Analysis of Graphomotor Tests with Machine Learning Algorithms for an Early and Universal Pre-Diagnosis of Dysgraphia.

Five to ten percent of school-aged children display dysgraphia, a neuro-motor disorder that causes difficulties in handwriting, which becomes a handicap in the daily life of these children. Yet, the diagnosis of dysgraphia remains tedious, subjective and dependent to the language besides stepping in late in the schooling. We propose a pre-diagnosis tool for dysgraphia using drawings called graphomotor tests. These tests are recorded using graphical tablets. We evaluate several machine-learning models and compare them to build this tool. A database comprising 305 children from the region of Grenoble, including 43 children with dysgraphia, has been established and diagnosed by specialists using the BHK test, which is the gold standard for the diagnosis of dysgraphia in France. We performed tests of classification by extracting, correcting and selecting features from the raw data collected with the tablets and achieved a maximum accuracy of 73% with cross-validation for three models. These promising results highlight the relevance of graphomotor tests to diagnose dysgraphia earlier and more broadly.

Quantitative comparison of PZT and CMUT probes for photoacoustic imaging: Experimental validation.

Photoacoustic (PA) signals are short ultrasound (US) pulses typically characterized by a single-cycle shape, often referred to as N-shape. The spectral content of such wideband signals ranges from a few hundred kilohertz to several tens of megahertz. Typical reception frequency responses of classical piezoelectric US imaging transducers, based on PZT technology, are not sufficiently broadband to fully preserve the entire information contained in PA signals, which are then filtered, thus limiting PA imaging performance. Capacitive micromachined ultrasonic transducers (CMUT) are rapidly emerging as a valid alternative to conventional PZT transducers in several medical ultrasound imaging applications. As compared to PZT transducers, CMUTs exhibit both higher sensitivity and significantly broader frequency response in reception, making their use attractive in PA imaging applications. This paper explores the advantages of the CMUT larger bandwidth in PA imaging by carrying out an experimental comparative study using various CMUT and PZT probes from different research laboratories and manufacturers. PA acquisitions are performed on a suture wire and on several home-made bimodal phantoms with both PZT and CMUT probes. Three criteria, based on the evaluation of pure receive impulse response, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) respectively, have been used for a quantitative comparison of imaging results. The measured fractional bandwidths of the CMUT arrays are larger compared to PZT probes. Moreover, both SNR and CNR are enhanced by at least 6 dB with CMUT technology. This work highlights the potential of CMUT technology for PA imaging through qualitative and quantitative parameters.

Targeting tumors with cyclic RGD-conjugated lipid nanoparticles loaded with an IR780 NIR dye: In vitro and in vivo evaluation.

Like several 50nm-large nanocarriers, lipid nanoparticles (LNPs) can passively accumulate in tumors through the Enhanced Permeability and Retention (EPR) effect. In this study, we developed PEGylated LNPs loaded with IR780 iodide as a contrast agent for NIR fluorescence imaging and modified them with cyclic RGD peptides in order to target integrin avß3. We demonstrate a specific targeting of the receptor with cRGD-LNPs but not with cRAD-LNP and standard LNP using HEK293(ß3), HEK293(ß3)-αvRFP, DU145 and PC3 cell lines. We also demonstrate that cRGD-LNPs bind to αvß3, interfere with cell adhesion to vitronectin and co-internalize with αvß3 within one hour. We then investigated their biodistribution and tumor targeting in mice bearing DU145 or M21 tumors. We observed no significant differences between cRGD-LNP and the non-targeted ones regarding their biodistribution and accumulation/retention in tumors. This suggested that despite an efficient formulation of the cRGD-LNPs, the cRGD-mediated targeting was not increasing the total amount of LNP that can already accumulate passively in the subcutaneous tumors via the EPR effect.

LipImage™ 815: novel dye-loaded lipid nanoparticles for long-term and sensitive in vivo near-infrared fluorescence imaging.

A new contrast agent, LipImage™ 815, has been designed and compared to previously described indocyanine green (ICG)-loaded lipid nanoparticles (ICG-lipidots®). Both contrast agents display similar size (50-nm diameter), zeta potential, high IC50 in cellular studies, near-infrared absorption and emission wavelengths in the "imaging window," long-term shelf colloidal and optical stabilities with high brightness (>106 L mol-1 cm-1) in ready-to-use storage conditions in aqueous buffer (4°C in dark), therefore being promising fluorescence contrast agents for in vivo imaging. However, while ICG-lipidots® display a relatively short plasma lifetime, LipImage™ 815 circulates in blood for longer times, allowing the efficient uptake of fluorescence signal in human prostate cancer cells implanted in mice. Prolonged tumor labeling is observed for more than 21 days.

A quantitative study to design an experimental setup for photoacoustic imaging.

During the last decade, a new modality called photoacoustic imaging has emerged. The increasing interest for this new modality is due to the fact that it combines advantages of ultrasound and optical imaging, i.e. the high contrast due to optical absorption and the low acoustic attenuation in biological tissues. It is thus possible to study vascularization because blood has high optical absorption coefficient. Papers in the literature often focus on applications and rarely discuss quantitative parameters. The goal of this paper is to provide quantitative elements to design an acquisition setup. By defining the targeted resolution and penetration depth, it is then possible to evaluate which kind of excitation and reception systems have to be used. First, we recall theoretical background related to photoacoustic effect before to describe the experiments based on a nanosecond laser at 1064 nm and 2.25-5 MHz transducers. Second, we present results about the relation linking fluence laser to signal amplitude and axial and lateral resolutions of our acquisition setup. We verify the linear relation between fluence and amplitude before to estimate axial resolution at 550 µm for a 2.25 MHz ultrasonic transducer. Concerning lateral resolution, we show that a reconstruction technique based on curvilinear acquisition of 30 lines improves it by a factor of 3 compared to a lateral displacement. Future works will include improvement of lateral resolution using probes, like in ultrasound imaging, instead of single-element transducers.

Fluorescence diffuse optical tomography for free-space and multifluorophore studies.

We present two major advances in preclinical fluorescence-enhanced diffuse optical tomography (fDOT) system and assess its performance. It is now possible to perform experiments without adaptation liquid or a glass plate over the animal, and our system is equipped with a filter wheel in order to discriminate two injected fluorophores. Evaluation carried out on characterization phantoms and in vivo on mice demonstrates enriched use of the system for biological studies on small animals.

Fluorescence time-resolved imaging system embedded in an ultrasound prostate probe.

Ultrasound imaging (US) of the prostate has a low specificity to distinguish tumors from the surrounding tissues. This limitation leads to systematic biopsies. Fluorescent diffuse optical imaging may represent an innovative approach to guide biopsies to tumors marked with high specificity contrast agents and therefore enable an early detection of prostate cancer. This article describes a time-resolved optical system embedded in a transrectal US probe, as well as the fluorescence reconstruction method and its performance. Optical measurements were performed using a pulsed laser, optical fibers and a time-resolved detection system. A novel fast reconstruction method was derived and used to locate a 45 µL ICG fluorescent inclusion at a concentration of 10 µM, in a liquid prostate phantom. Very high location accuracy (0.15 cm) was achieved after reconstruction, for different positions of the inclusion, in the three directions of space. The repeatability, tested with ten sequential measurements, was of the same order of magnitude. Influence of the input parameters (optical properties and lifetime) is presented. These results confirm the feasibility of using optical imaging for prostate guided biopsies.

Bimodal ultrasound and fluorescence approach for prostate cancer diagnosis.

Finding a way to combine ultrasound and fluorescence optical imaging on an endorectal probe may improve early detection of prostate cancer. The ultrasound provides morphological information about the prostate, while the optical system detects and locates fluorophore-marked tumors. A tissue-mimicking phantom, which is representative of prostate tissues both on its optical (absorption mu(a) and diffusion mu(s) (')) and its ultrasound properties, has been made by our team. A transrectal probe adapted to fluorescence diffuse optical tomography measurements was also developed. Measurements were taken on the prostate phantom with this probe based on a pulsed laser and a time-resolved detection system. A reconstruction algorithm was then used to help locate and quantify fluorescent inclusions of different concentrations at fixed depths.

In vivo mice lung tumor follow-up with fluorescence diffuse optical tomography.

We present in vivo experiments conducted with a new fluorescence diffuse optical tomographic (fDOT) system on cancerous mice bearing mammary murine tumors. We first briefly present this new system that has been developed and its associated reconstruction method. Its main specificity is its ability to reconstruct the fluorescence yield even in heterogeneous and highly attenuating body regions such as lungs and to enable mouse inspection without immersion in optical index matching liquid (Intralipid and ink). Some phantom experiments validate the performance of this new system for heterogeneous media inspection. Its use for a mice study is then related. It consists in the follow-up of the lungs at different stages of tumor development after injection of RAFT-(cRGD)4-Alexa700. As expected, the reconstructed fluorescence increases along with the tumor stage. These results validate the use of our system for biological studies of small animals.