Parallel and distributed encoding of speech across human auditory cortex.

Speech perception is thought to rely on a cortical feedforward serial transformation of acoustic into linguistic representations. Using intracranial recordings across the entire human auditory cortex, electrocortical stimulation, and surgical ablation, we show that cortical processing across areas is not consistent with a serial hierarchical organization. Instead, response latency and receptive field analyses demonstrate parallel and distinct information processing in the primary and nonprimary auditory cortices. This functional dissociation was also observed where stimulation of the primary auditory cortex evokes auditory hallucination but does not distort or interfere with speech perception. Opposite effects were observed during stimulation of nonprimary cortex in superior temporal gyrus. Ablation of the primary auditory cortex does not affect speech perception. These results establish a distributed functional organization of parallel information processing throughout the human auditory cortex and demonstrate an essential independent role for nonprimary auditory cortex in speech processing.

Regional variability in intracerebral properties of NREM to REM sleep transitions in humans.

Transitions between wake and sleep states show a progressive pattern underpinned by local sleep regulation. In contrast, little evidence is available on non-rapid eye movement (NREM) to rapid eye movement (REM) sleep boundaries, considered as mainly reflecting subcortical regulation. Using polysomnography (PSG) combined with stereoelectroencephalography (SEEG) in humans undergoing epilepsy presurgical evaluation, we explored the dynamics of NREM-to-REM transitions. PSG was used to visually score transitions and identify REM sleep features. SEEG-based local transitions were determined automatically with a machine learning algorithm using features validated for automatic intra-cranial sleep scoring (10.5281/zenodo.7410501). We analyzed 2988 channel-transitions from 29 patients. The average transition time from all intracerebral channels to the first visually marked REM sleep epoch was 8 s ± 1 min 58 s, with a great heterogeneity between brain areas. Transitions were observed first in the lateral occipital cortex, preceding scalp transition by 1 min 57 s ± 2 min 14 s (d = -0.83), and close to the first sawtooth wave marker. Regions with late transitions were the inferior frontal and orbital gyri (1 min 1 s ± 2 min 1 s, d = 0.43, and 1 min 1 s ± 2 min 5 s, d = 0.43, after scalp transition). Intracranial transitions were earlier than scalp transitions as the night advanced (last sleep cycle, d = -0.81). We show a reproducible gradual pattern of REM sleep initiation, suggesting the involvement of cortical mechanisms of regulation. This provides clues for understanding oneiric experiences occurring at the NREM/REM boundary.

MerTK is a mediator of alpha-synuclein fibril uptake by human microglia.

Mer tyrosine kinase (MerTK) is a receptor tyrosine kinase that mediates non-inflammatory, homeostatic phagocytosis of diverse types of cellular debris. Highly expressed on the surface of microglial cells, MerTK is of importance in brain development, homeostasis, plasticity and disease. Yet, involvement of this receptor in the clearance of protein aggregates that accumulate with ageing and in neurodegenerative diseases has yet to be defined. The current study explored the function of MerTK in the microglial uptake of alpha-synuclein fibrils which play a causative role in the pathobiology of synucleinopathies. Using human primary and induced pluripotent stem cell-derived microglia, the MerTK-dependence of alpha-synuclein fibril internalization was investigated in vitro. Relevance of this pathway in synucleinopathies was assessed through burden analysis of MERTK variants and analysis of MerTK expression in patient-derived cells and tissues. Pharmacological inhibition of MerTK and siRNA-mediated MERTK knockdown both caused a decreased rate of alpha-synuclein fibril internalization by human microglia. Consistent with the non-inflammatory nature of MerTK-mediated phagocytosis, alpha-synuclein fibril internalization was not observed to induce secretion of pro-inflammatory cytokines such as IL-6 or TNF, and downmodulated IL-1ß secretion from microglia. Burden analysis in two independent patient cohorts revealed a significant association between rare functionally deleterious MERTK variants and Parkinson's disease in one of the cohorts (P = 0.002). Despite a small upregulation in MERTK mRNA expression in nigral microglia from Parkinson's disease/Lewy body dementia patients compared to those from non-neurological control donors in a single-nuclei RNA-sequencing dataset (P = 5.08 × 10-21), no significant upregulation in MerTK protein expression was observed in human cortex and substantia nigra lysates from Lewy body dementia patients compared to controls. Taken together, our findings define a novel role for MerTK in mediating the uptake of alpha-synuclein fibrils by human microglia, with possible involvement in limiting alpha-synuclein spread in synucleinopathies such as Parkinson's disease. Upregulation of this pathway in synucleinopathies could have therapeutic values in enhancing alpha-synuclein fibril clearance in the brain.

Ionophores.

Ionophores are a class of polyether antibiotics that are commonly used as anticoccidial agents and growth promotants in ruminant diets. Ionophores transport ions across lipid membranes and down concentration gradients, which results in mitochondrial destruction, reduced cellular energy production, and ultimately cell death. Cardiomyocytes are the primary target in equine patients when exposed to toxic concentrations and the clinical disease syndrome is related to myocardial damage. Animals can survive acute exposures but can have permanent heart damage that may result in acute death at future time points. Animals that survive a poisoning incident may live productive breeding lives, but physical performance can be greatly impacted. Animals with myocardial damage are at risk of sudden death and pose a risk to riders.

Systematic comparison of culture media uncovers phenotypic shift of primary human microglia defined by reduced reliance to CSF1R signaling.

Efforts to understand microglia function in health and diseases have been hindered by the lack of culture models that recapitulate in situ cellular properties. In recent years, the use of serum-free media with brain-derived growth factors (colony stimulating factor 1 receptor [CSF1R] ligands and TGF-ß1/2) have been favored for the maintenance of rodent microglia as they promote morphological features observed in situ. Here we study the functional and transcriptomic impacts of such media on human microglia (hMGL). Media formulation had little impact on microglia transcriptome assessed by RNA sequencing which was sufficient to significantly alter microglia capacity to phagocytose myelin debris and to elicit an inflammatory response to lipopolysaccharide. When compared to immediately ex vivo microglia from the same donors, the addition of fetal bovine serum to culture media, but not growth factors, was found to aid in the maintenance of key signature genes including those involved in phagocytic processes. A phenotypic shift characterized by CSF1R downregulation in culture correlated with a lack of reliance on CSF1R signaling for survival. Consequently, no improvement in cell survival was observed following culture supplementation with CSF1R ligands. Our study provides better understanding of hMGL in culture, with observations that diverge from those previously made in rodent microglia.

Analysis of the microglia transcriptome across the human lifespan using single cell RNA sequencing.

BACKGROUND: Microglia are tissue resident macrophages with a wide range of critically important functions in central nervous system development and homeostasis. METHOD: In this study, we aimed to characterize the transcriptional landscape of ex vivo human microglia across different developmental ages using cells derived from pre-natal, pediatric, adolescent, and adult brain samples. We further confirmed our transcriptional observations using ELISA and RNAscope. RESULTS: We showed that pre-natal microglia have a distinct transcriptional and regulatory signature relative to their post-natal counterparts that includes an upregulation of phagocytic pathways. We confirmed upregulation of CD36, a positive regulator of phagocytosis, in pre-natal samples compared to adult samples in situ. Moreover, we showed adult microglia have more pro-inflammatory signature compared to microglia from other developmental ages. We indicated that adult microglia are more immune responsive by secreting increased levels of pro-inflammatory cytokines in response to LPS treatment compared to the pre-natal microglia. We further validated in situ up-regulation of IL18 and CXCR4 in human adult brain section compared to the pre-natal brain section. Finally, trajectory analysis indicated that the transcriptional signatures adopted by microglia throughout development are in response to a changing brain microenvironment and do not reflect predetermined developmental states. CONCLUSION: In all, this study provides unique insight into the development of human microglia and a useful reference for understanding microglial contribution to developmental and age-related human disease.

Human Oligodendrocyte Myelination Potential; Relation to Age and Differentiation.

OBJECTIVE: Myelin regeneration in the human central nervous system relies on progenitor cells within the tissue parenchyma, with possible contribution from previously myelinating oligodendrocytes (OLs). In multiple sclerosis, a demyelinating disorder, variables affecting remyelination efficiency include age, severity of initial injury, and progenitor cell properties. Our aim was to investigate the effects of age and differentiation on the myelination potential of human OL lineage cells. METHODS: We derived viable primary OL lineage cells from surgical resections of pediatric and adult brain tissue. Ensheathment capacity using nanofiber assays and transcriptomic profiles from RNA sequencing were compared between A2B5+ antibody-selected progenitors and mature OLs (non-selected cells). RESULTS: We demonstrate that pediatric progenitor and mature cells ensheathed nanofibers more robustly than did adult progenitor and mature cells, respectively. Within both age groups, the percentage of fibers ensheathed and ensheathment length per fiber were greater for A2B5+ progenitors. Gene expression of OL progenitor markers PDGFRA and PTPRZ1 were higher in A2B5+ versus A2B5- cells and in pediatric A2B5+ versus adult A2B5+ cells. The p38 MAP kinases and actin cytoskeleton-associated pathways were upregulated in pediatric cells; both have been shown to regulate OL process outgrowth. Significant upregulation of "cell senescence" genes was detected in pediatric samples; this could reflect their role in development and the increased susceptibility of pediatric OLs to activating cell death responses to stress. INTERPRETATION: Our findings identify specific biological pathways relevant to myelination that are differentially enriched in human pediatric and adult OL lineage cells and suggest potential targets for remyelination enhancing therapies. ANN NEUROL 2022;91:178-191.

Interictal high-frequency oscillations, spikes, and connectivity profiles: A fingerprint of epileptogenic brain pathologies.

OBJECTIVE: Focal cortical dysplasia (FCD), hippocampal sclerosis (HS), nonspecific gliosis (NG), and normal tissue (NT) comprise the majority of histopathological results of surgically treated drug-resistant epilepsy patients. Epileptic spikes, high-frequency oscillations (HFOs), and connectivity measures are valuable biomarkers of epileptogenicity. The question remains whether they could also be utilized for preresective differentiation of the underlying brain pathology. This study explored spikes and HFOs together with functional connectivity in various epileptogenic pathologies. METHODS: Interictal awake stereoelectroencephalographic recordings of 33 patients with focal drug-resistant epilepsy with seizure-free postoperative outcomes were analyzed (15 FCD, 8 HS, 6 NT, and 4 NG). Interictal spikes and HFOs were automatically identified in the channels contained in the overlap of seizure onset zone and resected tissue. Functional connectivity measures (relative entropy, linear correlation, cross-correlation, and phase consistency) were computed for neighboring electrode pairs. RESULTS: Statistically significant differences were found between the individual pathologies in HFO rates, spikes, and their characteristics, together with functional connectivity measures, with the highest values in the case of HS and NG/NT. A model to predict brain pathology based on all interictal measures achieved up to 84.0% prediction accuracy. SIGNIFICANCE: The electrophysiological profile of the various epileptogenic lesions in epilepsy surgery patients was analyzed. Based on this profile, a predictive model was developed. This model offers excellent potential to identify the nature of the underlying lesion prior to resection. If validated, this model may be particularly valuable for counseling patients, as depending on the lesion type, different outcomes are achieved after epilepsy surgery.

A multi-scale cortical wiring space links cellular architecture and functional dynamics in the human brain.

The vast net of fibres within and underneath the cortex is optimised to support the convergence of different levels of brain organisation. Here, we propose a novel coordinate system of the human cortex based on an advanced model of its connectivity. Our approach is inspired by seminal, but so far largely neglected models of cortico-cortical wiring established by postmortem anatomical studies and capitalises on cutting-edge in vivo neuroimaging and machine learning. The new model expands the currently prevailing diffusion magnetic resonance imaging (MRI) tractography approach by incorporation of additional features of cortical microstructure and cortico-cortical proximity. Studying several datasets and different parcellation schemes, we could show that our coordinate system robustly recapitulates established sensory-limbic and anterior-posterior dimensions of brain organisation. A series of validation experiments showed that the new wiring space reflects cortical microcircuit features (including pyramidal neuron depth and glial expression) and allowed for competitive simulations of functional connectivity and dynamics based on resting-state functional magnetic resonance imaging (rs-fMRI) and human intracranial electroencephalography (EEG) coherence. Our results advance our understanding of how cell-specific neurobiological gradients produce a hierarchical cortical wiring scheme that is concordant with increasing functional sophistication of human brain organisation. Our evaluations demonstrate the cortical wiring space bridges across scales of neural organisation and can be easily translated to single individuals.

Regional and age-related diversity of human mature oligodendrocytes.

Morphological and emerging molecular studies have provided evidence for heterogeneity within the oligodendrocyte population. To address the regional and age-related heterogeneity of human mature oligodendrocytes (MOLs) we applied single-cell RNA sequencing to cells isolated from cortical/subcortical, subventricular zone brain tissue samples, and thoracolumbar spinal cord samples. Unsupervised clustering of cells identified transcriptionally distinct MOL subpopulations across regions. Spinal cord MOLs, but not microglia, exhibited cell-type-specific upregulation of immune-related markers compared to the other adult regions. SVZ MOLs showed an upregulation of select number of development-linked transcription factors compared to other regions; however, pseudotime trajectory analyses did not identify a global developmental difference. Age-related analysis of cortical/subcortical samples indicated that pediatric MOLs, especially from under age 5, retain higher expression of genes linked to development and to immune activity with pseudotime analysis favoring a distinct developmental stage. Our regional and age-related studies indicate heterogeneity of MOL populations in the human CNS that may reflect developmental and environmental influences.

Correcting for physiological ripples improves epileptic focus identification and outcome prediction.

OBJECTIVE: The integration of high-frequency oscillations (HFOs; ripples [80-250 Hz], fast ripples [250-500 Hz]) in epilepsy evaluation is hampered by physiological HFOs, which cannot be reliably differentiated from pathological HFOs. We evaluated whether defining abnormal HFO rates by statistical comparison to region-specific physiological HFO rates observed in the healthy brain improves identification of the epileptic focus and surgical outcome prediction. METHODS: We detected HFOs in 151 consecutive patients who underwent stereo-electroencephalography and subsequent resective epilepsy surgery at two tertiary epilepsy centers. We compared how HFOs identified the resection cavity and predicted seizure-free outcome using two thresholds from the literature (HFO rate > 1/min; 50% of the total number of a patient's HFOs) and three thresholds based on normative rates from the Montreal Neurological Institute Open iEEG Atlas (https://mni-open-ieegatlas. RESEARCH: mcgill.ca/): global Atlas threshold, regional Atlas threshold, and regional + 10% threshold after regional Atlas correction. RESULTS: Using ripples, the regional + 10% threshold performed best for focus identification (77.3% accuracy, 27% sensitivity, 97.1% specificity, 80.6% positive predictive value [PPV], 78.2% negative predictive value [NPV]) and outcome prediction (69.5% accuracy, 58.6% sensitivity, 76.3% specificity, 60.7% PPV, 74.7% NPV). This was an improvement for focus identification (+1.1% accuracy, +17.0% PPV; p < .001) and outcome prediction (+12.0% sensitivity, +1.0% PPV; p = .05) compared to the 50% threshold. The improvement was particularly marked for foci in cortex, where physiological ripples are frequent (outcome: +35.3% sensitivity, +5.3% PPV; p = .014). In these cases, the regional + 10% threshold outperformed fast ripple rate > 1/min (+3.6% accuracy, +26.5% sensitivity, +21.6% PPV; p < .001) and seizure onset zone (+13.5% accuracy, +29.4% sensitivity, +17.0% PPV; p < .05-.01) for outcome prediction. Normalization did not improve the performance of fast ripples. SIGNIFICANCE: Defining abnormal HFO rates by statistical comparison to rates in healthy tissue overcomes an important weakness in the clinical use of ripples. It improves focus identification and outcome prediction compared to standard HFO measures, increasing their clinical applicability.

The Changing Nature of Epilepsy Surgery: A Retrospective Review of Practice Profiles.

OBJECTIVES: Recent literature documents a trend of gradual decline in temporal lobe (resective) epilepsy surgery over the past decade. Amongst these, a large scale, comprehensive survey done in selected European, Australian and American centres documents trends of resective temporal epilepsy surgery across two decades. Montreal Neurological Institute has been the leading epilepsy surgery centre for more than 50 years now. It has been at the forefront of investigating and managing epilepsy in Canada. We have looked into the trends of epilepsy surgery in our institute in the past 44 years. METHODS: The records of all adult epilepsy surgery procedures (excluding reoperations) performed by the senior authors were analysed from 1971 to 2015. Data retrieved for analysis included type of surgery (intracranial recording, resective, and neuromodulatory) and the specific surgical target for resection. Procedures were grouped into temporal resective, extratemporal (ET) resective and placement of intracranial electrodes (stereotactic electroencephalogram (SEEG)). RESULTS: A total of 2,078 new procedures were performed from 1971 to 2015 at the Montreal Neurological Institute. Temporal procedures constituted the bulk of the proportion of all procedures each year and the entire study period. SEEG group shows linear increase in the number of cases over the years catching up with the total number of temporal procedures. CONCLUSIONS: Our study involving a homogenous dataset spanning nearly 50 years shows a decline in temporal lobe surgeries and an increase in intracranial investigations despite the class I evidence of its effectiveness. This corroborates the trends in epilepsy surgery practice profiles in tertiary centres of developed countries.

Patient specific prediction of temporal lobe epilepsy surgical outcomes.

OBJECTIVE: Drug-resistant temporal lobe epilepsy (TLE) is the most common type of epilepsy for which patients undergo surgery. Despite the best clinical judgment and currently available prediction algorithms, surgical outcomes remain variable. We aimed to build and to evaluate the performance of multidimensional Bayesian network classifiers (MBCs), a type of probabilistic graphical model, at predicting probability of seizure freedom after TLE surgery. METHODS: Clinical, neurophysiological, and imaging variables were collected from 231 TLE patients who underwent surgery at the University of California, San Francisco (UCSF) or the Montreal Neurological Institute (MNI) over a 15-year period. Postsurgical Engel outcomes at year 1 (Y1), Y2, and Y5 were analyzed as primary end points. We trained an MBC model on combined data sets from both institutions. Bootstrap bias corrected cross-validation (BBC-CV) was used to evaluate the performance of the models. RESULTS: The MBC was compared with logistic regression and Cox proportional hazards according to the area under the receiver-operating characteristic curve (AUC). The MBC achieved an AUC of 0.67 at Y1, 0.72 at Y2, and 0.67 at Y5, which indicates modest performance yet superior to what has been reported in the state-of-the-art studies to date. SIGNIFICANCE: The MBC can more precisely encode probabilistic relationships between predictors and class variables (Engel outcomes), achieving promising experimental results compared to other well-known statistical methods. Multisite application of the MBC could further optimize its classification accuracy with prospective data sets. Online access to the MBC is provided, paving the way for its use as an adjunct clinical tool in aiding pre-operative TLE surgical counseling.

In vivo hippocampal cornu ammonis 1-3 glutamatergic abnormalities are associated with temporal lobe epilepsy surgery outcomes.

OBJECTIVE: Previous positron emission tomography (PET) studies using [11 C]ABP688 show reduced metabotropic glutamate receptor type 5 (mGluR5) allosteric binding site availability in the epileptogenic hippocampus of mesial temporal lobe epilepsy (MTLE) patients. However, the link between mGluR5 abnormalities and postsurgical outcomes remains unclear. Here, we test whether reduced PET [11 C]ABP688 binding in cornu ammonis (CA) sectors more vulnerable to glutamatergic excitotoxicity relates to surgical outcomes. METHODS: We obtained magnetic resonance imaging (MRI) and [11 C]ABP688-PET from 31 unilateral MTLE patients and 30 healthy controls. MRI hippocampal subfields were segmented using FreeSurfer. To respect the lower PET special resolution, MRI-derived anatomical subfields were combined into CA1-3, CA4/dentate gyrus, and Subiculum. Partial volume corrected [11 C]ABP688 nondisplaceable binding potential (BPND ) values were averaged across each subfield, and Z-scores were calculated. Subfield [11 C]ABP688-BPND was compared between seizure-free and non-seizure-free patients. In addition, we also assessed subfield volumes and [18 F]fluorodeoxyglucose (FDG) uptake in each clinical group. RESULTS: MTLE [11 C]ABP688-BPND was reduced in ipsilateral (epileptogenic) CA1-3 and CA4/dentate-gyrus (p < .001, 95% confidence interval [CI] = .29-.51) compared to controls, with no difference in Subiculum. [11 C]ABP688-BPND and subfield volumes were compared between seizure-free (Engel IA, n = 13) and non-seizure-free patients (Engel IC-III, n = 10). In ipsilateral CA1-3 only, [11 C]ABP688-BPND was lower in seizure-free patients than in non-seizure-free patients (p = .012, 95% CI = 1.46-11.0) independently of volume. A subset analysis of 12 patients with [11 C]ABP688-PET+[18 F]FDG-PET showed no between-group significant difference in [18 F]FDG uptake, whereas CA1-3 [11 C]ABP688-BPND remained significantly lower in the seven of 12 seizure-free patients (p = .03, 95% CI = -3.13 to -.21). SIGNIFICANCE: Reduced mGluR5 allosteric site availability in hippocampal CA1-3, measured in vivo by [11 C]ABP688-PET, is associated with postsurgery seizure freedom independent of atrophy or hypometabolism. Information derived from hippocampal CA1-3 [11 C]ABP688-PET is a promising imaging biomarker potentially impactful in surgical decisions for MRI-negative/PET-negative MTLE patients.

Radiofrequency Thermocoagulation in Refractory Focal Epilepsy: The Montreal Neurological Institute Experience.

BACKGROUND: Radiofrequency thermocoagulation (RF-TC) is a minimally invasive ablative option for refractory focal epilepsy. METHODS: A retrospective chart review was conducted of all patients who underwent stereoelectroencephalography (SEEG)-guided RF-TC at our institution. RESULTS: Fourteen patients underwent robot-guided electrode implantation and subsequent RF-TC. After RF-TC, one of the three patients with PVNH was seizure free, one had 18 months of seizure freedom (Engel 2b), and one required temporal neocortical/PVNH resection (Engel 1a). One of the four patients with focal cortical dysplasia (FCD) was seizure free (Engel 1a), two attained seizure freedom after resection (Engel 1a and 1b), while one continues to have significant seizures (Engel 4b). One patient with cavernoma and low central area epileptogenic zone (EZ) did not benefit from RF-TC and is planned for resection. Two of the MRI-negative patients achieved seizure freedom for 3 months and 1 year, respectively, subsequently requiring resection (Engel 1a). One remains seizure free at 4 weeks. Three had seizure recurrence immediately (Engel 4b). With RF-TC alone, two patients (14%) achieved Engel 1a, two were seizure free at 1 year, one had 3 months of seizure freedom, while the rest had recurrence immediately or within a few weeks. 7/14 patients underwent secondary interventions after RF-TC. Overall, seven patients achieved Engel 1a or 1b, one each 2b and 3a, and five Engel 4b. CONCLUSION: At our institution, RF-TC is a safe ablative procedure for refractory focal epilepsy. It can serve as a segue to secondary interventions and appears promising in PVNH cases. Its role in MRI-negative cases is less clear.

Accuracy and spatial properties of distributed magnetic source imaging techniques in the investigation of focal epilepsy patients.

Source localization of interictal epileptiform discharges (IEDs) is clinically useful in the presurgical workup of epilepsy patients. We aimed to compare the performance of four different distributed magnetic source imaging (dMSI) approaches: Minimum norm estimate (MNE), dynamic statistical parametric mapping (dSPM), standardized low-resolution electromagnetic tomography (sLORETA), and coherent maximum entropy on the mean (cMEM). We also evaluated whether a simple average of maps obtained from multiple inverse solutions (Ave) can improve localization accuracy. We analyzed dMSI of 206 IEDs derived from magnetoencephalography recordings in 28 focal epilepsy patients who had a well-defined focus determined through intracranial EEG (iEEG), epileptogenic MRI lesions or surgical resection. dMSI accuracy and spatial properties were quantitatively estimated as: (a) distance from the epilepsy focus, (b) reproducibility, (c) spatial dispersion (SD), (d) map extension, and (e) effect of thresholding on map properties. Clinical performance was excellent for all methods (median distance from the focus MNE = 2.4 mm; sLORETA = 3.5 mm; cMEM = 3.5 mm; dSPM = 6.8 mm, Ave = 0 mm). Ave showed the lowest distance between the map maximum and epilepsy focus (Dmin lower than cMEM, MNE, and dSPM, p = .021, p = .008, p < .001, respectively). cMEM showed the best spatial features, with lowest SD outside the focus (SD lower than all other methods, p < .001 consistently) and high contrast between the generator and surrounding regions. The average map Ave provided the best localization accuracy, whereas cMEM exhibited the lowest amount of spurious distant activity. dMSI techniques have the potential to significantly improve identification of iEEG targets and to guide surgical planning, especially when multiple methods are combined.

In vivo metabotropic glutamate receptor type 5 abnormalities localize the epileptogenic zone in mesial temporal lobe epilepsy.

OBJECTIVE: Surgical specimens from patients with mesial temporal lobe epilepsy (MTLE) show abnormalities in tissue concentrations of metabotropic glutamate receptor type 5 (mGluR5). To clarify whether these abnormalities are specific to the epileptogenic zone (EZ), we characterized in vivo whole-brain mGluR5 availability in MTLE patients using positron emission tomography (PET) and [11 C]ABP688, a radioligand that binds specifically to the mGluR5 allosteric site. METHODS: Thirty-one unilateral MTLE patients and 30 healthy controls underwent [11 C]ABP688 PET. We compared partial volume corrected [11 C]ABP688 nondisplaceable binding potentials (BPND ) between groups using region-of-interest and whole-brain voxelwise analyses. [18 F]Fluorodeoxyglucose (FDG) PET was acquired in 15 patients, for whom we calculated asymmetry indices of [11 C]ABP688 BPND and [18 F]FDG uptake to compare lateralization and localization differences. RESULTS: [11 C]ABP688 BPND was focally reduced in the epileptogenic hippocampal head and amygdala (p < 0.001). Patients with hippocampal atrophy showed more extensive abnormalities, including the ipsilateral temporal neocortex (p = 0.006). [11 C]ABP688 BPND showed interhemispheric differences of higher magnitude and discriminated the epileptogenic structures more accurately when compared to [18 F]FDG uptake, which showed more widespread hypometabolism. Among 23 of 25 operated patients with >1 year of follow-up, 13 were seizure-free (Engel Ia) and showed significantly lower [11 C]ABP688 BPND in the ipsilateral entorhinal cortex. INTERPRETATION: [11 C]ABP688 PET provides a focal biomarker for the EZ in MTLE with higher spatial accuracy compared to [18 F]FDG PET. Focally reduced mGluR5 availability in the EZ might reflect receptor internalization or conformational changes in response to excessive extracellular glutamate, supporting a potential role for mGluR5 as therapeutic target in human MTLE. Ann Neurol 2019; 1-11 ANN NEUROL 2019;85:218-228.

Treatment of Epilepsy Associated with Periventricular Nodular Heterotopia.

PURPOSE OF REVIEW: Epilepsy associated with periventricular nodular heterotopia (PNH), a developmental malformation, is frequently drug-resistant and requires focal therapeutic intervention. Invasive EEG study is usually necessary to delineate the epileptogenic zone, but constructing an accurate hypothesis to define an appropriate electrode implantation scheme and the treatment is challenging. This article reviews recent studies that help understanding the epileptogenicity and potential therapeutic options in PNH. RECENT FINDINGS: New noninvasive diagnostic and intracerebral EEG analytic tools demonstrated that cortical hyperexcitability and aberrant connectivity (between nodules and cortices and among nodules) are likely mechanisms causing epilepsy in most patients. The deeply seated PNH, if epileptogenic, are ideal target for stereotactic ablative techniques, which offer concomitant ablation of multiple regions with relatively satisfactory seizure outcome. Advance in diagnostic and analytic tools have enhanced our understanding of the complex epileptogenicity in PNH. Development in stereotactic ablative techniques now offers promising therapeutic options for these patients.

NREM sleep is the state of vigilance that best identifies the epileptogenic zone in the interictal electroencephalogram.

OBJECTIVE: Interictal epileptiform anomalies such as epileptiform discharges or high-frequency oscillations show marked variations across the sleep-wake cycle. This study investigates which state of vigilance is the best to localize the epileptogenic zone (EZ) in interictal intracranial electroencephalography (EEG). METHODS: Thirty patients with drug-resistant epilepsy undergoing stereo-EEG (SEEG)/sleep recording and subsequent open surgery were included; 13 patients (43.3%) had good surgical outcome (Engel class I). Sleep was scored following standard criteria. Multiple features based on the interictal EEG (interictal epileptiform discharges, high-frequency oscillations, univariate and bivariate features) were used to train a support vector machine (SVM) model to classify SEEG contacts placed in the EZ. The performance of the algorithm was evaluated by the mean area under the receiver-operating characteristic (ROC) curves (AUCs) and positive predictive values (PPVs) across 10-minute sections of wake, non-rapid eye movement sleep (NREM) stages N2 and N3, REM sleep, and their combination. RESULTS: Highest AUCs were achieved in NREM sleep stages N2 and N3 compared to wakefulness and REM (P < .01). There was no improvement when using a combination of all four states (P > .05); the best performing features in the combined state were selected from NREM sleep. There were differences between good (Engel I) and poor (Engel II-IV) outcomes in PPV (P < .05) and AUC (P < .01) across all states. The SVM multifeature approach outperformed spikes and high-frequency oscillations (P < .01) and resulted in results similar to those of the seizure-onset zone (SOZ; P > .05). SIGNIFICANCE: Sleep improves the localization of the EZ with best identification obtained in NREM sleep stages N2 and N3. Results based on the multifeature classification in 10 minutes of NREM sleep were not different from the results achieved by the SOZ based on 12.7 days of seizure monitoring. This finding might ultimately result in a more time-efficient intracranial presurgical investigation of focal epilepsy.

Spike-related haemodynamic responses overlap with high frequency oscillations in patients with focal epilepsy.

Simultaneous scalp EEG/functional MRI measures non-invasively haemodynamic responses to interictal epileptic discharges, which are related to the epileptogenic zone. High frequency oscillations are also an excellent indicator of this zone, but are primarily recorded from intracerebral EEG. We studied the spatial overlap of these two important markers in patients with drug-resistant epilepsy to assess if their combination could help better define the extent of the epileptogenic zone. We included patients who underwent EEG-functional MRI and later intracerebral EEG. Based on intracerebral EEG findings, we separated patients with unifocal seizures from patients with multifocal or unknown onset seizures. Haemodynamic t-maps were coregistered with the intracerebral electrode positions. Each EEG channel was classified as pertaining to one of the following categories: primary haemodynamic cluster (maximum t-value), secondary cluster (t-value > 90% of the primary cluster) or outside the primary and secondary clusters. We marked high frequency oscillations (ripples: 80-250 Hz; fast ripples: 250-500 Hz) during 1 h of slow wave sleep, and compared their rates in each haemodynamic category. After classifying channels as high- or low-rate, the proportion of high-rate channels within the primary or primary plus secondary clusters was compared to the proportion expected by chance. Twenty-five patients, 11 with unifocal and 14 with multifocal/unknown seizure onsets, were studied. We found a significantly higher median high frequency oscillation rate in the primary cluster compared to secondary cluster and outside these two clusters for the unifocal group (P < 0.0001), but not for the multifocal/unknown group. For the unifocal group, the number of high-rate channels within the primary or primary plus secondary clusters was significantly higher than expected by chance. This held only for the high-ripple-rate channels in the multifocal/unknown group. At the patient level, most patients (18/25, or 72%) had at least one high-rate channel within a primary cluster. In patients with unifocal epilepsy, the maximum haemodynamic response (primary cluster) related to scalp interictal discharges overlaps with the tissue generating high frequency oscillations at high rates. If intracranial EEG is warranted, this response should be explored. As a tentative clinical use of the combination of these techniques we propose that higher high frequency oscillation rates inside than outside the maximum response indicates that the patient has indeed a focal epileptogenic zone demarcated by this response, whereas similar rates inside and outside may indicate a widespread epileptogenic zone or an epileptogenic zone not covered by the implantation.