P.C. van Rijen

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.

The IL-1β system in epilepsy-associated malformations of cortical development

Focal cortical dysplasia (FCD) and glioneuronal tumors (GNT) are recognized causes of chronic intractable epilepsy. The cellular mechanism(s) underlying their epileptogenicity remain largely unknown. Compelling evidence in experimental models of seizures indicates an important role of interleukin (IL)-1beta in the mechanisms of hyperexcitability leading to the occurrence of seizures. We immunocytochemically investigated the brain expression and cellular distribution pattern of IL-1beta, IL-1 receptor (IL-1R) types I and II and IL-1R antagonist (IL-1Ra) in FCD and GNT specimens, and we correlate these parameters with the clinical history of epilepsy in patients with medically intractable seizures. In normal control cortex, and in perilesional regions with histologically normal cortex, IL-1beta, IL-1Rs and IL-1Ra expression was undetectable. In all FCD and GNT specimens, IL-1beta and its signalling receptor IL-1RI were highly expressed by more than 30% of neurons and glia whereas the decoy receptor IL-RII and IL-Ra were expressed to a lesser extent by approximately 10% and 20% of cells, respectively. These findings show a high expression of IL-1beta and its functional receptor (IL-1RI) in FCD and GNT specimens together with a relative paucity of mechanisms (IL-1RII and IL-1Ra) apt to inactivate IL-1beta actions. Moreover, the number of IL-1beta- and IL-1RI-positive neurons was positively correlated with the frequency of seizures, whereas the number of IL-1Ra-positive neurons and astroglial cells was negatively correlated with the duration of epilepsy prior to surgery. The expression of IL-1beta family members in these developmental lesions may contribute to their intrinsic and high epileptogenicity, thus possibly representing a novel target for antiepileptic strategies.

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.

Cerebral lactate detected by regional proton magnetic resonance spectroscopy in a patient with cerebral infarction.

Water-suppressed image-guided localized proton magnetic resonance spectroscopy was performed in a 59-year-old woman with two major brain infarcts. Spectra were measured in the infarcts, in an area between the infarcts, and in the healthy hemisphere. The volumes of interest were selected on the basis of a fast T2-weighted image. A 1331-2662 Hahn spin-echo sequence was used to suppress the water in the 8-cm3 volume that was selected by means of spatially resolved spectroscopy or stimulated echoes. The spectra were obtained in 5 minutes accumulation time. Spectral editing was applied to separate the resonance of lactate from that of other substances. Our results show no increase of lactate concentration within the infarcts after 6 months; however, a resonance was observed at 1.6 ppm, which is assigned to fatty acids. Peak intensities of brain-specific compounds were decreased. Six months after the onset of clinical symptoms (at the time of bypass surgery), a fivefold increase in lactate concentration compared with normal values was observed in the area between the two infarcts. Four months after bypass surgery, the lactate concentration in this area had decreased to only twice normal. We speculate that lactate is a marker of reversible or impending brain damage.

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.

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.

Differential expression patterns of chloride transporters, Na+-K+-2Cl−-cotransporter and K+-Cl−-cotransporter, in epilepsy-associated malformations of cortical development

Malformations of cortical development are recognized causes of chronic medically intractable epilepsy. An increasing number of observations suggests an important role for cation-chloride co-transporters (CCTs) in controlling neuronal function. Deregulation of their expression may contribute to the mechanisms of hyperexcitability that lead to seizures. In the present study the expression and cell-specific distribution of Na+-K+-2Cl--cotransporter (NKCC1) and K+-Cl--cotransporter (KCC2) were studied immunocytochemically in different developmental lesions, including focal cortical dysplasia (FCD) type IIB (n=9), hemimegalencephaly (HMEG, n=6) and ganglioglioma (GG, n=9) from patients with medically intractable epilepsy and in age-matched controls. In normal control adult cortex, NKCC1 displayed low neuronal and glial expression levels. In contrast KCC2 showed strong and diffuse neuropil staining. Notable glial immunoreactivity (IR) was not found for KCC2. NKCC1 was highly expressed in the majority of FCD, HMEG and GG specimens. NKCC1 IR was observed in neurons of different size, including large dysplastic neurons, in balloon cells (in FCD and HMEG cases) and in glial cells with astrocytic morphology. The immunoreactivity pattern of KCC2 in FCD, HMEG and GG specimens was characterized by less neuropil staining and more intrasomatic IR compared with control. KCC2 IR was observed in neurons of different size, including large dysplastic neurons, but not in balloon cells or in glial cells with astrocytic morphology. Double-labeling experiments confirmed the differential cellular distribution of the two CCTs and their expression in GABA(A) receptor (alpha1 subunit)-positive dysplastic neurons. The cellular distribution of CCTs, with high expression of NKCC1 in dysplastic neurons and altered subcellular distribution of KCC2 resembles that of immature cortex and suggests a possible contribution of CCTs to the high epileptogenicity of malformations of cortical development.