Eliane Kobayashi

Combining EEG and fMRI: A multimodal tool for epilepsy research

Patients with epilepsy often present in their electroencephalogram (EEG) short electrical potentials (spikes or spike‐wave bursts) that are not accompanied by clinical manifestations but are of important diagnostic significance. They result from a population of abnormally hyperactive and hypersynchronous neurons. It is not easy to determine the location of the cerebral generators and the other brain regions that may be involved as a result of this abnormal activity. The possibility to combine EEG recording with functional MRI (fMRI) scanning opens the opportunity to uncover the regions of the brain showing changes in the fMRI signal in response to epileptic spikes seen in the EEG. These regions are presumably involved in the abnormal neuronal activity at the origin of epileptic discharges. This paper reviews the methodology involved in performing such studies, particularly the challenge of recording a good quality EEG inside the MR scanner while scanning is taking place, and the methods required for the statistical analysis of the combined EEG and fMRI time series. We review the results obtained in patients with different types of epileptic disorders and discuss the difficult theoretical problems raised by the interpretation of an increase (activation) and decrease (deactivation) in blood oxygen level dependent (BOLD) signal, both frequently seen in response to spikes. J. Magn. Reson. Imaging 2006.

EEG-fMRI of focal epileptic spikes: Analysis with multiple haemodynamic functions and comparison with gadolinium-enhanced MR angiograms

Combined EEG‐fMRI has recently been used to explore the BOLD responses to interictal epileptiform discharges. This study examines whether misspecification of the form of the haemodynamic response function (HRF) results in significant fMRI responses being missed in the statistical analysis. EEG‐fMRI data from 31 patients with focal epilepsy were analysed with four HRFs peaking from 3 to 9 sec after each interictal event, in addition to a standard HRF that peaked after 5.4 sec. In four patients, fMRI responses were correlated with gadolinium‐enhanced MR angiograms and with EEG data from intracranial electrodes. In an attempt to understand the absence of BOLD responses in a significant group of patients, the degree of signal loss occurring as a result of magnetic field inhomogeneities was compared with the detected fMRI responses in ten patients with temporal lobe spikes. Using multiple HRFs resulted in an increased percentage of data sets with significant fMRI activations, from 45% when using the standard HRF alone, to 62.5%. The standard HRF was good at detecting positive BOLD responses, but less appropriate for negative BOLD responses, the majority of which were more accurately modelled by an HRF that peaked later than the standard. Co‐registration of statistical maps with gadolinium‐enhanced MRIs suggested that the detected fMRI responses were not in general related to large veins. Signal loss in the temporal lobes seemed to be an important factor in 7 of 12 patients who did not show fMRI activations with any of the HRFs. Hum. Brain Mapp. 22:179–192, 2004.

Negative BOLD responses to epileptic spikes

Simultaneous electroencephalogram/functional magnetic resonance imaging (EEG‐fMRI) during interictal epileptiform discharges can result in positive (activation) and negative (deactivation) changes in the blood oxygenation level‐dependent (BOLD) signal. Activation probably reflects increased neuronal activity and energy demand, but deactivation is more difficult to explain. Our objective was to evaluate the occurrence and significance of deactivations related to epileptiform discharges in epilepsy. We reviewed all EEG‐fMRI studies from our database, identified those with robust responses (P = 0.01, with ≥5 contiguous voxels with a |t| > 3.1, including ≥1 voxel at |t| > 5.0), and divided them into three groups: activation (A = 8), deactivation (D = 9), and both responses (AD = 43). We correlated responses with discharge type and location and evaluated their spatial relationship with regions involved in the “default” brain state (Raichle et al. [ 2001 ]: Proc Natl Acad Sci 98:676–682]. Deactivations were seen in 52/60 studies (AD+D): 26 related to focal discharges, 12 bilateral, and 14 generalized. Deactivations were usually distant from anatomical areas related to the discharges and more frequently related to polyspike‐ and spike‐and‐slow waves than to spikes. The “default” pattern occurred in 10/43 AD studies, often associated with bursts of generalized discharges. In conclusion, deactivations are frequent, mostly with concomitant activation, for focal and generalized discharges. Discharges followed by a slow wave are more likely to result in deactivation, suggesting neuronal inhibition as the underlying phenomenon. Involvement of the “default” areas, related to bursts of generalized discharges, provides evidence of a subclinical effect of the discharges, temporarily suspending normal brain function in the resting state. Hum Brain Mapp, 2005.

Seizure outcome and hippocampal atrophy in familial mesial temporal lobe epilepsy

Objective: To describe the clinical, genetic and MR characteristics of patients with familial mesial temporal lobe epilepsy (MTLE). Design/Methods: The familial occurrence of MTLE was identified by a systematic search of family history of seizures in patients followed in the authors’ epilepsy clinic. All probands and, whenever possible, other affected family members underwent EEG and MR investigations. Results: Twenty-two unrelated families with at least two individuals with MTLE were identified by clinical and EEG findings. Ninety-eight individuals with history of seizures were evaluated. Sixty-eight patients fulfilled the diagnostic criteria for MTLE. MRI was performed in 84 patients, and showed hippocampal atrophy with increased T2 signal in 48 (57%). The distribution of hippocampal atrophy according to the seizure outcome groups was 6 of 13 patients (46%) with seizure remission, 16 of 31 (51%) with good seizure control under medication, and all 16 patients with refractory MTLE. Hippocampal atrophy was found also in patients that did not fulfill the criteria for MTLE: 3 of 10 (30%) patients with febrile seizure alone, 6 of 10 (60%) patients with recurrent generalized tonic-clonic seizures, and 1 of 4 (25%) patients with a single partial seizure. Conclusion: Familial MTLE is a clinically heterogeneous syndrome. Hippocampal atrophy was observed in 57% of patients, including those with benign course or seizure remission, indicating that the relationship between hippocampal atrophy and severity of epilepsy might be more complex than previously suspected. In addition, these findings indicate the presence of a strong genetic component determining the development of mesial temporal sclerosis in these families.

Temporal and Extratemporal BOLD Responses to Temporal Lobe Interictal Spikes

Summary:  Purpose: Simultaneous EEG and functional MRI (fMRI) allows measuring metabolic changes related to interictal spikes. Our objective was to investigate blood oxygenation level–dependent (BOLD) responses to temporal lobe (TL) spikes by using EEG‐fMRI recording.

Different structures involved during ictal and interictal epileptic activity in malformations of cortical development: an EEG-fMRI study

Malformations of cortical development (MCDs) are commonly complicated by intractable focal epilepsy. Epileptogenesis in these disorders is not well understood and may depend on the type of MCD. The cellular mechanisms involved in interictal and ictal events are notably different, and could be influenced independently by the type of pathology. We evaluated the relationship between interictal and ictal zones in eight patients with different types of MCD in order to better understand the generation of these activities: four had nodular heterotopia, two focal cortical dysplasia and two subcortical band heterotopia (double-cortex). We used the non-invasive EEG-fMRI technique to record simultaneously all cerebral structures with a high spatio-temporal resolution. We recorded interictal and ictal events during the same session. Ictal events were either electrical only or clinical with minimal motion. BOLD changes were found in the focal cortical dysplasia during interictal and ictal epileptiform events in the two patients with this disorder. Heterotopic and normal cortices were involved in BOLD changes during interictal and ictal events in the two patients with double cortex, but the maximum BOLD response was in the heterotopic band in both patients. Only two of the four patients with nodular heterotopia showed involvement of a nodule during interictal activity. During seizures, although BOLD changes affected the lesion in two patients, the maximum was always in the overlying cortex and never in the heterotopia. For two patients intracranial recordings were available and confirm our findings. The dysplastic cortex and the heterotopic cortex of band heterotopia were involved in interictal and seizure processes. Even if the nodular gray matter heterotopia may have the cellular substrate to produce interictal events, the often abnormal overlying cortex is more likely to be involved during the seizures. The non-invasive BOLD study of interictal and ictal events in MCD patients may help to understand the role of the lesion in epileptogenesis and also determine the potential surgical target.

Hemodynamic and metabolic responses to activation, deactivation and epileptic discharges.

To investigate the coupling between the hemodynamic and metabolic changes following functional brain activation as well as interictal epileptiform discharges (IEDs), blood oxygenation level dependent (BOLD), perfusion and oxygen consumption responses to a unilateral distal motor task and interictal epileptiform discharges (IEDs) were examined via continuous EEG-fMRI. Seven epilepsy patients performed a periodic (1 Hz) right-hand pinch grip using approximately 8% of their maximum voluntary contraction, a paradigm previously shown to produce contralateral MI neuronal excitation and ipsilateral MI neuronal inhibition. A multi-slice interleaved pulsed arterial spin labeling and T(2)*-weighted gradient echo sequence was employed to quantify cerebral blood flow (CBF) and BOLD changes. EEG was recorded throughout the imaging session and reviewed to identify the IEDs. During the motor task, BOLD, CBF and cerebral metabolic rate of oxygen consumption (CMR(O(2))) signals increased in the contra- and decreased in the ipsilateral primary motor cortex. The relative changes in CMR(O(2)) and CBF were linearly related, with a slope of 0.46 +/- 0.05. The ratio of contra- to ipsilateral CBF changes was smaller in the present group of epilepsy patients than in the healthy subjects examined previously. IEDs produced both increases and decreases in BOLD and CBF signals. In the two case studies for which the estimation criteria were met, the coupling ratio between IED-induced CMR(O(2)) and CBF changes was estimated at 0.48 +/- 0.17. These findings provide evidence for a preserved coupling between hemodynamic and metabolic changes in response to both functional activation and, for the two case studies available, in response to interictal epileptiform activity.

Hippocampal atrophy and T2-weighted signal changes in familial mesial temporal lobe epilepsy

Objective: To correlate the clinical phenotype with hippocampal volumes (HcVs) and signal changes in patients with familial mesial temporal lobe epilepsy (FMTLE). Methods: FMTLE was defined when at least two first-degree relatives in a family had a clinical-EEG diagnosis of MTLE. Hippocampal formation measurements were performed using 1- to 3-mm coronal T1-weighted MRIs. The presence of hyperintense T2 signal was evaluated by visual analysis. For statistical analyses, analysis of variance, χ2 test, and regression analysis were used. Results: A total of 142 patients from 45 unrelated families were studied: 113 individuals with MTLE (80 with good seizure control) and 29 family members with other seizure types. There were 99 patients (69.7%) with hippocampal atrophy (HA). Sixty-seven of the 99 patients with HA also had a hyperintense T2 signal. Hyperintense T2 signal was associated with more severe HA (p = 0.04). Patients with refractory FMTLE had more frequent HA (p = 0.03) and hyperintense T2 signal (p = 0.004) and more severe atrophy (p < 0.0001). Duration of epilepsy correlated with HcV asymmetry index (r2 = 0.12, p = 0.00008) and with the more atrophic hippocampi but not with contralateral hippocampi. Conclusion: In familial mesial temporal lobe epilepsy, seizure severity is variable in affected individuals. Hippocampal atrophy was present in 70% of these patients and 69% of these had an associated hyperintense T2 signal. Although hippocampal atrophy associated with abnormal T2 signal was more frequent and more severe in patients with poor seizure control, it was also frequent in affected individuals across families. These observations suggest that one or more genes resulting in familial mesial temporal lobe epilepsy predisposes both to the clinical features of mesial temporal lobe epilepsy and to the development of hippocampal sclerosis.

Differences in memory performance and other clinical characteristics in patients with mesial temporal lobe epilepsy with and without hippocampal atrophy

Mesial temporal lobe epilepsy (MTLE) is usually accompanied by memory deficits due to damage to the hippocampal system. In most studies, however, the influence of hippocampal atrophy (HA) is confounded with other variables, such as: type of initial precipitating injury and pathological substrate, effect of lesion (HA) lateralization, history of febrile seizures, status epilepticus, age of seizure onset, duration of epilepsy, seizure frequency, and antiepileptic drugs (AEDs). To investigate the relationship between memory deficits and these variables, we studied 20 patients with MTLE and signs of HA on MRI and 15 MTLE patients with normal high-resolution MRI. The findings indicated that (1) HA, earlier onset of seizures, longer duration of epilepsy, higher seizure frequency, and AEDs (polytherapy) are associated with memory deficits; and (2) there is a close relationship between deficits of verbal memory and left HA, but not between visual memory and right HA.

Medial temporal lobe atrophy in patients with refractory temporal lobe epilepsy

Objective: The objective of this study was to assess the volumes of medial temporal lobe structures using high resolution magnetic resonance images from patients with chronic refractory medial temporal lobe epilepsy (MTLE). Methods: We studied 30 healthy subjects, and 25 patients with drug refractory MTLE and unilateral hippocampal atrophy (HA). We used T1 magnetic resonance images with 1 mm isotropic voxels, and applied a field non-homogeneity correction and a linear stereotaxic transformation into a standard space. The structures of interest are the entorhinal cortex, perirhinal cortex, parahippocampal cortex, temporopolar cortex, hippocampus, and amygdala. Structures were identified by visual examination of the coronal, sagittal, and axial planes. The threshold of statistical significance was set to p<0.05. Results: Patients with right and left MTLE showed a reduction in volume of the entorhinal (p<0.001) and perirhinal (p<0.01) cortices ipsilateral to the HA, compared with normal controls. Patients with right MTLE exhibited a significant asymmetry of all studied structures; the right hemisphere structures had smaller volume than their left side counterparts. We did not observe linear correlations between the volumes of different structures of the medial temporal lobe in patients with MTLE. Conclusion: Patients with refractory MTLE have damage in the temporal lobe that extends beyond the hippocampus, and affects the regions with close anatomical and functional connections to the hippocampus.