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1.
Biol Psychiatry ; 86(4): 315-326, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31010580

RESUMO

BACKGROUND: Autism spectrum disorder and attention-deficit/hyperactivity disorder (ADHD) are associated with complex changes as revealed by functional magnetic resonance imaging. To date, neuroimaging-based models are not able to characterize individuals with sufficient sensitivity and specificity. Further, although evidence shows that ADHD traits occur in individuals with autism spectrum disorder, and autism spectrum disorder traits in individuals with ADHD, the neurofunctional basis of the overlap is undefined. METHODS: Using individuals from the Autism Brain Imaging Data Exchange and ADHD-200, we apply a data-driven, subject-level approach, connectome-based predictive modeling, to resting-state functional magnetic resonance imaging data to identify brain-behavior associations that are predictive of symptom severity. We examine cross-diagnostic commonalities and differences. RESULTS: Using leave-one-subject-out and split-half analyses, we define networks that predict Social Responsiveness Scale, Autism Diagnostic Observation Schedule, and ADHD Rating Scale scores and confirm that these networks generalize to novel subjects. Networks share minimal overlap of edges (<2%) but some common regions of high hubness (Brodmann areas 10, 11, and 21, cerebellum, and thalamus). Further, predicted Social Responsiveness Scale scores for individuals with ADHD are linked to ADHD symptoms, supporting the hypothesis that brain organization relevant to autism spectrum disorder severity shares a component associated with attention in ADHD. Predictive connections and high-hubness regions are found within a wide range of brain areas and across conventional networks. CONCLUSIONS: An individual's functional connectivity profile contains information that supports dimensional, nonbinary classification in autism spectrum disorder and ADHD. Furthermore, we can determine disorder-specific and shared neurofunctional pathology using our method.

2.
J Magn Reson Imaging ; 46(2): 505-517, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28703413

RESUMO

PURPOSE: Stroke is the leading cause of adult disability worldwide. The absence of more effective interventions in the chronic stage-that most patients stand to benefit from-reflects uncertainty surrounding mechanisms that govern recovery. The present work investigated the effects of a novel treatment (selective cyclooxygenase-1, COX-1, inhibition) in a model of focal ischemia. MATERIALS AND METHODS: FR122047 (COX-1 inhibitor) was given beginning 7 days following stroke (cortical microinjection of endothelin-1) in 23 adult male rats. Longitudinal continuous-arterial-spin-labeling was performed prior to treatment (7 days), and repeated following treatment (21 days) on a 7T magnetic resonance imaging (MRI) system to estimate resting perfusion and reactivity to hypercapnia. These in vivo measurements were buttressed by immunohistochemistry. RESULTS: Stroke caused an increase in perilesional resting perfusion (peri-/contralesional perfusion ratio of 170 ± 10%) and perfusion responses to hypercapnia (180 ± 10%) at 7 days. At 21 days, placebo-administered rats showed normalized perilesional perfusion (100 ± 20%) but persistent hyperreactivity (190 ± 20%). Treated animals exhibited sustained perilesional hyperperfusion (180 ± 10%). Further, reactivity lateralization did not persist following treatment (peri- vs. contralesional reactivity: P = 0.002 at 7 vs. P = 0.2 at 21 days). Hemodynamic changes were accompanied by neuronal loss, increased endothelial density, and widespread microglial and astrocytic activation. Moreover, relative to controls, treated rats showed increased perilesional neuronal survival (22 ± 1% vs. 14.9 ± 0.8%, P = 0.02) and decreased microglia/macrophage recruitment (17 ± 1% vs. 20 ± 1%, P = 0.05). Finally, perilesional perfusion was correlated with neuronal survival (slope = 0.14 ± 0.05; R2 = 0.7, P = 0.03). CONCLUSION: These findings shed light on the role of COX-1 in chronic ischemic injury and suggest that delayed selective COX-1 inhibition exerts multiple beneficial effects on the neurogliovascular unit. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 4 J. MAGN. RESON. IMAGING 2017;46:505-517.


Assuntos
Inibidores de Ciclo-Oxigenase/farmacologia , Isquemia/diagnóstico por imagem , Imagem por Ressonância Magnética , Proteínas de Membrana/antagonistas & inibidores , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/fisiopatologia , Animais , Ciclo-Oxigenase 1 , Modelos Animais de Doenças , Endotelina-1/química , Macrófagos/patologia , Masculino , Microglia/patologia , Neuroglia/patologia , Neurônios/patologia , Perfusão , Piperazinas/química , Ratos , Ratos Sprague-Dawley , Marcadores de Spin , Tiazóis/química
3.
Neuroimage ; 146: 869-882, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-27664828

RESUMO

Brain plasticity following focal cerebral ischaemia has been observed in both stroke survivors and in preclinical models of stroke. Endogenous neurovascular adaptation is at present incompletely understood yet its potentiation may improve long-term functional outcome. We employed longitudinal MRI, intracranial array electrophysiology, Montoya Staircase testing, and immunofluorescence to examine function of brain vessels, neurons, and glia in addition to forelimb skilled reaching during the subacute stage of ischemic injury progression. Focal ischemic stroke (~100mm3 or ~20% of the total brain volume) was induced in adult Sprague-Dawley rats via direct injection of endothelin-1 (ET-1) into the right sensori-motor cortex, producing sustained impairment in left forelimb reaching ability. Resting perfusion and vascular reactivity to hypercapnia in the peri-lesional cortex were elevated by approximately 60% and 80% respectively seven days following stroke. At the same time, the normal topological pattern of local field potential (LFP) responses to peripheral somatosensory stimulation was abolished and the average power of spontaneous LFP activity attenuated by approximately 50% relative to the contra-lesional cortex, suggesting initial response attenuation within the peri-infarct zone. By 21 days after stroke, perilesional blood flow resolved, but peri-lesional vascular reactivity remained elevated. Concomitantly, the LFP response amplitudes increased with distance from the site of ET-1 injection, suggesting functional remodelling from the core of the lesion to its periphery. This notion was further buttressed by the lateralization of spontaneous neuronal activity: by day 21, the average ipsi-lesional power of spontaneous LFP activity was almost twice that of the contra-lesional cortex. Over the observation period, the peri-lesional cortex exhibited increased vascular density, along with neuronal loss, astrocytic activation, and recruitment and activation of microglia and macrophages, with neuronal loss and inflammation extending beyond the peri-lesional cortex. These findings highlight the complex relationship between neurophysiological state and behaviour and provide evidence of highly dynamic functional changes in the peri-infarct zone weeks following the ischemic insult, suggesting an extended temporal window for therapeutic interventions.


Assuntos
Isquemia Encefálica/fisiopatologia , Encéfalo/irrigação sanguínea , Encéfalo/fisiopatologia , Córtex Somatossensorial/irrigação sanguínea , Córtex Somatossensorial/fisiopatologia , Acidente Vascular Cerebral/fisiopatologia , Remodelação Vascular , Animais , Encéfalo/metabolismo , Isquemia Encefálica/induzido quimicamente , Isquemia Encefálica/complicações , Ondas Encefálicas , Encefalite/complicações , Encefalite/metabolismo , Endotelina-1/administração & dosagem , Hipercapnia/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Destreza Motora , Neuroglia/metabolismo , Neurônios/metabolismo , Estimulação Física , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Córtex Sensório-Motor/efeitos dos fármacos , Acidente Vascular Cerebral/induzido quimicamente , Acidente Vascular Cerebral/complicações , Percepção do Tato/fisiologia
4.
Eur Arch Psychiatry Clin Neurosci ; 267(5): 369-376, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27629158

RESUMO

Imaging and postmortem studies into the severe mental illnesses of major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ) have revealed deficiencies in the myelination of deep white matter tracts of the brain. Recent studies have further suggested that deficits could extend to myelinated fibers running through the cortex in those illnesses. Disruptions in this intracortical myelin may underlie functional symptomology in MDD, BD, and SZ; thus, in this study, we hypothesized that individuals with these illnesses may have reduced myelin staining relative to controls in the cerebral cortex. We stained 60 sections of dorsolateral prefrontal cortex for myelin with Luxol® fast blue in four groups: 15 BD, 15 MDD, 15 SZ, and 15 controls with no psychiatric illness. We digitally measured optical tissue attenuation reflecting the amount of myelin staining across six cortical depths in the middle frontal gyrus (MFG), in superficial white matter in the crown of the MFG, and in deep white matter. We found that a diagnosis of MDD or SZ meant that optical tissue attenuation was significantly reduced in the shallowest depths of the cortex. Furthermore, there was a trend toward reduced optical tissue attenuation in all illnesses across all myelinated regions we studied. These results encourage future studies into potential reductions in intracortical myelin in severe mental illness.


Assuntos
Transtorno Bipolar/patologia , Transtorno Depressivo Maior/patologia , Bainha de Mielina/patologia , Córtex Pré-Frontal/patologia , Esquizofrenia/patologia , Adulto , Amidinas/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Bainha de Mielina/metabolismo , Fibras Nervosas Mielinizadas/patologia
5.
Artigo em Inglês | MEDLINE | ID: mdl-27574307

RESUMO

Ischaemic stroke is the leading cause of adult disability worldwide. Effective rehabilitation is hindered by uncertainty surrounding the underlying mechanisms that govern long-term ischaemic injury progression. Despite its potential as a sensitive non-invasive in vivo marker of brain function that may aid in the development of new treatments, blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) has found limited application in the clinical research on chronic stage stroke progression. Stroke affects each of the physiological parameters underlying the BOLD contrast, markedly complicating the interpretation of BOLD fMRI data. This review summarizes current progress on application of BOLD fMRI in the chronic stage of ischaemic injury progression and discusses means by which more information may be gained from such BOLD fMRI measurements. Concomitant measurements of vascular reactivity, neuronal activity and metabolism in preclinical models of stroke are reviewed along with illustrative examples of post-ischaemic evolution in neuronal, glial and vascular function. The realization of the BOLD fMRI potential to propel stroke research is predicated on the carefully designed preclinical research establishing an ischaemia-specific quantitative model of BOLD signal contrast to provide the framework for interpretation of fMRI findings in clinical populations.This article is part of the themed issue 'Interpreting BOLD: a dialogue between cognitive and cellular neuroscience'.


Assuntos
Mapeamento Encefálico/métodos , Imagem por Ressonância Magnética/métodos , Acidente Vascular Cerebral/diagnóstico por imagem , Progressão da Doença , Humanos , Oxigênio/sangue , Acidente Vascular Cerebral/fisiopatologia
6.
J Cereb Blood Flow Metab ; 35(10): 1601-9, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25966952

RESUMO

To aid in development of chronic stage treatments for sensorimotor deficits induced by ischemic stroke, we investigated the effects of GABA antagonism on brain structure and fine skilled reaching in a rat model of focal ischemia induced via cortical microinjections of endothelin-1 (ET-1). Beginning 7 days after stroke, animals were administered a gamma-aminobutyric acid (GABAA) inverse agonist, L-655,708, at a dose low enough to afford α5-GABAA receptor specificity. A week after stroke, the ischemic lesion comprised a small hypointense necrotic core (6±1 mm(3)) surrounded by a large (62±11 mm(3)) hyperintense perilesional region; the skilled reaching ability on the Montoya staircase test was decreased to 34%±2% of the animals' prestroke performance level. On L-655,708 treatment, animals showed a progressive decrease in total stroke volume (13±4 mm(3) per week), with no change in animals receiving placebo. Concomitantly, treated animals' skilled reaching progressively improved by 9%±1% per week, so that after 2 weeks of treatment, these animals performed at 65%±6% of their baseline ability, which was 25%±11% better than animals given placebo. These data indicate beneficial effects of delayed, sustained low-dose GABAA antagonism on neuroanatomic injury and skilled reaching in the chronic stage of stroke recovery in an ET-1 rat model of focal ischemia.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/psicologia , Destreza Motora/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/psicologia , Animais , Comportamento Animal/efeitos dos fármacos , Endotelina-1/farmacologia , Antagonistas GABAérgicos/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Imidazóis/farmacologia , Masculino , Necrose , Consumo de Oxigênio/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/efeitos dos fármacos , Recuperação de Função Fisiológica/efeitos dos fármacos , Taxa Respiratória/efeitos dos fármacos , Volume Sistólico/efeitos dos fármacos
7.
J Neurosci Methods ; 235: 92-100, 2014 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-24970578

RESUMO

BACKGROUND: The most commonly used animal models of spinal cord injury (SCI) involve surgical exposure of the dorsal spinal cord followed by transection, contusion or compression. This high level of invasiveness often requires significant post-operative care and can limit post-operative imaging, as the surgical incision site can interfere with coil placement for magnetic resonance imaging (MRI) during the acute phase of SCI. While these models are considered to be similar to human SCI, they do not occur in a closed vertebral system as do the majority of human injuries. NEW METHOD: Here we describe a novel, non-surgical model of SCI in the rat using MR-guided focused ultrasound (FUS) in combination with intravenous injection of microbubbles, applied to the cervical spinal cord. RESULTS: The injury was well-tolerated and resulted in cervical spinal cord damage in 60% of the animals. The area of Gd-enhancement immediately post-FUS and area of signal abnormality at 24h were correlated with the degree of injury. The extent of injury was easily visualized with T2-weighted MRI and was confirmed using histology. COMPARISON WITH EXISTING METHOD(S): Pathology was similar to that seen in other rat models of direct spinal cord contusion and compression. Unlike these methods, FUS is non-surgical and has lower mortality than seen in other models of cervical SCI. CONCLUSIONS: We developed a novel model of SCI which was non-surgical, well-tolerated, localized, and replicated the pathology seen in other models of SCI.


Assuntos
Medula Cervical/lesões , Modelos Animais de Doenças , Doença Aguda , Animais , Medula Cervical/patologia , Doença Crônica , Meios de Contraste , Gadolínio , Injeções Intravenosas , Imagem por Ressonância Magnética , Masculino , Microbolhas , Atividade Motora , Ratos Wistar , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Fatores de Tempo , Ultrassonografia
8.
Biochim Biophys Acta ; 1788(12): 2563-74, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19799854

RESUMO

Proteorhodopsins are typical retinal-binding light-driven proton pumps of heptahelical architecture widely distributed in marine and freshwater bacteria. Recently, we have shown that green proteorhodopsin (GPR) can be prepared in a lipid-bound state that gives well-resolved magic angle spinning (MAS) NMR spectra in samples with different patterns of reverse labelling. Here, we present 3D and 4D sequential chemical shift assignments identified through experiments conducted on a uniformly (13)C,(15)N-labelled sample. These experiments provided the assignments for 153 residues, with a particularly high density in the transmembrane regions ( approximately 74% of residues). The extent of assignments permitted a detailed examination of the secondary structure and dynamics in GPR. In particular, we present experimental evidence of mobility of the protein's termini and of the A-B, C-D, and F-G loops, the latter being possibly coupled to the GPR ion-transporting function.


Assuntos
Proteínas de Bactérias/química , Rodopsina/química , Bactérias/química , Bactérias/genética , Proteínas de Bactérias/genética , Ressonância Magnética Nuclear Biomolecular/métodos , Estrutura Secundária de Proteína/fisiologia , Rodopsina/genética , Rodopsinas Microbianas
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