Johannes C. Baayen

Expression and Cellular Distribution of Multidrug Resistance–related Proteins in the Hippocampus of Patients with Mesial Temporal Lobe Epilepsy

Summary:  Purpose: This study investigated the cellular distribution of different multidrug resistance (MDR)‐related proteins such as P‐glycoprotein (P‐gp), the multidrug resistance–associated proteins (MRP) 1 and 2, and the major vault protein (MVP) in normal and sclerotic hippocampus of patients with medically refractory mesial temporal lobe epilepsy (MTLE).

Expression pattern of miR‐146a, an inflammation‐associated microRNA, in experimental and human temporal lobe epilepsy

Increasing evidence supports the involvement of inflammatory and immune processes in temporal lobe epilepsy (TLE). MicroRNAs (miRNA) represent small regulatory RNA molecules that have been shown to act as negative regulators of gene expression controlling different biological processes, including immune‐system homeostasis and function. We investigated the expression and cellular distribution of miRNA‐146a (miR‐146a) in a rat model of TLE as well as in human TLE. miR‐146a analysis in rat hippocampus was performed by polymerase chain reaction and immunocytochemistry at 1 week and 3–4 months after induction of status epilepticus (SE). Prominent upregulation of miR‐146a activation was evident at 1 week after SE and persisted in the chronic phase. The miR‐146a expression was confirmed to be present in reactive astrocytes. In human TLE with hippocampal sclerosis, increased astroglial expression of miR‐146a was observed mainly in regions where neuronal cell loss and reactive gliosis occurred. The increased and persistent expression of miR‐146a in reactive astrocytes supports the possible involvement of miRNAs in the modulation of the astroglial inflammatory response occurring in TLE and provides a target for future studies aimed at developing strategies against pro‐epileptogenic inflammatory signalling.

Localization of breast cancer resistance protein (BCRP) in microvessel endothelium of human control and epileptic brain

Summary:  Purpose: Breast cancer resistance protein (BCRP) is a half adenosine triphosphate (ATP)‐binding cassette (ABC) transporter expressed on cellular membranes and included in the group of multidrug resistant (MDR)‐related proteins. Recently, upregulation of different MDR proteins has been shown in human epilepsy‐associated conditions. This study investigated the expression and cellular distribution of BCRP in human control and epileptic brain, including a large number of both neoplastic and nonneoplastic specimens from patients with chronic pharmacoresistant epilepsy.

How do brain tumors alter functional connectivity? A magnetoencephalography study

This study was undertaken to test the hypothesis that brain tumors interfere with normal brain function by disrupting functional connectivity of brain networks.

Long-Term Effects of Temporal Lobe Epilepsy on Local Neural Networks: A Graph Theoretical Analysis of Corticography Recordings

Purpose Pharmaco-resistant temporal lobe epilepsy (TLE) is often treated with surgical intervention at some point. As epilepsy surgery is considered a last resort by most physicians, a long history of epileptic seizures prior to surgery is not uncommon. Little is known about the effects of ongoing TLE on neural functioning. A better understanding of these effects might influence the moment of surgical intervention. Functional connectivity (interaction between spatially distributed brain areas) and network structure (integration and segregation of information processing) are thought to be essential for optimal brain functioning. We report on the impact of TLE duration on temporal lobe functional connectivity and network characteristics. Methods Functional connectivity of the temporal lobe at the time of surgery was assessed by means of interictal electrocorticography (ECoG) recordings of 27 TLE patients by using the phase lag index (PLI). Graphs (abstract network representations) were reconstructed from the PLI matrix and characterized by the clustering coefficient C (local clustering), the path length L (overall network interconnectedness), and the “small world index” S (network configuration). Results Functional connectivity (average PLI), clustering coefficients, and the small world index were negatively correlated with TLE duration in the broad frequency band (0.5–48 Hz). Discussion Temporal lobe functional connectivity is lower in patients with longer TLE history, and longer TLE duration is correlated with more random network configuration. Our findings suggest that the neural networks of TLE patients become more pathological over time, possibly due to temporal lobe changes associated with long-standing lesional epilepsy.

Evaluation of the innate and adaptive immunity in type I and type II focal cortical dysplasias

Purpose:  Induction of inflammatory pathways has been reported in epileptic patients with focal malformations of cortical development. In the present study we examined the innate and adaptive immune responses in focal cortical dysplasia (FCD) with different histopathologic and pathogenetic features.

Upregulation of adenosine kinase in astrocytes in experimental and human temporal lobe epilepsy

Purpose:  Adenosine kinase (ADK) represents the key metabolic enzyme for the regulation of extracellular adenosine levels in the brain. In adult brain, ADK is primarily present in astrocytes. Several lines of experimental evidence support a critical role of ADK in different types of brain injury associated with astrogliosis, which is also a prominent morphologic feature of temporal lobe epilepsy (TLE). We hypothesized that dysregulation of ADK is an ubiquitous pathologic hallmark of TLE.

Epilepsy surgery outcome and functional network alterations in longitudinal MEG: A minimum spanning tree analysis

Seizure freedom after resective epilepsy surgery is not obtained in a substantial number of patients with medically intractable epilepsy. Functional neural network analysis is a promising technique for more accurate identification of the target areas for epilepsy surgery, but a better understanding of the correlations between changes in functional network organization due to surgery and postoperative seizure status is required. We explored these correlations in longitudinal magnetoencephalography (MEG) recordings of 20 lesional epilepsy patients. Resting-state MEG recordings were obtained at baseline (preoperatively; T0) and at 3-7 (T1) and 9-15months after resection (T2). We assessed frequency-specific functional connectivity and performed a minimum spanning tree (MST) network analysis. The MST captures the most important connections in the network. We found a significant positive correlation between functional connectivity in the lower alpha band and seizure frequency at T0, especially in regions where lesions were located. MST leaf fraction, a measure of integration of information in the network, was significantly increased between T0 and T2, only for the seizure-free patients. This is in line with previous work, which showed that lower functional network integration in lesional epilepsy patients is related to higher epilepsy burden. Finally, eccentricity and betweenness centrality, which are measures of hub-status, decreased between T0 and T2 in seizure free patients, also in regions that were anatomically close to resection cavities. Our results increase insight into functional network changes in successful epilepsy surgery and might eventually be utilized for optimization of neurosurgical approaches.

The localization of spontaneous brain activity: first results in patients with cerebral tumors

OBJECTIVE From EEG studies, it is known that structural brain lesions are accompanied by abnormal rhythmic electric activity. With the better spatial resolution of MEG, MEG dipole analysis can extend the knowledge based on EEG power spectra. This study presents the first results of a completely automatic analysis method applied to spontaneous MEG. METHODS Spontaneous MEG data of 5 patients with cerebral brain tumors and 4 controls were collected using a whole-head MEG system. Signals were bandpass-filtered with cut-off frequencies according to standard EEG bands. A moving dipole model was fitted to samples with at least twice the average sample power. Dipoles explaining 90% or more of the magnetic variance were projected onto a matched MR scan. RESULTS In controls, dipole distributions are symmetrical with respect to the mid-sagittal plane whereas distributions in patients often are asymmetrical to it. Dipoles describing gamma activity were located contralateral, and dipoles describing delta and theta activity were located ipsilateral to lesions. CONCLUSIONS The automatic method gives plausible 3-dimensional information about generator foci of abnormal slow waves and other rhythms with respect to lesion foci and thereby adds physiological knowledge to that derived from EEG power spectra.

The influence of brain tumor treatment on pathological delta activity in MEG.

The goal of the MEG study was to investigate the influence of tumor treatment on pathological delta activity (1-4 Hz). The treatment consisted of neurosurgery, and in some of the patients, additional radiotherapy. MEG and MR recordings were made both before and after the treatment in 17 patients. The signal power in the delta frequency band was determined for each recording. The malignant tumors were associated with large tumor volumes. Furthermore, both malignant tumors and tumor volume were associated with high signal powers in the delta band, indicating a correlation of delta power with the severity of the lesions. In all patients with high grade tumors, the delta power was lower after the treatment. The sources underlying the delta signals were estimated with an automatic single dipole analysis method. Estimated sources were projected onto MR scans. Preoperatively 14 clusters of equivalent sources describing focal activity were found in 12 out of 17 patients. Thirteen of these clusters were located near the tumor, and one cluster near an edema border. The locations near tumors are plausible and suggest that in general the source estimation was reliable. After the operation, 13 such clusters were found in 12 patients. Eleven clusters were located near the lesion border and one cluster near the edema border. Furthermore a cluster contralateral to the lesion in the other hemisphere indicated that brain lesions can affect the functioning of more distant brain areas than just the peritumoral brain tissue. Of the 12 patients who had preoperatively peritumoral clusters, 11 patients had postoperatively perilesional sources. In these cases the shift in source locations was in general considerably smaller than the dimension of the preoperative tumors. This finding indicates that similar areas generate the pre- and postoperative delta activity. Furthermore, focal delta sources were found in a case without tumor recurrence, and also in cases that most tumor tissue was removed. These findings suggest that the pathology underlying the slow waves is not the presence of the tumor bulk but the structural damage done by the tumors on the surrounding white/gray matter.