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1.
Cells ; 8(5)2019 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-31072055

RESUMO

As genome-wide association studies (GWAS) have grown in size, the number of genetic variants that have been associated per disease has correspondingly increased. Despite this increase in the number of single-nucleotide polymorphisms (SNPs) identified per disease, their biological interpretation has in many cases remained elusive. To address this, we have combined GWAS results with orthogonal sources of evidence, namely the current knowledge of molecular pathways; real-world clinical data from six million patients; RNA expression across tissues from Alzheimer's disease (AD) patients, and purpose-built rodent models for experimental validation. In more detail, first we show that when examined at a pathway level, analysis of all GWAS studies groups AD in a cluster with disorders of immunity and inflammation. Using clinical data, we show that the degree of comorbidity of these diseases with AD correlates with the strength of their genetic association with molecular participants in the Janus kinases/signal transducer and activator of transcription (JAK-STAT) pathway. Using four independent RNA expression datasets we then find evidence for the altered regulation of JAK-STAT pathway genes in AD. Finally, we use both in vitro and in vivo rodent models to demonstrate that Aß induces gene expression of the key drivers of this pathway, providing experimental evidence to validate these data-driven observations. These results therefore nominate JAK-STAT anomalies as a prominent aetiopathological event in AD and hence a potential target for therapeutic development, and moreover demonstrate a de novo multi-modal approach to derive information from rapidly increasing genomic datasets.

2.
Alzheimers Dement ; 15(6): 776-787, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31047856

RESUMO

INTRODUCTION: Plasma biomarkers for Alzheimer's disease (AD) diagnosis/stratification are a "Holy Grail" of AD research and intensively sought; however, there are no well-established plasma markers. METHODS: A hypothesis-led plasma biomarker search was conducted in the context of international multicenter studies. The discovery phase measured 53 inflammatory proteins in elderly control (CTL; 259), mild cognitive impairment (MCI; 199), and AD (262) subjects from AddNeuroMed. RESULTS: Ten analytes showed significant intergroup differences. Logistic regression identified five (FB, FH, sCR1, MCP-1, eotaxin-1) that, age/APOε4 adjusted, optimally differentiated AD and CTL (AUC: 0.79), and three (sCR1, MCP-1, eotaxin-1) that optimally differentiated AD and MCI (AUC: 0.74). These models replicated in an independent cohort (EMIF; AUC 0.81 and 0.67). Two analytes (FB, FH) plus age predicted MCI progression to AD (AUC: 0.71). DISCUSSION: Plasma markers of inflammation and complement dysregulation support diagnosis and outcome prediction in AD and MCI. Further replication is needed before clinical translation.

3.
Sci Adv ; 5(2): eaau7220, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30775436

RESUMO

A blood-based assessment of preclinical disease would have huge potential in the enrichment of participants for Alzheimer's disease (AD) therapeutic trials. In this study, cognitively unimpaired individuals from the AIBL and KARVIAH cohorts were defined as Aß negative or Aß positive by positron emission tomography. Nontargeted proteomic analysis that incorporated peptide fractionation and high-resolution mass spectrometry quantified relative protein abundances in plasma samples from all participants. A protein classifier model was trained to predict Aß-positive participants using feature selection and machine learning in AIBL and independently assessed in KARVIAH. A 12-feature model for predicting Aß-positive participants was established and demonstrated high accuracy (testing area under the receiver operator characteristic curve = 0.891, sensitivity = 0.78, and specificity = 0.77). This extensive plasma proteomic study has unbiasedly highlighted putative and novel candidates for AD pathology that should be further validated with automated methodologies.

4.
Sci Rep ; 8(1): 12089, 2018 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-30108252

RESUMO

Observational studies have shown consistently increased likelihood of dementia or mild cognitive impairment diagnoses in people with higher air pollution exposure history, but evidence has been less consistent for associations with cognitive test performance. We estimated the association between baseline neighbourhood-level exposure to airborne pollutants (particulate matter and nitrogen oxides) and (1) cognitive test performance at baseline and (2) cognitive score change between baseline and 2.8-year follow-up, in 86,759 middle- to older-aged adults from the UK Biobank general population cohort. Unadjusted regression analyses indicated small but consistent negative associations between air pollutant exposure and baseline cognitive performance. Following adjustment for a range of key confounders, associations were inconsistent in direction and of very small magnitude. The largest of these indicated that 1 interquartile range higher air pollutant exposure was associated on average with 0.35% slower reaction time (95% CI: 0.13, 0.57), a 2.92% higher error rate on a visuospatial memory test (95% CI: 1.24, 4.62), and numeric memory scores that were 0.58 points lower (95% CI: -0.96, -0.19). Follow-up analyses of cognitive change scores did not show evidence of associations. The findings indicate that in this sample, which is five-fold larger than any previous cross-sectional study, the association between air pollution exposure and cognitive performance was weak. Ongoing follow-up of the UK Biobank cohort will allow investigation of longer-term associations into old age, including longitudinal tracking of cognitive performance and incident dementia outcomes.

5.
Genome Med ; 10(1): 51, 2018 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-29954452

RESUMO

BACKGROUND: Studies have shown that low haemoglobin and anaemia are associated with poor cognition, and anaemia is known to be associated with Alzheimer's disease (AD), but the mechanism of this risk is unknown. Here, we first seek to confirm the association between cognition and anaemia and secondly, in order to further understand the mechanism of this association, to estimate the direction of causation using Mendelian randomisation. METHODS: Two independent cohorts were used in this analysis: AddNeuroMed, a longitudinal study of 738 subjects including AD and age-matched controls with blood cell measures, cognitive assessments and gene expression data from blood; and UK Biobank, a study of 502,649 healthy participants, aged 40-69 years with cognitive test measures and blood cell indices at baseline. General linear models were calculated using cognitive function as the outcome with correction for age, sex and education. In UK Biobank, SNPs with known blood cell measure associations were analysed with Mendelian randomisation to estimate direction of causality. In AddNeuroMed, gene expression data was used in pathway enrichment analysis to identify associations reflecting biological function. RESULTS: Both sample sets evidence a reproducible association between cognitive performance and mean corpuscular haemoglobin (MCH), a measure of average mass of haemoglobin per red blood cell. Furthermore, in the AddNeuroMed cohort, where longitudinal samples were available, we showed a greater decline in red blood cell indices for AD patients when compared to controls (p values between 0.05 and 10-6). In the UK Biobank cohort, we found lower haemoglobin in participants with reduced cognitive function. There was a significant association for MCH and red blood cell distribution width (RDW, a measure of cell volume variability) compared to four cognitive function tests including reaction time and reasoning (p < 0.0001). Using Mendelian randomisation, we then showed a significant effect of MCH on the verbal-numeric and numeric traits, implying that anaemia has causative effect on cognitive performance. CONCLUSIONS: Lower haemoglobin levels in blood are associated to poor cognitive function and AD. We have used UK Biobank SNP data to determine the relationship between cognitive testing and haemoglobin measures and suggest that haemoglobin level and therefore anaemia does have a primary causal impact on cognitive performance.


Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/fisiopatologia , Disfunção Cognitiva/sangue , Disfunção Cognitiva/fisiopatologia , Índices de Eritrócitos , Idoso , Anemia , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Regulação da Expressão Gênica , Hemoglobinas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Característica Quantitativa Herdável
6.
Redox Biol ; 13: 444-451, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28704727

RESUMO

Failure to translate successful neuroprotective preclinical data to a clinical setting in Alzheimer's disease (AD) indicates that amyloidopathy and tauopathy alone provide an incomplete view of disease. We have tested here the relevance of additional homeostatic deviations that result from loss of activity of transcription factor NRF2, a crucial regulator of multiple stress responses whose activity declines with ageing. A transcriptomic analysis demonstrated that NRF2-KO mouse brains reproduce 7 and 10 of the most dysregulated pathways of human ageing and AD brains, respectively. Then, we generated a mouse that combines amyloidopathy and tauopathy with either wild type (AT-NRF2-WT) or NRF2-deficiency (AT-NRF2-KO). AT-NRF2-KO brains presented increased markers of oxidative stress and neuroinflammation as well as higher levels of insoluble phosphorylated-TAU and Aß*56 compared to AT-NRF2-WT mice. Young adult AT-NRF2-KO mice exhibited deficits in spatial learning and memory and reduced long term potentiation in the perforant pathway. This study demonstrates the relevance of normal homeostatic responses that decline with ageing, such as NRF2 activity, in the protection against proteotoxic, inflammatory and oxidative stress and provide a new strategy to fight AD.


Assuntos
Doença de Alzheimer/metabolismo , Fator 2 Relacionado a NF-E2/genética , Transcriptoma , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Humanos , Potenciação de Longa Duração , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/deficiência , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Proteínas tau/genética , Proteínas tau/metabolismo
7.
Alzheimers Res Ther ; 9(1): 31, 2017 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-28441961

RESUMO

BACKGROUND: Insulin resistance (IR) has previously been associated with an increased risk of developing Alzheimer's disease (AD), although the relationship between IR and AD is not yet clear. Here, we examined the influence of IR on AD using plasma and cerebrospinal fluid (CSF) biomarkers related to IR and AD in cognitively healthy men. We also aimed to characterise the shared protein signatures between IR and AD. METHODS: Fifty-eight cognitively healthy men, 28 IR and 30 non-IR (age and APOE ε4 matched), were drawn from the Metabolic Syndrome in Men study in Kuopio, Finland. CSF AD biomarkers (amyloid ß-peptide (Aß), total tau and tau phosphorylated at the Thr181 epitope) were examined with respect to IR. Targeted proteomics using ELISA and Luminex xMAP assays were performed to assess the influence of IR on previously identified CSF and plasma protein biomarker candidates of AD pathology. Furthermore, CSF and plasma SOMAscan was performed to discover proteins that associate with IR and CSF AD biomarkers. RESULTS: CSF AD biomarkers did not differ between IR and non-IR groups, although plasma insulin correlated with CSF Aß/tau across the whole cohort. In total, 200 CSF and 487 plasma proteins were differentially expressed between IR and non-IR subjects, and significantly enriched pathways, many of which have been previously implicated in AD, were identified. CSF and plasma proteins significantly associated with CSF AD biomarkers were also discovered, and those sensitive to both IR and AD were identified. CONCLUSIONS: These data indicate that IR is not directly related to the level of CSF AD pathology in cognitively healthy men. Proteins that associated with both AD and IR are potential markers indicative of shared pathology.


Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteína E4/sangue , Apolipoproteína E4/líquido cefalorraquidiano , Resistência à Insulina , Animais , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
8.
Artigo em Inglês | MEDLINE | ID: mdl-27872687

RESUMO

Alzheimer's disease (AD) represents a substantial unmet need, due to increasing prevalence in an ageing society and the absence of a disease modifying therapy. Epidemiological evidence shows a protective effect of non steroidal anti inflammatory (NSAID) drugs, and genome wide association studies (GWAS) show consistent linkage to inflammatory pathways; both observations suggesting anti-inflammatory compounds might be effective in AD therapy although clinical trials to date have not been positive. In this study, we use pathway enrichment and fuzzy logic to identify pathways (KEGG database) simultaneously affected in both AD and by NSAIDs (Sulindac, Piroxicam, Paracetamol, Naproxen, Nabumetone, Ketoprofen, Diclofenac and Aspirin). Gene expression signatures were derived for disease from both blood (n = 344) and post-mortem brain (n = 690), and for drugs from immortalised human cell lines exposed to drugs of interest as part of the Connectivity Map platform. Using this novel approach to combine datasets we find striking overlap between AD gene expression in blood and NSAID induced changes in KEGG pathways of Ribosome and Oxidative Phosphorylation. No overlap was found in non NSAID comparison drugs. In brain we find little such overlap, although Oxidative Phosphorylation approaches our pre-specified significance level. These findings suggest that NSAIDs might have a mode of action beyond inflammation and moreover that their therapeutic effects might be mediated in particular by alteration of Oxidative Phosphorylation and possibly the Ribosome pathway. Mining of such datasets might prove increasingly productive as they increase in size and richness.

9.
BMJ Open ; 6(11): e012177, 2016 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-27903560

RESUMO

OBJECTIVE: To investigate medications associated with cognitive function. DESIGN: Population-based cross-sectional cohort study. SETTING: UK Biobank. PARTICIPANTS: UK Biobank participants aged 37-73 years who completed cognitive tests at the baseline visit in 2006-2010. MAIN OUTCOME MEASURES: Cognitive test outcomes on verbal-numerical reasoning test (n=165 493), memory test (n=482 766) and reaction time test (n=496 813). RESULTS: Most drugs (262 of 368) were not associated with any cognitive tests after adjusting for age, gender, education, household income, smoking, alcohol status, psychostimulant/nootropic medication use, assessment centre, and concurrent diagnoses and medications. Drugs used for nervous system disorders were associated with poorer cognitive performance (antiepileptics, eg, topiramate breasoning(score) -0.65 (95% CI -1.05 to -0.24), bmemory(score) -1.41 (-1.79 to -1.04); antipsychotics, eg, risperidone breaction time(ms) -33 (-46 to -20), negative values indicate poor cognitive performance and vice versa). Drugs used for non-nervous system conditions also showed significant negative association with cognitive score, including those where such an association might have been predicted (antihypertensives, eg, amlodipine breasoning -0.1 (-0.15 to -0.06), bmemory -0.08 (-0.13 to -0.03), breaction time -3 (-5 to -2); antidiabetics, eg, insulin breaction time -13 (-17 to -10)) and others where such an association was a surprising observation (proton pump inhibitors, eg, omeprazole breasoning -0.11 (-0.15 to -0.06), bmemory -0.08 (-0.12 to -0.04), breaction time -5 (-6 to -3); laxatives, eg, contact laxatives breaction time -13 (-19 to -8)). Finally, only a few medications and health supplements showed association towards a positive effect on cognitive function (anti-inflammatory agents, eg, ibuprofen breasoning 0.05 (0.02 to 0.08), breaction time 4 (3, 5); glucosamine breasoning 0.09 (0.03 to 0.14), breaction time 5 (3 to 6)). CONCLUSIONS: In this large volunteer study, some commonly prescribed medications were associated with poor cognitive performance. Some associations may reflect underlying diseases for which the medications were prescribed, although the analysis controlled for the possible effect of diagnosis. Other drugs, whose association cannot be linked to the effect of any disease, may need vigilance for their implications in clinical practice.


Assuntos
Analgésicos Opioides/efeitos adversos , Antidepressivos/efeitos adversos , Bancos de Espécimes Biológicos , Fármacos do Sistema Nervoso Central/efeitos adversos , Transtornos Cognitivos/induzido quimicamente , Cognição/efeitos dos fármacos , Psicotrópicos/efeitos adversos , Adulto , Idoso , Transtornos Cognitivos/epidemiologia , Estudos Transversais , Medicamentos Genéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Medição de Risco , Autocuidado , Reino Unido/epidemiologia
10.
Neuropsychologia ; 78: 29-40, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26432343

RESUMO

Action observation is known to trigger predictions of the ongoing course of action and thus considered a hallmark example for predictive perception. A related task, which explicitly taps into the ability to predict actions based on their internal representations, is action segmentation; the task requires participants to demarcate where one action step is completed and another one begins. It thus benefits from a temporally precise prediction of the current action. Formation and exploitation of these temporal predictions of external events is now closely associated with a network including the basal ganglia and prefrontal cortex. Because decline of dopaminergic innervation leads to impaired function of the basal ganglia and prefrontal cortex in Parkinson's disease (PD), we hypothesised that PD patients would show increased temporal variability in the action segmentation task, especially under medication withdrawal (hypothesis 1). Another crucial aspect of action segmentation is its reliance on a semantic representation of actions. There is no evidence to suggest that action representations are substantially altered, or cannot be accessed, in non-demented PD patients. We therefore expected action segmentation judgments to follow the same overall patterns in PD patients and healthy controls (hypothesis 2), resulting in comparable segmentation profiles. Both hypotheses were tested with a novel classification approach. We present evidence for both hypotheses in the present study: classifier performance was slightly decreased when it was tested for its ability to predict the identity of movies segmented by PD patients, and a measure of normativity of response behaviour was decreased when patients segmented movies under medication-withdrawal without access to an episodic memory of the sequence. This pattern of results is consistent with hypothesis 1. However, the classifier analysis also revealed that responses given by patients and controls create very similar action-specific patterns, thus delivering evidence in favour hypothesis 2. In terms of methodology, the use of classifiers in the present study allowed us to establish similarity of behaviour across groups (hypothesis 2). The approach opens up a new avenue that standard statistical methods often fail to provide and is discussed in terms of its merits to measure hypothesised similarities across study populations.


Assuntos
Memória , Modelos Psicológicos , Percepção de Movimento , Doença de Parkinson/psicologia , Adulto , Idoso , Antiparkinsonianos/uso terapêutico , Gânglios da Base/fisiopatologia , Simulação por Computador , Agonistas de Dopamina/uso terapêutico , Humanos , Julgamento/fisiologia , Memória/efeitos dos fármacos , Memória/fisiologia , Pessoa de Meia-Idade , Modelos Neurológicos , Percepção de Movimento/efeitos dos fármacos , Percepção de Movimento/fisiologia , Destreza Motora/efeitos dos fármacos , Destreza Motora/fisiologia , Testes Neuropsicológicos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Estimulação Luminosa , Semântica
11.
PLoS One ; 9(10): e111300, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25333512

RESUMO

Actions expressed prematurely without regard for their consequences are considered impulsive. Such behaviour is governed by a network of brain regions including the prefrontal cortex (PFC) and nucleus accumbens (NAcb) and is prevalent in disorders including attention deficit hyperactivity disorder (ADHD) and drug addiction. However, little is known of the relationship between neural activity in these regions and specific forms of impulsive behaviour. In the present study we investigated local field potential (LFP) oscillations in distinct sub-regions of the PFC and NAcb on a 5-choice serial reaction time task (5-CSRTT), which measures sustained, spatially-divided visual attention and action restraint. The main findings show that power in gamma frequency (50-60 Hz) LFP oscillations transiently increases in the PFC and NAcb during both the anticipation of a cue signalling the spatial location of a nose-poke response and again following correct responses. Gamma oscillations were coupled to low-frequency delta oscillations in both regions; this coupling strengthened specifically when an error response was made. Theta (7-9 Hz) LFP power in the PFC and NAcb increased during the waiting period and was also related to response outcome. Additionally, both gamma and theta power were significantly affected by upcoming premature responses as rats waited for the visual cue to respond. In a subgroup of rats showing persistently high levels of impulsivity we found that impulsivity was associated with increased error signals following a nose-poke response, as well as reduced signals of previous trial outcome during the waiting period. Collectively, these in-vivo neurophysiological findings further implicate the PFC and NAcb in anticipatory impulsive responses and provide evidence that abnormalities in the encoding of rewarding outcomes may underlie trait-like impulsive behaviour.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Comportamento de Escolha/fisiologia , Comportamento Impulsivo/fisiologia , Córtex Pré-Frontal/fisiologia , Animais , Humanos , Masculino , Atividade Motora/fisiologia , Núcleo Accumbens/fisiologia , Ratos , Tempo de Reação , Recompensa
12.
J Physiol ; 592(7): 1429-55, 2014 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-24344162

RESUMO

In Parkinsonism, subthalamic nucleus (STN) neurons and two types of external globus pallidus (GP) neuron inappropriately synchronise their firing in time with slow (∼1 Hz) or beta (13-30 Hz) oscillations in cortex. We recorded the activities of STN, Type-I GP (GP-TI) and Type-A GP (GP-TA) neurons in anaesthetised Parkinsonian rats during such oscillations to constrain a series of computational models that systematically explored the effective connections and physiological parameters underlying neuronal rhythmic firing and phase preferences in vivo. The best candidate model, identified with a genetic algorithm optimising accuracy/complexity measures, faithfully reproduced experimental data and predicted that the effective connections of GP-TI and GP-TA neurons are quantitatively different. Estimated inhibitory connections from striatum were much stronger to GP-TI neurons than to GP-TA neurons, whereas excitatory connections from thalamus were much stronger to GP-TA and STN neurons than to GP-TI neurons. Reciprocal connections between GP-TI and STN neurons were matched in weight, but those between GP-TA and STN neurons were not; only GP-TI neurons sent substantial connections back to STN. Different connection weights between and within the two types of GP neuron were also evident. Adding to connection differences, GP-TA and GP-TI neurons were predicted to have disparate intrinsic physiological properties, reflected in distinct autonomous firing rates. Our results elucidate potential substrates of GP functional dichotomy, and emphasise that rhythmic inputs from striatum, thalamus and cortex are important for setting activity in the STN-GP network during Parkinsonian beta oscillations, suggesting they arise from interactions between most nodes of basal ganglia-thalamocortical circuits.


Assuntos
Globo Pálido/fisiopatologia , Doença de Parkinson/fisiopatologia , Núcleo Subtalâmico/fisiopatologia , Potenciais de Ação , Algoritmos , Animais , Simulação por Computador , Modelos Animais de Doenças , Dopamina/metabolismo , Globo Pálido/metabolismo , Masculino , Modelos Neurológicos , Inibição Neural , Vias Neurais/fisiopatologia , Neurônios/metabolismo , Doença de Parkinson/metabolismo , Periodicidade , Ratos Sprague-Dawley , Núcleo Subtalâmico/metabolismo , Fatores de Tempo
13.
Neuroimage ; 59(3): 2374-92, 2012 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-21945471

RESUMO

In this paper we propose that the dynamic evolution of EEG activity during epileptic seizures may be characterised as a path through parameter space of a neural mass model, reflecting gradual changes in underlying physiological mechanisms. Previous theoretical studies have shown how boundaries in parameter space of the model (so-called bifurcations) correspond to transitions in EEG waveforms between apparently normal, spike and wave and subsequently poly-spike and wave activity. In the present manuscript, we develop a multi-objective genetic algorithm that can estimate parameters of an underlying model from clinical data recordings. A standard approach to this problem is to transform both clinical data and model output into the frequency domain and then choose parameters that minimise the difference in their respective power spectra. Instead in the present manuscript, we estimate parameters in the time domain, their choice being determined according to the best fit obtained between the model output and specific features of the observed EEG waveform. This results in an approximate path through the bifurcation plane of the model obtained from clinical data. We present comparisons of such paths through parameter space from separate seizures from an individual subject, as well as between different subjects. Differences in the path reflect subtleties of variation in the dynamics of EEG, which at present appear indistinguishable using standard clinical techniques.


Assuntos
Eletroencefalografia/estatística & dados numéricos , Epilepsia/fisiopatologia , Algoritmos , Axônios/fisiologia , Encéfalo/fisiopatologia , Córtex Cerebral/fisiopatologia , Análise por Conglomerados , Simulação por Computador , Interpretação Estatística de Dados , Bases de Dados Factuais , Epilepsia Generalizada/fisiopatologia , Genética/estatística & dados numéricos , Humanos , Modelos Neurológicos , Modelos Estatísticos , Vias Neurais/fisiopatologia , Receptores de GABA-B/fisiologia , Reprodutibilidade dos Testes , Processamento de Sinais Assistido por Computador , Sinapses/fisiologia , Tálamo/fisiopatologia
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