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Quantitative study of perivascular spaces (PVSs) in brain magnetic resonance (MR) images is important for understanding the brain lymphatic system and its relationship with neurological diseases. One of the major challenges is the accurate extraction of PVSs that have very thin tubular structures with various directions in three-dimensional (3D) MR images. In this paper, we propose a learning-based PVS segmentation method to address this challenge. Specifically, we first determine a region of interest (ROI) by using the anatomical brain structure and the vesselness information derived from eigenvalues of image derivatives. Then, in the ROI, we extract a number of randomized Haar features which are normalized with respect to the principal directions of the underlying image derivatives. The classifier is trained by the random forest model that can effectively learn both discriminative features and classifier parameters to maximize the information gain. Finally, a sequential learning strategy is used to further enforce various contextual patterns around the thin tubular structures into the classifier. For evaluation, we apply our proposed method to the 7T brain MR images scanned from 17 healthy subjects aged from 25 to 37. The performance is measured by voxel-wise segmentation accuracy, cluster-wise classification accuracy, and similarity of geometric properties, such as volume, length, and diameter distributions between the predicted and the true PVSs. Moreover, the accuracies are also evaluated on the simulation images with motion artifacts and lacunes to demonstrate the potential of our method in segmenting PVSs from elderly and patient populations. The experimental results show that our proposed method outperforms all existing PVS segmentation methods., (Copyright © 2016 Elsevier Inc. All rights reserved.)

There is an unmet medical need for noninvasive imaging of regional brain oxygenation to manage stroke, tumor, and neurodegenerative diseases. Oxygenation imaging from magnetic susceptibility in MRI is a promising new technique to measure local venous oxygen extraction fraction (OEF) along the cerebral venous vasculature. However, this approach has not been tested in vivo at different levels of oxygenation. The primary goal of this study was to test whether susceptibility imaging of oxygenation can detect OEF changes induced by hypercapnia, via CO2 inhalation, within selected a priori brain regions. Ten healthy subjects were scanned at 3T with a 32-channel head coil. The end-tidal CO2 (ETCO2) was monitored continuously and inspired gases were adjusted to achieve steady-state conditions of eucapnia (41±3mmHg) and hypercapnia (50±4mmHg). Gradient echo phase images and pseudo-continuous arterial spin labeling (pcASL) images were acquired to measure regional OEF and CBF respectively during eucapnia and hypercapnia. By assuming constant cerebral oxygen consumption throughout both gas states, regional CBF values were computed to predict the local change in OEF in each brain region. Hypercapnia induced a relative decrease in OEF of -42.3% in the straight sinus, -39.9% in the internal cerebral veins, and approximately -50% in pial vessels draining each of the occipital, parietal, and frontal cortical areas. Across volunteers, regional changes in OEF correlated with changes in ETCO2. The reductions in regional OEF (via phase images) were significantly correlated (P<0.05) with predicted reductions in OEF derived from CBF data (via pcASL images). These findings suggest that susceptibility imaging is a promising technique for OEF measurements, and may serve as a clinical biomarker for brain conditions with aberrant regional oxygenation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Resting-state functional MRI (RS-fMRI) is a widely used method for inferring connectivity between brain regions or nodes. As with task-based fMRI, the spatial specificity of the connectivity maps can be distorted by the strong biasing effect of the BOLD signal in macroscopic veins. In RS-fMRI this effect is exacerbated by the temporal coherences of physiological origin between large veins that are widely distributed in the brain. In gradient echo based EPI, used for the vast majority of RS-fMRI, macroscopic veins that carry BOLD-related changes exhibit a strong phase response. This allows for post-processing identification and removal of venous signals using a phase regressor technique. Here, we employ this approach to suppress macrovascular venous contributions in high-field whole-brain RS-fMRI data sets, resulting in significant changes to both the spatial localization of the networks and the correlations between the network nodes. These effects were observed at both the individual and group analysis level, suggesting that venous contamination is a confounding factor for RS-fMRI studies even at relatively low image resolutions. Suppression of the macrovascular signal using the phase regression approach may therefore help to better identify, delineate, and interpret the true structure of large-scale brain networks., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Vascular domains have been described as being coupled to neuronal functional units enabling dynamic blood supply to the cerebral cyto-architecture. Recent experiments have shown that penetrating arterioles of the grey matter are the building blocks for such units. Nevertheless, vascular territories are still poorly known, as the collection and analysis of large three-dimensional micro-vascular networks are difficult. By using an exhaustive reconstruction of the micro-vascular network in an 18 mm(3) volume of marmoset cerebral cortex, we numerically computed the blood flow in each blood vessel. We thus defined arterial and venular territories and examined their overlap. A large part of the intracortical vascular network was found to be supplied by several arteries and drained by several venules. We quantified this multiple potential to compensate for deficiencies by introducing a new robustness parameter. Robustness proved to be positively correlated with cortical depth and a systematic investigation of coupling maps indicated local patterns of overlap between neighbouring arteries and neighbouring venules. However, arterio-venular coupling did not have a spatial pattern of overlap but showed locally preferential functional coupling, especially of one artery with two venules, supporting the notion of vascular units. We concluded that intra-cortical perfusion in the primate was characterised by both very narrow functional beds and a large capacity for compensatory redistribution, far beyond the nearest neighbour collaterals., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Vessel size imaging is an emerging magnetic resonance imaging (MRI) technique which has been demonstrated to provide clinically relevant information about microvascular morphology. While previous studies of vessel size in humans relied on MRI contrast agents or hypercapnia-induced changes in blood oxygenation, the technique described here uses transient hyperoxia to alter the venous blood oxygenation. The experimental paradigm consisted of two 3-minute intervals of breathing 100% O(2) interleaved with three 2-minute intervals of breathing room air. Parametric maps of the mean venous vessel radius were calculated from changes in the blood oxygenation level dependent (BOLD) contrast which were measured using a combined spin-echo (SE) and gradient echo (GE) echo-planar imaging (EPI) sequence. The corresponding mean values in grey and white matter were r=6.5±0.3 μm and r=6.2±0.3 μm (n=6). While the hypercapnia technique requires a specialised gas mixture containing a low concentration of CO(2) (typically 5-6%), the hyperoxia technique presented here uses the inhalation of medical oxygen (100% O(2)) which is routinely available in a clinical environment. Furthermore, 100% O(2) is generally better tolerated than low doses of CO(2) which makes this technique particularly suitable for applications in critically ill patients., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Although there exist some reference and stereotactic anatomical human brain atlases, there is no equivalent cerebrovascular atlas. A 3D reference atlas of the human cerebrovasculature that is interactive, stereotactic, very detailed, completely parcellated, fully labeled, extendable, dissectible, deformable, and user friendly, is needed in education, training, research, and clinical applications. We constructed a sophisticated and very detailed cerebrovascular atlas with 1325 vascular segments, the smallest of 80 μm in diameter. The atlas was created from multiple 3 and 7T scans by employing tools and methods developed in our lab. In contrast to a sort of "sampled" vascular geometry cited in the literature, we provide information about the "continuous" geometry of the vascular model measurable in 3D at every location and along any vascular segment for both hemispheres. This cerebrovascular atlas was validated taking into account domain knowledge from various fields including angiography, neurosurgery, neuroradiology, (clinical) neuroanatomy, and terminology. Validation was considered as a confirmation of the created vascular model to a typical (conventional) cerebrovascular system with nearly average dimensions. It was done in terms of vessel subdivision, origin, course, surrounding anatomy, patterns, length, diameter, and branches. This validation demonstrates that the constructed cerebrovascular model generally represents a normal, typical cerebrovasculature with its dimensions close to average. This 7T atlas along with the vascular model is a rich source of knowledge about the human cerebrovasculature. The atlas is applicable in education, research, and clinical applications; it has already been applied in deep brain stimulation., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The veins of the dentate nucleus are composed of several channels draining the external surface and one single vein draining the internal surface. We analyzed specimens of the human cerebellum and described the central vein of the nucleus dentatus as the main venous outflow of the nucleus. The central vein of the nucleus dentatus is formed by a network of smaller vessels draining the sinuosities of the gray matter; it emerges from the hilum of the nucleus and runs along the superior cerebellar peduncle, opening in the anterior vermian vein. We looked for this structure and for the surrounding veins on ultra-high-field (7 Tesla) MR, using susceptibility-weighted imaging. An anatomical and radiological description of the veins of the dentate nucleus is provided, with some remarks on the future clinical applications that these findings could provide., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The brain is characterized by an extremely rich blood supply, regulated by changes in blood vessel diameter and blood flow, depending on metabolic demands. The blood-brain barrier (BBB)-a functional and structural barrier separating the intravascular and neuropil compartments-characterizes the brain's vascular bed and is essential for normal brain functions. Disruptions to the regional cerebral blood supply, to blood drainage and to BBB properties have been described in most common neurological disorders, but there is a lack of quantitative methods for assessing blood flow dynamics and BBB permeability in small blood vessels under both physiological and pathological conditions. Here, we present a quantitative image analysis approach that allows the characterization of relative changes in the regional cerebral blood flow (rCBF) and BBB properties in small surface cortical vessels. In experiments conducted using the open window technique in rats, a fluorescent tracer was injected into the tail vein, and images of the small vessels at the surface of the cortex were taken using a fast CCD camera. Pixel-based image analysis included registration and characterization of the changes in fluorescent intensity, followed by cluster analysis. This analysis enabled the characterization of rCBF in small arterioles and venules and changes in BBB permeability. The method was implemented successfully under experimental conditions, including increased rCBF induced by neural stimulation, bile salt-induced BBB breakdown, and photothrombosis-mediated local ischemia. The new approach may be used to study changes in rCBF, neurovascular coupling and BBB permeability under normal and pathological brain conditions.

Caffeine lowers the blood oxygenation level-dependent (BOLD) signal by acting as an adenosine antagonist, thus decreasing the cerebral blood flow (CBF). The aims of this study were to demonstrate the sensitivity of susceptibility-weighted imaging (SWI) to caffeine-induced changes in CBF and to investigate the time course and magnitude of signal change in caffeine-habituated and -abstinent volunteers. High-resolution susceptibility-weighted images were acquired with both groups at 1.5 T using a fully velocity compensated 3D gradient echo sequence. Following a native scan, subjects were given a tablet containing 200 mg of caffeine. Scans were repeated for about 1 h and the acquired 3D data sets were co-registered to each other. BOLD signal changes of several venous vessels were analyzed in dedicated ROIs. Maps of relative signal change clearly visualized the caffeine-induced signal response of veins. Only very weak signal changes of about -2+/-1% were found in both, grey and white matter and -1+/-2% in the ventricles. Maximum signal decrease of veins occurred 40-50 min after caffeine ingestion. The signal decrease was -16.5+/-6.5% and -22.7+/-8.3% for the caffeine users group and abstainers, respectively. The signal difference of both groups was statistically significant (Student's t-test, t=2.16, p=0.021). Data acquired at 1.5, 3 and 7 T with echo times scaled to the respective field strength display very similar temporal signal behavior.

The increased susceptibility effects and high signal-to-noise ratio at 7.0 T enable imaging of the brain using the phase of the magnetic resonance signal. This study describes and evaluates a robust method for calculating phase images from gradient-recalled echo (GRE) scans. The GRE scans were acquired at 7.0 T using an eight-channel receive coil at spatial resolutions up to 0.195 x 0.260 x 2.00 mm. The entire 7.0 T protocol took less than 10 min. Data were acquired from forty-seven subjects including clinical patients with multiple sclerosis (MS) or brain tumors. The phase images were post-processed using a fully automated phase unwrapping algorithm that combined the data from the different channels. The technique was used to create the first phase images of MS patients at any field strength and the first phase images of brain tumor patients above 1.5 T. The clinical images showed novel contrast in MS plaques and depicted microhemorrhages and abnormal vasculature in brain tumors with unsurpassed resolution and contrast.

Studies of mouse cerebral vasculature to date have focused on the circle of Willis without examining the morphological distribution of blood vessels through the rest of the brain. Since mouse models are frequently used in brain-related studies, there is a need for a comprehensive cerebral vasculature atlas for the mouse with an emphasis on the location of vessels with respect to neuroanatomical structures, the watershed regions associated with specific arteries, as well as a consistent nomenclature of the cerebral vessels. This article describes such an atlas, based on a combination of magnetic resonance and computed tomography technology to yield high-resolution volumetric and vasculature data on CBA mouse. This three-dimensional vasculature dataset provides an anatomical resource for future mouse studies.

The cortical hemodynamic response to somatosensory stimulus is investigated at the level of individual vascular compartments using both depth-resolved optical imaging and in-vivo two-photon microscopy. We utilize a new imaging and spatiotemporal analysis approach that exploits the different characteristic dynamics of responding arteries, arterioles, capillaries and veins to isolate their three-dimensional spatial extent within the cortex. This spatial delineation is validated using vascular casts. Temporal delineation is supported by in-vivo two-photon microscopy of the temporal dynamics and vascular mechanisms of the arteriolar and venous responses. Using these techniques we have been able to characterize the roles of the different vascular compartments in generating and controlling the hemodynamic response to somatosensory stimulus. We find that changes in arteriolar total hemoglobin concentration agree well with arteriolar dilation dynamics, which in turn correspond closely with changes in venous blood flow. For 4-s stimuli, we see only small changes in venous hemoglobin concentration, and do not detect measurable dilation or ballooning in the veins. Instead, we see significant evidence of capillary hyperemia. We compare our findings to historical observations of the composite hemodynamic response from other modalities including functional magnetic resonance imaging. Implications of our results are discussed with respect to mathematical models of cortical hemodynamics, and to current theories on the mechanisms underlying neurovascular coupling. We also conclude that our spatiotemporal analysis approach is capable of isolating and localizing signals from the capillary bed local to neuronal activation, and holds promise for improving the specificity of other hemodynamic imaging modalities.

We used two different methods of region of interest (ROI) definition to investigate the spatial accuracy of functional magnetic resonance imaging (fMRI) at low and high spatial resolution. The "single-condition localizer" consisted of block alternation between a target stimulus and a mean gray background. The "differential localizer" consisted of block alternation between the target stimulus and another stimulus that filled the complement of the visual field. A separate series of scans, in which the target stimulus was presented briefly with long inter-stimulus intervals, was used to measure the hemodynamic impulse response function (HIRF). As expected, the differential localizer defined more restricted ROIs that better matched the predicted cortical representation of the target stimulus. However, at low resolution (3-mm isotropic) many voxels that responded positively to the target stimulus in the differential protocol responded negatively to the target stimulus in the single-condition localizer and in the HIRF measurements. The localization errors were attributed to voxels near large veins, which were identified based on low mean intensity and high variance. At high resolution (1.2-mm isotropic), the effects of large veins were present, but affected a smaller number of voxels. Thus, the use of differential localizers does not necessarily result in a more accurate indication of the underlying neural activity. Localization errors are reduced at higher spatial resolutions and can be eliminated by identification and removal of voxels dominated by large veins.

MRI at high magnetic field strength potentially allows for an increase in resolution and image contrast. The gains are particularly dramatic for T(2)(*)-weighted imaging, which is sensitive to susceptibility effects caused by a variety of sources, including deoxyhemoglobin, iron concentration, and tissue microstructure. On the other hand, the acquisition of high quality whole brain MRI at high field is hampered by the increased inhomogeneity in B(o) and B(1) fields. In this report, high-resolution gradient echo MRI was performed using an 8-channel detector to obtain T(2)(*)-weighted images over large brain areas. The high SNR achieved with the multi-channel array enabled T(2)(*)-weighted images of the brain with an unprecedented spatial resolution of up to 0.2 x 0.2 x 0.5 mm(3). This high resolution greatly facilitated the detection of microscopic susceptibility effects. In addition to the expected contrast between gray, white matter, cerebral spinal fluid, and veins, a large degree of heterogeneity in contrast was observed throughout the white matter of normal brain. The measured T(2)(*) values in white matter varied as much as 30% with some of the variation apparently correlating with the presence of large fiber bundles.

The optimum parameters for single-shot gradient-recalled (GR) EPI-based fMRI studies of the limbic region are systematically established at 3 T via their ability to mitigate intravoxel dephasing-measured via SNR and T2* in the amygdalae-and their implications for temporal resolution (or brain coverage). Conventional imaging parameters (64 x 64 matrix size and 4-6 mm thick slices) are confirmed to be inadequate for functional studies at 3 T. Measurements of main magnetic field variations across the amygdalae suggest that such variations are equal in the craniocaudal and anterior-posterior directions, and slightly lower in the mediolateral direction, with this and other considerations leading us to conclude an oblique axial orientation to be most suitable. In-plane resolution of approximately 1.7 mm was sufficient to recover signal in the area of the amygdalae. SNR was found to peak at a slice thickness of between 2.0 and 2.5 mm, dependent on the subject. T2* time in the amygdalae was measured with a standard EPI protocol to be 22 +/- 3 ms. Using the optimized (high resolution) EPI protocol proposed here, the measured T2* time increased to 48 +/- 2 ms (compared with 43 +/- 3 ms for a reference FLASH scan), only slightly lower than the cortex (49 +/- 2 ms measured with optimized EPI and 52 +/- 2 ms with FLASH). The FLASH measurement of 43 ms is taken to be a suitable effective echo time (TE(eff)) to achieve maximum BOLD sensitivity in the amygdalae. Time series data acquired with these parameters showed a 60% increase in SNR in the amygdala over that obtained with a standard low-resolution protocol and suggest sufficient SNR and BOLD sensitivity to make functional studies feasible. Arteries, but no substantial draining veins, were found in high-resolution BOLD venograms of the region. Our results indicate that EPI protocols need to be carefully optimized for structures of interest if reliable results from single subjects are to be established in this brain region.

Inflow effects on activation-related BOLD signal changes in event-related fMRI experiments were assessed by varying the repetition time (TR) and flip angle (FA) values for gradient-echo echo-planar imaging (GE-EPI). Surprisingly, both increases and decreases were detected in these signal changes with increased T(1) weighting (reduced TR, increased FA). The well-known "positive" effect is attributed to inflow of fresh spins in the slice, leading to an apparent reduction in T(1). The "negative" effect is attributed to voxels containing pure parenchyma, where large-vessel inflow effects are very small and the BOLD effect is dominated by microvascular blood volume and oxygenation changes. Because blood T(1) is greater than tissue T(1) at 1.5 T, the fractional BOLD effect decreases with increased T(1) weighting. To aid in the interpretation of these experimental results, numerical simulations were performed based on a physiological multicompartment model, including pure tissue, large vessels (arteries, veins), microvessels (arterioles, capillaries, venules), and cerebrospinal fluid.