Association of EEG-fMRI Responses and Outcome After Epilepsy Surgery.

OBJECTIVE: To assess the utility of EEG-fMRI for epilepsy surgery, we evaluated surgical outcome in relation to the resection of the most significant EEG-fMRI response. METHODS: Patients with post-operative neuroimaging and follow-up of at least one year were included. In EEG-fMRI responses, we defined as "primary" the cluster with the highest absolute t-value located in the cortex, and evaluated three levels of confidence for the results. The threshold for low confidence was t ≥ 3.1 (p < 0.005); the one for medium confidence corresponded to correction for multiple comparisons with a false discovery rate of 0.05; and a result reached high confidence when the primary cluster was much more significant than the next highest cluster. Concordance with the resection was determined by comparison to post-operative neuroimaging. RESULTS: We evaluated 106 epilepsy surgeries in 84 patients. An increasing association between concordance and surgical outcome with higher levels of confidence was demonstrated. If the peak response was not resected, the surgical outcome was likely to be poor: for the high confidence level, no patient had a good outcome; for the medium and low levels, only 18% and 28% had a good outcome. The positive predictive value remained low for all confidence levels, indicating that removing the maximum cluster did not ensure seizure freedom. CONCLUSION: Resection of the primary EEG-fMRI cluster, especially in high confidence cases, is necessary to obtain a good outcome, but not sufficient. CLASSIFICATION OF EVIDENCE: This study provided Class II evidence that failure to resect the primary EEG-fMRI cluster is associated with poorer epilepsy surgery outcomes.

Reliable Acquisition of Electroencephalography Data during Simultaneous Electroencephalography and Functional MRI.

Simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), EEG-fMRI, combines the complementary properties of scalp EEG (good temporal resolution) and fMRI (good spatial resolution) to measure neuronal activity during an electrographic event, through hemodynamic responses known as blood-oxygen-level-dependent (BOLD) changes. It is a non-invasive research tool that is utilized in neuroscience research and is highly beneficial to the clinical community, especially for the management of neurological diseases, provided that proper equipment and protocols are administered during data acquisition. Although recording EEG-fMRI is apparently straightforward, the correct preparation, especially in placing and securing the electrodes, is not only important for safety but is also critical in ensuring the reliability and analyzability of the EEG data obtained. This is also the most experience-demanding part of the preparation. To address these issues, a straightforward protocol that ensures data quality was developed. This article provides a step-by-step guide for acquiring reliable EEG data during EEG-fMRI using this protocol that utilizes readily available medical products. The presented protocol can be adapted to different applications of EEG-fMRI in research and clinical settings, and may be beneficial to both inexperienced and expert operators.

Co-existence of idiopathic generalized and focal epilepsy suggested by simultaneous EEG-fMRI: a case report.

We present a rare patient clinically suspected to have mixed idiopathic generalized and focal epilepsy, which was supported by BOLD pattern based on EEG-fMRI. A 37-year-old female with three types of refractory seizures starting at age six - tonic with breathing difficulties and confusion, generalized tonic-clonic, and focal with brief impairment of awareness and versive head movement, initially thought to represent atypical absences - was evaluated by EEG-fMRI. She was also shown to have three types of interictal epileptic discharges: generalized spike or polyspikes and slow waves, and left fronto-temporal and right fronto-temporal discharges. We assessed BOLD activation and deactivation for each type. For generalized patterns, the BOLD activation and deactivation were typical of that seen in primary generalized epilepsy. Whereas maximum activation for left fronto-temporal EEG patterns was observed in the left superior frontal gyrus and posterior superior temporal gyrus, maximum activation for right fronto-temporal patterns was bilateral in the right posterior middle temporal gyrus and left posterior middle temporal gyrus. The EEG-fMRI results suggested that the patient had both refractory idiopathic generalized and focal epilepsy, and not a generalized epilepsy originating from a focus.

Internodular functional connectivity in heterotopia-related epilepsy.

OBJECTIVE: A vast network involving the nodules and overlying cortices is believed to be responsible for the epileptogenicity in gray matter heterotopia with multiple nodules, which often associated with difficult-to-treat epilepsy. We sought to determine if functional magnetic resonance imaging (fMRI) could detect internodular functional connectivity (FC), and if this connectivity reflects an actual synchronized neuronal activity and partakes in epileptogenicity. METHODS: We studied 16 epilepsy patients with multiple heterotopic nodules; eight underwent subsequent intracerebral EEG. We examined the internodular FC using fMRI and its correspondence with internodular synchrony of intracerebral interictal activity. We then compared the spreading speed of ictal activity between connected and unconnected nodules; and the FC among possible combinations of nodule pairs in terms of their involvement at seizure onset. RESULTS: Seventy nodules were studied: 83% have significant connection to at least one other nodule. Among the 49 pairs studied with intracerebral EEG, (1) synchronized interictal activity is more prevalent in fMRI-connected pairs (P < 0.05), (2) ictal activity spreads faster between connected pairs (P < 0.0001), and (3) stronger FC was observed between pairs in which both nodules were involved at seizure onset (P < 0.01). INTERPRETATION: fMRI could reliably and noninvasively detect the FC between heterotopic nodules. These functional connections correspond to the synchrony of interictal epileptic activity between the nodules and to the ability of nodules to generate synchronous seizure onsets or rapid seizure spread. These findings may help in understanding the complexity of the epileptogenic network in multiple heterotopic nodules and better targeting the likely epileptogenic nodules.

Widespread interictal epileptic discharge more likely than focal discharges to unveil the seizure onset zone in EEG-fMRI.

OBJECTIVE: We hypothesized that the number of interictal epileptic discharges (IEDs) during scan and their spatial extent are contributing factors in obtaining appropriate activations that reveal the seizure onset zone (SOZ) in EEG-fMRI. METHODS: 157 IED types, each corresponding to one EEG scalp distribution, in 64 consecutive EEG-fMRI studies from 64 patients with refractory localization-related epilepsy were reviewed. To determine reliable activation, we used the threshold corresponding to corrected whole-brain topological false discovery rate (FDR). The location with maximum activation was compared to the presumed SOZ as defined by a comprehensive evaluation for each patient. RESULTS: The number of IEDs was significantly higher in the types with t-value above FDR than with t-value below FDR. The presumed SOZ could be delineated in 30 of the 64 patients. Among these patients, the types of IED concordant with the SOZ had significantly larger extent on scalp EEG than the IED types discordant with the SOZ. CONCLUSIONS: The number of IEDs is important factor in obtaining reliable activations in EEG-fMRI. IEDs with larger spatial extent are more likely to reveal, on maximum BOLD, accurate location of the SOZ. SIGNIFICANCE: Widespread discharges are more likely to yield a reliable activation for SOZ in EEG-fMRI.

Spatio-temporal patterns of cognitive control revealed with simultaneous electroencephalography and functional magnetic resonance imaging.

Optimal performance depends in part on the ability to inhibit the automatic processing of irrelevant information and also on the adjusting the level of control from one trial to the next. In this study, we investigated the spatio-temporal neural correlates of cognitive control using simultaneous functional magnetic resonance imaging and electroencephalography, while 22 participants (10 women) performed a numerical Stroop task. We investigated the spatial and temporal dynamic of the conflict adaptation effects (i.e., reduced interference on items that follow an incongruent stimulus compared to after a congruent stimulus). Joint independent component analysis linked the N200 component to activation of anterior cingulate cortex (ACC) and the conflict slow potential to widespread activations within the fronto-parietal executive control network. Connectivity analyses with psychophysiological interactions and dynamic causal modeling demonstrated coordinated engagement of the cognitive control network after the processing of an incongruent item, and this was correlated with better behavioral performance. Our results combined high spatial and temporal resolution to propose the following network of conflict adaptation effect and specify the time course of activation within this model: first, the anterior insula and inferior frontal gyrus are activated when incongruence is detected. These regions then signal the need for higher control to the ACC, which in turn activates the fronto-parietal executive control network to improve the performance on the next trial.

The spike onset zone: The region where epileptic spikes start and from where they propagate.

OBJECTIVE: To determine whether the maximum hemodynamic response to scalp interictal epileptic discharges (IEDs) corresponds to the region where IEDs originate and from where they propagate. METHODS: We studied 19 patients who underwent first an EEG-fMRI showing responses in the gray matter, and then intracranial EEG (iEEG). We coregistered the hemodynamic responses to the iEEG electrode contacts and analyzed IEDs in the iEEG channel adjacent to a maximum response (labeled the main channel), in relation to IEDs in other channels during a widespread intracranial IED event. IEDs in the main channel were aligned at their peak, and IEDs in each channel were averaged time-locked to these instants. The beginning and peak of IEDs in the averaged trace were identified, blinded to the identity of the main channel. The latency of IEDs was computed between the earliest and all other channels. RESULTS: The median latency of IEDs in the main channel was significantly smaller than in other channels for either the peak (15.5 vs 67.5 milliseconds, p = 0.00037) or the beginning (46.5 vs 118.4 milliseconds, p = 0.000048). The latency of IED was significantly correlated to the distance from the maximum hemodynamic response (p < 0.0001 for either the peak or the beginning). CONCLUSION: IED adjacent to a maximum hemodynamic response, which often corresponds to the seizure onset zone, is more likely to precede IEDs in remote locations during a widespread intracranial discharge. Thus, EEG-fMRI is a unique noninvasive method to reveal the origin of IEDs, which we propose to label the spike onset zone.

DeepIED: An epileptic discharge detector for EEG-fMRI based on deep learning.

Presurgical evaluation that can precisely delineate the epileptogenic zone (EZ) is one important step for successful surgical resection treatment of refractory epilepsy patients. The noninvasive EEG-fMRI recording technique combined with general linear model (GLM) analysis is considered an important tool for estimating the EZ. However, the manual marking of interictal epileptic discharges (IEDs) needed in this analysis is challenging and time-consuming because the quality of the EEG recorded inside the scanner is greatly deteriorated compared to the usual EEG obtained outside the scanner. This is one of main impediments to the widespread use of EEG-fMRI in epilepsy. We propose a deep learning based semi-automatic IED detector that can find the candidate IEDs in the EEG recorded inside the scanner which resemble sample IEDs marked in the EEG recorded outside the scanner. The manual marking burden is greatly reduced as the expert need only edit candidate IEDs. The model is trained on data from 30 patients. Validation of IEDs detection accuracy on another 37 consecutive patients shows our method can improve the median sensitivity from 50.0% for the previously proposed template-based method to 84.2%, with false positive rate as 5 events/min. Reproducibility validation on 15 patients is applied to evaluate if our method can produce similar hemodynamic response maps compared with the manual marking ground truth results. We explore the concordance between the maximum hemodynamic response and the intracerebral EEG defined EZ and find that both methods produce similar percentage of concordance (76.9%, 10 out of 13 patients, electrode was absent in the maximum hemodynamic response in two patients). This tool will make EEG-fMRI analysis more practical for clinical usage.

Epileptic networks in action: Synchrony between distant hemodynamic responses.

OBJECTIVE: Structural and functional imaging studies in focal epilepsy often reveal distributed regions of abnormality. These are interpreted as representing the existence of epileptic networks, but the presence of actual neuronal interactions between these regions has not been demonstrated. We sought to determine whether the distributed hemodynamic responses often seen in functional magnetic resonance imaging (fMRI) studies of scalp interictal epileptic discharges (IEDs) actually correspond to synchronized neuronal activities when examining the intracerebral electroencephalogram (iEEG) at distant nodes of the network. METHODS: We studied 28 patients who underwent first EEG-fMRI and then iEEG, and had significant hemodynamic responses in the gray matter. We coregistered the hemodynamic responses to the iEEG electrode contact positions and analyzed synchrony, measured by correlation, between IEDs recorded by iEEG in regions with and without hemodynamic responses. RESULTS: The synchrony of intracerebral IED activity between pairs of regions showing a hemodynamic response was higher compared to that between pairs of regions without (p < 0.0001) and between pairs of regions, one with and one without hemodynamic response (p < 0.0001). These differences were found during the interictal periods with IEDs but were absent during the interictal periods without IEDs. Higher synchrony was also observed between regions involved at seizure onset (p < 0.0001). INTERPRETATION: EEG-fMRI studies are unique in their ability to reveal hemodynamic concomitants of IEDs anywhere in the brain. This study proves that iEEG activity is synchronized between these regions of hemodynamic response, thus demonstrating the existence of an actual neuronally based interictal epileptic network. This also validates the EEG-fMRI approach to reveal this network noninvasively. Ann Neurol 2017;82:57-66.

Temporal lobe spikes: EEG-fMRI contributions to the "mesial vs. lateral" debate.

OBJECTIVE: It has been reported that interictal epileptic discharges (IEDs) recorded in temporal regions on scalp EEG are unlikely to originate from mesial temporal structures. However, EEG-fMRI sometimes show mesial temporal activation. We hypothesized that BOLD activation in the temporal neocortex is weaker than in the mesial structures, reflecting the fact that propagated activity has less metabolic demand than the original discharge. METHODS: Twelve patients with epilepsy who have BOLD response in mesial temporal structures were selected from our EEG-fMRI database. We searched the temporal lobe ipsilateral to IEDs and checked whether there is positive BOLD response in the neocortex. RESULTS: All IED types showed a BOLD response in the temporal neocortex ipsilateral to the mesial temporal BOLD response. T-values were higher in mesial temporal structures than in neocortex in 13/16 cases. CONCLUSIONS: Hemodynamic changes were observed in the mesial temporal lobe at the time of IEDs recorded from the temporal region on the scalp. The finding of smaller BOLD changes in the ipsilateral neocortex is in agreement with our hypothesis. SIGNIFICANCE: Our study indicates that scalp-recorded temporal lobe spikes are likely to result from mesial temporal spikes propagating neuronally to the neocortex.

The hemodynamic response to interictal epileptic discharges localizes the seizure-onset zone.

OBJECTIVE: Intracranial electroencephalography (EEG), performed presurgically in patients with drug-resistant and difficult-to-localize focal epilepsy, samples only a small fraction of brain tissue and thus requires strong hypotheses regarding the possible localization of the epileptogenic zone. EEG/fMRI (functional magnetic resonance imaging), a noninvasive tool resulting in hemodynamic responses, could contribute to the generation of these hypotheses. This study assessed how these responses, despite their interictal origin, predict the seizure-onset zone (SOZ). METHODS: We retrospectively studied 37 consecutive patients who underwent stereo-EEG (SEEG) and EEG/fMRI that resulted in significant hemodynamic responses. Hemodynamic response maps were co-registered to postimplantation anatomic imaging, allowing inspection of these responses in relation to SEEG electrode's location. The area containing the most significant t-value (primary cluster) explored with an electrode was assessed for concordance with SEEG-defined SOZ. Discriminant analysis was performed to distinguish the primary clusters having a high probability of localizing the SOZ. RESULTS: Thirty-one patients had at least one study with primary cluster explored with an electrode, and 24 (77%) had at least one study with primary cluster concordant with the SOZ. Each patient could have multiple types of interictal discharge and therefore multiple studies. Among 59 studies from the 37 patients, 44 had a primary cluster explored with an electrode and 30 (68%) were concordant with the SOZ. Discriminant analysis showed that the SOZ is predictable with high confidence (>90%) if the primary cluster is highly significant and if the next significant cluster is much less significant or absent. SIGNIFICANCE: The most significant hemodynamic response to interictal discharges delineates the subset of the irritative zone that generates seizures in a high proportion of patients with difficult-to-localize focal epilepsy. EEG/fMRI generates responses that are valuable targets for electrode implantation and may reduce the need for implantation in patients in whom the most significant response satisfies the condition of our discriminant analysis.

Sleep influences the intracerebral EEG pattern of focal cortical dysplasia.

OBJECTIVE: Focal cortical dysplasia (FCD) is able to generate an intrinsic pathological EEG activity characterized by a continuous or near-continuous spiking. Different patterns of discharge were described. We examined quantitatively the distribution of the intracerebral FCD patterns in relation to sleep in order to investigate whether this activity is independent of thalamocortical influences. METHODS: We analyzed the first sleep cycle of 5 patients with a diagnosis of FCD type II who underwent combined scalp-intracranial electroencephalography (EEG), and showed an intracranial EEG pattern typical for FCD. Three patterns of FCD intracranial EEG activity were identified in all 5 patients, and visually marked for a maximum of 30min of each stage (wake, N1, N2, N3, REM): spike or polyspike exceeding 2Hz (pattern 1), spike or polyspike interrupted by flat periods below 2Hz (pattern 2) and discharges of >15Hz low-voltage rhythmic activity with regular morphology (pattern 3). After marking, the percentages of the three patterns across the different stages were calculated. RESULTS: The three patterns of FCD were present between 45% and 97% of the total time analyzed. Pattern 1 was the predominant pattern in wakefulness (73-100%), N1 (76-97%) and N2 (58-88.5%) in all patients, and in REM in 4 of 5 patients (91-100%). During N2 and N3, there was an increase in pattern 2 in all patients, becoming the predominant pattern in 3 of the 5 patients during N3 (63-89%). Pattern 3 was rare and only sporadically observed during N2 and N3. Wakefulness and REM sleep showed a similar pattern (pattern 1) with a slight amplitude reduction in REM sleep. SIGNIFICANCE: Despite the presence of an almost continuous discharge, sleep is an important modulator of the pathological EEG patterns found in FCD type II. This might suggest that dysplastic tissue is influenced by the thalamo-cortical control mechanisms involved in the generation of sleep.