Colin Hawco

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.

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.

BOLD changes occur prior to epileptic spikes seen on scalp EEG

This study examined BOLD changes prior to interictal discharges in the EEG of patients with epilepsy. From a database of 143 EEG-fMRI studies, we selected the 16 data sets that showed both strong fMRI activation in the original analysis and only a single spike type in the EEG. Scans were then analyzed using seven model HRFs, peaking 3 or 1 s before the event, or 1, 3, 5, 7, or 9 s after it. An HRF was calculated using a deconvolution method for all activations seen in each analysis. The results showed that seven data sets had HRFs that peaked 1 s after the event or earlier, indicating a BOLD change starting prior to the spike seen on the scalp EEG. This is surprising since the BOLD change is expected to result from the spike. For most of the data sets with early peaking HRFs, the maximum activation in all of the statistical maps was when the model HRF peaked 1 s after the event, suggesting that the early activation was at least as important as any later activation. We suggest that this early activity is the result of neuronal changes occurring several seconds prior to a surface EEG event, but that these changes are not visible on the scalp. This is the first report of a BOLD response occurring several seconds prior to an interictal event seen on the scalp and could have important implications for our understanding of the generation of epileptic discharges.

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.

Hemodynamic Responses to Interictal Epileptiform Discharges in Children with Symptomatic Epilepsy

Purpose: Simultaneous electroencephalogram (EEG) and functional magnetic resonance imaging (fMRI) (EEG‐fMRI) recording is a noninvasive tool for investigating epileptogenic networks. Most EEG‐fMRI studies in epilepsy have been performed in adults. Childhood epilepsies, however, differ from those in adults due to interactions between epileptogenic and developmental processes. The purpose of this study was to investigate EEG‐fMRI in children with lesional epilepsies.

Widespread and intense BOLD changes during brief focal electrographic seizures

Background: Combined recording of EEG and fMRI has shown changes in blood oxygenation level dependent (BOLD) signal during focal interictal epileptic spikes. Due to difficult assessment of seizures inside the scanner little is known about BOLD changes during seizures. Objectives: To describe BOLD changes related to brief focal electrographic seizures in a patient with right temporo-parietal gray matter nodular heterotopia. Methods: The patient underwent two EEG-fMRI sessions during which several focal seizures were recorded. EEG was acquired continuously during scanning and seizure timing was used for statistical analysis. Functional maps were thresholded to disclose positive (activation) and negative (deactivation) BOLD changes. Results: Twenty-five focal electrographic seizures were analyzed, consisting of runs of polyspikes lasting 2 to 6 s in the right temporal region. Activation included a large volume, involving the heterotopia and the abnormal temporo-parietal cortex overlying the nodule, with a clear maximum over the angular gyrus. Deactivation was bilateral and maximum in the occipital regions. The hemodynamic response function showed a return to baseline of the BOLD signal 30 s after seizure end. Conclusions: The brief focal seizures resulted in high amplitude and widespread blood oxygenation level dependent (BOLD) responses taking 30 s to return to baseline. This suggests that such brief events could have important behavioral consequences despite absent overt manifestations. A clear focal BOLD peak was found at some distance from the main EEG discharge, raising the possibility that the seizure could have started in a region that did not generate a visible EEG change despite its superficial location.

Variability of the hemodynamic response as a function of age and frequency of epileptic discharge in children with epilepsy.

EEG-fMRI is a non-invasive tool to investigate epileptogenic networks in patients with epilepsy. Different patterns of BOLD responses have been observed in children as compared to adults. A high intra- and intersubject variability of the hemodynamic response function (HRF) to epileptic discharges has been observed in adults. The actual HRF to epileptic discharges in children and its dependence on age are unknown. We analyzed 64 EEG-fMRI event types in 37 children (3 months to 18 years), 92% showing a significant BOLD response. HRFs were calculated for each BOLD cluster using a Fourier basis set. After excluding HRFs with a low signal-to-noise ratio, 126 positive and 98 negative HRFs were analyzed. We evaluated age-dependent changes as well as the effect of increasing numbers of spikes. Peak time, amplitude and signal-to-noise ratio of the HRF and the t-statistic score of the cluster were used as dependent variables. We observed significantly longer peak times of the HRF in the youngest children (0 to 2 years), suggesting that the use of multiple HRFs might be important in this group. A different coupling between neuronal activity and metabolism or blood flow in young children may cause this phenomenon. Even if the t-value increased with frequent spikes, the amplitude of the HRF decreased significantly with spike frequency. This reflects a violation of the assumptions of the General Linear Model and therefore the use of alternative analysis techniques may be more appropriate with high spiking rates, a common situation in children.

Cortical and thalamic fMRI responses in partial epilepsy with focal and bilateral synchronous spikes

OBJECTIVE To determine the blood oxygen level-dependent (BOLD) responses to epileptic discharges in the thalamus and cerebral cortex in patients with partial epilepsy. METHODS Among 64 tested patients, 40 had EEG spikes during scanning and were divided in two groups: unilateral or bilateral independent spikes (29 patients) and bilaterally synchronous spikes (11 patients). Each spike topography was analyzed separately, yielding 40 studies in the first group and 17 in the second. RESULTS Forty-five percent of focal spike studies showed significant BOLD responses. Cortical activation (positive BOLD) represented the dominant response and had a better correlation with spike location than cortical deactivation (negative BOLD). In the second group, all patients had significant BOLD responses; they were more widespread compared to the first group, and deactivated areas were as important as activated regions. A thalamic response was seen in 12.5% of studies in the first group and 55% in the second. CONCLUSIONS The thalamus is involved in partial epilepsy during interictal discharges. This involvement and also cortical deactivation are more commonly seen with bilateral spikes than focal discharges. SIGNIFICANCE These findings show evidence for a role for the thalamus and a more important role for inhibition in secondary bilateral synchrony.

Analysis of the EEG–fMRI response to prolonged bursts of interictal epileptiform activity

The use of combined EEG-fMRI to study interictal epileptiform activity is increasing and has great potential as a clinical tool, but the haemodynamic response to epileptiform activity remains incompletely characterised. To this end, 19 data sets from 14 patients with prolonged bursts of focal or generalised interictal epileptiform activity lasting up to 15 s were analysed. To determine whether the inclusion of the durations of the epileptic events in the general linear model resulted in increased statistical significance of activated regions, statistical maps were generated with and without the event durations. The mean differences when including the durations were a 14.5% increase in peak t value and a 29.5% increase in volume of activation. This suggests that when analysing EEG-fMRI data from patients with prolonged bursts of interictal epileptiform activity, it is better to include the event durations. To determine whether the amplitudes and latencies of the measured responses were consistent with the general linear model, the haemodynamic response functions for bursts of different durations were calculated and compared with the model predictions. The measured amplitude of the response to the shortest duration events was consistently larger than predicted, which is consistent with studies in normal subjects. For the two data sets with the widest range of event durations, the measured amplitudes increased with the durations of the events without evidence of the plateau that was expected from the general linear model. There were no consistent differences between the measured and modelled latencies.

Separating Phonological and semantic processing in auditory sentence processing: A high-resolution event-related brain potential study

Phonological and semantic processing was studied using high‐resolution event‐related brain potentials (ERPs) during a sentence‐matching task to investigate the spatial distribution of the phonological mismatch negativity (PMN) and the N400 response. It was hypothesized that the two components were spatially separable and that the activity matched prior localization knowledge. Participants examined visual–auditory sentence pairs that related within a semantic hierarchy (e.g., visual: “The man is teaching in the classroom”; Auditory: “The man is in the…school/barn”). Semantic congruency was varied for the final words of the spoken sentences. Incongruent words mismatched expectation in terms of both the initial phonological features (unexpected sound) and semantic features (unexpected meaning). In addition, the category–exemplar probability of the final words was either high or low, with low probability words being more difficult to anticipate. Low probability words were predicted to selectively affect PMN activity. We found that incongruent words elicited a PMN (287 msec) and a N400 (424 msec), for both the high and low probability words. As expected, low probability congruent words elicited a small PMN but no N400. In contrast, high probability congruent words elicited neither a detectible PMN nor a N400. The primary PMN sources were in left inferior frontal and inferior parietal lobes. The primary N400 source activation occurred along the left perisylvian cortex, consistent with prior N400 source localization work. From these results, it was concluded that the PMN and N400 were localized to separate cortical language (and memory) regions and had different source activation patterns. Hum. Brain Mapping 22:42–53, 2004.