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Anoctamins are a family of Ca2+-activated proteins that may act as ion channels and/or phospholipid scramblases with limited understanding of function and disease association. Here, we identified five de novo and two inherited missense variants in ANO4 (alias TMEM16D) as a cause of fever-sensitive developmental and epileptic or epileptic encephalopathy (DEE/EE) and generalized epilepsy with febrile seizures plus (GEFS+) or temporal lobe epilepsy. In silico modeling of the ANO4 structure predicted that all identified variants lead to destabilization of the ANO4 structure. Four variants are localized close to the Ca2+ binding sites of ANO4, suggesting impaired protein function. Variant mapping to the protein topology suggests a preliminary genotype-phenotype correlation. Moreover, the observation of a heterozygous ANO4 deletion in a healthy individual suggests a dysfunctional protein as disease mechanism rather than haploinsufficiency. To test this hypothesis, we examined mutant ANO4 functional properties in a heterologous expression system by patch-clamp recordings, immunocytochemistry, and surface expression of annexin A5 as a measure of phosphatidylserine scramblase activity. All ANO4 variants showed severe loss of ion channel function and DEE/EE associated variants presented mild loss of surface expression due to impaired plasma membrane trafficking. Increased levels of Ca2+-independent annexin A5 at the cell surface suggested an increased apoptosis rate in DEE-mutant expressing cells, but no changes in Ca2+-dependent scramblase activity were observed. Co-transfection with ANO4 wild-type suggested a dominant-negative effect. In summary, we expand the genetic base for both encephalopathic sporadic and inherited fever-sensitive epilepsies and link germline variants in ANO4 to a hereditary disease.
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Anoctaminas , Mutação de Sentido Incorreto , Humanos , Anoctaminas/genética , Anoctaminas/metabolismo , Mutação de Sentido Incorreto/genética , Masculino , Feminino , Epilepsia/genética , Criança , Proteínas de Transferência de Fosfolipídeos/genética , Proteínas de Transferência de Fosfolipídeos/metabolismo , Estudos de Associação Genética , Linhagem , Cálcio/metabolismo , Genes Dominantes , Pré-Escolar , Células HEK293 , AdolescenteRESUMO
Both sleep alterations and epileptiform activity are associated with the accumulation of amyloid-ß and tau pathology and are currently investigated for potential therapeutic interventions in Alzheimer's disease (AD). However, a bidirectional intertwining relation between sleep and neuronal hyperexcitability might modulate the effects of AD pathology on the corresponding associations. To investigate this, we performed multiple day simultaneous foramen ovale (FO) plus scalp EEG and polysomnography (PSG) recordings and acquired 18F-MK6240 tau PET-MR in three patients in the prodromal stage of AD and in two patients with mild and moderate dementia due to AD, respectively. As an eligibility criterion for the present study, subjects either had a history of a recent seizure (n = 2) or subclinical epileptiform activity (SEA) on a previous scalp EEG taken in a research context (n = 3). The 18F-MK6240 standard uptake value ratio (SUVR) and asymmetry index (AI) were calculated in a priori defined volumes of interest (VOIs). Linear mixed effects models were used to study associations between interictal epileptiform discharges (IEDs), PSG parameters and 18F-MK6240 SUVR. Epileptiform activity was bilateral but asymmetrically present on FO electrodes in all patients and ≥ 95% of IEDs were not visible on scalp EEG. In one patient two focal seizures were detected on FO electrodes, both without visual scalp EEG correlate. We observed lateralized periodic discharges, brief potentially ictal rhythmic discharges and lateralized rhythmic delta activity on FO electrodes in four patients. Unlike scalp EEG, intracranial electrodes showed a lateralization of epileptiform activity. Although the amount of IEDs on intracranial electrodes was not associated to the 18F-MK6240 SUVR binding in different VOIs, there was a congruent asymmetry of the 18F-MK6240 binding towards the most epileptic hemisphere for the mesial (P = 0.007) and lateral temporal cortex (P = 0.006). IEDs on intracranial electrodes were most abundant during slow wave sleep (SWS) (92/h) and N2 (81/h), followed by N1 (33/h) and least frequent during wakefulness (17/h) and REM sleep (9/h). The extent of IEDs during sleep was not reflected in the relative time in each sleep stage spent (REM% (P = 0.415), N1% (P = 0.668), N2% (P = 0.442), SWS% (P = 0.988)), and not associated with the arousal index (P = 0.317), apnea-hypopnea index (P = 0.846) or oxygen desaturation index (P = 0.746). Together, our observations suggest a multi-directional interaction between sleep, epileptiform activity and tau pathology in AD.
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Encephalocraniocutaneous lipomatosis (ECCL) is a sporadic congenital condition characterised by ocular, cutaneous and central nervous system involvement. Mosaic activating variants in FGFR1 and KRAS have been reported in several individuals with this syndrome. We report on a patient with neurofibromatosis type 1 (NF1) with a germline pathogenic variant in the NF1 gene and an ECCL phenotype, suggesting ECCL to be part of a spectrum of malformations associated with NF1 pathogenic variants. An anatomical hemispherectomy was performed for intractable epilepsy. Through genetic analysis of blood, cerebral tissue and giant cell lesions in both jaws, we identified the germline NF1 pathogenic variant in all samples and a second-hit pathogenic NF1 variant in cerebral tissue and both giant cell lesions. Both NF1 variants were located on different alleles resulting in somatic mosaicism for a biallelic NF1 inactivation originating in early embryogenesis (second-hit mosaicism or Happle type 2 mosaicism). The biallelic deficit in NF1 in the left hemicranium explains the severe localised, congenital abnormality in this patient. Identical first and second-hit variants in a giant cell lesion of both upper and lower jaws provide confirmatory evidence for an early embryonic second hit involving at least the neural crest. We suggest that the ECCL phenotype may be part of a spectrum of congenital problems associated with mosaic NF1 nullisomy originating during early embryogenesis. The biallelic NF1 inactivation during early embryogenesis mimics the severe activation of the RAS-MAPK pathway seen in ECCL caused by embryonic mosaic activating FGFR1 and KRAS variants in the cranial region. We propose that distinct mechanisms of mosaicism can cause the ECCL phenotype through convergence on the RAS-MAPK pathway.
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Epilepsy is one of the most frequent neurological conditions with an estimated prevalence of more than 50 million people worldwide and an annual incidence of two million. Although pharmacotherapy with anti-seizure medication (ASM) is the treatment of choice, ~30% of patients with epilepsy do not respond to ASM and become drug resistant. Focal epilepsy is the most frequent form of epilepsy. In patients with drug-resistant focal epilepsy, epilepsy surgery is a treatment option depending on the localisation of the seizure focus for seizure relief or seizure freedom with consecutive improvement in quality of life. Beside examinations such as scalp video/electroencephalography (EEG) telemetry, structural, and functional magnetic resonance imaging (MRI), which are primary standard tools for the diagnostic work-up and therapy management of epilepsy patients, molecular neuroimaging using different radiopharmaceuticals with single-photon emission computed tomography (SPECT) and positron emission tomography (PET) influences and impacts on therapy decisions. To date, there are no literature-based praxis recommendations for the use of Nuclear Medicine (NM) imaging procedures in epilepsy. The aims of these guidelines are to assist in understanding the role and challenges of radiotracer imaging for epilepsy; to provide practical information for performing different molecular imaging procedures for epilepsy; and to provide an algorithm for selecting the most appropriate imaging procedures in specific clinical situations based on current literature. These guidelines are written and authorized by the European Association of Nuclear Medicine (EANM) to promote optimal epilepsy imaging, especially in the presurgical setting in children, adolescents, and adults with focal epilepsy. They will assist NM healthcare professionals and also specialists such as Neurologists, Neurophysiologists, Neurosurgeons, Psychiatrists, Psychologists, and others involved in epilepsy management in the detection and interpretation of epileptic seizure onset zone (SOZ) for further treatment decision. The information provided should be applied according to local laws and regulations as well as the availability of various radiopharmaceuticals and imaging modalities.
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Epilepsia , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada de Emissão de Fóton Único , Humanos , Epilepsia/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Tomografia por Emissão de Pósitrons/normas , Medicina Nuclear , Europa (Continente)RESUMO
OBJECTIVE: Home monitoring of 3-Hz spike-wave discharges (SWDs) in patients with refractory absence epilepsy could improve clinical care by replacing the inaccurate seizure diary with objective counts. We investigated the use and performance of the Sensor Dot (Byteflies) wearable in persons with absence epilepsy in their home environment. METHODS: Thirteen participants (median age = 22 years, 11 female) were enrolled at the university hospitals of Leuven and Freiburg. At home, participants had to attach the Sensor Dot and behind-the-ear electrodes to record two-channel electroencephalogram (EEG), accelerometry, and gyroscope data. Ground truth annotations were created during a visual review of the full Sensor Dot recording. Generalized SWDs were annotated if they were 3 Hz and at least 3 s on EEG. Potential 3-Hz SWDs were flagged by an automated seizure detection algorithm, (1) using only EEG and (2) with an additional postprocessing step using accelerometer and gyroscope to discard motion artifacts. Afterward, two readers (W.V.P. and L.S.) reviewed algorithm-labeled segments and annotated true positive detections. Sensitivity, precision, and F1 score were calculated. Patients had to keep a seizure diary and complete questionnaires about their experiences. RESULTS: Total recording time was 394 h 42 min. Overall, 234 SWDs were captured in 11 of 13 participants. Review of the unimodal algorithm-labeled recordings resulted in a mean sensitivity of .84, precision of .93, and F1 score of .89. Visual review of the multimodal algorithm-labeled segments resulted in a similar F1 score and shorter review time due to fewer false positive labels. Participants reported that the device was comfortable and that they would be willing to wear it on demand of their neurologist, for a maximum of 1 week or with intermediate breaks. SIGNIFICANCE: The Sensor Dot improved seizure documentation at home, relative to patient self-reporting. Additional benefits were the short review time and the patients' device acceptance due to user-friendliness and comfortability.
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Epilepsia Resistente a Medicamentos , Epilepsia Tipo Ausência , Dispositivos Eletrônicos Vestíveis , Adulto , Feminino , Humanos , Adulto Jovem , Eletrodos , Eletroencefalografia/métodos , Convulsões/diagnóstico , MasculinoRESUMO
PURPOSE: We present the case of a 67-year-old woman with severely reduced renal clearance suffering from ceftazidime-induced encephalopathy. Subsequently, we search the literature to review and describe the neurotoxicity of ceftazidime. METHODS: A search string was developed to search PubMed for relevant cases from which relevant information was extracted. Using the collected data a ROC analysis was performed in R to determine a neurotoxicity threshold. RESULTS: Our patient suffered from progressive loss of consciousness and myoclonic seizures, with improvements noted a few days after discontinuation of treatment. The dose was not appropriately reduced to take into account her reduced renal function. The highest ceftazidime concentration recorded was 234.9 mg/mL. Using the Naranjo score we found a probable relationship between our patient's encephalopathy and ceftazidime administration. In the literature we found a total of 32 similar cases, most of which also had some form of renal impairment. Using our collected data and ceftazidime concentrations provided in the literature, a ROC analysis provided a neurotoxicity threshold of 78 mg/L for ceftazidime neurotoxicity. CONCLUSION: Ceftazidime-related neurotoxicity is a known issue, especially in patients with severe renal impairment. Yet no concrete toxicity threshold has been reported so far. We propose the first toxicity threshold for ceftazidime of 78 mg/L. Future prospective studies are needed to validate and optimize the neurotoxicity threshold as upper limit for ceftazidime therapeutic drug monitoring.
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Antibacterianos , Ceftazidima , Síndromes Neurotóxicas , Humanos , Ceftazidima/efeitos adversos , Ceftazidima/uso terapêutico , Feminino , Idoso , Antibacterianos/efeitos adversos , Síndromes Neurotóxicas/etiologia , Insuficiência Renal/induzido quimicamenteRESUMO
PURPOSE: Seizures are characterized by periictal autonomic changes. Wearable devices could help improve our understanding of these phenomena through long-term monitoring. In this study, we used wearable electrocardiogram (ECG) data to evaluate differences between temporal and extratemporal focal impaired awareness (FIA) seizures monitored in the hospital and at home. We assessed periictal heart rate, respiratory rate, heart rate variability (HRV), and respiratory sinus arrhythmia (RSA). METHODS: We extracted ECG signals across three time points - five minutes baseline and preictal, ten minutes postictal - and the seizure duration. After automatic Rpeak selection, we calculated the heart rate and estimated the respiratory rate using the ECG-derived respiration methodology. HRV was calculated in both time and frequency domains. To evaluate the influence of other modulators on the HRV after removing the respiratory influences, we recalculated the residual power in the high-frequency (HF) and low-frequency (LF) bands using orthogonal subspace projections. Finally, 5-minute and 30-second (ultra-short) ECG segments were used to calculate RSA using three different methods. Seizures from temporal and extratemporal origins were compared using mixed-effects models and estimated marginal means. RESULTS: The mean preictal heart rate was 69.95 bpm (95 % CI 65.6 - 74.3), and it increased to 82 bpm, 95 % CI (77.51 - 86.47) and 84.11 bpm, 95 % CI (76.9 - 89.5) during the ictal and postictal periods. Preictal, ictal and postictal respiratory rates were 16.1 (95 % CI 15.2 - 17.1), 14.8 (95 % CI 13.4 - 16.2) and 15.1 (95 % CI 14 - 16.2), showing not statistically significant bradypnea. HRV analysis found a higher baseline power in the LF band, which was still significantly higher after removing the respiratory influences. Postictally, we found decreased power in the HF band and the respiratory influences in both frequency bands. The RSA analysis with the new methods confirmed the lower cardiorespiratory interaction during the postictal period. Additionally, using ultra-short ECG segments, we found that RSA decreases before the electroclinical seizure onset. No differences were observed in the studied parameters between temporal and extratemporal seizures. CONCLUSIONS: We found significant increases in the ictal and postictal heart rates and lower respiratory rates. Isolating the respiratory influences on the HRV showed a postictal reduction of respiratory modulations on both LF and HF bands, suggesting a central role of respiratory influences in the periictal HRV, unlike the baseline measurements. We found a reduced cardiorespiratory interaction during the periictal period using other RSA methods, suggesting a blockade in vagal efferences before the electroclinical onset. These findings highlight the importance of respiratory influences in cardiac dynamics during seizures and emphasize the need to longitudinally assess HRV and RSA to gain insights into long-term autonomic dysregulation.
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OBJECTIVE: The aim is to report the performance of an electroencephalogram (EEG) seizure-detector algorithm on data obtained with a wearable device (WD) in patients with focal refractory epilepsy and their experience. METHODS: Patients used a WD, the Sensor Dot (SD), to measure two channels of EEG using dry electrode patches during presurgical evaluation and at home for up to 8 months. An automated seizure detection algorithm flagged EEG regions with possible seizures, which we reviewed to evaluate the algorithm's diagnostic yield. In addition, we collected data on usability, side effects, and patient satisfaction with an electronic seizure diary application (Helpilepsy). RESULTS: Sixteen inpatients used the SD for up to 5 days and had 21 seizures. Sixteen outpatients used the device for up to 8 months and reported 101 focal impaired awareness seizures during the periods selected for analysis. Focal seizure detection sensitivity based on behind-the-ear EEG was 52% in inpatients and 23% in outpatients. False detections/h, positive predictive value (PPV), and F1 scores were 7.13%, .11%, and .002% for inpatients and 7.77%, .04%, and .001% for outpatients. Artifacts and low signal quality contributed to poor performance metrics. The seizure detector identified 19 nonreported seizures during sleep, when the signal quality was better. Regarding patients' experience, the likelihood of using the device at 6 months was 62%, and side effects were the main reason for dropping out. Finally, daily and monthly questionnaire completion rates were 33% and 65%, respectively. SIGNIFICANCE: Focal seizure detection sensitivity based on behind-the-ear EEG was 52% in inpatients and 23% in outpatients, with high false alarm rates and low PPV and F1 scores. This unobtrusive wearable seizure detection device was well received but had side effects. The current workflow and low performance limit its implementation in clinical practice. We suggest different steps to improve these performance metrics and patient experience.
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Epilepsias Parciais , Dispositivos Eletrônicos Vestíveis , Humanos , Epilepsias Parciais/diagnóstico , Convulsões/diagnóstico , Algoritmos , Eletroencefalografia , HospitaisRESUMO
OBJECTIVE: To investigate the performance of a multimodal wearable device for the offline detection of tonic seizures (TS) in a pediatric childhood epilepsy cohort, with a focus on patients with Lennox-Gastaut syndrome. METHODS: Parallel with prolonged video-electroencephalography (EEG), the Plug 'n Patch system, a multimodal wearable device using the Sensor Dot and replaceable electrode adhesives, was used to detect TS. Multiple biosignals were recorded: behind-the-ear EEG, surface electromyography, electrocardiography, and accelerometer/gyroscope. Biosignals were annotated blindly by a neurologist. Seizure characteristics were described, and performance was assessed by sensitivity, positive predictive value (PPV), F1 score, and false alarm rate (FAR) per hour. Performance was compared to seizure diaries kept by the caretaker. RESULTS: Ninety-nine TS were detected in 13 patients. Seven patients (54%) had Lennox-Gastaut syndrome and six patients (46%) had other forms of (developmental) epileptic encephalopathies or drug-resistant epilepsy. All but one patient had intellectual disability. Overall sensitivity was 41%, with a PPV of 9%, an F1 score of 14%, and a median FAR per hour of 0.75. Performance increased to an F1 score of 66% for nightly seizures lasting at least 10 s (sensitivity 66%, PPV 66%) and 71% for nightly seizures lasting at least 20 s (sensitivity 62%, PPV 82%). For these seizures there were no false alarms in 10 of 13 patients. Sensitivity of seizure diaries reached a maximum of 52% for prolonged (≥20 s) nightly seizures, even though caretakers slept in the same room. SIGNIFICANCE: We showed that it is feasible to use a multimodal wearable device with multiple adhesive sites in children with epilepsy and intellectual disability. For prolonged nightly seizures, offline manual detection of TS outperformed seizure diaries. The recognition of seizure-specific signatures using multiple modalities can help in the development of automated TS detection algorithms.
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Epilepsia , Deficiência Intelectual , Síndrome de Lennox-Gastaut , Estado Epiléptico , Dispositivos Eletrônicos Vestíveis , Humanos , Criança , Estudos de Coortes , Deficiência Intelectual/complicações , Deficiência Intelectual/diagnóstico , Convulsões/diagnóstico , Epilepsia/diagnóstico , EletroencefalografiaRESUMO
The exquisite capacity of primates to detect and recognize faces is crucial for social interactions. Although disentangling the neural basis of human face recognition remains a key goal in neuroscience, direct evidence at the single-neuron level is limited. We recorded from face-selective neurons in human visual cortex in a region characterized by functional magnetic resonance imaging (fMRI) activations for faces compared with objects. The majority of visually responsive neurons in this fMRI activation showed strong selectivity at short latencies for faces compared with objects. Feature-scrambled faces and face-like objects could also drive these neurons, suggesting that this region is not tightly tuned to the visual attributes that typically define whole human faces. These single-cell recordings within the human face processing system provide vital experimental evidence linking previous imaging studies in humans and invasive studies in animal models.SIGNIFICANCE STATEMENT We present the first recordings of face-selective neurons in or near an fMRI-defined patch in human visual cortex. Our unbiased multielectrode array recordings (i.e., no selection of neurons based on a search strategy) confirmed the validity of the BOLD contrast (faces-objects) in humans, a finding with implications for all human imaging studies. By presenting faces, feature-scrambled faces, and face-pareidolia (perceiving faces in inanimate objects) stimuli, we demonstrate that neurons at this level of the visual hierarchy are broadly tuned to the features of a face, independent of spatial configuration and low-level visual attributes.
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Mapeamento Encefálico/métodos , Reconhecimento Facial/fisiologia , Neurônios/fisiologia , Córtex Visual/fisiologia , Adulto , Eletrodos Implantados , Feminino , Humanos , Imageamento por Ressonância Magnética/métodosRESUMO
Data fusion refers to the joint analysis of multiple datasets that provide different (e.g., complementary) views of the same task. In general, it can extract more information than separate analyses can. Jointly analyzing electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) measurements has been proved to be highly beneficial to the study of the brain function, mainly because these neuroimaging modalities have complementary spatiotemporal resolution: EEG offers good temporal resolution while fMRI is better in its spatial resolution. The EEG-fMRI fusion methods that have been reported so far ignore the underlying multiway nature of the data in at least one of the modalities and/or rely on very strong assumptions concerning the relation of the respective datasets. For example, in multisubject analysis, it is commonly assumed that the hemodynamic response function is a priori known for all subjects and/or the coupling across corresponding modes is assumed to be exact (hard). In this article, these two limitations are overcome by adopting tensor models for both modalities and by following soft and flexible coupling approaches to implement the multimodal fusion. The obtained results are compared against those of parallel independent component analysis and hard coupling alternatives, with both synthetic and real data (epilepsy and visual oddball paradigm). Our results demonstrate the clear advantage of using soft and flexible coupled tensor decompositions in scenarios that do not conform with the hard coupling assumption.
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Encéfalo , Eletroencefalografia/métodos , Neuroimagem Funcional/métodos , Imageamento por Ressonância Magnética/métodos , Rede Nervosa , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Epilepsia/diagnóstico por imagem , Feminino , Humanos , Masculino , Modelos Teóricos , Imagem Multimodal , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/fisiologia , Adulto JovemRESUMO
The human lateral occipital complex (LOC) is more strongly activated by images of objects compared to scrambled controls, but detailed information at the neuronal level is currently lacking. We recorded with microelectrode arrays in the LOC of 2 patients and obtained highly selective single-unit, multi-unit, and high-gamma responses to images of objects. Contrary to predictions derived from functional imaging studies, all neuronal properties indicated that the posterior subsector of LOC we recorded from occupies an unexpectedly high position in the hierarchy of visual areas. Notably, the response latencies of LOC neurons were long, the shape selectivity was spatially clustered, LOC receptive fields (RFs) were large and bilateral, and a number of LOC neurons exhibited three-dimensional (3D)-structure selectivity (a preference for convex or concave stimuli), which are all properties typical of end-stage ventral stream areas. Thus, our results challenge prevailing ideas about the position of the more posterior subsector of LOC in the hierarchy of visual areas.
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Córtex Visual/fisiologia , Percepção Visual/fisiologia , Mapeamento Encefálico , Humanos , Imageamento por Ressonância MagnéticaRESUMO
[This corrects the article DOI: 10.1371/journal.pbio.3000280.].
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EEG-correlated fMRI analysis is widely used to detect regional BOLD fluctuations that are synchronized to interictal epileptic discharges, which can provide evidence for localizing the ictal onset zone. However, the typical, asymmetrical and mass-univariate approach cannot capture the inherent, higher order structure in the EEG data, nor multivariate relations in the fMRI data, and it is nontrivial to accurately handle varying neurovascular coupling over patients and brain regions. We aim to overcome these drawbacks in a data-driven manner by means of a novel structured matrix-tensor factorization: the single-subject EEG data (represented as a third-order spectrogram tensor) and fMRI data (represented as a spatiotemporal BOLD signal matrix) are jointly decomposed into a superposition of several sources, characterized by space-time-frequency profiles. In the shared temporal mode, Toeplitz-structured factors account for a spatially specific, neurovascular 'bridge' between the EEG and fMRI temporal fluctuations, capturing the hemodynamic response's variability over brain regions. By analyzing interictal data from twelve patients, we show that the extracted source signatures provide a sensitive localization of the ictal onset zone (10/12). Moreover, complementary parts of the IOZ can be uncovered by inspecting those regions with the most deviant neurovascular coupling, as quantified by two entropy-like metrics of the hemodynamic response function waveforms (9/12). Hence, this multivariate, multimodal factorization provides two useful sets of EEG-fMRI biomarkers, which can assist the presurgical evaluation of epilepsy. We make all code required to perform the computations available at https://github.com/svaneynd/structured-cmtf.
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Mapeamento Encefálico/métodos , Encéfalo/diagnóstico por imagem , Eletroencefalografia/métodos , Epilepsia/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Adulto , Encéfalo/fisiopatologia , Epilepsia/fisiopatologia , Feminino , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Masculino , Imagem Multimodal/métodos , Acoplamento Neurovascular/fisiologiaRESUMO
RORα, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy. Consistent with the human and mouse data, disruption of the D. rerio ortholog, roraa, causes significant reduction in the size of the developing cerebellum. Systematic in vivo complementation studies showed that, whereas wild-type human RORA mRNA could complement the cerebellar pathology, missense variants had two distinct pathogenic mechanisms of either haploinsufficiency or a dominant toxic effect according to their localization in the ligand-binding or DNA-binding domains, respectively. This dichotomous direction of effect is likely relevant to the phenotype in humans: individuals with loss-of-function variants leading to haploinsufficiency show ID with autistic features, while individuals with de novo dominant toxic variants present with ID, ataxia, and cerebellar atrophy. Our combined genetic and functional data highlight the complex mutational landscape at the human RORA locus and suggest that dual mutational effects likely determine phenotypic outcome.
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Transtorno Autístico/genética , Ataxia Cerebelar/genética , Genes Dominantes , Deficiência Intelectual/genética , Mutação de Sentido Incorreto/genética , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Adolescente , Adulto , Idoso de 80 Anos ou mais , Alelos , Animais , Transtorno Autístico/complicações , Encéfalo/patologia , Ataxia Cerebelar/complicações , Criança , Pré-Escolar , Variações do Número de Cópias de DNA/genética , Modelos Animais de Doenças , Feminino , Teste de Complementação Genética , Humanos , Deficiência Intelectual/complicações , Larva/genética , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Células de Purkinje/metabolismo , Células de Purkinje/patologia , Síndrome , Peixe-Zebra/genéticaRESUMO
OBJECTIVE: Patients with absence epilepsy sensitivity <10% of their absences. The clinical gold standard to assess absence epilepsy is a 24-h electroencephalographic (EEG) recording, which is expensive, obtrusive, and time-consuming to review. We aimed to (1) investigate the performance of an unobtrusive, two-channel behind-the-ear EEG-based wearable, the Sensor Dot (SD), to detect typical absences in adults and children; and (2) develop a sensitive patient-specific absence seizure detection algorithm to reduce the review time of the recordings. METHODS: We recruited 12 patients (median age = 21 years, range = 8-50; seven female) who were admitted to the epilepsy monitoring units of University Hospitals Leuven for a 24-h 25-channel video-EEG recording to assess their refractory typical absences. Four additional behind-the-ear electrodes were attached for concomitant recording with the SD. Typical absences were defined as 3-Hz spike-and-wave discharges on EEG, lasting 3 s or longer. Seizures on SD were blindly annotated on the full recording and on the algorithm-labeled file and consequently compared to 25-channel EEG annotations. Patients or caregivers were asked to keep a seizure diary. Performance of the SD and seizure diary were measured using the F1 score. RESULTS: We concomitantly recorded 284 absences on video-EEG and SD. Our absence detection algorithm had a sensitivity of .983 and false positives per hour rate of .9138. Blind reading of full SD data resulted in sensitivity of .81, precision of .89, and F1 score of .73, whereas review of the algorithm-labeled files resulted in scores of .83, .89, and .87, respectively. Patient self-reporting gave sensitivity of .08, precision of 1.00, and F1 score of .15. SIGNIFICANCE: Using the wearable SD, epileptologists were able to reliably detect typical absence seizures. Our automated absence detection algorithm reduced the review time of a 24-h recording from 1-2 h to around 5-10 min.
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Epilepsia Tipo Ausência , Dispositivos Eletrônicos Vestíveis , Adolescente , Adulto , Algoritmos , Criança , Eletroencefalografia/métodos , Epilepsia Tipo Ausência/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Convulsões/diagnóstico , Adulto JovemRESUMO
OBJECTIVE: Wearable seizure detection devices could provide more reliable seizure documentation outside the hospital compared to seizure self-reporting by patients, which is the current standard. Previously, during the SeizeIT1 project, we studied seizure detection based on behind-the-ear electroencephalography (EEG). However, the obtained sensitivities were too low for practical use, because not all seizures are associated with typical ictal EEG patterns. Therefore, in this paper, we aim to develop a multimodal automated seizure detection algorithm integrating behind-the-ear EEG and electrocardiography (ECG) for detecting focal seizures. In this framework, we quantified the added value of ECG to behind-the-ear EEG. METHODS: This study analyzed three multicenter databases consisting of 135 patients having focal epilepsy and a total of 896 seizures. A patient-specific multimodal automated seizure detection algorithm was developed using behind-the-ear/temporal EEG and single-lead ECG. The EEG and ECG data were processed separately using machine learning methods. A late integration approach was applied for fusing those predictions. RESULTS: The multimodal algorithm outperformed the EEG-based algorithm in two of three databases, with an increase of 11% and 8% in sensitivity for the same false alarm rate. SIGNIFICANCE: ECG can be of added value to an EEG-based seizure detection algorithm using only behind-the-ear/temporal lobe electrodes for patients with focal epilepsy.
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Epilepsias Parciais , Dispositivos Eletrônicos Vestíveis , Algoritmos , Eletrocardiografia , Eletroencefalografia/métodos , Epilepsias Parciais/diagnóstico , Humanos , Convulsões/diagnósticoRESUMO
OBJECTIVE: Focal cortical dysplasias (FCDs) are a common cause of drug-resistant focal epilepsy but frequently remain undetected by conventional magnetic resonance imaging (MRI) assessment. The visual detection can be facilitated by morphometric analysis of T1-weighted images, for example, using the Morphometric Analysis Program (v2018; MAP18), which was introduced in 2005, independently validated for its clinical benefits, and successfully integrated in standard presurgical workflows of numerous epilepsy centers worldwide. Here we aimed to develop an artificial neural network (ANN) classifier for robust automated detection of FCDs based on these morphometric maps and probe its generalization performance in a large, independent data set. METHODS: In this retrospective study, we created a feed-forward ANN for FCD detection based on the morphometric output maps of MAP18. The ANN was trained and cross-validated on 113 patients (62 female, mean age ± SD =29.5 ± 13.6 years) with manually segmented FCDs and 362 healthy controls (161 female, mean age ± SD =30.2 ± 9.6 years) acquired on 13 different scanners. In addition, we validated the performance of the trained ANN on an independent, unseen data set of 60 FCD patients (28 female, mean age ± SD =30 ± 15.26 years) and 70 healthy controls (42 females, mean age ± SD = 40.0 ± 12.54 years). RESULTS: In the cross-validation, the ANN achieved a sensitivity of 87.4% at a specificity of 85.4% on the training data set. On the independent validation data set, our method still reached a sensitivity of 81.0% at a comparably high specificity of 84.3%. SIGNIFICANCE: Our method shows a robust automated detection of FCDs and performance generalizability, largely independent of scanning site or MR-sequence parameters. Taken together with the minimal input requirements of a standard T1 image, our approach constitutes a clinically viable and useful tool in the presurgical diagnostic routine for drug-resistant focal epilepsy.
Assuntos
Epilepsia Resistente a Medicamentos/diagnóstico por imagem , Epilepsia Resistente a Medicamentos/fisiopatologia , Imageamento Tridimensional/normas , Imageamento por Ressonância Magnética/normas , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Malformações do Desenvolvimento Cortical/fisiopatologia , Redes Neurais de Computação , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Imageamento Tridimensional/métodos , Lactente , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
Wearable technology will become available and allow prolonged electroencephalography (EEG) monitoring in the home environment of patients with epilepsy. Neurologists analyse the EEG visually and annotate all seizures, which patients often under-report. Visual analysis of a 24-h EEG recording typically takes one to two hours. Reliable automated seizure detection algorithms will be crucial to reduce this analysis. We investigated such algorithms on a dataset of behind-the-ear EEG measurements. Our first aim was to develop a methodology where part of the data is deferred to a human expert, who performs perfectly, with the goal of obtaining an (almost) perfect detection sensitivity (DS). Prediction confidences are determined by temperature scaling of the classification model outputs and trust scores. A DS of approximately 90% (99%) can be achieved when deferring around 10% (40%) of the data. Perfect DS can be achieved when deferring 50% of the data. Our second contribution demonstrates that a common modelling strategy, where predictions from several short EEG segments are combined to obtain a final prediction, can be improved by filtering out untrustworthy segments with low trust scores. The false detection rate shows a relative decrease between 21% and 43%, and the DS shows a small increase or decrease.
Assuntos
Epilepsia , Confiança , Algoritmos , Eletroencefalografia , Epilepsia/diagnóstico , Humanos , Convulsões/diagnóstico , Sensibilidade e EspecificidadeRESUMO
The human amygdala is considered a key region for successful emotion recognition. We recently reported that temporal lobe surgery (TLS), including resection of the amygdala, does not affect emotion recognition performance (Journal of Neuroscience, 2018, 38, 9263). In the present study, we investigate the neural basis of this preserved function at the network level. We use generalized psychophysiological interaction and graph theory indices to investigate network level characteristics of the emotion recognition network in TLS patients and healthy controls. Based on conflicting emotion processing theories, we anticipated two possible outcomes: a substantial increase of the non-amygdalar connections of the emotion recognition network to compensate functionally for the loss of the amygdala, in line with basic emotion theory versus only minor changes in network level properties as predicted by psychological construction theory. We defined the emotion recognition network in the total sample and investigated group differences on five network level indices (i.e. characteristic path length, global efficiency, clustering coefficient, local efficiency and small-worldness). The results did not reveal a significant increase in the left or right temporal lobectomy group (compared to the control group) in any of the graph measures, indicating that preserved behavioural emotion recognition in TLS is not associated with a massive connectivity increase between non-amygdalar nodes at network level. We conclude that the emotion recognition network is robust and functionally able to compensate for structural damage without substantial global reorganization, in line with a psychological construction theory.