Networks involved in seizure initiation. A reading epilepsy case studied with EEG-fMRI and MEG.

OBJECTIVE: To define the ictal cortical/subcortical network of reading-induced seizures. METHODS: We analyzed ictal magnetoencephalography (MEG) and EEG-correlated fMRI (EEG-fMRI) data in a unique patient with reading epilepsy (RE) affected by frequent perioral reflex myocloni triggered by reading silently. RESULTS: Ictal MEG corroborated EEG localization and revealed activity extending precentrally into Brodmann area (BA) 6. fMRI blood oxygen level-dependent (BOLD) signal changes in the left deep piriform cortex (PFC) and left BA6 preceded seizures and occurred before BOLD changes were observed in thalamus and right inferior frontal gyrus (BA44). Dynamic causal modeling provided evidence of a causal link between hemodynamic changes in the left PFC and reading-evoked seizures. CONCLUSION: Our findings support the important role of deep cortical and subcortical structures, in particular the frontal PFC, as key regions in initiating and modulating seizure activity. In our patient with RE, BA6 appeared to be the area linking cognitive activation and seizure activity.

EEG correlated functional MRI and postoperative outcome in focal epilepsy.

BACKGROUND: The main challenge in assessing patients with epilepsy for resective surgery is localising seizure onset. Frequently, identification of the irritative and seizure onset zones requires invasive EEG. EEG correlated functional MRI (EEG-fMRI) is a novel imaging technique which may provide localising information with regard to these regions. In patients with focal epilepsy, interictal epileptiform discharge (IED) correlated blood oxygen dependent level (BOLD) signal changes were observed in approximately 50% of patients in whom IEDs are recorded. In 70%, these are concordant with expected seizure onset defined by non-invasive electroclinical information. Assessment of clinical validity requires post-surgical outcome studies which have, to date, been limited to case reports of correlation with intracranial EEG. The value of EEG-fMRI was assessed in patients with focal epilepsy who subsequently underwent epilepsy surgery, and IED correlated fMRI signal changes were related to the resection area and clinical outcome. METHODS: Simultaneous EEG-fMRI was recorded in 76 patients undergoing presurgical evaluation and the locations of IED correlated preoperative BOLD signal change were compared with the resected area and postoperative outcome. RESULTS: 21 patients had activations with epileptic activity on EEG-fMRI and 10 underwent surgical resection. Seven of 10 patients were seizure free following surgery and the area of maximal BOLD signal change was concordant with resection in six of seven patients. In the remaining three patients, with reduced seizure frequency post-surgically, areas of significant IED correlated BOLD signal change lay outside the resection. 42 of 55 patients who had no IED related activation underwent resection. CONCLUSION: These results show the potential value of EEG-fMRI in presurgical evaluation.

Imaging seizure activity: a combined EEG/EMG-fMRI study in reading epilepsy.

PURPOSE: To characterize the spatial relationship between activations related to language-induced seizure activity, language processing, and motor control in patients with reading epilepsy. METHODS: We recorded and simultaneously monitored several physiological parameters [voice-recording, electromyography (EMG), electrocardiography (ECG), electroencephalography (EEG)] during blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) in nine patients with reading epilepsy. Individually tailored language paradigms were used to induce and record habitual seizures inside the MRI scanner. Voxel-based morphometry (VBM) was used for structural brain analysis. Reading-induced seizures occurred in six out of nine patients. RESULTS: One patient experienced abundant orofacial reflex myocloni during silent reading in association with bilateral frontal or generalized epileptiform discharges. In a further five patients, symptoms were only elicited while reading aloud with self-indicated events. Consistent activation patterns in response to reading-induced myoclonic seizures were observed within left motor and premotor areas in five of these six patients, in the left striatum (n = 4), in mesiotemporal/limbic areas (n = 4), in Brodmann area 47 (n = 3), and thalamus (n = 2). These BOLD activations were overlapping or adjacent to areas physiologically activated during language and facial motor tasks. No subtle structural abnormalities common to all patients were identified using VBM, but one patient had a left temporal ischemic lesion. DISCUSSION: Based on the findings, we hypothesize that reflex seizures occur in reading epilepsy when a critical mass of neurons are activated through a provoking stimulus within corticoreticular and corticocortical circuitry subserving normal functions.

Modelling large motion events in fMRI studies of patients with epilepsy.

EEG-correlated fMRI can provide localisation information on the generators of epileptiform discharges in patients with focal epilepsy. To increase the technique's clinical potential, it is important to consider ways of optimising the yield of each experiment while minimizing the risk of false-positive activation. Head motion can lead to severe image degradation and result in false-positive activation and is usually worse in patients than in healthy subjects. We performed general linear model fMRI data analysis on simultaneous EEG-fMRI data acquired in 34 cases with focal epilepsy. Signal changes associated with large inter-scan motion events (head jerks) were modelled using modified design matrices that include 'scan nulling' regressors. We evaluated the efficacy of this approach by mapping the proportion of the brain for which F-tests across the additional regressors were significant. In 95% of cases, there was a significant effect of motion in 50% of the brain or greater; for the scan nulling effect, the proportion was 36%; this effect was predominantly in the neocortex. We conclude that careful consideration of the motion-related effects in fMRI studies of patients with epilepsy is essential and that the proposed approach can be effective.

Temporal lobe interictal epileptic discharges affect cerebral activity in "default mode" brain regions.

A cerebral network comprising precuneus, medial frontal, and temporoparietal cortices is less active both during goal-directed behavior and states of reduced consciousness than during conscious rest. We tested the hypothesis that the interictal epileptic discharges affect activity in these brain regions in patients with temporal lobe epilepsy who have complex partial seizures. At the group level, using electroencephalography-correlated functional magnetic resonance imaging in 19 consecutive patients with focal epilepsy, we found common decreases of resting state activity in 9 patients with temporal lobe epilepsy (TLE) but not in 10 patients with extra-TLE. We infer that the functional consequences of TLE interictal epileptic discharges are different from those in extra-TLE and affect ongoing brain function. Activity increases were detected in the ipsilateral hippocampus in patients with TLE, and in subthalamic, bilateral superior temporal and medial frontal brain regions in patients with extra-TLE, possibly indicating effects of different interictal epileptic discharge propagation.

Hemodynamic correlates of epileptiform discharges: an EEG-fMRI study of 63 patients with focal epilepsy.

Using continuous EEG-correlated fMRI, we investigated the Blood Oxygen Level Dependent (BOLD) signal correlates of interictal epileptic discharges (IEDs) in 63 consecutively recruited patients with focal epilepsy. Semi-automated spike detection and advanced modeling strategies are introduced to account for different EEG event types, and to minimize false activations from uncontrolled motion. We show that: (1) significant hemodynamic correlates were detectable in over 68% of patients in whom discharges were captured and were highly, but not entirely, concordant with site(s) of presumed seizure generation where known; (2) deactivations were less concordant and may non-specifically reflect the consequential or downstream effects of IEDs on brain activity; (3) a striking pattern of retrosplenial deactivation was observed in 7 cases mainly with focal discharges; (4) the basic hemodynamic response to IEDs is physiological; (5) incorporating information about different types of IEDs, their durations and saturation effects resulted in more powerful models for the detection of fMRI correlates; (6) focal activations were more likely when there was good electroclinical localization, frequent stereotyped spikes, less head motion and less background EEG abnormality, but were also seen in patients in whom the electroclinical focus localization was uncertain. These findings provide important new information on the optimal use and interpretation of EEG-fMRI in focal epilepsy and suggest a possible role for EEG-fMRI in providing new targets for invasive EEG monitoring.

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.

EEG/functional MRI in epilepsy: The Queen Square Experience.

The recording of EEG during functional MRI scanning (EEG/fMRI) has opened up new dimensions in brain research. The simultaneous recording of EEG activity and its temparospatial haemodynamic correlates is a powerful tool in the non-invasive mapping of normal and pathological brain function. The technological constraints imposed by having a conductor (the EEG) within the magnetic environment of the MRI scanner have been sufficiently overcome for high quality EEG recording during MRI. The initial applications of EEG/fMRI were in the study of epileptiform discharges in epilepsy. This has been rapidly followed by studies of normal EEG rhythms and evoked response in healthy subjects. The ability to map brain areas involved in the generation of epileptiform discharges recorded on the surface EEG has been shown using EEG/fMRI in patients with epilepsy. This has potential clinical applications in providing additional localizing information in the pre-surgical workup of epilepsy patients and in gaining a greater understanding of the neurobiology of interictal epileptiform discharges and epileptic seizures. In this review we address the issues in recording EEG during fMRI and review the application of EEG/fMRI in the study of patients with epilepsy at our centre.

The MR detection of neuronal depolarization during 3-Hz spike-and-wave complexes in generalized epilepsy.

Previously, an analysis of activations observed in a patient with idiopathic generalized epilepsy using electroencephalogram-correlated functional magnetic resonance imaging (MRI) during runs of 3-Hz generalized spike-wave discharge (GSWD) was presented by Salek-Haddadi. Time-locked, bilateral, thalamic blood oxygenation level-dependent increases were reported to be accompanied by widespread, symmetric, cortical deactivation with a frontal maximum. In light of recent investigations into MRI detection of the magnetic field perturbations caused by neuronal current loops during depolarization, we revisited the analysis of the data of Salek-Haddadi as a preliminary search for a neuroelectric signal. We modeled the MRI response as the sum of a fast signal and a slower signal and demonstrated significant MRI activity at a time scale of the order of 30 ms associated with GSWDs. Further work is necessary before firm conclusions may be drawn about the nature of this signal.

Combined functional MRI and tractography to demonstrate the connectivity of the human primary motor cortex in vivo.

In this study, we combined advanced MR techniques to explore primary motor cortex (M1) connectivity in the human brain. We matched functional and anatomical information using motor functional MRI (fMRI) and white matter tractography inferred from diffusion tensor imaging (DTI). We performed coregistered DTI and motor task fMRI in 8 right-handed healthy subjects and in 1 right-handed patient presenting with a left precentral tumour. We used the fast-marching tractography (FMT) algorithm to define 3D connectivity maps within the whole brain, from seed points selected in the white matter adjacent to the location of the maximum of fMRI activation. Connectivity maps were then anatomically normalised and analysed using statistical parametric mapping software (SPM99) allowing group comparisons (left versus right hemisphere in control subjects and patient versus control subjects). The results demonstrated, in all control subjects, strong connections from M1 to the pyramidal tracts, premotor areas, parietal cortices, thalamus, and cerebellum. M1 connectivity was asymmetric, being more extensive in the dominant hemisphere. The patient had differences in M1 connectivity from the control group. Thus, fMRI-correlated DTI-FMT is a promising tool to study the structural basis of functional networks in the human brain in vivo.

Functional magnetic resonance imaging of human absence seizures.

We studied a patient with idiopathic generalized epilepsy and frequent absences, using electroencephalogram-correlated functional magnetic resonance imaging. Four prolonged runs of generalized spike-wave discharge occurred during a 35-minute experiment. Time-locked activation was observed bilaterally within the thalami in conjunction with widespread but symmetrical cortical deactivation with a frontal maximum. We demonstrate the reciprocal participation of focal thalamic and widespread cortical networks during human absence seizures and suggest reductions in cortical blood flow, in response to synchronized electroencephalogram activity.

EEG quality during simultaneous functional MRI of interictal epileptiform discharges.

This article concerns the evaluation of the quality of interictal epileptiform EEG discharges recorded throughout simultaneous echo planar imaging (EPI). BOLD (blood oxygen level dependent) functional MRI (fMRI) images were acquired continuously on a patient with intractable epilepsy. EEG was sampled simultaneously, during and after imaging, with removal of pulse and imaging artifacts by subtraction of channel-specific running averages. Contiguous EEG epochs recorded with and without fMRI (fMRI+ve vs. fMRI-ve) were next randomized and presented to two blinded observers. Epileptiform discharges were identified retrospectively, and comparison was made in terms of the number of identified events, their amplitude, and spatiotemporal distribution. A spectral analysis was also performed on the EEG. In the randomized comparison of EEG segments, 80 (fMRI+ve) vs. 69 (fMRI-ve) discharges were noted with good interobserver agreement (69%). There were no significant differences in amplitude or spatio-temporal distribution. Comparison of the events detected and measured by two expert observers demonstrated that the Interictal Epileptiform Discharge (IED) characteristics were indistinguishable with and without scanning. We review briefly the existing literature on EEG recording quality for combined EEG/fMRI.

Mapping of spikes, slow waves, and motor tasks in a patient with malformation of cortical development using simultaneous EEG and fMRI.

We report on the simultaneous and continuous acquisition of EEG and functional MRI data in a patient with a left hemiparesis and focal epilepsy secondary to malformation of cortical development in the right hemisphere. EEG-triggered fMRI localization was previously demonstrated in this patient. In the experiments reported here, 322 spikes maximum at electrode C4 and 126 focal slow waves were identified offline. A hierarchy of models was explored in order to assess the relative contributions of each type of EEG event. Modeling the BOLD response to C4 spikes alone showed an area of activation within the large malformation, adjacent to the area of infolding cortex. However, also modeling slow-waves gave rise to a broader and stronger activation, suggesting that the generators overlap. Motor mapping of the right hand showed activation in the left sensorimotor cortex; left-hand tapping led to a more diffuse area of activation, displaced superiorly into the superior frontal gyrus, and a small area of activation within the lesion. In conclusion, continuous EEG-fMRI is useful to compare the functional mapping of epileptiform activity and eloquent cortices in individual patients.

Simultaneous EEG-Correlated Ictal fMRI.

The ability to continuously acquire simultaneous EEG and fMRI data during seizures presents a formidable challenge both clinically and technically. Published ictal fMRI reports have so far been unable to benefit from simultaneous electrographic recordings and remain largely assumptive. Unique findings from a Continuous EEG-correlated fMRI experiment are presented in which a focal subclinical seizure was captured in its entirety. For the first time dynamic and biphasic Blood Oxygen Level Dependent (BOLD) signal changes are shown using statistical parametric mapping time-locked to the ictal EEG activity localizing seizure generation and propagation sites, with millimeter resolution, to electroclinically concordant gray matter structures. Though presently of limited clinical applicability, a new avenue is opened for further research.

Role of functional magnetic resonance imaging in the evaluation of patients with malformations caused by cortical development.

As functional MR imaging (fMRI) continues to offer unparalleled advantages in probing neural activity, diagnostic applications continue to flourish. The evaluation of malformations caused by abnormalities of cortical development is an area in which fMRI has an emerging role and potential to provide new insights into epileptogenesis through multimodal integration with electroencephalagraphy. The clinical impact, however, is just beginning to be felt as new data emerge.