BOLD signal physiology: Models and applications.

The BOLD contrast mechanism has a complex relationship with functional brain activity, oxygen metabolism, and neurovascular factors. Accurate interpretation of the BOLD signal for neuroscience and clinical applications necessitates a clear understanding of the sources of BOLD contrast and its relationship to underlying physiology. This review describes the physiological components that contribute to the BOLD signal and the steady-state calibrated BOLD models that enable quantification of functional changes with a separate challenge paradigm. The principles derived from these biophysical models are then used to interpret BOLD measurements in different neurological disorders in the presence of confounding vascular factors related to disease.

[Switching and stopping antidepressants]. / Recommandations pour switcher et arrêter les antidépresseurs.

Major depressive disorder (MDD) is a common, typically recurrent, sometimes chronic and very disabling disorder, with a lifetime prevalence of 20%. Moreover, antidepressant treatments may be partially effective. Studies have found that up to 60% of patients with MDD do not fully respond to the first antidepressant prescribed. Thus, switching antidepressants is a common strategy for antidepressant non-responders. When switching between antidepressants, an appropriate switching strategy should be used, depending on the characteristics of the first and the second antidepressant and patient's background. Patients should be informed that antidepressants can cause discontinuation symptoms if stopped abruptly after prolonged used. Relapse and exacerbation of depression can also occur during a switch. Thus, all antidepressant switches must be carried out cautiously and under close observation. This article summarizes the recommendations for an optimal antidepressant switch.

Serotonergic paraneurones in the female mouse urethral epithelium and their potential role in peripheral sensory information processing.

AIM: The mechanisms underlying detection and transmission of sensory signals arising from visceral organs, such as the urethra, are poorly understood. Recently, specialized ACh-expressing cells embedded in the urethral epithelium have been proposed as chemosensory sentinels for detection of bacterial infection. Here, we examined the morphology and potential role in sensory signalling of a different class of specialized cells that express serotonin (5-HT), termed paraneurones. METHODS: Urethrae, dorsal root ganglia neurones and spinal cords were isolated from adult female mice and used for immunohistochemistry and calcium imaging. Visceromotor reflexes (VMRs) were recorded in vivo. RESULTS: We identified two morphologically distinct groups of 5-HT+ cells with distinct regional locations: bipolar-like cells predominant in the mid-urethra and multipolar-like cells predominant in the proximal and distal urethra. Sensory nerve fibres positive for calcitonin gene-related peptide, substance P, and TRPV1 were found in close proximity to 5-HT+ paraneurones. In vitro 5-HT (1 µm) stimulation of urethral primary afferent neurones, mimicking 5-HT release from paraneurones, elicited changes in the intracellular calcium concentration ([Ca2+ ]i ) mediated by 5-HT2 and 5-HT3 receptors. Approximately 50% of 5-HT responding cells also responded to capsaicin with changes in the [Ca2+ ]i . In vivo intra-urethral 5-HT application increased VMRs induced by urethral distention and activated pERK in lumbosacral spinal cord neurones. CONCLUSION: These morphological and functional findings provide insights into a putative paraneurone-neural network within the urethra that utilizes 5-HT signalling, presumably from paraneurones, to modulate primary sensory pathways carrying nociceptive and non-nociceptive (mechano-sensitive) information to the central nervous system.

A novel interferometric method for the study of the viscoelastic properties of ultra-thin polymer films determined from nanobubble inflation.

Glass formation and glassy behavior remain as the important areas of investigation in soft matter physics with many aspects which are still not completely understood, especially at the nanometer size-scale. In the present work, we show an extension of the "nanobubble inflation" method developed by O'Connell and McKenna [Rev. Sci. Instrum. 78, 013901 (2007)] which uses an interferometric method to measure the topography of a large array of 5 µm sized nanometer thick films subjected to constant inflation pressures during which the bubbles grow or creep with time. The interferometric method offers the possibility of making measurements on multiple bubbles at once as well as having the advantage over the AFM methods of O'Connell and McKenna of being a true non-contact method. Here we demonstrate the method using ultra-thin films of both poly(vinyl acetate) (PVAc) and polystyrene (PS) and discuss the capabilities of the method relative to the AFM method, its advantages and disadvantages. Furthermore we show that the results from experiments on PVAc are consistent with the prior work on PVAc, while high stress results with PS show signs of a new non-linear response regime that may be related to the plasticity of the ultra-thin film.

Neuroimaging evidence of brain abnormalities in mastocytosis.

Mastocytosis is a rare disease in which chronic symptoms are related to mast cell accumulation and activation. Patients can display depression-anxiety-like symptoms and cognitive impairment. The pathophysiology of these symptoms may be associated with tissular mast cell infiltration, mast cell mediator release or both. The objective of this study is to perform morphological or functional brain analyses in mastocytosis to identify brain changes associated with this mast cell disorder. We performed a prospective and monocentric comparative study to evaluate the link between subjective psycho-cognitive complaints, psychiatric evaluation and objective medical data using magnetic resonance imaging with morphological and perfusion sequences (arterial spin-labeled perfusion) in 39 patients with mastocytosis compared with 33 healthy controls. In the test cohort of 39 mastocytosis patients with psycho-cognitive complaints, we found that 49% of them had morphological brain abnormalities, mainly abnormal punctuated white matter abnormalities (WMA). WMA were equally frequent in cutaneous mastocytosis patients and indolent forms of systemic mastocytosis patients (42% and 41% of patients with WMA, respectively). Patients with WMA showed increased perfusion in the putamen compared with patients without WMA and with healthy controls. Putamen perfusion was also negatively correlated with depression subscores. This study demonstrates, for we believe the first time, a high prevalence of morphological and functional abnormalities in the brains of mastocytosis patients with neuropsychiatric complaints. Further studies are required to determine the mechanism underpinning this association and to ascertain its specificity.

Radiocarbon dating minute amounts of bone (3-60 mg) with ECHoMICADAS.

Because hard tissues can be radiocarbon dated, they are key to establishing the archaeological chronologies, palaeoenvironmental reconstructions and historical-biogeographical processes of the last 50,000 years. The advent of accelerator mass spectrometers (AMS) has revolutionized the field of archaeology but routine AMS dating still requires 60-200 mg of bone, which far exceeds that of small vertebrates or remains which hold a patrimonial value (e.g. hominid remains or worked bone artefacts). Here, we present the first radiocarbon dates obtained from minute amounts of bone (3-60 mg) using a MIni CArbon DAting System (MICADAS). An optimized protocol allowed us to extract enough material to produce between 0.2 and 1.0 mg of carbon for graphite targets. Our approach was tested on known-age samples dating back to 40,000 BP, and served as proof of concept. The method was then applied to two archaeological sites where reliable dates were obtained from the single bones of small mammals. These results open the way for the routine dating of small or key bone samples.

Investigation of the confounding effects of vasculature and metabolism on computational anatomy studies.

Computational anatomy studies typically use T1-weighted magnetic resonance imaging contrast to look at local differences in cortical thickness or grey matter volume across time or subjects. This type of analysis is a powerful and non-invasive tool to probe anatomical changes associated with neurodevelopment, aging, disease or experience-induced plasticity. However, these comparisons could suffer from biases arising from vascular and metabolic subject- or time-dependent differences. Differences in blood flow and volume could be caused by vasodilation or differences in vascular density, and result in a larger signal contribution of the blood compartment within grey matter voxels. Metabolic changes could lead to differences in dissolved oxygen in brain tissue, leading to T1 shortening. Here, we analyze T1 maps and T1-weighted images acquired during different breathing conditions (ambient air, hypercapnia (increased CO2) and hyperoxia (increased O2)) to evaluate the effect size that can be expected from changes in blood flow, volume and dissolved O2 concentration in computational anatomy studies. Results show that increased blood volume from vasodilation during hypercapnia is associated with an overestimation of cortical thickness (1.85%) and grey matter volume (3.32%), and that both changes in O2 concentration and blood volume lead to changes in the T1 value of tissue. These results should be taken into consideration when interpreting existing morphometry studies and in future study design. Furthermore, this study highlights the overlap in structural and physiological MRI, which are conventionally interpreted as two independent modalities.

Pigmented skin patches without scleroderma as a predominant clinical symptom revealing systemic sclerosis.

Skin induration remains the major clinical symptom of systemic sclerosis (SSc), an autoimmune disease with potentially life-threatening visceral involvement. However, skin induration can be absent in some patients, making the diagnosis difficult to confirm and leading to delay in management. Skin pigmentation abnormalities have been reported in patients with SSc, and can be important to recognize for diagnosis. We report two patients who developed hyperpigmented skin patches without any sign of scleroderma, as a major clinical skin symptom of incipient SSc.

A new tribological experimental setup to study confined and sheared monolayers.

We have developed an original experimental setup, coupling tribology, and velocimetry experiments together with a direct visualization of the contact. The significant interest of the setup is to measure simultaneously the apparent friction coefficient and the velocity of confined layers down to molecular scale. The major challenge of this experimental coupling is to catch information on a nanometer-thick sheared zone confined between a rigid spherical indenter of millimetric radius sliding on a flat surface at constant speed. In order to demonstrate the accuracy of this setup to investigate nanometer-scale sliding layers, we studied a model lipid monolayer deposited on glass slides. It shows that our experimental setup will, therefore, help to highlight the hydrodynamic of such sheared confined layers in lubrication, biolubrication, or friction on solid polymer.

[Therapeutic effects of oxytocin in autism: Current status of the research]. / Applications thérapeutiques de l'ocytocine dans l'autisme : premiers résultats et pistes de recherche.

The neuropeptide oxytocin (OT) is an evolutionary highly conserved molecule that plays a part in the regulation of complex social cognition and behaviours. From a pathophysiological point of view, several studies have evidenced dysfunctions of the oxytocinergic system in autism spectrum disorders (ASD): a lowering of plasma OT and genetic or epigenetic anomalies of the OT receptor. Therefore, some authors have hypothesized that an abnormality in the OT neurotransmission may account for several features of autism and that a treatment restoring a normal OT pathway functioning could improve social abilities. OT administration has thus been used in clinical trials, especially in groups of subjects suffering from autism. Some studies found that OT decreased repetitive behaviours, enhanced emotional understanding of speech intonation, improved performance of the Reading the Mind in the Eyes Test and reinforced cooperation. Nevertheless, the findings of the OT administration studies on clinical samples show great diversity. The context, the personality and childhood experiences of the subject could be moderators influencing the effect of exogenous OT. Besides, three mechanisms could play a part in the action of OT on ASD social symptoms: anxiety reduction (with a lowering in the hypothalamic-pituitary-adrenal axis responsiveness and in the amygdale reactivity to social stimuli), increased affiliative motivation (involving the dopaminergic pathway and several regions of the social brain) and enhanced perceptual selectivity and social stimuli salience. To conclude, OT could be a promising molecule used as a treatment to promote social behaviours, helping individuals with ASD to develop new relationships. OT could be administered during a cognitive-behavioural therapy to reinforce the efficacy of such procedures. More studies are needed, on larger samples, to investigate the safety and efficacy of OT administration and to specify optimal dosages and characteristics of patients who may benefit from this treatment.

Increased ß2-adrenergic vasorelaxation at the early phase of endotoxemic shock in rats.

BACKGROUND AND PURPOSE: The early management of the cardiovascular dysfunction of septic shock is critical as it is associated with a poor outcome. Although the use of catecholamines is a common therapy in this syndrome, no data are available on the involvement of ß-adrenoceptor (ß-AR) subtypes and only few studies report an alteration of ß-adrenergic-induced vasodilation in septic shock. The purpose of the study was to evaluate vascular ß1, ß2 and ß3-AR expression and function in an endotoxemic rat model. EXPERIMENTAL APPROACH: Endotoxemia was induced in rats by intravenous injection of lipopolysaccharide (LPS). ß1, ß2 and ß3-AR mRNA expression was evaluated by RT-PCR in aorta and vascular ß1, ß2 and ß3-AR responses were determined on conducting (aorta) and/or resistance (mesenteric and renal) arteries by constructing relaxation curves in response to different ß-AR agonists. RESULTS: The maximal effect of isoproterenol decreased by 31 to 61% in the three vascular beds of LPS-treated rats compared to controls. In aortas from LPS-treated rats, ß1 and ß3-AR mRNA expression was decreased and associated to a reduced ß1 and ß3-induced vasodilation. Conversely, albeit ß2-AR mRNA was unchanged, the maximal ß2-AR-induced vasodilation increased by 49% in aortas from LPS-treated rats compared to controls. This increase was not affected by endothelium removal but was abolished in the presence of a ß2-AR antagonist or an adenylate cyclase inhibitor. CONCLUSIONS: In endotoxemia, ß2-AR vasodilation was increased by a potential recruitment of ß2-AR located on smooth muscle cells. This study suggests that vascular ß2-AR should be a putative new therapeutic target in septic shock.

Circulating CXCR5+CD4+helper T cells in systemic lupus erythematosus patients share phenotypic properties with germinal center follicular helper T cells and promote antibody production.

OBJECTIVE: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies. Recently, a specific highly activated T helper cell subset, follicular helper T (Tfh) cell, has emerged as a key immunoregulator of germinal center (GC) formation and high-affinity antibody production. To identify the pathophysiological role of Tfh cells in SLE patients, we compared the phenotypic and functional properties of circulating Tfh-like cells in lupus patients to GC-Tfh cells, and correlated the percentage of Tfh-like cells with autoantibody production and SLE disease activity. METHODS: Peripheral blood was collected from 29 lupus patients and 25 healthy controls. Tonsils were obtained surgically from non-SLE controls and used as a source of GC-Tfh cells. Tfh cells were defined by their signature surface markers (CXCR5, ICOS, CD57, PD-1 and BTLA) via flow cytometry. IL-21 expression levels from Tfh cells were measured by real-time PCR and intracellular staining. The function of Tfh cells was carried out by co-culture of Tfh cells and autologous B cells in vitro. IgG in the culture supernatant was detected by ELISA. RESULTS: The frequency of circulating Tfh-like cells was significantly increased in SLE patients compared to healthy controls (p < 0.05). The Tfh-like cells not only display similar phenotypes and signature cytokines with GC-Tfh cells, but also are capable of driving B cells to differentiate into IgG-secreting plasma cells in vitro. In addition, the frequency of Tfh-like cells correlated positively with the percentage of circulating plasmablasts, levels of serum anti-dsDNA antibodies and ANA. CONCLUSION: The accumulated circulating Tfh-like cells in lupus patients share phenotypic and functional properties with GC-Tfh cells. Tfh-like cells may serve as perpetuators in the pathogenesis of SLE by enhancing the self-reactive B cell clones to further differentiate into auto antibody-producing plasmablasts, and ultimately cause autoimmunity.

Surgical management of Moyamoya disease and syndrome: Current concepts and personal experience.

In this focus, we review, in the light of the recent literature, the modalities and indications of surgical cerebral revascularization for Moyamoya (MM) disease or syndrome. We also report our experience in the surgical management of adult MM. In symptomatic forms, with presence of severe disturbances of perfusion or cerebrovascular reactivity on multimodal imaging work-up, the risks of recurrent ischemic or hemorrhagic stroke is high (respectively 10-13%/yr and 2-7%/yr). The objective of treatment is to augment cerebral perfusion (in ischemic forms) or to reduce lenticulo-striate neovessel overload (in hemorrhagic forms), by initiating the development of a cortical neovascularization and/or by directly increasing cerebral blood flow. The risk of immediate postoperative death or stroke is similar between indirect and direct or combined techniques and respectively 0-0.5% and 3-6%, provided a strict perioperative anesthetic management is applied (normocapnia, normoxia and controlled hypertension). Indirect techniques (i.e. encephalo-duro-arterio-myo-periosteo-synangiosis or multiple burr-holes) are technically easy, allow wide cortical revascularization and are very efficient in children: absence of clinical recurrence in more than 95% of cases and presence of a good neovascularization in 83%. However, their effect is delayed for several months, the impact on the hemorrhagic risk is moderate and the global response is uncertain in adults. Direct (superficial temporal artery to middle cerebral artery bypass) or combined techniques improve cerebral blood flow immediately and significantly. They are associated with a higher rate of stroke-free survival at 5 years (95% vs 85%). A recent randomized study has proven that they could reduce the hemorrhagic risk by 2- to 3-fold in comparison with conservative treatment alone. However, their feasibility in children is limited by the very small size of vessels. We present also our results in the surgical management of 12 adult MM patients (mean age 41.3, sex ratio=1) operated between 2009 and 2014 (14 revascularization procedures: EDAMS 2, multiple burr-holes 1, combined revascularization procedures 11). MM types according to clinical presentation were the following: ischemic 8, hemorrhagic 2, combined 2. All patients were recently symptomatic, with recurrent ischemic/hemorrhagic events (2/3) or crescendo neurological deficit (1/3) in association with severe alterations of cerebral blood flow. Mean clinical and radiological follow-up was 22 months. Postoperative mRS at 6 months was improved or stable in 92%. None of the patients suffered recurring stroke. In conclusion, surgical treatment should be discussed quickly in symptomatic forms of MM (progressive or recurring) because of their poor outcome. Indirect techniques are favored in pediatric patients due to their simplicity and good clinical results. Direct, or preferentially combined techniques would be more effective in adult patients to prevent the recurrence of ischemic or hemorrhagic stroke.

Evaluation of the accuracy of a veterinary dynamometric wire tensioner.

OBJECTIVES: The purpose of this study was to determine the accuracy of a commonly used veterinary wire tensioner. METHODS: Wire tension was measured using a load cell after each of five tensioners were used to tension each of six wires to the 66, 84, and 118 mm ring settings in an adjustable custom testing fixture. Each tensioner then experienced simulated aging and testing was repeated. Percentage error was calculated for each ring size, before and after tensioner aging. Measured tension values were compared to manufacturer reported tension values for each ring size using a one-sample two-way t-test; p <0.05 was considered significant. RESULTS: Compared to the manufacturer reported values, measured wire tension values were significantly lower for 66 mm and 84 mm rings and significantly higher for 118 mm rings, before and after simulated aging. Mean wire tension values did not significantly differ between individual wire tensioners. CLINICAL SIGNIFICANCE: The tensioners tested achieved significantly different wire tension values than those reported by the manufacturer. This discrepancy could lead to under-tensioning and allowing excessive movement at a fracture site or over-tensioning, leading to wire breakage. We recommend tensioning wires at least to the recommended line on the device for 66 mm and 84 mm rings and at most to the recommended line for 118 mm rings. Further studies are needed to evaluate other veterinary wire tensioners and to develop a calibration method for these devices in practice.

The effect of surgically assisted rapid maxillary expansion on sleep architecture: an exploratory risk study in healthy young adults.

Maxillary transverse deficiencies (MTD) cause malocclusions. Rapid maxillary expansion treatment is commonly used treatment for correcting such deficiencies and has been found to be effective in improving respiration and sleep architecture in children with obstructive sleep apnoea (OSA). However, thus far, the effect of surgically assisted rapid maxillary expansion (SARME) treatment on sleep architecture and breathing of normal subjects has not been assessed. We hypothesised that sleep quality will improve after maxillary expansion treatment. The objective of this study is to access the effect of maxillary expansion treatment on sleep structure and respiratory functions in healthy young adults with severe MTD. This is a prospective and exploratory clinical study. Twenty-eight consecutive young adult patients (15 males and 13 females, mean age 20·6 ± 5·8 years) presenting with severe MTD at the orthodontic examination were recruited into the study. All the participants underwent a standardised SARME procedure (mean expansion 6·5 ± 1·8 and 8·2 ± 1·8 mm, intercanine and intermolar distance, respectively) to correct malocclusion caused by MTD. An overnight in-laboratory polysomnography, before and after the treatment, was performed. The mean follow-up time was 9 months. The main outcome parameters were the changes in sleep architecture, including sleep stages, arousals, slow-wave activity (SWA) and respiratory variables. Before surgery, young adult patients with MTD presented no evidence of sleep breathing problems. At baseline sleep recording, 7 of 28 (25%) had apnoea-hypopnoea index (AHI) ≥ 5 events per hour. No negative effect of the SARME was observed in questionnaires or sleep laboratory parameters. In the patients with a higher baseline AHI (AHI ≥ 5 h of sleep), we observed a reduction in AHI after surgical treatment (P = 0·028). SARME did not have a negative effect on any sleep or respiration parameters in healthy young individuals with MTD. It normalised the breathing index in the patients with a mild AHI index.

Comparison of the axial stiffness of carbon composite and aluminium alloy circular external skeletal fixator rings.

OBJECTIVES: The purpose of this study was to compare the axial stiffness of aluminium alloy and carbon composite single-ring constructs. METHODS: Single-ring constructs were made with rings of different material compositions (aluminium alloy and carbon composite), diameters (55 mm, 85 mm, and 115 mm), and thicknesses (6 mm for the single-ring, 12 mm for the double-ring) with all other components remaining constant. Stiffness of each construct was determined under loading in axial compression with a materials testing machine. The axial stiffness of each group was compared using a three-factor factorial analysis of variance investigating all main effects and interactions between ring diameter, ring thickness, and ring material composition; p <0.05 was considered significant. RESULTS: Carbon composite constructs were 16-55% as stiff as corresponding aluminium alloy constructs. Within each combination of ring material composition and ring diameter, stiffness did not significantly increase when the ring thickness was doubled. Within each combination of ring material composition and ring thickness, stiffness significantly decreased with increased ring diameter. CLINICAL SIGNIFICANCE: Aluminium alloy rings were found to be significantly stiffer than carbon composite rings. Although the carbon composite rings were considerably less stiff, clinical recommendations cannot be made from a single-ring in vitro analysis. Further studies are needed to evaluate the behaviour of these rings in vivo.

Analysis of local properties during a scratch test on a polymeric surface using molecular dynamics simulations.

This work demonstrates a possible route to connect a particle (chain) based understanding with continuum mechanical questions about contact mechanics. The bond orientation, chain conformation and stress field of a polymer film were analyzed during scratch tests (tangential contact) using a molecular dynamics (MD) simulation approach. Scratch tests with a conical tip at constant scratching velocity were simulated on linear amorphous polymer surfaces at various temperatures and roughnesses of the tip and for various interactions between the tip and the particles of the polymer chains. The second Legendre polynomial (computed for small domains around the tip) gave the bond orientation inside the polymer film during sliding of the tip. The gyration tensor (layer-resolved in the direction of the polymer film thickness) provided information about the conformation of the polymer chains. These results allowed us to argue in favor of Briscoe's hypothesis (thin film sheared vs. "bulk" compressive behavior) concerning the friction properties of the polymer surfaces. Finally, the first stress measurements of the virial stress tensor (in sub-boxes placed in the MD cell) revealed a complex combination between compressive hydrostatic pressure and shear stress, which may be interpreted as a complex sheared domain at the interface.

Absolute quantification of resting oxygen metabolism and metabolic reactivity during functional activation using QUO2 MRI.

We have recently described an extension of calibrated MRI, which we term QUO2 (for QUantitative O(2) imaging), providing absolute quantification of resting oxidative metabolism (CMRO(2)) and oxygen extraction fraction (OEF(0)). By combining BOLD, arterial spin labeling (ASL) and end-tidal O(2) measurements in response to hypercapnia, hyperoxia and combined hyperoxia/hypercapnia manipulations, and the same MRI measurements during a task, a comprehensive set of vascular and metabolic measurements can be obtained using a generalized calibration model (GCM). These include the baseline absolute CBF in units of ml/100g/min, cerebrovascular reactivity (CVR) in units of %Δ CBF/mm Hg, M in units of percent, OEF(0) and CMRO(2) at rest in units of µmol/100g/min, percent evoked CMRO(2) during the task and n, the value for flow-metabolic coupling associated with the task. The M parameter is a calibration constant corresponding to the maximal BOLD signal that would occur upon removal of all deoxyhemoglobin. We have previously shown that the GCM provides estimates of the above resting parameters in grey matter that are in excellent agreement with literature. Here we demonstrate the method using functionally-defined regions-of-interest in the context of an activation study. We applied the method under high and low signal-to-noise conditions, corresponding respectively to a robust visual stimulus and a modified Stroop task. The estimates fall within the physiological range of literature values, showing the general validity of the GCM approach to yield non-invasively an extensive array of relevant vascular and metabolic parameters.