High-Frequency Transient Elastography Prototype to Assess Skin (Dermis) Fibrosis: A Diagnostic Study in Patients with Venous Insufficiency and Controls.

PURPOSE: High-frequency transient elastography (HF-TE) is a noninvasive technique for assessing shear-wave speed and finally elasticity in thin tissue such as the skin. It has never been validated for monitoring fibrotic skin diseases. The purpose was to evaluate the potential of HF-TE to assess skin fibrosis in patients with chronic venous disorders (CVD). MATERIALS AND METHODS: This clinical study enrolled 48 patients at various stages of CVD and 48 paired healthy volunteers. Subjects underwent a clinical examination with an evaluation of Rodnan's fibrosis skin score. We studied the dermis thickness measured using ultrasound (US) and elasticity measurements using cutometer and HF-TE studied according to 3 cutaneous zones positioned on the leg. The area under the receiver operating characteristic curve (AUC) was calculated to evaluate the diagnosis performance for a combined parameter (PRL) based on a logistic regression model using both elasticity and dermal thickness. RESULTS: Patients with CVD had significantly higher values of skin elasticity than healthy subjects, 134.5 kPa and 132.1 kPa vs. 91.3 kPa, respectively. The dermis thickness also increased with escalation in CVD stage for all studied zones. The PRL parameter had an AUC value of 0.79 for all zones and stages of CVD clustered. The discriminating power of PRL increased with escalation of the CVD stage; with an AUC value of up to 0.89 for evolved stages, and a sensitivity and specificity of 0.79 and 0.89, respectively. CONCLUSION: HF-TE, coupled with a US measurement of dermis thickness, made it possible to propose a new biomarker, which proved to be a good diagnostic tool for skin fibrosis.

The pupil: a window on social automatic processing in autism spectrum disorder children.

BACKGROUND: Faces are crucial social stimuli, eliciting automatic processing associated with increased physiological arousal in observers. The level of arousal can be indexed by pupil diameter (the 'Event-Related Pupil Dilation', ERPD). However, many parameters could influence the arousal evoked by a face and its social saliency (e.g. virtual vs. real, neutral vs. emotional, static vs. dynamic). A few studies have shown an atypical ERPD in autism spectrum disorder (ASD) patients using several kinds of faces but no study has focused on identifying which parameter of the stimulus is the most interfering with face processing in ASD. METHODS: In order to disentangle the influence of these parameters, we propose an original paradigm including stimuli along an ecological social saliency gradient: from static objects to virtual faces to dynamic emotional faces. This strategy was applied to 186 children (78 ASD and 108 typically developing (TD) children) in two pupillometric studies (22 ASD and 47 TD children in the study 1 and 56 ASD and 61 TD children in the study 2). RESULTS: Strikingly, the ERPD in ASD children is insensitive to any of the parameters tested: the ERPD was similar for objects, static faces or dynamic faces. On the opposite, the ERPD in TD children is sensitive to all the parameters tested: the humanoid, biological, dynamic and emotional quality of the stimuli. Moreover, ERPD had a good discriminative power between ASD and TD children: ASD had a larger ERPD than TD in response to virtual faces, while TD had a larger ERPD than ASD for dynamic faces. CONCLUSIONS: This novel approach evidences an abnormal physiological adjustment to socially relevant stimuli in ASD.

Guidelines for successful motor cortex ultrasonic neurostimulation in mice.

BACKGROUND: Ultrasound neurostimulation (USNS) is a non-invasive neuromodulation technique that might hold promise for treating neuropsychiatric disorders with regards to its noninvasiveness, penetration depth, and high resolution. OBJECTIVE: We sought in this experimental study to provide detailed and optimized protocol and methodology for a successful ultrasonic neurostimulation of the Primary Motor Cortex (M1) in mice addressed to young researchers/students beginning their research in the field of ultrasonic neurostimulation and encountering practical challenges. METHODS: A 500 kHz single-element transducer was used for stimulating the primary motor cortex at different acoustic pressures in C57BL/6 mice at various anesthesia levels. To further illustrate the effect of anesthesia, real time visual observations of motor responses validated with video recordings as well as electromyography were employed for evaluating the success and reliability of the stimulations. RESULTS: Detailed experimental procedure for a successful stimulations including targeting and anesthesia is presented. Our study demonstrates that we can achieve high stimulation success rates (91 % to 100 %) at acoustic pressures ranging from 330 kPa to 550 kPa at anesthesia washout period. CONCLUSIONS: This study shows a reliable and detailed methodology for successful USNS in mice addressed to beginners in ultrasonic brain stimulation topic. We showed an effective USNS protocol. We offered a simple and consistent non-invasive technique for locating and targeting brain zones. Moreover, we illustrated the acoustic pressure and stimulation success relationship and focused on the effect of anesthesia level for successful stimulation.

High frequency ultrasound imaging of whole blood gelation and retraction during in vitro coagulation.

Blood coagulation is a series of biochemical reactions resulting in the mechanical transformation of liquid blood into a gel. As a consequence, ultrasound, being mechanical waves, can provide specific details on the dynamics of coagulation. In fact, previous high-frequency ultrasound monitoring studies have shown drastic changes in ultrasound velocity and attenuation during whole blood coagulation and a model discussing the observed mechanical transformations was proposed. In this paper, a technique of visualization of the clotting mechanism is introduced, which complements and revises the previous hypotheses. This method is based on the monitoring of scatterers (red blood cells) movement through a time correlation of 20 MHZ rf signals. It allows the computing of both a displacement map revealing local details and disparities and a parameter quantifying the global structural behavior. Qualitative results for two typical samples show that the technique provides new insights on the gelation dynamics. A quantitative analysis computed from 12 healthy subjects found that the changes in the structural parameters are significantly correlated to the changes in velocity and attenuation, both dependent on the mechanical transformations in the sample. The previous model is therefore revised and a new way to measure gel and retraction times is proposed.

Relationship between Behavioral and Objective Measures of Sound Intensity in Normal-Hearing Listeners and Hearing-Aid Users: A Pilot Study.

Background: For hearing-impaired individuals, hearing aids are clinically fit according to subjective measures of threshold and loudness. The goal of this study was to evaluate objective measures of loudness perception that might benefit hearing aid fitting. Method: Seventeen adult hearing aid users and 17 normal-hearing adults participated in the study. Outcome measures including categorical loudness scaling, cortical auditory evoked potentials (CAEPs), and pupillometry. Stimuli were 1-kHz tone bursts presented at 40, 60, and 80 dBA. Results: Categorical loudness scaling showed that loudness significantly increased with intensity for all participants (p < 0.05). For CAEPs, high intensity was associated with greater P1, N1, and P2 peak amplitude for all listeners (p < 0.05); a significant but small effect of hearing aid amplification was observed. For all participants, pupillometry showed significant effects of high intensity on pupil dilation (p < 0.05); there was no significant effect of hearing aid amplification. A Focused Principal Component analysis revealed significant correlations between subjective loudness and some of the objective measures. Conclusion: The present data suggest that intensity had a significant impact on loudness perception, CAEPs, and pupil response. The correlations suggest that pupillometry and/or CAEPs may be useful in determining comfortable amplification for hearing aids.

Atypical Response to Affective Touch in Children with Autism: Multi-Parametric Exploration of the Autonomic System.

This study aimed at evaluating the autonomic response to pleasant affective touch in children with Autism Spectrum Disorders (ASD) and age-matched typically developing (TD) peers, thanks to multiple autonomic nervous system (ANS) parameters and by contrasting CT (C-tactile fibers) high- vs. low-density territory stimulations. We measured pupil diameter, skin conductance, and heart rate during gentle stroking of two skin territories (CT high- and low-density, respectively, forearm and palm of the hand) in thirty 6-12-year-old TD children and twenty ASD children. TD children showed an increase in pupil diameter and skin conductance associated with a heart rate deceleration in response to tactile stimulations at the two locations. Only the pupil was influenced by the stimulated location, with a later dilation peak following CT low-density territory stimulation. Globally, ASD children exhibited reduced autonomic responses, as well as different ANS baseline values compared to TD children. These atypical ANS responses to pleasant touch in ASD children were not specific to CT-fiber stimulation. Overall, these results point towards both basal autonomic dysregulation and lower tactile autonomic evoked responses in ASD, possibly reflecting lower arousal and related to social disengagement.

Autonomic tone in children and adults: Pupillary, electrodermal and cardiac activity at rest.

Considering the suspected involvement of the autonomic nervous system (ANS) in several neurodevelopmental disorders, a description of its tonus in typical populations and of its maturation between childhood and adulthood is necessary. We aimed to arrive at a better understanding of the maturation of the sympathetic (SNS) and parasympathetic (PNS) tonus by comparing children and adults at rest, via recordings of multiple ANS indices. We recorded simultaneously pupil diameter, electrodermal activity (EDA) and cardiac activity (RR interval and HRV: heart rate variability) in 29 children (6-12 years old) and 30 adults (20-42 years old) during a 5-min rest period. Children exhibited lower RR intervals, higher LF peak frequencies, and lower LF/HF (low frequency/high frequency) ratios compared to adults. Children also produced more spontaneous EDA peaks, reflected in a larger EDA AUC (area under the curve), in comparison with adults. Finally, children displayed a larger median pupil diameter and a higher pupillary hippus frequency than adults. Our results converged towards higher SNS and PNS tones in children compared to adults. Childhood would thus be characterized by a high autonomic tone, possibly reflecting a physiological state compatible with developmental acquisitions.

Atypical Sound Perception in ASD Explained by Inter-Trial (In)consistency in EEG.

A relative indifference to the human voice is a characteristic of Autism Spectrum Disorder (ASD). Yet, studies of voice perception in ASD provided contradictory results: one study described an absence of preferential response to voices in ASD while another reported a larger activation to vocal sounds than environmental sounds, as seen in typically developed (TD) adults. In children with ASD, an absence of preferential response to vocal sounds was attributed to an atypical response to environmental sounds. To have a better understanding of these contradictions, we re-analyzed the data from sixteen children with ASD and sixteen age-matched TD children to evaluate both inter- and intra-subject variability. Intra-subject variability was estimated with a single-trial analysis of electroencephalographic data, through a measure of inter-trial consistency, which is the proportion of trials showing a positive activity in response to vocal and non-vocal sounds. Results demonstrate a larger inter-subject variability in response to non-vocal sounds, driven by a subset of children with ASD (7/16) who do not show the expected negative Tb peak in response to non-vocal sounds around 200 ms after the start of the stimulation due to a reduced inter-trial consistency. A logistic regression model with age and clinical parameters allowed demonstrating that not a single parameter discriminated the subgroups of ASD participants. Yet, the electrophysiologically-based groups differed on a linear combination of parameters. Children with ASD showing a reduced inter-trial consistency were younger and characterized by lower verbal developmental quotient and less attempt to communicate by voice. This data suggests that a lack of specialization for processing social signal may stem from an atypical processing of environmental sounds, linked to the development of general communication abilities. Discrepancy reported in the literature may arise from that heterogeneity and it may be inadequate to divide children with ASD based only on intellectual quotient or language abilities. This analysis could be a useful tool in providing complementary information for the functional diagnostic of ASD and evaluating verbal communication impairment.

A strategic plan to identify key neurophysiological mechanisms and brain circuits in autism.

Autism and Autism Spectrum Disorder (ASD) cover a large variety of clinical profiles which share two main dimensions: social and communication impairment and repetitive behaviors or restricted interests, which are present during childhood. There is now no doubt that genetic factors are a major component in the etiology of autism but precise physiopathological pathways are still being investigated. Furthermore, developmental trajectories combined with compensatory mechanisms will lead to various clinical and neurophysiological profiles which together constitute this Autism Spectrum Disorder. To better understand the pathophysiology of autism, comprehension of key neurophysiological mechanisms and brain circuits underlying the different bioclinical profiles is thus crucial. To achieve this goal we propose a strategy which investigates different levels of information processing from sensory perception to complex cognitive processing, taking into account the complexity of the stimulus and whether it is social or non-social in nature. In order to identify different developmental trajectories and to take into account compensatory mechanisms, we further propose that such protocols should be carried out in individuals from childhood to adulthood representing a wide variety of clinical forms.

High-Resolution Elastography for Thin-Layer Mechanical Characterization: Toward Skin Investigation.

Interest in elasticity estimation for thin layers is increasing because of the various potential applications, including dermatology and cosmetology. In this context, we propose a dedicated elastographic system using 1-D high-frequency transient elastography (HF-TE) to estimate the 1-D Young's modulus through the dermis and hypodermis, which are the two human skin layers of interest in this study. An experimental validation of the HF-TE method was first carried out on two homogeneous tissue-mimicking hard and soft phantoms. The Young's modulus values obtained in these phantoms were compared with those obtained by two complementary shear wave propagation techniques: shear wave-induced resonance elastography (SWIRE) and supersonic shear imaging (SSI). A third two-layer thin phantom, with mechanical properties similar to those of skin, was used to validate the ability of HF-TE to distinguish layers and measure elasticity. Finally, preliminary in vivo experiments conducted on forearm and cheek skin revealed the promising performance of HF-TE in measuring elasticity in the dermis and hypodermis.

In-vivo imaging of skin under stress: potential of high-frequency (20 MHz) static 2-D elastography.

The aim of this study was to evaluate the potential of high-frequency static two-dimensional (2-D) elastography for in vivo exploration of the mechanical behavior of skin. Our device was based on the combination of a 20 MHz sonographer and a patented extensiometer device able to apply calibrated uniaxial stretching of the skin. We used a new algorithm to compute elastograms that improve elastographic signal-to-noise ratio (SNRe) without sacrificing resolution. Mechanical behavior was described according to the axial strain and lateral displacements induced in the tissue. The efficacy of the strain anpolyvinyl alcohol first evaluated in polyvinyl alcohol (PVA)-cryogel phantoms. Several in vivo experiments then were conducted, mainly with the multistretching averaging method, and demonstrated the potential of this technique in the evaluation of mechanical behavior of the dermis and the hypodermis under stress.

Axial ultrasound B-scans of the entire eye with a 20-MHz linear array: correction of crystalline lens phase aberration by applying Fermat's principle.

In ophthalmic ultrasonography the crystalline lens is known to be the main source of phase aberration, causing a significant decrease in resolution and distortion effects on axial B-scans. This paper proposes a computationally efficient method to correct the phase aberration arising from the crystalline lens, including refraction effects using a bending ray tracing approach based on Fermat's principle. This method is used as a basis to perform eye-adapted beamforming (BF), with appropriate focusing delays for a 128-element 20-MHz linear array in both emission and reception. Implementation was achieved on an in-house developed experimental ultrasound scanning device, the ECODERM. The proposed BF was tested in vitro by imaging a wire phantom through an eye phantom consisting of a synthetic gelatin lens anatomically set up in an appropriate liquid (turpentine) to approach the in vivo velocity ratio. Both extremes of accommodation shapes of the human crystalline lens were investigated. The performance of the developed BF was evaluated in relation to that in homogeneous medium and compared to a conventional delay-and-sum (DAS) BF and a second adapted BF which was simplified to ignore the lens refraction. Global expectations provided by our method with the transducer array are reviewed by an analysis quantifying both image quality and spatial fidelity, as well as the detrimental effects of a crystalline lens in conventional reconstruction. Compared to conventional array imaging, the results indicated a two-fold improvement in the lateral resolution, greater sensitivity and a considerable reduction of spatial distortions that were sufficient to envisage reliable biometry directly in B-mode, especially phakometry.

Skin anisotropy in vivo and initial natural stress effect: a quantitative study using high-frequency static elastography.

BACKGROUND: Most studies on skin anisotropy are carried out in an "average" context, e.g. with an extension/compression test on the skin in vivo, the elastic modulus being estimated for the stretched zone overall. Furthermore, the natural tension of the skin is not taken into account either in the experimental protocols or in the models studied. In this study, a battery of elastographic tests was carried out to investigate forearm skin anisotropy quantitatively by measuring local through-thickness strain in the dermis by means of high frequency elastography. The biaxial tensile effect and influence of the natural forearm skin tension were also analyzed. METHODS: The elastographic test was carried out using a combination of an extensiometer device and a real time ultrasound scanner. The extensiometer was used to apply a stress cycle, i.e. stretching, holding and release, on the internal face of the forearm in vivo. Parallel to the mechanical test, 2D real time ultrasound acquisitions were performed to track local displacements and to estimate local through-thickness strain using an elastographic algorithm. Local through-thickness strain kinetics were then extracted and used as a quantified indicator. We studied anisotropy in two stretching situations: stretching parallel and stretching perpendicular to Langer's lines. Elastographic tests were performed for two upper arm/forearm angles, i.e. outstretched and bent forearm, in order to check the natural skin tension effect. RESULTS: The results showed the effectiveness of elastographic tests to describe and quantify the anisotropic behavior of the forearm skin in vivo. Elastographic results were distinctly different according to forearm positions: the anisotropic behavior was reversed from the bent forearm to the outstretched forearm. CONCLUSIONS: The local anisotropic behavior of the skin in vivo could be easily studied using the elastographic test. Nevertheless, the initial skin tension is an important parameter which strongly affects the mechanical behavior of the skin in vivo, in particular its anisotropic properties.

Mechanical skin thinning-to-thickening transition observed in vivo through 2D high frequency elastography.

This study was based on two dimensional (2D) high frequency elastography to describe quantitatively the mechanical behavior of the human dermis in vivo. The study was conducted on the forearm skin and elastographic tests were performed using a combination of two devices: an extensiometer developed for the in vivo study of the mechanical behavior of the skin using uniaxial stretching stress, and a 20MHz real time sonographer (Dermcup 2020™) for ultrasound skin imaging. The staggered strain estimation algorithm (SSE) was used to produce elastograms. A temporal cumulative technique was applied to improve elastogram quality and to monitor variations in skin strain during stretching. The influence of the natural skin tension controlled by arm bending was studied and distinctive mechanical behavior was observed for low and high mechanical stress levels. In a preliminary analysis, the reproducibility of measurements was assessed by means of coefficient of variation (CV) in 5 selected healthy volunteers.Finally, two hypotheses linked to the geometrical and structural properties of the dermis are proposed to account for the new findings described in this study.