Three-dimensional gradient and spin-echo readout for time-encoded pseudo-continuous arterial spin labeling: Influence of segmentation factor and flow compensation.

PURPOSE: To monitor the complete passage of the labeled blood through the vascular tree into tissue and improve the quantification of ASL maps, we evaluated the effect of 3D gradient and spin-echo (GRASE) readout segments on temporal SNR (tSNR) and image blurriness for time-encoded pseudo-continuous arterial spin labeling and the effect of flow-compensation gradients on the presence of intravascular signal. METHODS: Fifteen volunteers were scanned using time-encoded pCASL with 2D EPI and single-segment, two-segments, and three-segments 3D-GRASE readouts with first-order flow compensation (FC) gradients. Two-segments 3D-GRASE scans were acquired with 25%, 50%, 75%, and 100% of full first-order FC. Temporal SNR was assessed, and cerebral blood flow and arterial blood volume were quantified for all readout strategies. RESULTS: For single-segment 3D GRASE, tSNR was comparable to 2D EPI for perfusion signal but worse for the arterial signal. Two-segments and three-segments 3D GRASE resulted in higher tSNR than 2D EPI for perfusion and arterial signal. The arterial signal was not well visualized for 3D-GRASE data without FC. Visualization of the intravascular signal at postlabeling delays of 660 ms and 1060 ms was restored with FC. Adequate visualization of the intravascular signal was achieved from 75% of FC gradient strength at a postlabeling delay of 660 ms. For a postlabeling delay of 1060 ms, full-FC gradients were the best option to depict intravascular signal. CONCLUSION: Segmented GRASE provided higher effective tSNR compared with 2D-EPI and single-segment GRASE. Flow compensation with GRASE readout should be carefully controlled when applying for time-encoded pCASL to visualize intravascular signal.

Mononitrate Isosorbide as an Adjunctive Therapy in Schizophrenia: A Randomized Controlled Crossover Trial.

BACKGROUND: Schizophrenia is a complex disabling mental disorder, and many patients present poor response to available treatments. Accumulating evidence about the role of the glutamate/nitric oxide pathway in mediating the positive and negative symptoms of schizophrenia suggests potential benefits of drugs that modulate this system. The aim of this study was to test the efficacy of isosorbide mononitrate (ISMN) as an adjunctive therapy for symptomatic outpatients with schizophrenia. METHODS: This was a 2-month randomized, double-blind, placebo-controlled trial with 24 schizophrenia patients. Participants were treated with ISMN 50 mg for 1 month and placebo for another month in a crossover design. The Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Scale, Global Assessment of Functioning, and MATRICS Cognitive Consensual Battery were used for symptom assessment and arterial spin labeling was used to assess brain activation patterns. RESULTS: We found significant differences in the total, general, and positive subscales of the PANSS, Global Assessment of Functioning scores, and Clinical Global Impression scores during treatment with ISMN relative to placebo. No treatment effects were found comparing scores in the MATRICS Cognitive Consensual Battery and the negative subscale of the PANSS between the active and placebo conditions. A post hoc analysis of neuroimaging data showed reduced activity in the thalamus in subgroup of patients with severe psychopathology. CONCLUSIONS: Schizophrenia patients with persistent symptoms showed significant improvement after 4 weeks of treatment with ISMN 50 mg/d compared with placebo. Isosorbide mononitrate added beneficial effects to antipsychotic treatment in terms of positive symptoms and functioning.

Quantification of BOLD fMRI parameters to infer cerebrovascular reactivity of the middle cerebral artery.

PURPOSE: To quantify the amplitude and temporal aspects of the blood oxygenation level-dependent (BOLD) response to an auditory stimulus during normocapnia and hypercapnia in healthy subjects in order to establish which BOLD parameters are best suited to infer the cerebrovascular reactivity (CVR) in the middle cerebral artery (MCA) territory. MATERIALS AND METHODS: Twenty healthy volunteers (mean age: 23.6 ± 3.7 years, 11 women) were subjected to a functional paradigm composed of five epochs of auditory stimulus (3 sec) intercalated by six intervals of rest (21 sec). Two levels of hypercapnia were achieved by a combination of air and CO2 while the end-tidal CO2 (ETCO2 ) was continually measured. An autoregressive method was applied to analyze four parameters of the BOLD signal: onset-time, time-to-peak, full-width-at-half-maximum (FWHM), and amplitude. RESULTS: BOLD onset time (P < 0.001) and full-width at half-maximum (FWHM) (P < 0.05) increased linearly, while BOLD amplitude decreased (P < 0.001) linearly with increasing levels of hypercapnia. Test-retest for reproducibility in five subjects revealed excellent concordance for onset time and amplitude. CONCLUSION: The robust linear dependence of BOLD onset time, FWHM, and amplitude to hypercapnia suggest future application of this protocol in clinical studies aimed at evaluating CVR of the MCA territory.

Magnetic resonance imaging quantification of regional cerebral blood flow and cerebrovascular reactivity to carbon dioxide in normotensive and hypertensive rats.

Hypertension afflicts 25% of the general population and over 50% of the elderly. In the present work, arterial spin labeling MRI was used to non-invasively quantify regional cerebral blood flow (CBF), cerebrovascular resistance and CO(2) reactivity in spontaneously hypertensive rats (SHR) and in normotensive Wistar Kyoto rats (WKY), at two different ages (3 months and 10 months) and under the effects of two anesthetics, α-chloralose and 2% isoflurane (1.5 MAC). Repeated CBF measurements were highly consistent, differing by less than 10% and 18% within and across animals, respectively. Under α-chloralose, whole brain CBF at normocapnia did not differ between groups (young WKY: 61 ± 3ml/100g/min; adult WKY: 62 ± 4ml/100g/min; young SHR: 70 ± 9ml/100g/min; adult SHR: 69 ± 8ml/100g/min), indicating normal cerebral autoregulation in SHR. At hypercapnia, CBF values increased significantly, and a linear relationship between CBF and PaCO(2) levels was observed. In contrast, 2% isoflurane impaired cerebral autoregulation. Whole brain CBF in SHR was significantly higher than in WKY rats at normocapnia (young SHR: 139 ± 25ml/100g/min; adult SHR: 104 ± 23ml/100g/min; young WKY: 55± 9ml/100g/min; adult WKY: 71 ± 19ml/100g/min). CBF values increased significantly with increasing CO(2); however, there was a clear saturation of CBF at PaCO(2) levels greater than 70mmHg in both young and adult rats, regardless of absolute CBF values, suggesting that isoflurane interferes with the vasodilatory mechanisms of CO(2). This behavior was observed for both cortical and subcortical structures. Under either anesthetic, CO(2) reactivity values in adult SHR were decreased, confirming that hypertension, when combined with age, increases cerebrovascular resistance and reduces cerebrovascular compliance.

The stability of the blood oxygenation level-dependent functional MRI response to motor tasks is altered in patients with chronic ischemic stroke.

BACKGROUND AND PURPOSE: Functional MRI is a powerful tool to investigate recovery of brain function in patients with stroke. An inherent assumption in functional MRI data analysis is that the blood oxygenation level-dependent (BOLD) signal is stable over the course of the examination. In this study, we evaluated the validity of such assumption in patients with chronic stroke. METHODS: Fifteen patients performed a simple motor task with repeated epochs using the paretic and the unaffected hand in separate runs. The corresponding BOLD signal time courses were extracted from the primary and supplementary motor areas of both hemispheres. Statistical maps were obtained by the conventional General Linear Model and by a parametric General Linear Model. RESULTS: Stable BOLD amplitude was observed when the task was executed with the unaffected hand. Conversely, the BOLD signal amplitude in both primary and supplementary motor areas was progressively attenuated in every patient when the task was executed with the paretic hand. The conventional General Linear Model analysis failed to detect brain activation during movement of the paretic hand. However, the proposed parametric General Linear Model corrected the misdetection problem and showed robust activation in both primary and supplementary motor areas. CONCLUSIONS: The use of data analysis tools that are built on the premise of a stable BOLD signal may lead to misdetection of functional regions and underestimation of brain activity in patients with stroke. The present data urge the use of caution when relying on the BOLD response as a marker of brain reorganization in patients with stroke.

Non-classical behavior of the default mode network regions during an information processing task.

The default mode network (DMN) efficient deactivation and suppressed functional connectivity (FC) during goal-directed tasks, which require attentional resources, have been considered essential to healthy brain cognition. However, recent studies have shown that DMN regions do not always show the expected behavior. Then, we aimed to investigate the functional activation and connectivity of DMN nodes in young, healthy controls during a goal-directed task. We used an adaptation of the symbol digit modalities test (SDMT) to evaluate the information processing speed (IPS). Twenty-four subjects (10 women, age: 29 ± 7 years) underwent two functional Magnetic Resonance Imaging experiments: one during resting-state and one during a block-designed SDMT paradigm. We superimposed the templates of the DMN on the group activation map and observed the reorganization of the network. For the posterior cingulate cortex (PCC) node of the DMN, which is spatially extensive, comprising the precuneus (dorsal portion) and the posterior cingulate gyrus (PCG, ventral portion), the extent of each region was different between conditions, suggesting different functional roles for them. Therefore, for the functional connectivity (FC) analysis, we split the DMN-PCC region into two regions: left precuneus (BA 7) and PCG. The left precuneus (BA 7) was positively correlated with the left lingual gyrus (BA 17), a task-positive region, and negatively associated with the DMN nodes when comparing task performance with the resting-state condition. The other DMN regions presented the classical antagonistic role during the attentional task. In conclusion, we found that the activation and functional connectivity of the DMN is, in general, suppressed during the information processing. However, the left precuneus BA 7 presented a context-dependent modulatory behavior, working as a transient in-between hub connecting the DMN to task-positive areas. Such findings support studies that show increased activation and excitatory functional connectivity of DMN portions during goal-directed tasks. Moreover, our results may contribute to defining more precise functional correlates of IPS deficits in a wide range of clinical and neurological diseases.

Intravoxel incoherent motion MRI in neurological and cerebrovascular diseases.

Intravoxel Incoherent Motion (IVIM) is a recently rediscovered noninvasive magnetic resonance imaging (MRI) method based on diffusion-weighted imaging. It enables the separation of the intravoxel signal into diffusion due to Brownian motion and perfusion-related contributions and provides important information on microperfusion in the tissue and therefore it is a promising tool for applications in neurological and neurovascular diseases. This review focuses on the basic principles and outputs of IVIM and details it major applications in the brain, such as stroke, tumor, and cerebral small vessel disease. A bi-exponential model that considers two different compartments, namely capillaries, and medium-sized vessels, has been frequently used for the description of the IVIM signal and may be important in those clinical applications cited before. Moreover, the combination of IVIM and arterial spin labeling MRI enables the estimation of water permeability across the blood-brain barrier (BBB), suggesting a potential imaging biomarker for disrupted-BBB diseases.

Brain functional and perfusional alterations in schizophrenia: an arterial spin labeling study.

Schizophrenia is a severe mental disorder that affects the anatomy and function of the brain, with an impact on one's thoughts, feelings, and behavior. The purpose of the study was to investigate cerebral blood flow (CBF) and brain connectivity in a group of patients with schizophrenia. Pseudo-continuous arterial spin labeling (pCASL) images were acquired from 28 patients in treatment and 28 age-matched healthy controls. Mean CBF and connectivity patterns were assessed. Schizophrenia patients had decreased CBF in the bilateral frontal pole and superior frontal gyrus, right medial frontal gyrus, triangular and opercular parts of the inferior frontal gyrus, posterior division of the left supramarginal gyrus, superior and inferior divisions of the left lateral occipital cortex, and bilateral occipital pole. Moreover, through different methods to assess connectivity, our results showed abnormal connectivity patterns in regions involved in motor, sensorial, and cognitive functions. Using pCASL, a non-invasive technique, we found CBF deficits and altered functional organization of the brain in schizophrenia patients that are associated with the symptoms and characteristics of the disorder.

Phenylephrine-induced hypertension during transient middle cerebral artery occlusion alleviates ischemic brain injury in spontaneously hypertensive rats.

Arterial hypertension is a major risk factor for ischemic stroke. However, the management of preexisting hypertension is still controversial in the treatment of acute stroke in hypertensive patients. The present study evaluates the influence of preserving hypertension during focal cerebral ischemia on stroke outcome in a rat model of chronic hypertension, the spontaneously hypertensive rats (SHR). Focal cerebral ischemia was induced by transient (1h) occlusion of the middle cerebral artery, during which mean arterial blood pressure was maintained at normotension (110-120mm Hg, group 1, n=6) or hypertension (160-170mm Hg, group 2, n=6) using phenylephrine. T2-, diffusion- and perfusion-weighted MRI were performed serially at five different time points: before and during ischemia, and at 1, 4 and 7 days after ischemia. Lesion volume and brain edema were estimated from apparent diffusion coefficient maps and T2-weighted images. Regional cerebral blood flow (rCBF) was measured within and outside the perfusion deficient lesion and in the corresponding regions of the contralesional hemisphere. Neurological deficits were evaluated after reperfusion. Infarct volume, edema, and neurological deficits were significantly reduced in group 2 vs. group 1. In addition, higher values and rapid restoration of rCBF were observed in group 2, while rCBF in both hemispheres was significantly decreased in group 1. Maintaining preexisting hypertension alleviates ischemic brain injury in SHR by increasing collateral circulation to the ischemic region and allowing rapid restoration of rCBF. The data suggest that maintaining preexisting hypertension is a valuable approach to managing hypertensive patients suffering from acute ischemic stroke.

Arterial spin labeling measurements of cerebral perfusion territories in experimental ischemic stroke.

Collateral circulation, defined as the supplementary vascular network that maintains cerebral blood flow (CBF) when the main vessels fail, constitutes one important defense mechanism of the brain against ischemic stroke. In the present study, continuous arterial spin labeling (CASL) was used to quantify CBF and obtain perfusion territory maps of the major cerebral arteries in spontaneously hypertensive rats (SHRs) and their normotensive Wistar-Kyoto (WKY) controls. Results show that both WKY and SHR have complementary, yet significantly asymmetric perfusion territories. Right or left dominances were observed in territories of the anterior (ACA), middle and posterior cerebral arteries, and the thalamic artery. Magnetic resonance angiography showed that some of the asymmetries were correlated with variations of the ACA. The leptomeningeal circulation perfusing the outer layers of the cortex was observed as well. Significant and permanent changes in perfusion territories were obtained after temporary occlusion of the right middle cerebral artery in both SHR and WKY, regardless of their particular dominance. However, animals with right dominance presented a larger volume change of the left perfusion territory (23 ± 9%) than animals with left dominance (7 ± 5%, P < 0.002). The data suggest that animals with contralesional dominance primarily safeguard local CBF values with small changes in contralesional perfusion territory, while animals with ipsilesional dominance show a reversal of dominance and a substantial increase in contralesional perfusion territory. These findings show the usefulness of CASL to probe the collateral circulation.

Assessing Cerebrovascular Reactivity in Carotid Steno-Occlusive Disease Using MRI BOLD and ASL Techniques.

Impaired cerebrovascular reactivity (CVR), a predictive factor of imminent stroke, has been shown to be associated with carotid steno-occlusive disease. Magnetic resonance imaging (MRI) techniques, such as blood oxygenation level-dependent (BOLD) and arterial spin labeling (ASL), have emerged as promising noninvasive tools to evaluate altered CVR with whole-brain coverage, when combined with a vasoactive stimulus, such as respiratory task or injection of acetazolamide. Under normal cerebrovascular conditions, CVR has been shown to be globally and homogenously distributed between hemispheres, but with differences among cerebral regions. Such differences can be explained by anatomical specificities and different biochemical mechanisms responsible for vascular regulation. In patients with carotid steno-occlusive disease, studies have shown that MRI techniques can detect impaired CVR in brain tissue supplied by the affected artery. Moreover, resulting CVR estimations have been well correlated to those obtained with more established techniques, indicating that BOLD and ASL are robust and reliable methods to assess CVR in patients with cerebrovascular diseases. Therefore, the present paper aims to review recent studies which use BOLD and ASL to evaluate CVR, in healthy individuals and in patients with carotid steno-occlusive disease, providing a source of information regarding the obtained results and the methodological difficulties.

Longitudinal functional magnetic resonance imaging in animal models.

Functional magnetic resonance imaging (fMRI) has had an essential role in furthering our understanding of brain physiology and function. fMRI techniques are nowadays widely applied in neuroscience research, as well as in translational and clinical studies. The use of animal models in fMRI studies has been fundamental in helping elucidate the mechanisms of cerebral blood-flow regulation, and in the exploration of basic neuroscience questions, such as the mechanisms of perception, behavior, and cognition. Because animals are inherently non-compliant, most fMRI performed to date have required the use of anesthesia, which interferes with brain function and compromises interpretability and applicability of results to our understanding of human brain function. An alternative approach that eliminates the need for anesthesia involves training the animal to tolerate physical restraint during the data acquisition. In the present chapter, we review these two different approaches to obtaining fMRI data from animal models, with a specific focus on the acquisition of longitudinal data from the same subjects.