ICA Extracts Epileptic Sources from fMRI in EEG-Negative Patients: A Retrospective Validation Study

Simultaneous EEG-fMRI has proven to be useful in localizing interictal epileptic activity. However, the applicability of traditional GLM-based analysis is limited as interictal spikes are often not seen on the EEG inside the scanner. Therefore, we aim at extracting epileptic activity purely from the fMRI time series using independent component analysis (ICA). To our knowledge, we show for the first time that ICA can find sources related to epileptic activity in patients where no interictal spikes were recorded in the EEG. The epileptic components were identified retrospectively based on the known localization of the ictal onset zone (IOZ). We demonstrate that the selected components truly correspond to epileptic activity, as sources extracted from patients resemble significantly better the IOZ than sources found in healthy controls. Furthermore, we show that the epileptic components in patients with and without spikes recorded inside the scanner resemble the IOZ in the same degree. We conclude that ICA of fMRI has the potential to extend the applicability of EEG-fMRI for presurgical evaluation in epilepsy.     

Epileptic Discharges Affect the Default Mode Network – fMRI and Intracerebral EEG Evidence

Functional neuroimaging studies of epilepsy patients often show, at the time of epileptic activity, deactivation in default mode network (DMN) regions, which is hypothesized to reflect altered consciousness. We aimed to study the metabolic and electrophysiological correlates of these changes in the DMN regions. We studied six epilepsy patients that underwent scalp EEG-fMRI and later stereotaxic intracerebral EEG (SEEG) sampling regions of DMN (posterior cingulate cortex, Pre-cuneus, inferior parietal lobule, medial prefrontal cortex and dorsolateral frontal cortex) as well as non-DMN regions. SEEG recordings were subject to frequency analyses comparing sections with interictal epileptic discharges (IED) to IED-free baselines in the IED-generating region, DMN and non-DMN regions. EEG-fMRI and SEEG were obtained at rest. During IEDs, EEG-fMRI demonstrated deactivation in various DMN nodes in 5 of 6 patients, most frequently the pre-cuneus and inferior parietal lobule, and less frequently the other DMN nodes. SEEG analyses demonstrated decrease in gamma power (50–150 Hz), and increase in the power of lower frequencies (<30 Hz) at times of IEDs, in at least one DMN node in all patients. These changes were not apparent in the non-DMN regions. We demonstrate that, at the time of IEDs, DMN regions decrease their metabolic demand and undergo an EEG change consisting of decreased gamma and increased lower frequencies. These findings, specific to DMN regions, confirm in a pathological condition a direct relationship between DMN BOLD activity and EEG activity. They indicate that epileptic activity affects the DMN, and therefore may momentarily reduce the consciousness level and cognitive reserve.     

Localizational concepts in epilepsy: past, present and future

The clinical seizure pattern, particularly the initial phenomena, plus the EEG, when satisfactory recording of the seizure onset can be achieved, determine the primary localization of epileptic phenomena. The EEG has also demonstrated, by the presence of interictal epileptiform spike discharges, the presence of a second-order localization of epileptic phenomena, namely, the location and extent of cortex adjacent to the site of origin of the neuronal seizure discharge that is recruited into action in a clinical epileptic seizure. Experience with cortical resection in the treatment of focal epilepsy has demonstrated the importance of a third-order localization of epileptic phenomena, namely, how much of the potentially epileptogenic cortex must be excised in order to produce a satisfactory reduction of the seizure tendency.     

Epilepsy due to malformations of cortical development--correlation of clinical, MRI and Tc-99mECD SPECT findings

Malformations of cortical development (MCD) have been increasingly recognized as an important cause of intractable epilepsy. The aim of our study was to define epileptogenicity of MCDs by correlating MRI, EEG and semiology of epileptic attacks, and to determine the effect of MCD on drug resistant epilepsy. We also intended to reveal the utility of interictal single photo emission computed tomography (SPECT) in verification of MCD lesions and relative prevalence of different MCDs. Based on interictal EEG finding, semiology of the epileptic attacks and brain magnetic resonance imaging (MRI) "electroclinical epileptogenicity" of MCD was defined. Brain MRI revealed cortical dysplasia (CD) in nine patients, polymicrogyria in four patients, lissencephaly and schizencephaly in one patient each. Three patients had a combination of malformations. The localization of SPECT hypoperfusion corresponded to MCD lesion in ten (66.67%) patients. Electroclinically confirmed epileptogenicity of MCD overlapped with MR and interictal SPECT findings in fourteen (93.3%) and nine (60.0%) patients, respectively. Our study results demonstrated the MCD lesions to be highly epileptogenic and a frequent cause of intractability.     

Concordance of Epileptic Networks Associated with Epileptic Spikes Measured by High-Density EEG and Fast fMRI

Objective

The present study aims to investigate whether a newly developed fast fMRI called MREG (magnetic resonance encephalography) measures metabolic changes related to interictal epileptic discharges (IED). For this purpose BOLD changes are correlated with the IED distribution and variability.

Methods

Patients with focal epilepsy underwent EEG-MREG using a 64 channel cap. IED voltage maps were generated using 32 and 64 channels and compared regarding their correspondence to the BOLD response. The extents of IEDs (defined as number of channels with >50% of maximum IED negativity) were correlated with the extents of positive and negative BOLD responses. Differences in inter-spike variability were investigated between interictal epileptic discharges (IED) sets with and without concordant positive or negative BOLD responses.

Results

17 patients showed 32 separate IED types. In 50% of IED types the BOLD changes could be confirmed by another independent imaging method. The IED extent significantly correlated with the positive BOLD extent (p = 0.04). In 6 patients the 64-channel EEG voltage maps better reflected the positive or negative BOLD response than the 32-channel EEG; in all others no difference was seen. Inter-spike variability was significantly lower in IED sets with than without concordant positive or negative BOLD responses (with p = 0.04).

Significance

Higher density EEG and fast fMRI seem to improve the value of EEG-fMRI in epilepsy. The correlation of positive BOLD and IED extent could suggest that widespread BOLD responses reflect the IED network. Inter-spike variability influences the likelihood to find IED concordant positive or negative BOLD responses, which is why single IED analysis may be promising.     

Using network dynamic fMRI for detection of epileptogenic foci

Background

Epilepsy is one of the most prevalent neurological disorders. It remains medically intractable for about one-third of patients with focal epilepsy, for whom precise localization of the epileptogenic zone responsible for seizure initiation may be critical for successful surgery. Existing fMRI literature points to widespread network disturbances in functional connectivity. Per previous scalp and intracranial EEG studies and consistent with excessive local synchronization during interictal discharges, we hypothesized that, relative to same regions in healthy controls, epileptogenic foci would exhibit less chaotic dynamics, identifiable via entropic analyses of resting state fMRI time series.

Methods

In order to first validate this hypothesis on a cohort of patients with known ground truth, here we test individuals with well-defined epileptogenic foci (left mesial temporal lobe epilepsy). We analyzed voxel-wise resting-state fMRI time-series using the autocorrelation function (ACF), an entropic measure of regulation and feedback, and performed follow-up seed-to-voxel functional connectivity analysis. Disruptions in connectivity of the region exhibiting abnormal dynamics were examined in relation to duration of epilepsy and patients’ cognitive performance using a delayed verbal memory recall task.

Results

ACF analysis revealed constrained (less chaotic) functional dynamics in left temporal lobe epilepsy patients, primarily localized to ipsilateral temporal pole, proximal to presumed focal points. Autocorrelation decay rates differentiated, with 100 % accuracy, between patients and healthy controls on a subject-by-subject basis within a leave-one-subject out classification framework. Regions identified via ACF analysis formed a less efficient network in patients, as compared to controls. Constrained dynamics were linked with locally increased and long-range decreased connectivity that, in turn, correlated significantly with impaired memory (local left temporal connectivity) and epilepsy duration (left temporal – posterior cingulate cortex connectivity).

Conclusions

Our current results suggest that data driven functional MRI methods that target network dynamics hold promise in providing clinically valuable tools for identification of epileptic regions.

     

癫痫病人脑电信号的奇异谱

癫痫是一种常见的神经系统疾患,其唯一客观证据为脑电图的癫痫样发放。在癫痫发作间期,仅有偶发的很难辨别的癫痫样放电,为了正确诊断癫痫病,往往需要医生长时间监测病人的脑电信号,在对脑电信号进行相空间重构,进而对其进行奇异系统分析,发现癫痫病人无论在癫痫发作前、发作中、发作后,其脑电信号的奇异谱曲线不存在噪声平台,明显区别于正常人。是否可以认为脑电信号的奇异谱正代表着大脑的一种基本状态,癫痫患者在未发作时,大脑的基本状态已经处于异常。无论如休,奇异系统分析方法使得可以利用很短的一段脑电数据诊断癫痫。无疑为癫痫病人的临床诊断提供了一条简单、有效的途径。     

Neurosurgical management of epilepsy: a personal perspective in 1983

The therapeutic goal in the neurosurgical treatment of medically intractable epilepsy is complete seizure control, for both biologic and psychosocial reasons. Cortical resections are more likely to accomplish this than other surgical alternatives for epilepsy. Although abnormalities on new imaging techniques (CT, positron emission scanning) aid in identifying the epileptic focus, interictal epileptiform EEG changes remain the main indicator of focal origin of the seizures. Where this is equivocal, direct brain recording of spontaneous seizures with subdural electrodes is of value in identifying the side and lobe of seizure onset. The cortical resection is then tailored by the extent of the interictal electrocorticographic abnormalities and functional identification of essential areas such as those for language, using an electrical stimulation mapping technique, under local anesthesia. With this approach, half of the patients with temporal lobe foci are seizure-free since the time of operation, over two-thirds become so with time, and over three-quarters have at least very major reductions in seizure frequency.     

In vivo optical mapping of epileptic foci and surround inhibition in ferret cerebral cortex

The population of neurons participating in an epileptiform event varies from moment to moment. Most techniques currently used to localize epileptiform events in vivo have spatial and/or temporal sampling limitations. Here we show in an animal model that optical imaging based on intrinsic signals is an excellent method for in vivo mapping of clinically relevant epileptiform events, such as interictal spikes, ictal onsets, ictal spread and secondary homotopic foci. In addition, a decrease in the optical signal correlates spatially with a decrease in neuronal activity recorded from cortex surrounding an epileptic focus. Optical mapping of epilepsy might be a useful adjunct in the surgical treatment of neocortical epilepsy, which critically depends on the precise localization of intrinsically epileptogenic neurons.     

Multiway analysis of epilepsy tensors

MOTIVATION: The success or failure of an epilepsy surgery depends greatly on the localization of epileptic focus (origin of a seizure). We address the problem of identification of a seizure origin through an analysis of ictal electroencephalogram (EEG), which is proven to be an effective standard in epileptic focus localization. SUMMARY: With a goal of developing an automated and robust way of visual analysis of large amounts of EEG data, we propose a novel approach based on multiway models to study epilepsy seizure structure. Our contributions are 3-fold. First, we construct an Epilepsy Tensor with three modes, i.e. time samples, scales and electrodes, through wavelet analysis of multi-channel ictal EEG. Second, we demonstrate that multiway analysis techniques, in particular parallel factor analysis (PARAFAC), provide promising results in modeling the complex structure of an epilepsy seizure, localizing a seizure origin and extracting artifacts. Third, we introduce an approach for removing artifacts using multilinear subspace analysis and discuss its merits and drawbacks. RESULTS: Ictal EEG analysis of 10 seizures from 7 patients are included in this study. Our results for 8 seizures match with clinical observations in terms of seizure origin and extracted artifacts. On the other hand, for 2 of the seizures, seizure localization is not achieved using an initial trial of PARAFAC modeling. In these cases, first, we apply an artifact removal method and subsequently apply the PARAFAC model on the epilepsy tensor from which potential artifacts have been removed. This method successfully identifies the seizure origin in both cases.     

Radiosurgical treatment of epilepsy

Focal irradiation of epileptic foci has been performed in a group of 6 epileptic patients, of whom 2 presented with epilepsy and 4 with epileptic psychoses. The epileptic focus was localized by means of conventional scalp EEG, electrocorticography and stereoelectroencephalography. Radiosurgery was performed by coupling a stereoguide to a 60Co unit using a 10-mm diameter collimator. An estimated dose of 10 Gy was administered. Results are presented and the mechanism of action of radiation discussed.     

Analysis of Epileptic Discharges from Implanted Subdural Electrodes in Patients with Sturge-Weber Syndrome

ObjectiveAlmost two-thirds of patients with Sturge-Weber syndrome (SWS) have epilepsy, and half of them require surgery for it. However, it is well known that scalp electroencephalography (EEG) does not demonstrate unequivocal epileptic discharges in patients with SWS. Therefore, we analyzed interictal and ictal discharges from intracranial subdural EEG recordings in patients treated surgically for SWS to elucidate epileptogenicity in this disorder.MethodsFive intractable epileptic patients with SWS who were implanted with subdural electrodes for presurgical evaluation were enrolled in this study. We examined the following seizure parameters: seizure onset zone (SOZ), propagation speed of seizure discharges, and seizure duration by visual inspection. Additionally, power spectrogram analysis on some frequency bands at SOZ was performed from 60 s before the visually detected seizure onset using the EEG Complex Demodulation Method (CDM).ResultsWe obtained 21 seizures from five patients for evaluation, and all seizures initiated from the cortex under the leptomeningeal angioma. Most of the patients presented with motionless staring and respiratory distress as seizure symptoms. The average seizure propagation speed and duration were 3.1 ± 3.6 cm/min and 19.4 ± 33.6 min, respectively. Significant power spectrogram changes at the SOZ were detected at 10–30 Hz from 15 s before seizure onset, and at 30–80 Hz from 5 s before seizure onset.SignificanceIn patients with SWS, seizures initiate from the cortex under the leptomeningeal angioma, and seizure propagation is slow and persists for a longer period. CDM indicated beta to low gamma-ranged seizure discharges starting from shortly before the visually detected seizure onset. Our ECoG findings indicate that ischemia is a principal mechanism underlying ictogenesis and epileptogenesis in SWS.     

Improved Diagnosis in Children with Partial Epilepsy Using a Multivariable Prediction Model Based on EEG Network Characteristics

Background

Electroencephalogram (EEG) acquisition is routinely performed to support an epileptic origin of paroxysmal events in patients referred with a possible diagnosis of epilepsy. However, in children with partial epilepsies the interictal EEGs are often normal. We aimed to develop a multivariable diagnostic prediction model based on electroencephalogram functional network characteristics.

Methodology/Principal Findings

Routinely performed interictal EEG recordings at first presentation of 35 children diagnosed with partial epilepsies, and of 35 children in whom the diagnosis epilepsy was excluded (control group), were used to develop the prediction model. Children with partial epilepsy were individually matched on age and gender with children from the control group. Periods of resting-state EEG, free of abnormal slowing or epileptiform activity, were selected to construct functional networks of correlated activity. We calculated multiple network characteristics previously used in functional network epilepsy studies and used these measures to build a robust, decision tree based, prediction model. Based on epileptiform EEG activity only, EEG results supported the diagnosis of with a sensitivity and specificity of 0.77 and 0.91 respectively. In contrast, the prediction model had a sensitivity of 0.96 [95% confidence interval: 0.78–1.00] and specificity of 0.95 [95% confidence interval: 0.76–1.00] in correctly differentiating patients from controls. The overall discriminative power, quantified as the area under the receiver operating characteristic curve, was 0.89, defined as an excellent model performance. The need of a multivariable network analysis to improve diagnostic accuracy was emphasized by the lack of discriminatory power using single network characteristics or EEG''s power spectral density.

Conclusions/Significance

Diagnostic accuracy in children with partial epilepsy is substantially improved with a model combining functional network characteristics derived from multi-channel electroencephalogram recordings. Early and accurate diagnosis is important to start necessary treatment as soon as possible and inform patients and parents on possible risks and psychosocial aspects in relation to the diagnosis.     

Comparative characteristics of spatial hearing of patients with different forms of cortical epilepsy

Perception of signals modeling directed movement of a sound source by three groups of patients with (1) temporal epilepsy, (2) epileptic foci in the frontal region, and (3) the epileptic syndrome due to local organic lesions in the temporal or frontal lobes was studied. It was established that the features and degree of spatial (binaural) hearing disorders in temporal epilepsy were determined not only by the localization and the extent of a lesion in the temporal lobe, but also by the areas beyond it that were involved in the epileptic process. Patients with organic lesions (tumors, cysts) involving the temporal lobe cortex may reveal more severe spatial hearing disorders than temporal epilepsy patients with the same localization of the foci of convulsive activity. A relatively isolated lesion of the frontal region cortex does not influence the assessment of the parameters of moving sound signals used. Possible neurophysiological mechanisms underlying the found spatial hearing disorders as well as the possibility of using the results obtained to solve the problems of differential diagnosis are considered.     

Acute unstable depressive syndrome (AUDS) is associated more frequently with epilepsy than major depression

Background  

Depressive disorders are frequent in epilepsy and associated with reduced seizure control. Almost 50% of interictal depressive disorders have to be classified as atypical depressions according to DSM-4 criteria. Research has mainly focused on depressive symptoms in defined populations with epilepsy (e.g., patients admitted to tertiary epilepsy centers). We have chosen the opposite approach. We hypothesized that it is possible to define by clinical means a subgroup of psychiatric patients with higher than expected prevalence of epilepsy and seizures. We hypothesized further that these patients present with an Acute Unstable Depressive Syndrome (AUDS) that does not meet DSM-IV criteria of a Major Depressive Episode (MDE). In a previous publication we have documented that AUDS patients indeed have more often a history of epileptic seizures and abnormal EEG recordings than MDE patients (Vaaler et al. 2009). This study aimed to further classify the differences of depressive symptoms at admittance and follow-up of patients with AUDS and MDE.     

Des sources neuronales aux signaux EEG : modèle et interprétation des activités épileptiques

This work deals with the interpretation of electrophysiological patients recorded in epileptic patients candidate to surgery. This issue is addressed through a physiologically relevant model for the generation of scalp and intracerebral electroencephalographic (EEG) signals. The proposed model is based on a spatiotemporal representation of the sources of brain activity, which combines a distributed dipole source model and a model of coupled neuronal populations. Signals recorded by sensors (scalp and intracerebral) are then computed by solving the forward problem in the head volume conductor. In this paper, the EEG generation model is used to study the influence of some source-related parameters (spatial extent, position, synchronization) on simulated signals, during epileptic transient activity (interictal spikes). Results show that the model allows for studying, on the one hand, the relationship between the spatiotemporal organization of neuronal sources and the properties of the observed signals and, on the other hand, the relationship between surface and depth EEG signals.     

Stability of synchronization clusters and seizurability in temporal lobe epilepsy

Purpose

Identification of critical areas in presurgical evaluations of patients with temporal lobe epilepsy is the most important step prior to resection. According to the “epileptic focus model”, localization of seizure onset zones is the main task to be accomplished. Nevertheless, a significant minority of epileptic patients continue to experience seizures after surgery (even when the focus is correctly located), an observation that is difficult to explain under this approach. However, if attention is shifted from a specific cortical location toward the network properties themselves, then the epileptic network model does allow us to explain unsuccessful surgical outcomes.

Methods

The intraoperative electrocorticography records of 20 patients with temporal lobe epilepsy were analyzed in search of interictal synchronization clusters. Synchronization was analyzed, and the stability of highly synchronized areas was quantified. Surrogate data were constructed and used to statistically validate the results. Our results show the existence of highly localized and stable synchronization areas in both the lateral and the mesial areas of the temporal lobe ipsilateral to the clinical seizures. Synchronization areas seem to play a central role in the capacity of the epileptic network to generate clinical seizures. Resection of stable synchronization areas is associated with elimination of seizures; nonresection of synchronization clusters is associated with the persistence of seizures after surgery.

Discussion

We suggest that synchronization clusters and their stability play a central role in the epileptic network, favoring seizure onset and propagation. We further speculate that the stability distribution of these synchronization areas would differentiate normal from pathologic cases.     

Dynamic EEG topography and analysis of epileptic spikes and evoked potentials following thalamic stimulation

Dynamic EEG topography is used to study evoked potentials following thalamic stimulation as well as epileptic spikes and spike-wave complexes during stereotactic operations. Dynamic EEG topography is an effective method for displaying the distribution pattern of evoked potentials following thalamic stimulation. This technique makes it possible to observe successive increases in augmenting responses and to define the localization of epileptic foci.     

Abnormal interictal gamma activity may manifest a seizure onset zone in temporal lobe epilepsy

Even though recent studies have suggested that seizures do not occur suddenly and that before a seizure there is a period with an increased probability of seizure occurrence, neurophysiological mechanisms of interictal and pre-seizure states are unknown. The ability of mathematical methods to provide much more sensitive tools for the detection of subtle changes in the electrical activity of the brain gives promise that electrophysiological markers of enhanced seizure susceptibility can be found even during interictal periods when EEG of epilepsy patients often looks 'normal'. Previously, we demonstrated in animals that hippocampal and neocortical gamma-band rhythms (30-100 Hz) intensify long before seizures caused by systemic infusion of kainic acid. Other studies in recent years have also drawn attention to the fast activity (>30 Hz) as a possible marker of epileptogenic tissue. The current study quantified gamma-band activity during interictal periods and seizures in intracranial EEG (iEEG) in 5 patients implanted with subdural grids/intracranial electrodes during their pre-surgical evaluation. In all our patients, we found distinctive (abnormal) bursts of gamma activity with a 3 to 100 fold increase in power at gamma frequencies with respect to selected by clinicians, quiescent, artifact-free, 7-20 min "normal" background (interictal) iEEG epochs 1 to 14 hours prior to seizures. Increases in gamma activity were largest in those channels which later displayed the most intensive electrographic seizure discharges. Moreover, location of gamma-band bursts correlated (with high specificity, 96.4% and sensitivity, 83.8%) with seizure onset zone (SOZ) determined by clinicians. Spatial localization of interictal gamma rhythms within SOZ suggests that the persistent presence of abnormally intensified gamma rhythms in the EEG may be an important tool for focus localization and possibly a determinant of epileptogenesis.     

Brain Source Imaging in Preclinical Rat Models of Focal Epilepsy using High-Resolution EEG Recordings

Electroencephalogram (EEG) has been traditionally used to determine which brain regions are the most likely candidates for resection in patients with focal epilepsy. This methodology relies on the assumption that seizures originate from the same regions of the brain from which interictal epileptiform discharges (IEDs) emerge. Preclinical models are very useful to find correlates between IED locations and the actual regions underlying seizure initiation in focal epilepsy. Rats have been commonly used in preclinical studies of epilepsy¹; hence, there exist a large variety of models for focal epilepsy in this particular species. However, it is challenging to record multichannel EEG and to perform brain source imaging in such a small animal. To overcome this issue, we combine a patented-technology to obtain 32-channel EEG recordings from rodents² and an MRI probabilistic atlas for brain anatomical structures in Wistar rats to perform brain source imaging. In this video, we introduce the procedures to acquire multichannel EEG from Wistar rats with focal cortical dysplasia, and describe the steps both to define the volume conductor model from the MRI atlas and to uniquely determine the IEDs. Finally, we validate the whole methodology by obtaining brain source images of IEDs and compare them with those obtained at different time frames during the seizure onset.