<p>The images illustrate the typical activation pattern that was found in all experimental birds. The signal shown here is for all sounds presented and all brain images averaged together. The left panel shows the... more
<p>The images illustrate the typical activation pattern that was found in all experimental birds. The signal shown here is for all sounds presented and all brain images averaged together. The left panel shows the <i>P</i>-values of significant activated pixels, the right panel shows the signal strength relative to the mean signal difference. The three lines show the division in regions of interest conform <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0003184#pone-0003184-g003" target="_blank">Figure 3</a>.</p
Research Interests: Neuroscience and Medicine
Huntington’s disease (HD) is a neurodegenerative disorder caused by expanded (≥40) glutamine-encoding CAG repeats in the huntingtin gene, which leads to dysfunction and death of predominantly striatal and cortical neurons. While the... more
Huntington’s disease (HD) is a neurodegenerative disorder caused by expanded (≥40) glutamine-encoding CAG repeats in the huntingtin gene, which leads to dysfunction and death of predominantly striatal and cortical neurons. While the genetic profile and behavioural signs of the disease are better known, changes in the functional architecture of the brain, especially before the behavioural symptoms become apparent, are not fully and consistently characterized. In this study, we sought markers at pre, early and late manifest states of phenotypic progression in the heterozygous (HET) zQ175 delta-neo (DN) mouse model, using resting-state functional magnetic resonance imaging (RS-fMRI). This mouse model shows molecular, cellular and circuitry alterations that resemble those seen in HD in humans. Specifically, we investigated, longitudinally, changes in co-activation patterns (CAPs) that are the transient states of brain activity constituting the resting-state networks (RSNs). Most robust ...
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<p>Results are superimposed on sagittal anatomical slices coming from the zebra finch MRI atlas. T values are color coded according to the scale displayed at the bottom of the figure. Note that in the figure other auditory regions... more
<p>Results are superimposed on sagittal anatomical slices coming from the zebra finch MRI atlas. T values are color coded according to the scale displayed at the bottom of the figure. Note that in the figure other auditory regions (Field L and caudo-medial mesopallium) seem not activated only because the statistical analysis was restricted to NCM (for the whole activation pattern in the telencephalic auditory regions, see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0061764#pone-0061764-g002" target="_blank">fig. 2</a>). Only significant voxels (one-tailed t-test, p<0.05, corrected at NCM level) are displayed. D: dorsal, V: ventral, A: anterior, P: posterior.</p
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<p>TUT, BOS and CON responsiveness are expressed as the mean amplitude estimates of the BOLD activations [TUT minus Rest], [BOS minus Rest] and [CON minus Rest], in non-dimensional unit) in the left NCM cluster illustrated in <a... more
<p>TUT, BOS and CON responsiveness are expressed as the mean amplitude estimates of the BOLD activations [TUT minus Rest], [BOS minus Rest] and [CON minus Rest], in non-dimensional unit) in the left NCM cluster illustrated in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0061764#pone-0061764-g008" target="_blank">Fig. 8</a>. Note that the R<sup>2</sup> value in the left panel (0.3089) corresponds to the correlation value between learning strength and the [TUT minus Rest] signal averaged over the NCM cluster illustrated in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0061764#pone-0061764-g008" target="_blank">Fig. 8</a> whereas the value reported in the text (0.36) corresponds to the correlation in the voxel where this correlation is the highest (R<sup>2</sup><sub>max</sub>). These two R<sup>2</sup> values are significantly different than 0. Correlation of BOS and CON responsiveness with learning strength are not significant.</p
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1Thyroid hormones clearly play a role in the seasonal regulation of reproduction, but any role they might play in song behavior and the associated seasonal neuroplasticity in songbirds remains to be elucidated. To pursue this question, we... more
1Thyroid hormones clearly play a role in the seasonal regulation of reproduction, but any role they might play in song behavior and the associated seasonal neuroplasticity in songbirds remains to be elucidated. To pursue this question, we first established seasonal patterns in the expression of thyroid hormone regulating genes in male European starlings employing in situ hybridization methods. Thyroid hormone transporter LAT1 expression in the song nucleus HVC was elevated during the photosensitive phase, pointing towards an active role of thyroid hormones during this window of possible neuroplasticity. In contrast DIO3 expression was high in HVC during the photostimulated phase, limiting the possible effect of thyroid hormones to maintain song stability during the breeding season. Next, we studied the effect of hypothyroidism on song behavior and neuroplasticity using in vivo MRI. Hypothyroidism inhibited the photostimulation-induced increase in testosterone, confirming the role of...
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Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by expanded CAG repeats in the gene (). Although mutant HTT is expressed during embryonic development and throughout life, clinical HD usually manifests... more
Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by expanded CAG repeats in the gene (). Although mutant HTT is expressed during embryonic development and throughout life, clinical HD usually manifests later in adulthood. A number of studies document neurodevelopmental changes associated with mutant , but whether these are reversible under therapy remains unclear. Here, we identify very early behavioral, molecular, and cellular changes in preweaning transgenic HD rats and mice. Reduced ultrasonic vocalization, loss of prepulse inhibition, and increased risk taking are accompanied by disturbances of dopaminergic regulation in vivo, reduced neuronal differentiation capacity in subventricular zone stem/progenitor cells, and impaired neuronal and oligodendrocyte differentiation of mouse embryo-derived neural stem cells in vitro. Interventional treatment of this early phenotype with the histone deacetylase inhibitor (HDACi) LBH589 led to significant impr...
Research Interests: Neuroscience, Biology, Medicine, Multidisciplinary, Transgenic Mice, and 15 moreCell Differentiation, Humans, Mutation, Female, Animals, Disease, Male, Neurons, Huntingtin, Rats, Huntington disease, Hydroxamic Acids, HUMAN MEDICINE, Histone deacetylase inhibitors, and Modern Sciences and Engineering Technology
There is currently a lack of prognostic biomarkers to predict the different sequelae following traumatic brain injury (TBI). The present study investigated the hypothesis that subacute neuroinflammation and microstructural changes... more
There is currently a lack of prognostic biomarkers to predict the different sequelae following traumatic brain injury (TBI). The present study investigated the hypothesis that subacute neuroinflammation and microstructural changes correlate with chronic TBI deficits. Rats were subjected to Controlled Cortical Impact (CCI) injury, sham surgery or skin incision (naïve). CCI-injured (n=18) and sham-operated rats (n=6) underwent positron emission tomography (PET) imaging with the translocator protein (TSPO) radioligand [18F]PBR111 and diffusion tensor imaging (DTI) in the subacute phase (≤3 weeks post-injury) to quantify inflammation and microstructural alterations. CCI-injured, sham-operated and naïve rats (n=8) underwent behavioural testing in the chronic phase (5.5-10 months post-injury): open field and sucrose preference tests, two one-week video-EEG monitoring periods, pentylenetetrazole seizure susceptibility tests, and a Morris water maze test. In vivo imaging revealed pronounced...
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Subtle adjustment of the activation status of CNS resident microglia and peripheral macrophages, to promote their neuroprotective and neuroregenerative functions, may facilitate research towards curing neurodegenerative disorders. In the... more
Subtle adjustment of the activation status of CNS resident microglia and peripheral macrophages, to promote their neuroprotective and neuroregenerative functions, may facilitate research towards curing neurodegenerative disorders. In the present study, we investigated whether targeted intracerebral delivery of the anti-inflammatory cytokine interleukin (IL)13, by means of transplanting IL13-expressing mesenchymal stem cells (IL13-MSCs), can promote a phenotypic switch in both microglia and macrophages during the pro-inflammatory phase in a mouse model of ischemic stroke. We used the CXCR1 CCR2 transgenic mouse model to separately recognize brain-resident microglia from infiltrated macrophages. Quantitative immunohistochemical analyses were applied to characterize polarization phenotypes of both cell types. Distinct behaviors of both cell populations were noted dependent on the anatomical site of the lesion. Immunohistochemistry revealed that mice grafted with IL13-MSCs, in contrast ...
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Time-resolved 'dynamic' over whole-period 'static' analysis of low frequency (LF) blood-oxygen level dependent (BOLD) fluctuations provides many additional insights into the macroscale organization and dynamics of neural... more
Time-resolved 'dynamic' over whole-period 'static' analysis of low frequency (LF) blood-oxygen level dependent (BOLD) fluctuations provides many additional insights into the macroscale organization and dynamics of neural activity. Although there has been considerable advancement in the development of mouse resting state fMRI (rsfMRI), very little remains known about its dynamic repertoire. Here, we report for the first time the detection of a set of recurring spatiotemporal Quasi-Periodic Patterns (QPPs) in mice, which show spatial similarity with known resting state networks. Furthermore, we establish a close relationship between several of these patterns and the global signal. We acquired high temporal rsfMRI scans under conditions of low (LA) and high (HA) medetomidine-isoflurane anesthesia. We then employed the algorithm developed by Majeed et al. (2011), previously applied in rats and humans, which detects and averages recurring spatiotemporal patterns in the LF...
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Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in the elderly population. In this study, we used the APP/PS1 transgenic mouse model to explore the feasibility of using... more
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in the elderly population. In this study, we used the APP/PS1 transgenic mouse model to explore the feasibility of using diffusion kurtosis imaging (DKI) as a tool for the early detection of microstructural changes in the brain due to amyloid-β (Aβ) plaque deposition. We longitudinally acquired DKI data of wild-type (WT) and APP/PS1 mice at 2, 4, 6 and 8 months of age, after which these mice were sacrificed for histological examination. Three additional cohorts of mice were also included at 2, 4 and 6 months of age to allow voxel-based co-registration between diffusion tensor and diffusion kurtosis metrics and immunohistochemistry. Changes were observed in diffusion tensor (DT) and diffusion kurtosis (DK) metrics in many of the 23 regions of interest that were analysed. Mean and axial kurtosis were greatly increased owing to Aβ-induced pathological changes in the motor cor...
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Amyloid-β (Aβ) peptides occur in the brains of patients with Alzheimer's disease (AD), but their role in functional impairment is still debated. High levels of APP and APP fragments in mice that overexpress APP might confound their... more
Amyloid-β (Aβ) peptides occur in the brains of patients with Alzheimer's disease (AD), but their role in functional impairment is still debated. High levels of APP and APP fragments in mice that overexpress APP might confound their use in preclinical research. We examined the occurrence of behavioral, cognitive and neuroimaging changes in APPNL-G-F knock-in mice that display Aβ42 amyloidosis in the absence of APP overexpression. Female APPNL-G-F mice (carrying Swedish, Iberian and Arctic APP mutations) were compared to APPNL mice (APP Swedish) at 3, 7 and 10 months. Mice were subjected to a test battery that referred to clinical AD symptoms, comprising cage activity, open field, elevated plus maze, social preference and novelty test, and spatial learning, reversal learning and spatial reference memory performance. Our assessment confirmed that behavior at these early ages was largely unaffected in these mice in accordance with previous reports, with some subtle behavioral change...
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Despite being commonly referenced throughout neuroscientific research on songbirds, reports of hemispheric specialization in the processing of song remain controversial. The notion of such asymmetries in songbirds is further complicated... more
Despite being commonly referenced throughout neuroscientific research on songbirds, reports of hemispheric specialization in the processing of song remain controversial. The notion of such asymmetries in songbirds is further complicated by evidence that both cerebral hemispheres in humans may be specialized for different aspects of speech perception. Some studies suggest that the auditory neural substrates in the left and right hemispheres of humans process temporal and spectral elements within speech sounds, respectively. To determine whether songbirds process their conspecific songs in such a complementary, bilateral manner, we performed functional magnetic resonance imaging (fMRI) on 15 isoflurane anesthetized adult male zebra finches (Taeniopygia guttata) while presenting them with (1) non-manipulated, (2) spectrally-filtered (reduced spectral structure), and (3) temporally-filtered (reduced temporal structure) conspecific song. Our results revealed sensitivity of both primary (...
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Significance Cells from the innate immune system, namely microglia and macrophages (mononuclear phagocytes, MPs), play a central role in the progression of neurological disorders such as multiple sclerosis. Such cells can contribute to... more
Significance Cells from the innate immune system, namely microglia and macrophages (mononuclear phagocytes, MPs), play a central role in the progression of neurological disorders such as multiple sclerosis. Such cells can contribute to lesion formations (proinflammatory) or participate in remyelinating processes (neuroprotective). When differentiated to a proinflammatory phenotype, MPs experience metabolic reprogramming leading to increased glycolysis and production of lactate. In this study we showed that a new metabolic imaging method, namely 13 C magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized pyruvate, can detect increased lactate production from proinflammatory MPs, a mechanism mediated by pyruvate dehydrogenase kinase 1 upregulation, in a preclinical model of multiple sclerosis. These findings validate the potential of 13 C MRSI of hyperpolarized pyruvate for in vivo detection of neuroinflammation.
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It is increasingly recognized that brain-derived estrogens (neuroestrogens) can regulate brain physiology and behavior much faster than what was previously known from the transcriptional action of estrogens on nuclear receptors. One of... more
It is increasingly recognized that brain-derived estrogens (neuroestrogens) can regulate brain physiology and behavior much faster than what was previously known from the transcriptional action of estrogens on nuclear receptors. One of the best examples of such neuromodulation by neuroestrogens concerns the acute regulation of sensory coding by the auditory cortex as demonstrated by electrophysiological studies of selected neurons in zebra finches. Yet, the spatial extent of such modulation by neuroestrogens is not known. Using functional magnetic resonance imaging, we demonstrate here that acute estrogen depletion alters within minutes auditory processing in male European starlings. These effects are confined to very specific but large areas of the auditory cortex. They are also specifically lateralized to the left hemisphere. Interestingly, the modulation of auditory responses by estrogens was much larger (both in amplitude and in topography) in March than in December or May/June....
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Intracerebral injection of the excitotoxic, endogenous tryptophan metabolite, quinolinic acid (QA), constitutes a chemical model of neurodegenerative brain disease. Complementary techniques were combined to examine the consequences of QA... more
Intracerebral injection of the excitotoxic, endogenous tryptophan metabolite, quinolinic acid (QA), constitutes a chemical model of neurodegenerative brain disease. Complementary techniques were combined to examine the consequences of QA injection into medial prefrontal cortex (mPFC) of C57BL6 mice. In accordance with the NMDAR-mediated synapto- and neurotoxic action of QA, we found an initial increase in excitability and an augmentation of hippocampal long-term potentiation, converting within two weeks into a reduction and impairment, respectively, of these processes. QA-induced mPFC excitotoxicity impaired behavioral flexibility in a reversal variant of the hidden-platform Morris water maze (MWM), whereas regular, extended MWM training was unaffected. QA-induced mPFC damage specifically affected the spatial-cognitive strategies that mice use to locate the platform during reversal learning. These behavioral and cognitive defects coincided with changes in cortical functional connect...
Research Interests: Neuroscience, Long Term Potentiation, Magnetic Resonance Imaging, Biology, Medicine, and 13 morePrefrontal Cortex, Neuroplasticity, Hippocampus, Mice, Female, Animals, Neuronal Plasticity, Neurons, Reversal Learning, Maze Learning, Modern Sciences and Engineering Technology, Hippocampal formation, and quinolinic acid
Research Interests: Immunology, Magnetic Resonance Imaging, Biology, Cytokines, Medicine, and 15 moreMesenchymal stem cells, Mice, Animals, Microglia, Mesenchymal Stem Cell, Clinical Sciences, Glial Fibrillary Acidic Protein, Mesenchymal Stromal Cells, HUMAN MEDICINE, Interleukin, Cuprizone, Gliosis, Demyelinating diseases, myelin basic protein, and Monoamine oxidase inhibitors
Detrimental inflammatory responses in the central nervous system are a hallmark of various brain injuries and diseases. With this study we provide evidence that lentiviral vector-mediated expression of the immune-modulating cytokine... more
Detrimental inflammatory responses in the central nervous system are a hallmark of various brain injuries and diseases. With this study we provide evidence that lentiviral vector-mediated expression of the immune-modulating cytokine interleukin 13 (IL-13) induces an alternative activation program in both microglia and macrophages conferring protection against severe oligodendrocyte loss and demyelination in the cuprizone mouse model for multiple sclerosis (MS). First, IL-13 mediated modulation of cuprizone induced lesions was monitored using T2 -weighted magnetic resonance imaging and magnetization transfer imaging, and further correlated with quantitative histological analyses for inflammatory cell influx, oligodendrocyte death, and demyelination. Second, following IL-13 immune gene therapy in cuprizone-treated eGFP(+) bone marrow chimeric mice, we provide evidence that IL-13 directs the polarization of both brain-resident microglia and infiltrating macrophages towards an alternati...
Research Interests: Immunology, Magnetic Resonance Imaging, Biology, Cytokines, Inflammation, and 15 moreMacrophages, Medicine, Genetic Enhancement, Mice, Animals, Demyelination, Immune system, Bone Marrow Transplantation, Glia, Encephalitis, HUMAN MEDICINE, Interleukin, Cuprizone, Genetic Therapy, and Demyelinating diseases
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Background: Arterial stiffness is an independent predictor of cardiovascular risk. The aim of this study was to investigate the effects of arterial stiffness on the progression of atherosclerosis. ...
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In Alzheimer's disease (AD), pathologic amyloid-beta (Aβ) is synaptotoxic and impairs neuronal function at the microscale, influencing brain networks at the macroscale before Aβ deposition. The latter can be detected noninvasively,... more
In Alzheimer's disease (AD), pathologic amyloid-beta (Aβ) is synaptotoxic and impairs neuronal function at the microscale, influencing brain networks at the macroscale before Aβ deposition. The latter can be detected noninvasively, in vivo, using resting-state functional MRI (rsfMRI), a technique used to assess brain functional connectivity (FC). RsfMRI was performed longitudinally in TG2576 and PDAPP mice, starting before Aβ deposition to determine the earliest FC changes. Additionally, the role of soluble Aβ on early FC alterations was investigated by treating TG2576 mice with the 3D6 anti-Aβ-antibody. Both transgenic models showed hypersynchronized FC before Aβ deposition and hyposynchronized FC at later stages. Early anti-Aβ treatment in TG2576 mice prevented hypersynchronous FC and the associated synaptic impairments and excitatory/inhibitory disbalances. Hypersynchrony of FC may be used as a new noninvasive read-out of early AD and can be recovered by anti-Aβ treatment, en...
Research Interests: Neuroscience, Epidemiology, Magnetic Resonance Imaging, Developmental neuroscience, Health Policy, and 15 moreMedicine, Brain Mapping, Brain, Animals, Clinical Sciences, In Vivo, Longitudinal Studies, Disease Progression, Cellular and Molecular Neuroscience, Neural pathways, Alzheimer Disease, Geriatrics and Gerontology, Autoantibodies, Amyloidosis, and Neuroprotective Agents
Transplantation of mesenchymal stem cells (MSCs) into injured or diseased tissue—for the in situ delivery of a wide variety of MSC-secreted therapeutic proteins—is an emerging approach for the modulation of the clinical course of several... more
Transplantation of mesenchymal stem cells (MSCs) into injured or diseased tissue—for the in situ delivery of a wide variety of MSC-secreted therapeutic proteins—is an emerging approach for the modulation of the clinical course of several diseases and traumata. From an emergency point-of-view, allogeneic MSCs have numerous advantages over patient-specific autologous MSCs since “off-the-shelf” cell preparations could be readily available for instant therapeutic intervention following acute injury. Although we confirmed the in vitro immunomodulatory capacity of allogeneic MSCs on antigen-presenting cells with standard coculture experiments, allogeneic MSC grafts were irrevocably rejected by the host's immune system upon either intramuscular or intracerebral transplantation. In an attempt to modulate MSC allograft rejection in vivo, we transduced MSCs with an interleukin-13 (IL13)-expressing lentiviral vector. Our data clearly indicate that prolonged survival of IL13-expressing allo...
Research Interests: Immunology, Biology, Macrophages, Medicine, Dendritic Cells, and 15 moreGenetic Engineering, Biological Sciences, Mice, Animals, Microglia, Immunomodulation, Mesenchymal Stem Cell, Allografts, Immune system, Mesenchymal Stromal Cells, HUMAN MEDICINE, Antigen presenting cells, Interleukin, Macrophage activation, and Medical and Health Sciences
Learning and memory formation are known to require dynamic CpG (de)methylation and gene expression changes. Here, we aimed at establishing a genome-wide DNA methylation map of the zebra finch genome, a model organism in neuroscience, as... more
Learning and memory formation are known to require dynamic CpG (de)methylation and gene expression changes. Here, we aimed at establishing a genome-wide DNA methylation map of the zebra finch genome, a model organism in neuroscience, as well as identifying putatively epigenetically regulated genes. RNA- and MethylCap-seq experiments were performed on two zebra finch cell lines in presence or absence of 5-aza-2'-deoxycytidine induced demethylation. First, the MethylCap-seq methodology was validated in zebra finch by comparison with RRBS-generated data. To assess the influence of (variable) methylation on gene expression, RNA-seq experiments were performed as well. Comparison of RNA-seq and MethylCap-seq results showed that at least 357 of the 3,457 AZA-upregulated genes are putatively regulated by methylation in the promoter region, for which a pathway analysis showed remarkable enrichment for neurological networks. A subset of genes was validated using Exon Arrays, quantitative ...
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The existence of numerous interesting mouse models of neurological disorders enables the investigation of causal relations between pathological events and the effect of treatment regimes. However, mouse models of a specific neurological... more
The existence of numerous interesting mouse models of neurological disorders enables the investigation of causal relations between pathological events and the effect of treatment regimes. However, mouse models of a specific neurological disease are often generated using different background strains, which raises the question whether the observed effects are specific to pathology or depend on the used strain. This study used two independent in vivo functional imaging techniques to evaluate whether mouse strain differences exist in functional connectivity (FC) and brain glucose metabolism i.e. indirect measures of neuronal activity. For this purpose, C57BL/6, BALB/C and SJL mice (N=15/group, male) were evaluated using resting-state functional MRI (rsfMRI) and static [18F]-fluorodeoxyglucose Positron Emission Tomography ([18F]-FDG PET). RsfMRI and [18F]-FDG PET data were analyzed with independent component analysis (ICA). FC was quantified by calculating the mean network-specific FC st...
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A hallmark in the neuropathology of temporal lobe epilepsy is brain inflammation which has been suggested as both a biomarker and a new mechanistic target for treatments. The translocator protein (TSPO), due to its high upregulation under... more
A hallmark in the neuropathology of temporal lobe epilepsy is brain inflammation which has been suggested as both a biomarker and a new mechanistic target for treatments. The translocator protein (TSPO), due to its high upregulation under neuroinflammatory conditions and the availability of selective PET tracers, is a candidate target. An important step to exploit this target is a thorough characterisation of the spatiotemporal profile of TSPO during epileptogenesis. TSPO expression, microglial activation, astrocyte reactivity and cell loss in several brain regions were evaluated at five time points during epileptogenesis, including the chronic epilepsy phase in the kainic acid-induced status epilepticus (KASE) model (n=52) and control Wistar Han rats (n=33). Seizure burden was also determined in the chronic phase. Furthermore, (18)F-PBR111 PET/MRI scans were acquired longitudinally in an additional four KASE animals. TSPO expression measured with in vitro and in vivo techniques was...
Research Interests: Magnetic Resonance Imaging, Epilepsy, Immunohistochemistry, Medicine, Brain, and 15 moreChronic Disease, Animals, Microglia, Male, Clinical Sciences, In Vivo, Longitudinal Studies, Autoradiography, Electrocorticography, Disease Progression, Encephalitis, HUMAN MEDICINE, Kainic acid, binding sites, and Epileptogenesis
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Resting-state functional MRI (rsfMRI) is a widely implemented technique used to investigate large-scale topology in the human brain during health and disease. Studies in mice provide additional advantages, including the possibility to... more
Resting-state functional MRI (rsfMRI) is a widely implemented technique used to investigate large-scale topology in the human brain during health and disease. Studies in mice provide additional advantages, including the possibility to flexibly modulate the brain by pharmacological or genetic manipulations in combination with high-throughput functional connectivity (FC) investigations. Pharmacological modulations that target specific neurotransmitter systems, partly mimicking the effect of pathological events, could allow discriminating the effect of specific systems on functional network disruptions. The current study investigated the effect of cholinergic and serotonergic antagonists on large-scale brain networks in mice. The cholinergic system is involved in cognitive functions and is impaired in, e.g., Alzheimer's disease, while the serotonergic system is involved in emotional and introspective functions and is impaired in, e.g., Alzheimer's disease, depression and autism...
Research Interests: Neuroscience, Psychology, Cognitive Science, Magnetic Resonance Imaging, Biology, and 15 moreMedicine, Brain Mapping, Brain, Mice, Animals, Male, Acetylcholine, Medical Physiology, Neural pathways, Retrosplenial Cortex, Neurotransmitter, Neurosciences, HUMAN MEDICINE, Medetomidine, and Scopolamine hydrobromide
Non-invasive measures of well-known pathological hallmarks of multiple sclerosis (MS) such as demyelination, inflammation and axonal injury would serve as useful markers to monitor disease progression and evaluate potential therapies. To... more
Non-invasive measures of well-known pathological hallmarks of multiple sclerosis (MS) such as demyelination, inflammation and axonal injury would serve as useful markers to monitor disease progression and evaluate potential therapies. To this end, in vivo localized proton magnetic resonance spectroscopy ((1)H-MRS) provides a powerful means to monitor metabolic changes in the brain and may be sensitive to these pathological hallmarks. In our study, we used the cuprizone mouse model to study pathological features of MS, such as inflammation, de- and remyelination, in a highly reproducible manner. C57BL/6J mice were challenged with a 0.2% cuprizone diet for 6-weeks to induce demyelination, thereafter mice were put on a cuprizone free diet for another 6 weeks to induce spontaneous remyelination. We employed in vivo(1)H-MRS to longitudinally monitor metabolic changes in the corpus callosum of cuprizone-fed mice during the demyelination (week 4 and 6) and spontaneous remyelination (week 1...
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The cuprizone mouse model allows the investigation of the complex molecular mechanisms behind nonautoimmune-mediated demyelination and spontaneous remyelination. While it is generally accepted that oligodendrocytes are specifically... more
The cuprizone mouse model allows the investigation of the complex molecular mechanisms behind nonautoimmune-mediated demyelination and spontaneous remyelination. While it is generally accepted that oligodendrocytes are specifically vulnerable to cuprizone intoxication due to their high metabolic demands, a comprehensive overview of the etiology of cuprizone-induced pathology is still missing to date. In this review we extensively describe the physico-chemical mode of action of cuprizone and discuss the molecular and enzymatic mechanisms by which cuprizone induces metabolic stress, oligodendrocyte apoptosis, myelin degeneration and eventually axonal and neuronal pathology. In addition, we describe the dual effector function of the immune system which tightly controls demyelination by effective induction of oligodendrocyte apoptosis, but in contrast also paves the way for fast and efficient remyelination by the secretion of neurotrophic factors and the clearance of cellular and myelin...
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The presence of amyloid plaques in the brain is one of the pathological hallmarks of Alzheimer's disease, which might already be present in the early stage of the disease. Therefore it is important to track amyloid plaques as early as... more
The presence of amyloid plaques in the brain is one of the pathological hallmarks of Alzheimer's disease, which might already be present in the early stage of the disease. Therefore it is important to track amyloid plaques as early as possible. In this paper, we report magnetization transfer contrast magnetic resonance imaging (MTC MRI) as a novel approach to detect amyloid plaques in vivo. Two mice models, APP/PS1 and BRI, developing amyloid pathology were investigated with MTC MRI, T2 relaxation measurements and immunohistochemistry (IHC). MT-ratios of several brain regions were compared to T2-values and correlated with quantitative IHC, revealing amyloid load and gliosis in different brain regions. APP/PS1 mice develop large compact plaques, resembling late stage Alzheimer's disease, while rather small and diffuse plaques are deposited in BRI mice, reflecting early stage of Alzheimer's disease. We found significantly higher MT-ratio's in the brain of APP/PS1 mice ...
Research Interests: Pathology, Computer Science, Magnetic Resonance Imaging, Biology, Immunohistochemistry, and 15 moreMedicine, Transgenic Mice, Brain, Mice, Female, Animals, Neuroimage, Male, Alzheimer Disease, Contrast Media, HUMAN MEDICINE, Senile Plaques, Gliosis, Psychology and Cognitive Sciences, and Medical and Health Sciences
Endogenous neural stem cells (eNSCs) reside in defined regions of the adult brain and have the potential to generate new brain cells, including neurons. Stimulation of adult neurogenesis presents an enormous potential for regenerative... more
Endogenous neural stem cells (eNSCs) reside in defined regions of the adult brain and have the potential to generate new brain cells, including neurons. Stimulation of adult neurogenesis presents an enormous potential for regenerative therapies in the central nervous system. However, the methods used to monitor the proliferation, migration, differentiation, and functional integration of eNSCs and their progeny are often invasive and limited in studying dynamic processes. To overcome this limitation, novel techniques and contrast mechanisms for in vivo imaging of neurogenesis have recently been developed and successfully applied. In vivo labeling of endogenous neuronal progenitor cells in situ with contrast agents or tracers enables longitudinal visualization of their proliferation and/or migration. Labeling of these cells with magnetic nanoparticles has proven to be very useful for tracking neuroblast migration with MRI. Alternatively, genetic labeling using reporter gene technology...
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Automated voxel-based or predefined volume-of-interest (VOI) analysis of rodent small-animal PET data is necessary for optimal use of information because the number of available resolution elements is limited. We have mapped metabolic... more
Automated voxel-based or predefined volume-of-interest (VOI) analysis of rodent small-animal PET data is necessary for optimal use of information because the number of available resolution elements is limited. We have mapped metabolic ((18)F-FDG), dopamine transporter (DAT) (2'-(18)F-fluoroethyl(1R-2-exo-3-exe)-8-methyl-3-(4-chlorophenyl)-8-azabicyclo[3.2.1]-octane-2-carboxylate [(18)F-FECT]), and dopaminergic D(2) receptor ((11)C-raclopride) small-animal PET data onto a 3-dimensional T2-weighted MRI rat brain template oriented according to the rat brain Paxinos atlas. In this way, ligand-specific templates for sensitive analysis and accurate anatomic localization were created. Registration accuracy and test-retest and intersubject variability were investigated. Also, the feasibility of individual rat brain statistical parametric mapping (SPM) was explored for (18)F-FDG and DAT imaging of a 6-hydroxydopamine (6OHDA) model of Parkinson's disease. Ten adult Wistar rats were sc...
Research Interests: Algorithms, Magnetic Resonance Imaging, Biology, Nuclear medicine, Positron Emission Tomography, and 15 moreMedicine, Probability, Molecular Imaging, Nuclear, Brain Mapping, Brain, Female, Animals, Clinical Sciences, Dimensional, Dopamine Transporter, Brain Structure, Ligands, Parkinson Disease, and Raclopride
In this chapter we have surveyed the basis for the design and modus operandi of MRI contrast agents being paramagnetic metal complexes, including responsive agents, and iron oxide particles. A substantial amount of attention goes to the... more
In this chapter we have surveyed the basis for the design and modus operandi of MRI contrast agents being paramagnetic metal complexes, including responsive agents, and iron oxide particles. A substantial amount of attention goes to the application of Manganese as a biological Ca2+ analogue in Manganese Enhanced MRI (MEMRI). All these agents act by providing contrast enhancements that add molecular, physiological and functional information to the outstanding anatomical resolution of MR images. MEMRI relies on the relaxation enhancement brought about by the administration of Mn2+ ions, whereas the development of paramagnetic contrast agents basically involves the use of chelating moieties as the release of the toxic metal ions or iron is of primary concern for the clinical translation of these diagnostic agents. Iron oxides are also considered as prototypes of high sensitive, particulate agents.
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ABSTRACT Diffusion Tensor Magnetic Resonance Imaging (DTI) is a well known technique that can provide information about the neuronal fiber structure of the brain. However, since DTI requires a large amount of data, a high speed MRI... more
ABSTRACT Diffusion Tensor Magnetic Resonance Imaging (DTI) is a well known technique that can provide information about the neuronal fiber structure of the brain. However, since DTI requires a large amount of data, a high speed MRI acquisition technique is needed to acquire these data within a reasonable time. Echo Planar Imaging (EPI) is a technique that provides the desired speed. Unfortunately, the advantage of speed is overshadowed by image artifacts, especially at high fields. EPI artifacts originate from susceptibility differences in adjacent tissues and correction techniques are required to obtain reliable images. In this work, the fieldmap method, which tries to measure distortion effects, is optimized by using a non linear least squares estimator for calculating pixel shifts. This method is tested on simulated data and proves to be more robust against noise compared to previously suggested methods. Another advantage of this new method is that other parameters like relaxation and the odd/even phase difference are estimated. This new way of estimating the field map is demonstrated on a hardware phantom, which consists of parallel bundles made of woven strands of Micro Dyneema fibers. Using a modified EPI-sequence, reference data was measured for the calculation of fieldmaps. This allows one to reposition the pixels in order to obtain images with less distortions. The correction is applied to non-diffusion weighted images as well as diffusion weighted images and fiber tracking is performed on this corrected data.