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Background: This study aims to address the potential of ex vivo diffusion tensor imaging to provide insight into the microstructural composition and morphological arrangement of aged human atherosclerotic carotid arteries. Methods: In this study, whole human carotid arteries were investigated both anatomically and by comparing healthy and diseased regions. Nonrigid image registration was used with unsupervised segmentation to investigate the influence of elastin, collagen, cell density, glycosaminoglycans, and calcium on diffusion tensor imaging derived metrics (fractional anisotropy and mean diffusivity). Early stage atherosclerotic features were also investigated in terms of microstructural components and diffusion tensor imaging metrics. Results: All vessels displayed a dramatic decrease in fractional anisotropy compared with healthy animal arterial tissue, while the mean diffusivity was sensitive to regions of advanced disease. Elastin content strongly correlated with both fractional anisotropy (r>0.7, P −0.79, P Conclusions: These different investigations point to the potential of diffusion tensor imaging to identify characteristics of arterial disease progression, at early and late-stage lesion development.

The purpose of this study was to characterize the alterations in microstructural organization of arterial tissue using higher-order diffusion magnetic resonance schemes. Three porcine carotid artery models namely; native, collagenase treated and decellularized, were used to estimate the contribution of collagen and smooth muscle cells (SMC) on diffusion signal attenuation using gaussian and non-gaussian schemes. The samples were imaged in a 7 T preclinical scanner. High spatial and angular resolution diffusion weighted images (DWIs) were acquired using two multi-shell (max b-value = 3000 s/mm2) acquisition protocols. The processed DWIs were fitted using monoexponential, stretched-exponential, kurtosis and bi-exponential schemes. Directionally variant and invariant microstructural parametric maps of the three artery models were obtained from the diffusion schemes. The parametric maps were used to assess the sensitivity of each diffusion scheme to collagen and SMC composition in arterial microstructural environment. The inter-model comparison showed significant differences across the considered models. The bi-exponential scheme based slow diffusion compartment (Ds) was highest in the absence of collagen, compared to native and decellularized microenvironments. In intra-model comparison, kurtosis along the radial direction was the highest. Overall, the results of this study demonstrate the efficacy of higher order dMRI schemes in mapping constituent specific alterations in arterial microstructure.

Recent proposals in quantum gravity have suggested that unknown systems can mediate entanglement between two known quantum systems, if and only if the mediator itself is non-classical. This approach may be applicable to the brain, where speculations about quantum operations in consciousness and cognition have a long history. Proton spins of bulk water, which most likely interfere with any brain function, can act as the known quantum systems. If an unknown mediator exists, then NMR methods based on multiple quantum coherence (MQC) can act as entanglement witness. However, there are doubts that today's NMR signals can contain quantum correlations in general, and specifically in the brain environment. Here, we used a witness protocol based on zero quantum coherence (ZQC) whereby we minimised the classical signals to circumvent the NMR detection limits for quantum correlation. For short repetitive periods, we found evoked signals in most parts of the brain, whereby the temporal appearance resembled heartbeat-evoked potentials (HEPs). We found that those signals had no correlates with any classical NMR contrast. Similar to HEPs, the evoked signal depended on conscious awareness. Consciousness-related or electrophysiological signals are unknown in NMR. Remarkably, these signals only appeared if the local properties of the magnetisation were reduced. Our findings suggest that we may have witnessed entanglement mediated by consciousness-related brain functions. Those brain functions must then operate non-classically, which would mean that consciousness is non-classical., Comment: We changed the introduction and discussion substantially to make it, as we hope, more accessible. We will continue to try to get this work published and incorporate criticisms if brought forward

Task-free functional connectivity in animal models provides an experimental framework to examine connectivity phenomena under controlled conditions and allows comparison with invasive or terminal procedures. To date, animal acquisitions are performed with varying protocols and analyses that hamper result comparison and integration. We introduce StandardRat, a consensus rat functional MRI acquisition protocol tested across 20 centers. To develop this protocol with optimized acquisition and processing parameters, we initially aggregated 65 functional imaging datasets acquired in rats from 46 centers. We developed a reproducible pipeline for the analysis of rat data acquired with diverse protocols and determined experimental and processing parameters associated with a more robust functional connectivity detection. We show that the standardized protocol enhances biologically plausible functional connectivity patterns, relative to pre-existing acquisitions. The protocol and processing pipeline described here are openly shared with the neuroimaging community to promote interoperability and cooperation towards tackling the most important challenges in neuroscience.

Among the changes that typify Alzheimer’s disease (AD) are neuroinflammation and microglial activation, amyloid deposition perhaps resulting from compromised microglial function and iron accumulation. Data from Genome Wide Association Studies (GWAS) identified a number of gene variants that endow a significant risk of developing AD and several of these encode proteins expressed in microglia and proteins that are implicated in the immune response. This suggests that neuroinflammation and the accompanying microglial activation are likely to contribute to the pathogenesis of the disease. The trigger(s) leading to these changes remain to be identified. In this study, we set out to examine the link between the inflammatory, metabolic and iron‐retentive signature of microglia in vitro and in transgenic mice that overexpress the amyloid precursor protein (APP) and presenilin 1 (PS1; APP/PS1 mice), a commonly used animal model of AD. Stimulation of cultured microglia with interferon (IFN)γ and amyloid‐β (Aβ) induced an inflammatory phenotype and switched the metabolic profile and iron handling of microglia so that the cells became glycolytic and iron retentive, and the phagocytic and chemotactic function of the cells was reduced. Analysis of APP/PS1 mice by magnetic resonance imaging (MRI) revealed genotype‐related hypointense areas in the hippocampus consistent with iron deposition, and immunohistochemical analysis indicated that the iron accumulated in microglia, particularly in microglia that decorated Aβ deposits. Isolated microglia prepared from APP/PS1 mice were characterized by a switch to a glycolytic and iron‐retentive phenotype and phagocytosis of Aβ was reduced in these cells. This evidence suggests that the switch to glycolysis in microglia may kick‐start a cascade of events that ultimately leads to microglial dysfunction and Aβ accumulation.

In this study we investigated the potential of diffusion tensor imaging (DTI) for providing insight into microstructural changes in arterial tissue by exploring the influence that cell, collagen and elastin content have on fractional anisotropy (FA), mean diffusivity (MD) and tractography. Five ex vivo porcine carotid artery models (n = 6 vessels each) – native, fixed native, collagen degraded, elastin degraded and decellularised – were developed to selectively remove components of arterial microstructure. Intact vessels were imaged at 7 T using a DTI protocol with b = 0 and 800 s/mm2and 10 isotopically distributed directions. FA and MD values were evaluated in the medial layer of vessels and compared across tissue models. FA values measured in native and fixed native vessels were significantly higher (p

Getting older affects both the structure of the brain and some cognitive capabilities. Until now, magnetic resonance imaging (MRI) approaches have been unable to give a coherent reflection of the cognitive declines. It shows the limitation of the contrast mechanisms used in most MRI investigations, which are indirect measures of brain activities depending on multiple physiological and cognitive variables. However, MRI signals may contain information of brain activity beyond these commonly used signals caused by the neurovascular response. Here, we apply a zero-spin echo (ZSE) weighted MRI sequence, which can detect heartbeat evoked signals (HES). Remarkably, these MRI signals have properties only known from electrophysiology. We investigated the complexity of the HES arising from this sequence in two age groups; young (18-29 years) and old (over 65 years). While comparing young and old participants, we show that the complexity of the HES decreases with age, where the stability and chaoticity of these HES are particularly sensitive to age. However, we also found individual differences which were independent of age. Complexity measures were related to scores from different cognitive batteries and showed that higher complexity may be related to better cognitive performance. These findings underpin the affinity of the HES to electrophysiological signals. The profound sensitivity of these changes in complexity shows the potential of HES for understanding brain dynamics that need to be tested in more extensive and diverse populations with clinical relevance for all neurovascular diseases.

Introduction To understand brain function it is necessary to characterize the underlying structural connectivity between neurons. Insects are ideal for analysing how neuronal connectivity shapes complex behaviour. Whilst the nervous system of insects is much simpler than vertebrates, they are animals that demonstrate a varied and complex behavioural repertoire. Previous research on insect brain connectivity has used microscopy techniques to examine the organization of neuronal networks. Methods The brain of the desert locust, Schistercera gregaria (Forksȧl) is an ideal insect to explore neuronal connectivity as it has a relatively large brain for an insect. Here we present a novel methodology to understand neuronal connectivity in the insect brain by using diffusion magnetic resonance imaging (dMRI). The diffusion-weighted imaging (DWI) data were acquired on a horizontal bore 7T Biospec micro-MRI system (Bruker, Etlingen Germany) using a customised multi-shell diffusion MRI scheme. Diffusion sensitizing gradients were applied in 26 diffusion encoding directions. Contrasts from the averaged DWIs and Diffusion Kurtosis Imaging (DKI) scheme were applied to classify various anatomical features and diffusion patterns in neuropils, respectively. Results This study explores the application of MRI to an insect model system, the locust Schistercera gregaria . It is demonstrated that micro-MRI and dMRI modelling enables anatomical regions and connectivity in the locust brain to be identified. Further the possibility of quantifying structural changes in samples of the locust brain is shown by the use of indices derived from the kurtosis model that include fractional anisotropy (FA), mean diffusivity (MD) and kurtosis anisotropy (KA). Discussion/Conclusion The application of dMRI to the locust brain provides a novel approach to characterizing neuronal connectivity in insect brains. As dMRI can be applied non-invasively in live animals, future work offers the possibility of monitoring neuronal connectivity longitudinally, as well as providing metrics to quantify the effect of environmental stressors.

Alterations in astrocyte number and function have been implicated in the pathophysiology of a number of psychiatric disorders. The development of magnetic resonance imaging (MRI) as a tool in the animal laboratory has enabled an investigation of the relationship between pathological and neuroimaging markers in animal models. However the physiological processes which underlie these markers and their role in mediating behavioural deficits is still poorly understood. Rodent models have provided us with important insights into physiological and cellular mechanisms which may mediate anxiety and depression-related behaviours. The Wistar-Kyoto (WKY) rat is a strain which endogenously expresses highly anxious and depressive-like behaviours and has previously been reported to exhibit alterations in immunoreactivity for the astrocytic marker glial fibrillary acidic protein (GFAP) in brain sub-regions relative to more stress resilient out-bred strains. Here we report that the depressive and anxiety-like behaviours exhibited by the WKY rat strain are associated with alterations in brain morphology including a decrease in hippocampal volume, coupled with reduced resting state frontal cortical perfusion as assessed by MR bolus tracking arterial spin labelling (bt-ASL) relative to the out-bred Wistar strain. Pre-limbic cortical GFAP immunoreactivity and astrocyte cell number were positively correlated with cortical blood perfusion in the WKY strain. These experiments provide a link between pathological and neuroimaging markers of aberrant astrocytic function and add validity to the WKY rat as a model for co-morbid anxiety and depression.

The aim of this study was to investigate the aging-related structural changes of the cingulum, one of the major components of the limbic network, which has a critical role in emotion, attention, and memory. Thirty-five healthy young adults (22.3 ± 2.7 years) and 33 healthy older adults (69.5 ± 3.5 years) were recruited. Diffusion weighted imaging data were acquired with a b-value = 2000 sec/mm2 and 61 diffusion directions and 4 non-weighted images. The fiber directions in each voxel were based on the constrained spherical deconvolution model. The cingulum was segmented into three branches using deterministic tractography (subgenual, retrosplenial, and parahippocampal), using a region-of-interest-based approach. Atlas-based tractography was the method used to obtain the output tracts of each branch of the cingulum. Along-tract analysis was performed on each branch. We found a statistically significant change with aging in the left subgenual branch of the cingulum with a decrease in fractional anisotropy and axial diffusivity, as well as an increase in radial diffusivity. No statistically significant differences were found between young and older groups in the other two branches. This study adds to knowledge about how the cingulum changes structurally along its entire length during aging in a more detailed way, thanks to an advanced methodological approach.

The aim of this study was to investigate the aging-related structural changes of the cingulum, one of the major components of the limbic network, which has a critical role in emotion, attention, and memory. Thirty-five healthy young adults (22.3 ± 2.7 years) and 33 healthy older adults (69.5 ± 3.5 years) were recruited. Diffusion weighted imaging data were acquired with a b-value = 2000 sec/mm2 and 61 diffusion directions and 4 non-weighted images. The fiber directions in each voxel were based on the constrained spherical deconvolution model. The cingulum was segmented into three branches using deterministic tractography (subgenual, retrosplenial, and parahippocampal), using a region-of-interest-based approach. Atlas-based tractography was the method used to obtain the output tracts of each branch of the cingulum. Along-tract analysis was performed on each branch. We found a statistically significant change with aging in the left subgenual branch of the cingulum with a decrease in fractional anisotropy and axial diffusivity, as well as an increase in radial diffusivity. No statistically significant differences were found between young and older groups in the other two branches. This study adds to knowledge about how the cingulum changes structurally along its entire length during aging in a more detailed way, thanks to an advanced methodological approach.

Diffusion magnetic resonance imaging (dMRI) can provide insights into the microstructure of intact arterial tissue. The current study employed high magnetic field MRI to obtain ultra-high resolution dMRI at an isotropic voxel resolution of 117 µm3 in less than 2 h of scan time. A parameter selective single shell (128 directions) diffusion-encoding scheme based on Stejskel-Tanner sequence with echo-planar imaging (EPI) readout was used. EPI segmentation was used to reduce the echo time (TE) and to minimise the susceptibility-induced artefacts. The study utilised the dMRI analysis with diffusion tensor imaging (DTI) framework to investigate structural heterogeneity in intact arterial tissue and to quantify variations in tissue composition when the tissue is cut open and flattened. For intact arterial samples, the region of interest base comparison showed significant differences in fractional anisotropy and mean diffusivity across the media layer (p

Acute administration of the recreational drug of abuse 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy) has previously been shown to increase cerebro-cortical perfusion as determined by bolus-tracking arterial spin labelling (btASL) MRI. The purpose of the current study was to assess the mechanisms mediating these changes following systemic administration of MDMA to rats. Pharmacological manipulation of serotonergic, dopaminergic and nitrergic transmission was carried out to determine the mechanism of action of MDMA-induced increases in cortical perfusion using btASL MRI. Fenfluramine (10 mg/kg), like MDMA (20 mg/kg), increased cortical perfusion. Increased cortical perfusion was not obtained with the 5-HT2 receptor agonist 2,5-dimethoxy-4-iodophenyl-aminopropane hydrochloride (DOI) (1 mg/kg). Depletion of central 5-HT following systemic administration of the tryptophan hydroxylase inhibitor para-chlorophenylalanine (pCPA) produced effects similar to those observed with MDMA. Pre-treatment with the 5-HT receptor antagonist metergoline (4 mg/kg) or with the 5-HT reuptake inhibitor citalopram (30 mg/kg), however, failed to produce any effect alone or influence the response to MDMA. Pre-treatment with the dopamine D1 receptor antagonist SCH 23390 (1 mg/kg) failed to influence the changes in cortical perfusion obtained with MDMA. Treatment with the neuronal nitric oxide (NO) synthase inhibitor 7-nitroindazole (7-NI) (25 mg/kg) provoked no change in cerebral perfusion alone yet attenuated the MDMA-related increase in cortical perfusion. Cortical 5-HT depletion is associated with increases in perfusion although this mechanism alone does not account for MDMA-related changes. A role for NO, a key regulator of cerebrovascular perfusion, is implicated in MDMA-induced increases in cortical perfusion.

Nitric oxide synthase (NOS) inhibitors possess antidepressant-like properties in preclinical tests and in the current investigation the brain penetrant NOS inhibitor N ω -nitro- l -arginine ( l -NA) and the preferential inhibitor of neuronal NOS (nNOS) 1-(2-trifluoromethylphenyl) imidazole (TRIM) were assessed in the olfactory bulbectomised (OB) rat, a well-established animal model of depression. Magnetic resonance imaging (MRI) was employed to assess regional brain volumes, blood perfusion and T1 and T2 relaxometry times both with and without drug treatment. l -NA (10 mg/kg, once daily p.o. for 10 days) attenuated OB-related hyperactivity in the “open field” test in a comparable fashion to the tricyclic antidepressant imipramine (20 mg/kg, once daily p.o. for 14 days) indicative of an antidepressant-like response in the model. Treatment with TRIM (50 mg/kg, once daily s.c.) attenuated OB-related hyperactivity following 7 days of treatment when compared to vehicle treated controls. OB is associated with enlarged ventricular volume, increased periventicular perfusion and a decrease in T2 relaxation times in cortical and hippocampal regions, with enhanced perfusion and reduced T2 times attenuated by l -NA treatment. l -NA treatment was also associated with an increase in T1 relaxation times in limbic and cortical regions and found to reduce resting state hippocampal blood perfusion in OB animals. Behavioural observations are consistent with an antidepressant action of NOS inhibitors where associated changes in perfusion and T2 relaxation times may be related to the antidepressant action of l -NA in the model.

Diffusion tensor imaging analysis was applied to fresh and frozen porcine aortas in order to determine fibre orientation. Fresh and stored frozen porcine aortas were imaged in a 7T scanner with a diffusion weighted spin echo sequence (six gradient directions, matrix 128×128 pixels, 2.8cm×2.8cm field of view). The images were taken for different b values, ranging from 200s/mm 2 to 1600s/mm 2 . For each dataset the diffusion tensor was evaluated, fractional anisotropy (FA) maps were calculated, and the fibres mapped. The arterial fibres resulting were postprocessed and their fibre angle evaluated. The FA maps, the dominant fibre angle, and the fibre pattern in the arterial wall thickness were compared in the fresh and in the stored frozen aortas. The technique was able to determine a fibre pattern in the fresh healthy aorta that is in accordance with the data available in literature and to identify an alteration in the fibre pattern caused by freezing. This study shows that this technique has potential for studying fibre orientation and fibre distribution in humans and could be further developed to diagnose fibre alterations due to cardiovascular diseases. In fact, our results suggest that DTI has the potential to determine the fibrous structure of arteries non-invasively. This capability could be further developed to study the natural remodelling of the aorta in vivo due to age and/or gender or to obtain information on aortic diseases at an early stage of their evolution.

Exposure to severe and prolonged stress has detrimental effects on the hippocampus. However, relatively little is known about the gradual changes in hippocampal structure and its behavioral consequences, over the course of repeated stress. Behavioral analyses during 10 days of chronic stress pointed to a delayed decline in spatial memory, the full impact of which is evident only after the end of stress. In contrast, concurrent volumetric measurements in the same animals revealed significant reduction in hippocampal volumes in stressed animals relative to their unstressed counterparts, as early as the third day of stress. Notably, animals that were behaviorally the worst affected at the end of chronic stress suffered the most pronounced early loss in hippocampal volume. Together, these findings support the view that not only is smaller hippocampal volume linked to stress-induced memory deficits, but it may also act as an early risk factor for the eventual development of cognitive impairments seen in stress-related psychiatric disorders.

Blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) is the most widely used method for mapping neural activity in the brain. The interpretation of altered BOLD signals is problematic when cerebral blood flow (CBF) or cerebral blood volume change because of aging and/or neurodegenerative diseases. In this study, a recently developed quantitative arterial spin labeling (ASL) approach, bolus-tracking ASL (btASL), was applied to an fMRI experiment in the rat brain. The mean transit time (MTT), capillary transit time (CTT), relative cerebral blood volume of labeled water (rCBVlw), relative cerebral blood flow (rCBF), and perfusion coefficient in the forelimb region of the somatosensory cortex were quantified during neuronal activation and in the resting state. The average MTT and CTT were 1.939±0.175 and 1.606±0.106 secs, respectively, in the resting state. Both times decreased significantly to 1.616±0.207 and 1.305±0.201 secs, respectively, during activation. The rCBVlw, rCBF, and perfusion coefficient increased on average by a factor of 1.123±0.006, 1.353±0.078, and 1.479±0.148, respectively, during activation. In contrast to BOLD techniques, btASL yields physiologically relevant indices of the functional hyperemia that accompanies neuronal activation.

Neuregulin-1 (NRG1) has been shown to play a role in glutamatergic neurotransmission and is a risk gene for schizophrenia, in which there is evidence for hypoglutamatergic function. Sensitivity to the behavioural effects of the psychotomimetic N-methyl-D-aspartate receptor antagonists MK-801 and phencyclidine (PCP) was examined in mutant mice with heterozygous deletion of NRG1. Social behaviour (sociability, social novelty preference and dyadic interaction), together with exploratory activity, was assessed following acute or subchronic administration of MK-801 (0.1 and 0.2 mg/kg) or PCP (5 mg/kg). In untreated NRG1 mutants, levels of glutamate, N-acetylaspartate and GABA were determined using high-performance liquid chromatography and regional brain volumes were assessed using magnetic resonance imaging at 7T. NRG1 mutants, particularly males, displayed decreased responsivity to the locomotor-activating effects of acute PCP. Subchronic MK-801 and PCP disrupted sociability and social novelty preference in mutants and wildtypes and reversed the increase in both exploratory activity and social dominance-related behaviours observed in vehicle-treated mutants. No phenotypic differences were demonstrated in N-acetylaspartate, glutamate or GABA levels. The total ventricular and olfactory bulb volume was decreased in mutants. These data indicate a subtle role for NRG1 in modulating several schizophrenia-relevant processes including the effects of psychotomimetic N-methyl-D-aspartate receptor antagonists.

Hippocampal sclerosis is a common pathological finding in patients with temporal lobe epilepsy, including children, but a causal relationship to early-life seizures remains in question. Neonatal status epilepticus in animals can result in neuronal death within the hippocampus, although macroscopic features of hippocampal shrinkage are not evident at adulthood. Here, we examined electrophysiological and pathological consequences of focally evoked status epilepticus triggered by intra-amygdala microinjection of kainic acid in postnatal day 10 rat pups. Neonatal status epilepticus resulted in extensive neuronal death in the ipsilateral hippocampal CA1 and CA3 subfields and hilus, as assessed by DNA fragmentation and Fluoro-Jade B staining 72 hours later. The contralateral hippocampus was not significantly damaged. Histopathology at P55/P65 revealed unilateral hippocampal sclerosis (grade IV, modified Wyler/Watson scale) comprising >50% CA1 and CA3 neuron loss and astrogliosis. Additional features included hydrocephalus ex vacuo, modest dentate granule cell layer widening, and altered neuropeptide Y immunoreactivity indicative of synaptic rearrangement. Hippocampal atrophy was also evident on magnetic resonance imaging. Depth electrode recordings at adulthood detected spontaneous seizures that involved the ipsilateral hippocampus and amygdala. A significant positive correlation was found between hippocampal pathology grade and both frequency and duration of epileptic seizures at adulthood. The current study demonstrates that experimental neonatal status epilepticus can result in classical unilateral hippocampal sclerosis and temporal lobe epilepsy.

Background The blood-brain barrier (BBB) contains tight junctions (TJs) which reduce the space between adjacent endothelial cells lining the fine capillaries of the microvasculature of the brain to form a selective and regulatable barrier. Methods Using a hydrodynamic approach, we delivered siRNA targeting the TJ protein claudin-5 to the endothelial cells of the BBB in mice. Results We have shown a significant decrease in claudin-5 mRNA levels 24 and 48 hours post-delivery of siRNA, with levels of protein expression decreasing up to 48 hours post-injection compared to uninjected, phosphate-buffered saline (PBS)-injected and non-targeting siRNA-injected mice. We observed increased permeability at the BBB to molecules up to 742 Da, but not 4400 Da, using tracer molecule perfusion and MRI analysis. To illustrate the functional efficacy of size-selective and transient barrier opening, we have shown that enhanced delivery of the small neuropeptide thyrotropin-releasing hormone (TRH) (MW 360 Da) to the brains of mice 48 hours post-injection of siRNA targeting claudin-5 significantly modifies behavioural output. Conclusions These data demonstrate that it is now possible to transiently and size-selectively open the BBB in mice, allowing in principle the delivery of a wide range of agents for the establishment and treatment of experimental mouse models of neurodegenerative, neuropsychiatric and malignant diseases. Copyright © 2008 John Wiley & Sons, Ltd.

Individuals with borderline personality disorder (BPD) commonly display deficits in emotion regulation, but findings in the area of social cognitive (e.g., theory of mind, ToM) capacities have been heterogeneous. The aims of the current study were to investigate differences between patients with BPD and controls in functional connectivity (1) between the emotion and ToM network and (2) in the default mode network (DMN). Functional magnetic resonance imaging was used to investigate 19 healthy controls and 17 patients with BPD at rest and during ToM processing. Functional coupling was analysed. Significantly decreased functional connectivity was found for patients compared with controls between anterior cingulate cortex and three brain areas involved in ToM processes: the left superior temporal lobe, right supramarginal/inferior parietal lobes, and right middle cingulate cortex. Increased functional connectivity was found in patients compared with controls between the precuneus as the DMN seed and the left inferior frontal lobe, left precentral/middle frontal, and left middle occipital/superior parietal lobes during rest. Reduced functional coupling between the emotional and the ToM network during ToM processing is in line with emotion-regulation dysfunctions in BPD. The increased connectivity between precuneus and frontal regions during rest might be related to extensive processing of internal thoughts and self-referential information in BPD.

The blood oxygen level dependent (BOLD) response, as measured with fMRI, offers good spatial resolution compared to other non-invasive neuroimaging methods. The use of a spin echo technique rather than the conventional gradient echo technique may further improve the resolution by refocusing static dephasing effects around the larger vessels, so sensitizing the signal to the microvasculature. In this work the width of the point spread function (PSF) of the BOLD response at a field strength of 3 Tesla is compared for these two approaches. A double echo EPI pulse sequence with simultaneous collection of gradient echo and spin echo signal allows a direct comparison of the techniques. Rotating multiple-wedge stimuli of different spatial frequencies are used to estimate the width of the BOLD response. Waves of activation are created on the surface of the visual cortex, which begin to overlap as the wedge separation decreases. The modulation of the BOLD response decreases with increasing spatial frequency in a manner dependent on its width. The spin echo response shows a 13% reduction in the width of the PSF, but at a cost of at least 3-fold reduction in contrast to noise ratio.

Item does not contain fulltext The blood oxygenation level-dependent (BOLD) response to entrained neuronal firing in the human visual cortex and lateral geniculate nuclei was investigated. Periodic checkerboard flashes at a range of frequencies (4-20 Hz) were used to drive the visual cortex neurons into entrained oscillatory firing. This is compared to a checkerboard flashing aperiodically, with the same average number of flashes per unit time. A magnetoencephalography (MEG) measurement was made to confirm that the periodic paradigm elicited entrainment. We found that for frequencies of 10 and 15 Hz, the periodic stimulus gave a smaller BOLD response than for the aperiodic stimulus. Detailed investigation at 15 Hz showed that the aperiodic stimulus gave a similar BOLD increase regardless of the magnitude of jitter (+/-17 ms compared to +/-33 ms), indicating that flashes need to be precise to at least 17 ms to maintain entrainment. This is also evidence that for aperiodic stimuli, the amplitude of the BOLD response ordinarily reflects the total number of flashes per unit time, irrespective of the precise spacing between them, suggesting that entrainment is the main cause of the BOLD reduction in the periodic condition. The results indicate that, during entrainment, there is a reduction in the neuronal metabolic demand. We suggest that because of the selective frequency band of this effect, it could be connected to synchronised reverberations around an internal feedback loop.

Background Diagnosis of cerebral venous thrombosis (CVT) is usually achieved by digital subtraction angiography or magnetic resonance angiography, while structural brain tissue damage can be assessed by computed tomography or magnetic resonance imaging (MRI). Using perfusion and diffusion weighted imaging (PWI, DWI) we aimed in this study to identify pathophysiological patterns corresponding to only functional and hence reversible tissue involvement. Methods PWI, DWI, and conventional MRI were performed in six CVT patients acutely and after 16–26 days when their clinical condition had improved. All patients were treated with partial thromboplastin time-effective intravenous heparin. After intravenous administration of a paramagnetic contrast agent, bolus track PWI allows pixel based determination of mean transit time (MTT) and cerebral blood volume (CBV). DWI was performed with two different b values (0, 1000 s/mm2) for calculation of apparent diffusion coefficient (ADC) maps. Results In five of six cases increased MTT values were observed initially, whereas the CBV was normal, indicating a reduction of cerebral blood flow. ADC values were normal. On follow up after clinical recovery MTT prolongations had resolved. Areas with prolonged MTT did not evolve into structural lesions. Conclusion In patients with CVT, prolongations of MTT in the absence of changes in CBV and ADC seem to indicate reversible involvement of brain tissue, a situation corresponding to the ischaemic penumbra.

Characterization of the mechanical properties of arterial tissues usually involves an invasive procedure requiring tissue removal. In this work we propose a non-invasive method to perform a biomechanical analysis of cardiovascular aortic tissue. This method is based on combining medical imaging and finite element analysis (FEA). Magnetic resonance imaging (MRI) was chosen since it presents relatively low risks for human health. A finite element model was created from the MRI images and loaded with systolic physiological pressures. By means of an optimization routine, the structural material properties were changed until average strains matched those measured by MRI. The method outlined in this work produced an estimate of the in situ properties of cardiovascular tissue based on non-invasive image datasets and finite element analysis.

A fast version of the arterial spin tagging technique for the detection of cerebral perfusion is presented. Based on adiabatic spin inversion in combination with snapshot FLASH imaging our technique allows the recording of perfusion changes with a temporal resolution of about 3 s. Differences of cerebral perfusion dependent on the choice of anesthesia were observed in rat brain. Furthermore, with this arterial spin tagging method we demonstrated perfusion increases in the somatosensory cortex of anaesthetized rats during forepaw stimulation. Comparison of the activated areas in the T 2 * -weighted BOLD images and the perfusion-weighted images showed good spatial correspondence, but the sensitivity to the functional activation was more than ten times higher in the perfusion technique.

Volumetric abnormalities of the hippocampus and frontal cortex are of major interest in the study of borderline personality disorder (BPD). To our knowledge, no study has examined volumetric abnormalities in the hippocampal subregions (head, body, and tail). Our aims were to investigate hippocampal volumetric abnormalities as well as abnormalities in the gray and white matter of the frontal cortex, basal ganglia, and anterior cingulate cortex in BPD in a sample of BPD patients compared to healthy controls. Using manual volumetry as well as optimized voxel based morphometry (VBM) we assessed the volumetric differences in a sample of females with BPD (n=20), compared to healthy female controls (n=21) (HC). The analyses revealed reductions in the left hippocampal head, body, and tail, and the right hippocampal tail. Hippocampal changes were confirmed also using VBM and additional volumetric reductions were found in the caudate and dorsolateral prefrontal cortex of the BPD group. Our study reaffirms the existence of hippocampal volumetric, prefrontal and caudate abnormalities in BPD and lends support to the stress-related explanation of these reductions, whilst also bringing new data to the topic in terms of the abnormalities found in the subregions.

Traumatic brain injury is the leading cause of death in children and young adults globally. Malignant cerebral oedema has a major role in the pathophysiology that evolves after severe traumatic brain injury. Added to this is the significant morbidity and mortality from cerebral oedema associated with acute stroke, hypoxic ischemic coma, neurological cancers and brain infection. Therapeutic strategies to prevent cerebral oedema are limited and, if brain swelling persists, the risks of permanent brain damage or mortality are greatly exacerbated. Here we show that a temporary and size-selective modulation of the blood-brain barrier allows enhanced movement of water from the brain to the blood and significantly impacts on brain swelling. We also show cognitive improvement in mice with focal cerebral oedema following administration in these animals of short interfering RNA directed against claudin-5. These observations may have profound consequences for early intervention in cases of traumatic brain injury, or indeed any neurological condition where cerebral oedema is the hallmark pathology.

Functional magnetic resonance imaging (fMRI) techniques highlight cerebral vascular responses which are coupled to changes in neural activation. However, two major difficulties arise when employing these techniques in animal studies. First is the disturbance of cerebral blood flow due to anaesthesia and second is the difficulty of precise reproducible quantitative measurements. These difficulties were surmounted in the current study by using propofol and quantitative arterial spin labelling (QASL) to measure relative cerebral blood volume of labelled water (rCBVlw), mean transit time (MTT) and capillary transit time (CTT). The ASL method was applied to measure the haemodynamic response in the primary somatosensory cortex following forepaw stimulation in the rat. Following stimulation an increase in signal intensity and rCBVlw was recorded, this was accompanied by a significant decrease in MTT (1.97 ± 0.06 s to 1.44 ± 0.04 s) and CTT (1.76 ± 0.06 s to 1.39 ± 0.07 s). Two animals were scanned repeatedly on two different experimental days. Stimulation in the first animal was applied to the same forepaw during the initial and repeat scan. In the second animal stimulation was applied to different forepaws on the first and second days. The control and activated ASL signal intensities, rCBVlw on both days were almost identical in both animals. The basal MTT and CTT during the second scan were also very similar to the values obtained during the first scan. The MTT recorded from the animal that underwent stimulation to the same paw during both scanning sessions was very similar on the first and second days. In conclusion, propofol induces little physiological disturbance and holds potential for longitudinal QASL fMRI studies.

MR diffusion tensor imaging (DTI) was used to analyze the fibrous structure of aortic tissue. A fresh porcine aorta was imaged at 7T using a spin echo sequence with the following parameters: matrix 128 128 pixel; slice thickness 0.5 mm; interslice spacing 0.1 mm; number of slices 16; echo time 20.3 s; field of view 28 mm 28 mm. Eigenvectors from the diffusion tensor images were calculated for the central image slice and the averaged tensors and the eigenvector corresponding to the largest eigenvalue showed two distinct angles corresponding to near and to the transverse plane of the aorta. Fibre tractography within the aortic volume imaged confirmed that fibre angles were oriented helically with lead angles of and . The findings correspond to current histological and microscopy data on the fibrous structure of aortic tissue, and therefore the eigenvector maps and fibre tractography appear to reflect the alignment of the fibers in the aorta. In view of current efforts to develop noninvasive diagnostic tools for cardiovascular diseases, DTI may offer a technique to assess the structural properties of arterial tissue and hence any changes or degradation in arterial tissue.

PUBLISHED, Degenerative retinopathies, including age-related macular degeneration, diabetic retinopathy, and hereditary retinal disorders?major causes of world blindness?are potentially treatable by using low-molecular weight neuroprotective, antiapoptotic, or antineovascular drugs. These agents are, however, not in current systemic use owing to, among other factors, their inability to passively diffuse across the microvasculature of the retina because of the presence of the inner blood?retina barrier (iBRB). Moreover, preclinical assessment of the efficacies of new formulations in the treatment of such conditions is similarly compromised. We describe here an experimental process for RNAi-mediated, size-selective, transient, and reversible modulation of the iBRB in mice to molecules up to 800 Da by suppression of transcripts encoding claudin-5, a protein component of the tight junctions of the inner retinal vasculature. MRI produced no evidence indicative of brain or retinal edema, and the process resulted in minimal disturbance of global transcriptional patterns analyzed in neuronal tissue. We show that visual function can be improved in IMPDH1?/? mice, a model of autosomal recessive retinitis pigmentosa, and that the rate of photoreceptor cell death can be reduced in a model of light-induced retinal degeneration by systemic drug delivery after reversible barrier opening. These findings provide a platform for high-throughput drug screening in models of retinal degeneration, and they ultimately could result in the development of a novel ?humanized? approach to therapy for conditions with little or no current forms of treatment., The Ocular Genetics Unit at TCD is supported by Science Foundation Ireland,TheWellcomeTrust,EuropeanVision Institute, EVI-Genoret Grant LSHG-CT-2005-512036, Fighting Blindness Ireland, and Enterprise Ireland.

Neuroinflammation is a significant and consistent feature of many neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). The greatest risk factor for neurodegenerative disorders is age and a proinflammatory phenotype in the aged brain is believed to contribute to these neurodegenerative conditions. In animal models, neuroinflammatory changes, characterized by increased microglial activation, have been associated with a loss of synaptic plasticity and here we show that treatment of aged rats with the PPARγ agonist, rosiglitazone, modulates the inflammatory changes and restores synaptic function. The evidence presented highlights an important role for astrocytes in inducing inflammatory changes and suggests that the age-related astrogliosis and astrocytosis is responsible for the increase in the proinflammatory cytokine, tumor necrosis factor alpha (TNF-α). Magnetic resonance (MR) imaging revealed an age-related increase in T1 relaxation time and, importantly, treatment of aged rats with rosiglitazone reversed the age-related increases in astrogliosis and astrocytosis, TNF-α concentration and T1 relaxation time. The evidence indicates that the site of action for rosiglitazone is endothelial cells, and suggests that its effect on astrocytes is secondary to its effect on endothelial cells.

In recent years, a strong link between the failure of the aortic anatomical structure and the development of cardiovascular diseases has become more evident [1]. Aortas, like arteries in general, can be regarded as anisotropic structures, due to the presence of fibres oriented at an angle within the arterial wall.Copyright © 2009 by ASME

Arterial spin labelling (ASL) is a magnetic resonance imaging (MRI) technique that can be used to provide a quantitative assessment of cerebral perfusion. Despite the development of a number of theoretical models to facilitate quantitative ASL, some key challenges still remain. The purpose of this study is to develop a novel quantitative ASL method based on a macroscopic model that reduces the number of variables required to describe the physiological processes involved. To this end, a novel Fokker-Planck equation consisting of stochastically varying macroscopic variables was derived from a general Langevin equation. ASL data from the rat brain was acquired using a bolus-tracking ASL protocol where a bolus of labelled spins flowing from an inversion plane in the neck into an imaging plane in the brain can be observed. Bolus durations of 1.5 s, 2.0 s and 3.0 s were used and the solution to the Fokker-Planck equation for the boundary conditions of bolus-tracking ASL was fitted to the experimental data using a least-squares fit. The mean transit time (MTT) and capillary transit time (CTT) were calculated from the first and second moments of the resultant curve respectively and the arterial transit time (ATT) was calculated by subtracting the CTT from the MTT. The average MTT, CTT and ATT values were 1.75 +/- 0.22 s, 1.43 +/- 0.12 s and 0.32 +/- 0.04 s respectively. In conclusion, a new ASL protocol has been developed by combining the theoretical model with ASL experiments. The technique has the unique ability to provide solutions for varying bolus volumes and the generality of the new model is demonstrated by the derivation of additional solutions for the continuous and pulsed ASL (CASL and PASL) techniques.

In spite of marked disability, patients with primary progressive multiple sclerosis (PPMS) display smaller lesion volumes on conventional magnetic resonance imaging (MRI) compared with other forms of multiple sclerosis (MS). Hence, damage to the normal-appear ing brain tissue (NA BT) may play an important role in explaining the patho genesis of disability in PPMS. Diffusion-weighted MRI (DW-MRI) probes water diffusion in vivo that can be altered by patho logic changes. Using DW-MRI we investigated diffusion in the NA BT of 15 patients with PPMS over one year. The average apparent diffusion coefficient (A DC av) was measured in 10 regions of interest located in the normal- appearing thalamus and the normal-appearing white matter (NAWM). Six healthy subjects served as a reference. In contrast to healthy subjects, patients with PPMS showed an increment within 12 months of the A DC av in NAWM which was associated with an increase of the T2- and T1-lesion volumes. The A DC av in frontal NAWM was associated with disability as measured by the MS Functio nal C omposite Measure. Serial DW-MRI depicts progressive changes in the NAWM of patients with PPMS. O ur preliminary findings suggest that the processes causing structural damage in NAWM and lesions in patients with PPMS are partially linked and that changes of water diffusion in NAWM depicted by DW-MRI are clinically relevant.

The inbred Wistar-Kyoto (WKY) rat is a putative animal model of depression previously reported to exhibit decreased cell numbers immunoreactive for astroglial cell marker glial fibrillary acidic protein (GFAP). The WKY strain exhibit a depressive and anxiety like phenotype across the range of behavioural paradigms including the FST, EPM, OF and light/dark box relative to other rat strains including the Wistar background strain. We sought to investigate if WKY rats displayed any differences in regional cerebral blood flow (CBF) in cortical and limbic regions of the brain as measured by bolus tracking Arterial Spin Labelling (bt-ASL) when compared to the Wistar strain. Male Wistar and WKY rats (200–250 g, n = 7–10 per group) were subjected to a series of behavioural tests referred to above to establish the behavioural phenotype. MR-btASL scans were undertaken in a 7-Tesla Bruker BioSpec 70/30 magnet system. The WKY strain exhibits a significant decrease in CBF measures in pre-frontal cortical (PFC) regions relative to WIS controls. A significant negative correlation was found between MRI perfusion parameters and GFAP positive cell number in the PFC of WKY but not Wistar rats. These data suggest that changes in GFAP positive cell number in the WKY rat model may be associated with changes in resting state CBF in the frontal cortex.

Stroke is caused by a disorder of brain blood flow and a concomitant reduction in substrate delivery, particularly of oxygen. Cerebral blood flow and hemoglobin oxygenation can be monitored in patients by noninvasive methods, such as magnetic resonance imaging (MRI) and near-infrared spectroscopy (NIRS). Monitoring these parameters may be used to: (1) investigate stroke pathophysiology in humans; (2) “stage” patients according to their current pathopysiological status to guide pathophysiologically oriented therapy and for inclusion (or exclusion) into studies; and (3) monitor the outcome of therapy and brain reorganization. We try to demonstrate initial attempts to achieve these goal with MRI and NIRS. We speculate that modern noninvasive techniques for studying brain morphology, metabolism, and function may hold the key to establishing successful, pathophysiologically oriented stroke therapy.

Six patients who had suffered small cerebral ischemia affecting subcortical gray matter were examined with diffusion weighted imaging (DWI) and T2-weighted imaging within the first 8 h, during the next 2 days and after 5-16 days. Areas of apparent diffusion coefficient (ADC) decreases were observed acutely and reached the maximum size during the subsequent 2 days. Noticeably, in all subjects, a large portion of the ADC lesion was reversible as judged from the lesion size on final T2 image. The regular reversibility of the ADC decreases in this setting may indicate a hitherto not understood pathophysiological process occurring in small ischemic stroke.

Using a one-step procedure we have prepared magnetic fluids comprising of polyelectrolyte stabilized magnetite nanoparticles. These nanocomposites are comprised of linear, chain-like assemblies of magnetic nanoparticles, which can be aligned in parallel arrays by an external magnetic field. We have shown the potential use of these materials as contrast agents by measuring their MR response in live rats. The new magnetic fluids have demonstrated good biocompatibility and potential for in vivo MRI diagnostics.

The effect of thrombolytic therapy was studied in rats submitted to thromboembolic stroke by intracarotid injection of autologous blood clots. Thrombolysis was initiated after 15 minutes with an intracarotid infusion of recombinant tissue-type activator (10 mg/kg body weight). Reperfusion was monitored for 3 hours using serial perfusion- and diffusion magnetic resonance imaging, and the outcome of treatment was quantified by pictorial measurements of ATP, tissue pH, and blood flow. In untreated animals, clot embolism resulted in an immediate decrease in blood flow and a sharp decrease in the apparent diffusion coefficient (ADC) that persisted throughout the observation period. Thrombolysis successfully recanalized the embolized middle cerebral artery origin and led to gradual improvement of blood flow and a slowly progressing reversal of ADC changes in the periphery of the ischemic territory, but only to transient and partial improvement in the center. Three hours after initiation of thrombolysis, the tissue volume with ADC values less than 80% of control was 39 ± 22% as compared to 61 ± 20% of ipsilateral hemisphere in untreated animals (means ± SD, P = .03) and the volume of ATP-depleted brain tissue was 25 ± 31% as compared to 46 ± 29% in untreated animals. Recovery of ischemic brain injury after thromboembolism is incomplete even when therapy is started as early as 15 minutes after clot embolism. Possible explanations for our findings include downstream displacement of clot material, microembolism of the vascular periphery, and events associated with reperfusion injury.