Non-epileptic Brain Research Articles

Identification of epileptic networks with graph convolutional network incorporating oscillatory activities and evoked synaptic responses

Stereoelectroencephalography (SEEG) offers unique neural data from in-depth brain structures with fine temporal resolutions to better investigate the origin of epileptic brain activities. Although oscillatory patterns from different frequency bands and functional connectivity computed from the SEEG datasets are employed to study the epileptic zones, direct electrical stimulation-evoked electrophysiological recordings of synaptic responses, namely cortical-cortical evoked potentials (CCEPs), from the same SEEG electrodes are not explored for the localization of epileptic zones. Here we proposed a two-stream model with unsupervised learning and graph convolutional network tailored to the SEEG and CCEP datasets in individual patients to perform localization of epileptic zones. We compared our localization results with the clinically marked electrode sites determined for surgical resections. Our model had good classification capability when compared to other state-of-the-art methods. Furthermore, based on our prediction results we performed group-level brain-area mapping analysis for temporal, frontal and parietal epilepsy patients and found that epileptic and non-epileptic brain networks were distinct in patients with different types of focal epilepsy. Our unsupervised data-driven model provides personalized localization analysis for the epileptic zones. The epileptic and non-epileptic brain areas disclosed by the prediction model provide novel insights into the network-level pathological characteristics of epilepsy.

Tailoring Materials for Epilepsy Imaging: From Biomarkers to Imaging Probes.

Excising epileptic foci (EF) is the most efficient approach for treating drug-resistant epilepsy (DRE). However, owing to the vast heterogeneity of epilepsies, EF in one-third of patients cannot be accurately located, even after exhausting all current diagnostic strategies. Therefore, identifying biomarkers that truly represent the status of epilepsy and fabricating probes with high targeting specificity are prerequisites for identifying the "concealed" EF. However, no systematic summary of this topic has been published. Herein, the potential biomarkers of EF are first summarized and classified into three categories: functional, molecular, and structural aberrances during epileptogenesis, a procedure of nonepileptic brain biasing toward epileptic tissue. The materials used to fabricate these imaging probes and their performance in defining the EF in preclinical and clinical studies are highlighted. Finally, perspectives for developing the next generation of probes and their challenges in clinical translation are discussed. In general, this review can be helpful in guiding the development of imaging probes defining EF with improved accuracy and holds promise for increasing the number of DRE patients who are eligible for surgical intervention.

Evaluation of serum high-mobility group box 1 concentration in dogs with epilepsy: A case-control study.

BackgroundHigh‐mobility group box 1 (HMGB1) is a key mediator of neuroinflammation and there are increased HMGB1 levels in laboratory animal models of epilepsy and human patients with epilepsy.ObjectivesTo determine serum HMGB1 levels in dogs with epilepsy.AnimalsTwenty‐eight epileptic dogs, 12 dogs with nonepileptic brain diseases, and 26 healthy dogs.MethodsIn this case‐control study, serum HMGB1 concentrations were estimated using the canine‐specific enzyme‐linked immunosorbent assay kit. Diagnosis of dogs with epilepsy was based on medical history, physical and neurological examination findings, laboratory test results, magnetic resonance image, and cerebrospinal fluid analysis.ResultsSerum HMGB1 levels were significantly higher in epileptic dogs (median = 0.41 ng/mL; range, 0.03‐5.28) than in healthy dogs (median = 0.12 ng/mL; range, 0.02‐1.45; P = .002). In contrast, serum HMGB1 levels of dogs with non‐epileptic brain diseases (median = 0.19 ng/mL; range, 0.03‐1.04) were not significantly increased compared to those of healthy dogs (P = .12). Regarding idiopathic epilepsy, dogs with an epilepsy course of >3 months showed a higher serum HMGB1 concentration (median = 0.87 ng/mL; range, 0.42‐2.88) than those with that of ≤3 months (median = 0.26 ng/mL; range, 0.03‐0.88; P = .02).Conclusions and Clinical ImportanceSerum HMGB1 could be a biomarker of epilepsy.

Estimation of the epileptogenic-zone with HFO sub-groups exhibiting various levels of epileptogenicity.

High-Frequency-Oscillations (HFO) are biomarkers of the epileptogenic-zone (EZ) and thus a potential aid in guiding epilepsy-surgery. HFO are normally sub-divided according to their oscillating-frequency into Ripples (80-250 Hz) and Fast-Ripples (FR) (250-500 Hz) and are known to also occur in the non-epileptic brain. We address two challenges faced by HFO: firstly, estimating the margins of the EZ using the HFO occurrence-rate from each intracranial EEG channel; secondly, selecting HFO sub-groups with a higher probability of being purely epileptic. We propose the clustering of channels with high HFO occurrence-rates as a deterministic method to delimit the EZ. Additionally, we perform the EZ estimation using 9 sub-groups of HFO; these sub-groups are determined by their temporal and spatial coincidence with intracranial interictal-epileptic-spikes (IES) and are assumed to have varying levels of epileptogenicity. The EZ estimated with the different HFO-sub-groups are compared between themselves and with a proxy of the factually undefinable EZ, namely the resected-volume (RV). The proposed clustering method proved to be deterministic and allowed estimating the EZ for each patient and each HFO-sub-group. Those Ripples assumed to be more epileptogenic occurred in lower numbers than all Ripples but showed the highest correspondence with the RV. All FR sub-groups showed a high specificity to the RV. The proposed clustering method successfully extracted the information from the HFO occurrence-rate to estimate the EZ. The selection of more epileptogenic HFO based on their coincidence with IES proved to be of value for both Ripples and FR.

Multimodal, noninvasive seizure network mapping software: A novel tool for preoperative epilepsy evaluation

BackgroundDespite rigorous preoperative evaluation, epilepsy surgery achieves seizure freedom in only two-thirds of cases. Current preoperative evaluation does not include a detailed network analysis despite the association of network-level changes with epilepsy. ObjectiveWe sought to create a software algorithm to map individualized epilepsy networks by combining noninvasive electroencephalography (EEG) source localization and nonconcurrent resting state functional magnetic resonance imaging (rsfMRI). MethodsScalp EEG and rsfMRI data were acquired for three sample cases: one healthy control case, one case of right temporal lobe epilepsy, and one case of bitemporal seizure onset. Data from rsfMRI were preprocessed, and a time-series function was extracted. Connection coefficients were used to threshold out spurious connections and model global functional networks in a 3D map. Epileptic discharges were localized using a forward model of cortical mesh dipoles followed by an empirical Bayesian approach of inverse source reconstruction and co-registered with rsfMRI. Co-activating brain regions were mapped. ResultsThree illustrative sample cases are presented. In the healthy control case, the software showed symmetrical global connectivity. In the right temporal lobe epilepsy case, asymmetry was found in the global connectivity metrics with a paucity of connectivity ipsilateral to the epileptogenic cortex. The superior longitudinal fasciculus, uncinate fasciculus, and commissural fibers connecting disparate and discontinuous cortical regions involved in the epilepsy network were visualized. In the case with bitemporal lobe epilepsy, global connectivity was symmetric. It showed a network of correlating cortical activity local to epileptogenic tissue in both temporal lobes. The network involved white matter tracks in a similar pattern to those seen in the right temporal case. ConclusionsThis modeling algorithm allows better definition of the global brain network and potentially demonstrates differences in connectivity between an epileptic and a non-epileptic brain. This finding may be useful for mapping cortico-cortical connections representing the putative epilepsy networks. With this methodology, we localized the epileptogenic brain and showed network asymmetry and long-distance cortical co-activation. This software tool is the first to use a multimodal, nonconcurrent, and noninvasive approach to model and visualize the epilepsy network.

LORETA indicates frequency-specific suppressions of current sources within the cerebrums of blindfolded subjects from patterns of blue light flashes applied over the skull.

An array of eight cloistered (completely covered) 470-nm LEDs was attached to the right caudal scalp of subjects while each sat blindfolded within a darkened chamber. The LEDs were activated by a computer-generated complex (frequency-modulated) temporal pattern that, when applied as weak magnetic fields, has elicited sensed presences and changes in LORETA (low-resolution electromagnetic tomography) configurations. Serial 5-min on to 5-min off presentations of the blue light (10,000lx) resulted in suppression of gamma activity within the right cuneus (including the extrastriate area), beta activity within the left angular and right superior temporal regions, and alpha power within the right parahippocampal region. The effect required about 5min to emerge followed by a transient asymptote for about 15 to 20min when diminished current source density was evident even during no light conditions. Subjective experiences, as measured by our standard exit questionnaire, reflected sensations similar to those reported when the pattern was presented as a weak magnetic field. Given previous evidence that photon flux density of this magnitude can penetrate the skull, these results suggest that properly configured LEDs that generate physiologically patterned light sequences might be employed as noninvasive methods to explore the dynamic characteristics of cerebral activity in epileptic and nonepileptic brains.

Perampanel, an antagonist of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, for the treatment of epilepsy: studies in human epileptic brain and nonepileptic brain and in rodent models.

Perampanel [Fycompa, 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile hydrate 4:3; Eisai Inc., Woodcliff Lake, NJ] is an AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor antagonist used as an adjunctive treatment of partial-onset seizures. We asked whether perampanel has AMPA receptor antagonist activity in both the cerebral cortex and hippocampus associated with antiepileptic efficacy and also in the cerebellum associated with motor side effects in rodent and human brains. We also asked whether epileptic or nonepileptic human cortex is similarly responsive to AMPA receptor antagonism by perampanel. In rodent models, perampanel decreased epileptic-like activity in multiple seizure models. However, doses of perampanel that had anticonvulsant effects were within the same range as those engendering motor side effects. Perampanel inhibited native rat and human AMPA receptors from the hippocampus as well as the cerebellum that were reconstituted into Xenopus oocytes. In addition, with the same technique, we found that perampanel inhibited AMPA receptors from hippocampal tissue that had been removed from a patient who underwent surgical resection for refractory epilepsy. Perampanel inhibited AMPA receptor-mediated ion currents from all the tissues investigated with similar potency (IC50 values ranging from 2.6 to 7.0 μM). Cortical slices from the left temporal lobe derived from the same patient were studied in a 60-microelectrode array. Large field potentials were evoked on at least 45 channels of the array, and 10 μM perampanel decreased their amplitude and firing rate. Perampanel also produced a 33% reduction in the branching parameter, demonstrating the effects of perampanel at the network level. These data suggest that perampanel blocks AMPA receptors globally across the brain to account for both its antiepileptic and side-effect profile in rodents and epileptic patients.

Differences in MMPI-2 FBS and RBS Scores in Brain Injury, Probable Malingering, and Conversion Disorder Groups: A Preliminary Study

This study examined differences in raw scores on the Symptom Validity Scale and Response Bias Scale (RBS) from the Minnesota Multiphasic Personality Inventory-2 in three criterion groups: (i) valid traumatic brain injured, (ii) invalid traumatic brain injured, and (iii) psychogenic non-epileptic seizure disorders. Results indicate that a >30 raw score cutoff for the Symptom Validity Scale accurately identified 50% of the invalid traumatic brain injured group, while misclassifying none of the valid traumatic brain injured group and 6% of the psychogenic non-epileptic seizure disorder group. Using a >15 RBS raw cutoff score accurately classified 50% of the invalid traumatic brain injured group and misclassified fewer than 10% of the valid traumatic brain injured and psychogenic non-epileptic seizure disorder groups. These cutoff scores used conjunctively did not misclassify any members of the psychogenic non-epileptic seizure disorder or valid traumatic brain injured groups, while accurately classifying 44% of the invalid traumatic brain injured individuals. Findings from this preliminary study suggest that the conjunctive use of the Symptom Validity Scale and the RBS from the Minnesota Multiphasic Personality Inventory-2 may be useful in differentiating probable malingering from individuals with brain injuries and conversion disorders.

Antidepressant therapy in epilepsy: can treating the comorbidities affect the underlying disorder?

There is a high incidence of psychiatric comorbidity in people with epilepsy (PWE), particularly depression. The manifold adverse consequences of comorbid depression have been more clearly mapped in recent years. Accordingly, considerable efforts have been made to improve detection and diagnosis, with the result that many PWE are treated with antidepressant drugs, medications with the potential to influence both epilepsy and depression. Exposure to older generations of antidepressants (notably tricyclic antidepressants and bupropion) can increase seizure frequency. However, a growing body of evidence suggests that newer ('second generation') antidepressants, such as selective serotonin reuptake inhibitors or serotonin-noradrenaline reuptake inhibitors, have markedly less effect on excitability and may lead to improvements in epilepsy severity. Although a great deal is known about how antidepressants affect excitability on short time scales in experimental models, little is known about the effects of chronic antidepressant exposure on the underlying processes subsumed under the term 'epileptogenesis': the progressive neurobiological processes by which the non-epileptic brain changes so that it generates spontaneous, recurrent seizures. This paper reviews the literature concerning the influences of antidepressants in PWE and in animal models. The second section describes neurobiological mechanisms implicated in both antidepressant actions and in epileptogenesis, highlighting potential substrates that may mediate any effects of antidepressants on the development and progression of epilepsy. Although much indirect evidence suggests the overall clinical effects of antidepressants on epilepsy itself are beneficial, there are reasons for caution and the need for further research, discussed in the concluding section.

Vigabatrin for focal drug delivery in epilepsy: Bilateral microinfusion into the subthalamic nucleus is more effective than intranigral or systemic administration in a rat seizure model

Vigabatrin is a rationally developed antiepileptic drug, which acts by increasing GABA levels in the brain by irreversibly inhibiting GABA degradation. However, its clinical use in epilepsy is restricted by severe side effects, including vision loss, which is thought to be a consequence of drug exposure of the retina and nonepileptic brain regions. Targeted delivery into brain regions involved in seizure generation and propagation would overcome this problem. Previous studies in rat models of seizures or epilepsy have shown that anticonvulsant effects can be achieved by bilateral microinjection of vigabatrin into the substantia nigra pars reticulata (SNr), a basal ganglia output structure that plays an important role in the modulation of seizures. In the present study, we compared the anticonvulsant efficacy of vigabatrin after systemic and intranigral administration in a rat model, in which seizure susceptibility can be determined by timed intravenous infusion of pentylenetetrazol (PTZ) before and after drug injection in individual animals. Furthermore, because the subthalamic nucleus (STN) plays a crucial role as a regulator of basal ganglia outflow by providing excitatory glutamatergic input into the two output nuclei of the basal ganglia, SNr and entopeduncular nucleus, we evaluated the effects of bilateral focal delivery of vigabatrin into the STN on PTZ seizure threshold. A significant increase in seizure threshold was observed following systemic (i.p.) administration of high (600 or 1200mg/kg) doses of vigabatrin. Bilateral microinjection of vigabatrin (10μg) into either the anterior or posterior SNr also increased seizure threshold, but less markedly than systemic treatment. In contrast, focal delivery into the STN increased seizure threshold more markedly than either intranigral or systemic administration of vigabatrin. Furthermore, focal inhibition of STN was not associated with the severe adverse effects associated with systemic treatment. The data demonstrate that vigabatrin is an interesting substance for focal drug delivery in epilepsy and may be advantageous compared to more commonly evaluated compounds such as muscimol.

Plasticity of glutamate synaptic mechanisms

SummaryEnhanced glutamate synaptic transmission may be expected to alter the balance of excitation and inhibition in brain, leading to seizures. Several differences between epileptic and nonepileptic brains in presynaptic and postsynaptic glutamate mechanisms have been reported. These findings suggest that altered glutamate mechanisms contribute to the hyperexcitability of epileptic brain. For an expanded treatment of this topic see Jasper’s Basic Mechanisms of the Epilepsies, Fourth Edition (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado‐Escueta AV, eds) published by Oxford University Press (available on the National Library of Medicine Bookshelf [NCBI] at http://www.ncbi.nlm.nih.gov/books).

State dependent properties of epileptic brain networks: Comparative graph–theoretical analyses of simultaneously recorded EEG and MEG

To investigate whether functional brain networks of epilepsy patients treated with antiepileptic medication differ from networks of healthy controls even during the seizure-free interval. We applied different rules to construct binary and weighted networks from EEG and MEG data recorded under a resting-state eyes-open and eyes-closed condition from 21 epilepsy patients and 23 healthy controls. The average shortest path length and the clustering coefficient served as global statistical network characteristics. Independent on the behavioral condition, epileptic brains exhibited a more regular functional network structure. Similarly, the eyes-closed condition was characterized by a more regular functional network structure in both groups. The amount of network reorganization due to behavioral state changes was similar in both groups. Consistent findings could be achieved for networks derived from EEG but hardly from MEG recordings, and network construction rules had a rather strong impact on our findings. Despite the locality of the investigated processes epileptic brain networks differ in their global characteristics from non-epileptic brain networks. Further methodological developments are necessary to improve the characterization of disturbed and normal functional networks. An increased regularity and a diminished modulation capability appear characteristic of epileptic brain networks.

Convection-Enhanced Delivery in the Treatment of Epilepsy

Convection-enhanced delivery (CED) is a novel drug-delivery technique that uses positive hydrostatic pressure to deliver a fluid containing a therapeutic substance by bulk flow directly into the interstitial space within a localized region of the brain parenchyma. CED circumvents the blood-brain barrier and provides a wider, more homogenous distribution than bolus deposition (focal injection) or other diffusion-based delivery approaches. A potential use of CED is for the local delivery of antiseizure agents, which would provide an epilepsy treatment approach that avoids the systemic toxicities of orally administered antiepileptic drugs and bystander effects on nonepileptic brain regions. Recent studies have demonstrated that brief CED infusions of nondiffusible peptides that inhibit the release of excitatory neurotransmitters, including omega-conotoxins and botulinum neurotoxins, can produce long-lasting (weeks to months) seizure protection in the rat amygdala-kindling model. Seizure protection is obtainable without detectable neurological or behavioral side effects. Although conventional diffusible antiepileptic drugs do confer seizure protection when administered locally by CED, the effect is transitory. CED is a potential approach for seizure protection that could represent an alternative to resective surgery in the treatment of focal epilepsies that are resistant to orally-administered antiepileptic drugs. The prolonged duration of action of nondiffusible toxins would allow seizure protection to be maintained chronically with infrequent reinfusions.

Introduction Posttraumatic epilepsy: Treatable epileptogenesis

Introduction Posttraumatic epilepsy: Treatable epileptogenesis

Independent delta/theta rhythms in the human hippocampus and entorhinal cortex

Theta oscillations in the medial temporal lobe (MTL) of mammals are involved in various functions such as spatial navigation, sensorimotor integration, and cognitive processing. While the theta rhythm was originally assumed to originate in the medial septum, more recent studies suggest autonomous theta generation in the MTL. Although coherence between entorhinal and hippocampal theta activity has been found to influence memory formation, it remains unclear whether these two structures can generate theta independently. In this study we analyzed intracranial electroencephalographic (EEG) recordings from 22 patients with unilateral hippocampal sclerosis undergoing presurgical evaluation prior to resection of the epileptic focus. Using a wavelet-based, frequency-band-specific measure of phase synchronization, we quantified synchrony between 10 different recording sites along the longitudinal axis of the hippocampal formation in the non-epileptic brain hemisphere. We compared EEG synchrony between adjacent recording sites (i) within the entorhinal cortex, (ii) within the hippocampus, and (iii) between the hippocampus and entorhinal cortex. We observed a significant interregional gap in synchrony for the delta and theta band, indicating the existence of independent delta/theta rhythms in different subregions of the human MTL. The interaction of these rhythms could represent the temporal basis for the information processing required for mnemonic encoding and retrieval.

Inhibitory GABA Current Rundown in Epileptic Brain: Use-Dependent and Pathology-Specific Mechanisms

Rundown of GABA Type A Receptors Is a Dysfunction Associated with Human Drug-Resistant Mesial Temporal Lobe Epilepsy Ragozzino D, Palma E, Di Angelantonio S, Amici M, Mascia A, Arcella A, Giangaspero F, Cantore G, Di Gennaro G, Manfredi M, Esposito V, Quarato PP, Miledi R, Eusebi F Proc Natl Acad Sci U S A 2005;102(42):15219–15223 Pharmacotherapeutic strategies have been difficult to develop for several forms of temporal lobe epilepsy, which are consequently treated by surgical resection. To examine this problem, we have studied the properties of transmitter receptors of tissues removed during surgical treatment. We find that when cell membranes, isolated from the temporal neocortex of patients afflicted with drug-resistant mesial temporal lobe epilepsy (TLE), are injected into frog oocytes they acquire GABA type A receptors (GABAA-receptors) that display a marked rundown during repetitive applications of GABA. In contrast, GABAA-receptor function is stable in oocytes injected with cell membranes isolated from the temporal lobe of TLE patients afflicted with neoplastic, dysgenetic, traumatic, or ischemic temporal lesions (lesional TLE, LTLE). Use-dependent GABAA-receptor rundown is also found in the pyramidal neurons of TLE neocortical slices and is antagonized by BDNF. Pyramidal neurons in cortical slices of a traumatic LTLE patient did not show GABAA-receptor rundown. However, the apparent affinity of GABAA-receptor in oocytes microtransplanted with membranes from all of the epileptic patients studied was smaller than the affinity of receptors transplanted from the nonepileptic brain. We conclude that the use-dependent rundown of neocortical GABAA-receptor represents a TLE-specific dysfunction, whereas the reduced affinity may be a general feature of brains of both TLE and LTLE patients, and we speculate that our findings may help to develop new treatments for TLE and LTLE.

Cerebral cortical effects of desflurane in sheep: comparison with isoflurane, sevoflurane and enflurane

Different volatile anesthetic agents have differing propensities for inducing seizures. A measure of the predilection to develop seizures is the presence of interictal spike discharges (spikes) on the electrocorticogram (ECoG). In this study, we investigated the propensity of desflurane to induce cortical spikes and made a direct objective comparison with enflurane, isoflurane, and sevoflurane. The ECoG effects of desflurane have not been previously reported. After establishment of invasive monitoring and a parasagittal array of eight electrodes to record the ECoG; eight adult merino sheep were given a series of short inhalational anesthetics (using desflurane, enflurane, sevoflurane and isoflurane); each titrated to ECoG burst suppression. Anesthetic effect was estimated by the effects on the approximate entropy of the ECoG. The effect of anesthetic on the spike-rate in the ECoG was analyzed using a non-linear mixed-effect method with a sigmoid Emax model. A similar 'depth of anesthesia' was achieved for each agent, as estimated by the approximate entropy. The mean (SD) values of Emax for the spike-rate vs. approximate entropy relationship were desflurane 0.5 (0.9), enflurane 17.2 (4.0), isoflurane 0.7 (1.2), and sevoflurane 5.3 (1.2) spikes/min. The spike rate caused by desflurane was similar to isoflurane and significantly lower than that of enflurane (P < 0.001), and sevoflurane (P = 0.009). Desflurane induces minimal cerebral cortical spike activity when administered to burst suppression, consistent with its low propensity for inducing seizures in non-epileptic brains. The agents can be ranked by their relative ability to cause spike activity: enflurane >> sevoflurane > isoflurane = desflurane.

Rundown of GABA type A receptors is a dysfunction associated with human drug-resistant mesial temporal lobe epilepsy

Pharmacotherapeutic strategies have been difficult to develop for several forms of temporal lobe epilepsy, which are consequently treated by surgical resection. To examine this problem, we have studied the properties of transmitter receptors of tissues removed during surgical treatment. We find that when cell membranes, isolated from the temporal neocortex of patients afflicted with drug-resistant mesial temporal lobe epilepsy (TLE), are injected into frog oocytes they acquire GABA type A receptors (GABA(A)-receptors) that display a marked rundown during repetitive applications of GABA. In contrast, GABA(A)-receptor function is stable in oocytes injected with cell membranes isolated from the temporal lobe of TLE patients afflicted with neoplastic, dysgenetic, traumatic, or ischemic temporal lesions (lesional TLE, LTLE). Use-dependent GABA(A)-receptor rundown is also found in the pyramidal neurons of TLE neocortical slices and is antagonized by BDNF. Pyramidal neurons in cortical slices of a traumatic LTLE patient did not show GABA(A)-receptor rundown. However, the apparent affinity of GABA(A)-receptor in oocytes microtransplanted with membranes from all of the epileptic patients studied was smaller than the affinity of receptors transplanted from the nonepileptic brain. We conclude that the use-dependent rundown of neocortical GABA(A)-receptor represents a TLE-specific dysfunction, whereas the reduced affinity may be a general feature of brains of both TLE and LTLE patients, and we speculate that our findings may help to develop new treatments for TLE and LTLE.

Fatty acid amidohydrolase in human neocortex—activity in epileptic and non-epileptic brain tissue and inhibition by putative endocannabinoids

Increased levels of the endocannabinoid anandamide (AEA) have been observed in connection with neuronal disorders like epilepsy. In order to investigate whether an impaired enzymatic AEA hydrolysis contributes to this phenomenon, the present study determined the activity of fatty acid amidohydrolase (FAAH) in epileptic and non-epileptic human neocortical brain tissue. Additionally, we investigated whether other putative endocannabinoids (2-arachidonylglycerol (2-AG), noladin ether, virodhamine) may also interact with FAAH. AEA hydrolysis was measured by the formation of the product [ 3H]-ethanolamine after separation from the substrate using activated charcoal. FAAH activity was found to be similar in epileptic and non-epileptic human neocortex (0.29 and 0.37 nmol ethanolamine/mg protein/min, respectively). FAAH activity was about 55% higher in rat neocortex. While in human, neocortex noladin ether did not influence AEA hydrolysis, FAAH activity was concentration-dependently inhibited by AEA, 2-AG and virodhamine (IC 50 values 3.3, 3.5 and 13.8 μM, respectively). Our results suggest that, in the course of epilepsy, increased AEA levels are likely due to enhanced formation and not due to decreased hydrolysis. To further increase endocannabinoid activity, the application of FAAH inhibitors might be therapeutically useful in the treatment of neuronal hyperexcitability. Whereas noladin ether did not interact with AEA hydrolysis, this compound, 2-AG and virodhamine may share common enzymatic inactivation mechanisms in human neocortex.

Activation of electrocorticographic activity with remifentanil and alfentanil during neurosurgical excision of epileptogenic focus

Opioids are known to stimulate surface electroencephalographic activity in patients with temporal lobe epilepsy. The objective of the current study was to compare the electrocorticographic activation effects of the newer short-acting opioid remifentanil with those of alfentanil during epilepsy surgery under general anaesthesia. Thirteen patients undergoing temporal lobe epilepsy surgery under general anaesthesia received alfentanil 30 microg kg(-1) and remifentanil 1 microg kg(-1) as i.v. boluses in sequence. The design was a randomized double-blind cross-over study. After opening the dura, electrocorticogram (ECoG) electrode contact strips were placed over the temporal and supratemporal neocortex and depth electrodes were inserted in the amygdala and hippocampus. Alfentanil 30 microg kg(-1) or remifentanil 1 microg kg(-1) were administered randomly in a blinded fashion. The ECoG was recorded continuously before and after the injection of each drug. The interictal epileptiform activity (spikes and sharp waves) above baseline was analysed. Both drugs increased epileptiform activity especially that recorded from depth electrodes in the temporal limbic structures. No epileptiform activity was recorded from the electrodes overlying the supratemporal neocortex before or after drug administration. The more potent activator was alfentanil, which caused an increase in activation from baseline of 99.8% compared with 67.4% for remifentanil. In addition, alfentanil activated the epileptiform activity in 3 patients in which remifentanil had no effect. There were no changes in heart rate after the opioid boluses. Both remifentanil and alfentanil caused significant reductions in blood pressure at 3 and 5 min after administration. We conclude that at the doses used in this study, alfentanil is the better opioid for intraoperative activation of the ECoG in neurosurgical patients undergoing resection of a temporal lobe epileptic focus. This pharmacological activation of epileptiform activity assists in localizing and confirming the site of surgical excision. Neither alfentanil nor remifentanil activated epileptiform activity in non-epileptic brain tissue.