Sustained reduction of essential tremor with low-power non-thermal transcranial focused ultrasound stimulations in humans.

BACKGROUND: Transcranial ultrasound stimulation (TUS) is a non-invasive brain stimulation technique; when skull aberrations are compensated for, this technique allows, with millimetric accuracy, circumvention of the invasive surgical procedure associated with deep brain stimulation (DBS) and the limited spatial specificity of transcranial magnetic stimulation. OBJECTIVE: /hypothesis: We hypothesize that MR-guided low-power TUS can induce a sustained decrease of tremor power in patients suffering from medically refractive essential tremor. METHODS: The dominant hand only was targeted, and two anatomical sites were sonicated in this exploratory study: the ventral intermediate nucleus of the thalamus (VIM) and the dentato-rubro-thalamic tract (DRT). Patients (N = 9) were equipped with MR-compatible accelerometers attached to their hands to monitor their tremor in real-time during TUS. RESULTS: VIM neurostimulations followed by a low-duty cycle (5 %) DRT stimulation induced a substantial decrease in the tremor power in four patients, with a minimum of 89.9 % reduction when compared with the baseline power a few minutes after the DRT stimulation. The only patient stimulated in the VIM only and with a low duty cycle (5 %) also experienced a sustained reduction of the tremor (up to 93.4 %). Four patients (N = 4) did not respond. The temperature at target was 37.2 ± 1.4 °C compared to 36.8 ± 1.4 °C for a 3 cm away control point. CONCLUSIONS: MR-guided low power TUS can induce a substantial and sustained decrease of tremor power. Follow-up studies need to be conducted to reproduce the effect and better to understand the variability of the response amongst patients. MR thermometry during neurostimulations showed no significant thermal rise, supporting a mechanical effect.

Ultra-short time-echo based ray tracing for transcranial focused ultrasound aberration correction in human calvaria.

OBJECTIVE: Magnetic resonance guided transcranial focused ultrasound holds great promises for treating neurological disorders. This technique relies on skull aberration correction which requires computed tomography (CT) scans of the skull of the patients. Recently, ultra-short time-echo (UTE) magnetic resonance (MR) sequences have unleashed the MRI potential to reveal internal bone structures. In this study, we measure the efficacy of transcranial aberration correction using UTE images. Approach. We compare the efficacy of transcranial aberration correction using UTE scans to CT based correction on four skulls and two targets using a clinical device (Exablate Neuro, Insightec, Israel). We also evaluate the performance of a custom ray tracing algorithm using both UTE and CT estimates of acoustic properties and compare these against the performance of the manufacturer's proprietary aberration correction software. Main results. UTE estimated skull maps in Hounsfield units (HU) had a mean absolute error of 242 ± 20 HU (n=4). The UTE skull maps were sufficiently accurate to improve pressure at the target (no correction: 0.44 ± 0.10, UTE correction: 0.79 ± 0.05, manufacturer CT: 0.80 ± 0.05), pressure confinement ratios (no correction: 0.45 ± 0.10, UTE correction: 0.80 ± 0.05, manufacturer CT: 0.81 ± 0.05), and targeting error (no correction: 1.06 ± 0.42 mm, UTE correction 0.30 ± 0.23 mm, manufacturer CT: 0.32 ± 0.22) (n=8 for all values). When using CT, our ray tracing algorithm performed slightly better than UTE based correction with pressure at the target (UTE: 0.79 ± 0.05, CT: 0.84 ± 0.04), pressure confinement ratios (UTE: 0.80 ± 0.05, CT: 0.84 ± 0.04), and targeting error (UTE: 0.30 ± 0.23 mm, CT: 0.17 ± 0.15). Significance. These 3D transcranial measurements suggest that UTE sequences could replace CT scans in the case of MR guided focused ultrasound with minimal reduction in performance which will avoid ionizing radiation exposure to the patients and reduce procedure time and cost. .

What do brain endocasts tell us? A comparative analysis of the accuracy of sulcal identification by experts and perspectives in palaeoanthropology.

Palaeoneurology is a complex field as the object of study, the brain, does not fossilize. Studies rely therefore on the (brain) endocranial cast (often named endocast), the only available and reliable proxy for brain shape, size and details of surface. However, researchers debate whether or not specific marks found on endocasts correspond reliably to particular sulci and/or gyri of the brain that were imprinted in the braincase. The aim of this study is to measure the accuracy of sulcal identification through an experiment that reproduces the conditions that palaeoneurologists face when working with hominin endocasts. We asked 14 experts to manually identify well-known foldings in a proxy endocast that was obtained from an MRI of an actual in vivo Homo sapiens head. We observe clear differences in the results when comparing the non-corrected labels (the original labels proposed by each expert) with the corrected labels. This result illustrates that trying to reconstruct a sulcus following the very general known shape/position in the literature or from a mean specimen may induce a bias when looking at an endocast and trying to follow the marks observed there. We also observe that the identification of sulci appears to be better in the lower part of the endocast compared to the upper part. The results concerning specific anatomical traits have implications for highly debated topics in palaeoanthropology. Endocranial description of fossil specimens should in the future consider the variation in position and shape of sulci in addition to using models of mean brain shape. Moreover, it is clear from this study that researchers can perceive sulcal imprints with reasonably high accuracy, but their correct identification and labelling remains a challenge, particularly when dealing with extinct species for which we lack direct knowledge of the brain.

A new open, high-resolution, multishell, diffusion-weighted imaging dataset of the living squirrel monkey.

Although very well adapted to brain study, Magnetic Resonance Imaging (MRI) remains limited by the facilities and capabilities required to acquire data, especially for non-human primates. Addressing the data gaps resulting from these limitations requires making data more accessible and open. In contempt of the regular use of Saimiri sciureus in neuroscience research, in vivo diffusion has yet to be openly available for this species. Here we built and made openly available a unique new resource consisting of a high-resolution, multishell diffusion-weighted dataset in the anesthetized Saimiri sciureus. The data were acquired on 11 individuals with an 11.7 T MRI scanner (isotropic resolution of 400 µm3). This paper presents an overview of our dataset and illustrates some of its possible use through example analyses. To assess the quality of our data, we analyzed long-range connections (whole-brain tractography), microstructure (Neurite Orientation Dispersion and Density Imaging), and axon diameter in the corpus callosum (ActiveAx). Constituting an essential new resource for primate evolution studies, all data are openly available.

Low-Intensity Pulsed Ultrasound-Mediated Blood-Brain Barrier Opening Increases Anti-Programmed Death-Ligand 1 Delivery and Efficacy in Gl261 Mouse Model.

Therapeutic antibodies targeting immune checkpoints have shown limited efficacy in clinical trials in glioblastoma (GBM) patients. Ultrasound-mediated blood-brain barrier opening (UMBO) using low-intensity pulsed ultrasound improved drug delivery to the brain. We explored the safety and the efficacy of UMBO plus immune checkpoint inhibitors in preclinical models of GBM. A blood-brain barrier (BBB) opening was performed using a 1 MHz preclinical ultrasound system in combination with 10 µL/g microbubbles. Brain penetration of immune checkpoint inhibitors was determined, and immune cell populations were evaluated using flow cytometry. The impact of repeated treatments on survival was determined. In syngeneic GL261-bearing immunocompetent mice, we showed that UMBO safely and repeatedly opened the BBB. BBB opening was confirmed visually and microscopically using Evans blue dye and magnetic resonance imaging. UMBO plus anti-PDL-1 was associated with a significant improvement of overall survival compared to anti-PD-L1 alone. Using mass spectroscopy, we showed that the penetration of therapeutic antibodies can be increased when delivered intravenously compared to non-sonicated brains. Furthermore, we observed an enhancement of activated microglia percentage when combined with anti-PD-L1. Here, we report that the combination of UMBO and anti-PD-L1 dramatically increases GL261-bearing mice's survival compared to their counterparts treated with anti-PD-L1 alone. Our study highlights the BBB as a limitation to overcome in order to increase the efficacy of anti-PD-L1 in GBM and supports clinical trials combining UMBO and in GBM patients.

Pilot study of repeated blood-brain barrier disruption in patients with mild Alzheimer's disease with an implantable ultrasound device.

BACKGROUND: Temporary disruption of the blood-brain barrier (BBB) using pulsed ultrasound leads to the clearance of both amyloid and tau from the brain, increased neurogenesis, and mitigation of cognitive decline in pre-clinical models of Alzheimer's disease (AD) while also increasing BBB penetration of therapeutic antibodies. The goal of this pilot clinical trial was to investigate the safety and efficacy of this approach in patients with mild AD using an implantable ultrasound device. METHODS: An implantable, 1-MHz ultrasound device (SonoCloud-1) was implanted under local anesthesia in the skull (extradural) of 10 mild AD patients to target the left supra-marginal gyrus. Over 3.5 months, seven ultrasound sessions in combination with intravenous infusion of microbubbles were performed twice per month to temporarily disrupt the BBB. 18F-florbetapir and 18F-fluorodeoxyglucose positron emission tomography (PET) imaging were performed on a combined PET/MRI scanner at inclusion and at 4 and 8 months after the initiation of sonications to monitor the brain metabolism and amyloid levels along with cognitive evaluations. The evolution of cognitive and neuroimaging features was compared to that of a matched sample of control participants taken from the Alzheimer's Disease Neuroimaging Initiative (ADNI). RESULTS: A total of 63 BBB opening procedures were performed in nine subjects. The procedure was well-tolerated. A non-significant decrease in amyloid accumulation at 4 months of - 6.6% (SD = 7.2%) on 18F-florbetapir PET imaging in the sonicated gray matter targeted by the ultrasound transducer was observed compared to baseline in six subjects that completed treatments and who had evaluable imaging scans. No differences in the longitudinal change in the glucose metabolism were observed compared to the neighboring or contralateral regions or to the change observed in the same region in ADNI participants. No significant effect on cognition evolution was observed in comparison with the ADNI participants as expected due to the small sample size and duration of the trial. CONCLUSIONS: These results demonstrate the safety of ultrasound-based BBB disruption and the potential of this technology to be used as a therapy for AD patients. Research of this technique in a larger clinical trial with a device designed to sonicate larger volumes of tissue and in combination with disease-modifying drugs may further enhance the effects observed. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03119961.

The Terrific Skink bite force suggests insularity as a likely driver to exceptional resource use.

Natural history museum collections hold extremely rare, extinct species often described from a single known specimen. On occasions, rediscoveries open new opportunities to understand selective forces acting on phenotypic traits. Recent rediscovery of few individuals of Bocourt´s Terrific Skink Phoboscincus bocourti, from a small and remote islet in New Caledonia allowed to genetically identify a species of land crab in its diet. To explore this further, we CT- and MRI-scanned the head of the holotype, the only preserved specimen dated to about 1870, segmented the adductor muscles of the jaw and bones, and estimated bite force through biomechanical models. These data were compared with those gathered for 332 specimens belonging to 44 other skink species. Thereafter we recorded the maximum force needed to generate mechanical failure of the exoskeleton of a crab specimen. The bite force is greater than the prey hardness, suggesting that predation on hard-shelled crabs may be an important driver of performance. The high bite force seems crucial to overcome low or seasonal variations in resource availability in these extreme insular environments. Phoboscincus bocourti appears to be an apex predator in a remote and harsh environment and the only skink known to predate on hard-shelled land crabs.

The spatiotemporal changes in dopamine, neuromelanin and iron characterizing Parkinson's disease.

In Parkinson's disease, there is a progressive reduction in striatal dopaminergic function, and loss of neuromelanin-containing dopaminergic neurons and increased iron deposition in the substantia nigra. We tested the hypothesis of a relationship between impairment of the dopaminergic system and changes in the iron metabolism. Based on imaging data of patients with prodromal and early clinical Parkinson's disease, we assessed the spatiotemporal ordering of such changes and relationships in the sensorimotor, associative and limbic territories of the nigrostriatal system. Patients with Parkinson's disease (disease duration < 4 years) or idiopathic REM sleep behaviour disorder (a prodromal form of Parkinson's disease) and healthy controls underwent longitudinal examination (baseline and 2-year follow-up). Neuromelanin and iron sensitive MRI and dopamine transporter single-photon emission tomography were performed to assess nigrostriatal levels of neuromelanin, iron, and dopamine. For all three functional territories of the nigrostriatal system, in the clinically most and least affected hemispheres separately, the following was performed: cross-sectional and longitudinal intergroup difference analysis of striatal dopamine and iron, and nigral neuromelanin and iron; in Parkinson's disease patients, exponential fitting analysis to assess the duration of the prodromal phase and the temporal ordering of changes in dopamine, neuromelanin or iron relative to controls; and voxel-wise correlation analysis to investigate concomitant spatial changes in dopamine-iron, dopamine-neuromelanin and neuromelanin-iron in the substantia nigra pars compacta. The temporal ordering of dopaminergic changes followed the known spatial pattern of progression involving first the sensorimotor, then the associative and limbic striatal and nigral regions. Striatal dopaminergic denervation occurred first followed by abnormal iron metabolism and finally neuromelanin changes in the substantia nigra pars compacta, which followed the same spatial and temporal gradient observed in the striatum but shifted in time. In conclusion, dopaminergic striatal dysfunction and cell loss in the substantia nigra pars compacta are interrelated with increased nigral iron content.

Inflammation-driven glial alterations in the cuprizone mouse model probed with diffusion-weighted magnetic resonance spectroscopy at 11.7 T.

Inflammation of brain tissue is a complex response of the immune system to the presence of toxic compounds or to cell injury, leading to a cascade of pathological processes that include glial cell activation. Noninvasive MRI markers of glial reactivity would be very useful for in vivo detection and monitoring of inflammation processes in the brain, as well as for evaluating the efficacy of personalized treatments. Due to their specific location in glial cells, myo-inositol (mIns) and choline compounds (tCho) seem to be the best candidates for probing glial-specific intra-cellular compartments. However, their concentrations quantified using conventional proton MRS are not specific for inflammation. In contrast, it has been recently suggested that mIns intra-cellular diffusion, measured using diffusion-weighted MRS (DW-MRS) in a mouse model of reactive astrocytes, could be a specific marker of astrocytic hypertrophy. In order to evaluate the specificity of both mIns and tCho diffusion to inflammation-driven glial alterations, we performed DW-MRS in a volume of interest containing the corpus callosum and surrounding tissue of cuprizone-fed mice after 6 weeks of intoxication, and evaluated the extent of astrocytic and microglial alterations using immunohistochemistry. Both mIns and tCho apparent diffusion coefficients were significantly elevated in cuprizone-fed mice compared with control mice, and histologic evaluation confirmed the presence of severe inflammation. Additionally, mIns and tCho diffusion showed, respectively, strong and moderate correlations with histological measures of astrocytic and microglial area fractions, confirming DW-MRS as a promising tool for specific detection of glial changes under pathological conditions.

Exploring the ontogenetic development of the inner ear in Aardvarks.

The aardvark is the last living Tubulidentata, an order of afrotherian mammals. Afrotheria is supported strongly by molecular analyses, yet sparingly by morphological characters. Moreover, the biology of the aardvark remains incompletely known. The inner ear, and its ontogeny in particular, has not been studied in details yet, though it bears key ecomorphological characters and phylogenetical signal. The aim of this study is to decipher and discuss the ontogenetic development of the different areas of the inner ear of Orycteropus afer. We focused in particular on their relative size and morphological rates of development. Specimens were scanned with 3D imaging techniques. 3D and 2D geometric morphometrics coupled with qualitative descriptions of the petrosal ossification allowed us to evidence several stages through development. Based on our sample, the cochlea is the first structure of the inner ear to reach adult size, but it is the last one to acquire its adult morphology close to parturition. In contrast, after a delayed growth spurt, the semicircular canals reach their mature morphology before the cochlea, concomitantly with the increase of petrosal ossification. The ontogeny of the aardvark inner ear shows similarities with that of other species, but the apex of the cochlea presents some autapomorphies. This work constitutes a first step in the study of the ontogeny of this sensorial organ in Afrotheria.

Development and growth of the pelvic fin in the extant coelacanth Latimeria chalumnae.

The ontogeny of the paired appendages has been extensively studied in lungfishes and tetrapods, but remains poorly known in coelacanths. Recent work has shed light on the anatomy and development of the pectoral fin in Latimeria chalumnae. Yet, information on the development of the pelvic fin and girdle is still lacking. Here, we described the development of the pelvic fin and girdle in Latimeria chalumnae based on 3D reconstructions generated from conventional and X-ray synchrotron microtomography, as well as MRI acquisitions. As in other jawed vertebrates, the development of the pelvic fin occurs later than that of the pectoral fin in Latimeria. Many elements of the endoskeleton are not yet formed at the earliest stage sampled. The four mesomeres are already formed in the fetus, but only the most proximal radial elements (preaxial radial 0-1) are formed and individualized at this stage. We suggest that all the preaxial radial elements in the pelvic and pectoral fin of Latimeria are formed through the fragmentation of the mesomeres. We document the progressive ossification of the pelvic girdle, and the presence of a trabecular system in the adult. This trabecular system likely reinforces the cartilaginous girdle to resist the muscle forces exerted during locomotion. Finally, the presence of a preaxial element in contact with the pelvic girdle from the earliest stage of development onward questions the mono-basal condition of the pelvic fin in Latimeria. However, the particular shape of the mesomeres may explain the presence of this element in contact with the girdle.

Machine learning based white matter models with permeability: An experimental study in cuprizone treated in-vivo mouse model of axonal demyelination.

The intra-axonal water exchange time (τi), a parameter associated with axonal permeability, could be an important biomarker for understanding and treating demyelinating pathologies such as Multiple Sclerosis. Diffusion-Weighted MRI (DW-MRI) is sensitive to changes in permeability; however, the parameter has so far remained elusive due to the lack of general biophysical models that incorporate it. Machine learning based computational models can potentially be used to estimate such parameters. Recently, for the first time, a theoretical framework using a random forest (RF) regressor suggests that this is a promising new approach for permeability estimation. In this study, we adopt such an approach and for the first time experimentally investigate it for demyelinating pathologies through direct comparison with histology. We construct a computational model using Monte Carlo simulations and an RF regressor in order to learn a mapping between features derived from DW-MRI signals and ground truth microstructure parameters. We test our model in simulations, and find strong correlations between the predicted and ground truth parameters (intra-axonal volume fraction f: R2 =0.99, τi: R2 =0.84, intrinsic diffusivity d: R2 =0.99). We then apply the model in-vivo, on a controlled cuprizone (CPZ) mouse model of demyelination, comparing the results from two cohorts of mice, CPZ (N=8) and healthy age-matched wild-type (WT, N=8). We find that the RF model estimates sensible microstructure parameters for both groups, matching values found in literature. Furthermore, we perform histology for both groups using electron microscopy (EM), measuring the thickness of the myelin sheath as a surrogate for exchange time. Histology results show that our RF model estimates are very strongly correlated with the EM measurements (ρ = 0.98 for f, ρ = 0.82 for τi). Finally, we find a statistically significant decrease in τi in all three regions of the corpus callosum (splenium/genu/body) of the CPZ cohort (<τi>=310ms/330ms/350ms) compared to the WT group (<τi>=370ms/370ms/380ms). This is in line with our expectations that τi is lower in regions where the myelin sheath is damaged, as axonal membranes become more permeable. Overall, these results demonstrate, for the first time experimentally and in vivo, that a computational model learned from simulations can reliably estimate microstructure parameters, including the axonal permeability .

Simultaneous proton density, T1 , T2 , and flip-angle mapping of the brain at 7 T using multiparametric 3D SSFP imaging and parallel-transmission universal pulses.

PURPOSE: Performing simultaneous quantitative MRI at ultrahigh field is challenging, as B0 and B1+ heterogeneities as well as specific absorption rate increase. Too large deviations of flip angle from the target can induce biases and impair SNR in the quantification process. In this work, we use calibration-free parallel transmission, a dedicated pulse-sequence parameter optimization and signal fitting to recover 3D proton density, flip angle, T1 , and T2 maps over the whole brain, in a clinically suitable time. METHODS: Eleven optimized contrasts were acquired with an unbalanced SSFP sequence by varying flip-angle amplitude and RF phase-cycling increment, at a 1.0 × 1.0 × 3.0 mm3 resolution. Acquisition time was 16 minutes 36 seconds for the whole brain. Parallel transmission and universal pulses were used to mitigate B1+ heterogeneity, to improve the results' reliability over 6 healthy volunteers (3 females/3 males, age 22.6 ± 2.7 years old). Quantification of the physical parameters was performed by fitting the acquired contrasts to the simulated ones using the Bloch-Torrey equations with a realistic diffusion coefficient. RESULTS: Whole-brain 3D maps of effective flip angle, proton density, and relaxation times were estimated. Parallel transmission improved the robustness of the results at 7 T. Results were in accordance with literature and with measurements from standard methods. CONCLUSION: These preliminary results show robust proton density, flip angle, T1 , and T2 map retrieval. Other parameters, such as ADC, could be assessed. With further optimization in the acquisition, scan time could be reduced and spatial resolution increased to bring this multiparametric quantification method to clinical research routine at 7 T.

Iron Imaging as a Diagnostic Tool for Parkinson's Disease: A Systematic Review and Meta-Analysis.

Background: Parkinson's disease (PD) is a progressive neurodegenerative disease whose main neuropathological feature is the loss of dopaminergic neurons of the substantia nigra (SN). There is also an increase in iron content in the SN in postmortem and imaging studies using iron-sensitive MRI techniques. However, MRI results are variable across studies. Objectives: We performed a systematic meta-analysis of SN iron imaging studies in PD to better understand the role of iron-sensitive MRI quantification to distinguish patients from healthy controls. We also studied the factors that may influence iron quantification and analyzed the correlations between demographic and clinical data and iron load. Methods: We searched PubMed and ScienceDirect databases (from January 1994 to December 2019) for studies that analyzed iron load in the SN of PD patients using T2*, R2*, susceptibility weighting imaging (SWI), or quantitative susceptibility mapping (QSM) and compared the values with healthy controls. Details for each study regarding participants, imaging methods, and results were extracted. The effect size and confidence interval (CI) of 95% were calculated for each study as well as the pooled weighted effect size for each marker over studies. Hence, the correlations between technical and clinical metrics with iron load were analyzed. Results: Forty-six articles fulfilled the inclusion criteria including 27 for T2*/R2* measures, 10 for SWI, and 17 for QSM (3,135 patients and 1,675 controls). Eight of the articles analyzed both R2* and QSM. A notable effect size was found in the SN in PD for R2* increase (effect size: 0.84, 95% CI: 0.60 to 1.08), for SWI measurements (1.14, 95% CI: 0.54 to 1.73), and for QSM increase (1.13, 95% CI: 0.86 to 1.39). Correlations between imaging measures and Unified Parkinson's Disease Rating Scale (UPDRS) scores were mostly observed for QSM. Conclusions: The consistent increase in MRI measures of iron content in PD across the literature using R2*, SWI, or QSM techniques confirmed that these measurements provided reliable markers of iron content in PD. Several of these measurements correlated with the severity of motor symptoms. Lastly, QSM appeared more robust and reproducible than R2* and more suited to multicenter studies.

Monitoring Dual VEGF Inhibition in Human Pancreatic Tumor Xenografts With Dynamic Contrast-Enhanced Ultrasound.

BACKGROUND: Association of drugs acting against different antiangiogenic mechanisms may increase therapeutic effect and reduce resistance. Noninvasive monitoring of changes in the antiangiogenic response of individual tumors could guide selection and administration of drug combinations. Noninvasive detection of early therapeutic response during dual, vertical targeting of the vascular endothelial growth factor pathway was investigated in an ectopic subcutaneous xenograft model for human pancreatic tumor. METHODS: Dynamic contrast-enhanced ultrasound 12 MHz was used to monitor tumor-bearing Naval Medical Research Institute mice beginning 15 days after tumor implantation. Mice received therapy from 15 to 29 days with sorafenib (N = 9), ziv-aflibercept (N = 11), combined antiangiogenic agents (N = 11), and placebo control (N = 14). Sorafenib (BAY 43-9006; Nexavar), a multikinase inhibitor acting on Raf kinase and receptor tyrosine kinases-including vascular endothelial growth factor receptors 2 and 3-was administered daily (60 mg/kg, per os). Ziv-aflibercept (ZALTRAP), a high-affinity ligand trap blocking the activity of vascular endothelial growth factor A, vascular endothelial growth factor B, and placental growth factor was administered twice per week (40 mg/kg, intraperitoneally). RESULTS: Functional evaluation with dynamic contrast-enhanced ultrasound indicated stable tumor vascularization for the control group while revealing significant and sustained reduction after 1 day of therapy in the combined group (P = .007). There was no survival benefit or penalty due to drug combination. The functional progression-free survival assessed with dynamic contrast-enhanced ultrasound was significantly higher for the 3 treated groups; whereas, the progression-free survival based on tumor size did not discriminate therapeutic effect. CONCLUSIONS: Dynamic contrast-enhanced ultrasound, therefore, presents strong potential to monitor microvascular modifications during antiangiogenic therapy, a key role to monitoring antiangiogenic combining therapy to adapt dose range drug.

The spectrum of spinal cord lesions in a primate model of multiple sclerosis.

BACKGROUND: Experimental autoimmune encephalomyelitis (EAE) in the common marmoset is a nonhuman primate model of multiple sclerosis (MS) that shares numerous clinical, radiological, and pathological features with MS. Among the clinical features are motor and sensory deficits that are highly suggestive of spinal cord (SC) damage. OBJECTIVE: To characterize the extent and nature of SC damage in symptomatic marmosets with EAE using a combined magnetic resonance imaging (MRI) and histopathology approach. MATERIALS AND METHODS: SC tissues from five animals were scanned using 7 T MRI to collect high-resolution ex vivo images. Lesions were segmented and classified based on shape, size, and distribution along the SC. Tissues were processed for histopathological characterization (myelin and microglia/macrophages). Statistical analysis, using linear mixed-effects models, evaluated the association between MRI and histopathology. RESULTS: Marmosets with EAE displayed two types of SC lesions: focal and subpial lesions. Both lesion types were heterogeneous in size and configuration and corresponded to areas of marked demyelination with high density of inflammatory cells. Inside the lesions, the MRI signal was significantly correlated with myelin content (p < 0.001). CONCLUSIONS: Our findings underscore the relevance of this nonhuman primate EAE model for better understanding mechanisms of MS lesion formation in the SC.

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

GABA is an inhibitory neurotransmitter that is maintained outside the brain by the blood brain barrier in normal condition. In this paper we demonstrate the feasibility of modulating brain activity in the visual cortex of non-human primates by transiently permeabilizing the blood brain barrier (BBB) using focused ultrasound (FUS) coupled with ultrasound contrast agents (UCA), followed by intra-venous injection of GABA. The visual evoked potentials exhibited a significant and GABA-dose-depend decrease in activity. The effect of the sonication only (with and without UCA) was also investigated and was shown to decrease the activity 8.7 times less than the GABA-induced inhibition enabled by BBB permeabilization. Finally, the UCA harmonic response was monitored during sonication to estimate the level of stable cavitation (a signature of the effectiveness of BBB permeabilization) and to avoid damage due to inertial cavitation (the sonication was automatically shut down when this condition was detected). Our results extend the promise of the exploration and treatment of the brain using non-invasive, controllable, repeatable, and reversible neuromodulation.

Development and growth of the pectoral girdle and fin skeleton in the extant coelacanth Latimeria chalumnae.

The monobasal pectoral fins of living coelacanths and lungfishes are homologous to the forelimbs of tetrapods and are thus critical to investigate the origin thereof. However, it remains unclear whether the similarity in the asymmetrical endoskeletal arrangement of the pectoral fins of coelacanths reflects the evolution of the pectoral appendages in sarcopterygians. Here, we describe for the first time the development of the pectoral fin and shoulder girdle in the extant coelacanth Latimeria chalumnae, based on the tomographic acquisition of a growth series. The pectoral girdle and pectoral fin endoskeleton are formed early in development with a radially outward growth of the endoskeletal elements. The visualization of the pectoral girdle during development shows a reorientation of the girdle between the fetus and pup 1 stages, creating a contact between the scapulocoracoids and the clavicles in the ventro-medial region. Moreover, we observed a splitting of the pre- and post-axial cartilaginous plates in respectively pre-axial radials and accessory elements on one hand, and in post-axial accessory elements on the other hand. However, the mechanisms involved in the splitting of the cartilaginous plates appear different from those involved in the formation of radials in actinopterygians. Our results show a proportional reduction of the proximal pre-axial radial of the fin, rendering the external morphology of the fin more lobe-shaped, and a spatial reorganization of elements resulting from the fragmentation of the two cartilaginous plates. Latimeria development hence supports previous interpretations of the asymmetrical pectoral fin skeleton as being plesiomorphic for coelacanths and sarcopterygians.

MRI monitoring of temperature and displacement for transcranial focus ultrasound applications.

BACKGROUND: Transcranial focus ultrasound applications applied under MRI-guidance benefit from unrivaled monitoring capabilities, allowing the recording of real-time anatomical information and biomarkers like the temperature rise and/or displacement induced by the acoustic radiation force. Having both of these measurements could allow for better targeting of brain structures, with improved therapy monitoring and safety. METHOD: We investigated the use of a novel MRI-pulse sequence described previously in Bour et al., (2017) to quantify both the displacement and temperature changes under various ultrasound sonication conditions and in different regions of the brain. The method was evaluated in vivo in a non-human primate under anesthesia using a single-element transducer (f = 850 kHz) in a setting that could mimic clinical applications. Acquisition was performed at 3 T on a clinical imaging system using a modified single-shot gradient echo EPI sequence integrating a bipolar motion-sensitive encoding gradient. Four slices were acquired sequentially perpendicularly or axially to the direction of the ultrasound beam with a 1-Hz update frequency and an isotropic spatial resolution of 2-mm. A total of twenty-four acquisitions were performed in three different sets of experiments. Measurement uncertainty of the sequence was investigated under different acoustic power deposition and in different regions of the brain. Acoustic simulation and thermal modeling were performed and compared to experimental data. RESULTS: The sequence simultaneously provides relevant information about the focal spot location and visualization of heating of brain structures: 1) The sequence localized the acoustic focus both along as well as perpendicular to the ultrasound direction. Tissue displacements ranged from 1 to 2 µm. 2) Thermal rise was only observed at the vicinity of the skull. Temperature increase ranged between 1 and 2 °C and was observed delayed relative the sonication due to thermal diffusion. 3) The fast frame rate imaging was able to highlight magnetic susceptibility artifacts related to breathing, for the most caudal slices. We demonstrated that respiratory triggering successfully restored the sensitivity of the method (from 0.7 µm to 0.2 µm). 4) These results were corroborated by acoustic simulations. CONCLUSIONS: The current rapid, multi-slice acquisition and real-time implementation of temperature and displacement visualization may be useful in clinical practices. It may help defining operational safety margins, improving therapy precision and efficacy. Simulations were in good agreement with experimental data and may thus be used prior treatment for procedure planning.

Clinical Integration of Automated Processing for Brain Quantitative Susceptibility Mapping: Multi-Site Reproducibility and Single-Site Robustness.

BACKGROUND AND PURPOSE: Quantitative susceptibility mapping (QSM) of the brain has become highly reproducible and has applications in an expanding array of diseases. To translate QSM from bench to bedside, it is important to automate its reconstruction immediately after data acquisition. In this work, a server system that automatically reconstructs QSM and exchange images with the scanner using the DICOM standard is demonstrated using a multi-site, multi-vendor reproducibility study and a large, single-site, multi-scanner image quality review study in a clinical environment. METHODS: A single healthy subject was scanned with a 3D multi-echo gradient echo sequence at nine sites around the world using scanners from three manufacturers. A high-resolution (HiRes, .5 × .5 × 1 mm3 reconstructed) and standard-resolution (StdRes, .5 × .5 × 3 mm3 ) protocol was performed. ROI analysis of various white matter and gray matter regions was performed to investigate reproducibility across sites. At one institution, a retrospective multi-scanner image quality review was carried out of all clinical QSM images acquired consecutively in 1 month. RESULTS: Reconstruction times using a GPU were 29 ± 22 seconds (StdRes) and 55 ± 39 seconds (HiRes). ROI standard deviation across sites was below 24 ppb (StdRes) and 17 ppb (HiRes). Correlations between ROI averages across sites were on average .92 (StdRes) and .96 (HiRes). Image quality review of 873 consecutive patients revealed diagnostic or excellent image quality in 96% of patients. CONCLUSION: Online QSM reconstruction for a variety of sites and scanner platforms with low cross-site ROI standard deviation is demonstrated. Image quality review revealed diagnostic or excellent image quality in 96% of 873 patients.