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In JoVE (1)
Other Publications (7)
- The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
- Brain Research
- Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism
- Stroke; a Journal of Cerebral Circulation
- International Journal of Molecular Imaging
- Psychopharmacology
- EJNMMI Research
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Articles by Willy Gsell in JoVE
JoVE Clinical and Translational Medicine
Использование фармакологических-вызов МРТ в доклинических исследований: Приложение к 5-HT системы
1Department of Radiology, Brain Imaging Center, Academic Medical Center Amsterdam, 2Biological Imaging Centre, MRC Clinical Sciences Centre, Imperial College London
Цель этого метода состоит в оценке серотонина (5-HT) нейромедиатора функции в живой и свободной дыхания животных с фармакологическими магнитно-резонансной томографии (phMRI) и внутривенное проблемы с селективным ингибитором обратного захвата серотонина (СИОЗС), флуоксетин.
Other articles by Willy Gsell on PubMed
Differential Effects of NMDA and AMPA Glutamate Receptors on Functional Magnetic Resonance Imaging Signals and Evoked Neuronal Activity During Forepaw Stimulation of the Rat
Most of the currently used methods for functional brain imaging do not visualize neuronal activity directly but rather rely on the elicited hemodynamic and/or metabolic responses. Glutamate, the major excitatory neurotransmitter, plays an important role in the neurovascular/neurometabolic coupling, but the specific mechanisms are still poorly understood. To investigate the role of the two major ionotropic glutamate receptors [NMDA receptors (NMDA-Rs) and AMPA receptors (AMPA-Rs)] for the generation of functional magnetic resonance imaging (fMRI) signals, we used fMRI [measurements of blood oxygenation level-dependent (BOLD), perfusion-weighted imaging (PWI), and cerebral blood volume (CBV)] together with recordings of somatosensory evoked potentials (SEPs) during electrical forepaw stimulation in the alpha-chloralose anesthetized rat. Intravenous injection of the NMDA-R antagonist MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate] (0.06 mg/kg plus 3.6 microg x kg(-1) x h(-1)) significantly decreased BOLD (-51 +/- 19%; n = 5) and PWI (-57 +/- 26%; n = 5) responses but reduced the SEPs only mildly (approximately -10%). Systemic application of the AMPA-R antagonist GYKI-53655 [1-(4-aminophenyl)-3-methylcarbamyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine] significantly decreased both the hemodynamic response (BOLD, -49 +/- 13 and -65 +/- 15%; PWI, -22 +/- 48 and -68 +/- 4% for 5 and 7 mg/kg, i.v., respectively; CBV, -80 +/- 7% for 7 mg/kg; n = 4) and the SEPs (up to -60%). These data indicate that the interaction of glutamate with its postsynaptic and/or glial receptors is necessary for the generation of blood flow and BOLD responses and illustrate the differential role of NMDA-Rs and AMPA-Rs in the signaling chain leading from increased neuronal activity to the hemodynamic response in the somatosensory cortex.
Estrogen Receptor Beta Agonist Diarylpropiolnitrile (DPN) Does Not Mediate Neuroprotection in a Rat Model of Permanent Focal Ischemia
Selective estrogen receptor (ER) agonists can indicate which receptor subtypes are implicated in neuroprotection. This study investigated the contribution of ERbeta, using the selective agonist diarylpropiolnitrile (DPN), in a rat model of stroke. Lister Hooded rats were ovariectomized and implanted with mini-pumps containing either DPN (8 mg kg(-1) day(-1)) (n=7) or vehicle (n=5). Sensorimotor function was assessed using a neurological score and the spontaneous forelimb use asymmetry (cylinder) test. One week later the animals received a middle cerebral artery occlusion (MCAO), and T(2)-weighted MRI at 48 h post-MCAO quantified ischemic damage. Functional recovery was tested for 7 days post-MCAO and brains processed for histological verification of infarct size. The MRI images revealed no significant differences in hemispheric lesion volumes between vehicle- and DPN-treated groups (35.6+/-3.5% and 30.8+/-1.7%, respectively [mean+/-SEM]; Student's unpaired t-test df=10, t=-1.357, p=0.453); this was confirmed histologically at 7 days. MCAO induced significant decline in neurological score performance (from 22 to 11 at 2 h post-MCAO) in the vehicle-treated animals, which was not significantly influenced by DPN. MCAO also induced significant changes in forelimb use in the cylinder test (10% reduction in contralateral, 20% reduction in both, and 30% increase in ipsilateral forelimb use) but this response was not significantly different between groups [F(1,1)=2.929, p=0.118, repeated-measures ANOVA]. In conclusion, pretreatment with the ERbeta agonist DPN did not influence infarct size or sensorimotor function in rats exposed to MCAO.
Potential Use of Oxygen As a Metabolic Biosensor in Combination with T2*-weighted MRI to Define the Ischemic Penumbra
We describe a novel magnetic resonance imaging technique for detecting metabolism indirectly through changes in oxyhemoglobin:deoxyhemoglobin ratios and T2(*) signal change during 'oxygen challenge' (OC, 5 mins 100% O(2)). During OC, T2(*) increase reflects O(2) binding to deoxyhemoglobin, which is formed when metabolizing tissues take up oxygen. Here OC has been applied to identify tissue metabolism within the ischemic brain. Permanent middle cerebral artery occlusion was induced in rats. In series 1 scanning (n=5), diffusion-weighted imaging (DWI) was performed, followed by echo-planar T2(*) acquired during OC and perfusion-weighted imaging (PWI, arterial spin labeling). Oxygen challenge induced a T2(*) signal increase of 1.8%, 3.7%, and 0.24% in the contralateral cortex, ipsilateral cortex within the PWI/DWI mismatch zone, and ischemic core, respectively. T2(*) and apparent diffusion coefficient (ADC) map coregistration revealed that the T2(*) signal increase extended into the ADC lesion (3.4%). In series 2 (n=5), FLASH T2(*) and ADC maps coregistered with histology revealed a T2(*) signal increase of 4.9% in the histologically defined border zone (55% normal neuronal morphology, located within the ADC lesion boundary) compared with a 0.7% increase in the cortical ischemic core (92% neuronal ischemic cell change, core ADC lesion). Oxygen challenge has potential clinical utility and, by distinguishing metabolically active and inactive tissues within hypoperfused regions, could provide a more precise assessment of penumbra.
Differences in the Evolution of the Ischemic Penumbra in Stroke-prone Spontaneously Hypertensive and Wistar-Kyoto Rats
Stroke-prone spontaneously hypertensive rats (SHRSP) are a highly pertinent stroke model with increased sensitivity to focal ischemia compared with the normotensive reference strain (Wistar-Kyoto rats; WKY). Study aims were to investigate temporal changes in the ischemic penumbra in SHRSP compared with WKY.
Molecular SPECT Imaging: An Overview
Molecular imaging has witnessed a tremendous change over the last decade. Growing interest and emphasis are placed on this specialized technology represented by developing new scanners, pharmaceutical drugs, diagnostic agents, new therapeutic regimens, and ultimately, significant improvement of patient health care. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) have their signature on paving the way to molecular diagnostics and personalized medicine. The former will be the topic of the current paper where the authors address the current position of the molecular SPECT imaging among other imaging techniques, describing strengths and weaknesses, differences between SPECT and PET, and focusing on different SPECT designs and detection systems. Radiopharmaceutical compounds of clinical as well-preclinical interest have also been reviewed. Moreover, the last section covers several application, of μSPECT imaging in many areas of disease detection and diagnosis.
Age-dependent Effects of Chronic Fluoxetine Treatment on the Serotonergic System One Week Following Treatment
RATIONALE: Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are increasingly used for the treatment of depression in children. Limited data are, however, available on their effects on brain development and their efficacy remains debated. Moreover, previous experimental studies are seriously hampered in their clinical relevance. OBJECTIVES: The aim of the present study was to investigate putative age-related effects of a chronic treatment with fluoxetine (5 mg/kg, either orally or i.p. for 3 weeks, 1 week washout) using conventional methods (behavioral testing and binding assay using [(123)I]β-CIT) and a novel magnetic resonance imaging (MRI) approach. METHODS: Behavior was assessed, as well as serotonin transporter (SERT) availability and function through ex vivo binding assays and in vivo pharmacological MRI (phMRI) with an acute fluoxetine challenge (10 mg/kg oral or 5 mg/kg i.v.) in adolescent and adult rats. RESULTS: Fluoxetine caused an increase in anxiety-like behavior in treated adult, but not adolescent, rats. On the binding assays, we observed increased SERT densities in most cortical brain regions and hypothalamus in adolescent, but not adult, treated rats. Finally, reductions in brain activation were observed with phMRI following treatment, in both adult and adolescent treated animals. CONCLUSION: Collectively, our data indicate that the short-term effects of fluoxetine on the 5-HT system may be age-dependent. These findings could reflect structural and functional rearrangements in the developing brain that do not occur in the matured rat brain. phMRI possibly will be well suited to study this important issue in the pediatric population.
Imaging Technologies for Preclinical Models of Bone and Joint Disorders
ABSTRACT: Preclinical models for musculoskeletal disorders are critical for understanding the pathogenesis of bone and joint disorders in humans and the development of effective therapies. The assessment of these models primarily relies on morphological analysis which remains time consuming and costly, requiring large numbers of animals to be tested through different stages of the disease. The implementation of preclinical imaging represents a keystone in the refinement of animal models allowing longitudinal studies and enabling a powerful, non-invasive and clinically translatable way for monitoring disease progression in real time. Our aim is to highlight examples that demonstrate the advantages and limitations of different imaging modalities including magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), single-photon emission computed tomography (SPECT) and optical imaging. All of which are in current use in preclinical skeletal research. MRI can provide high resolution of soft tissue structures, but imaging requires comparatively long acquisition times; hence, animals require long-term anaesthesia. CT is extensively used in bone and joint disorders providing excellent spatial resolution and good contrast for bone imaging. Despite its excellent structural assessment of mineralized structures, CT does not provide in vivo functional information of ongoing biological processes. Nuclear medicine is a very promising tool for investigating functional and molecular processes in vivo with new tracers becoming available as biomarkers. The combined use of imaging modalities also holds significant potential for the assessment of disease pathogenesis in animal models of musculoskeletal disorders, minimising the use of conventional invasive methods and animal redundancy.
