Relationship between direct cortical stimulation and induced high-frequency activity for language mapping during SEEG recording.

OBJECTIVE: The authors assessed the clinical relevance of preoperative task-induced high-frequency activity (HFA) for language mapping in patients with refractory epilepsy during stereoelectroencephalography recording. Although HFA evaluation was described as a putative biomarker of cognition, its clinical relevance for mapping language networks was assessed predominantly by studies using electrocorticography (ECOG). METHODS: Forty-two patients with epilepsy who underwent intracranial electrode implantation during both task-induced HFA and direct cortical stimulation (DCS) language mapping were evaluated. The spatial and functional relevance of each method in terms of specificity and sensitivity were evaluated. RESULTS: The results showed that the two methods were able to map classic language regions, and a large and bilateral language network was obtained with induced HFA. At a regional level, differences were observed between methods for parietal and temporal lobes: HFA recruited a larger number of cortical parietal sites, while DCS involved more cortical temporal sites. Importantly, the results showed that HFA predicts language interference induced by DCS with high specificity (92.4%; negative predictive value 95.9%) and very low sensitivity (8.9%; positive predictive value 4.8%). CONCLUSIONS: DCS language mapping appears to be more appropriate for an extensive temporal mapping than induced HFA mapping. Furthermore, induced HFA should be used as a complement to DCS to preselect the number of stimulated sites during DCS, by omitting those reported as HFA-. This may be a considerable advantage because it allows a reduction in the duration of the stimulation procedure. Several parameters to be used for each method are discussed and the results are interpreted in relation to previous results reported in ECOG studies.

Epileptogenicity Maps of Intracerebral Fast Activities (60-100 Hz) at Seizure Onset in Epilepsy Surgery Candidates.

Fast activities (FA) at seizure onset have been increasingly described as a useful signature of the epileptogenic zone (EZ) in patients undergoing intracranial EEG recordings. Different computer-based signal analysis methods have thus been developed for objectively quantifying ictal FA. Whether these methods detect FA in all forms of focal epilepsies, whether they provide similar information than visual analysis (VA), and whether they might help for the surgical decision remain crucial issues. We thus conducted a retrospective study in 21 consecutive patients suffering from drug-resistant seizures studied by SEEG recordings. Ictal FA were quantified using the Epileptogenicity Maps (EM) method that we recently developed and which generates, by adopting a neuroimaging approach, statistical parametric maps of FA ranging from 60 to 100 Hz (FA60-100). Ictal FA were analyzed blindly using VA and EM, and the prognostic significance of removing areas exhibiting FA60-100 at seizure onset was evaluated. A significant ictal FA60-100 activation was found in all patients, and in 92.6% of all the 68 seizures recorded, whatever the epilepsy type. The overlap ratio (OR) between VA and EM was significantly better for defining the regions spared at seizure onset than those from which seizure arose (p < 0.001), especially in temporal or temporal "plus" epilepsies. EM and VA were much more discordant to define the EZ, with a mean number of electrode contacts involved at seizure onset significantly higher with EM than with VA (p = <0.0001). Seizure outcome correlated with the resection ratio for FA60-100, which was significantly higher in seizure-free (Engel's class Ia) than in non seizure-free patients (class Ic-IV) (p = 0.048). The quantification of FA at seizure onset can bring information additional to clinical expertise that might contribute to define accurately the cortical region to be resected.

Multimodal assessment of language and memory reorganization: a proof of concept in two patients with drug-resistant temporal lobe epilepsy.

We report two patients suffering from drug-resistant temporal lobe epilepsy to show how their neuroplasticity can be apprehended using a multimodal, integrative and clinically relevant approach. This is a proof of concept based on using multimodal data including: (1) white matter structural connectivity (DTI) of the main tracts involved in language and memory; (2) neurophysiological biomarkers (fMRI-BOLD signal and LI lateralization indices); and (3) cognitive scores as measured during the neuropsychological assessment. We characterized tri-modal data for each patient using a descriptive integrative approach, in terms of reorganization and by comparing with a group of healthy participants. This proof of concept suggests that the inclusion of multimodal data in clinical studies is currently a major challenge. Since the various datasets obtained from MRI neuroimaging and cognitive scores are probably interrelated, it is important to go beyond the mono-modal approach and move towards greater integration of several multimodal data. Multimodal integration of anatomical, functional, and cognitive data facilitates the identification of comprehensive neurocognitive patterns in epileptic patients, thus enabling clinicians to differentiate between reorganization profiles and help to predict post-surgical outcomes for curative neurosurgery.

Association of Cortical Stimulation-Induced Seizure With Surgical Outcome in Patients With Focal Drug-Resistant Epilepsy.

IMPORTANCE: Cortical stimulation is used during presurgical epilepsy evaluation for functional mapping and for defining the cortical area responsible for seizure generation. Despite wide use of cortical stimulation, the association between cortical stimulation-induced seizures and surgical outcome remains unknown. OBJECTIVE: To assess whether removal of the seizure-onset zone resulting from cortical stimulation is associated with a good surgical outcome. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from 2 tertiary epilepsy centers: Montreal Neurological Institute in Montreal, Quebec, Canada, and Grenoble-Alpes University Hospital in Grenoble, France. Participants included consecutive patients (n = 103) with focal drug-resistant epilepsy who underwent stereoelectroencephalography between January 1, 2007, and January 1, 2017. Participant selection criteria were cortical stimulation during implantation, subsequent open surgical procedure with a follow-up of 1 or more years, and complete neuroimaging data sets for superimposition between intracranial electrodes and the resection. MAIN OUTCOMES AND MEASURES: Cortical stimulation-induced typical electroclinical seizures, the volume of the surgical resection, and the percentage of resected electrode contacts inducing a seizure or encompassing the cortical stimulation-informed and spontaneous seizure-onset zones were identified. These measures were correlated with good (Engel class I) and poor (Engel classes II-IV) surgical outcomes. Electroclinical characteristics associated with cortical stimulation-induced seizures were analyzed. RESULTS: In total, 103 patients were included, of whom 54 (52.4%) were female, and the mean (SD) age was 31 (11) years. Fifty-nine patients (57.3%) had cortical stimulation-induced seizures. The percentage of patients with cortical stimulation-induced electroclinical seizures was higher in the good outcome group than in the poor outcome group (31 of 44 [70.5%] vs 28 of 59 [47.5%]; P = .02). The percentage of the resected contacts encompassing the cortical stimulation-informed seizure-onset zone correlated with surgical outcome (median [range] percentage in good vs poor outcome: 63.2% [0%-100%] vs 33.3% [0%-84.6%]; Spearman ρ = 0.38; P = .003). A similar result was observed for spontaneous seizures (median [range] percentage in good vs poor outcome: 57.1% [0%-100%] vs 32.7% [0%-100%]; Spearman ρ = 0.32; P = .002). Longer elapsed time since the most recent seizure was associated with a higher likelihood of inducing seizures (>24 hours: 64.7% vs <24 hours: 27.3%; P = .04). CONCLUSIONS AND RELEVANCE: Seizure induction by cortical stimulation appears to identify the epileptic generator as reliably as spontaneous seizures do; this finding might lead to a more time-efficient intracranial presurgical investigation of focal epilepsy as the need to record spontaneous seizures is reduced.

IntrAnat Electrodes: A Free Database and Visualization Software for Intracranial Electroencephalographic Data Processed for Case and Group Studies.

In some cases of pharmaco-resistant and focal epilepsies, intracranial recordings performed epidurally (electrocorticography, ECoG) and/or in depth (stereoelectroencephalography, SEEG) can be required to locate the seizure onset zone and the eloquent cortex before surgical resection. In SEEG, each electrode contact records brain's electrical activity in a spherical volume of 3 mm diameter approximately. The spatial coverage is around 1% of the brain and differs between patients because the implantation of electrodes is tailored for each case. Group studies thus need a large number of patients to reach a large spatial sampling, which can be achieved more easily using a multicentric approach such as implemented in our F-TRACT project (f-tract.eu). To facilitate group studies, we developed a software-IntrAnat Electrodes-that allows to perform virtual electrode implantation in patients' neuroanatomy and to overlay results of epileptic and functional mapping, as well as resection masks from the surgery. IntrAnat Electrodes is based on a patient database providing multiple search criteria to highlight various group features. For each patient, the anatomical processing is based on a series of software publicly available. Imaging modalities (Positron Emission Tomography (PET), anatomical MRI pre-implantation, post-implantation and post-resection, functional MRI, diffusion MRI, Computed Tomography (CT) with electrodes) are coregistered. The 3D T1 pre-implantation MRI gray/white matter is segmented and spatially normalized to obtain a series of cortical parcels using different neuroanatomical atlases. On post-implantation images, the user can position 3D models of electrodes defined by their geometry. Each electrode contact is then labeled according to its position in the anatomical atlases, to the class of tissue (gray or white matter, cerebro-spinal fluid) and to its presence inside or outside the resection mask. Users can add more functionally informed labels on contact, such as clinical responses after electrical stimulation, cortico-cortical evoked potentials, gamma band activity during cognitive tasks or epileptogenicity. IntrAnat Electrodes software thus provides a means to visualize multimodal data. The contact labels allow to search for patients in the database according to multiple criteria representing almost all available data, which is to our knowledge unique in current SEEG software. IntrAnat Electrodes will be available in the forthcoming release of BrainVisa software and tutorials can be found on the F-TRACT webpage.

The link between structural connectivity and neurocognition illustrated by focal epilepsy.

Increasing attention is being paid to the assessment of white matter properties and its structural connectivity, both in healthy subjects and patients with cerebral lesions. Within this framework, new neurocognitive models based on hodological properties have been developed under a connectomic perspective in order to explain substrates and cognitive mechanisms related to cerebral functions such as language and memory. With regards to focal and drug-resistant epilepsy conceived as a network disorder, new insights in terms of structural connectivity have led to significant advances in epilepsy research, concerning fundamental research (neurocognitive mechanisms of plasticity) and clinical application (optimization of decision making for curative surgery). We believe that such findings in the literature, focused on the role of white matter in cerebral functioning in relation to neurocognition, may be helpful for both researchers and clinicians working in the field of epilepsy.

Facing the hidden wall in mesial extratemporal lobe epilepsy.

Refractory extratemporal lobe epilepsy (ETLE) tends to have a less favourable surgical outcome in comparison to temporal lobe epilepsy. ETLE poses specific diagnostic and therapeutic challenges, particularly in cases where seizures develop from the midline. This review focuses on the diagnostic challenges and therapeutic strategies in mesial ETLE. The great diversity of interhemispheric functional areas and extensive connectivity to extramesial structures results in very heterogeneous seizure semiology. Specific signs, such as ictal body turning, can suggest a mesial onset. The hidden cortex of the mesial wall furthermore gives rise to specific diagnostic difficulties due to the low localizing value of scalp EEG. Advanced imaging, as well as targeted intracranial studies, can substantially contribute to depict the seizure onset zone since electroclinical findings are difficult to interpret in most cases. Surgical accessibility of the interhemispheric space can be challenging, both for the placement of subdural grids, as well as for resective surgery. When facing the hidden cortex on the mesial wall of the hemispheres, targeted intra- or extra-operative intracranial recordings can lead to satisfactory outcomes in properly selected cases.

The Insula in Temporal Plus Epilepsy.

Temporal lobe epilepsy (TLE) surgery is the most common type of surgical treatment offered to patients with drug-resistant focal seizures. However, the proportion of patients experiencing long-term freedom from seizures after TLE surgery remains suboptimal. Temporal plus epilepsy, which is characterized by a primary temporal epileptogenic zone extending to neighboring regions, has been demonstrated to be a major predictor of TLE surgery failures. In the context of the temporoperisylvian epilepsies, i.e., the most common type of temporal plus epilepsy, a possible role of the insula has often been hypothesized. As this area is buried deep within the lateral sulcus, the use of invasive recordings is often required. Identifying patients with temporal plus seizures is a relevant issue, as they appear to have a worse postsurgical seizure outcome compared with patients with "pure" temporal lobe seizures. Owing to these prognostic implications, it becomes important to identify, among patients suffering from "atypical" nonlesional TLEs, those who should undergo invasive investigations, in particular to explore the insula. In fact, only a primary involvement of the insula in the epileptogenic network may require to include this area in the resection to achieve seizure freedom. Using modern neurosurgical techniques, insular epilepsy surgery has proved to be safe and beneficial, making the "true" role of the insula in TLE surgery failures more relevant to understand. Further studies are needed to evaluate the efficacy of multilobar resections in patients with temporal plus epilepsy, in particular, when eloquent or difficult to access areas such as insula are suspected to be involved.

Correlation of FDG-PET hypometabolism and SEEG epileptogenicity mapping in patients with drug-resistant focal epilepsy.

OBJECTIVE: Interictal [18F]fluorodeoxyglucose-positron emission tomography (FDG-PET) is used in the presurgical evaluation of patients with drug-resistant focal epilepsy. We aimed at clarifying its relationships with ictal high-frequency oscillations (iHFOs) shown to be a relevant marker of the seizure-onset zone. METHODS: We studied the correlation between FDG-PET and epileptogenicity maps in an unselected series of 37 successive patients having been explored with stereo-electroencephalography (SEEG). RESULTS: At the group level, we found a significant correlation between iHFOs and FDG-PET interictal hypometabolism only in cases of temporal lobe epilepsy. This correlation was found with HFOs, and the same comparison between FDG-PET and ictal SEEG power of lower frequencies during the same epochs did not show the same significance. SIGNIFICANCE: This finding suggests that interictal FDG-PET and ictal HFOs may share common underlying pathophysiologic mechanisms of ictogenesis in temporal lobe epilepsy, and combining both features may help to identify the seizure-onset zone.

Stimulation artifact correction method for estimation of early cortico-cortical evoked potentials.

BACKGROUND: Effective connectivity can be explored using direct electrical stimulations in patients suffering from drug-resistant focal epilepsies and investigated with intracranial electrodes. Responses to brief electrical pulses mimic the physiological propagation of signals and manifest as cortico-cortical evoked potentials (CCEP). The first CCEP component is believed to reflect direct connectivity with the stimulated region but the stimulation artifact, a sharp deflection occurring during a few milliseconds, frequently contaminates it. NEW METHOD: In order to recover the characteristics of early CCEP responses, we developed an artifact correction method based on electrical modeling of the electrode-tissue interface. The biophysically motivated artifact templates are then regressed out of the recorded data as in any classical template-matching removal artifact methods. RESULTS: Our approach is able to make the distinction between the physiological responses time-locked to the stimulation pulses and the non-physiological component. We tested the correction on simulated CCEP data in order to quantify its efficiency for different stimulation and recording parameters. We demonstrated the efficiency of the new correction method on simulations of single trial recordings for early responses contaminated with the stimulation artifact. The results highlight the importance of sampling frequency for an accurate analysis of CCEP. We then applied the approach to experimental data. COMPARISON WITH EXISTING METHOD: The model-based template removal was compared to a correction based on the subtraction of the averaged artifact. CONCLUSIONS: This new correction method of stimulation artifact will enable investigators to better analyze early CCEP components and infer direct effective connectivity in future CCEP studies.

The pivotal role of the supplementary motor area in startle epilepsy as demonstrated by SEEG epileptogenicity maps.

Startle seizures belong to reflex epilepsy syndromes. They usually occur in patients with mental deficiency and showing widely extended cortical lesions, often involving the sensorimotor area. Here we report three cases who did not fulfill these criteria, and in whom stereotactic electroencephalography (SEEG) recordings demonstrated the prominent involvement of the supplementary motor area (SMA). Visual analysis was complemented by time-frequency analysis of SEEG signals using a neuroimaging approach (Epileptogenicity Maps), which showed at seizure onset a significant increase of high frequency oscillations (HFOs, 60-100 Hz) over the premotor and prefrontal areas. Critically, in all cases, the SMA showed ictal HFOs at seizure onset and was included in the surgical resection. All patients became seizure-free after surgery, and histopathological examinations showed no specific lesion. These cases suggest the prominent but not exclusive role of SMA in startle seizures, and highlight the fact that surgery can be considered even in the absence of any magnetic resonance imaging (MRI) lesion.

Prognostic value of insular lobe involvement in temporal lobe epilepsy: a stereoelectroencephalographic study.

PURPOSE: Failure of anterior temporal lobectomy for temporal lobe epilepsy has raised the question of insular cortex involvement in these seizures. Because of difficulties in exploring the insula with invasive electroencephalography (EEG) recordings, only few studies have been performed and this question remains unanswered. METHODS: Here, we studied 17 patients who underwent surgery for drug-resistant temporal lobe epilepsy, explored with intracerebral electrodes, with at least one electrode coplanar to the insula. We analyzed seizure propagation patterns from temporal lobe structures to the insula, and their effect on outcome. We used an objective measure of the epileptogenicity of the insula for individual cases and group analysis between patients who were seizure-free after surgery and the others. KEY FINDINGS: All temporal lobe seizures propagated to the insular cortex, with a shorter propagation delay in the case of mesiolateral temporal lobe seizures, thus supporting the existence of a perilimbic network. Epileptogenicity of the insular cortex was not a prognostic factor for outcome after surgery. SIGNIFICANCE: Insular involvement in temporal lobe seizure is not per se a prognostic factor for surgical outcome. Prognosis may be correlated with larger epileptogenic zones that our stereoelectroencephalography spatial sampling could have underestimated.

Probabilistic functional tractography of the human cortex.

Single-pulse direct electrical stimulation of cortical regions in patients suffering from focal drug-resistant epilepsy who are explored using intracranial electrodes induces cortico-cortical potentials that can be used to infer functional and anatomical connectivity. Here, we describe a neuroimaging framework that allows development of a new probabilistic atlas of functional tractography of the human cortex from those responses. This atlas is unique because it allows inference in vivo of the directionality and latency of cortico-cortical connectivity, which are still largely unknown at the human brain level. In this technical note, we include 1535 stimulation runs performed in 35 adult patients. We use a case of frontal lobe epilepsy to illustrate the asymmetrical connectivity between the posterior hippocampal gyrus and the orbitofrontal cortex. In addition, as a proof of concept for group studies, we study the probabilistic functional tractography between the posterior superior temporal gyrus and the inferior frontal gyrus. In the near future, the atlas database will be continuously increased, and the methods will be improved in parallel, for more accurate estimation of features of interest. Generated probabilistic maps will be freely distributed to the community because they provide critical information for further understanding and modelling of large-scale brain networks.

Imaging the seizure onset zone with stereo-electroencephalography.

Stereo-electroencephalography is used to localize the seizure onset zone and connected neuronal networks in surgical candidates suffering from intractable focal epilepsy. The concept of an epileptogenicity index has been proposed recently to represent the likelihood of various regions being part of the seizure onset zone. It quantifies low-voltage fast activity, the electrophysiological signature of seizure onset usually assessed visually by neurologists. Here, we revisit epileptogenicity in light of neuroimaging tools such as those provided in statistical parametric mapping software. Our goal is to propose a robust approach, allowing easy exploration of patients' brains in time and space. The procedure is based upon statistical parametric mapping, which is an established framework for comparing multi-dimensional image data that allows one to correct for inherent multiple comparisons. Statistics can also be performed at the group level, between seizures in the same patient or between patients suffering from the same type of epilepsy using normalization of brains to a common anatomic atlas. Results are obtained from three case studies (insular reflex epilepsy, cryptogenic frontal epilepsy and lesional occipital epilepsy) where tailored resection was performed, and from a group of 10 patients suffering from mesial temporal lobe epilepsy. They illustrate the basics of the technique and demonstrate its very good reproducibility and specificity. Most importantly, the proposed approach to the quantification of the seizure onset zone allows one to summarize complex signals in terms of a time-series of statistical parametric maps that can support clinical decisions. Quantitative neuroimaging of stereo-electroencephalographic features of seizures might thus help to provide better pre-surgical assessment of patients undergoing resective surgery.