C.W.M. van Veelen

Development of a functional magnetic resonance imaging protocol for intraoperative localization of critical temporoparietal language areas.

The aim of this study was to evaluate the use of functional magnetic resonance imaging as an alternative to intraoperative electrocortical stimulation mapping for the localization of critical language areas in the temporoparietal region. We investigated several requirements that functional magnetic resonance imaging must fulfill for clinical implementation: high predictive power for the presence as well as the absence of critical language function in regions of the brain, user‐independent statistical methodology, and high spatial accuracy. Thirteen patients with temporal lobe epilepsy performed four different functional magnetic resonance imaging language tasks (ie, verb generation, picture naming, verbal fluency, and sentence comprehension) before epilepsy surgery that included intraoperative electrocortical stimulation mapping. To assess the optimal statistical threshold for functional magnetic resonance imaging, images were analyzed with three different statistical thresholds. Functional magnetic resonance imaging information was read into a surgical guidance system for identification of cortical areas of interest. Intraoperative electrocortical stimulation mapping was recorded by video camera, and stimulation sites were digitized. Next, a computer algorithm indicated whether significant functional magnetic resonance imaging activation was present or absent within the immediate vicinity (<6.4mm) of intraoperative electrocortical stimulation mapping sites. In 2 patients, intraoperative electrocortical stimulation mapping failed during surgery. Intraoperative electrocortical stimulation mapping detected critical language areas in 8 of the remaining 11 patients. Correspondence between functional magnetic resonance imaging and intraoperative electrocortical stimulation mapping depended heavily on statistical threshold and varied between patients and tasks. In 7 of 8 patients, sensitivity of functional magnetic resonance imaging was 100% with a combination of 3 functional magnetic resonance imaging tasks (ie, functional magnetic resonance imaging correctly detected all critical language areas with high spatial accuracy). In 1 patient, sensitivity was 38%; in this patient, functional magnetic resonance imaging was included in a larger area found with intraoperative electrocortical stimulation mapping. Overall, specificity was 61%. Functional magnetic resonance imaging reliably predicted the absence of critical language areas within the region exposed during surgery, indicating that such areas can be safely resected without the need for intraoperative electrocortical stimulation mapping. The presence of functional magnetic resonance imaging activity at noncritical language sites limited the predictive value of functional magnetic resonance imaging for the presence of critical language areas to 51%. Although this precludes current replacement of intraoperative electrocortical stimulation mapping, functional magnetic resonance imaging can at present be used to speed up intraoperative electrocortical stimulation mapping procedures and to guide the extent of the craniotomy.

fMRI-Determined Language Lateralization in Patients with Unilateral or Mixed Language Dominance According to the Wada Test

Due to the reported variability of the language laterality index (LI) across fMRI studies, reliable distinction between patients with unilateral and mixed language dominance is currently not possible, preventing clinical implementation of fMRI as a replacement for the invasive Wada test. Variability of the LI may be related to differences in experimental and control tasks, and statistical methodology. The goal of this study was to improve detection power of fMRI for hemispheric language dominance by using a combined analysis of four different language tasks (CTA), that has previously shown more reliable and robust Lls in groups of normal volunteers than individual task analyses (see Ramsey et al). The CTA targets brain areas that are common to different language tasks, thereby focusing on areas that are critical for language processing. Further advantage of the CTA is that it is relatively independent of specific task and control conditions. 18 patients with typical (i.e., left-sided, n = 11) and atypical (i.e., right-sided or mixed, respectively, n = 3 and n = 4) language dominance according to the Wada test underwent fMRI (groups respectively denoted as WadaL, WadaR, and WadaM patients). Statistical methodology (including thresholding of activity maps) was fixed to assure a user-independent approach. CTA yielded better results than any of the individual task analyses: it was more robust (on average 2.5 times more brain activity was detected due to its higher statistical power) and more reliable (concordance for WadaL, WadaM and WadaR patients was respectively 10/11 (91%), 3/4 (75%), and 2/3 patients (67%)). Overall, a significant correlation was observed between frontal and temporoparietal LIs. Remarkably, brain activity for WadaM patients was significantly lower than for WadaL or WadaR patients, and a dissociation in lateralization was observed between frontal (right-sided) and temporoparietal (left-sided) activity in three of four patients. Of the individual task analyses, the verb generation task yielded best results for patients with unilateral language dominance (same concordance as CTA). However, in contrast to CTA results, the verb generation task was unable to identify WadaM patients (concordance in one of four patients). In conclusion, the CTA is a promising approach for clinical implementation of fMRI for the prediction of hemispheric language dominance.

Expression and cellular distribution of multidrug transporter proteins in two major causes of medically intractable epilepsy: focal cortical dysplasia and glioneuronal tumors.

The cell-specific distribution of multidrug resistance extrusion pumps was studied in developmental glioneuronal lesions, including focal cortical dysplasia (15 cases) and ganglioglioma (15 cases) from patients with medically intractable epilepsy. Lesional, perilesional, as well as normal brain regions were examined for the expression of the multidrug resistance gene 1 encoded P-glycoprotein (P-gp) and the multidrug resistance-associated protein 1 (MRP1) by immunocytochemistry. In normal brain MRP1 expression was below detection, whereas P-gp staining was present only in blood vessels. MRP1 and P-gp immunoreactivity was observed in dysplastic neurons of 11/15 cases of focal cortical dysplasia, as well as in the neuronal component of 14/15 ganglioglioma. Glial cells with astrocytic morphology within the lesion showed multidrug-resistant protein immunoreactivity (P-gp>MRP1). Moderate to strong MRP1 and P-gp immunoreactivity was observed in a population of large ballooned neuroglial cells. P-gp appeared to be most frequently expressed in glial fibrillary acidic protein-positive balloon cells (glial type), whereas MRP1 was more frequently expressed in microtubule-associated protein 2-positive balloon cells (neuronal type). In both types of lesions strong P-gp immunoreactivity was found in lesional vessels. Perilesional regions did not show increased staining in vessels or in neuronal cells compared with normal cortex. The predominant intralesional cell-specific distribution of multidrug transporter proteins supports the hypothesis of a constitutive overexpression as common mechanism underlying the intrinsic pharmaco-resistance to antiepileptic drugs of both malformative and neoplastic glioneuronal developmental lesions.

Reproducibility of fMRI-determined language lateralization in individual subjects.

This study investigated within-subject test-retest reproducibility (i.e., reliability) of language lateralization obtained with fMRI. Nine healthy subjects performed the same set of three different language tasks during two fMRI sessions on separate days (verb generation, antonym generation, and picture naming). A fourth task analysis was added in which the three tasks were analyzed conjointly (combined task analysis, CTA). The CTA targets brain areas that are commonly used in different language tasks, aiming more selectively at language-critical structures. The number of active voxels (i.e., robustness) and calculated lateralization index (LI) were compared across sessions, tasks, subjects, and two a priori defined volumes of interest (classical language regions versus whole hemisphere) for a wide range of statistical thresholds. Robustness and reliability strongly varied between task analyses. The CTA was a robust detector of language-related brain activity, in contrast to the single task approaches. The CTA and verb generation task allowed for reliable calculation of the LI. Higher thresholds yielded a clear increase in left lateralization, which was largest when calculated from active voxels in classical language regions.

Reduced glutamine synthetase in hippocampal areas with neuron loss in temporal lobe epilepsy

Background: Increased levels of glutamate have been reported in the epileptogenic hippocampus of patients with temporal lobe epilepsy (TLE). This sustained increase, which may contribute to the initiation and propagation of seizure activity, indicates impaired clearance of glutamate released by neurons. Glutamate is predominantly cleared by glial cells through the excitatory amino acid transporter 2 (EAAT2) and its subsequent conversion to glutamine by the glial enzyme glutamine synthetase (GS). Methods: The authors examined the hippocampal distribution of GS, EAAT2, and glial fibrillary acidic protein (GFAP) by immunohistochemistry in TLE patients with (HS group) and without hippocampal sclerosis (non-HS group), and in autopsy controls. In hippocampal homogenates the authors measured relative protein amounts by immunoblotting and GS enzyme activity. Results: In the autopsy control and non-HS group GS immunoreactivity (IR) was predominantly found in glia in the neuropil of the subiculum, of the pyramidal cell layer of all CA fields, and in the supragranular layer of the dentate gyrus. In the HS group, GS and EAAT2 IR were markedly reduced in subfields showing neuron loss (CA1 and CA4), whereas GFAP IR was increased. The reduction in GS IR in the HS group was confirmed by immunoblotting and paralleled by decreased GS enzyme activity. Conclusions: Glial glutamine synthetase is downregulated in the hippocampal sclerosis (HS) hippocampus of temporal lobe epilepsy (TLE) patients in areas with severe neuron loss. This downregulation appears to be pathology-related, rather than seizure-related, and may be part of the mechanism underlying impaired glutamate clearance found in the hippocampus of TLE patients with HS.

Measurement of the Conductivity of Skull, Temporarily Removed During Epilepsy Surgery

The conductivity of the human skull plays an important role in source localization of brain activity, because it is low as compared to other tissues in the head. The value usually taken for the conductivity of skull is questionable. In a carefully chosen procedure, in which sterility, a stable temperature, and relative humidity were guaranteed, we measured the (lumped, homogeneous) conductivity of the skull in five patients undergoing epilepsy surgery, using an extended four-point method. Twenty-eight current configurations were used, in each of which the potential due to an applied current was measured. A finite difference model, incorporating the geometry of the skull and the electrode locations, derived from CT data, was used to mimic the measurements. The conductivity values found were ranging from 32 mS/m to 80 mS/m, which is much higher than the values reported in other studies. Causes for these higher conductivity values are discussed.

Nonlinear dynamics of epileptic seizures on basis of intracranial EEG recordings

SummaryPurpose: An understanding of the principles governing the behavior of complex neuronal networks, in particular their capability of generating epileptic seizures implies the characterization of the conditions under which a transition from the interictal to the ictal state takes place. Signal analysis methods derived from the theory of nonlinear dynamics provide new tools to characterize the behavior of such networks, and are particularly relevant for the analysis of epileptiform activity.Methods: We calculated the correlation dimension, tested for irreversibility, and made recurrence plots of EEG signals recorded intracranially both during interictal and ictal states in temporal lobe epilepsy patients who were surgical candidates.Results: Epileptic seizure activity often, but not always, emerges as a low-dimensional oscillation. In general, the seizure behaves as a nonstationary phenomenon during which both phases of low and high complexity may occur. Nevertheless a low dimension may be found mainly in the zone of ictal onset and nearby structures. Both the zone of ictal onset and the pattern of propagation of seizure activity in the brain could be identified using this type of analysis. Furthermore, the results obtained were in close agreement with visual inspection of the EEG records.Conclusions: Application of these mathematical tools provides novel insights into the spatio-temporal dynamics of “epileptic brain states”. In this way it may be of practical use in the localization of an epileptogenic region in the brain, and thus be of assistance in the presurgical evaluation of patients with localization-related epilepsy.

Language area localization with three-dimensional functional magnetic resonance imaging matches intrasulcal electrostimulation in Broca's area

In this study, intraoperative electrocortical stimulation mapping (ioESM), the current gold standard for the localization of critical language areas, is compared with functional magnetic resonance imaging (fMRI) in a 14‐year‐old girl with medically intractable epilepsy caused by a tumor in the region of Brocas area. Prior to the operation, four different fMRI tasks that target inferior frontal language areas were applied. Prior to the resection, ioESM as well as fMRI detected no language areas at the exposed cortical area. After removal of the tumor, a unique opportunity presented itself, where ioESM could be performed in the depth of a now exposed and intact gyrus. One specific locus that was indicated to be a critical language area by multiple‐task fMRI was targeted. IoESM selectively confirmed the location of this language area to within an estimated 3 mm. We propose that the combined use of different fMRI tasks increases the sensitivity and specificity for the detection of essential language areas.

Combined use of subdural and intracerebral electrodes in preoperative evaluation of epilepsy.

For intracranial recording of partial seizures considered to originate from one of the temporal or frontal lobes, the team in the Utrecht Academic Hospital has used subdural, multicontact, flexible electrodes since 1972. These are introduced through bilateral, frontocentral trephine holes and are manipulated under fluoroscopy to cover most of the cerebral convexity. It became evident that in many patients, additional placements to record from intracerebral structures were indispensable. Therefore, using the same trephine holes, an additional 2 to 4 depth electrodes were stereotactically implanted in the mesial temporal and/or frontal structures, as appropriate. An extensive intra- and extracerebral spatial representation of the epileptogenic zone was thus obtained. We report here the methods for manufacturing and applying these electrodes and our clinical experience with 28 patients. The results obtained so far stress the value of combining subdural and depth electroencephalographic monitoring in the presurgical selection of patients suffering from medically refractory complex partial seizures. By miniaturizing the electrodes, extensive areas of the brain can be investigated without craniotomy or multiple burr holes.

Verbal memory decline after temporal epilepsy surgery?: A 6-year multiple assessments follow-up study.

Objective: To assess the long-term effects of temporal lobe epilepsy surgery on verbal memory. Methods: We assessed verbal memory performance as measured by a verbal learning test (“15 Words Test,” a Dutch adaptation of Reys Auditory Verbal Learning Test) before surgery and at three specific times after surgery: 6 months, 2 years, and 6 years in 85 patients (34 left temporal lobe [LTL] vs. 51 right temporal lobe [RTL]). An amygdalo-hippocampectomy and a neocortical temporal resection between 2.5 and 8 cm were carried out in all patients. Results: LTL patients showed an ongoing memory decline for consolidation and acquisition of verbal material (both 2/3 SDs) for up to 2 years after surgery. RTL patients at first showed a gain in both memory acquisition and consolidation, which vanished in the long term. Breaking the group up into a mesiotemporal (MTS) group and a non-MTS group showed clear differences. The group with pure MTS showed an overall lower verbal memory performance than the group without pure MTS, in the LTL group more pronounced than in the RTL group. After surgery, both pathology groups showed an ongoing decline for up to 2 years, but the degree of decline was greater for the LTL patients with MTS compared with the non-MTS group. Becoming and remaining seizure-free after surgery does not result in a better performance in the long term. Predictors of postoperative verbal memory performance at 6 years after surgery were side of surgery, preoperative memory score, and age. Conclusions: The results provide evidence for a dynamic decline of verbal memory functions up to 2 years after left temporal lobectomy, which then levels off.