Cerebral Blood Volume Imaging Research Articles

Co-variations of cerebral blood volume and single neurons discharge during resting state and visual cognitive tasks in non-human primates

To better understand how the brain allows primates to perform various sets of tasks, the ability to simultaneously record neural activity at multiple spatiotemporal scales is challenging but necessary. However, the contribution of single-unit activities (SUAs) to neurovascular activity remains to be fully understood. Here, we combine functional ultrasound imaging of cerebral blood volume (CBV) and SUA recordings in visual and fronto-medial cortices of behaving macaques. We show that SUA provides a significant estimate of the neurovascular response below the typical fMRI spatial resolution of 2mm3. Furthermore, our results also show that SUAs and CBV activities are statistically uncorrelated during the resting state but correlate during tasks. These results have important implications for interpreting functional imaging findings while one constructs inferences of SUA during resting state or tasks.

Radiomic features from dynamic susceptibility contrast perfusion-weighted imaging improve the three-class prediction of molecular subtypes in patients with adult diffuse gliomas.

To investigate whether radiomic features extracted from dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI) can improve the prediction of the molecular subtypes of adultdiffuse gliomas, and to further develop and validate a multimodal radiomic model by integrating radiomic features from conventional and perfusion MRI. We extracted 1197 radiomic features from each sequence of conventional MRI and DSC-PWI, respectively. The Boruta algorithm was used for feature selection and combination, and a three-class random forest method was applied to construct the models. We also constructed a combined model by integrating radiomic features and clinical metrics. The models' diagnostic performance for discriminating the molecular subtypes (IDH wild type [IDHwt], IDH mutant and 1p/19q-noncodeleted [IDHmut-noncodel], and IDH mutant and 1p/19q-codeleted [IDHmut-codel]) was compared using AUCs in the validation set. We included 272 patients (training set, n = 166; validation set, n = 106) with grade II-IV gliomas (mean age, 48.7years; range, 19-77years). The proportions of the molecular subtypes were 66.2% IDHwt, 15.1% IDHmut-noncodel, and 18.8% IDHmut-codel. Nineteen radiomic features (13 from conventional MRI and 6 from DSC-PWI) were selected to build the multimodal radiomic model. In the validation set, the multimodal radiomic model showed better performance than the conventional radiomic model did in predicting the IDHwt and IDHmut-codel subtypes, which was comparable to the conventional radiomic model in predicting the IDHmut-noncodel subtype. The multimodal radiomic model yielded similar performance as the combined model in predicting the three molecular subtypes. Adding DSC-PWI to conventional MRI can improve molecular subtype prediction in patients with diffuse gliomas. • The multimodal radiomic model outperformed conventional MRI when predicting both the IDH wild type and IDH mutant and 1p/19q-codeleted subtypes of gliomas. • The multimodal radiomic model showed comparable performance to the combined model in the prediction of the three molecular subtypes. • Radiomic features from T1-weighted gadolinium contrast-enhanced and relative cerebral blood volume images played an important role in the prediction of molecular subtypes.

Separating spin compartments in arterial spin labeling using delays alternating with nutation for tailored excitation (DANTE) pulse: A validation study using T2 -relaxometry and application to arterial cerebral blood volume imaging.

To clarify the type of spin compartment in arterial spin labeling (ASL) that is eliminated by delays alternating with nutation for tailored excitation (DANTE) pulse using T2 -relaxometry, and to demonstrate the feasibility of arterial cerebral blood volume (CBVa ) imaging using DANTE-ASL in combination with a simplified two-compartment model. The DANTE and T2 -preparation modules were combined into a single ASL sequence. T2 values under the application of DANTE were determined to evaluate changes in T2 , along with the post-labeling delay (PLD) and the relationship between transit time without DANTE (TTnoVS ) and T2 . The reference tissue T2 (T2_ref ) was also obtained. Subsequently, the DANTE module was embedded into the Hadamard-encoded ASL. Cerebral blood flow (CBF) and CBVa were computed using two Hadamard-encoding datasets (with and without DANTE) in a rest and breath-holding (BH) task. While T2 without DANTE (T2_noVS ) decreased as the PLD increased, T2 with DANTE (T2_DANTE ) was equivalent to T2_ref and did not change with the PLD. Although there was a significant positive correlation between TTnoVS and T2_noVS with short PLD, T2_DANTE was not correlated with TTnoVS nor PLD. Baseline CBVa values obtained at rest were 0.64 ± 0.12, 0.64 ± 0.11, and 0.58 ± 0.15 mL/100 g for anterior, middle, and posterior cerebral arteries, respectively. Significant CBF and CBVa elevations were observed in the BH task. Microvascular compartment signals were eliminated from the total ASL signals by DANTE. CBVa can be measured using Hadamard-encoded DANTE-ASL in combination with a simplified two-compartment model.

Prediction of an oxygen extraction fraction map by convolutional neural network: validation of input data among MR and PET images

PurposeOxygen extraction fraction (OEF) is a biomarker for the viability of brain tissue in ischemic stroke. However, acquisition of the OEF map using positron emission tomography (PET) with oxygen-15 gas is uncomfortable for patients because of the long fixation time, invasive arterial sampling, and radiation exposure. We aimed to predict the OEF map from magnetic resonance (MR) and PET images using a deep convolutional neural network (CNN) and to demonstrate which PET and MR images are optimal as inputs for the prediction of OEF maps.MethodsCerebral blood flow at rest (CBF) and during stress (sCBF), cerebral blood volume (CBV) maps acquired from oxygen-15 PET, and routine MR images (T1-, T2-, and T2*-weighted images) for 113 patients with steno-occlusive disease were learned with U-Net. MR and PET images acquired from the other 25 patients were used as test data. We compared the predicted OEF maps and intraclass correlation (ICC) with the real OEF values among combinations of MRI, CBF, CBV, and sCBF.ResultsAmong the combinations of input images, OEF maps predicted by the model learned with MRI, CBF, CBV, and sCBF maps were the most similar to the real OEF maps (ICC: 0.597 ± 0.082). However, the contrast of predicted OEF maps was lower than that of real OEF maps.ConclusionThese results suggest that the deep CNN learned useful features from CBF, sCBF, CBV, and MR images and predict qualitatively realistic OEF maps. These findings suggest that the deep CNN model can shorten the fixation time for 15O PET by skipping 15O2 scans. Further training with a larger data set is required to predict accurate OEF maps quantitatively.

Comparison of BOLD and CBV using 3D EPI and 3D GRASE for cortical layer functional MRI at 7 T.

Functional MRI (fMRI) at the mesoscale of cortical layers and columns requires both sensitivity and specificity, the latter of which can be compromised if the imaging method is affected by vascular artifacts, particularly cortical draining veins at the pial surface. Recent studies have shown that cerebral blood volume (CBV) imaging is more specific to the actual laminar locus of neural activity than BOLD imaging using standard gradient-echo EPI sequences. Gradient and spin-echo (GRASE) BOLD imaging has also shown greater specificity when compared with standard gradient-echo EPI BOLD. Here we directly compare CBV and BOLD contrasts in high-resolution imaging of the primary motor cortex for laminar functional MRI in four combinations of signal labeling, CBV using slice-selective slab-inversion vascular space occupancy (VASO) and BOLD, each with 3D gradient-echo EPI and zoomed 3D-GRASE image readouts. Activations were measured using each sequence and contrast combination during a motor task. Activation profiles across cortical depth were measured to assess the sensitivity and specificity (pial bias) of each method. Both CBV imaging using gradient-echo 3D-EPI and BOLD imaging using 3D-GRASE show similar specificity and sensitivity and are therefore useful tools for mesoscopic functional MRI in the human cortex. The combination of GRASE and VASO did not demonstrate high levels of sensitivity, nor show increased specificity. Three-dimensional EPI with VASO contrast and 3D-GRASE with BOLD contrast both demonstrate sufficient sensitivity and specificity for laminar functional MRI to be used by neuroscientists in a wide range of investigations of depth-dependent neural circuitry in the human brain.

A rat model of somatosensory-evoked reflex seizures induced by peripheral stimulation

ObjectiveWe introduce a novel animal model of somatosensory stimulation-induced reflex seizures which generates focal seizures without causing damage to the brain. MethodsSpecifically, we electrically stimulated digits or forepaws of adult rats sedated with dexmedetomidine while imaging cerebral blood volume and recording neurophysiological activity in cortical area S1FL. For the recordings, we either inserted a linear probe into the D3 digit representation or we performed surface electrocorticography (ECoG) recordings. ResultsPeripheral stimulation of a digit or the forepaw elicited seizures that were followed by a refractory period with decreased neuronal activity, or another seizure or normal response. LFP amplitudes in response to electrical pulses during the seizures (0.28 ± 0.03 mV) were higher than during normal evoked responses (0.25 ± 0.05 mV) and refractory periods (0.2 ± 0.08 mV). Seizures generated during the stimulation period showed prolonged after-discharges that were sustained for 20.9 ± 1.9 s following the cessation of the stimulus. High-frequency oscillations were observed prior to and during the seizures, with amplitudes higher than those associated with normal evoked responses. The seizures were initially focal. Optical imaging of the cerebral blood volume response showed that they propagated from the onset zone to adjacent cortical areas, beyond the S1FL representation of the stimulated digit or forepaw. The spatial extent during seizures was on average 1.74 times larger during the stimulation and 4.1 times following its cessation relative to normal evoked responses. Seizures were recorded not only by probes inserted into cortex but also with ECoG arrays (24.1 ± 5.8 seizures per rat) placed over the dura matter, indicating that the seizures were not induced by damage caused by inserting the probes to the cortex. Stimulation of the forepaw elicited more seizures (18.8 ± 8.5 seizures per rat) than stimulation of a digit (1.7 ± 0.7). Unlike rats sedated with dexmedetomidine, rats anesthetized with urethane showed no seizures, indicating that the seizures may depend on the use of the mild sedative dexmedetomidine. SignificanceOur proposed animal model generates seizures induced by electrical sensory stimulation free of artifacts and brain damage. It can be used for studying the mechanisms underlying the generation and propagation of reflex seizures and for evaluating antiepileptic drugs.

Statistical properties of cerebral CT perfusion imaging systems. Part I. Cerebral blood volume maps generated from nondeconvolution-based systems.

The development and clinical employment of a computed tomography (CT) imaging system benefit from a thorough understanding of the statistical properties of the output images; cerebral CT perfusion (CTP) imaging system is no exception. A series of articles will present statistical properties of CTP systems and the dependence of these properties on system parameters. This Part I paper focuses on the signal and noise properties of cerebral blood volume (CBV) maps calculated using a nondeconvolution-based method. The CBV imaging chain was decomposed into a cascade of subimaging stages, which facilitated the derivation of analytical models for the probability density function, mean value, and noise variance of CBV. These models directly take CTP source image acquisition, reconstruction, and postprocessing parameters as inputs. Both numerical simulations and in vivo canine experiments were performed to validate these models. The noise variance of CBV is linearly related to the noise variance of source images and is strongly influenced by the noise variance of the baseline images. Uniformly partitioning the total radiation dose budget across all time frames was found to be suboptimal, and an optimal dose partition method was derived to minimize CBV noise. Results of the numerical simulation and animal studies validated the derived statistical properties of CBV. The statistical properties of CBV imaging systems can be accurately modeled by extending the linear CT systems theory. Based on the statistical model, several key signal and noise characteristics of CBV were identified and an optimal dose partition method was developed to improve the image quality of CBV.

Multi-scale mapping along the auditory hierarchy using high-resolution functional UltraSound in the awake ferret.

A major challenge in neuroscience is to longitudinally monitor whole brain activity across multiple spatial scales in the same animal. Functional UltraSound (fUS) is an emerging technology that offers images of cerebral blood volume over large brain portions. Here we show for the first time its capability to resolve the functional organization of sensory systems at multiple scales in awake animals, both within small structures by precisely mapping and differentiating sensory responses, and between structures by elucidating the connectivity scheme of top-down projections. We demonstrate that fUS provides stable (over days), yet rapid, highly-resolved 3D tonotopic maps in the auditory pathway of awake ferrets, thus revealing its unprecedented functional resolution (100/300µm). This was performed in four different brain regions, including very small (1-2 mm3 size), deeply situated subcortical (8 mm deep) and previously undescribed structures in the ferret. Furthermore, we used fUS to map long-distance projections from frontal cortex, a key source of sensory response modulation, to auditory cortex.

Ultra-high resolution blood volume fMRI and BOLD fMRI in humans at 9.4 T: Capabilities and challenges

Functional mapping of cerebral blood volume (CBV) changes has the potential to reveal brain activity with high localization specificity at the level of cortical layers and columns. Non-invasive CBV imaging using Vascular Space Occupancy (VASO) at ultra-high magnetic field strengths promises high spatial specificity but poses unique challenges in human applications. As such, 9.4 T B1+ and B0 inhomogeneities limit efficient blood tagging, while the specific absorption rate (SAR) constraints limit the application of VASO-specific RF pulses. Moreover, short T2* values at 9.4 T require short readout duration, and long T1 values at 9.4 T can cause blood-inflow contaminations.In this study, we investigated the applicability of layer-dependent CBV-fMRI at 9.4 T in humans. We addressed the aforementioned challenges by combining multiple technical advancements: temporally alternating pTx B1+ shimming parameters, advanced adiabatic RF-pulses, 3D-EPI signal readout, optimized GRAPPA acquisition and reconstruction, and stability-optimized RF channel combination. We found that a combination of suitable advanced methodology alleviates the challenges and potential artifacts, and that VASO fMRI provides reliable measures of CBV change across cortical layers in humans at 9.4 T. The localization specificity of CBV-fMRI, combined with the high sensitivity of 9.4 T, makes this method an important tool for future studies investigating cortical micro-circuitry in humans.

Resting-state functional connectivity analysis of the mouse brain using intrinsic optical signal imaging of cerebral blood volume dynamics

Objective: Resting-state functional connectivity (rsFC) of the human brain is closely related with neurological and psychiatric disorders. Mice are widely used to investigate the physiological mechanisms of such disorders, because of the applicability of invasive experimental techniques. Thus, studies on rsFC of the mouse brain are essential to link physiological mechanisms with these disorders in humans. In this study, we investigated the applicability of intrinsic optical signal imaging of cerebral blood volume (IOSI-CBV) for rsFC analysis of the mouse brain. Approach: Transcranial IOSI-CBV images were collected from the brains of un-anesthetized wild-type mice with a cooled-CCD camera. The time traces of all pixels were averaged to create a global signal (GS). Marginal and partial correlation analyses were performed to estimate the rsFC based on CBV signals both with and without GS removal. The consistency of the results were confirmed by comparing them with to the rsFCs data reported in the previous studies. Main results: We confirmed that GS correlated with heart rate fluctuation in the FC frequency band. The marginal correlation coefficient of CBV with GS removal was consistent with measurements using conventional optical imaging methods relying on oxygenated hemoglobin concentration and cerebral blood flow. Significance: These results suggest the applicability and usefulness of the transcranial IOSI-CBV method to estimate rsFC of the mouse brain.

Noninvasive imaging of cerebral blood volume in piglets with vascular occupancy MR imaging and inflow vascular space occupancy with dynamic subtraction

Accurate quantitative non-invasive assessments of arterial cerebral blood volume (aCBV) can greatly benefit the study of cerebral vascular health in both humans and in animal models. In recent years, progress has been made in the techniques available to quantify CBV with magnetic resonance imaging (MRI). Here, we compared a non-invasive technique, measuring inflowing vascular space occupancy with dynamic subtraction (iVASO-ds) with a contrast-based vascular space occupancy measurement in piglets. In addition, we measured how the iVASO-ds derived aCBV changed with piglet development from 4 weeks to 8 weeks. Our results indicate that there is a significant correlation between the non-invasive iVASO-ds derived aCBV and CBV quantified using a gadolinium contrast agent, despite the contrast-based method providing significantly higher estimates of CBV resulting from challenges inherent to using the contrast-based technique. In addition, it was possible to see significant increases in blood volume across 4 weeks to 8 weeks in pig development with the non-invasive technique. Our results suggest that the non-invasive technique, iVASO-ds can assess aCBV in the developing piglet, both cross-sectionally and longitudinally, and has significant advantages over the contrast-based quantification method.

Temporal lobe epilepsy lateralization using retrospective cerebral blood volume MRI.

Steady-state cerebral blood volume (CBV) is tightly coupled to regional cerebral metabolism, and CBV imaging is a variant of MRI that has proven useful in mapping brain dysfunction. CBV derived from exogenous contrast-enhanced MRI can generate sub-millimeter functional maps. Higher resolution helps to more accurately interrogate smaller cortical regions, such as functionally distinct regions of the hippocampus. Many MRIs have fortuitously adequate sequences required for CBV mapping. However, these scans vary substantially in acquisition parameters. Here, we determined whether previously acquired contrast-enhanced MRI scans ordered in patients with unilateral temporal lobe epilepsy can be used to generate hippocampal CBV. We used intrinsic reference regions to correct for intensity scaling on a research CBV dataset to identify white matter as a robust marker for scaling correction. Next, we tested the technique on a sample of unilateral focal epilepsy patients using clinical MRI scans. We find evidence suggestive of significant hypometabolism in the ipsilateral-hippocampus of unilateral TLE subjects. We also highlight the subiculum as a potential driver of this effect. This study introduces a technique that allows CBV maps to be generated retrospectively from clinical scans, potentially with broad application for mapping dysfunction throughout the brain.

Full 3D dynamic functional ultrasound imaging of neuronal activity in mice

Introduction: In vivo neuronal activity imaging is key to understand the mechanisms of complex brain behavior. 2D Functional Ultrasound (fUS) Imaging is a powerful tool for measuring brain activation with high spatiotemporal sampling (80μm, 1 ms) using neurovascular coupling. Here, we demonstrated the proof of concept of in vivo full 3-D fUS and extend the research work toward 3D functional connectivity imaging in mice. Method: A fully programmable 1024-channel ultrasound platform was used to drive 32 x 32 matrix phased arrays (9 MHz central frequency) at ultrafast frame rates (500 volumes per second). Successive plane wave emissions were compounded to produce high sensitivity vascular volumetric images of the brain of anesthetized (Ketamine-Xylazine) and craniotomized mice. Whiskers were alternatively (6 seconds ON/OFF) stimulated during acquisition. Results: High-quality 3D images of cerebral blood volume were obtained and showed the feasibility of task-activated 3D fUS imaging. The activation maps depi...

Glial Calcium Waves are Triggered by Seizure Activity and Not Essential for Initiating Ictal Onset or Neurovascular Coupling.

It has been postulated that glia play a critical role in modifying neuronal activity, mediating neurovascular coupling, and in seizure initiation. We investigated the role of glia in ictogenesis and neurovascular coupling through wide-field multicell and 2-photon single cell imaging of calcium and intrinsic signal imaging of cerebral blood volume in an in vivo rat model of focal neocortical seizures. Ictal events triggered a slowly propagating glial calcium wave that was markedly delayed after both neuronal and hemodynamic onset. Glial calcium waves exhibited a stereotypical spread that terminated prior to seizure offset and propagated to an area ~60% greater than the propagation area of neural and vascular signals. Complete blockage of glial activity with fluoroacetate resulted in no change in either neuronal or hemodynamic activity. These ictal glial waves were blocked by carbenoxolone, a gap junction blocker. Our in vivo data reveal that ictal events trigger a slowly propagating, stereotypical glial calcium wave, mediated by gap junctions, that is spatially and temporally independent of neuronal and hemodynamic activities. We introduce a novel ictally triggered propagating glial calcium wave calling into question the criticality of glial calcium wave in both ictal onset and neurovascular coupling.

Multi-delay ASL can identify leptomeningeal collateral perfusion in endovascular therapy of ischemic stroke.

Background and PurposeMulti-delay arterial spin-labeling (ASL) perfusion imaging has been used as a promising modality to evaluate cerebral perfusion. Our aim was to assess the association of leptomeningeal collateral perfusion scores based on ASL parameters with outcome of endovascular treatment in patients with acute ischemic stroke (AIS) in the middle cerebral artery (MCA) territory.Materials and MethodsASL data at 4 post-labeling delay (PLD) times (PLD = 1.5, 2, 2.5, 3 s) were acquired during routine clinical magnetic resonance examination on AIS patients prior to endovascular treatment. A 3-point scale of leptomeningeal collateral perfusion grade on 10 anatomic regions was determined based on arterial transit times (ATT), cerebral blood flow (CBF), and arterial cerebral blood volume (CBV), estimated by the multi-delay ASL protocol. Based on a 90-day modified Rankin Scale (mRS), the patients were dichotomized to moderate/good (mRS 03) and poor outcome (mRS 46) and the regional collateral flow scores were compared.ResultsFifty-five AIS patients with unilateral MCA stroke (mean 73.9514.82 years) including 23 males were enrolled. Compared with poor outcome patients, patients with moderate to good outcomes had a significantly higher leptomeningeal collateral perfusion scores on CBV (3.012.11 vs. 1.821.51, p=0.024) but no differences on scores on CBF (2.311.61 vs. 1.661.32, p=0.231) and ATT (2.672.33 vs. 3.423.37, p=0.593).ConclusionsHigher leptomeningeal collateral perfusion scores on CBV images by ASL may be a specific marker of clinical outcome after endovascular treatment in patients with acute MCA ischemic stroke. Further study with larger sample size is warranted.

CBV_ASPECTS Improvement over CT_ASPECTS on Determining Irreversible Ischemic Lesion Decreases over Time

The Alberta Stroke Program Early CT Score (ASPECTS) is a useful scoring system for assessing early ischemic signs on noncontrast computed tomography (CT). Cerebral blood volume (CBV) on CT perfusion defines the core lesion assumed to be irreversibly damaged. We aim to explore the advantages of CBV_ASPECTS over CT_ASPECTS in the prediction of final infarct volume according to time. Methods: Consecutive patients with anterior circulation stroke who underwent endovascular reperfusion according to initial CT_ASPECTS ≥7 were studied. CBV_ASPECTS was assessed blindly later on. Recanalization was defined as thrombolysis in cerebral ischemia score 2b-3. Final infarct volumes were measured on follow-up imaging. We compared ASPECTS on CBV and CT images, and defined ASPECTS agreement as: CT_ASPECTS - CBV_ASPECTS ≤1. Results: Sixty-five patients, with a mean age of 67 ± 14 years and a median National Institutes of Health Stroke Scale score of 16 (range 10-20), were studied. The recanalization rate was 78.5%. The median CT_ASPECTS was 9 (range 8-10), and the CBV_ASPECTS was 8 (range 8-10). The mean time from symptoms to CT was 219 ± 143 min. Fifty patients (76.9%) showed ASPECTS agreement. The ASPECTS difference was inversely correlated to the time from symptoms to CT (r = -0.36, p < 0.01). A ROC curve defined 120 min as the best cutoff point after which the ASPECTS difference becomes more frequently ≤1. After 120 min, 89.5% of the patients showed ASPECTS agreement (as compared with 37.5% for <120 min, p < 0.01). CBV_ASPECTS but not CT_ASPECTS correlated with final infarct (r = -0.33, p < 0.01). However, if CT was done >2 h after symptom onset, CT_ASPECTS also correlated to final infarct (r = -0.39, p = 0.01). Conclusions: In acute stroke, CBV_ASPECTS correlates with the final infarct volume. However, when CT is performed after 120 min from symptom onset, CBV_ASPECTS does not add relevant information to CT_ASPECTS.

Nonlinear estimation of BOLD signals with the aid of cerebral blood volume imaging.

BackgroundThe hemodynamic balloon model describes the change in coupling from underlying neural activity to observed blood oxygen level dependent (BOLD) response. It plays an increasing important role in brain research using magnetic resonance imaging (MRI) techniques. However, changes in the BOLD signal are sensitive to the resting blood volume fraction (i.e., V_0) associated with the regional vasculature. In previous studies the value was arbitrarily set to a physiologically plausible value to circumvent the ill-posedness of the inverse problem. These approaches fail to explore actual V_0 value and could yield inaccurate model estimation.MethodsThe present study represents the first empiric attempt to derive the actual V_0 from data obtained using cerebral blood volume imaging, with the aim of augmenting the existing estimation schemes. Bimanual finger tapping experiments were performed to determine how V_0 influences the model estimation of BOLD signals within a single-region and multiple-regions (i.e., dynamic causal modeling). In order to show the significance of applying the true V_0, we have presented the different results obtained when using the real V_0 and assumed V_0 in terms of single-region model estimation and dynamic causal modeling.ResultsThe results show that V_0 significantly influences the estimation results within a single-region and multiple-regions. Using the actual V_0 might yield more realistic and physiologically meaningful model estimation results.ConclusionIncorporating regional venous information in the analysis of the hemodynamic model can provide more reliable and accurate parameter estimations and model predictions, and improve the inference about brain connectivity based on fMRI data.

Transcranial functional ultrasound imaging of the brain using microbubble-enhanced ultrasensitive Doppler

Functional ultrasound (fUS) is a novel neuroimaging technique, based on high-sensitivity ultrafast Doppler imaging of cerebral blood volume, capable of measuring brain activation and connectivity in rodents with high spatiotemporal resolution (100μm, 1ms). However, the skull attenuates acoustic waves, so fUS in rats currently requires craniotomy or a thinned-skull window. Here we propose a non-invasive approach by enhancing the fUS signal with a contrast agent, inert gas microbubbles. Plane-wave illumination of the brain at high frame rate (500Hz compounded sequence with three tilted plane waves, PRF=1500Hz with a 128 element 15MHz linear transducer), yields highly-resolved neurovascular maps. We compared fUS imaging performance through the intact skull bone (transcranial fUS) versus a thinned-skull window in the same animal. First, we show that the vascular network of the adult rat brain can be imaged transcranially only after a bolus intravenous injection of microbubbles, which leads to a 9dB gain in the contrast-to-tissue ratio. Next, we demonstrate that functional increase in the blood volume of the primary sensory cortex after targeted electrical-evoked stimulations of the sciatic nerve is observable transcranially in presence of contrast agents, with high reproducibility (Pearson's coefficient ρ=0.7±0.1, p=0.85). Our work demonstrates that the combination of ultrafast Doppler imaging and injection of contrast agent allows non-invasive functional brain imaging through the intact skull bone in rats. These results should ease non-invasive longitudinal studies in rodents and open a promising perspective for the adoption of highly resolved fUS approaches for the adult human brain.

Usefulness of an Anisotropic Diffusion Method in Cerebral CT Perfusion Study Using Multi-Detector Row CT

Purpose: To present an application of the anisotropic diffusion (AD) method to improve the accuracy of the functional images of perfusion parameters such as cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) generated from cerebral CT perfusion studies using multi-detector row CT (MDCT). Materials and Methods: Continuous scans (1 sec/rotation ×60 sec) consisting of four 5-mm-thick contiguous slices were acquired after an intravenous injection of iodinated contrast material in 6 patients with cerebrovascular disease using an MDCT scanner with a tube voltage of 80 kVp and a tube current of 200 mA. New image data were generated by thinning out the above original images at an interval of 2 sec or 3 sec. The thinned-out images were then interpolated by linear interpolation to generate the same number of images as originally acquired. The CBF, CBV and MTT images were generated using deconvolution analysis based on singular value decomposition. Results: When using the AD method, the correlation coefficient between the MTT values obtained from the original and thinned-out images was significantly improved. Furthermore, the coefficients of variation of the CBF, CBV and MTT values in the white matter significantly decreased as compared to not using the AD method. Conclusion: Our results suggest that the AD method is useful for improving the accuracy of the functional images of perfusion parameters and for reducing radiation exposure in cerebral CT perfusion studies using MDCT.

Microvascular Plasticity After Experimental Stroke: A Molecular and MRI Study

Background: Microvasculature plays a key role in stroke pathophysiology both during initial damage and extended neural repair. Moreover, angiogenesis processes seem to be a promising target for future neurorestorative therapies. However, dynamic changes of microvessels after stroke still remain unclear, and MRI follow-up could be interesting as an in vivo biomarker of these. Methods: The aim of this study is to characterize the microvascular plasticity 25 days after ischemic stroke using both in vivo microvascular 7T-MRI (vascular permeability, cerebral blood volume (CBV), vessel size index (VSI), vascular density) and quantification of angiogenic factor expressions by RT-qPCR in a transient middle cerebral artery occlusion rat model. CBV and VSI (perfused vessel caliber) imaging was performed using a steady-state approach with a multi gradient-echo spin-echo sequence before and 2 min after intravenous (IV) injection of ultrasmall superparamagnetic iron particles. Vascular density (per mm²) was derived from the ratio [ΔR₂/(ΔR₂*)^2/3]. Blood brain barrier leakage was assessed using T₁W images before and after IV injection of Gd-DOTA. Additionally, microvessel immunohistology was done. Results: 3 successive stages were observed: 1) ‘Acute stage' from day 1 to day 3 post-stroke (D1-D3) characterized by high levels of angiopoietin-2 (Ang2), vascular endothelial growth factor receptor-2 (VEGFR-2) and endothelial NO synthase (eNOS) that may be associated with deleterious vascular permeability and vasodilation; 2) ‘Transition stage' (D3-D7) that involves transforming the growth factors β1 (TGFβ1), Ang1, and tyrosine kinase with immunoglobulin-like and endothelial growth factor-like domains 1 (Tie1), stromal-derived factor-1 (SDF-1), chemokine receptor type 4 (CXCR-4); and 3) ‘Subacute stage' (D7-D25) with high levels of Ang1, Ang2, VEGF, VEGFR-1 and TGFβ1 leading to favorable stabilization and maturation of microvessels. In vivo MRI appeared in line with the angiogenic factors changes with a delay of at least 1 day. All MRI parameters varied over time, revealing the different aspects of the post-stroke microvascular plasticity. At D25, despite a normal CBV, MRI revealed a limited microvessel density, which is insufficient to support a good neural repair. Conclusions: Microvasculature MRI can provide imaging of different states of functional (perfused) microvessels after stroke. These results highlight that multiparametric MRI is useful to assess post-stroke angiogenesis, and could be used as a biomarker notably for neurorestorative therapy studies. Additionally, we identified that endogenous vessel maturation and stabilization occur during the ‘subacute stage'. Thus, pro-angiogenic treatments, such as cell-based therapy, would be relevant during this subacute phase of stroke.