EEG–fMRI of idiopathic and secondarily generalized epilepsies

We used simultaneous EEG and functional MRI (EEG–fMRI) to study generalized spike wave activity (GSW) in idiopathic and secondary generalized epilepsy (SGE). Recent studies have demonstrated thalamic and cortical fMRI signal changes in association with GSW in idiopathic generalized epilepsy (IGE). We report on a large cohort of patients that included both IGE and SGE, and give a functional interpretation of our findings. Forty-six patients with GSW were studied with EEG–fMRI; 30 with IGE and 16 with SGE. GSW-related BOLD signal changes were seen in 25 of 36 individual patients who had GSW during EEG–fMRI. This was seen in thalamus (60%) and symmetrically in frontal cortex (92%), parietal cortex (76%), and posterior cingulate cortex/precuneus (80%). Thalamic BOLD changes were predominantly positive and cortical changes predominantly negative. Group analysis showed a negative BOLD response in the cortex in the IGE group and to a lesser extent a positive response in thalamus. Thalamic activation was consistent with its known role in GSW, and its detection in individual cases with EEG–fMRI may in part be related to the number and duration of GSW epochs recorded. The spatial distribution of the cortical fMRI response to GSW in both IGE and SGE involved areas of association cortex that are most active during conscious rest. Reduction of activity in these regions during GSW is consistent with the clinical manifestation of absence seizures

Lennox-Gastaut Syndrome: A State of the Art Review.

Lennox-Gastaut syndrome (LGS) is a severe age-dependent epileptic encephalopathy usually with onset between 1 and 8 years of age. Functional neuroimaging studies recently introduced the concept of Lennox-Gastaut as "secondary network epilepsy" resulting from dysfunctions of a complex system involving both cortical and subcortical structures (default-mode network, corticoreticular connections, and thalamus). These dysfunctions are produced by different disorders including hypoxic-ischemic encephalopathies, meningoencephalitis, cortical malformations, neurocutaneous disorders, or tumors. The list of etiologies was expanded to pathogenic copy number variants at whole-genome array comparative genomic hybridization associated with late-onset cases or pathogenic mutations involving genes, such as GABRB3, ALG13, SCN8A, STXBP1, DNM1, FOXG1, or CHD2. Various clinical trials demonstrated the usefulness of different drugs (including rufinamide, clobazam, lamotrigine, topiramate, or felbamate), ketogenic diet, resective surgery, corpus callosotomy, and vagus nerve stimulation in the treatment of epileptic manifestations. The outcome of LGS often remains disappointing regarding seizure control or cognitive functioning. The realization of animal models, which are still lacking, and the full comprehension of molecular mechanisms involved in epileptogenesis and cognitive impairment would give a relevant support to further improvements in therapeutic strategies for LGS patients

An investigation of the relationship between BOLD and perfusion signal changes during epileptic generalised spike wave activity

In pathological conditions interpretation of functional magnetic resonance imaging (fMRI) results can be difficult. This is due to a reliance on the assumed coupling between neuronal activity and changes in cerebral blood flow (CBF) and oxygenation. We wanted to investigate the coupling between blood oxygen level dependant contrast (BOLD) and CBF time courses in epilepsy patients with generalised spike wave activity (GSW) to better understand the underlying mechanisms behind the EEG-fMRI signal changes observed, especially in regions of negative BOLD response (NBR). Four patients with frequent GSW were scanned with simultaneous electroencephalographic (EEG)-fMRI with BOLD and arterial spin labeling (ASL) sequences. We examined the relationship between simultaneous CBF and BOLD measurements by looking at the correlation of the two signals in terms of percentage signal change on a voxel-by-voxel basis. This method is not reliant on coincident activation. BOLD and CBF were positively correlated in patients with epilepsy during background EEG activity and GSW. The subject average value of the ΔCBF/ΔBOLD slope lay between +19 and +36 and also showed spatial variation which could indicate areas with altered vascular response. There was not a significant difference between ΔCBF/ΔBOLD during GSW, suggesting that neurovascular coupling to BOLD signal is generally maintained between states and, in particular, within areas of NBR

BOLD and perfusion changes during epileptic generalised spike wave activity

It is unclear whether neurovascular coupling is maintained during epileptic discharges. Knowing this is important to allow appropriate inferences from functional imaging studies of epileptic activity. Recent blood oxygen level-dependent (BOLD) functional MRI (fMRI) studies have demonstrated negative BOLD responses (NBR) in frontal, parietal and posterior cingulate cortices during generalised spike wave activity (GSW). We hypothesized that GSW-related NBR commonly reflect decreased cerebral blood flow (CBF). We measured BOLD and cerebral blood flow responses using simultaneous EEG with BOLD and arterial spin label (ASL) fMRI at 3 T. Four patients with epilepsy were studied; two with idiopathic generalized epilepsy (IGE) and two with secondary generalized epilepsy (SGE). We found GSW-related NBR in frontal, parietal and posterior cingulate cortices. We measured the coupling between BOLD and CBF changes during GSW and normal background EEG and found a positive correlation between the simultaneously measured BOLD and CBF throughout the imaged volume. Frontal and thalamic activation were seen in two patients with SGE, concordant with the electro-clinical features of their epilepsy. There was striking reproducibility of the GSW-associated BOLD response in subjects previously studied at 1.5 T. Our results show a preserved relationship between BOLD and CBF changes during rest and GSW activity consistent with normal neurovascular coupling in patients with generalized epilepsy and in particular during GSW activity. Cortical activations appear to reflect areas of discharge generation whilst deactivations reflect changes in conscious resting state activity

EEG-fMRI signatures of spontaneous brain activity in healthy volunteers and epilepsy patients

Background: Functional magnetic resonance imaging (fMRI) provides maps of haemodynamic activity with uniform resolution across the brain. Simultaneous recording of electroencephalography (EEG) during fMRI (EEG-fMRI) was developed to localize spontaneously occurring epileptiform discharges. In focal epilepsy, it can identify candidate brain regions for surgical removal as a treatment option in medically refractory epilepsy; and in generalized epilepsy syndromes reveals those involved during the EEG changes. In healthy subjects, EEG-fMRI has linked spontaneous ongoing EEG activity with fMRI resting state networks. Methods: After method refinements, patients with medically refractory focal epilepsy and those with generalized epilepsy were studied with EEG-fMRI and group analyses performed to identify typical sets of brain regions involved in the epileptic process. Findings: In individual patients with refractory focal epilepsy, EEG-fMRI can produce activity maps including the seizure onset zone and propagated epileptic activity. Clinically, these can be confirmatory of results from alternative diagnostic techniques, or alternatively serve to generate a hypothesis on the potential epileptic focus, but under certain conditions may also be of negative predictive value with respect to surgical treatment success. At the group level in patients with temporal lobe epilepsy and complex partial seizures as well as in patients with generalized epilepsy and absence seizures, altered resting state network activity during EEG changes were found in default mode brain regions fitting well the ictal semiology, because these are known to reduce their activity during states of reduced consciousness. In (1) lateralized temporal lobe epilepsies, (2) an unselected mix of focal epilepsies, and (3) generalized epilepsies, activity increases occurred in typical brain regions suggesting an associated “hub function”, namely ipsilateral to the presumed cortical focus in the hippocampus; in an area near the frontal piriform cortex; and bilaterally in the thalamus, respectively. These findings argue for a network rather than a zone concept of epilepsy

Neuronal networks underlying Jeavons-syndrome and eye closure sensitivity by using EEG source analysis methods

Eyelid myoclonia with absences (EMA) or Jeavons syndrome (JS) is considered to be the type of idiopathic generalized epilepsy, clinically characterized by eyelid myoclonia (EM) with or without absences, eye closure-induced electroencephalography (EEG) paroxysms, and photosensitivity. Interictal and ictal EEG mostly shows high amplitude discharges of generalised irregular spike/polyspike and waves (GSW) at 3-6 Hz often appearing immediately after closing the eyes (eye closure sensitivity). The mechanism underling eye closure sensitivity (ECS) and Jeavons syndrome is not well understood. The clinical and neuroimaging studies suggest that the occipital visual cortex and thalamus play the main role in the generation of EMA in the presence of light and eye closure. In our study, we attempted to estimate functional connectivity (FC) during ictal myoclonus and interictal generalized epileptic discharges using the imaginary part of coherency (iCoh) at the sensory and source level to find out what changes underlie JS and to find out whether there is a network-level difference between ictal and interictal discharges.The EEG data of 11 pediatric patients with the diagnosis of Jeavons syndrome were retrospectively collected and analyzed. In our FC study, we found a complex involvement of different brain networks. We saw the thalamus connection to the brain regions, which participate in state of consciousness, oculomotor control, myoclonus, eye closure sensitivity and photosensitivity. Our result complies with the previous results of fMRI studies performed in JS and IGEs Patients. However, when we compared the FC of ictal and interictal EEG paroxysms we could not find any significant differences. This could be due to the fact that we only selected one seizure type, myoclonus and excluded epochs with absences. We speculate that the reason we did not see any group differences is DM network is that the state of consciousness was not altered in the selected segmen

An EEG-fMRI Study on the Termination of Generalized Spike-And-Wave Discharges in Absence Epilepsy

INTRODUCTION: Different studies have investigated by means of EEG-fMRI coregistration the brain networks related to generalized spike-and-wave discharges (GSWD) in patients with idiopathic generalized epilepsy (IGE). These studies revealed a widespread GSWD-related neural network that involves the thalamus and regions of the default mode network. In this study we investigated which brain regions are critically involved in the termination of absence seizures (AS) in a group of IGE patients. METHODS: Eighteen patients (6 male; mean age 25 years) with AS were included in the EEG-fMRI study. Functional data were acquired at 3T with continuous simultaneous video-EEG recording. Event-related analysis was performed with SPM8 software, using the following regressors: (1) GSWD onset and duration; (2) GSWD offset. Data were analyzed at single-subject and at group level with a second level random effect analysis. RESULTS: A mean of 17 events for patient was recorded (mean duration of 4.2 sec). Group-level analysis related to GSWD onset respect to rest confirmed previous findings revealing thalamic activation and a precuneus/posterior cingulate deactivation. At GSWD termination we observed a decrease in BOLD signal over the bilateral dorsolateral frontal cortex respect to the baseline (and respect to GSWD onset). The contrast GSWD offset versus onset showed a BOLD signal increase over the precuneus-posterior cingulate region bilaterally. Parametric correlations between electro-clinical variables and BOLD signal at GSWD offset did not reveal significant effects. CONCLUSION: The role of the decreased neural activity of lateral prefrontal cortex at GSWD termination deserve future investigations to ascertain if it has a role in promoting the discharge offset, as well as in the determination of the cognitive deficits often present in patients with AS. The increased BOLD signal at precuneal/posterior cingulate cortex might reflect the recovery of neural activity in regions that are "suspended" during spike and waves activity, as previously hypothesized

Network Connectivity in Epilepsy: Resting State fMRI and EEG-fMRI Contributions.

There is a growing body of evidence pointing toward large-scale networks underlying the core phenomena in epilepsy, from seizure generation to cognitive dysfunction or response to treatment. The investigation of networks in epilepsy has become a key concept to unlock a deeper understanding of the disease. Functional imaging can provide valuable information to characterize network dysfunction; in particular resting state fMRI (RS-fMRI), which is increasingly being applied to study brain networks in a number of diseases. In patients with epilepsy, network connectivity derived from RS-fMRI has found connectivity abnormalities in a number of networks; these include the epileptogenic, cognitive and sensory processing networks. However, in majority of these studies, the effect of epileptic transients in the connectivity of networks has been neglected. EEG-fMRI has frequently shown networks related to epileptic transients that in many cases are concordant with the abnormalities shown in RS studies. This points toward a relevant role of epileptic transients in the network abnormalities detected in RS-fMRI studies. In this review, we summarize the network abnormalities reported by these two techniques side by side, provide evidence of their overlapping findings, and discuss their significance in the context of the methodology of each technique. A number of clinically relevant factors that have been associated with connectivity changes are in turn associated with changes in the frequency of epileptic transients. These factors include different aspects of epilepsy ranging from treatment effects, cognitive processes, or transition between different alertness states (i.e., awake-sleep transition). For RS-fMRI to become a more effective tool to investigate clinically relevant aspects of epilepsy it is necessary to understand connectivity changes associated with epileptic transients, those associated with other clinically relevant factors and the interaction between them, which represents a gap in the current literature. We propose a framework for the investigation of network connectivity in patients with epilepsy that can integrate epileptic processes that occur across different time scales such as epileptic transients and disease duration and the implications of this approach are discussed

Network Connectivity in Epilepsy: Resting State fMRI and EEG-fMRI Contributions.

There is a growing body of evidence pointing toward large-scale networks underlying the core phenomena in epilepsy, from seizure generation to cognitive dysfunction or response to treatment. The investigation of networks in epilepsy has become a key concept to unlock a deeper understanding of the disease. Functional imaging can provide valuable information to characterize network dysfunction; in particular resting state fMRI (RS-fMRI), which is increasingly being applied to study brain networks in a number of diseases. In patients with epilepsy, network connectivity derived from RS-fMRI has found connectivity abnormalities in a number of networks; these include the epileptogenic, cognitive and sensory processing networks. However, in majority of these studies, the effect of epileptic transients in the connectivity of networks has been neglected. EEG-fMRI has frequently shown networks related to epileptic transients that in many cases are concordant with the abnormalities shown in RS studies. This points toward a relevant role of epileptic transients in the network abnormalities detected in RS-fMRI studies. In this review, we summarize the network abnormalities reported by these two techniques side by side, provide evidence of their overlapping findings, and discuss their significance in the context of the methodology of each technique. A number of clinically relevant factors that have been associated with connectivity changes are in turn associated with changes in the frequency of epileptic transients. These factors include different aspects of epilepsy ranging from treatment effects, cognitive processes, or transition between different alertness states (i.e., awake-sleep transition). For RS-fMRI to become a more effective tool to investigate clinically relevant aspects of epilepsy it is necessary to understand connectivity changes associated with epileptic transients, those associated with other clinically relevant factors and the interaction between them, which represents a gap in the current literature. We propose a framework for the investigation of network connectivity in patients with epilepsy that can integrate epileptic processes that occur across different time scales such as epileptic transients and disease duration and the implications of this approach are discussed