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1.
PLoS Comput Biol ; 17(8): e1009252, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34379638

RESUMO

People with Alzheimer's disease (AD) are 6-10 times more likely to develop seizures than the healthy aging population. Leading hypotheses largely consider hyperexcitability of local cortical tissue as primarily responsible for increased seizure prevalence in AD. However, in the general population of people with epilepsy, large-scale brain network organization additionally plays a role in determining seizure likelihood and phenotype. Here, we propose that alterations to large-scale brain network organization seen in AD may contribute to increased seizure likelihood. To test this hypothesis, we combine computational modelling with electrophysiological data using an approach that has proved informative in clinical epilepsy cohorts without AD. EEG was recorded from 21 people with probable AD and 26 healthy controls. At the time of EEG acquisition, all participants were free from seizures. Whole brain functional connectivity derived from source-reconstructed EEG recordings was used to build subject-specific brain network models of seizure transitions. As cortical tissue excitability was increased in the simulations, AD simulations were more likely to transition into seizures than simulations from healthy controls, suggesting an increased group-level probability of developing seizures at a future time for AD participants. We subsequently used the model to assess seizure propensity of different regions across the cortex. We found the most important regions for seizure generation were those typically burdened by amyloid-beta at the early stages of AD, as previously reported by in-vivo and post-mortem staging of amyloid plaques. Analysis of these spatial distributions also give potential insight into mechanisms of increased susceptibility to generalized (as opposed to focal) seizures in AD vs controls. This research suggests avenues for future studies testing patients with seizures, e.g. co-morbid AD/epilepsy patients, and comparisons with PET and MRI scans to relate regional seizure propensity with AD pathologies.


Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/fisiopatologia , Encéfalo/fisiopatologia , Modelos Neurológicos , Convulsões/etiologia , Convulsões/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Doença de Alzheimer/patologia , Encéfalo/patologia , Estudos de Casos e Controles , Biologia Computacional , Simulação por Computador , Suscetibilidade a Doenças , Eletroencefalografia/estatística & dados numéricos , Fenômenos Eletrofisiológicos , Feminino , Humanos , Masculino , Rede Nervosa/patologia , Rede Nervosa/fisiopatologia , Redes Neurais de Computação , Convulsões/patologia
2.
Sci Rep ; 11(1): 16116, 2021 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-34373482

RESUMO

Prior diffusion tensor imaging (DTI) studies have investigated white matter (WM) changes in patients with primary restless legs syndrome (RLS), but the results were inconsistent. Here, we proposed using tract-specific statistical analysis (TSSA) to find alterations in specific WM tracts to clarify the pathophysiological mechanisms of RLS. We enrolled 30 patients with RLS and 31 age- and sex- matched controls who underwent brain magnetic resonance imaging, neuropsychological tests, and polysomnography. Fractional anisotropy (FA) maps obtained from whole-brain diffusion tensor imaging and TSSA were used to localize WM changes in patients with RLS. Subsequently, a comparison of FA values for each tract between patients and controls was performed. The associations between FA values and clinical, polysomnographic, and neuropsychological parameters in RLS patients were assessed. RLS patients demonstrated decreased FA values in the left corticospinal tract (CST) and cingulum, and in the right anterior thalamic radiation (ATR) and inferior fronto-occipital fasciculus (IFO). Patients' attention/executive function and visual memory scores positively correlated with FA values in the right ATR, and anxiety levels negatively correlated with FA values in the right IFO. Additionally, the number of periodic leg movements and movement arousal index were negatively correlated with FA values in the left CST. The TSSA method identified previously unknown tract-specific alterations in patients with RLS and significant associations with distinct clinical manifestations of RLS.


Assuntos
Síndrome das Pernas Inquietas/patologia , Substância Branca/patologia , Adulto , Anisotropia , Imagem de Tensor de Difusão/métodos , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Rede Nervosa/patologia , Neuroimagem/métodos , Testes Neuropsicológicos , Tratos Piramidais/patologia
3.
Sci Rep ; 11(1): 16790, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34408195

RESUMO

With diffuse infiltrative glioma being increasingly recognized as a systemic brain disorder, the macroscopically apparent tumor lesion is suggested to impact on cerebral functional and structural integrity beyond the apparent lesion site. We investigated resting-state functional connectivity (FC) and diffusion-MRI-based structural connectivity (SC) (comprising edge-weight (EW) and fractional anisotropy (FA)) in isodehydrogenase mutated (IDHmut) and wildtype (IDHwt) patients and healthy controls. SC and FC were determined for whole-brain and the Default-Mode Network (DMN), mean intra- and interhemispheric SC and FC were compared across groups, and partial correlations were analyzed intra- and intermodally. With interhemispheric EW being reduced in both patient groups, IDHwt patients showed FA decreases in the ipsi- and contralesional hemisphere, whereas IDHmut patients revealed FA increases in the contralesional hemisphere. Healthy controls showed strong intramodal connectivity, each within the structural and functional connectome. Patients however showed a loss in structural and reductions in functional connectomic coherence, which appeared to be more pronounced in IDHwt glioma patients. Findings suggest a relative dissociation of structural and functional connectomic coherence in glioma patients at the time of diagnosis, with more structural connectomic aberrations being encountered in IDHwt glioma patients. Connectomic profiling may aid in phenotyping and monitoring prognostically differing tumor types.


Assuntos
Encéfalo/diagnóstico por imagem , Conectoma , Glioma/diagnóstico por imagem , Encéfalo/patologia , Encéfalo/ultraestrutura , Imagem de Difusão por Ressonância Magnética , Imagem de Tensor de Difusão , Feminino , Glioma/patologia , Glioma/ultraestrutura , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/patologia , Giro do Cíngulo/ultraestrutura , Humanos , Masculino , Pessoa de Meia-Idade , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/patologia , Rede Nervosa/ultraestrutura
4.
Cells ; 10(7)2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34359997

RESUMO

The noradrenergic theory of Cognitive Reserve (Robertson, 2013-2014) postulates that the upregulation of the locus coeruleus-noradrenergic system (LC-NA) originating in the brainstem might facilitate cortical networks involved in attention, and protracted activation of this system throughout the lifespan may enhance cognitive stimulation contributing to reserve. To test the above-mentioned theory, a study was conducted on a sample of 686 participants (395 controls, 156 mild cognitive impairment, 135 Alzheimer's disease) investigating the relationship between LC volume, attentional performance and a biological index of brain maintenance (BrainPAD-an objective measure, which compares an individual's structural brain health, reflected by their voxel-wise grey matter density, to the state typically expected at that individual's age). Further analyses were carried out on reserve indices including education and occupational attainment. Volumetric variation across groups was also explored along with gender differences. Control analyses on the serotoninergic (5-HT), dopaminergic (DA) and cholinergic (Ach) systems were contrasted with the noradrenergic (NA) hypothesis. The antithetic relationships were also tested across the neuromodulatory subcortical systems. Results supported by Bayesian modelling showed that LC volume disproportionately predicted higher attentional performance as well as biological brain maintenance across the three groups. These findings lend support to the role of the noradrenergic system as a key mediator underpinning the neuropsychology of reserve, and they suggest that early prevention strategies focused on the noradrenergic system (e.g., cognitive-attentive training, physical exercise, pharmacological and dietary interventions) may yield important clinical benefits to mitigate cognitive impairment with age and disease.


Assuntos
Neurônios Adrenérgicos/patologia , Doença de Alzheimer/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Reserva Cognitiva/fisiologia , Substância Cinzenta/diagnóstico por imagem , Locus Cerúleo/diagnóstico por imagem , Rede Nervosa/diagnóstico por imagem , Idoso , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Atenção/fisiologia , Teorema de Bayes , Estudos de Casos e Controles , Neurônios Colinérgicos/patologia , Disfunção Cognitiva/patologia , Disfunção Cognitiva/fisiopatologia , Neurônios Dopaminérgicos/patologia , Escolaridade , Exercício Físico/fisiologia , Feminino , Substância Cinzenta/patologia , Substância Cinzenta/fisiopatologia , Humanos , Locus Cerúleo/patologia , Locus Cerúleo/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Modelos Neurológicos , Rede Nervosa/patologia , Rede Nervosa/fisiopatologia , Neuroimagem , Tamanho do Órgão , Neurônios Serotoninérgicos/patologia , Fatores Sexuais
5.
Cells ; 10(8)2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34440631

RESUMO

The extracellular matrix (ECM) plays a key role in synaptogenesis and the regulation of synaptic functions in the central nervous system. Recent studies revealed that in addition to dopaminergic and serotoninergic neuromodulatory systems, microglia also contribute to the regulation of ECM remodeling. In the present work, we investigated the physiological role of microglia in the remodeling of perineuronal nets (PNNs), predominantly associated with parvalbumin-immunopositive (PV+) interneurons, and the perisynaptic ECM around pyramidal neurons in the hippocampus. Adult mice were treated with PLX3397 (pexidartinib), as the inhibitor of colony-stimulating factor 1 receptor (CSF1-R), to deplete microglia. Then, confocal analysis of the ECM and synapses was performed. Although the elimination of microglia did not alter the overall number or intensity of PNNs in the CA1 region of the hippocampus, it decreased the size of PNN holes and elevated the expression of the surrounding ECM. In the neuropil area in the CA1 str. radiatum, the depletion of microglia increased the expression of perisynaptic ECM proteoglycan brevican, which was accompanied by the elevated expression of presynaptic marker vGluT1 and the increased density of dendritic spines. Thus, microglia regulate the homeostasis of pre- and postsynaptic excitatory terminals and the surrounding perisynaptic ECM as well as the fine structure of PNNs enveloping perisomatic-predominantly GABAergic-synapses.


Assuntos
Região CA1 Hipocampal/patologia , Sinapses Elétricas/patologia , Potenciais Pós-Sinápticos Excitadores , Matriz Extracelular/patologia , Microglia/patologia , Aminopiridinas/toxicidade , Animais , Brevicam/metabolismo , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Receptor 1 de Quimiocina CX3C/genética , Sinapses Elétricas/metabolismo , Matriz Extracelular/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Masculino , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Rede Nervosa/metabolismo , Rede Nervosa/patologia , Pirróis/toxicidade , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo , Ácido gama-Aminobutírico/metabolismo
6.
J Neurochem ; 159(1): 12-14, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34252196

RESUMO

Various neuroimaging approaches have reported alterations in brain connectivity in patients with autism spectrum disorder (ASD). Nevertheless, specific cellular and molecular mechanisms underlying these alterations remain to be elucidated. In the present Editorial, we highlight an article in the current issue of the Journal of Neurochemistry that provides first evidence for the structural and cellular basis of an atypical corpus callosum long-distance connectivity impairments observed in ASD patients. The authors used a juvenile valproic acid (VPA) rat model of ASD that presents with reduced myelin level, specifically in the corpus callosum, and with an altered myelin sheet structure that is closely associated with the behavioral alteration found in these rats. This hypomyelination occurs primarily during infancy prior to oligodendroglial alterations, implicating that axonal-oligodendroglial connections are compromised in this model. Concomitant with the hypomyelination, the ASD rat model showed an atypical brain metabolic pattern, with hypometabolic activity across the whole brain, and hypermetabolism in brain areas related to autistic-like behavior. These findings contribute to unravel the neurobiological basis underlying white matter alteration and altered long-distance brain connectivity as described in ASD, paving the way to the development of new early diagnostic markers and toward developing future specific therapies for ASD.


Assuntos
Transtorno Autístico/induzido quimicamente , Transtorno Autístico/metabolismo , Corpo Caloso/metabolismo , Rede Nervosa/metabolismo , Ácido Valproico/toxicidade , Animais , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/patologia , Transtorno Autístico/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Corpo Caloso/efeitos dos fármacos , Humanos , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/patologia , Ratos
7.
Int J Mol Sci ; 22(11)2021 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-34204090

RESUMO

The intravenous cocaine self-administration model is widely used to characterize the neurobiology of cocaine seeking. When studies are aimed at understanding relapse to cocaine-seeking, a post-cocaine abstinence period is imposed, followed by "relapse" tests to assess the ability of drug-related stimuli ("primes") to evoke the resumption of the instrumental response previously made to obtain cocaine. Here, we review the literature on the impact of post-cocaine abstinence procedures on neurobiology, finding that the prelimbic and infralimbic regions of the prefrontal cortex are recruited by extinction training, and are not part of the relapse circuitry when extinction training does not occur. Pairing cocaine infusions with discrete cues recruits the involvement of the NA, which together with the dorsal striatum, is a key part of the relapse circuit regardless of abstinence procedures. Differences in molecular adaptations in the NA core include increased expression of GluN1 and glutamate receptor signaling partners after extinction training. AMPA receptors and glutamate transporters are similarly affected by abstinence and extinction. Glutamate receptor antagonists show efficacy at reducing relapse following extinction and abstinence, with a modest increase in efficacy of compounds that restore glutamate homeostasis after extinction training. Imaging studies in humans reveal cocaine-induced adaptations that are similar to those produced after extinction training. Thus, while instrumental extinction training does not have face validity, its use does not produce adaptations distinct from human cocaine users.


Assuntos
Transtornos Relacionados ao Uso de Cocaína/genética , Transtornos Relacionados ao Uso de Cocaína/psicologia , Cocaína/efeitos adversos , Extinção Psicológica/fisiologia , Animais , Humanos , Rede Nervosa/patologia , Recidiva
8.
Sci Rep ; 11(1): 15400, 2021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-34321538

RESUMO

Network neuroscience shed some light on the functional and structural modifications occurring to the brain associated with the phenomenology of schizophrenia. In particular, resting-state functional networks have helped our understanding of the illness by highlighting the global and local alterations within the cerebral organization. We investigated the robustness of the brain functional architecture in 44 medicated schizophrenic patients and 40 healthy comparators through an advanced network analysis of resting-state functional magnetic resonance imaging data. The networks in patients showed more resistance to disconnection than in healthy controls, with an evident discrepancy between the two groups in the node degree distribution computed along a percolation process. Despite a substantial similarity of the basal functional organization between the two groups, the expected hierarchy of healthy brains' modular organization is crumbled in schizophrenia, showing a peculiar arrangement of the functional connections, characterized by several topologically equivalent backbones. Thus, the manifold nature of the functional organization's basal scheme, together with its altered hierarchical modularity, may be crucial in the pathogenesis of schizophrenia. This result fits the disconnection hypothesis that describes schizophrenia as a brain disorder characterized by an abnormal functional integration among brain regions.


Assuntos
Encéfalo/diagnóstico por imagem , Conectoma , Rede Nervosa/ultraestrutura , Esquizofrenia/diagnóstico , Adolescente , Adulto , Idoso , Encéfalo/fisiopatologia , Encéfalo/ultraestrutura , Mapeamento Encefálico , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/patologia , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/patologia , Adulto Jovem
9.
J Neurochem ; 159(1): 128-144, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34081798

RESUMO

Atypical connectivity between brain regions and altered structure of the corpus callosum (CC) in imaging studies supports the long-distance hypoconnectivity hypothesis proposed for autism spectrum disorder (ASD). The aim of this study was to unveil the CC ultrastructural and cellular changes employing the valproic acid (VPA) rat model of ASD. Male Wistar rats were exposed to VPA (450 mg/kg i.p.) or saline (control) during gestation (embryonic day 10.5), and maturation, exploration, and social behavior were subsequently tested. Myelin content, ultrastructure, and oligodendroglial lineage were studied in the CC at post-natal days 15 (infant) and 36 (juvenile). As a functional outcome, brain metabolic activity was determined by positron emission tomography. Concomitantly with behavioral deficits in juvenile VPA rats, the CC showed reduced myelin basic protein, conserved total number of axons, reduced percentage of myelinated axons, and aberrant and less compact arrangements of myelin sheath ultrastructure. Mature oligodendrocytes decreased and oligodendrocyte precursors increased in the absence of astrogliosis or microgliosis. In medial prefrontal and somatosensory cortices of juvenile VPA rats, myelin ultrastructure and oligodendroglial lineage were preserved. VPA animals exhibited global brain hypometabolism and local hypermetabolism in brain regions relevant for ASD. In turn, the CC of infant VPA rats showed reduced myelin content but preserved oligodendroglial lineage. Our findings indicate that CC hypomyelination is established during infancy and prior to oligodendroglial pattern alterations, which suggests that axon-oligodendroglia communication could be compromised in VPA animals. Thus, CC hypomyelination may underlie white matter alterations and contribute to atypical patterns of connectivity and metabolism found in ASD.


Assuntos
Transtorno do Espectro Autista/metabolismo , Corpo Caloso/metabolismo , Rede Nervosa/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Comportamento Social , Ácido Valproico/toxicidade , Animais , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/patologia , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Feminino , Masculino , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/patologia , Ratos , Ratos Wistar , Tomografia Computadorizada de Emissão de Fóton Único/métodos
10.
Aging (Albany NY) ; 13(11): 15491-15500, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34106878

RESUMO

PURPOSE: Previous studies in patients with Alzheimer's disease have shown amyloid beta accumulation in the brain and abnormal brain activity, with mild cognitive impairment (MCI) in early stages of the disease. The aim of the current study was to investigate functional connectivity in patients with MCI. METHODS: We recruited 24 subjects in total, including 12 patients with MCI (6 men and 6 women) and 12 healthy controls (HCs) (6 men and 6 women), matched for age, gender, and lifestyle factors. All subjects underwent resting-state functional magnetic resonance imaging scans and voxel-wise degree centrality (DC) was used to evaluate alterations in the strength of brain network connectivity. RESULTS: The DC value of the left inferior temporal gyrus was lower in MCI but significantly higher in the right fusiform gyrus and the left supplementary motor area, compared with HCs. The DC value in left inferior temporal gyrus correlated positively with disease duration and negatively with Mini-Mental State Examination. ROC curve analysis of brain regions showed acceptable specificity and accuracy of DC values between MCIs and HCs in the area under the curve (right fusiform gyrus, 0.955; left supplementary motor area, 0.992; left inferior temporal gyrus, 1.000). CONCLUSIONS: Abnormal functional connectivity in brain regions of patients with MCI may reflect the pathological process of Alzheimer's disease development and could prove useful in clinical diagnosis and treatment.


Assuntos
Algoritmos , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/patologia , Imageamento por Ressonância Magnética , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/patologia , Estudos de Casos e Controles , Feminino , Fundo de Olho , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC
11.
PLoS Comput Biol ; 17(6): e1009115, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34133417

RESUMO

Alzheimer's Disease (AD) is characterized by progressive neurodegeneration and cognitive impairment. Synaptic dysfunction is an established early symptom, which correlates strongly with cognitive decline, and is hypothesised to mediate the diverse neuronal network abnormalities observed in AD. However, how synaptic dysfunction contributes to network pathology and cognitive impairment in AD remains elusive. Here, we present a grid-cell-to-place-cell transformation model of long-term CA1 place cell dynamics to interrogate the effect of synaptic loss on network function and environmental representation. Synapse loss modelled after experimental observations in the APP/PS1 mouse model was found to induce firing rate alterations and place cell abnormalities that have previously been observed in AD mouse models, including enlarged place fields and lower across-session stability of place fields. Our results support the hypothesis that synaptic dysfunction underlies cognitive deficits, and demonstrate how impaired environmental representation may arise in the early stages of AD. We further propose that dysfunction of excitatory and inhibitory inputs to CA1 pyramidal cells may cause distinct impairments in place cell function, namely reduced stability and place map resolution.


Assuntos
Doença de Alzheimer/etiologia , Modelos Neurológicos , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Animais , Região CA1 Hipocampal/patologia , Região CA1 Hipocampal/fisiopatologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/patologia , Disfunção Cognitiva/fisiopatologia , Biologia Computacional , Simulação por Computador , Modelos Animais de Doenças , Células de Grade/patologia , Células de Grade/fisiologia , Humanos , Camundongos , Rede Nervosa/patologia , Rede Nervosa/fisiopatologia , Plasticidade Neuronal/fisiologia , Células de Lugar/patologia , Células de Lugar/fisiologia , Sinapses/patologia , Sinapses/fisiologia , Transmissão Sináptica/fisiologia
12.
PLoS One ; 16(6): e0251338, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34101741

RESUMO

Cognitive impairment is a common symptom in individuals with Multiple Sclerosis (MS), but meaningful, reliable biomarkers relating to cognitive decline have been elusive, making evaluation of the impact of therapeutics on cognitive function difficult. Here, we combine pathway-based MRI measures of structural and functional connectivity to construct a metric of functional decline in MS. The Structural and Functional Connectivity Index (SFCI) is proposed as a simple, z-scored metric of structural and functional connectivity, where changes in the metric have a simple statistical interpretation and may be suitable for use in clinical trials. Using data collected at six time points from a 2-year longitudinal study of 20 participants with MS and 9 age- and sex-matched healthy controls, we probe two common symptomatic domains, motor and cognitive function, by measuring structural and functional connectivity in the transcallosal motor pathway and posterior cingulum bundle. The SFCI is significantly lower in participants with MS compared to controls (p = 0.009) and shows a significant decrease over time in MS (p = 0.012). The change in SFCI over two years performed favorably compared to measures of brain parenchymal fraction and lesion volume, relating to follow-up measures of processing speed (r = 0.60, p = 0.005), verbal fluency (r = 0.57, p = 0.009), and score on the Multiple Sclerosis Functional Composite (r = 0.67, p = 0.003). These initial results show that the SFCI is a suitable metric for longitudinal evaluation of functional decline in MS.


Assuntos
Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Esclerose Múltipla/diagnóstico por imagem , Rede Nervosa/diagnóstico por imagem , Neuroimagem/métodos , Substância Branca/diagnóstico por imagem , Adulto , Encéfalo/patologia , Disfunção Cognitiva/patologia , Conectoma , Progressão da Doença , Feminino , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/patologia , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Esclerose Múltipla/patologia , Rede Nervosa/patologia , Testes Neuropsicológicos , Substância Branca/patologia
13.
Nat Commun ; 12(1): 2589, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33972524

RESUMO

Patients with Tuberous Sclerosis Complex (TSC) show aberrant wiring of neuronal connections formed during development which may contribute to symptoms of TSC, such as intellectual disabilities, autism, and epilepsy. Yet models examining the molecular basis for axonal guidance defects in developing human neurons have not been developed. Here, we generate human induced pluripotent stem cell (hiPSC) lines from a patient with TSC and genetically engineer counterparts and isogenic controls. By differentiating hiPSCs, we show that control neurons respond to canonical guidance cues as predicted. Conversely, neurons with heterozygous loss of TSC2 exhibit reduced responses to several repulsive cues and defective axon guidance. While TSC2 is a known key negative regulator of MTOR-dependent protein synthesis, we find that TSC2 signaled through MTOR-independent RHOA in growth cones. Our results suggest that neural network connectivity defects in patients with TSC may result from defects in RHOA-mediated regulation of cytoskeletal dynamics during neuronal development.


Assuntos
Orientação de Axônios/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Rede Nervosa/metabolismo , Neurogênese/genética , Neurônios/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo , Esclerose Tuberosa/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Adolescente , Orientação de Axônios/efeitos dos fármacos , Biópsia , Sistemas CRISPR-Cas , Linhagem Celular , Efrinas/farmacologia , Transferência Ressonante de Energia de Fluorescência , Haploinsuficiência , Heterozigoto , Humanos , Masculino , Miosinas/metabolismo , Rede Nervosa/patologia , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Organoides/citologia , Organoides/metabolismo , Biossíntese de Proteínas/efeitos dos fármacos , Biossíntese de Proteínas/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/metabolismo , Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética
14.
Nat Commun ; 12(1): 2590, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33972513

RESUMO

Thrombolysis with recombinant tissue plasminogen activator in acute ischemic stroke aims to restore compromised blood flow and prevent further neuronal damage. Despite the proven clinical efficacy of this treatment, little is known about the short-term effects of systemic thrombolysis on structural brain connectivity. In this secondary analysis of the WAKE-UP trial, we used MRI-derived measures of infarct size and estimated structural network disruption to establish that thrombolysis is associated not only with less infarct growth, but also with reduced loss of large-scale connectivity between grey-matter areas after stroke. In a causal mediation analysis, infarct growth mediated a non-significant 8.3% (CI95% [-8.0, 32.6]%) of the clinical effect of thrombolysis on functional outcome. The proportion mediated jointly through infarct growth and change of structural connectivity, especially in the border zone around the infarct core, however, was as high as 33.4% (CI95% [8.8, 77.4]%). Preservation of structural connectivity is thus an important determinant of treatment success and favourable functional outcome in addition to lesion volume. It might, in the future, serve as an imaging endpoint in clinical trials or as a target for therapeutic interventions.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Terapia Trombolítica/métodos , Ativador de Plasminogênio Tecidual/uso terapêutico , Idoso , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/patologia , Progressão da Doença , Fibrinolíticos/uso terapêutico , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Acidente Vascular Cerebral/fisiopatologia , Terapia Trombolítica/efeitos adversos , Fatores de Tempo
15.
Aging (Albany NY) ; 13(9): 13166-13178, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33972462

RESUMO

This study investigated functional alterations in the cerebral network of patients with hypertensive retinopathy (HR) by resting-state functional magnetic resonance imaging (rs-fMRI) and degree centrality (DC) methods. 31 patients with HR along with 31 healthy controls (HC) closely matched in gender and age were enrolled for the research. All participants were examined by rs-fMRI, and the DC method was applied to evaluate alterations in spontaneous cerebral activity between the 2 groups. We used the independent samples t test to evaluate demographic and general information differences between HR patients and HCs. The 2-sample t test was used to compare the DC values of different cerebral regions between the 2 groups. The accuracy of differential diagnostic HR was analyzed by receiver operating characteristic (ROC) curve method for rs-fMRI DC values changes. Pearson's correlation coefficient was applied to determine the correlation between differences in DC in specific cerebral areas and clinical manifestation. Results showed that DC values were higher in the left cerebellum posterior lobe (LCPL), left medial occipital gyrus (LMOG), and bilateral precuneus (BP) of HR patients compared to HCs. Mean DC values were lower in the right medial frontal gyrus/bilateral anterior cingulate cortex of HR patients. Anxiety and depression scores were positively correlated with DC values of LMOG and LCPL, respectively. Bilateral best-corrected visual acuity in HR patients was negatively correlated with the DC value of BP. Hence, changes in DC in specific cerebral areas of patients with HR reflect functional alterations that provide insight into the pathophysiologic mechanisms of HR.


Assuntos
Encéfalo/patologia , Retinopatia Hipertensiva/fisiopatologia , Imageamento por Ressonância Magnética , Rede Nervosa/patologia , Adulto , Encéfalo/fisiopatologia , Feminino , Humanos , Retinopatia Hipertensiva/patologia , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Rede Nervosa/fisiopatologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Curva ROC
16.
Epilepsia ; 62(7): 1701-1714, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34002378

RESUMO

OBJECTIVE: Early life seizures (ELSs) alter activity-dependent maturation of neuronal circuits underlying learning and memory. The pathophysiological mechanisms underpinning seizure-induced cognitive impairment are not fully understood, and critical variables such as sex and dynamic brain states with regard to cognitive outcomes have not been explored. We hypothesized that in comparison to control (CTL) rats, ELS rats would exhibit deficits in spatial cognition correlating with impaired dynamic neural signal coordination between the hippocampus and medial prefrontal cortex (mPFC). METHODS: Male and female rat pups were given 50 flurothyl-induced seizures over 10 days starting at postnatal Day 15. As adults, spatial cognition was tested through active avoidance on a rotating arena. Microwire tetrodes were implanted in the mPFC and CA1 subfield. Single cells and local field potentials were recorded and analyzed in each region during active avoidance and sleep. RESULTS: ELS males exhibited avoidance impairments, whereas female rats were unaffected. During avoidance, hippocampus-mPFC coherence was higher in CTL females than CTL males across bandwidths. In comparison to CTL males, ELS male learners exhibit increased coherence within theta bandwidth as well as altered burst-timing in mPFC cell activity. Hippocampus-mPFC coherence levels are predictive of cognitive outcome in the active avoidance spatial task. SIGNIFICANCE: Spatial cognitive outcome post-ELS is sex-dependent, as females fare better than males. ELS males that learn the task exhibit increased mPFC coherence levels at low-theta frequency, which may compensate for ELS effects on mPFC cell timing. These results suggest that coherence may serve as a biomarker for spatial cognitive outcome post-ELS and emphasize the significance of analyzing sex and dynamic cognition as variables in understanding seizure effects on the developing brain.


Assuntos
Encéfalo/patologia , Hipocampo/patologia , Rede Nervosa/patologia , Córtex Pré-Frontal/patologia , Convulsões/patologia , Animais , Aprendizagem da Esquiva , Encéfalo/fisiopatologia , Região CA1 Hipocampal/patologia , Cognição , Convulsivantes , Eletrodos Implantados , Eletroencefalografia , Feminino , Flurotila , Masculino , Aprendizagem em Labirinto , Ratos , Ratos Sprague-Dawley , Convulsões/induzido quimicamente , Convulsões/psicologia , Caracteres Sexuais , Sono , Percepção Espacial , Ritmo Teta
17.
Neuroimage ; 237: 118112, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-33940145

RESUMO

The preterm brain has been analysed after birth by a large body of neuroimaging studies; however, few studies have focused on white matter alterations in preterm subjects beyond infancy, especially in individuals born at extremely low gestation age - before 28 completed weeks. Neuroimaging data of extremely preterm young adults are now available to investigate the long-term structural alterations of disrupted neurodevelopment. We examined white matter hierarchical organisation and microstructure in extremely preterm young adults. Specifically, we first identified the putative hubs and peripheral regions in 85 extremely preterm young adults and compared them with 53 socio-economically matched and full-term born peers. Moreover, we analysed Fractional Anisotropy (FA), Mean Diffusivity (MD), Neurite Density Index (NDI), and Orientation Dispersion Index (ODI) of white matter in hubs, peripheral regions, and over the whole brain. Our results suggest that the hierarchical organisation of the extremely preterm adult brain remains intact. However, there is evidence of significant alteration of white matter connectivity at both the macro- and microstructural level, with overall diminished connectivity, reduced FA and NDI, increased MD, and comparable ODI; suggesting that, although the spatial configuration of WM fibres is comparable, there are less WM fibres per voxel. These alterations are found throughout the brain and are more prevalent along the pathways between deep grey matter regions, frontal regions and cerebellum. This work provides evidence that white matter abnormalities associated with the premature exposure to the extrauterine environment not only are present at term equivalent age but persist into early adulthood.


Assuntos
Encéfalo/patologia , Imagem de Tensor de Difusão , Lactente Extremamente Prematuro , Rede Nervosa/patologia , Substância Branca/patologia , Adulto , Encéfalo/diagnóstico por imagem , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Rede Nervosa/diagnóstico por imagem , Substância Branca/diagnóstico por imagem
18.
Neuroimage ; 237: 118126, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-33957234

RESUMO

Tau neurofibrillary tangles, a pathophysiological hallmark of Alzheimer's disease (AD), exhibit a stereotypical spatiotemporal trajectory that is strongly correlated with disease progression and cognitive decline. Personalized prediction of tau progression is, therefore, vital for the early diagnosis and prognosis of AD. Evidence from both animal and human studies is suggestive of tau transmission along the brains preexisting neural connectivity conduits. We present here an analytic graph diffusion framework for individualized predictive modeling of tau progression along the structural connectome. To account for physiological processes that lead to active generation and clearance of tau alongside passive diffusion, our model uses an inhomogenous graph diffusion equation with a source term and provides closed-form solutions to this equation for linear and exponential source functionals. Longitudinal imaging data from two cohorts, the Harvard Aging Brain Study (HABS) and the Alzheimer's Disease Neuroimaging Initiative (ADNI), were used to validate the model. The clinical data used for developing and validating the model include regional tau measures extracted from longitudinal positron emission tomography (PET) scans based on the 18F-Flortaucipir radiotracer and individual structural connectivity maps computed from diffusion tensor imaging (DTI) by means of tractography and streamline counting. Two-timepoint tau PET scans were used to assess the goodness of model fit. Three-timepoint tau PET scans were used to assess predictive accuracy via comparison of predicted and observed tau measures at the third timepoint. Our results show high consistency between predicted and observed tau and differential tau from region-based analysis. While the prognostic value of this approach needs to be validated in a larger cohort, our preliminary results suggest that our longitudinal predictive model, which offers an in vivo macroscopic perspective on tau progression in the brain, is potentially promising as a personalizable predictive framework for AD.


Assuntos
Doença de Alzheimer , Imagem de Tensor de Difusão , Progressão da Doença , Modelos Neurológicos , Rede Nervosa , Tomografia por Emissão de Pósitrons , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Conjuntos de Dados como Assunto , Feminino , Humanos , Estudos Longitudinais , Masculino , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/metabolismo , Rede Nervosa/patologia , Prognóstico
19.
Laryngoscope ; 131(8): 1863-1868, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33811641

RESUMO

OBJECTIVES: To investigate neuroanatomic volume differences in tinnitus and hearing loss. STUDY DESIGN: Cross-sectional. METHODS: Sixteen regions of interest (ROIs) in adults (43 male, 29 female) were examined using 3Tesla structural magnetic resonance imaging in four cohorts: 1) tinnitus with moderate hearing loss (N = 31), 2) moderate hearing loss only (N = 15), 3) tinnitus with normal hearing (N = 17), and 4) normal hearing only (N = 13). ROI volumes were corrected for brain size, age, and sex variations. Analysis of covariance (ANCOVA) and post hoc Tukey's test were used to isolate the effects of tinnitus and hearing loss on volume differences. Effect sizes were calculated as the fraction of total variance (η2 ) in ANCOVA models and percent of mean volume difference relative to mean total volume. RESULTS: The four cohort ANCOVA revealed tinnitus and hearing loss cohorts to have increased volume in the corona radiata (η2  = 0.192; P = .0018) and decreased volume in the nucleus accumbens (η2  = 0.252; P < .0001), caudate nucleus (η2  = 0.188; P = .002), and inferior fronto-occipital fasciculus (η2  = 0.250; P = .0001). Tinnitus with normal hearing showed decreased volume in the nucleus accumbens (22.0%; P = .001) and inferior fronto-occipital fasciculus (18.1%; P = .002), and hearing loss only showed increased volume in the corona radiata (10.7%; P = .01) and decreased volume in the nucleus accumbens (22.1%; P = .001), caudate nucleus (16.1%; P = .004), and inferior fronto-occipital fasciculus (18.3%; P = .003). CONCLUSION: Tinnitus and hearing loss have overlapping effects on neurovolumetric alterations, especially impacting the nucleus accumbens and inferior fronto-occipital fasciculus. Neurovolumetric studies on tinnitus or hearing loss can be more complete by accounting for those two clinical dimensions separately and jointly. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:1863-1868, 2021.


Assuntos
Encéfalo/patologia , Perda Auditiva/patologia , Imageamento por Ressonância Magnética , Rede Nervosa/patologia , Zumbido/patologia , Adulto , Idoso , Análise de Variância , Encéfalo/diagnóstico por imagem , Estudos Transversais , Feminino , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/patologia , Perda Auditiva/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Rede Nervosa/diagnóstico por imagem , Núcleo Accumbens/diagnóstico por imagem , Núcleo Accumbens/patologia , Lobo Occipital/diagnóstico por imagem , Lobo Occipital/patologia , Tamanho do Órgão , Zumbido/diagnóstico por imagem
20.
Neuroimage ; 236: 118089, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33882347

RESUMO

White matter hyperintensities (WMH) are a prominent feature of cerebral small vessel disease and are associated with cognitive impairment. These deficits in cognition may be caused by the disruption of large-scale functional networks due to the presence of WMHs. However, knowledge regarding the relevance of these lesions on functional networks remains inconclusive. These inconsistencies may derive from issues with interpreting functional imaging data from clinical populations. Lesion network mapping is a technique that allows the overlaying of lesions from a patient population to the functional connectivity of a human connectome derived from healthy adults. This allows researchers to identify functional networks that would be disrupted in a healthy population should the WMHs seen in cerebral small vessel disease be present. We hypothesized that the extent to which these functional networks are disrupted by WMHs is associated with cognitive performance in older adults with cerebral small vessel disease. This cross-sectional study combined baseline data from four studies to create a total sample of 164 older adults (aged ≥55) from metropolitan Vancouver with cerebral small vessel disease. Using lesion network mapping, we assessed the percentage overlap between voxels functionally connected with both the WMHs (lesion network) and five common functional networks: (1) visual; (2) dorsal attention; (3) ventral attention; (4) sensorimotor; and (5) frontoparietal. Cognition was assessed using: (1) Montreal Cognitive Assessment (MoCA); (2) Stroop Colour Word Test (3-2); (3) Trail Making Tests (Part B-A); and (4) Digit Symbol Substitution Test. A One-Way ANOVA and Tukey post-hoc tests were performed to identify the functional networks with greatest percentage overlap with the lesion network. Partial correlations controlling for age were used to analyse whether the extent of the overlap between the lesion and functional networks was associated with poorer cognition. The visual, ventral attention, and frontoparietal networks had significantly greater overlap with the lesion network. After controlling for multiple comparisons, level of lesion network overlap with both the sensorimotor network (p<.001) and ventral attention network (p <. 001) was significantly correlated with MoCA score. Thus, the greater the disruption to the sensorimotor and ventral attention networks, the poorer the global cognition. Our results reveal that the visual, ventral attention, and frontoparietal networks are most vulnerable to disruptions stemming from WMHs. Additionally, we identified that disruption to the sensorimotor and ventral attention networks, as a result of WMHs, may underlie deficits in global cognition in older adults with cerebral small vessel disease.


Assuntos
Doenças de Pequenos Vasos Cerebrais , Disfunção Cognitiva , Conectoma , Estudos Transversais , Função Executiva/fisiologia , Leucoaraiose , Rede Nervosa , Idoso , Idoso de 80 Anos ou mais , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Doenças de Pequenos Vasos Cerebrais/patologia , Doenças de Pequenos Vasos Cerebrais/fisiopatologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/patologia , Disfunção Cognitiva/fisiopatologia , Feminino , Humanos , Leucoaraiose/diagnóstico por imagem , Leucoaraiose/patologia , Leucoaraiose/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/patologia , Rede Nervosa/fisiopatologia , Testes Neuropsicológicos
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