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Summary: Background: Colposcopy, currently included in WHO recommendations as an option to triage human papillomavirus (HPV)-positive women, remains as the reference standard to guide both biopsy for confirmation of cervical precancer and cancer and treatment approaches. We aim to evaluate the performance of colposcopy to detect cervical precancer and cancer for triage in HPV-positive women. Methods: This cross-sectional, multicentric screening study was conducted at 12 centres (including primary and secondary care centres, hospitals, laboratories, and universities) in Latin America (Argentina, Bolivia, Colombia, Costa Rica, Honduras, Mexico, Paraguay, Peru, and Uruguay). Eligible women were aged 30–64 years, sexually active, did not have a history of cervical cancer or treatment for cervical precancer or a hysterectomy, and were not planning to move outside of the study area. Women were screened with HPV DNA testing and cytology. HPV-positive women were referred to colposcopy using a standardised protocol, including biopsy collection of observed lesions, endocervical sampling for transformation zone (TZ) type 3, and treatment as needed. Women with initial normal colposcopy or no high-grade cervical lesions on histology (less than cervical intraepithelial neoplasia [CIN] grade 2) were recalled after 18 months for another HPV test to complete disease ascertainment; HPV-positive women were referred for a second colposcopy with biopsy and treatment as needed. Diagnostic accuracy of colposcopy was assessed by considering a positive test result when the colposcopic impression at the initial colposcopy was positive minor, positive major, or suspected cancer, and was considered negative otherwise. The main study outcome was histologically confirmed CIN3+ (defined as grade 3 or worse) detected at the initial visit or 18-month visit. Findings: Between Dec 12, 2012, and Dec 3, 2021, 42 502 women were recruited, and 5985 (14·1%) tested positive for HPV. 4499 participants with complete disease ascertainment and follow-up were included in the analysis, with a median age of 40·6 years (IQR 34·7–49·9). CIN3+ was detected in 669 (14·9%) of 4499 women at the initial visit or 18-month visit (3530 [78·5%] negative or CIN1, 300 [6·7%] CIN2, 616 [13·7%] CIN3, and 53 [1·2%] cancers). Sensitivity was 91·2% (95% CI 88·9–93·2) for CIN3+, whereas specificity was 50·1% (48·5–51·8) for less than CIN2 and 47·1% (45·5–48·7) for less than CIN3. Sensitivity for CIN3+ significantly decreased in older women (93·5% [95% CI 91·3–95·3] in those aged 30–49 years vs 77·6% [68·6–85·0] in those aged 50–65 years; p

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., (© 2023 The Authors. Journal of Anatomy published by John Wiley & Sons Ltd on behalf of Anatomical Society.)

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 µm 3 ). 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., (© 2023. The Author(s).)

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. 18 F-florbetapir and 18 F-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 18 F-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., (© 2022. The Author(s).)

Introduction: A 12-year long, prospective, single center study was conducted, comparing two frameless systems for brain biopsies: ROSA robotic-assisted stereotaxy and BrainLab Varioguide image-guided stereotaxy (Image Guided Surgery, IGS)., Method: All consecutive adult and pediatric patients undergoing frameless brain biopsies were included. Successfully achieving diagnosis was the primary endpoint, analysis of all periprocedural complications was the secondary endpoint, and the tertiary endpoint was the length of the procedure, with the aim of assessing of the learning curve for each operator over time. The results for the ROSA robot and the Varioguide system were compared and benchmarked to data from the literature., Results: We performed 526 on 516 patients, 314 with the ROSA robot (Group A) and 212 with the IGS Varioguide (Group B). Histological diagnosis was achieved in 97.4% of cases in Group A, versus 93.3% in Group B (p < 0.05). No statistically significant difference was found for secondary and tertiary endpoints. The complication rate appeared similar between the 2 frameless systems, with a hemorrhagic complications rate of 3.5% in Group A and 4.7% in Group B. Permanent neurological deterioration was only recorded in 0.8% of cases from Group B. Mortality was recorded in 0.3% in Group A and 0.4% in Group B., Conclusion: This study provides evidence to confirm that robotic surgery lives up to its promises of increased safety, accuracy, and reliability., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

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., (© 2020 Anatomical Society.)

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., (© 2021 John Wiley & Sons, Ltd.)

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., (© 2020 American Association for Anatomy.)

Aims: Impairment of blood-brain barrier (BBB) is involved in numerous neurological diseases from developmental to aging stages. Reliable imaging of increased BBB permeability is therefore crucial for basic research and preclinical studies. Today, the analysis of extravasation of exogenous dyes is the principal method to study BBB leakage. However, these procedures are challenging to apply in pups and embryos and may appear difficult to interpret. Here we introduce a novel approach based on agonist-induced internalization of a neuronal G protein-coupled receptor widely distributed in the mammalian brain, the somatostatin receptor type 2 (SST2)., Methods: The clinically approved SST2 agonist octreotide (1 kDa), when injected intraperitoneally does not cross an intact BBB. At sites of BBB permeability, however, OCT extravasates and induces SST2 internalization from the neuronal membrane into perinuclear compartments. This allows an unambiguous localization of increased BBB permeability by classical immunohistochemical procedures using specific antibodies against the receptor., Results: We first validated our approach in sensory circumventricular organs which display permissive vascular permeability. Through SST2 internalization, we next monitored BBB opening induced by magnetic resonance imaging-guided focused ultrasound in murine cerebral cortex. Finally, we proved that after intraperitoneal agonist injection in pregnant mice, SST2 receptor internalization permits analysis of BBB integrity in embryos during brain development., Conclusions: This approach provides an alternative and simple manner to assess BBB dysfunction and development in different physiological and pathological conditions., (© 2020 British Neuropathological Society.)

Purpose: Performing simultaneous quantitative MRI at ultrahigh field is challenging, as B 0 and B 1 + 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, T 1 , and T 2 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 mm 3 resolution. Acquisition time was 16 minutes 36 seconds for the whole brain. Parallel transmission and universal pulses were used to mitigate B 1 + 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, T 1 , and T 2 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., (© 2020 International Society for Magnetic Resonance in Medicine.)

Background: Rhabdomyosarcoma is a rare malignant tumor originating from striated muscle cells. It accounts for only 3% of all soft tissue sarcomas in adults, and its metastases can also reach the central nervous system. Only sporadic cases of primary brain rhabdomyosarcoma (PBRMS) have been reported so far., Case Description: We discuss the atypical presentation and diagnostic challenge of PBRMS in a 65-year-old man. He presented with a 3-day history of progressive right hemiparesis caused by an unspecific left frontoparietal heterogeneously enhancing lesion. Total body computed tomography and positron emission tomography scans performed at baseline did not reveal other secondarisms. The patient underwent radical excision of the lesion, which allowed to establish the diagnosis, with immunohistochemical staining positive for desmin and myogenin. Stereotactic radiotherapy guaranteed local disease control; nonetheless, the patient also required adjuvant chemotherapy when he developed large right lung metastases 6 months postoperatively., Conclusions: PBRMS can be hardly distinguished from other malignant brain tumors during preoperative radiologic workup; only histology can raise the suspicion of primary or metastatic rhabdomyosarcoma, depending on the presence of other distant lesions. Our review of the literature demonstrates that prognosis is poor: 44% of patients die within 1 year from diagnosis. Overall, survival seems to correlate with radical resection, tolerance of stereotactic or if necessary full neuraxis radiotherapy, and adjuvant chemotherapy. Given the high relapse rate, close monitoring and restaging are imperative., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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.

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., (© 2019 Anatomical Society.)

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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 mm 3 reconstructed) and standard-resolution (StdRes, .5 × .5 × 3 mm 3 ) 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., (© 2019 by the American Society of Neuroimaging.)

The neurocranium of sarcopterygian fishes was originally divided into an anterior (ethmosphenoid) and posterior (otoccipital) portion by an intracranial joint, and underwent major changes in its overall geometry before fusing into a single unit in lungfishes and early tetrapods 1 . Although the pattern of these changes is well-documented, the developmental mechanisms that underpin variation in the form of the neurocranium and its associated soft tissues during the evolution of sarcopterygian fishes remain poorly understood. The coelacanth Latimeria is the only known living vertebrate that retains an intracranial joint 2,3 . Despite its importance for understanding neurocranial evolution, the development of the neurocranium of this ovoviviparous fish remains unknown. Here we investigate the ontogeny of the neurocranium and brain in Latimeria chalumnae using conventional and synchrotron X-ray micro-computed tomography as well as magnetic resonance imaging, performed on an extensive growth series for this species. We describe the neurocranium at the earliest developmental stage known for Latimeria, as well as the major changes that the neurocranium undergoes during ontogeny. Changes in the neurocranium are associated with an extreme reduction in the relative size of the brain along with an enlargement of the notochord. The development of the notochord appears to have a major effect on the surrounding cranial components, and might underpin the formation of the intracranial joint. Our results shed light on the interplay between the neurocranium and its adjacent soft tissues during development in Latimeria, and provide insights into the developmental mechanisms that are likely to have underpinned the evolution of neurocranial diversity in sarcopterygian fishes.

Background: Diffusion weighted imaging (DWI) is the only in vivo technique allowing for the mapping of tissue fiber architecture. Post mortem DWI is an increasingly popular method, since longer acquisition times (compared to in vivo) allow higher spatial and angular resolutions to be achieved. However, DWI protocols must be adapted to post mortem tissue (e.g., tuning acquisition parameters to account for changes in T1/T2). New method: In this work, we developed a framework to obtain high quality diffusion weighted images on post mortem large samples by using a combination of fast imaging with 3D diffusion-weighted segmented EPI (3D-DW seg-EPI), Gadolinium soaking and data denoising. Analyses including tractography were used to check the quality of the acquired data, including a comparison with 3D-DW SE acquisitions. Comparison with existing method: Effects on diffusion data of each of the components of the framework were tested: 3D-DW seg-EPI versus 3D-DW SE EPI; with and without data denoising; with and without Gd-soaking., Conclusions: Our study demonstrated the feasibility of analysing anatomical connectivity using diffusion imaging of a post mortem macaque brain with a 3D-DW seg-EPI sequence acquired at ultra-high field. The combination of high angular and spatial resolution DWI with Gd-soaking and denoising provided data allowing us to perform diffusion tractography with results very similar to those obtained with a 3D-DW SE acquisition (with shorter acquisition times: 222 h versus 37 h for 3D-DW seg-EPI)., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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, T 1 , T 2 , 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 mm 3 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, T 1 , T 2 , concentration and ADC of 23 Na for clinical research. With further optimization of the acquired QuICS contrasts, scan time could be reduced to be suitable with in vivo applications., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: Magnetic resonance imaging (MRI) shows slight spatial variations in brain white matter (WM). We used quantitative multi-parametric MRI to evaluate in what respect these inhomogeneities could correspond to WM subtypes with specific characteristics and spatial distribution., Materials and Methods: Twenty-six controls (12 women, 38 ±9 Y) took part in a 60-min session on a 3T scanner measuring 7 parameters: R1 and R2, diffusion tensor imaging which allowed to measure Axial and Radial Diffusivity (AD, RD), magnetization transfer imaging which enabled to compute the Macromolecular Proton Fraction (MPF), and a susceptibility-weighted sequence which permitted to quantify R2* and magnetic susceptibility (χm). Spatial independent component analysis was used to identify WM subtypes with specific combination of quantitative parameters values., Results: Three subtypes could be identified. t-WM (track) mostly mapped on well-formed projection and commissural tracts and came with high AD values (all p < 10(-18)). The two other subtypes were located in subcortical WM and overlapped with association fibers: f-WM (frontal) was mostly anterior in the frontal lobe whereas c-WM (central) was underneath the central cortex. f-WM and c-WM had higher MPF values, indicating a higher myelin content (all p < 1.7 10(-6)). This was compatible with their larger χm and R2, as iron is essentially stored in oligodendrocytes (all p < 0.01). Although R1 essentially showed the same, its higher value in t-WM relative to c-WM might be related to its higher cholesterol concentration., Conclusions: Thus, f- and c-WMs were less structured, but more myelinated and probably more metabolically active regarding to their iron content than WM related to fasciculi (t-WM). As known WM bundles passed though different WM subtypes, myelination might not be uniform along the axons but rather follow a spatially consistent regional variability. Future studies might examine the reproducibility of this decomposition and how development and pathology differently affect each subtype., Competing Interests: The authors have declared that no competing interests exist.

Background: An isolated rupture of the alar ligament is a rare occurrence with only a few cases reported in the literature., Case Report: The objective was to report the case of a young man with a unilateral rupture of the alar ligament that we closely monitored, clinically and radiologically, in order to describe the evolution of the alar ligament lesions., Conclusion: Radiological diagnosis using cervical MRI and duration of the conservative treatment remain debated and we proposed a close radiological follow-up in order to best understand the nature of these ligament lesions and their evolution following specific treatment., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

The basal ganglia are key structures for motor, cognitive and behavioral functions. They undergo several changes with aging and disease, such as Parkinson's or Huntington's disease, for example. Iron accumulation in basal ganglia is often related to these diseases, which is conventionally monitored by the transverse relaxation rate (R 2 *). 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 Parkinson's 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 R 2 * 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 R 2 * 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 © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

OBJECTIVE The main limitation to the efficacy of chemotherapy for brain tumors is the restricted access to the brain because of the limited permeability of the blood-brain barrier (BBB). Previous animal studies have shown that the application of pulsed ultrasound (US), in combination with the intravenous injection of microbubbles, can temporarily disrupt the BBB to deliver drugs that normally cannot reach brain tissue. Although many previous studies have been performed with external focused US transducers, the device described in the current work emits US energy using an unfocused transducer implanted in the skull thickness. This method avoids distortion of the US energy by the skull bone and allows for simple, repetitive, and broad disruption of the BBB without the need for MRI monitoring. The purpose of the present study was to determine if the BBB can be safely and repeatedly disrupted using such an implantable unfocused US device in a primate model. METHODS An 11.5-mm-diameter, 1-MHz, planar US device was implanted via a bur hole into the skull of 3 primates (2 Papio anubis [olive] baboons and 1 Macaca fascicularis [macaque]) for 4 months. Pulsed US sonications were applied together with the simultaneous intravenous injection of sulfur hexafluoride microbubbles (SonoVue) every 2 weeks to temporarily disrupt the BBB. In each primate, a total of 7 sonications were performed with a 23.2-msec burst length (25,000 cycles) and a 1-Hz pulse repetition frequency at acoustic pressure levels of 0.6-0.8 MPa. Potential toxicity induced by repeated BBB opening was analyzed using MRI, PET, electroencephalography (EEG), somatosensory evoked potential (SSEP) monitoring, behavioral scales, and histopathological analysis. RESULTS The T1-weighted contrast-enhanced MR images acquired after each sonication exhibited a zone of hypersignal underneath the transducer that persisted for more than 4 hours, indicating a broad region of BBB opening in the acoustic field of the implant. Positron emission tomography images with fluorine-18-labeled fluorodeoxyglucose (FDG) did not indicate any changes in the cerebral metabolism of glucose. Neither epileptic signs nor pathological central nerve conduction was observed on EEG and SSEP recordings, respectively. Behavior in all animals remained normal. Histological analysis showed no hemorrhagic processes, no petechia, and extravasation of only a few erythrocytes. CONCLUSIONS The studies performed confirm that an implantable, 1-MHz US device can be used to repeatedly open the BBB broadly in a large-animal model without inducing any acute, subacute, or chronic lesions.

Pelizaeus-Merzbacher disease (PMD) results from an X-linked misexpression of proteolipid protein 1 (PLP1). This leukodystrophy causes severe hypomyelination with progressive inflammation, leading to neurological dysfunctions and shortened life expectancy. While no cure exists for PMD, experimental cell-based therapy in the dysmyelinated shiverer model suggested that human oligodendrocyte progenitor cells (hOPCs) or human neural precursor cells (hNPCs) are promising candidates to treat myelinopathies. However, the fate and restorative advantages of human NPCs/OPCs in a relevant model of PMD has not yet been addressed. Using a model of Plp1 overexpression, resulting in demyelination with progressive inflammation, we compared side-by-side the therapeutic benefits of intracerebrally grafted hNPCs and hOPCs. Our findings reveal equal integration of the donor cells within presumptive white matter tracks. While the onset of exogenous remyelination was earlier in hOPCs-grafted mice than in hNPC-grafted mice, extended lifespan occurred only in hNPCs-grafted animals. This improved survival was correlated with reduced neuroinflammation (microglial and astrocytosis loads) and microglia polarization toward M2-like phenotype followed by remyelination. Thus modulation of neuroinflammation combined with myelin restoration is crucial to prevent PMD pathology progression and ensure successful rescue of PMD mice. These findings should help to design novel therapeutic strategies combining immunomodulation and stem/progenitor cell-based therapy for disorders associating hypomyelination with inflammation as observed in PMD., (© 2015 AlphaMed Press.)

Extracellular deposition of β amyloid plaques is an early event associated to Alzheimer's disease. Here, we have used in vivo gadolinium-stained high resolution (29(∗)29(∗)117 μm(3)) magnetic resonance imaging (MRI) to follow-up in a longitudinal way individual amyloid plaques in APP/PS1 mice and evaluate the efficacy of a new immunotherapy (SAR255952) directed against protofibrillar and fibrillary forms of Aβ. APP/PS1 mice were treated for 5 months between the age of 3.5 and 8.5 months. SAR255952 reduced amyloid load in 8.5-months-old animals, but not in 5.5-months animals compared to mice treated with a control antibody (DM4). Histological evaluation confirmed the reduction of amyloid load and revealed a lower density of amyloid plaques in 8.5-months SAR255952-treated animals. The longitudinal follow-up of individual amyloid plaques by MRI revealed that plaques that were visible at 5.5 months were still visible at 8.5 months in both SAR255952 and DM4-treated mice. This suggests that the amyloid load reduction induced by SAR255952 is related to a slowing down in the formation of new plaques rather than to the clearance of already formed plaques.

Histology is the gold standard to unveil microscopic brain structures and pathological alterations in humans and animal models of disease. However, due to tedious manual interventions, quantification of histopathological markers is classically performed on a few tissue sections, thus restricting measurements to limited portions of the brain. Recently developed 3D microscopic imaging techniques have allowed in-depth study of neuroanatomy. However, quantitative methods are still lacking for whole-brain analysis of cellular and pathological markers. Here, we propose a ready-to-use, automated, and scalable method to thoroughly quantify histopathological markers in 3D in rodent whole brains. It relies on block-face photography, serial histology and 3D-HAPi (Three Dimensional Histology Analysis Pipeline), an open source image analysis software. We illustrate our method in studies involving mouse models of Alzheimer's disease and show that it can be broadly applied to characterize animal models of brain diseases, to evaluate therapeutic interventions, to anatomically correlate cellular and pathological markers throughout the entire brain and to validate in vivo imaging techniques.

Myopia is a common ocular disorder generally due to increased axial length of the eye-globe. Its extreme form high myopia (HM) is a multifactorial disease leading to retinal and scleral damage, visual impairment or loss and is an important health issue. Mutations in the endocytic receptor LRP2 gene result in Donnai-Barrow (DBS) and Stickler syndromes, both characterized by HM. To clearly establish the link between Lrp2 and congenital HM we inactivated Lrp2 in the mouse forebrain including the neural retina and the retinal and ciliary pigment epithelia. High resolution in vivo MRI imaging and ophthalmological analyses showed that the adult Lrp2-deficient eyes were 40% longer than the control ones mainly due to an excessive elongation of the vitreal chamber. They had an apparently normal intraocular pressure and developed chorioretinal atrophy and posterior scleral staphyloma features reminiscent of human myopic retinopathy. Immunomorphological and ultrastructural analyses showed that increased eye lengthening was first observed by post-natal day 5 (P5) and that it was accompanied by a rapid decrease of the bipolar, photoreceptor and retinal ganglion cells, and eventually the optic nerve axons. It was followed by scleral thinning and collagen fiber disorganization, essentially in the posterior pole. We conclude that the function of LRP2 in the ocular tissues is necessary for normal eye growth and that the Lrp2-deficient eyes provide a unique tool to further study human HM.

The study of spontaneous brain activity using fMRI is central to mapping brain networks. However, current fMRI methodology has limitations in the study of small animal brain organization using ultra-high field fMRI experiments, as imaging artifacts are difficult to control and the relationship between classical neuroanatomy and spontaneous functional BOLD activity is not fully established. Challenges are especially prevalent during the fMRI study of individual rodent brains, which could be instrumental to studies of disease progression and pharmacology. A recent advance in fMRI methodology enables unbiased, accurate, and comprehensive identification of functional BOLD signals by interfacing multi-echo (ME) fMRI acquisition, NMR signal decay analysis, and independent components analysis (ICA), in a procedure called ME-ICA. Here we present a pilot study on the suitability of ME-ICA for ultra high field animal fMRI studies of spontaneous brain activity under anesthesia. ME-ICA applied to 11.7 T fMRI data of rats first showed robust performance in automatic high dimensionality estimation and ICA decomposition, similar to that previously reported for 3.0 T human data. ME sequence optimization for 11.7 T indicated that 3 echoes, 0.5mm isotropic voxel size and TR=3s was adequate for sensitive and specific BOLD signal acquisition. Next, in seeking optimal inhaled isoflurane anesthesia dosage, we report that progressive increase in anesthesia goes with concomitant decrease in statistical complexity of "global" functional activity, as measured by the number of BOLD components, or degrees of freedom (DOF). Finally, BOLD functional connectivity maps for individual rodents at the component level show that spontaneous BOLD activity follows classical neuroanatomy, and seed-based analysis shows plausible cortical-cortical and cortical-subcortical functional interactions., (Copyright © 2014. Published by Elsevier Inc.)

In this article, we report in vivo (1)H 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 Hotelling's 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 © 2014 John Wiley & Sons, Ltd.)

Amyloid plaques are one of the major microscopic lesions that characterize Alzheimer's disease. Current approaches to detect amyloid plaques by using magnetic resonance imaging (MRI) contrast agents require invasive procedures to penetrate the blood-brain barrier (BBB) and to deliver the contrast agent into the vicinity of amyloid plaques. Here we have developed a new protocol (US-Gd-staining) that enables the detection of amyloid plaques in the brain of an APP/PS1 transgenic mouse model of amyloidosis after intra-venous injection of a non-targeted, clinically approved MRI contrast agent (Gd-DOTA, Dotarem®) by transiently opening the BBB with unfocused ultrasound (1 MHz) and clinically approved microbubbles (Sonovue®, Bracco). This US-Gd-staining protocol can detect amyloid plaques with a short imaging time (32 min) and high in-plane resolution (29 μm). The sensitivity and resolution obtained is at least equal to that provided by MRI protocols using intra-cerebro-ventricular injection of contrast agents, a reference method used to penetrate the BBB. To our knowledge this is the first study to demonstrate the ability of MR imaging to detect amyloid plaques by using a peripheral intra-venous injection of a clinically approved NMR contrast agent., (Copyright © 2013. Published by Elsevier Inc.)

Cerebral aging is often associated with the occurrence of neurodegenerative diseases leading to dementia. Animal models are critical to elucidate mechanisms associated to dementia and to evaluate neuroprotective drugs. Rats that received intracerebroventricular injection of streptozotocin (icv-STZ) have been reported as a model of dementia. In these animals, this drug induces oxidative stress and brain glucose metabolism impairments associated to insulin signal transduction failure. These mechanisms are reported to be involved in the pathogenesis of Alzheimer's disease and other dementia. Icv-STZ rats also display memory impairments. However, little is known about the precise location of the lesions induced by STZ administration. In this context, the present study characterized the cerebral lesions induced by two-doses of icv-STZ by using high-field magnetic resonance imaging to easily and longitudinally detect cerebral abnormalities and by using immunohistochemistry to evaluate neuronal loss and neuroinflammation (astrocytosis and microgliosis). We showed that, at high doses, icv-STZ induces severe and acute neurodegenerative lesions in the septum and corpus callosum. The lesions are associated with an inflammation process. They are less severe and more progressive at low doses. The relevance of high and low doses of icv-STZ to mimic dementia and evaluate new drugs is discussed in the final part of this article.

This work combines modeling and experiment to assess encapsulated microbubble oscillations associated with broadband pressure peaks detected after microbubble excitation (postexcitation signals). Data were acquired from albumin-shelled and phospholipid-shelled microbubbles using a passive cavitation detector consisting of a confocally aligned 2.8-MHz transmitter and 13-MHz receiver. Microbubbles in weak solutions were insonified with a 5-cycle pulse at a peak rarefactional pressure of 2.0+/-0.2 MPa. For each microbubble type, at least 100 received signals were identified as individual-microbubble responses. The average broadband noise from signals with postexcitation response was 4.2-7.2 dB higher than from signals without postexcitation. Pressure-time responses for each microbubble type were simulated using the model by Marmottant et al. [J. Acoust. Soc. Am. 118, 3499-3505 (2005)], with insonification conditions matching the experiment. Increased broadband noise predicted for microbubbles with postexcitation response was consistent with that observed experimentally (4.0-8.9 dB). The model predicted that postexcitation signals occur only when the radial oscillation exceeds both the shell break-up threshold and twice the initial radius (free bubble inertial cavitation threshold).