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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.

Over the last two decades, technological advances in electroencephalography (EEG) have allowed us to extend its clinical utility for the evaluation of patients with epilepsy. This article reviews three main areas in which substantial advances have been made in the diagnosis and pre-surgical planning of patients with epilepsy. Firstly, the development of small portable video-EEG systems have allowed some patients to record their attacks at home, thereby improving diagnosis, with consequent substantial healthcare and economic implications. Secondly, in specialist centres carrying out epilepsy surgery, there has been considerable interest in whether bursts of very high frequency EEG activity can help to determine the regions of the brain likely to be generating the seizures. Identification of these discharges, initially only recorded from intracranial electrodes, may thus allow better surgical planning and improve surgical outcomes. Finally we discuss the contribution of electrical source imaging in the pre-surgical evaluation of patients with focal epilepsy, and its prospects for the future.

Accurately characterising the brain networks involved in seizure activity may have important implications for our understanding of epilepsy. Intracranial EEG-fMRI can be used to capture focal epileptic events in humans with exquisite electrophysiological sensitivity and allows for identification of brain structures involved in this phenomenon over the entire brain. We investigated ictal BOLD networks using the simultaneous intracranial EEG-fMRI (icEEG-fMRI) in a 30 year-old male undergoing invasive presurgical evaluation with bilateral depth electrode implantations in amygdalae and hippocampi for refractory temporal lobe epilepsy. One spontaneous focal electrographic seizure was recorded. The aims of the data analysis were firstly to map BOLD changes related to the ictal activity identified on icEEG and secondly to compare different fMRI modelling approaches. Visual inspection of the icEEG showed an onset dominated by beta activity involving the right amygdala and hippocampus lasting 6.4 s (ictal onset phase), followed by gamma activity bilaterally lasting 14.8 s (late ictal phase). The fMRI data was analysed using SPM8 using two modelling approaches: firstly, purely based on the visually identified phases of the seizure and secondly, based on EEG spectral dynamics quantification. For the visual approach the two ictal phases were modelled as 'ON' blocks convolved with the haemodynamic response function; in addition the BOLD changes during the 30 s preceding the onset were modelled using a flexible basis set. For the quantitative fMRI modelling approach two models were evaluated: one consisting of the variations in beta and gamma bands power, thereby adding a quantitative element to the visually-derived models, and another based on principal components analysis of the entire spectrogram in attempt to reduce the bias associated with the visual appreciation of the icEEG. BOLD changes related to the visually defined ictal onset phase were revealed in the medial and lateral right temporal lobe. For the late ictal phase, the BOLD changes were remote from the SOZ and in deep brain areas (precuneus, posterior cingulate and others). The two quantitative models revealed BOLD changes involving the right hippocampus, amygdala and fusiform gyrus and in remote deep brain structures and the default mode network-related areas. In conclusion, icEEG-fMRI allowed us to reveal BOLD changes within and beyond the SOZ linked to very localised ictal fluctuations in beta and gamma activity measured in the amygdala and hippocampus. Furthermore, the BOLD changes within the SOZ structures were better captured by the quantitative models, highlighting the interest in considering seizure-related EEG fluctuations across the entire spectrum.

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., (Copyright © 2012 Elsevier Inc. All rights reserved.)

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.

Objective: Surgical treatment of focal epilepsy in patients with focal cortical dysplasia (FCD) is most successful if all epileptogenic tissue is resected. This may not be evident on structural magnetic resonance imaging (MRI), so intracranial electroencephalography (icEEG) is needed to delineate the seizure onset zone (SOZ). EEG-functional MRI (fMRI) can reveal interictal discharge (IED)-related hemodynamic changes in the irritative zone (IZ). We assessed the value of EEG-fMRI in patients with FCD-associated focal epilepsy by examining the relationship between IED-related hemodynamic changes, icEEG findings, and postoperative outcome., Methods: Twenty-three patients with FCD-associated focal epilepsy undergoing presurgical evaluation including icEEG underwent simultaneous EEG-fMRI at 3T. IED-related hemodynamic changes were modeled, and results were overlaid on coregistered T1-weighted MRI scans fused with computed tomography scans showing the intracranial electrodes. IED-related hemodynamic changes were compared with the SOZ on icEEG and postoperative outcome at 1 year., Results: Twelve of 23 patients had IEDs during recording, and 11 of 12 had significant IED-related hemodynamic changes. The fMRI results were concordant with the SOZ in 5 of 11 patients, all of whom had a solitary SOZ on icEEG. Four of 5 had >50% reduction in seizure frequency following resective surgery. The remaining 6 of 11 patients had widespread or discordant regions of IED-related fMRI signal change. Five of 6 had either a poor surgical outcome (<50% reduction in seizure frequency) or widespread SOZ precluding surgery., Interpretation: Comparison of EEG-fMRI with icEEG suggests that EEG-fMRI may provide useful additional information about the SOZ in FCD. Widely distributed discordant regions of IED-related hemodynamic change appear to be associated with a widespread SOZ and poor postsurgical outcome., (Copyright © 2011 American Neurological Association.)

Rationale: Reproducible direct measurement of neuronal electrical activity using MRI signal changes due to local magnetic field perturbations would represent a step change in neuroimaging methods. While some previous studies using experiments based on evoked and spontaneous activity provided encouraging results no clear demonstration of neuronal current-related MR changes in the human brain has emerged to date. The availability of simultaneously acquired EEG-fMRI in patients with frequent interictal epileptic discharges (IED), which have significantly greater amplitude than evoked potentials, offers the opportunity to further investigate the phenomenon., Methods: We re-analysed simultaneously acquired EEG-fMRI data in 6 epilepsy patients with very frequent focal IED and a well-localised generator. A model of MRI signal changes due to fast activity and BOLD signal changes was used to identify fast MR signal changes, potentially directly reflecting neuronal activity. Simultaneously-acquired EEG allowed the comparison of electrical source localisation (ESI), clinical epilepsy localisation and BOLD signal changes with the fast MR signal changes., Results: Clusters of IED-related fast MR signal change were observed in all cases. Spatial correspondence between the IED-related fast MR, BOLD, ESI clusters and irritative zone (IZ) was observed in one slice of a single dataset. The other IED-related fast MR clusters were remote from electro-clinically determined generators of interictal activity. The sign and magnitude of the fast MR signal changes varied across regions and subjects., Conclusion: The observed fast MR changes cannot be confidently attributed to the direct effect of neuronal currents due to lack of spatial concordance with generators of interictal activity, IED-related BOLD clusters and ESI estimates., (Copyright 2009 Elsevier Inc. All rights reserved.)

In epilepsy patients who have electrodes implanted in their brains as part of their pre-surgical assessment, simultaneous intracranial EEG and fMRI (icEEG-fMRI) may provide important localising information and improve understanding of the underlying neuropathology. However, patient safety during icEEG-fMRI has not been addressed. Here the potential health hazards associated with icEEG-fMRI were evaluated theoretically and the main risks identified as: mechanical forces on electrodes from transient magnetic effects, tissue heating due to interaction with the pulsed RF fields and tissue stimulation due to interactions with the switched magnetic gradient fields. These potential hazards were examined experimentally in vitro on a Siemens 3 T Trio, 1.5 T Avanto and a GE 3 T Signa Excite scanner using a Brain Products MR compatible EEG system. No electrode flexion was observed. Temperature measurements demonstrated that heating well above guideline limits can occur. However heating could be kept within safe limits (<1.0 degrees C) by using a head transmit RF coil, ensuring EEG cable placement to exit the RF coil along its central z-axis, using specific EEG cable lengths and limiting MRI sequence specific absorption rates (SARs). We found that the risk of tissue damage due to RF-induced heating is low provided implant and scanner specific SAR limits are observed with a safety margin used to account for uncertainties (e.g. in scanner-reported SAR). The observed scanner gradient switching induced current (0.08 mA) and charge density (0.2 microC/cm(2)) were well within safety limits (0.5 mA and 30 microC/cm(2), respectively). Site-specific testing and a conservative approach to safety are required to avoid the risk of adverse events.