CTS) in Self-limited epilepsy with Centro-Temporal Spikes (SeLECTS). Here, we explore this relationship and whether fluctuations in wakefulness influence the brain networks involved in CTS generation. METHODS: Functional MRI (fMRI) and electroencephalography (EEG) was simultaneously acquired in 25 SeLECTS. A multispectral EEG index quantified drowsiness ('EWI': EEG Wakefulness Index). EEG (Pearson Correlation, Cross Correlation, Trend Estimation, Granger Causality) and fMRI (PPI: psychophysiological interactions) analytic approaches were adopted to explore respectively: (a) the relationship between EWI and changes in CTS frequency and (b) the functional connectivity of the networks involved in CTS generation and wakefulness oscillations. EEG analyses were repeated on a sample of routine EEG from the same patient's cohort. RESULTS: No correlation was found between EWI fluctuations and CTS density during the EEG-fMRI recordings, while they showed an anticorrelated trend when drowsiness was followed by proper sleep in routine EEG traces. According to PPI findings, EWI fluctuations modulate the connectivity between the brain networks engaged by CTS and the left frontal operculum. CONCLUSIONS: While CTS frequency per se seems unrelated to drowsiness, wakefulness oscillations modulate the connectivity between CTS generators and key regions of the language circuitry, a cognitive function often impaired in SeLECTS. SIGNIFICANCE: This work advances our understanding of (a) interaction between CTS occurrence and vigilance fluctuations and (b) possible mechanisms responsible for language disruption in SeLECTS.

Measurement of the Mapping between Intracranial EEG and fMRI Recordings in the Human Brain.

There are considerable gaps in our understanding of the relationship between human brain activity measured at different temporal and spatial scales. Here, electrocorticography (ECoG) measures were used to predict functional MRI changes in the sensorimotor cortex in two brain states: at rest and during motor performance. The specificity of this relationship to spatial co-localisation of the two signals was also investigated. We acquired simultaneous ECoG-fMRI in the sensorimotor cortex of three patients with epilepsy. During motor activity, high gamma power was the only frequency band where the electrophysiological response was co-localised with fMRI measures across all subjects. The best model of fMRI changes across states was its principal components, a parsimonious description of the entire ECoG spectrogram. This model performed much better than any others that were based either on the classical frequency bands or on summary measures of cross-spectral changes. The region-specific fMRI signal is reflected in spatially and spectrally distributed EEG activity.

Mapping interictal epileptic discharges using mutual information between concurrent EEG and fMRI.

OBJECTIVE: The mapping of haemodynamic changes related to interictal epileptic discharges (IED) in simultaneous electroencephalography (EEG) and functional MRI (fMRI) studies is usually carried out by means of EEG-correlated fMRI analyses where the EEG information specifies the model to test on the fMRI signal. The sensitivity and specificity critically depend on the accuracy of EEG detection and the validity of the haemodynamic model. In this study we investigated whether an information theoretic analysis based on the mutual information (MI) between the presence of epileptic activity on EEG and the fMRI data can provide further insights into the haemodynamic changes related to interictal epileptic activity. The important features of MI are that: 1) both recording modalities are treated symmetrically; 2) no requirement for a-priori models for the haemodynamic response function, or assumption of a linear relationship between the spiking activity and BOLD responses, and 3) no parametric model for the type of noise or its probability distribution is necessary for the computation of MI. METHODS: Fourteen patients with pharmaco-resistant focal epilepsy underwent EEG-fMRI and intracranial EEG and/or surgical resection with positive postoperative outcome (seizure freedom or considerable reduction in seizure frequency) was available in 7/14 patients. We used nonparametric statistical assessment of the MI maps based on a four-dimensional wavelet packet resampling method. The results of MI were compared to the statistical parametric maps obtained with two conventional General Linear Model (GLM) analyses based on the informed basis set (canonical HRF and its temporal and dispersion derivatives) and the Finite Impulse Response (FIR) models. RESULTS: The MI results were concordant with the electro-clinically or surgically defined epileptogenic area in 8/14 patients and showed the same degree of concordance as the results obtained with the GLM-based methods in 12 patients (7 concordant and 5 discordant). In one patient, the information theoretic analysis improved the delineation of the irritative zone compared with the GLM-based methods. DISCUSSION: Our findings suggest that an information theoretic analysis can provide clinically relevant information about the BOLD signal changes associated with the generation and propagation of interictal epileptic discharges. The concordance between the MI, GLM and FIR maps support the validity of the assumptions adopted in GLM-based analyses of interictal epileptic activity with EEG-fMRI in such a manner that they do not significantly constrain the localization of the epileptogenic zone.

Localisation of epileptic foci using novel imaging modalities.

PURPOSE OF REVIEW: This review examines recent reports on the use of advanced techniques to map the regions and networks involved during focal epileptic seizure generation in humans. RECENT FINDINGS: A number of imaging techniques are capable of providing new localizing information on the ictal processes and epileptogenic zone. Evaluating the clinical utility of these findings has been mainly performed through post-hoc comparison with the findings of invasive EEG and ictal single-photon emission computed tomography, using postsurgical seizure reduction as the main outcome measure. Added value has been demonstrated in MRI-negative cases. Improved understanding of the human ictiogenic processes and the focus vs. network hypothesis is likely to result from the application of multimodal techniques that combine electrophysiological, semiological, and whole-brain coverage of brain activity changes. SUMMARY: On the basis of recent research in the field of neuroimaging, several novel imaging modalities have been improved and developed to provide information about the localization of epileptic foci.

Mapping hemodynamic correlates of seizures using fMRI: A review.

Functional magnetic resonance imaging (fMRI) is able to detect changes in blood oxygenation level associated with neuronal activity throughout the brain. For more than a decade, fMRI alone or in combination with simultaneous EEG recording (EEG-fMRI) has been used to investigate the hemodynamic changes associated with interictal and ictal epileptic discharges. This is the first literature review to focus on the various fMRI acquisition and data analysis methods applied to map epileptic seizure-related hemodynamic changes from the first report of an fMRI scan of a seizure to the present day. Two types of data analysis approaches, based on temporal correlation and data driven, are explained and contrasted. The spatial and temporal relationship between the observed hemodynamic changes using fMRI and other non-invasive and invasive electrophysiological and imaging data is considered. We then describe the role of fMRI in localizing and exploring the networks involved in spontaneous and triggered seizure onset and propagation. We also discuss that fMRI alone and combined with EEG hold great promise in the investigation of seizure-related hemodynamic changes non-invasively in humans. We think that this will lead to significant improvements in our understanding of seizures with important consequences for the treatment of epilepsy.

Imaging the interaction: epileptic discharges, working memory, and behavior.

Interictal generalized epileptiform discharges may impair cognition. We used simultaneous video-electroencephalography and functional imaging to quantify changes, induced by epileptiform discharges, in the task-related activations during a spatial working-memory paradigm. The number of epileptiform discharges increased during the task with its level of complexity, but were not significantly associated with wrong responses during the task. We observed hemodynamic responses in working-memory related frontal-lobe-network, motor-cortex, precuneus, and parietal lobes in the absence of epileptiform discharges. In the presence of epileptiform discharges during the task, task-related hemodynamic changes were seen only in motor-cortex, precuneus, and parietal lobes. These findings suggest that generalized epileptiform discharges during a high demanding working memory task may change the working memory-related hemodynamic responses in frontal-lobe-network.

Mapping preictal and ictal haemodynamic networks using video-electroencephalography and functional imaging.

Ictal patterns on scalp-electroencephalography are often visible only after propagation, therefore rendering localization of the seizure onset zone challenging. We hypothesized that mapping haemodynamic changes before and during seizures using simultaneous video-electroencephalography and functional imaging will improve the localization of the seizure onset zone. Fifty-five patients with ≥2 refractory focal seizures/day, and who had undergone long-term video-electroencephalography monitoring were included in the study. 'Preictal' (30 s immediately preceding the electrographic seizure onset) and ictal phases, 'ictal-onset'; 'ictalestablished' and 'late ictal', were defined based on the evolution of the electrographic pattern and clinical semiology. The functional imaging data were analysed using statistical parametric mapping to map ictal phase-related haemodynamic changes consistent across seizures. The resulting haemodynamic maps were overlaid on co-registered anatomical scans, and the spatial concordance with the presumed and invasively defined seizure onset zone was determined. Twenty patients had typical seizures during functional imaging. Seizures were identified on video-electroencephalography in 15 of 20, on electroencephalography alone in two and on video alone in three patients. All patients showed significant ictal-related haemodynamic changes. In the six cases that underwent invasive evaluation, the ictal-onset phase-related maps had a degree of concordance with the presumed seizure onset zone for all patients. The most statistically significant haemodynamic cluster within the presumed seizure onset zone was between 1.1 and 3.5 cm from the invasively defined seizure onset zone, which was resected in two of three patients undergoing surgery (Class I post-surgical outcome) and was not resected in one patient (Class III post-surgical outcome). In the remaining 14 cases, the ictal-onset phase-related maps had a degree of concordance with the presumed seizure onset zone in six of eight patients with structural-lesions and five of six non-lesional patients. The most statistically significant haemodynamic cluster was localizable at sub-lobar level within the presumed seizure onset zone in six patients. The degree of concordance of haemodynamic maps was significantly better (P < 0.05) for the ictal-onset phase [entirely concordant/concordant plus (13/20; 65%) + some concordance (4/20; 20%) = 17/20; 85%] than ictal-established [entirely concordant/concordant plus (5/13; 38%) + some concordance (4/13; 31%) = 9/13; 69%] and late ictal [concordant plus (1/9; 11%) + some concordance (4/9; 44%) = 5/9; 55%] phases. Ictal propagation-related haemodynamic changes were also seen in symptomatogenic areas (9/20; 45%) and the default mode network (13/20; 65%). A common pattern of preictal changes was seen in 15 patients, starting between 98 and 14 s before electrographic seizure onset, and the maps had a degree of concordance with the presumed seizure onset zone in 10 patients. In conclusion, preictal and ictal haemodynamic changes in refractory focal seizures can non-invasively localize seizure onset at sub-lobar/gyral level when ictal scalp-electroencephalography is not helpful.