Baseline Cerebral Blood Volume Research Articles

Collateral status contributes to differences between observed and predicted 24-h infarct volumes in DEFUSE 3

We previously demonstrated that in the DEFUSE 3 trial, the union of the baseline core and the 24-h Tmax > 6 s perfusion lesion predicts the infarct volume at 24 h. Presently, we assessed if collateral robustness measured by the hypoperfusion intensity ratio (HIR) and cerebral blood volume (CBV) index accounts for the variance in these predictions. DEFUSE 3 patients underwent MRI/CT perfusion imaging at baseline and 24 h post-randomization. We compared baseline and follow-up HIR and CBV index across subgroups stratified by differences between predicted and observed 24-h infarct volumes. Of 123 eligible patients, 34 with 24-h infarcts larger than predicted had less favorable collaterals at baseline (HIR 0.43 vs. 0.32, p = 0.006; CBV Index 0.78 vs. 0.85, p = 0.001) and 24 h (HIR 0.56 vs. 0.07, p = 0.004; CBV Index 0.47 vs. 0.73, p = 0.006) compared to 71 patients with more accurate infarct volume prediction. Eighteen patients with 24-h infarcts smaller than predicted had similar baseline collateral scores but more favorable 24-h CBV indices (0.81 vs. 0.73, p = 0.040). Overall, patients with 24-h infarcts larger than predicted had evidence of less favorable baseline collaterals that fail within 24 h, while patients with 24-h infarcts smaller than predicted typically had favorable collaterals that persisted for 24 h.

Baseline ASPECTS and e-ASPECTS Correlation with Infarct Volume and Functional Outcome in Patients Undergoing Mechanical Thrombectomy.

The role of Alberta Stroke Program Early CT score (ASPECTS) in predicting which patients are likely to benefit from endovascular therapy (EVT) is not well defined. An automated software (e-ASPECTS) has been created to solve its poor interrater reliability. We aim to evaluate correlation between radiologist (Rx) and e-ASPECTS scoring with cerebral blood volume (CBV) infarct core and with final infarct volume; as well as with long-term functional outcome. We included patients with acute ischemic stroke and large vessel occlusion who underwent EVT. We measured baseline radiologist (Rx) ASPECTS and e-ASPECTS, and baseline CBV infarct core on CT perfusion. Final infarct volume was measured on 24-hour control CT. We included 184 patients, in which 82.1% of patients achieved complete recanalization. Median Rx-ASPECTS/e-ASPECTS was 9 (IQR 8-10 vs. IQR 7.75-10) and mean CBV lesion was 29.51 (±47.41) mL. Correlation (rs ) between ASPECTS and e-ASPECTS was .44 (P < .01). Both ASPECTS scores correlated with CBV after 180 minutes of symptom onset (rs = -.41 vs. -.54, P < .01) and with final infarct volume in patients with complete recanalization (rs = -.40 vs. -.43, P < .01). In a logistic regression, either Rx-ASPECTS, e-ASPECTS, and CBV (OR 1.60 vs. 1.87 vs. .96; P < .05) predicted a low infarct volume. Rx-ASPECTS and e-ASPECTS also predicted functional independence (mRS 0-2) at 3 months (1.52 vs. 1.37; P < .05). ASPECTS and e-ASPECTS showed a mild correlation with CBV. Rx-ASPECTS, e-ASPECTS, and CBV predicted a low infarct volume after thrombectomy in recanalized patients but only Rx-ASPECTS and e-ASPECTS predicted functional independence at 3 months.

Carotid Artery Stenting and Blood-Brain Barrier Permeability in Subjects with Chronic Carotid Artery Stenosis.

Failure of the blood-brain barrier (BBB) is a critical event in the development and progression of diseases such as acute ischemic stroke, chronic ischemia or small vessels disease that affect the central nervous system. It is not known whether BBB breakdown in subjects with chronic carotid artery stenosis can be restrained with postoperative recovery of cerebral perfusion. The aim of the study was to assess the short-term effect of internal carotid artery stenting on basic perfusion parameters and permeability surface area-product (PS) in such a population. Forty subjects (23 males) with stenosis of >70% within a single internal carotid artery and neurological symptoms who underwent a carotid artery stenting procedure were investigated. Differences in the following computed tomography perfusion (CTP) parameters were compared before and after surgery: global cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), time to peak (TTP) and PS. PS acquired by CTP is used to measure the permeability of the BBB to contrast material. In all baseline cases, the CBF and CBV values were low, while MTT and TTP were high on both the ipsi- and contralateral sides compared to reference values. PS was approximately twice the normal value. CBF was higher (+6.14%), while MTT was lower (−9.34%) on the contralateral than on the ipsilateral side. All perfusion parameters improved after stenting on both the ipsilateral (CBF +22.66%; CBV +18.98%; MTT −16.09%, TTP −7.62%) and contralateral (CBF +22.27%, CBV +19.72%, MTT −14.65%, TTP −7.46%) sides. PS decreased by almost half: ipsilateral −48.11%, contralateral −45.19%. The decline in BBB permeability was symmetrical on the ipsi- and contralateral sides to the stenosis. Augmented BBB permeability can be controlled by surgical intervention in humans.

Early computed tomography-based scores to predict decompressive hemicraniectomy after endovascular therapy in acute ischemic stroke.

BackgroundIdentification of patients requiring decompressive hemicraniectomy (DH) after endovascular therapy (EVT) is crucial as clinical signs are not reliable and early DH has been shown to improve clinical outcome. The aim of our study was to identify imaging-based scores to predict the risk for space occupying ischemic stroke and DH.MethodsProspectively derived data from patients with acute large artery occlusion within the anterior circulation and EVT was analyzed in this monocentric study. Predictive value of non-contrast cranial computed tomography (ncCT) and cerebral blood volume (CBV) Alberta Stroke Program Early CT score (ASPECTS) were investigated for DH using logistic regression models and Receiver Operating Characteristic Curve analysis.ResultsFrom 218 patients with EVT, DH was performed in 20 patients (9.2%). Baseline- (7 vs. 9; p = 0.009) and follow-up ncCT ASPECTS (1 vs. 7, p<0.001) as well as baseline CBV ASPECTS (5 vs. 7, p<0.001) were significantly lower in patients with DH. ncCT (baseline: OR 0.71, p = 0.018; follow-up: OR 0.32, p = <0.001) and CBV ASPECTS (OR 0.63, p = 0.008) predicted DH. Cut-off ncCT-ASPECTS on baseline was 7-, ncCT-ASPECTS on follow-up was 4- and CBV ASPECTS on baseline was 5 points.ConclusionsASPECTS could be useful to early identify patients requiring DH after EVT for acute large vessel occlusion.

Linking brain vascular physiology to hemodynamic response in ultra-high field MRI

Functional MRI using blood oxygenation level-dependent (BOLD) contrast indirectly probes neuronal activity via evoked cerebral blood volume (CBV) and oxygenation changes. Thus, its spatio-temporal characteristics are determined by vascular physiology and MRI parameters. In this paper, we focus on the spatial distribution and time course of the fMRI signal and their magnetic field strength dependence. Even though much is still unknown, the following consistent picture is emerging: a) For high spatial resolution imaging, fMRI contrast-to-noise increases supra-linearly with field strength. b) The location and spacing of penetrating arteries and ascending veins in the cortical tissue are not correlated to cortical columns, imposing limitations on achievable point-spread function (PSF) in fMRI. c) Baseline CBV distribution may vary over cortical layers biasing fMRI signal to layers with high CBV values. d) The largest CBV change is in the tissue microvasculature, less in surface arteries and even less in pial veins. e) Venous CBV changes are only relevant for longer stimuli, and oxygenation changes are largest in post-capillary blood vessels. f) The balloon effect (i.e. slow recovery of CBV to baseline) is located in the tissue, consistent with the fact that the post-stimulus undershoot has narrower spatial PSF than the positive BOLD response. g) The onset time following stimulation has been found to be shortest in middle/lower layers, both in optical imaging and high-resolution fMRI, but we argue and demonstrate with simulations that varying signal latencies can also be caused by vascular properties and, therefore, may potentially not be interpreted as neural latencies. With simulations, we illustrate the field strength dependency of fMRI signal transients, such as the adaptation during stimulation, initial dip and the post-stimulus undershoot. In sum, vascular structure and function impose limitations on the achievable PSF of fMRI and give rise to complex fMRI transients, which contain time-varying amount of excitatory and inhibitory neuronal information. Nevertheless, non-invasive fMRI at ultra-high magnetic fields not only provides high contrast-to-noise but also an unprecedented detailed view on cognitive processes in the human brain.

Evaluation of an fMRI USPIO-based assay in healthy human volunteers

To present the testretest and contrast dose effect results of cerebral blood volume (CBV) functional MRI (fMRI) in healthy human volunteers using ferumoxytol (Feraheme), an ultrasmall-superparamagnetic iron oxide (USPIO) nanoparticle. This was an open-label, two-period, fixed-sequence study in healthy young volunteers. In eight subjects, using a 3 Tesla field strength system, blood oxygen level dependent (BOLD) and CBV fMRI were acquired in response to a visual black-and-white checkboard stimulation paradigm using an escalating ferumoxytol dose design (250, 350, and 510 mg iron). Multiple outcome measures were analyzed including absolute percent signal change (|PSC|, primary endpoint), its contrast-to-noise ratio (CNR) and corresponding z-score, percent CBV change (ΔCBV) and respective CNR, concentration of Fe, and baseline CBV. The |PSC| in the visual cortex increased with ferumoxytol dose and was up to 3 × higher than BOLD fMRI. Test-retest reliability was comparable for BOLD and CBV fMRI. Intraclass correlation coefficients (ICCs) for |PSC| were 0.3 (one-sided 95% lower confidence limit = 0.00), 0.81 (0.47), 0.48 (0.00), and 0.3 (0.00) for BOLD and the 250-, 350-, and 510-mg doses of ferumoxytol, respectively. For ΔCBV, ICCs were 0.77 (0.37), 0.48 (0.00), and 0.49 (0.00) for 250 mg, 350 mg, and 510 mg, respectively. This work demonstrates that CBV fMRI techniques and endpoints are dose dependent, robust and have good test-retest repeatability. It also confirms previous findings that USPIO enhances sensitivity of fMRI stimulus-response endpoints. 1 J. MAGN. RESON. IMAGING 2017;46:124-133.

Contributions of structural connectivity and cerebrovascular parameters to functional magnetic resonance imaging signals in mice at rest and during sensory paw stimulation

Previously, we reported widespread bilateral increases in stimulus-evoked functional magnetic resonance imaging signals in mouse brain to unilateral sensory paw stimulation. We attributed the pattern to arousal-related cardiovascular changes overruling cerebral autoregulation thereby masking specific signal changes elicited by local neuronal activity. To rule out the possibility that interhemispheric neuronal communication might contribute to bilateral functional magnetic resonance imaging responses, we compared stimulus-evoked functional magnetic resonance imaging responses to unilateral hindpaw stimulation in acallosal I/LnJ, C57BL/6, and BALB/c mice. We found bilateral blood-oxygenation-level dependent signal changes in all three strains, ruling out a dominant contribution of transcallosal communication as reason for bilaterality. Analysis of functional connectivity derived from resting-state functional magnetic resonance imaging, revealed that bilateral cortical functional connectivity is largely abolished in I/LnJ animals. Cortical functional connectivity in all strains correlated with structural connectivity in corpus callosum as revealed by diffusion tensor imaging. Given the profound influence of systemic hemodynamics on stimulus-evoked functional magnetic resonance imaging outcomes, we evaluated whether functional connectivity data might be affected by cerebrovascular parameters, i.e. baseline cerebral blood volume, vascular reactivity, and reserve. We found that effects of cerebral hemodynamics on functional connectivity are largely outweighed by dominating contributions of structural connectivity. In contrast, contributions of transcallosal interhemispheric communication to the occurrence of ipsilateral functional magnetic resonance imaging response of equal amplitude to unilateral stimuli seem negligible.

Measurement of oxygen extraction fraction (OEF): An optimized BOLD signal model for use with hypercapnic and hyperoxic calibration

Several techniques have been proposed to estimate relative changes in cerebral metabolic rate of oxygen consumption (CMRO2) by exploiting combined BOLD fMRI and cerebral blood flow data in conjunction with hypercapnic or hyperoxic respiratory challenges. More recently, methods based on respiratory challenges that include both hypercapnia and hyperoxia have been developed to assess absolute CMRO2, an important parameter for understanding brain energetics. In this paper, we empirically optimize a previously presented “original calibration model” relating BOLD and blood flow signals specifically for the estimation of oxygen extraction fraction (OEF) and absolute CMRO2.To do so, we have created a set of synthetic BOLD signals using a detailed BOLD signal model to reproduce experiments incorporating hypercapnic and hyperoxic respiratory challenges at 3T. A wide range of physiological conditions was simulated by varying input parameter values (baseline cerebral blood volume (CBV0), baseline cerebral blood flow (CBF0), baseline oxygen extraction fraction (OEF0) and hematocrit (Hct)).From the optimization of the calibration model for estimation of OEF and practical considerations of hypercapnic and hyperoxic respiratory challenges, a new “simplified calibration model” is established which reduces the complexity of the original calibration model by substituting the standard parameters α and β with a single parameter θ. The optimal value of θ is determined (θ=0.06) across a range of experimental respiratory challenges. The simplified calibration model gives estimates of OEF0 and absolute CMRO2 closer to the true values used to simulate the experimental data compared to those estimated using the original model incorporating literature values of α and β. Finally, an error propagation analysis demonstrates the susceptibility of the original and simplified calibration models to measurement errors and potential violations in the underlying assumptions of isometabolism. We conclude that using the simplified calibration model results in a reduced bias in OEF0 estimates across a wide range of potential respiratory challenge experimental designs.

Abstract 138: Perfusion Imaging of Intracranial Atherosclerotic Disease in SAMMPRIS

Background: Noninvasive perfusion imaging with CT (CTP) or MRI (PWI) provides key physiologic data regarding hemodynamics of intracranial atherosclerotic disease (ICAD). Parameters of delayed perfusion such as Tmax, time to peak (TTP), mean transit time (MTT) and cerebral blood volume (CBV) or flow (CBF) may disclose important mechanisms of stroke in ICAD. We analyzed CTP and PWI acquired in SAMMPRIS to identify the principal perfusion patterns, correlation with conventional angiography and potential links with clinical outcome. Methods: CTP and PWI were identified in the SAMMPRIS imaging archive. Perfusion datasets were processed with Olea Sphere® to yield Tmax, TTP, MTT, CBV and CBF maps graded by 2 expert readers to identify markers of decreased, normal, or increased perfusion in the symptomatic territory. The resultant multiparametric perfusion patterns were correlated with clinical and angiographic variables, using Fisher’s exact test and Kaplan-Meier methods followed by log-rank tests. Results: Perfusion imaging was available in 59 subjects at baseline and 42 at follow-up. Baseline perfusion included Tmax (decreased in 2, normal in 18, increased in 39); TTP (decreased in 2, normal in 18, increased in 39); MTT (decreased in 2, normal in 27, increased in 30); CBV (decreased in 5, normal in 42, increased in 12); CBF (decreased in 7, normal in 48, increased in 4). The baseline Tmax increases in 66% of subjects were associated with the combined (TICI and collaterals) diminished angiographic flow patterns (p=0.016) and with increased 30-day SIT (p=0.015). Baseline CBV changes were associated with stroke as a qualifying event (p=0.007), NIHSS (p=0.039), presenting symptoms of hypoperfusion (p=0.071), severity of stenosis (p=0.015), and angiographic flow patterns (p=0.009). Follow-up CTP or PWI revealed similar patterns to baseline, although delay maps normalized in patients after stenting. Conclusions: Noninvasive perfusion imaging with CT or MRI discloses delayed flow caused by ICAD, often compensated by autoregulatory vasodilation (increased CBV) to maintain CBF in the downstream territory. Perfusion imaging parameters may reflect angiographic collateral flow patterns in ICAD, warranting further investigation as predictors of stroke risk.

Cortical lamina-dependent blood volume changes in human brain at 7 T

Cortical layer-dependent high (sub-millimeter) resolution functional magnetic resonance imaging (fMRI) in human or animal brain can be used to address questions regarding the functioning of cortical circuits, such as the effect of different afferent and efferent connectivities on activity in specific cortical layers. The sensitivity of gradient echo (GE) blood oxygenation level-dependent (BOLD) responses to large draining veins reduces its local specificity and can render the interpretation of the underlying laminar neural activity impossible. The application of the more spatially specific cerebral blood volume (CBV)-based fMRI in humans has been hindered by the low sensitivity of the noninvasive modalities available. Here, a vascular space occupancy (VASO) variant, adapted for use at high field, is further optimized to capture layer-dependent activity changes in human motor cortex at sub-millimeter resolution. Acquired activation maps and cortical profiles show that the VASO signal peaks in gray matter at 0.8–1.6mm depth, and deeper compared to the superficial and vein-dominated GE-BOLD responses. Validation of the VASO signal change versus well-established iron-oxide contrast agent based fMRI methods in animals showed the same cortical profiles of CBV change, after normalization for lamina-dependent baseline CBV. In order to evaluate its potential of revealing small lamina-dependent signal differences due to modulations of the input-output characteristics, layer-dependent VASO responses were investigated in the ipsilateral hemisphere during unilateral finger tapping. Positive activation in ipsilateral primary motor cortex and negative activation in ipsilateral primary sensory cortex were observed. This feature is only visible in high-resolution fMRI where opposing sides of a sulcus can be investigated independently because of a lack of partial volume effects. Based on the results presented here, we conclude that VASO offers good reproducibility, high sensitivity and lower sensitivity than GE-BOLD to changes in larger vessels, making it a valuable tool for layer-dependent fMRI studies in humans.

An explanation of why schizophrenia begins with excitotoxic damage to the hippocampus

A recent paper by Schobel et al. provides evidence that schizophrenia begins with excitotoxic damage in the hippocampus, primarily in the CA1 subfield. MRI measurement of cerebral blood volume (CBV) was taken to be a marker of basal metabolism. High baseline CBV in the CA1 subfield of subjects at high risk for schizophrenia predicted progression to psychosis and the development of hippocampal atrophy. A mouse model of ketamine excitotoxicity reproduced the human imaging study, i.e. hypermetabolism in CA1 led to atrophy. The authors do not explain the pathophysiology of selective excitotoxicity in the hippocampus.A recently published serotonin theory of schizophrenia provides a hypothetical explanation for these findings. The serotonin theory predicts that schizophrenia begins with stress-induced overdrive of serotonergic pacemaker cells in the dorsal raphe nucleus. The overdrive is passed via the entorhinal cortex to the hippocampus, where it causes excitotoxicity. Passage through the entorhinal cortex converts a serotonergic signal into a glutamate signal, glutamate being the neurotransmitter of exicitotoxicity.The remitting-relapsing pattern of schizophrenia is explained by a balance between excitotoxicity in the hippocampus and repopulation by neurogenesis in the subgranular zone. Injury is balanced by healing.

Exploratory Evaluation of MR Permeability with 18F-FDG PET Mapping in Pediatric Brain Tumors: A Report from the Pediatric Brain Tumor Consortium

The purpose of this study was to develop a method of registering (18)F-FDG PET with MR permeability images for investigating the correlation of (18)F-FDG uptake, permeability, and cerebral blood volume (CBV) in children with pediatric brain tumors and their relationship with outcome. Twenty-four children with brain tumors in a phase II study of bevacizumab and irinotecan underwent brain MR and (18)F-FDG PET within 2 wk. Tumor types included supratentorial high-grade astrocytoma (n = 7), low-grade glioma (n = 9), brain stem glioma (n = 4), medulloblastoma (n = 2), and ependymoma (n = 2). There were 33 cases (pretreatment only [n = 12], posttreatment only [n = 3], and both pretreatment [n = 9] and posttreatment [n = 9]). (18)F-FDG PET images were registered to MR images from the last time point of the T1 perfusion time series using mutual information. Three-dimensional regions of interest (ROIs) drawn on permeability images were automatically transferred to registered PET images. The quality of ROI registration was graded (1, excellent; 2, very good; 3, good; 4, fair; and 5, poor) by 3 independent experts. Spearman rank correlations were used to assess correlation of maximum tumor permeability (Kps(max)), maximum CBV (CBV(max)), and maximum (18)F-FDG uptake normalized to white matter (T/W(max)). Cox proportional hazards models were used to investigate associations of these parameters with progression-free survival (PFS). The quality of ROI registration between PET and MR was good to excellent in 31 of 33 cases. There was no correlation of baseline Kps(max) with CBV(max) (Spearman rank correlation = 0.018 [P = 0.94]) or T/W(max) (Spearman rank correlation = 0.07 [P = 0.76]). Baseline CBV(max) was correlated with T/W(max) (Spearman rank correlation = 0.47 [P = 0.036]). Baseline Kps(max), CBV(max), and T/W(max) were not significantly associated with PFS (P = 0.42, hazard ratio [HR] = 0.97, 95% confidence interval [CI] = 0.90-1.045, and number of events [n(events)] = 15 for Kps(max); P = 0.41, HR = 0.989, 95% CI = 0.963-1.015, and n(events) = 14 for CBV(max); and P = 0.17, HR = 1.49, 95% CI = 0.856-2.378, and n(events) = 15 for T/W(max)). (18)F-FDG PET and MR permeability images were successfully registered and compared across a spectrum of pediatric brain tumors. The lack of correlation between metabolism and permeability may be expected because these parameters characterize different molecular processes. The correlation of CBV and tumor metabolism may be related to an association with tumor grade. More patients are needed for a covariate analysis of these parameters and PFS by tumor histology.

Imaging Patients with Psychosis and a Mouse Model Establishes a Spreading Pattern of Hippocampal Dysfunction and Implicates Glutamate as a Driver

The hippocampus in schizophrenia is characterized by both hypermetabolism and reduced size. It remains unknown whether these abnormalities are mechanistically linked. Here we addressed this question by using MRI tools that can map hippocampal metabolism and structure in patients and mouse models. In at-risk patients, hypermetabolism was found to begin in CA1 and spread to the subiculum after psychosis onset. CA1 hypermetabolism at baseline predicted hippocampal atrophy, which occurred during progression to psychosis, most prominently in similar regions. Next, we used ketamine to model conditions of acute psychosis in mice. Acute ketamine reproduced a similar regional pattern of hypermetabolism, while repeated exposure shifted the hippocampus to a hypermetabolic basal state with concurrent atrophy and pathology in parvalbumin-expressing interneurons. Parallel invivo experiments using the glutamate-reducing drug LY379268 and direct measurements of extracellular glutamate showed that glutamate drives both neuroimaging abnormalities. These findings show that hippocampal hypermetabolism leads to atrophy in psychotic disorder and suggest glutamate as a pathogenic driver.

Abstract 14: Predicting Hemorrhagic Transformation in Ischemic Stroke - Very Low Cerebral Blood Volume versus Permeability Analysis

Background and purpose: Hemorrhagic transformation is the major complication of reperfusion therapies and carries a high risk of disability and death. Very low cerebral blood volume (VLCBV) and increased blood brain barrier permeability, both markers of severe ischemia, have been proposed as imaging predictors of hemorrhage risk. We aimed to compare the prognostic power of these two approaches using data from the DEFUSE 2 study. Methods: Acute ischemic stroke patients had perfusion-diffusion MRI before and within 12 hr after endovascular therapy. Baseline cerebral blood volume (CBV) maps were generated and the volume of VLCBV (CBV&lt;2.5 th percentile of the normal hemisphere) was calculated. Permeability was assessed using two recirculation parameters: "relative recirculation" (rR): the difference in area encompassed by the observed tissue-concentration curve and a theoretical fit of the first pass bolus; and "percent recovery" (%Recovery): the difference in signal intensity between peak bolus and average post-bolus. Parenchymal hematoma (PH) was defined using ECASS criteria. Reperfusion was defined as &gt;50% reduction in Tmax&gt;6sec lesion volume between baseline and post-procedure MRI. Logistic regression models were compared using Bayesian Information Criterion (BIC). Results: In DEFUSE 2, MRI prior to catheter angiography was performed in 110 patients, 59 had tPA pre-treatment and 25 developed PH. In 103 patients with technically adequate acute perfusion MR, preliminary receiver operating characteristic analysis identified &gt;40%rR and &lt;50%Rec as the optimal thresholds to assess the volume of tissue with increased permeability. In logistic regression, PH was associated with increased VLCBV (p=0.02) and rR permeability (p=0.05) but not %Recovery (p=0.17). The VLCBV model had better fit than rR permeability (BIC difference +2.1) and there was no significant interaction between parameters (p=0.33). Reperfusion was strongly associated with PH (p=0.01) and improved fit of the VLCBV model (BIC +7.2). Conclusions: VLCBV was a stronger predictor of early PH after reperfusion than permeability parameters in patients treated with endovascular therapy.

Cerebral blood volume MRI with intravascular superparamagnetic iron oxide nanoparticles

The cerebral blood volume (CBV) is a crucial physiological indicator of tissue viability and vascular reactivity. Thus, noninvasive CBV mapping has been of great interest. For this, ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles, including monocrystalline iron oxide nanoparticles, can be used as long-half-life, intravascular susceptibility agents of CBV MRI measurements. Moreover, CBV-weighted functional MRI (fMRI) with USPIO nanoparticles provides enhanced sensitivity, reduced large vessel contribution and improved spatial specificity relative to conventional blood oxygenation level-dependent fMRI, and measures a single physiological parameter that is easily interpretable. We review the physiochemical and magnetic properties, and pharmacokinetics, of USPIO nanoparticles in brief. We then extensively discuss quantifications of baseline CBV, vessel size index and functional CBV change. We also provide reviews of dose-dependent sensitivity, vascular filter function, specificity, characteristics and impulse response function of CBV fMRI. Examples of CBV fMRI specificity at the laminar and columnar resolution are provided. Finally, we briefly review the application of CBV measurements to functional and pharmacological studies in animals. Overall, the use of USPIO nanoparticles can determine baseline CBV and its changes induced by functional activity and pharmacological interventions.

Effects of the α2‐adrenergic receptor agonist dexmedetomidine on neural, vascular and BOLD fMRI responses in the somatosensory cortex

This article describes the effects of dexmedetomidine (DEX) - the active ingredient of medetomidine, which is the latest popular sedative for functional magnetic resonance imaging (fMRI) in rodents - on multiple unit activity, local field potential (LFP), cerebral blood flow (CBF), pial vessel diameter [indicative of cerebral blood volume (CBV)], and blood oxygenation level-dependent (BOLD) fMRI. These measurements were obtained from the rat somatosensory cortex during 10 s of forepaw stimulation. We found that the continuous intravascular systemic infusion of DEX (50 μg/kg/h, doses typically used in fMRI studies) caused epileptic activities, and that supplemental isoflurane (ISO) administration of ~0.3% helped to suppress the development of epileptic activities and maintained robust neuronal and hemodynamic responses for up to 3 h. Supplemental administration of N(2)O in addition to DEX nearly abolished hemodynamic responses even if neuronal activity remained. Under DEX + ISO anesthesia, spike firing rate and the delta power of LFP increased, whereas beta and gamma power decreased, as compared with ISO-only anesthesia. DEX administration caused pial arteries and veins to constrict nearly equally, resulting in decreases in baseline CBF and CBV. Evoked LFP and CBF responses to forepaw stimulation were largest at a frequency of 8-10 Hz, and a non-linear relationship was observed. Similarly, BOLD fMRI responses measured at 9.4 T were largest at a frequency of 10 Hz. Both pial arteries and veins dilated rapidly (artery, 32.2%; vein, 5.8%), and venous diameter returned to baseline slower than arterial diameter. These results will be useful for designing, conducting and interpreting fMRI experiments under DEX sedation.

Spatiotemporal characteristics and vascular sources of neural-specific and -nonspecific fMRI signals at submillimeter columnar resolution

The neural specificity of hemodynamic-based functional magnetic resonance imaging (fMRI) signals is dependent on both the vascular regulation and the sensitivity of the applied fMRI technique to different types and sizes of blood vessels. In order to examine the specificity of MRI-detectable hemodynamic responses, submillimeter blood oxygenation level-dependent (BOLD) and cerebral blood volume (CBV) fMRI studies were performed in a well-established cat orientation column model at 9.4 T. Neural-nonspecific and -specific signals were separated by comparing the fMRI responses of orthogonal orientation stimuli. The BOLD response was dominantly neural-nonspecific, mostly originating from pial and intracortical emerging veins, and thus was highly correlated with baseline blood volume. Uneven baseline CBV may displace or distort small functional domains in high-resolution BOLD maps. The CBV response in the parenchyma exhibited dual spatiotemporal characteristics, a fast and early neural-nonspecific response (with 4.3-s time constant) and a slightly slower and delayed neural-specific response (with 9.4-s time constant). The nonspecific CBV signal originates from early-responding arteries and arterioles, while the specific CBV response, which is not correlated with baseline blood volume, arises from late-responding microvessels including small pre-capillary arterioles and capillaries. Our data indicate that although the neural specificity of CBV fMRI signals is dependent on stimulation duration, high-resolution functional maps can be obtained from steady-state CBV studies.

Abstract 2941: Wide Variability of Cerebral Blood Volume Response in the Area with Impaired Cerebrovascular Reactivity to Acetazolamide due to Occlusive Carotid Artery Disease

Background and Purpose - Recent studies have suggested that hemodynamic and metabolic responses to reduced cerebral perfusion pressure (CPP) are not so simple in patients with occlusive carotid artery disease. Autoregulatory vasodilation reaches maximal and cerebral blood flow (CBF) starts to fall, when CPP critically falls beyond autoregulatory capacity. Theoretically, cerebral blood volume (CBV) is expressed as maximally elevated in the conditions that cerebrovascular reactivity (CVR) to acetazolamide (ACZ) is impaired. However, there are almost no studies that denote whether CBV is maximally elevated in the area with reduced CBF and CVR to ACZ (Kuroda’s Type 3 ischemia). Therefore, this study was aimed to investigate the CBV response to ACZ in the area with reduced CBF and CVR due to occlusive carotid artery disease. Methods- This study included totally 24 hemispheres of 20 patients with reduced CBF and CVR on 15 O-gas PET due to occlusive carotid artery disease. There were 8 men and 12 women with a mean age of 57.9 years ranging from 33 to 72 years. All of them were admitted to our hospital between 2004 and 2010. In all 20 patients, CBF, CBV, cerebral metabolic rate for oxygen (CMRO 2 ) and oxygen extraction fraction (OEF) were quantitatively measured, using 15 O-gas PET. Subsequently, ACZ was intravenously injected to determine the reactivity of CBF and CBV. Results- Both CBF and CVR were reduced in all 24 hemispheres (Type 3). Of these, OEF was elevated in 7 hemispheres (29%). Compared with normal control (3.4 ± 0.5 mL/100g), baseline CBV were significantly elevated both in elevated OEF group (5.2 ± 1.2 mL/100g) and normal OEF group (4.5 ± 0.9 mL/100g). Intravenous administration of ACZ further increased CBV in 4 of 7 hemispheres with elevated OEF and in all 17 hemispheres with normal OEF. %CBV reactivity was 9.5 ± 12% in elevated OEF group, being significantly lower than 22 ± 13% in normal OEF group (P = 0.04, un-paired t). CBV did not increase in patients with steal phenomenon after ACZ injection in elevated OEF group, but increased in normal OEF group. Conclusion- These findings strongly suggest that baseline CBV increases, but does not reach maximal in the area with reduced CBF and CVR due to occlusive carotid artery disease, indicating that CBF response to ACZ may imply more complicated mechanisms in the severe ischemic brain.

A review of the development of Vascular-Space-Occupancy (VASO) fMRI

Vascular-Space-Occupancy (VASO) fMRI is a non-invasive technique to detect brain activation based on changes in Cerebral Blood Volume (CBV), as opposed to conventional BOLD fMRI, which is based on changes in blood oxygenation. This technique takes advantage of the T1 difference between blood and surrounding tissue, and uses an inversion recovery pulse sequence to null blood signal while maintaining part of the tissue signal. The VASO signal intensity can thus be considered proportional to 1-CBV. When neural activation causes CBV to increase, the VASO signal will show a decrease, allowing the detection of activated regions in the brain. Activation-induced changes in VASO signal, ∆S/S, are in the order of -1%. Absolute quantification of ∆CBV requires additional assumptions on baseline CBV and water contents of the parenchyma and blood. The first VASO experiment was conducted approximately 10 years ago. The original goal of nulling the blood signal was to isolate and measure extravascular BOLD effects, thus a long TE of 50 ms was used in the inversion recovery experiment. Instead of a positive signal change, a slight decrease in signal was observed, which became more pronounced when TE was shortened to 10 ms. These findings led to the hypothesis of a CBV signal mechanism and the development of VASO fMRI. Since its discovery, VASO has been validated by comparison with MION-CBV studies in animals and has been used in humans and animals to understand metabolic and hemodynamic changes during brain activation and physiologic challenges. With recent development of more sensitive VASO acquisitions, the availability of arterial-based VASO sequences, and improvement in spatial coverage, this technique is finding its place in neuroscience and clinical studies.

High-grade gliomas treated with bevacizumab: Assessment of tumor response with functional MR.

e12505 Background: High grade gliomas are tumors with a poor prognosis. Bevacizumab (Bvz) is commonly employed for treatment of recurrence and is currently being evaluated as first line therapy. Bvz is known to alter imaging contrast enhancement that is sometime difficult to be interpreted. fMR (Functional Magnetic Resonance) can be used to measure CBV (cerebral blood volume) and vascular permeability and can be employed with widely used MR sequences and software. The goal of this study was to assess CBV and permeability as potentially biomarkers for survival at baseline and after treatment with Bvz. Methods: Retrospective study. Twenty-five patients with recurrent high grade glioma treated with Bvz, were evaluated with fMR at baseline and after treatment. Corticosteroids treatment was noted. All MRI examinations were reviewed by two radiologists reaching consensus about OMS size criteria, qualitative alterations, and quantitative functional criteria: CBV, permeability, calculated with DSC (dynamic susceptibility contrast) MR sequence and DPTools software (published and free available software). Statistical analysis compared actuarial survival with baseline and post Bvz fMR (Kaplan Meier curves). Results: Survival was not statistically related to baseline or post Bvz CBV or permeability (Logrank test: p>5%). There was no significant relationship between corticosteroid dose and vascular permeability at baseline (Spearman test: p>5%). The permeability values significantly decrease after Bvz (median=85%). Survival was not related to initial tumor size but was significantly decreased if the tumor progressed during Bvz treatment (Logrank test: p=0.011). Conclusions: This study confirms the ability of fMRI to demonstrate impact of Bvz on tumor vascular permeability. Our study did not find a significant effect of corticosteroid dose on vascular permeability in these recurrent tumors. CBV and vascular permeability measured by fMRI were not efficient biomarkers of survival in our study. Tumor progression in size remains an indicator of poor prognosis. Further studies are necessary to determine the role of fMRI for the prognostication of gliomas.