Converging PET and fMRI evidence for a common area involved in human focal epilepsies.

OBJECTIVES: Experiments in animal models have identified specific subcortical anatomic circuits, which are critically involved in the pathogenesis and control of seizure activity. However, whether such anatomic substrates also exist in human epilepsy is not known. METHODS: We studied 2 separate groups of patients with focal epilepsies arising from any cortical location using either simultaneous EEG-fMRI (n = 19 patients) or [¹¹C]flumazenil PET (n = 18). RESULTS: Time-locked with the interictal epileptiform discharges, we found significant hemodynamic increases common to all patients near the frontal piriform cortex ipsilateral to the presumed cortical focus. GABA(A) receptor binding in the same area was reduced in patients with more frequent seizures. CONCLUSIONS: Our findings of cerebral blood flow and GABAergic changes, irrespective of where interictal or ictal activity occurs in the cortex, suggest that this area of the human primary olfactory cortex may be an attractive new target for epilepsy therapy, including neurosurgery, electrical stimulation, and focal drug delivery.

Modelling cardiac signal as a confound in EEG-fMRI and its application in focal epilepsy studies.

Cardiac noise has been shown to reduce the sensitivity of functional Magnetic Resonance Imaging (fMRI) to an experimental effect due to its confounding presence in the blood oxygenation level-dependent (BOLD) signal. Its effect is most severe in particular regions of the brain and a method is yet to take it into account in routine fMRI analysis. This paper reports the development of a general and robust technique to improve the reliability of EEG-fMRI studies to BOLD signal correlated with interictal epileptiform discharges (IEDs). In these studies, ECG is routinely recorded, enabling cardiac effects to be modelled, as effects of no interest. Our model is based on an over-complete basis set covering a linear relationship between cardiac-related MR signal and the phase of the cardiac cycle or time after pulse (TAP). This method showed that, on average, 24.6 +/- 10.9% of grey matter voxels contained significant cardiac effects and 22.3 +/- 24.1% of those voxels exhibiting significantly IED-correlated BOLD signal also contained significant cardiac effects. We quantified the improvement of the TAP model over the original model, without cardiac effects, by evaluating changes in efficiency, with respect to estimating the contrast of the effects of interest. Over voxels containing significant, cardiac-related signal, efficiency was improved by 18.5 +/- 4.8%. Over the remaining voxels, no improvement was demonstrated. This suggests that, while improving sensitivity in particular regions of the brain, there is no risk that the TAP model will reduce sensitivity elsewhere.

Material-specific lateralization of memory encoding in the medial temporal lobe: blocked versus event-related design.

Lesion-deficit studies have provided evidence for a functional dissociation between the left medial temporal lobe (MTL) mediating verbal memory encoding and right MTL mediating non-verbal memory encoding. While a small number of functional MRI studies have demonstrated similar findings, none has looked specifically for material-specific lateralization using subsequent memory effects. In addition, in many fMRI studies, encoding activity has been located in posterior MTL structures, at odds with lesion-deficit and positron emission tomography (PET) evidence. In this study, we used an event-related fMRI memory encoding paradigm to demonstrate a material-specific lateralization of encoding in the medial temporal lobes of ten healthy control subjects. Activation was left-lateralized for word encoding, bilateral for picture encoding, and right-lateralized for face encoding. Secondly, we demonstrated the locations of activations revealed using an event-related analysis to be more anterior than those revealed using a blocked analysis of the same data. This suggests that anterior MTL structures underlie memory encoding as judged by subsequent memory effects, and that more posterior activity detected in other fMRI studies is related to deficiencies of blocked designs in the analysis of memory encoding.

fMRI temporal clustering analysis in patients with frequent interictal epileptiform discharges: comparison with EEG-driven analysis.

Temporal clustering analysis (TCA) is an exploratory data-driven technique that has been proposed for the analysis of resting fMRI to localise epileptiform activity without need for simultaneous EEG. Conventionally, fMRI of epileptic activity has been limited to those patients with subtle clinical events or frequent interictal epileptiform EEG discharges, requiring simultaneous EEG recording, from which a linear model is derived to make valid statistical inferences from the fMRI data. We sought to evaluate TCA by comparing the results with those of EEG correlated fMRI in eight selected cases. Cases were selected with clear epileptogenic localisation or lateralisation on the basis of concordant EEG and structural MRI findings, in addition to concordant activations seen on EEG-derived fMRI analyses. In three, areas of activation were seen with TCA but none corresponding to the electro-clinical localisation or activations obtained with EEG driven analysis. Temporal clusters were closely coincident with times of maximal head motion. We feel this is a serious confound to this approach and recommend that interpretation of TCA that does not address motion and physiological noise be treated with caution. New techniques to localise epileptogenic activity with fMRI alone require validation with an appropriate independent measure. In the investigation of interictal epileptiform activity, this is best done with simultaneous EEG recording.

Studying spontaneous EEG activity with fMRI.

The multifaceted technological challenge of acquiring simultaneous EEG-correlated fMRI data has now been met and the potential exists for mapping electrophysiological activity with unprecedented spatio-temporal resolution. Work has already begun on studying a host of spontaneous EEG phenomena ranging from alpha rhythm and sleep patterns to epileptiform discharges and seizures, with far reaching clinical implications. However, the transformation of EEG data into linear models suitable for voxel-based statistical hypothesis testing is central to the endeavour. This in turn is predicated upon a number of assumptions regarding the manner in which the generators of EEG phenomena may engender changes in the blood oxygen level dependent (BOLD) signal. Furthermore, important limitations are posed by a set of considerations quite unique to 'paradigmless fMRI'. Here, these issues are assembled and explored to provide an overview of progress made and unresolved questions, with an emphasis on applications in epilepsy.

Electroencephalographic signatures of attentional and cognitive default modes in spontaneous brain activity fluctuations at rest.

We assessed the relation between hemodynamic and electrical indices of brain function by performing simultaneous functional MRI (fMRI) and electroencephalography (EEG) in awake subjects at rest with eyes closed. Spontaneous power fluctuations of electrical rhythms were determined for multiple discrete frequency bands, and associated fMRI signal modulations were mapped on a voxel-by-voxel basis. There was little positive correlation of localized brain activity with alpha power (8-12 Hz), but strong and widespread negative correlation in lateral frontal and parietal cortices that are known to support attentional processes. Power in a 17-23 Hz range of beta activity was positively correlated with activity in retrosplenial, temporo-parietal, and dorsomedial prefrontal cortices. This set of areas has previously been characterized by high but coupled metabolism and blood flow at rest that decrease whenever subjects engage in explicit perception or action. The distributed patterns of fMRI activity that were correlated with power in different EEG bands overlapped strongly with those of functional connectivity, i.e., intrinsic covariations of regional activity at rest. This result indicates that, during resting wakefulness, and hence the absence of a task, these areas constitute separable and dynamic functional networks, and that activity in these networks is associated with distinct EEG signatures. Taken together with studies that have explicitly characterized the response properties of these distributed cortical systems, our findings may suggest that alpha oscillations signal a neural baseline with "inattention" whereas beta rhythms index spontaneous cognitive operations during conscious rest.

EEG-correlated fMRI of human alpha activity.

Electroencephalography-correlated functional magnetic resonance imaging (EEG/fMRI) can be used to identify blood oxygen level-dependent (BOLD) signal changes associated with both physiological and pathological EEG events. Here, we implemented continuous and simultaneous EEG/fMRI to identify BOLD signal changes related to spontaneous power fluctuations in the alpha rhythm (8-12 Hz), the dominant EEG pattern during relaxed wakefulness. Thirty-two channels of EEG were recorded in 10 subjects during eyes-closed rest inside a 1.5-T magnet resonance (MR) scanner using an MR-compatible EEG recording system. Functional scanning by echoplanar imaging covered almost the entire cerebrum every 4 s. Off-line MRI artifact subtraction software was applied to obtain continuous EEG data during fMRI acquisition. The average alpha power over 1-s epochs was derived at several electrode positions using a Fast Fourier Transform. The power time course was then convolved with a canonical hemodynamic response function, down-sampled, and used for statistical parametric mapping of associated signal changes in the image time series. At all electrode positions studied, a strong negative correlation of parietal and frontal cortical activity with alpha power was found. Conversely, only sparse and nonsystematic positive correlation was detected. The relevance of these findings is discussed in view of the current theories on the generation and significance of the alpha rhythm and the related functional neuroimaging findings.

Event-related fMRI with simultaneous and continuous EEG: description of the method and initial case report.

We report on the initial imaging findings with a new technique for the simultaneous and continuous acquisition of functional MRI data and EEG recording. Thirty-seven stereotyped interictal epileptiform discharges (spikes) were identified on EEG recorded continuously during the fMRI acquisition on a patient with epilepsy. Localization of the BOLD activation associated with the EEG events was consistent with previous findings and EEG source modeling. The time course of activation was comparable with the physiological hemodynamic response function (HRF). The new methodology could lead to novel and important applications in many areas of neuroscience.