Strong and reliable synaptic communication between pyramidal neurons in adult human cerebral cortex.

Synaptic transmission constitutes the primary mode of communication between neurons. It is extensively studied in rodent but not human neocortex. We characterized synaptic transmission between pyramidal neurons in layers 2 and 3 using neurosurgically resected human middle temporal gyrus (MTG, Brodmann area 21), which is part of the distributed language circuitry. We find that local connectivity is comparable with mouse layer 2/3 connections in the anatomical homologue (temporal association area), but synaptic connections in human are 3-fold stronger and more reliable (0% vs 25% failure rates, respectively). We developed a theoretical approach to quantify properties of spinous synapses showing that synaptic conductance and voltage change in human dendritic spines are 3-4-folds larger compared with mouse, leading to significant NMDA receptor activation in human unitary connections. This model prediction was validated experimentally by showing that NMDA receptor activation increases the amplitude and prolongs decay of unitary excitatory postsynaptic potentials in human but not in mouse connections. Since NMDA-dependent recurrent excitation facilitates persistent activity (supporting working memory), our data uncovers cortical microcircuit properties in human that may contribute to language processing in MTG.

Human Hippocampal Neurons Track Moments in a Sequence of Events.

An indispensable feature of episodic memory is our ability to temporally piece together different elements of an experience into a coherent memory. Hippocampal time cells-neurons that represent temporal information-may play a critical role in this process. Although these cells have been repeatedly found in rodents, it is still unclear to what extent similar temporal selectivity exists in the human hippocampus. Here, we show that temporal context modulates the firing activity of human hippocampal neurons during structured temporal experiences. We recorded neuronal activity in the human brain while patients of either sex learned predictable sequences of pictures. We report that human time cells fire at successive moments in this task. Furthermore, time cells also signaled inherently changing temporal contexts during empty 10 s gap periods between trials while participants waited for the task to resume. Finally, population activity allowed for decoding temporal epoch identity, both during sequence learning and during the gap periods. These findings suggest that human hippocampal neurons could play an essential role in temporally organizing distinct moments of an experience in episodic memory.SIGNIFICANCE STATEMENT Episodic memory refers to our ability to remember the what, where, and when of a past experience. Representing time is an important component of this form of memory. Here, we show that neurons in the human hippocampus represent temporal information. This temporal signature was observed both when participants were actively engaged in a memory task, as well as during 10-s-long gaps when they were asked to wait before performing the task. Furthermore, the activity of the population of hippocampal cells allowed for decoding one temporal epoch from another. These results suggest a robust representation of time in the human hippocampus.

Serotonin receptor expression in hippocampus and temporal cortex of temporal lobe epilepsy patients by postictal generalized electroencephalographic suppression duration.

OBJECTIVE: Prolonged postictal generalized electroencephalographic suppression (PGES) is a potential biomarker for sudden unexpected death in epilepsy (SUDEP), which may be associated with dysfunctional autonomic responses and serotonin signaling. To better understand molecular mechanisms, PGES duration was correlated to 5HT1A and 5HT2A receptor protein expression and RNAseq from resected hippocampus and temporal cortex of temporal lobe epilepsy patients with seizures recorded in preoperative evaluation. METHODS: Analyses included 36 cases (age = 14-64 years, age at epilepsy onset = 0-51 years, epilepsy duration = 2-53 years, PGES duration = 0-93 s), with 13 cases in all hippocampal analyses. 5HT1A and 5HT2A protein was evaluated by Western blot and histologically in hippocampus (n = 16) and temporal cortex (n = 9). We correlated PGES duration to our previous RNAseq dataset for serotonin receptor expression and signaling pathways, as well as weighted gene correlation network analysis (WGCNA) to identify correlated gene clusters. RESULTS: In hippocampus, 5HT2A protein by Western blot positively correlated with PGES duration (p = .0024, R2  = .52), but 5HT1A did not (p = .87, R2  = .0020). In temporal cortex, 5HT1A and 5HT2A had lower expression and did not correlate with PGES duration. Histologically, PGES duration did not correlate with 5HT1A or 5HT2A expression in hippocampal CA4, dentate gyrus, or temporal cortex. RNAseq identified two serotonin receptors with expression that correlated with PGES duration in an exploratory analysis: HTR3B negatively correlated (p = .043, R2  = .26) and HTR4 positively correlated (p = .049, R2  = .25). WGCNA identified four modules correlated with PGES duration, including positive correlation with synaptic transcripts (p = .040, Pearson correlation r = .52), particularly potassium channels (KCNA4, KCNC4, KCNH1, KCNIP4, KCNJ3, KCNJ6, KCNK1). No modules were associated with serotonin receptor signaling. SIGNIFICANCE: Higher hippocampal 5HT2A receptor protein and potassium channel transcripts may reflect underlying mechanisms contributing to or resulting from prolonged PGES. Future studies with larger cohorts should assess functional analyses and additional brain regions to elucidate mechanisms underlying PGES and SUDEP risk.

Seizure-mediated iron accumulation and dysregulated iron metabolism after status epilepticus and in temporal lobe epilepsy.

Neuronal dysfunction due to iron accumulation in conjunction with reactive oxygen species (ROS) could represent an important, yet underappreciated, component of the epileptogenic process. However, to date, alterations in iron metabolism in the epileptogenic brain have not been addressed in detail. Iron-related neuropathology and antioxidant metabolic processes were investigated in resected brain tissue from patients with temporal lobe epilepsy and hippocampal sclerosis (TLE-HS), post-mortem brain tissue from patients who died after status epilepticus (SE) as well as brain tissue from the electrically induced SE rat model of TLE. Magnetic susceptibility of the presumed seizure-onset zone from three patients with focal epilepsy was compared during and after seizure activity. Finally, the cellular effects of iron overload were studied in vitro using an acute mouse hippocampal slice preparation and cultured human fetal astrocytes. While iron-accumulating neurons had a pyknotic morphology, astrocytes appeared to acquire iron-sequestrating capacity as indicated by prominent ferritin expression and iron retention in the hippocampus of patients with SE or TLE. Interictal to postictal comparison revealed increased magnetic susceptibility in the seizure-onset zone of epilepsy patients. Post-SE rats had consistently higher hippocampal iron levels during the acute and chronic phase (when spontaneous recurrent seizures are evident). In vitro, in acute slices that were exposed to iron, neurons readily took up iron, which was exacerbated by induced epileptiform activity. Human astrocyte cultures challenged with iron and ROS increased their antioxidant and iron-binding capacity, but simultaneously developed a pro-inflammatory phenotype upon chronic exposure. These data suggest that seizure-mediated, chronic neuronal iron uptake might play a role in neuronal dysfunction/loss in TLE-HS. On the other hand, astrocytes sequester iron, specifically in chronic epilepsy. This function might transform astrocytes into a highly resistant, pro-inflammatory phenotype potentially contributing to pro-epileptogenic inflammatory processes.

microRNA-132 is overexpressed in glia in temporal lobe epilepsy and reduces the expression of pro-epileptogenic factors in human cultured astrocytes.

Temporal lobe epilepsy (TLE) is a chronic neurological disease in humans, which is refractory to pharmacological treatment in about 30% of the patients. Reactive glial cells are thought to play a major role during the development of epilepsy (epileptogenesis) via regulation of brain inflammation and remodeling of the extracellular matrix (ECM). These processes can be regulated by microRNAs (miRs), a class of small non-coding RNAs, which can control entire gene networks at a post-transcriptional level. The expression of miRs is known to change dynamically during epileptogenesis. miR-132 is one of the most commonly upregulated miRs in animal TLE models with important roles shown in neurons. However, the possible role of miR-132 in glia remains largely unknown. The aim of this study was to characterize the cell-type specific expression of miR-132 in the hippocampus of patients with TLE and during epileptogenesis in a rat TLE model. Furthermore, the potential role of miR-132 was investigated by transfection of human primary cultured astrocytes that were stimulated with the cytokines IL-1ß or TGF-ß1. We showed an increased expression of miR-132 in the human and rat epileptogenic hippocampus, particularly in glial cells. Transfection of miR-132 in human primary astrocytes reduced the expression of pro-epileptogenic COX-2, IL-1ß, TGF-ß2, CCL2, and MMP3. This suggests that miR-132, particularly in astrocytes, represents a potential therapeutic target that warrants further in vivo investigation.

Coding and non-coding transcriptome of mesial temporal lobe epilepsy: Critical role of small non-coding RNAs.

Our understanding of mesial temporal lobe epilepsy (MTLE), one of the most common form of drug-resistant epilepsy in humans, is derived mainly from clinical, imaging, and physiological data from humans and animal models. High-throughput gene expression studies of human MTLE have the potential to uncover molecular changes underlying disease pathogenesis along with novel therapeutic targets. Using RNA- and small RNA-sequencing in parrallel, we explored differentially expressed genes in the hippocampus and cortex of MTLE patients who had undergone surgical resection and non-epileptic controls. We identified differentially expressed genes in the hippocampus of MTLE patients and differentially expressed small RNAs across both the cortex and hippocampus. We found significant enrichment for astrocytic and microglial genes among up-regulated genes, and down regulation of neuron specific genes in the hippocampus of MTLE patients. The transcriptome profile of the small RNAs reflected disease state more robustly than mRNAs, even across brain regions which show very little pathology. While mRNAs segregated predominately by brain region for MTLE and controls, small RNAs segregated by disease state. In particular, our data suggest that specific miRNAs (e.g., let-7b-3p and let-7c-3p) may be key regulators of multiple pathways related to MTLE pathology. Further, we report a strong association of other small RNA species with MTLE pathology. As such we have uncovered novel elements that may contribute to the establishment and progression of MTLE pathogenesis and that could be leveraged as therapeutic targets.

Polymethyl Methacrylate in Patient-Specific Implants: Description of a New Three-Dimension Technique.

Polymethyl methacrylate (PMMA), an easily moldable and economical synthetic resin, has been used since the 1940s. In addition, PMMA has good mechanical properties and is one of the most biocompatible alloplastic materials currently available. The PMMA can serve as a spacer and as a delivery vehicle for antibiotics. Prior studies have indicated that no significant differences in infection rates exist between autologous and acrylic cranioplasty. Although inexpensive, the free-hand cranioplasty technique often yields unsatisfactory cosmetic results. In the present study, the application of a recently developed, economic modality for the perioperative application, and molding of PMMA to ensure a precise fit in 16 patients using computer-aided design, computer-aided manufacturing, and rapid prototyping was described.The mean defect size was 102.0 ±â€Š26.4 cm. The mean volume of PMMA required to perform the cranioplasty procedure was 51 mL. The cost of PMMA was approximately 6 Euro (&OV0556;) per mL. The costs of fabricating the implants varied from 119.8 &OV0556; to 1632.0 &OV0556; with a mean of 326.4 &OV0556; ±â€Š371.6. None of the implants required removal during the follow-up period.

Increased expression of matrix metalloproteinase 3 can be attenuated by inhibition of microRNA-155 in cultured human astrocytes.

BACKGROUND: Temporal lobe epilepsy (TLE) is a chronic neurological disease, in which about 30% of patients cannot be treated adequately with anti-epileptic drugs. Brain inflammation and remodeling of the extracellular matrix (ECM) seem to play a major role in TLE. Matrix metalloproteinases (MMPs) are proteolytic enzymes largely responsible for the remodeling of the ECM. The inhibition of MMPs has been suggested as a novel therapy for epilepsy; however, available MMP inhibitors lack specificity and cause serious side effects. We studied whether MMPs could be modulated via microRNAs (miRNAs). Several miRNAs mediate inflammatory responses in the brain, which are known to control MMP expression. The aim of this study was to investigate whether an increased expression of MMPs after interleukin-1ß (IL-1ß) stimulation can be attenuated by inhibition of the inflammation-associated miR-155. METHODS: We investigated the expression of MMP2, MMP3, MMP9, and MMP14 in cultured human fetal astrocytes after stimulation with the pro-inflammatory cytokine IL-1ß. The cells were transfected with miR-155 antagomiR, and the effect on MMP3 expression was investigated using real-time quantitative PCR and Western blotting. Furthermore, we characterized MMP3 and miR-155 expression in brain tissue of TLE patients with hippocampal sclerosis (TLE-HS) and during epileptogenesis in a rat TLE model. RESULTS: Inhibition of miR-155 by the antagomiR attenuated MMP3 overexpression after IL-1ß stimulation in astrocytes. Increased expression of MMP3 and miR-155 was also evident in the hippocampus of TLE-HS patients and throughout epileptogenesis in the rat TLE model. CONCLUSIONS: Our experiments showed that MMP3 is dynamically regulated by seizures as shown by increased expression in TLE tissue and during different phases of epileptogenesis in the rat TLE model. MMP3 can be induced by the pro-inflammatory cytokine IL-1ß and is regulated by miR-155, suggesting a possible strategy to prevent epilepsy via reduction of inflammation.

Activation of the innate immune system is evident throughout epileptogenesis and is associated with blood-brain barrier dysfunction and seizure progression.

OBJECTIVE: Because brain inflammation may contribute to the pathophysiology of temporal lobe epilepsy (TLE), we investigated the expression of various inflammatory markers of the innate and adaptive immune system in the epileptogenic human and rat hippocampus in relation to seizure activity and blood-brain barrier (BBB) dysfunction. METHODS: Immunohistochemistry was performed using various immune cell markers (for microglia, monocytes, macrophages, T lymphocytes, and dendritic cells) on hippocampal sections of drug-resistant TLE patients and patients who died after status epilepticus. The expression of these markers was also studied in the electrical post-status epilepticus rat model for TLE, during the acute, latent, and chronic epileptic phase. BBB dysfunction was assessed using albumin immunohistochemistry and the BBB tracer fluorescein. RESULTS: Monocyte infiltration, microglia, and perivascular macrophage activation were persistently increased in both epileptogenic human and rat hippocampus, whereas T lymphocytes and dendritic cells were not or were scarcely detected. In addition to this, increased expression of C-C motif ligand 2 (CCL2) and osteopontin was observed. In humans, the expression of CD68 and CCL2 was related to the duration of epilepsy and type of pathology. In rats, the expression of CD68, CCL2, and the perivascular macrophage marker CD163 was related to the duration of the initial insult and to the number of spontaneous seizures. Interestingly, the number of CD163-positive perivascular macrophages was also positively correlated to BBB dysfunction in chronic epileptic rats. SIGNIFICANCE: These data suggest a proepileptogenic role for monocytes/macrophages and other cells of the innate immune response, possibly via increased BBB leakage, and indicate that T cells and dendritic cells, which are closely associated with the adaptive immune response, are only sparsely infiltrated during epileptogenesis in the electrical post-status epilepticus rat model. Future studies should reveal the relative importance of these immune cells and whether specific manipulation can modify or prevent epileptogenesis.

Identifying the epileptogenic zone in interictal resting-state MEG source-space networks.

OBJECTIVE: In one third of patients, seizures remain after epilepsy surgery, meaning that improved preoperative evaluation methods are needed to identify the epileptogenic zone. A potential framework for such a method is network theory, as it can be applied to noninvasive recordings, even in the absence of epileptiform activity. Our aim was to identify the epileptogenic zone on the basis of hub status of local brain areas in interictal magnetoencephalography (MEG) networks. METHODS: Preoperative eyes-closed resting-state MEG recordings were retrospectively analyzed in 22 patients with refractory epilepsy, of whom 14 were seizure-free 1 year after surgery. Beamformer-based time series were reconstructed for 90 cortical and subcortical automated anatomic labeling (AAL) regions of interest (ROIs). Broadband functional connectivity was estimated using the phase lag index in artifact-free epochs without interictal epileptiform abnormalities. A minimum spanning tree was generated to represent the network, and the hub status of each ROI was calculated using betweenness centrality, which indicates the centrality of a node in a network. The correspondence of resection cavity to hub values was evaluated on four levels: resection cavity, lobar, hemisphere, and temporal versus extratemporal areas. RESULTS: Hubs were localized within the resection cavity in 8 of 14 seizure-free patients and in zero of 8 patients who were not seizure-free (57% sensitivity, 100% specificity, 73% accuracy). Hubs were localized in the lobe of resection in 9 of 14 seizure-free patients and in zero of 8 patients who were not seizure-free (64% sensitivity, 100% specificity, 77% accuracy). For the other two levels, the true negatives are unknown; hence, only sensitivity could be determined: hubs coincided with both the resection hemisphere and the resection location (temporal versus extratemporal) in 11 of 14 seizure-free patients (79% sensitivity). SIGNIFICANCE: Identifying hubs noninvasively before surgery is a valuable approach with the potential of indicating the epileptogenic zone in patients without interictal abnormalities.

Differentiation of edema and glioma infiltration: proposal of a DTI-based probability map.

Conflicting results on differentiating edema and glioma by diffusion tensor imaging (DTI) are possibly attributable to dissimilar spatial distribution of the lesions. Combining DTI-parameters and enhanced registration might improve prediction. Regions of edema surrounding 22 metastases were compared to tumor-infiltrated regions from WHO grade 2 (12), 3 (10) and 4 (18) gliomas. DTI data was co-registered using Tract Based Spatial Statistics (TBSS), to measure Fractional Anisotropy (FA) and Mean Diffusivity (MD) for white matter only, and relative changes compared to matching reference regions (dFA and dMD). A two-factor principal component analysis (PCA) on metastasis and grade 2 glioma was performed to explore a possible differentiating combined factor. Edema demonstrated equal MD and higher FA compared to grade 2 and 3 glioma (P < 0.001), but did not differ from glioblastoma. Differences were non-significant when corrected for spatial distribution, since reference regions differed strongly (P < 0.001). The second component of the PCA (PCA-C2) did differentiate edema and low-grade tumor (sensitivity 91.7%, specificity 86.4%). PCA-C2 scores were plotted voxel-wise as a probability-map, discerning distinct areas of presumed edema or tumor infiltration. Correction of spatial dependency appears essential when differentiating glioma from edema. A tumor-infiltration probability-map is presented, based on supplementary information of multiple DTI parameters and spatial normalization.

Individualized epidemic spreading models predict epilepsy surgery outcomes: A pseudo-prospective study.

Epilepsy surgery is the treatment of choice for drug-resistant epilepsy patients, but up to 50% of patients continue to have seizures one year after the resection. In order to aid presurgical planning and predict postsurgical outcome on a patient-by-patient basis, we developed a framework of individualized computational models that combines epidemic spreading with patient-specific connectivity and epileptogeneity maps: the Epidemic Spreading Seizure and Epilepsy Surgery framework (ESSES). ESSES parameters were fitted in a retrospective study (N = 15) to reproduce invasive electroencephalography (iEEG)-recorded seizures. ESSES reproduced the iEEG-recorded seizures, and significantly better so for patients with good (seizure-free, SF) than bad (nonseizure-free, NSF) outcome. We illustrate here the clinical applicability of ESSES with a pseudo-prospective study (N = 34) with a blind setting (to the resection strategy and surgical outcome) that emulated presurgical conditions. By setting the model parameters in the retrospective study, ESSES could be applied also to patients without iEEG data. ESSES could predict the chances of good outcome after any resection by finding patient-specific model-based optimal resection strategies, which we found to be smaller for SF than NSF patients, suggesting an intrinsic difference in the network organization or presurgical evaluation results of NSF patients. The actual surgical plan overlapped more with the model-based optimal resection, and had a larger effect in decreasing modeled seizure propagation, for SF patients than for NSF patients. Overall, ESSES could correctly predict 75% of NSF and 80.8% of SF cases pseudo-prospectively. Our results show that individualised computational models may inform surgical planning by suggesting alternative resections and providing information on the likelihood of a good outcome after a proposed resection. This is the first time that such a model is validated with a fully independent cohort and without the need for iEEG recordings.

Individualized computational models of epilepsy surgery capture some of the key aspects of seizure propagation and the resective surgery. It is to be established whether this information can be integrated during the presurgical evaluation of the patient to improve surgical planning and the chances of a good surgical outcome. Here we address this question with a pseudo-prospective study that applies a computational framework of seizure propagation and epilepsy surgery­the ESSES framework­in a pseudo-prospective study mimicking the presurgical conditions. We found that within this pseudo-prospective setting, ESSES could correctly predict 75% of NSF and 80.8% of SF cases. This finding suggests the potential of individualised computational models to inform surgical planning by suggesting alternative resections and providing information on the likelihood of a good outcome after a proposed resection.

Morpho-electric diversity of human hippocampal CA1 pyramidal neurons.

Hippocampal pyramidal neuron activity underlies episodic memory and spatial navigation. Although extensively studied in rodents, extremely little is known about human hippocampal pyramidal neurons, even though the human hippocampus underwent strong evolutionary reorganization and shows lower theta rhythm frequencies. To test whether biophysical properties of human Cornu Amonis subfield 1 (CA1) pyramidal neurons can explain observed rhythms, we map the morpho-electric properties of individual CA1 pyramidal neurons in human, non-pathological hippocampal slices from neurosurgery. Human CA1 pyramidal neurons have much larger dendritic trees than mouse CA1 pyramidal neurons, have a large number of oblique dendrites, and resonate at 2.9 Hz, optimally tuned to human theta frequencies. Morphological and biophysical properties suggest cellular diversity along a multidimensional gradient rather than discrete clustering. Across the population, dendritic architecture and a large number of oblique dendrites consistently boost memory capacity in human CA1 pyramidal neurons by an order of magnitude compared to mouse CA1 pyramidal neurons.

Therapeutic concentrations of anti-epileptic drugs do not inhibit the activity of the oncolytic adenovirus Delta24-RGD in malignant glioma.

BACKGROUND: The oncolytic adenovirus Delta24-RGD is currently being tested in phase I trials for the treatment of glioblastoma (GBM). Literature suggests that frequently prescribed anticonvulsants for these patients, phenytoin (PHE), valproic acid (VPA) and levetiracetam (LEV), may interfere with cellular mechanisms of cancer or oncolytic virus activity. We therefore investigated the direct effects of these drugs on Delta24-RGD infection and oncolytic activity. METHODS: The anticonvulsants PHE, VPA, and LEV were combined with Delta24-RGD treatment in established glioma cell lines as well as on a panel of patient-derived GBM cultures. Effects on infection efficiency were assessed using luciferase-encoding adenoviral vectors. Oncolytic activity was determined by WST-1 assay and viral progeny production was quantified by dilution titration. RESULTS: IC50 values of the anti-epileptic drugs on the four glioma cell lines were far above clinically-relevant concentrations. At therapeutic concentrations, the anti-epileptics generally did not alter the infection efficiency of RGD-modified adenovirus, nor affect progeny production or oncolytic activity of Delta24-RGD. The only exception was found in U373 cells, where VPA slightly antagonised the oncolytic effect of Delta24-RGD (from 29% to 55% viability, p<0.01) as well as viral progeny production (60% decrease, p<0.01). Oncolysis by Delta24-RGD was not inhibited by the anti-epileptics in any of the patient-derived glioma cultures (n=6). In fact, in one culture a slight enhancement of viral oncolysis by PHE and LEV was found, from 89.7% viability to 76% and 62.4%, respectively (p<0.01) CONCLUSIONS: Therapeutic levels of valproic acid, phenytoin and levetiracetam do not negatively interfere with the infection efficiency or oncolytic activity of Delta24-RGD in patient-derived GBM cells. Therefore, there is no indication that the choice of anticonvulsant for seizure control in glioma patients should take treatment with Delta24-RGD into account.

The role of epidemic spreading in seizure dynamics and epilepsy surgery.

Epilepsy surgery is the treatment of choice for drug-resistant epilepsy patients, but only leads to seizure freedom for roughly two in three patients. To address this problem, we designed a patient-specific epilepsy surgery model combining large-scale magnetoencephalography (MEG) brain networks with an epidemic spreading model. This simple model was enough to reproduce the stereo-tactical electroencephalography (SEEG) seizure propagation patterns of all patients (N = 15), when considering the resection areas (RA) as the epidemic seed. Moreover, the goodness of fit of the model predicted surgical outcome. Once adapted for each patient, the model can generate alternative hypothesis of the seizure onset zone and test different resection strategies in silico. Overall, our findings indicate that spreading models based on patient-specific MEG connectivity can be used to predict surgical outcomes, with better fit results and greater reduction on seizure propagation linked to higher likelihood of seizure freedom after surgery. Finally, we introduced a population model that can be individualized by considering only the patient-specific MEG network, and showed that it not only conserves but improves the group classification. Thus, it may pave the way to generalize this framework to patients without SEEG recordings, reduce the risk of overfitting and improve the stability of the analyses.

Resective Epilepsy Surgery, QUality of life and Economic evaluation (RESQUE): the change in quality of life after resective epilepsy surgery-protocol for a multicentre, prospective cohort study.

INTRODUCTION: Resective epilepsy surgery is often seen as a last resort when treating drug-resistant epilepsy. Positive results on quality of life (QoL) and economic benefits after surgery argue for a less restrictive attitude towards epilepsy surgery for drug-resistant epilepsy. QoL and economic benefits are country-dependent. The objective of the Resective Epilepsy Surgery, QUality of life and Economic evaluation (RESQUE) trial is to evaluate the change in QoL before and after epilepsy surgery in Dutch people with drug-resistant epilepsy. The results will form part of an economic evaluation of epilepsy surgery in people with epilepsy (PWE) in The Netherlands. METHODS AND ANALYSIS: A longitudinal prospective multicentre cohort study involving 100 PWE undergoing epilepsy surgery between 2019 and 2025 is being performed in three Dutch academic hospitals. Excluded are PWE who have a lower level of intelligence (TIQ<70) or who do not master the Dutch language. Before surgery and 3, 6, 12 and 24 months after surgery, PWE receive validated online questionnaires (QOLIE-31, EQ-5D, iMCQ and iPCQ) on QoL, cost of care, expectations and satisfaction. Primary outcome is the change in QoL. Secondary outcomes are change in generic QoL, seizure reduction (International League Against Epilepsy Outcome Classification), medical consumption, productivity, the correlation between QoL and seizure reduction and expectation of and satisfaction with the surgery. ETHICS AND DISSEMINATION: The study design has been approved by the Medical Ethics Review Committee (METC) of Maastricht UMC+ (2019-1134) and the Amsterdam UMC (vu). At the time of writing, UMC Utrecht is in the process of considering approval. The study will be conducted according to the Dutch Medical Research Involving Human Subjects Act and the Declaration of Helsinki. The results will be publicly disclosed and submitted for publication in international peer-reviewed scientific journals. There is no veto on publication by the involved parties. TRIAL REGISTRATION: NL8278; Pre-results.

Genes associated with cognitive ability and HAR show overlapping expression patterns in human cortical neuron types.

GWAS have identified numerous genes associated with human cognition but their cell type expression profiles in the human brain are unknown. These genes overlap with human accelerated regions (HARs) implicated in human brain evolution and might act on the same biological processes. Here, we investigated whether these gene sets are expressed in adult human cortical neurons, and how their expression relates to neuronal function and structure. We find that these gene sets are preferentially expressed in L3 pyramidal neurons in middle temporal gyrus (MTG). Furthermore, neurons with higher expression had larger total dendritic length (TDL) and faster action potential (AP) kinetics, properties previously linked to intelligence. We identify a subset of genes associated with TDL or AP kinetics with predominantly synaptic functions and high abundance of HARs.

Human voltage-gated Na+ and K+ channel properties underlie sustained fast AP signaling.

Human cortical pyramidal neurons are large, have extensive dendritic trees, and yet have unexpectedly fast input-output properties: Rapid subthreshold synaptic membrane potential changes are reliably encoded in timing of action potentials (APs). Here, we tested whether biophysical properties of voltage-gated sodium (Na+) and potassium (K+) currents in human pyramidal neurons can explain their fast input-output properties. Human Na+ and K+ currents exhibited more depolarized voltage dependence, slower inactivation, and faster recovery from inactivation compared with their mouse counterparts. Computational modeling showed that despite lower Na+ channel densities in human neurons, the biophysical properties of Na+ channels resulted in higher channel availability and contributed to fast AP kinetics stability. Last, human Na+ channel properties also resulted in a larger dynamic range for encoding of subthreshold membrane potential changes. Thus, biophysical adaptations of voltage-gated Na+ and K+ channels enable fast input-output properties of large human pyramidal neurons.

Structural and functional specializations of human fast-spiking neurons support fast cortical signaling.

Fast-spiking interneurons (FSINs) provide fast inhibition that synchronizes neuronal activity and is critical for cognitive function. Fast synchronization frequencies are evolutionary conserved in the expanded human neocortex despite larger neuron-to-neuron distances that challenge fast input-output transfer functions of FSINs. Here, we test in human neurons from neurosurgery tissue, which mechanistic specializations of human FSINs explain their fast-signaling properties in human cortex. With morphological reconstructions, multipatch recordings, and biophysical modeling, we find that despite threefold longer dendritic path, human FSINs maintain fast inhibition between connected pyramidal neurons through several mechanisms: stronger synapse strength of excitatory inputs, larger dendrite diameter with reduced complexity, faster AP initiation, and faster and larger inhibitory output, while Na+ current activation/inactivation properties are similar. These adaptations underlie short input-output delays in fast inhibition of human pyramidal neurons through FSINs, explaining how cortical synchronization frequencies are conserved despite expanded and sparse network topology of human cortex.

Epidemic models characterize seizure propagation and the effects of epilepsy surgery in individualized brain networks based on MEG and invasive EEG recordings.

Epilepsy surgery is the treatment of choice for drug-resistant epilepsy patients. However, seizure-freedom is currently achieved in only 2/3 of the patients after surgery. In this study we have developed an individualized computational model based on MEG brain networks to explore seizure propagation and the efficacy of different virtual resections. Eventually, the goal is to obtain individualized models to optimize resection strategy and outcome. We have modelled seizure propagation as an epidemic process using the susceptible-infected (SI) model on individual brain networks derived from presurgical MEG. We included 10 patients who had received epilepsy surgery and for whom the surgery outcome at least one year after surgery was known. The model parameters were tuned in in order to reproduce the patient-specific seizure propagation patterns as recorded with invasive EEG. We defined a personalized search algorithm that combined structural and dynamical information to find resections that maximally decreased seizure propagation for a given resection size. The optimal resection for each patient was defined as the smallest resection leading to at least a 90% reduction in seizure propagation. The individualized model reproduced the basic aspects of seizure propagation for 9 out of 10 patients when using the resection area as the origin of epidemic spreading, and for 10 out of 10 patients with an alternative definition of the seed region. We found that, for 7 patients, the optimal resection was smaller than the resection area, and for 4 patients we also found that a resection smaller than the resection area could lead to a 100% decrease in propagation. Moreover, for two cases these alternative resections included nodes outside the resection area. Epidemic spreading models fitted with patient specific data can capture the fundamental aspects of clinically observed seizure propagation, and can be used to test virtual resections in silico. Combined with optimization algorithms, smaller or alternative resection strategies, that are individually targeted for each patient, can be determined with the ultimate goal to improve surgery outcome. MEG-based networks can provide a good approximation of structural connectivity for computational models of seizure propagation, and facilitate their clinical use.