Charlie Demene

Spatiotemporal Clutter Filtering of Ultrafast Ultrasound Data Highly Increases Doppler and fUltrasound Sensitivity

Ultrafast ultrasonic imaging is a rapidly developing field based on the unfocused transmission of plane or diverging ultrasound waves. This recent approach to ultrasound imaging leads to a large increase in raw ultrasound data available per acquisition. Bigger synchronous ultrasound imaging datasets can be exploited in order to strongly improve the discrimination between tissue and blood motion in the field of Doppler imaging. Here we propose a spatiotemporal singular value decomposition clutter rejection of ultrasonic data acquired at ultrafast frame rate. The singular value decomposition (SVD) takes benefits of the different features of tissue and blood motion in terms of spatiotemporal coherence and strongly outperforms conventional clutter rejection filters based on high pass temporal filtering. Whereas classical clutter filters operate on the temporal dimension only, SVD clutter filtering provides up to a four-dimensional approach (3D in space and 1D in time). We demonstrate the performance of SVD clutter filtering with a flow phantom study that showed an increased performance compared to other classical filters (better contrast to noise ratio with tissue motion between 1 and 10mm/s and axial blood flow as low as 2.6 mm/s). SVD clutter filtering revealed previously undetected blood flows such as microvascular networks or blood flows corrupted by significant tissue or probe motion artifacts. We report in vivo applications including small animal fUltrasound brain imaging (blood flow detection limit of 0.5 mm/s) and several clinical imaging cases, such as neonate brain imaging, liver or kidney Doppler imaging.

3-D ultrafast doppler imaging applied to the noninvasive mapping of blood vessels in Vivo

Ultrafast Doppler imaging was introduced as a technique to quantify blood flow in an entire 2-D field of view, expanding the field of application of ultrasound imaging to the highly sensitive anatomical and functional mapping of blood vessels. We have recently developed 3-D ultrafast ultrasound imaging, a technique that can produce thousands of ultrasound volumes per second, based on a 3-D plane and diverging wave emissions, and demonstrated its clinical feasibility in human subjects in vivo. In this study, we show that noninvasive 3-D ultrafast power Doppler, pulsed Doppler, and color Doppler imaging can be used to perform imaging of blood vessels in humans when using coherent compounding of 3-D tilted plane waves. A customized, programmable, 1024-channel ultrasound system was designed to perform 3-D ultrafast imaging. Using a 32 × 32, 3-MHz matrix phased array (Vermon, Tours, France), volumes were beamformed by coherently compounding successive tilted plane wave emissions. Doppler processing was then applied in a voxel-wise fashion. The proof of principle of 3-D ultrafast power Doppler imaging was first performed by imaging Tygon tubes of various diameters, and in vivo feasibility was demonstrated by imaging small vessels in the human thyroid. Simultaneous 3-D color and pulsed Doppler imaging using compounded emissions were also applied in the carotid artery and the jugular vein in one healthy volunteer.

Ultrafast Doppler Reveals the Mapping of Cerebral Vascular Resistivity in Neonates

In vivo mapping of the full vasculature dynamics based on Ultrafast Doppler is showed noninvasively in the challenging case of the neonatal brain. Contrary to conventional pulsed-wave (PW) Doppler Ultrasound limited for >40 years to the estimation of vascular indices at a single location, the ultrafast frame rate (5,000 Hz) obtained using plane-wave transmissions leads to simultaneous estimation of full Doppler spectra in all pixels of wide field-of-view images within a single cardiac cycle and high sensitivity Doppler imaging. Consequently, 2D quantitative maps of the cerebro-vascular resistivity index (RI) are processed and found in agreement with local measurements obtained on large arteries of healthy neonates using conventional PW Doppler. Changes in 2D resistivity maps are monitored during recovery after therapeutic whole-body cooling of full-term neonates treated for hypoxic ischemic encephalopathy. Arterial and venous vessels are unambiguously differentiated on the basis of their distinct hemodynamics. The high spatial (250 × 250 μm2) and temporal resolution (<1 ms) of Ultrafast Doppler imaging combined with deep tissue penetration enable precise quantitative mapping of deep brain vascular dynamics and RI, which is far beyond the capabilities of any other imaging modality.

4D microvascular imaging based on ultrafast Doppler tomography.

4D ultrasound microvascular imaging was demonstrated by applying ultrafast Doppler tomography (UFD-T) to the imaging of brain hemodynamics in rodents. In vivo real-time imaging of the rat brain was performed using ultrasonic plane wave transmissions at very high frame rates (18,000 frames per second). Such ultrafast frame rates allow for highly sensitive and wide-field-of-view 2D Doppler imaging of blood vessels far beyond conventional ultrasonography. Voxel anisotropy (100 μm × 100 μm × 500 μm) was corrected for by using a tomographic approach, which consisted of ultrafast acquisitions repeated for different imaging plane orientations over multiple cardiac cycles. UFT-D allows for 4D dynamic microvascular imaging of deep-seated vasculature (up to 20 mm) with a very high 4D resolution (respectively 100 μm × 100 μm × 100 μm and 10 ms) and high sensitivity to flow in small vessels (>1 mm/s) for a whole-brain imaging technique without requiring any contrast agent. 4D ultrasound microvascular imaging in vivo could become a valuable tool for the study of brain hemodynamics, such as cerebral flow autoregulation or vascular remodeling after ischemic stroke recovery, and, more generally, tumor vasculature response to therapeutic treatment.

Hypothermic Total Liquid Ventilation Is Highly Protective Through Cerebral Hemodynamic Preservation and Sepsis-Like Mitigation After Asphyxial Cardiac Arrest.

Objectives:Total liquid ventilation provides ultrafast and potently neuro- and cardioprotective cooling after shockable cardiac arrest and myocardial infarction in animals. Our goal was to decipher the effect of hypothermic total liquid ventilation on the systemic and cerebral response to asphyxial cardiac arrest using an original pressure- and volume-controlled ventilation strategy in rabbits. Design:Randomized animal study. Setting:Academic research laboratory. Subjects:New Zealand Rabbits. Interventions:Thirty-six rabbits were submitted to 13 minutes of asphyxia, leading to cardiac arrest. After resumption of spontaneous circulation, they underwent either normothermic life support (control group, n = 12) or hypothermia induced by either 30 minutes of total liquid ventilation (total liquid ventilation group, n = 12) or IV cold saline (conventional cooling group, n = 12). Measurements and Main Results:Ultrafast cooling with total liquid ventilation (32°C within 5 min in the esophagus) dramatically attenuated the post–cardiac arrest syndrome regarding survival, neurologic dysfunction, and histologic lesions (brain, heart, kidneys, liver, and lungs). Final survival rate achieved 58% versus 0% and 8% in total liquid ventilation, control, and conventional cooling groups (p < 0.05), respectively. This was accompanied by an early preservation of the blood-brain barrier integrity and cerebral hemodynamics as well as reduction in the immediate reactive oxygen species production in the brain, heart, and kidneys after cardiac arrest. Later on, total liquid ventilation also mitigated the systemic inflammatory response through alteration of monocyte chemoattractant protein-1, interleukin-1&bgr;, and interleukin-8 transcripts levels compared with control. In the conventional cooling group, cooling was achieved more slowly (32°C within 90–120 min in the esophagus), providing none of the above-mentioned systemic or organ protection. Conclusions:Ultrafast cooling by total liquid ventilation limits the post–cardiac arrest syndrome after asphyxial cardiac arrest in rabbits. This protection involves an early limitation in reactive oxidative species production, blood-brain barrier disruption, and delayed preservation against the systemic inflammatory response.

Transcriptomic regulations in oligodendroglial and microglial cells related to brain damage following fetal growth restriction

Fetal growth restriction (FGR) is a major complication of human pregnancy, frequently resulting from placental vascular diseases and prenatal malnutrition, and is associated with adverse neurocognitive outcomes throughout life. However, the mechanisms linking poor fetal growth and neurocognitive impairment are unclear. Here, we aimed to correlate changes in gene expression induced by FGR in rats and abnormal cerebral white matter maturation, brain microstructure, and cortical connectivity in vivo. We investigated a model of FGR induced by low‐protein‐diet malnutrition between embryonic day 0 and birth using an interdisciplinary approach combining advanced brain imaging, in vivo connectivity, microarray analysis of sorted oligodendroglial and microglial cells and histology. We show that myelination and brain function are both significantly altered in our model of FGR. These alterations, detected first in the white matter on magnetic resonance imaging significantly reduced cortical connectivity as assessed by ultrafast ultrasound imaging. Fetal growth retardation was found associated with white matter dysmaturation as shown by the immunohistochemical profiles and microarrays analyses. Strikingly, transcriptomic and gene network analyses reveal not only a myelination deficit in growth‐restricted pups, but also the extensive deregulation of genes controlling neuroinflammation and the cell cycle in both oligodendrocytes and microglia. Our findings shed new light on the cellular and gene regulatory mechanisms mediating brain structural and functional defects in malnutrition‐induced FGR, and suggest, for the first time, a neuroinflammatory basis for the poor neurocognitive outcome observed in growth‐restricted human infants. GLIA 2016;64:2306–2320

Functional ultrasound imaging of brain activity in human newborns

Functional ultrasound imaging with high spatiotemporal resolution monitors brain function in babies. (f)USIng technologies to image the newborn brain Electroencephalography (EEG) and functional neuroimaging enable us to better understand brain functions and to detect abnormalities. However, it is challenging to use these technologies at the bedside because of their size, lack of portability, and cost. Demene et al. have developed a portable customized and noninvasive system, called fUSI (functional ultrasound imaging), that is capable of continuous video-EEG recording and fast ultrasound imaging of the brain microvasculature in newborn babies. They applied fUSI to monitor brain activity and neurovascular changes in two neonates with abnormal cortical development, demonstrating the value of fUSI for the bedside monitoring of cerebral activity in neonates. Functional neuroimaging modalities are crucial for understanding brain function, but their clinical use is challenging. Recently, the use of ultrasonic plane waves transmitted at ultrafast frame rates was shown to allow for the spatiotemporal identification of brain activation through neurovascular coupling in rodents. Using a customized flexible and noninvasive headmount, we demonstrate in human neonates that real-time functional ultrasound imaging (fUSI) is feasible by combining simultaneous continuous video–electroencephalography (EEG) recording and ultrafast Doppler (UfD) imaging of the brain microvasculature. fUSI detected very small cerebral blood volume variations in the brains of neonates that closely correlated with two different sleep states defined by EEG recordings. fUSI was also used to assess brain activity in two neonates with congenital abnormal cortical development enabling elucidation of the dynamics of neonatal seizures with high spatiotemporal resolution (200 μm for UfD and 1 ms for EEG). fUSI was then applied to track how waves of vascular changes were propagated during interictal periods and to determine the ictal foci of the seizures. Imaging the human brain with fUSI enables high-resolution identification of brain activation through neurovascular coupling and may provide new insights into seizure analysis and the monitoring of brain function.

In vivo real-time cavitation imaging in moving organs

The stochastic nature of cavitation implies visualization of the cavitation cloud in real-time and in a discriminative manner for the safe use of focused ultrasound therapy. This visualization is sometimes possible with standard echography, but it strongly depends on the quality of the scanner, and is hindered by difficulty in discriminating from highly reflecting tissue signals in different organs. A specific approach would then permit clear validation of the cavitation position and activity. Detecting signals from a specific source with high sensitivity is a major problem in ultrasound imaging. Based on plane or diverging wave sonications, ultrafast ultrasonic imaging dramatically increases temporal resolution, and the larger amount of acquired data permits increased sensitivity in Doppler imaging. Here, we investigate a spatiotemporal singular value decomposition of ultrafast radiofrequency data to discriminate bubble clouds from tissue based on their different spatiotemporal motion and echogenicity during histotripsy. We introduce an automation to determine the parameters of this filtering. This method clearly outperforms standard temporal filtering techniques with a bubble to tissue contrast of at least 20 dB in vitro in a moving phantom and in vivo in porcine liver.

Ultrasensitive Doppler based neuronavigation system for preclinical brain imaging applications

Ultrasensitive Doppler is a recent medical imaging technique enabling high sensitive acquisition of blood flows which can detect small vascular features without contrast agents. Applied to cerebral imaging of rodents, this method produces very fine vascular maps of the brain at high spatial resolution and leads to functional imaging of brain neuronal activity. These vascular networks contain crucial information about organs structure, and could be used as landmarks to 3D navigate the brain and register external atlas to the data. This study investigates a first step using a 2D correlation-based method to locate in real time young rat, rat, or mouse brain vascular prints in a 3D functional brain atlas.

Functional Ultrasound Imaging of the thalamo-cortical auditory tract in awake ferrets using ultrafast Doppler imaging

Large-scale functional imaging techniques are part of a fast growing field of neuroscience aiming at understanding whole brain activity. The recently introduced Functional Ultrasound Imaging (fUS), based on ultrafast Doppler, is a new very sensitive method monitoring changes in slow blood flow with a high spatial (~100μm) and temporal (down to the cardiac time scale) resolution for a typical imaged section of 15mm wide and 20mm deep (at 15MHz, typical for animal studies), which makes it an unequalled modality in the landscape or functional imaging. It opened a large field of applications in Neuroimaging from epilepsy to spatial representation. Here we present its use to study the functional organization of auditory cortex and thalamic nuclei in the awake ferret.