Unimpaired sentence comprehension after anterior temporal cortex resection.

UNLABELLED: Functional imaging studies have demonstrated involvement of the anterior temporal cortex in sentence comprehension. It is unclear, however, whether the anterior temporal cortex is essential for this function. We studied two aspects of sentence comprehension, namely syntactic and prosodic comprehension in temporal lobe epilepsy patients who were candidates for resection of the anterior temporal lobe. METHODS: Temporal lobe epilepsy patients (n=32) with normal (left) language dominance were tested on syntactic and prosodic comprehension before and after removal of the anterior temporal cortex. The prosodic comprehension test was also compared with performance of healthy control subjects (n=47) before surgery. RESULTS: Overall, temporal lobe epilepsy patients did not differ from healthy controls in syntactic and prosodic comprehension before surgery. They did perform less well on an affective prosody task. Post-operative testing revealed that syntactic and prosodic comprehension did not change after removal of the anterior temporal cortex. DISCUSSION: The unchanged performance on syntactic and prosodic comprehension after removal of the anterior temporal cortex suggests that this area is not indispensable for sentence comprehension functions in temporal epilepsy patients. Potential implications for the postulated role of the anterior temporal lobe in the healthy brain are discussed.

Standard versus tailored left temporal lobe resections: differences in cognitive outcome?

UNLABELLED: This study explores differences in cognitive outcome after a standard resection (SR) or tailored (TR) in 100 patients with left temporal lobe epilepsy, controlling for extent in the three lateral gyri. Comparing preoperative to 6-month postoperative performance on a battery of intelligence, language and verbal memory tests revealed the following: a differential effect of the procedure was found for digit span, a short-term memory and attention task, the SR group showing a gain and the TR group a loss postoperatively. This could be explained by a rather large improvement of the SR group with below average resection sizes in the superior temporal gyrus (STG) (<2.8 cm), which small resections are nearly absent in TR resections. Effect of larger extent on the STG in the SR group was related to a decrease in verbal intelligence and a tendency in auditory comprehension which poses a risk in 'large' standard resections. Differences in extent of resection on the other gyri did not cause differences in effects on language functioning or verbal memory. CONCLUSIONS: In standard anterior temporal lobe resections only (without intraoperative language mapping) up to a limit of 4.5 cm, large resections on the STG pose a risk for declining on verbal IQ and auditory comprehension. In general, tailored resections (with language mapping) result in decline on a task measuring short-term memory and attention.

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.

Alternative splicing of glutamate transporter EAAT2 RNA in neocortex and hippocampus of temporal lobe epilepsy patients.

RATIONALE: Altered expression of glutamate transporter EAAT2 protein has been reported in the hippocampus of patients with temporal lobe epilepsy (TLE). Two alternative EAAT2 mRNA splice forms, one resulting from a partial retention of intron 7 (I7R), the other from a deletion of exon 9 (E9S), were previously implicated in the loss of EAAT2 protein in patients with amyotrophic lateral sclerosis. METHODS: By RT-PCR we studied the occurrence of I7R and E9S in neocortical and hippocampal specimens from TLE patients and non-neurological controls. RESULTS: Both splice forms were found in all neocortical specimens from TLE patients (100% I7R, 100% E9S). This was significantly more than in controls (67% I7R, 60% E9S; P < 0.05). We also detected I7R and E9S in all seven motor cortex post-mortem samples from patients with amyotrophic lateral sclerosis. Within the TLE patient group, both splice variants appeared significantly more in non-sclerotic (100%), than in sclerotic hippocampi (69%, P < 0.05). CONCLUSION: These data indicate that the epileptic brain, especially that of TLE patients without hippocampal sclerosis, is highly prone to alternative EAAT2 mRNA splicing. Our data confirm that the presence of alternative EAAT2 splice forms is not disease specific.

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.

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 Rey's 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.

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.

Lateralization of auditory rhythm length in temporal lobe lesions.

In the visual modality, short rhythmic stimuli have been proven to be better processed (sequentially) by the left hemisphere, while longer rhythms appear to be better (holistically) processed by the right hemisphere. This study was set up to see if the same holds in the auditory modality. The rhythm task as originally designed by Seashore was computerized and is part of the Fepsy Neuropsychological battery. This task was performed by 85 patients with intractable temporal lobe epilepsy (left TLE = 32; right TLE = 53) enrolled in the Dutch Collaborative Epilepsy Surgery Program. They performed the task before and 6 months after surgery. The task consists of 30 pairs of rhythmic patterns in 3 series of 10 items. The series contains patterns of 5, 6, or 7 notes. The purpose is to indicate whether the two patterns are the same or different. Reaction times are also measured. If the hypothesis is true, the short-item sequence will be better processed by patients with right temporal lobe epilepsy (nonimpaired left temporal lobe), the longer sequence will be better processed by the left temporal epilepsy group (nonimpaired right temporal lobe). No overall laterality effect on rhythm perception could be found and no difference was found between both test moments. IQ did not correlate with rhythm performance. However, there was an interaction effect of laterality and rhythm length on performance and reaction time. This effect can be explained by the increase after the operation of the score of the left focus group and a decrease in the right focus group on the longer rhythms. This effect was somewhat less strong in the reaction times: a clear tendency for faster reaction times after surgery in the left and longer reaction times in the right focus group. The effect could not be explained for by the difference in extent of resection in either temporal lobe. This study showed that memory for and discrimination of auditory rhythm is dependent on which hemisphere is used in processing. The effect could be demonstrated for the right hemisphere, which uses a holistic processing of stimuli, which outperforms the left in rhythms consisting of a long sequence. In left temporal resections an improvement occurs on the longer rhythms and in right temporal resections the performance on the longest rhythms decreases.

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.

Synaptosomal glutamate and GABA transport in patients with temporal lobe epilepsy.

High-affinity glutamate and GABA transporters found in the plasma membrane of neurons and glial cells terminate neurotransmission by rapidly removing extracellular transmitter. Impairment of transporter function has been implicated in the pathophysiologic mechanisms underlying epileptogenesis. We characterized glutamate and gamma-aminobutyric acid (GABA) transport in synaptosomes, isolated from neocortical and hippocampal biopsies of patients with temporal lobe epilepsy (TLE). We analyzed K(+)-evoked release in the presence and absence of Ca(2+) to determine vesicular and transporter-mediated release, respectively. We also analyzed (3)H-glutamate and (3)H-GABA uptake, the effect of glutamate uptake inhibitors L-trans-pyrrolidine-2,4-dicarboxylic acid (tPDC) and DL-threo-beta-benzyloxyaspartate (TBOA), and GABA uptake inhibitor N-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid (SK&F 89976-A). Neocortical synaptosomes from TLE patients did not show vesicular glutamate release, strongly reduced transporter-mediated release, and an increased basal release compared to that in rat synaptosomes. Furthermore, basal release was less sensitive to tPDC, and (3)H-glutamate uptake was reduced compared to that in rat synaptosomes. Vesicular GABA release from neocortical synaptosomes of TLE patients was reduced compared to that in rat synaptosomes, whereas transporter-mediated release was hardly affected. Furthermore, basal GABA release was more than doubled, but neither basal nor stimulated release were increased by SK&F 89976-A, which did significantly increase both types of GABA release in rat synaptosomes. Finally, (3)H-GABA uptake by synaptosomes from TLE patients was reduced significantly in hippocampus (0.19 +/- 0.04%), compared to that in neocortex (0.32 +/- 0.04%). Control experiments with human peritumoral cortical tissue suggest that impaired uptake of glutamate, but not of GABA, was caused in part by the hypoxic state of the biopsy. Our findings provide evidence for impaired function of glutamate and GABA transporters in human TLE.

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.

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.

Long-term effects of temporal lobectomy on intelligence.

OBJECTIVE: To characterize the long-term effects of anterior temporal resection on intelligence. METHODS: Twenty-eight left temporal lobectomy (LTL) and 43 right temporal lobectomy (RTL) patients were followed at standard time points for at least 6 years after surgery. RESULTS: The average gain 6 years after operation was 3.6 Verbal IQ (VIQ) points and 10.3 Performance IQ (PIQ) points in LTL patients and 2.9 VIQ points and 7.7 PIQ points in RTL patients. A seizure-free outcome did not influence the increase in IQ, nor was the extent of resection related to IQ scores at the 6-year follow-up. Patients with exclusively mesial temporal sclerosis did not perform as well as patients with other pathologies, both before and after surgery. Major predictors of improved performance at 6 years were initial higher level of performance and lower age at surgery. Much of the observed improvement may be related to retest effects. CONCLUSIONS: The effects of epilepsy surgery on intelligence in the long term are limited. The largest gain in VIQ is seen from 2 to 6 years after surgery.

A novel germline mutation of PTEN associated with brain tumours of multiple lineages.

We have identified a novel germline mutation in the PTEN tumour suppressor gene. The mutation was identified in a patient with a glioma, and turned out to be a heterozygous germline mutation of PTEN (Arg234Gln), without loss of heterozygosity in tumour DNA. The biological consequences of this germline mutation were investigated by means of transfection studies of the mutant PTEN molecule compared to wild-type PTEN. In contrast to the wild-type molecule, the mutant PTEN protein is not capable of inducing apoptosis, induces increased cell proliferation and leads to high constitutive PKB/Akt activation, which cannot be increased anymore by stimulation with insulin. The reported patient, in addition to glioma, had suffered from benign meningioma in the past but did not show any clinical signs of Cowden disease or other hereditary diseases typically associated with PTEN germline mutations. The functional consequences of the mutation in transfection studies are consistent with high proliferative activity. Together, these findings suggest that the Arg234Gln missense mutation in PTEN has oncogenic properties and predisposes to brain tumours of multiple lineages.

Distribution of glutamate transporters in the hippocampus of patients with pharmaco-resistant temporal lobe epilepsy.

In patients suffering from temporal lobe epilepsy (TLE), increased extracellular glutamate levels in the epileptogenic hippocampus both during and after clinical seizures have been reported. These increased glutamate levels could be the result of malfunctioning and/or downregulation of glutamate transporters (also known as EAATs; excitatory amino acid transporters). In this study, the distribution of protein and mRNA of EAAT subtypes was examined in the hippocampus of TLE patients with hippocampal sclerosis (HS group) and without hippocampal sclerosis (non-HS group), and in autopsy controls without neurological disorders. EAAT protein localization was studied by immunohistochemistry on paraffin sections using specific poly- and monoclonal antibodies against the glial glutamate transporters EAAT1 and EAAT2 and the neuronal glutamate transporter EAAT3. Antibody specificity was shown by immunoblotting. In the HS group, a small decrease in EAAT1-immunoreactivity (IR) was observed in CA4 and in the polymorphic and supragranular layer of the dentate gyrus, compared with the control group. The strongest changes were found for EAAT2 levels. In the non-HS group, increased EAAT2-IR was detected in the CA1 and CA2 field, compared with non-epileptic controls. EAAT2-IR was decreased in the HS compared with the non-HS group. Fewer EAAT3-positive cells were found in the HS group than in the non-HS and control group. In both TLE groups, increased EAAT3 levels were observed in individual neurones. In the HS group, the percentage of EAAT3-IR neurones was increased in CA2 and in the granule cell layer of the dentate gyrus. Radioactive in situ hybridization for EAAT1-3 confirmed our immunohistochemical results. Non-radioactive in situ hybridization showed that not only astrocytes, but also neurones express EAAT2 mRNA. Taken together, differences in both mRNA and protein levels of glutamate transporter subtypes were found in specific regions in the TLE hippocampus, with most severe changes found for EAAT2 and EAAT3 levels. The results indicate an upregulation of EAAT2 protein expression in CA1 and CA2 in neurones in the non-HS group. This is in line with decreased EAAT2 protein levels in the HS group, since these hippocampi are characterized by severe neuronal cell loss. The functional consequences (glutamate transport capacity) of the reported changes in EAAT2 and EAAT3 remain to be determined.