Heinz Gregor Wieser

Human hippocampus establishes associations in memory

Studies of amnesia have demonstrated that the hippocampus is necessary for long‐term memory, but its precise role in memory is unknown. We designed a positron emission tomography experiment with tailored encoding and retrieval tasks that permitted the isolation of different mnemonic functions theorized to be mediated by the hippocampus. These functions included encoding single items, establishing interitem associations, novelty detection, and retrieving recently formed associations. Of these, we found hippocampal and parahippocampal activation only during associative learning. Our results indicate that the hippocampal formation may be particularly involved in the establishment of associations among components of an episode in memory. Hippocampus 7:249–256, 1997. © 1997 Wiley‐Liss, Inc.

Learning and retention of words and designs following excision from medial or lateral temporal-lobe structures

We sought to elucidate the contributions of the amygdala, hippocampus and temporal neocortex to learning and memory for verbal and visuospatial material. Two matched learning tasks, using abstract words versus abstract designs, were administered to patients with unilateral neocorticectomy (NCE; Dublin), selective amygdalohippocampectomy (AHE; Zurich) or anterior temporal-lobe resection invading the amygdala and hippocampus (ATL; Montreal). Data were analysed according to side and type of resection. Learning and recall for words was impaired in groups with resection from the left temporal lobe, irrespective of whether mediobasal structures were spared or temporal neocortex was spared. All right-resection groups were unimpaired. Learning for abstract designs was impaired across all trials in the right AHE and NCE groups, and on the last two trials in the right ATL group. Restricted deficits of lower magnitude were observed on some trials in left-resection groups. These results show a partial dissociation between side of excision and type of material, but the finding of similar deficits in all resection types was unexpected. We propose that excision from either the hippocampal region or temporal neocortex may result in a disconnection, giving a similar functional outcome, as both types of resection interrupt a circuit likely to be essential for normal storage and retrieval of information.

Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes.

Deletions at 16p13.11 are associated with schizophrenia, mental retardation, and most recently idiopathic generalized epilepsy. To evaluate the role of 16p13.11 deletions, as well as other structural variation, in epilepsy disorders, we used genome-wide screens to identify copy number variation in 3812 patients with a diverse spectrum of epilepsy syndromes and in 1299 neurologically-normal controls. Large deletions (> 100 kb) at 16p13.11 were observed in 23 patients, whereas no control had a deletion greater than 16 kb. Patients, even those with identically sized 16p13.11 deletions, presented with highly variable epilepsy phenotypes. For a subset of patients with a 16p13.11 deletion, we show a consistent reduction of expression for included genes, suggesting that haploinsufficiency might contribute to pathogenicity. We also investigated another possible mechanism of pathogenicity by using hybridization-based capture and next-generation sequencing of the homologous chromosome for ten 16p13.11-deletion patients to look for unmasked recessive mutations. Follow-up genotyping of suggestive polymorphisms failed to identify any convincing recessive-acting mutations in the homologous interval corresponding to the deletion. The observation that two of the 16p13.11 deletions were larger than 2 Mb in size led us to screen for other large deletions. We found 12 additional genomic regions harboring deletions > 2 Mb in epilepsy patients, and none in controls. Additional evaluation is needed to characterize the role of these exceedingly large, non-locus-specific deletions in epilepsy. Collectively, these data implicate 16p13.11 and possibly other large deletions as risk factors for a wide range of epilepsy disorders, and they appear to point toward haploinsufficiency as a contributor to the pathogenicity of deletions.

Mesiobasal versus lateral temporal lobe epilepsy Metabolic differences in the temporal lobe shown by interictal 18F‐FDG positron emission tomography

Metabolic abnormalities in the temporal lobe (TL) of 25 patients suffering from temporal lobe epilepsy of mesiobasal or lateral TL origin have been investigated using interictal [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET). The epileptogenic area was determined by ictal EEG recordings using foramen ovale and scalp electrodes in 20 patients, and by the use of stereo-electroencephalography in one patient. Four patients with structural lesions on their MRIs had noninvasive ictal surface EEG recordings. Sixteen patients had a clear-cut mesiobasal seizure onset, and in five patients the seizures originated from the lateral temporal neocortex. Twenty-four patients underwent selective surgery. Patients with temporal limbic seizures associated with mesial gliosis (n = 15) had the lowest FDG uptake in the entire TL, followed by patients with lateral temporal seizure origin (n = 5). Patients with tumors located in the mesiobasal TL (n = 5) showed, in general, only a slight decrease of glucose metabolism in all TL structures. There was no clear-cut correlation between the degree of hypometabolism and the location of EEG-defined epileptogenic focus. The metabolic pattern, however, differed between the patient groups and allowed a discrimination between patients of mesial temporal and lateral temporal seizure onset.

Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study

Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio <1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studies.

Distribution and functional activity of P-glycoprotein and multidrug resistance-associated proteins in human brain microvascular endothelial cells in hippocampal sclerosis.

Multidrug resistance protein, also referred as P-glycoprotein (P-gp, MDR1; ABCB1) and multidrug resistance-associated protein (MRP) 1 (ABCC1) and 2 (ABCC2) are, thus far, candidates to cause antiepileptic drug (AED) resistance epilepsy. In this study, we investigated P-gp, MRP1 and MRP2 expression, localization and functional activity on cryosections and isolated human brain-derived microvascular endothelial cells (HBMEC) from epileptic patients (HBMEC-EPI) with hippocampal sclerosis (HS), as compared with HBMEC isolated from normal brain cortex (HBMEC-CTR). We examined the expression and distribution of three transporters, P-gp, MRP1 and MRP2 on two major parts of the resected tissue, the hippocampus and the parahippocampal gyrus (Gph). P-gp showed diffuse expression not only in endothelium but also by parenchymal cells in both the hippocampus and the Gph. MRP1 labeling was observed in parenchymal cells in the Gph. By contrast, MRP2 was mainly found in endothelium of the hippocampus. P-gp and MRP1 expression in the Gph was relatively high in the patient with long-term seizure history. Quantitative RT-PCR analysis of HBMEC revealed that MDR1, MRP1 as well as MRP5 (ABCC5) and MRP6 (ABCC6) were overexpressed in HBMEC-EPI at the mRNA level. HBMEC from both normal and epilepsy groups displayed protein expression of P-gp, whereas MRP1 and MRP2 were seen only in HBMEC-EPI. Accordingly, it is of particular interest that MRP functional activities were observed in HBMEC-EPI, but not in HBMEC-CTR. Our results suggest that complex MDR expression changes not only in the hippocampus but in the Gph may play a role in AED pharmacoresistance in intractable epilepsy patients with mesial temporal lobe epilepsy (MTLE) by altering the permeability of AEDs across the blood-brain barrier (BBB).

Presurgical evaluation: current role of invasive EEG.

Summary: Our purpose was to review the current role of invasive and semi‐invasive EEG in the presurgical evaluation of candidates for epilepsy surgery. The use of stereotactically implanted intracranial depth (stereo‐EEG), subdural strip and grid, and foramen ovale electrodes, as well as intraoperative electrocorticography and electrical brain stimulation (“functional mapping”) at the Epilepsy Center University Hospital Zurich, from 1984 to 1998, is analyzed. Advantages and disadvantages of the various intracranial EEG techniques are critically discussed. Out of 422 selective amygdalohippocampectomies performed in Zurich, 54% had non‐invasive, 32% had semi‐invasive, and 14% had invasive presurgical EEG evaluation. Because patients currently referred to our center increasingly present with a complex history of disease, i.e., constitute so‐called “difficult cases”, there is trend to combine several invasive and semi‐invasive, pre‐ and intraoperative neurophysiological techniques.

H215O or 13NH3 PET and electromagnetic tomography (LORETA) during partial status epilepticus

The authors evaluated the feasibility and source localization utility of H215O or 13NH3 PET and low-resolution electromagnetic tomography (LORETA) in three patients with partial status epilepticus (SE). Results were correlated with findings from intraoperative electrocorticographic recordings and surgical outcomes. PET studies of cerebral blood flow and noninvasive source modeling with LORETA using statistical nonparametric mapping provided useful information for localizing the ictal activity in patients with partial SE.

Source localization of mesial temporal interictal epileptiform discharges : Correlation with intracranial foramen ovale electrode recordings

OBJECTIVE We have investigated the localization accuracy of low-resolution electromagnetic tomography (LORETA) for mesial temporal interictal epileptiform discharges (IED) on a statistical basis by using clinical electroencephalographic (EEG) data of simultaneous scalp and intracranial foramen ovale (FO) electrode recordings. METHODS We retrospectively analyzed the IED of 15 patients who underwent presurgical assessment for intractable temporal lobe epilepsy. All patients have subsequently undergone amygdalohippocampectomy. The scalp signals were averaged time-locked to the peak activity in bilateral 10-contact FO electrode recordings. Source modeling was carried out by using statistical non-parametric mapping (SNPM) of LORETA values and by calculating raw LORETA values of averaged IED. The results were compared to intracranial data obtained from FO electrode recordings. RESULTS Two thousand six hundred and fifteen discharges could be attributed to 19 different patterns of intracranial mesial temporal IED. SNPM of LORETA revealed confined ipsilateral mesial temporal solutions for 14 (73.7%) and no significant solutions for five (26.3%) of these patterns. Raw LORETA current density distributions of the 19 averaged IED patterns revealed ipsilateral basal to lateral temporal solutions for the 14 IED patterns with a sufficient signal to noise ratio (SNR), but spurious results for those five IED with a low SNR. CONCLUSIONS SNPM of LORETA but not LORETA analysis of averaged IED patterns accurately localizes the source generators of mesial temporal IEDs. SIGNIFICANCE SNPM of raw LORETA values might be appropriate for localizing restricted mesial temporal lobe sources.

Cortical activation with deep brain stimulation of the anterior thalamus for epilepsy

OBJECTIVE We studied the relation between thalamic stimulation parameters and the morphology, topographic distribution and cortical sources of the cerebral responses in patients with intractable epilepsy undergoing deep brain stimulation (DBS) of the thalamus. METHODS Bipolar and monopolar stimuli were delivered at a rate of 2 Hz to the anterior (AN, four patients), the dorsomedian (DM, four patients), and the centromedian nucleus (CM, one patient) using the programmable stimulation device (Medtronic ITREL II). Source modeling was carried out by using statistical non-parametric mapping of low-resolution electromagnetic tomography (LORETA) values. RESULTS All patients demonstrated reproducible time-locked cortical responses (CRs) consisting of a sequence of components with latencies between 20 and 320 ms. The morphology of these CRs, however, was very heterogeneous, depending primarily on the site of stimulation. Following AN stimulation, cortical activation was most prominent in ipsilateral cingulate gyrus, insular cortex and lateral neocortical temporal structures. Stimulation of the DM mainly showed activation of the ipsilateral orbitofrontal and mesial and lateral frontal areas, but also involvement of mesial temporal structures. Stimulation of the CM showed a rather diffuse (though still mainly ipsilateral) increase of cortical activity. The magnitude of cortical activation was positively related to the strength of the stimulus and inversely related to the impedance of the electrode. CONCLUSIONS The pattern of cortical activation corresponded with the hodology of the involved structures and may underscore the importance of optimal localization of DBS electrodes in patients with epilepsy. SIGNIFICANCE The method of analyzing sources of CRs could potentially be a useful tool for titration of DBS parameters in patients with electrode contacts in clinically silent areas. Furthermore, the inverse relation of the cortical activation and the impedance of the electrode contacts might suggest that these impedance measurements should be taken into consideration when adjusting DBS parameters in patients with epilepsy.