Mathieu Santin

Reproducibility of R2* and quantitative susceptibility mapping (QSM) reconstruction methods in the basal ganglia of healthy subjects

The basal ganglia are key structures for motor, cognitive and behavioral functions. They undergo several changes with aging and disease, such as Parkinsons or Huntingtons disease, for example. Iron accumulation in basal ganglia is often related to these diseases, which is conventionally monitored by the transverse relaxation rate (R2*). Quantitative susceptibility mapping (QSM) is a novel contrast mechanism in MRI produced by adding information taken from the phase of the MR signal to its magnitude. It has been shown to be more sensitive to subtle changes in Parkinsons disease. In order to be applied widely to various pathologies, its reproducibility must be evaluated in order to assess intra‐subject variability and to disseminate into clinical and pharmaceutical studies. In this work, we studied the reproducibility and sensitivity of several QSM techniques. Fourteen subjects were scanned four times, and QSM and R2* images were reconstructed and registered. An atlas of the basal ganglia was used to automatically define regions of interest. We found that QSM measurements are indeed reproducible in the basal ganglia of healthy subjects and can be widely used as a replacement for R2* mapping in iron‐rich regions. This reproducibility study could lead to several lines of research in relaxometry and susceptibility measurements, in vivo iron load evaluation as well as pharmacological assessment and biomarker development. Copyright

In vivo 1H MRS study in microlitre voxels in the hippocampus of a mouse model of Down syndrome at 11.7 T

In this article, we report in vivo 1H MRS performed in 1.8‐μL voxels in a mouse model of Down syndrome (DS). To characterise the excitation–inhibition imbalance observed in DS, metabolite concentrations in the hippocampi of adult Ts65Dn mice, which recapitulate features of DS, were compared with those of their euploid littermates at a voxel 42‐fold smaller than in a previously published study. Quantification of the metabolites was performed using a linear combination model. We detected 16 metabolites in the right and left hippocampi. Principal component analysis revealed that the absolute concentrations of the 16 detected metabolites could differentiate between Ts65Dn and euploid hippocampi. Although measurements in the left and right hippocampi were highly correlated, the concentration of individual metabolites was sometimes significantly different in the left and right structures. Thus, bilateral values from Ts65Dn and euploid mice were further compared with Hotellings test. The level of glutamine was found to be significantly lower, whereas myo‐inositol was significantly higher, in the hippocampi of Ts65Dn relative to euploid mice. However, γ‐aminobutyric acid (GABA) and glutamate levels remained similar between the groups. Thus, the excitation–inhibition imbalance described in DS does not appear to be related to a radical change in the levels of either GABA or glutamate in the hippocampus. In conclusion, microliter MRS appears to be a valuable tool to detect changes associated with DS, which may be useful in investigating whether differences can be rescued after pharmacological treatments or supplementation with glutamine. Copyright

Evolution of neocortical folding: A phylogenetic comparative analysis of MRI from 33 primate species

We present a comparative analysis of cerebral size and neocortical folding. Magnetic resonance imaging data was collected from 54 individuals belonging to 33 different primate species. We measured several neocortical folding parameters and studied their evolution using phylogenetic comparative methods. Our results suggest that the most likely model is one where phenotypical differences vary randomly through evolution (the Brownian Motion model). We present estimations of the ancestral primate phenotypes as well as estimations of the rates of phenotypic change.

Non-invasive ultrasonic modulation of visual evoked response by GABA delivery through the blood brain barrier

We demonstrate the feasibility of non-invasively modulating the visual cortex activity of non-human primates by local ultrasound-induced delivery of an inhibitory neurotransmitter (GABA). GABA was injected intravenously after the blood brain barrier (BBB) was transiently disrupted with focused ultrasound (FUS) coupled with ultrasound contrast agents (UCA). Visual evoked potentials exhibited a significant and progressive decrease of the activity. Combined effects of neuromodulation and BBB opening were shown to be 8.7 times less important than GABA-induced inhibition. During the sonication, the UCA harmonic response was monitored to estimate the level of stable cavitation (signature of BBB opening efficiency) and to avoid damages due to inertial cavitation (automatic shutdown of the sonication when detected). As recent developments in beam forming have shown that ultrasound beams can be focused non-invasively in deep-seated human brain locations, our results hold promise to explore and treat the brain with a non-invasive, controllable, repeatable and reversible method.

Inside/outside the brain binary cavitation localization based on the lowpass filter effect of the skull on the harmonic content: a proof of concept study

Cavitation activity induced by ultrasound may occur during high intensity focused ultrasound (HIFU) treatment, due to bubble nucleation under high peak negative pressure, and during blood-brain-barrier (BBB) disruption, due to injected ultrasound contrast agents (UCAs). Such microbubble activity has to be monitored to assess the safety and efficiency of ultrasonic brain treatments. In this study, we aim at assessing whether cavitation occurs within cerebral tissue by binary discriminating cavitation activity originating from the inside or the outside of the skull. The results were obtained from both in vitro experiments mimicking BBB opening, by using UCA flow, and in vitro thermal necrosis in calf brain samples. The sonication was applied using a 1 MHz focused transducer and the acoustic response of the microbubbles was recorded with a wideband passive cavitation detector. The spectral content of the recorded signal was used to localize microbubble activity. Since the skull acts as a low pass filter, the ratio of high harmonics to low harmonics is lower for cavitation events located inside the skull compared to events outside the skull. Experiments showed that the ratio of the 5/2 ultraharmonic to the 1/2 subharmonic for binary localization cavitation activity achieves 100% sensitivity and specificity for both monkey and human skulls. The harmonic ratio of the fourth to the second harmonic provided 100% sensitivity and 96% and 46% specificity on a non-human primate for thermal necrosis and BBB opening, respectively. Nonetheless, the harmonic ratio remains promising for human applications, as the experiments showed 100% sensitivity and 100% specificity for both thermal necrosis and BBB opening through the human skull. The study requires further validation on a larger number of skull samples.

Simultaneous multi-parametric mapping of total sodium concentration, T1, T2 and ADC at 7 T using a multi-contrast unbalanced SSFP

PURPOSE Quantifying multiple NMR properties of sodium could be of benefit to assess changes in cellular viability in biological tissues. A proof of concept of Quantitative Imaging using Configuration States (QuICS) based on a SSFP sequence with multiple contrasts was implemented to extract simultaneously 3D maps of applied flip angle (FA), total sodium concentration, T1, T2, and Apparent Diffusion Coefficient (ADC). METHODS A 3D Cartesian Gradient Recalled Echo (GRE) sequence was used to acquire 11 non-balanced SSFP contrasts at a 6 × 6 × 6 mm3 isotropic resolution with carefully-chosen gradient spoiling area, RF amplitude and phase cycling, with TR/TE = 20/3.2 ms and 25 averages, leading to a total acquisition time of 1 h 18 min. A least-squares fit between the measured and the analytical complex signals was performed to extract quantitative maps from a mono-exponential model. Multiple sodium phantoms with different compositions were studied to validate the ability of the method to measure sodium NMR properties in various conditions. RESULTS Flip angle maps were retrieved. Relaxation times, ADC and sodium concentrations were estimated with controlled precision below 15%, and were in accordance with measurements from established methods and literature. CONCLUSION The results illustrate the ability to retrieve sodium NMR properties maps, which is a first step toward the estimation of FA, T1, T2, concentration and ADC of 23Na for clinical research. With further optimization of the acquired QuICS contrasts, scan time could be reduced to be suitable with in vivo applications.

Abstract 2665: Dynamic contrast-enhanced ultrasound monitoring of tumor perfusion in a murine pancreatic tumor model to assess the effect of (ziv)-aflibercept and sorafenib, two anti-angiogenic drugs.

Background: anti-angiogenic drug combinations provide a promising new therapeutic approach. Noninvasive monitoring techniques would help to choose drug based on patient response. The effects on tumor perfusion by combining Ziv-aflibercept (VEGF-Trap is being developed as a part of a collaboration between Sanofi and Regeneron Pharmaceuticals, Inc.) and Sorafenib (Nexavar TM , Bayer Schering Pharma) was tested. Methods: pancreatic adenocarcinomas were induced by subcutaneous injection of 100 μl containing 1 x 10 6 MIA PaCa2 cells in the left flank of 50 female, 2-4 week-old, nude mice (Naval Medical Research Institute [NMRI] Elevage Janvier, Le Genest-St-Isle, France). Dynamic contrast-enhanced ultrasound (DCE-US) was performed using an Aplio 50 ultrasound imaging system with a 12-MHz probe (PLT 1202 S, TOSHIBA, Tokyo, Japan). DCE-US data sequences were acquired after intravenous injection of a 100 μl bolus of Luminity contrast agent. Data were acquired from each mouse on days 15, 16 and 24 after tumor cell injection. Treatment was started on day 15 just after DCE-US baseline scan. Fifty mice were included in this study: 15 controls received placebo, 11 mice were treated with sorafenib (60 mg/kg/day by gavage), 12 mice were treated with ziv-aflibercept (40 mg/kg 2 twice a week by injection) and 12 mice were treated with the combination of the two anti-angiogenic drugs. Image sequences were recorded in raw data format and extracted with TOSHIBA software (CHIQ) allowing calculation of the linear time-intensity curve in regions of interest within the tumor. Using in-house software, the time-intensity bolus curve was fit to a lognormal model from which the Area Under the Curve (AUC) was calculated to assess microvascular perfusion in the tumor. Statistical analysis was performed using Wilcoxon Signed-Rank tests. Results: the AUC decreased significantly from day 15 to day 16 for the group receiving ziv-aflibercept (p=0,020) and for the group receiving the combination of ziv-aflibercept and sorafenib (p=0,005), while no significant differences were found for the placebo or sorafenib monotherapy groups. From day 15 to day 24, the AUC obtained from the fit to the bolus curve decreased significantly for the group receiving the combination of ziv-aflibercept and sorafenib (p=0,031), while no significant differences were found for the three other groups. Conclusions: the DCE-US functional evaluation used in this study demonstrated that the association of the combination of ziv-aflibercept and sorafenib and ziv-aflibercept alone reduced functional perfusion in the tumor 24 hours after therapy onset. The long term (9 days) perfusion reduction was maintained for combined therapy but was not significant for placebo, ziv-aflibercept or sorafenib mono-therapy. Citation Format: Michele Lamuraglia, Guillaume Barrois, Mathieu Santin, Delphine Le Guillou-Buffello, Lori S. Bridal, Olivier Lucidarme. Dynamic contrast-enhanced ultrasound monitoring of tumor perfusion in a murine pancreatic tumor model to assess the effect of (ziv)-aflibercept and sorafenib, two anti-angiogenic drugs. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2665. doi:10.1158/1538-7445.AM2013-2665