In-vivo Measures Research Articles

Rationale and protocol of a double-blind, randomized, placebo-controlled trial to test the efficacy, safety, and tolerability of dimethyl fumarate in Friedreich Ataxia (DMF-FA-201).

Friedreich Ataxia (FRDA) is an autosomal recessive neurodegenerative disorder that causes gait and limb ataxia, dysarthria, and impaired vibratory sense, with cardiomyopathy being the predominant cause of death. There is no approved therapy, which results in the use of symptomatic treatments and the chronic support of physiotherapy. Dimethyl fumarate (DMF) is a fumaric acid ester used for the treatment of psoriasis and Multiple Sclerosis (MS). It induces Nrf2 in vitro and in vivo, and it increases frataxin in FRDA patient lymphoblasts, in mouse models, and in MS treated patients. The aim of our study is to investigate if DMF can increase the expression of the FXN gene and frataxin protein and ameliorate in-vivo detectable measures of mitochondrial dysfunction in FRDA. The study is composed of a screening visit and two sequential 12-week phases: a core phase and an extension phase. During the first phase (core), patients will be randomly assigned to either the DMF or a placebo group in a 1:1 ratio. During the first week, patients will receive a total daily dose of 240 mg of DMF or placebo; from the second week of treatment, the dose will be increased to two 120 mg tablets BID for a total daily dose of 480 mg. During the second phase (extension), all patients will be treated with DMF. EudraCT number 2021-006274-23. The primary endpoint will be a change in FXN gene expression level after 12 weeks of treatment. Secondary endpoints will be frataxin protein level, cardiopulmonary exercise test outputs, echocardiographic measures, Nrf2 pathway and mitochondrial biogenesis gene expression, safety, clinical scales, and quality of life scales. This is the first study aimed at exploring the ability of DMF, an already available treatment for MS and psoriasis, to correct the biological deficits of FRDA and potentially improve mitochondrial respiration in-vivo.

Combined proliferation and apoptosis index provides better risk stratification in breast cancer.

Breast cancer (BC) risk stratification is critical for predicting behaviour and guiding management decision-making. Despite the well-established prognostic value of cellular proliferation in BC, the interplay between proliferation and apoptosis remains to be defined. In this study, we hypothesised that the combined proliferation and apoptosis indices can provide a more accurate in-vivo growth rate measure and a precise prognostic predictor. Apoptotic and mitotic figures were counted in whole slide images (WSI) generated from haematoxylin and eosin-stained sections of 1545 BC cases derived from two well-defined BC cohorts. Counts were carried out visually within defined areas. There was a significant correlation between mitosis and apoptosis scores. High apoptotic counts were associated with features of aggressive behaviour, including high grade, high pleomorphism score and hormonal receptor negativity. Although the mitotic index (MI) and apoptotic index (AI) were independent prognostic indicators, the prognostic value was synergistically higher when combined. BCpatients with a high combined AI and MI had theshortest survival. Replacing the mitosis score with the mitosis-apoptosis index in the Nottingham grading system revealed that the modified grade with the new score had a higher significant association with BC-specific survival with a higher hazard ratio. Apoptotic figures count provides additional prognostic value in BC when combined with MI; such a combination can be implemented to assess the behaviour of BC and provides an accurate prognostic indicator. This can be considered when using artificial intelligence algorithms to assess proliferation in BC.

Decoding foot deformity and joint-destruction pathways in diabetes: Emerging insights from in-vivo foot joint kinetic measures

BackgroundA comprehensive insight into the effect of longstanding diabetes mellitus and neuropathy on foot joint kinetics during walking is lacking. Our goal was to assess the in-vivo kinetics of major foot joints in persons with diabetes. MethodsThree groups, matched for age, sex and walking speed were recruited in this study: 1) people with diabetic peripheral neuropathy, 2) people with diabetes without peripheral neuropathy, and 3) control subjects without diabetes. Participants were instrumented with retroreflective markers on both feet and lower limbs and underwent a barefoot gait analysis using a state-of-the-art multi-segment kinetic foot modelling approach in order to provide accurate joint loading measures at the ankle, midtarsal, tarso-metatarsal and hallux joints. FindingsThe group with neuropathy showed reduced ankle peak plantarflexion angular velocity compared to the control group (P = 0.002). Both groups with diabetes showed a significantly reduced midtarsal peak plantarflexion angular velocity, peak power generation and positive work compared to the control group (p < 0.01). Groups showed significant differences with respect to the tarsometatarsal peak dorsiflexion (p = 0.006) and plantarflexion angular velocity (P < 0.05). InterpretationThis study shows that both diabetes groups have similar joint loading and power absorption capacity but seem to lose their power generation capacity especially at the midtarsal joint. This loss of power generation capacity and the resulting decreased net mechanical work of the foot potentially embodies a foot that poorly supplements the body's mechanical energy during push-off. This phenomenon may cause excessive tissue stresses that contribute to foot deformity and joint-destruction mechanisms.

Investigating the contribution of cytoarchitecture to diffusion MRI measures in gray matter using histology.

Postmortem studies are currently considered a gold standard for investigating brain structure at the cellular level. To investigate cellular changes in the context of human development, aging, or disease treatment, non-invasive in-vivo imaging methods such as diffusion MRI (dMRI) are needed. However, dMRI measures are only indirect measures and require validation in gray matter (GM) in the context of their sensitivity to the underlying cytoarchitecture, which has been lacking. Therefore, in this study we conducted direct comparisons between in-vivo dMRI measures and histology acquired from the same four rhesus monkeys. Average and heterogeneity of fractional anisotropy and trace from diffusion tensor imaging and mean squared displacement (MSD) and return-to-origin-probability from biexponential model were calculated in nine cytoarchitectonically different GM regions using dMRI data. DMRI measures were compared with corresponding histology measures of regional average and heterogeneity in cell area density. Results show that both average and heterogeneity in trace and MSD measures are sensitive to the underlying cytoarchitecture (cell area density) and capture different aspects of cell composition and organization. Trace and MSD thus would prove valuable as non-invasive imaging biomarkers in future studies investigating GM cytoarchitectural changes related to development and aging as well as abnormal cellular pathologies in clinical studies.

Computational and Experimental Approaches for Evaluating Dose under a Block in TBI Geometry

Total Body Irradiation (TBI) patients are often treated at extended distances of several meters, with blocking made from high-Z materials placed close to the patients’ skin. Evaluating the dose under a block (e.g., for implanted medical device shielding purposes) in such a geometry is challenging. We compare the performance of two commonly used dose calculation algorithms, Anisotropic Analytical Algorithm (AAA) and Acuros XB, with Optically Stimulated Lumine- scence (OSLD) and ion chamber measurements in phantoms. The calculations and phantom measurements are also compared with in-vivo OSLD measure- ments. We find that OSLD and ion chamber measurements in phantom are good predictors of in-vivo measurements, while both AAA and Acuros XB sys- tematically overestimate the block transmission. We found Acuros XB to be accurate enough for a rough upper estimate (dose under block overestimated by 7% - 22%), while for AAA the overestimate was more severe (90% - 110%); the reason is that AAA does not account for the increase in pair production cro- ss-section in high-Z materials.

Perspectives on the translation of in-vitro studies to precision medicine in Cystic Fibrosis.

Recent strides towards precision medicine in Cystic Fibrosis (CF) have been made possible by patient-derived in-vitro assays with the potential to predict clinical response to small molecule-based therapies. Here, we discuss the status of primary and stem-cell derived tissues used to evaluate the preclinical efficacy of CFTR modulators highlighting both their potential and limitations. Validation of these assays requires correlation of in-vitro responses to in-vivo measures of clinical biomarkers of disease outcomes. While initial efforts have shown some success, this translation requires methodologies that are sensitive enough to capture treatment responses in a CF population that now predominantly has mild lung disease. Future development of in-vitro and in-vivo biomarkers will facilitate the generation of new therapeutics particularly for those patients with rare mutations where clinical trials are not feasible so that in the future every CF patient will have access to effective targeted therapies.

174 The effect of a microbial Muramidase on peptidoglycan content in the gut of swine using in-vitro and in-vivo measures

Abstract Bacterial debris in the gastrointestinal tract (GIT) are continuously being produced by the microbiota present upon bacterial division and death. One of the most abundant components in bacterial debris are peptidoglycans (PGN), a structural cell wall component in gram- positive and negative bacteria. The objective of this work was to investigate if addition of a novel microbial muramidase (Muramidase 007; MUR) that hydrolyzes PGN, would reduce PGN adhesion to porcine intestinal cells in-vitro and hydrolyze PGN in the GIT of swine. Adhesion efficacy of intact and MUR hydrolyzed fluorescein-isothiocyanate (FITC)-labelled PGN were compared using fluorescence-microscopy (3 wells/condition). Catalytic performance of MUR on intact FITC-labelled PGN adhered to intestinal cells were also tested. In-vivo MUR-supplementation at 50,000 LSU/kg diet to gestating and lactating sows and/or their subsequent offspring for 42-d post-weaning was investigated. Mass-spectroscopy was used to quantify soluble and total muramic acid, which is only found in PGN, in the ileal and cecal digesta (8 piglets/treatment) to calculate percentage soluble-PGN. Cell-culture data were analyzed using GraphPad-Prism 8.0 and in-vivo data using mixed-models in JMP 14.0. MUR hydrolyzed PGN adhered 10x less to the IPEC-J2 cell line culture compared to intact-PGN (P&amp;lt; 0.05). In addition, data show that MUR hydrolyzed PGN attached to cell surfaces by 2x, as attached PGN were also reduced by 50% following MUR incubation (P&amp;lt; 0.05). Offering sows MUR-diets had no carryover effect on the percentage soluble PGN in their piglets’ digesta, and there were no interactions observed for sow x piglet x tract neither (P &amp;gt;0.05). Percentage soluble-PGN increased in piglets fed MUR compared to control-piglets (47.18 vs. 29.84% SEM:1.624; P&amp;lt; 0.001) and was higher in cecal digesta compared to ileal digesta (49.91 vs. 27.11%; SEM:1.634; P&amp;lt; 0.001), irrespective of MUR-supplementation. These results suggest that MUR may reduce PGN adhesion to intestinal cells and may hydrolyze PGN found in the GIT.

A wide field-of-view, modular, high-density diffuse optical tomography system for minimally constrained three-dimensional functional neuroimaging.

The ability to produce high-quality images of human brain function in any environment and during unconstrained movement of the subject has long been a goal of neuroimaging research. Diffuse optical tomography, which uses the intensity of back-scattered near-infrared light from multiple source-detector pairs to image changes in haemoglobin concentrations in the brain, is uniquely placed to achieve this goal. Here, we describe a new generation of modular, fibre-less, high-density diffuse optical tomography technology that provides exceptional sensitivity, a large dynamic range, a field-of-view sufficient to cover approximately one-third of the adult scalp, and also incorporates dedicated motion sensing into each module. Using in-vivo measures, we demonstrate a noise-equivalent power of 318 fW, and an effective dynamic range of 142 dB. We describe the application of this system to a novel somatomotor neuroimaging paradigm that involves subjects walking and texting on a smartphone. Our results demonstrate that wearable high-density diffuse optical tomography permits three-dimensional imaging of the human brain function during overt movement of the subject; images of somatomotor cortical activation can be obtained while subjects move in a relatively unconstrained manner, and these images are in good agreement with those obtained while the subjects remain stationary. The scalable nature of the technology we described here paves the way for the routine acquisition of high-quality, three-dimensional, whole-cortex diffuse optical tomography images of cerebral haemodynamics, both inside and outside of the laboratory environment, which has profound implications for neuroscience.

Abstract TP485: Aortic Stiffness Detrimental Effect in Brain Blood Flow Autoregulation

Background: Cerebral hemodynamic dysfunction is associated with brain small artery disease and poorer cognition. With aging, systemic arteries stiffen, magnifying the spread of pulsatility to distal organs. The brain is especially susceptible to pulsatility due to low impedance to flow. Increased pulsatility causes abnormal brain arteriolar remodeling in animal models. Therefore, we hypothesize that measures of aortic stiffness relate to poorer cerebral autoregulation, an in-vivo measure of arteriolar function. Methods: We recruited participants in the Washington Heights-Inwood Community Aging Project for this study. For autoregulation, both middle cerebral arteries were insonated at a depth of 50-58 mm. End-tidal CO2 (EtCO2) was measured continuously with a facemask. After ten minutes of baseline recording, a mixture of air enriched with 5% CO2 was administered through the facemask for 2 minutes. Cerebrovascular reactivity was calculated as % change in mean CBFV (mCBFV) per 1 mm increase in mean EtCO2 during CO2 inhalation. We averaged the right and left CO2 reactivity percentage. For aortic stiffness, we acquired carotid-femoral pulse wave velocity (cfPWV) with non-invasive oscillometry using the Vicorder system (Skidmore Medical Limited, Bristol, UK). We used generalized linear model to obtain beta estimates of the association between CO2 reactivity and cfPWV. Results: We included 158 participants (mean age 77±6.4 years, 67% women, 40% non-Hispanic black, 38% non-Hispanic white, and 20% Hispanic). Hypertension was present in 54% of the participants. cfPWV was associated with poorer CO2 reactivity (B=-0.038, P=0.047), independent of age, sex, ethnicity, and hypertension. Brachial pulse pressure (B=0.007, P=0.38) and mean arterial pressure (B=-0.017, P=0.21) were not associated with CO2 reactivity, and adding brachial pulse pressure and mean arterial pressure to the adjusted model did not change the association between cfPWV and poorer CO2 reactivity. Conclusions: Aortic stiffness is associated with poorer CO2 reactivity independent of traditional measures of hypertension, a marker of cerebral autoregulation and arteriolar health. Poorer CO2 reactivity may mediate the reported effects of aortic stiffness on brain outcomes.

Sonographic and 3T-MRI-based evaluation of the tongue in ALS

A few systematic imaging studies employing ultrasound (HRUS) and magnetic resonance imaging (MRI) have suggested tongue measures to aid in diagnosis of amyotrophic lateral sclerosis (ALS). The relationship between structural tongue alterations and the ALS patients' bulbar and overall motor function has not yet been elucidated. We here thus aimed to understand how in-vivo tongue alterations relate to motor function and motor function evolution over time in ALS. Our study included 206 ALS patients and 104 age- and sex-matched controls that underwent HRUS and 3T MRI of the tongue at baseline. Sonographic measures comprised coronal tongue echointensity, area, height, width and height/width ratio, while MRI measures comprised sagittal T1 intensity, tongue area, position and shape. Imaging-derived markers were related to baseline and longitudinal bulbar and overall motor function. Baseline T1 intensity was lower in ALS patients with more severe bulbar involvement at baseline. Smaller baseline coronal (HRUS) and sagittal (MRI) tongue area, smaller coronal height (HRUS) and width (HRUS) as well as more rounded sagittal tongue shape predicated more rapid functional impairment - not only of bulbar, but also of overall motor function - in ALS. Our results suggest that in-vivo sonography und MRI tongue measures could aid as biomarkers to reflect bulbar and motor function impairment.

Applying the D50 disease progression model to gray and white matter pathology in amyotrophic lateral sclerosis.

Therapeutic management and research in Amyotrophic Laterals Sclerosis (ALS) have been limited by the substantial heterogeneity in progression and anatomical spread that are endemic of the disease. Neuroimaging biomarkers represent powerful additions to the current monitoring repertoire but have yielded inconsistent associations with clinical scores like the ALS functional rating scale. The D50 disease progression model was developed to address limitations with clinical indices and the difficulty obtaining longitudinal data in ALS. It yields overall disease aggressiveness as time taken to reach halved functionality (D50); individual disease covered in distinct phases; and calculated functional state and calculated functional loss as acute descriptors of local disease activity. It greatly reduces the noise of the ALS functional rating scale and allows the comparison of highly heterogeneous disease and progression subtypes. In this study, we performed Voxel-Based Morphometry for 85 patients with ALS (60.1±11.5 years, 36 female) and 62 healthy controls. Group-wise comparisons were performed separately for gray matter and white matter using ANCOVA testing with threshold-free cluster enhancement. ALS-related widespread gray and white matter density decreases were observed in the bilateral frontal and temporal lobes (p<0.001, family-wise error corrected). We observed a progressive spread of structural alterations along the D50-derived phases, that were primarily located in frontal, temporal and occipital gray matter areas, as well as in supratentorial neuronal projections (p<0.001 family-wise error corrected). ALS patients with higher overall disease aggressiveness (D50 < 30 months) showed a distinct pattern of supratentorial white matter density decreases relative to patients with lower aggressiveness; no significant differences were observed for gray matter density (p<0.001 family-wise error corrected). The application of the D50 disease progression model separates measures of disease aggressiveness from disease accumulation. It revealed a strong correlation between disease phases and in-vivo measures of cerebral structural integrity. This study underscores the proposed corticofugal spread of cerebral pathology in ALS. We recommend application of the D50 model in studies linking clinical data with neuroimaging correlates.

68Ga]-Dota Peptide PET/CT in Neuroendocrine Tumors: Main Clinical Applications.

Neuroendocrine Neoplasms (NENs) are generally defined as rare and heterogeneous tumors. The gastrointestinal system is the most frequent site of NENs localization, however they can be found in other anatomical regions, such as pancreas, lungs, ovaries, thyroid, pituitary, and adrenal glands. Neuroendocrine neoplasms have significant clinical manifestations depending on the production of active peptide. Imaging modalities play a fundamental role in initial diagnosis as well as in staging and treatment monitoring of NENs, in particular they vastly enhance the understanding of the physiopathology and diagnosis of NENs through the use of somatostatin analogue tracers labeled with appropriate radioisotopes. Additionally, the use of somatostatin analogues provides the ability to in-vivo measure the expression of somatostatin receptors on NEN cells, a process that might have important therapeutic implications. A large body of evidences showed improved accuracy of molecular imaging based on PET/CT radiotracer with SST analogues (e.g. [68Ga]-DOTA peptide) for the detection of NEN lesions in comparison to morphological imaging modalities. So far, the role of imaging technologies in assessing treatment response is still under debate. This review offers the systems of classification and grading of NENs and summarizes the more useful recommendations based on data recently published for the management of patients with NENs, with special focus on the role of imaging modalities based on SST targeting with PET / CT radiotracers.

Discrepancy between in-vivo measure and ex-vivo calculation of pulse wave velocity in retinal arteries

BackgroundPulse wave velocity (PWV) in large arteries is a pressure-dependent marker of arterial stiffness. The retinal vasculature provides unique access to the microcirculation. There is inconsistency between reported values of retinal PWV (rPWV). The pressure dependency of rPWV was measured in-vivo and calculated ex-vivo using retinal artery material properties to investigate the inconsistencies.MethodsHigh-speed fundus videos (125 fps) from three Sprague Dawley rats were recorded simultaneously with electrocardiogram and blood pressure. rPWV was measured using the cardiac component of retinal artery diameter waveforms at two retinal sites across a physiological range (70–130 mmHg) of mean arterial pressure (MAP). Ex-vivo tensile testing was performed on bovine retinal arteries, rat retinal arteries being too small for myography. Diameter and wall thickness of the retinal artery adjacent to the optic disc were measured using optical coherence tomography. Tensile testing was performed using a wire myograph in 9 bovine retinal artery specimens.ResultsIn-vivo results showed a significant positive correlation between rPWV (4.9 ±1.8 mm/s) and MAP (R2 = 0.58, p < 0.001) as expected. Ex-vivo, calculated rPWV using material stiffness and geometry measurement ranged between 4.6 and 7.0 m/s at effective distending pressures between 70 and 100 mmHg.ConclusionsEx-vivo and in-vivo results differed by three orders of magnitude but should be the same. Ex-vivo results are in the same order as measured in-vivo in large arteries. In-vivo rPWV was lower than expected yet was responsive to changes in MAP. Further studies are required to uncover what rPWV is a measurement of, if not arterial stiffness.

Effect of aging on tibiofemoral cartilage and meniscus stiffness constant

Purpose: Current clinical diagnostics of knee osteoarthritis (OA) are ineffective at detecting and monitoring early signs of joint degeneration. Measuring the deformation of knee soft tissue under loading could provide a more sensitive measure to detect OA earlier in the disease process. The objective of this research was to develop a novel in-vivo method to determine a cartilage-meniscus (C-M) stiffness constant using dual fluoroscopy (DF) and magnetic resonance (MR) imaging. Further, this study investigated the hypothesis that a C-M constant differs significantly with age in healthy males, with the goal of using these healthy participants as age-matched controls in further clinical research. Methods: Ten healthy males (n=5, 20-30 yrs old; n=5, 50-60 yrs old) with no history of lower limb injury or surgery volunteered for participation. The study was approved by the local ethics board (REB15-0554) and informed consent was obtained for all participants. Participants were non-weight bearing for a minimum of one hour prior to MR imaging. A high resolution MR scan (3T Discovery 750, GE USA) was conducted to generate subject-specific 3D bone and cartilage models in Amira (FES, Germany); scan parameters: slice thickness 1 mm; between slice spacing 0.5 mm; field of view 24x24 cm; matrix 512x512 pixels; number of slices 200; echo time 2.32 ms; repetition time 7.513 ms; flip angle 35°; acquisition time 2ʹ45ʺ. Thereafter, participants were assisted by wheelchair to the DF lab, where they were fit with a custom knee brace. Participants stood on the contralateral limb and shifted their weight to the test limb on instruction. Standing weight bearing DF images (0.155 mm x 0.155 mm) were collected at 20 Hz for 5 min (1 min continuously, 30 sec intervals [2 sec duration each] for the remaining 4 minutes). Image distortion correction and calibration was conducted using software tools by Brown University, USA and custom written code in Matlab (v2016b, MathWorks, USA). Bone kinematics were reconstructed using 2D-3D registration in Joint Track Biplane (University of Florida, USA). Bone kinematics obtained from registration were then applied to co-registered cartilage models to calculate cartilage motion. C-M deformations were estimated as the change in median proximity of all femoral cartilage model faces, with respect to the tibial cartilage, at each DF frame collected. Ground reaction forces were collected using an instrumented treadmill (Bertec, USA). The force acting at the knee was determined as the vertical ground reaction force minus the weight applied by the foot and shank of the imaged limb. The C-M constant (analogous to a measure of soft tissue stiffness during continuous loading) was calculated as the median change in force divided by the change in median proximity. This median value was calculated between 10 seconds and 5 minutes of the standing loading trial. A 2-tailed Mann Whitney U non-parametric t-test was performed in SPSS to determine differences between the C-M constant between younger and older age groups. Results: C-M constant was found to significantly increase by 12.51 N/mm (p=0.009) with age. The 20-30 year old group median was 3.39 N/mm (interquartile range (IQR)=2.01-7.29 N/mm) while the 50-60 year old group median was 15.90 N/mm (IQR=11.35-21.17 N/mm) (Figure 1). Conclusions: The finding of a significant increase in the C-M stiffness constant with age indicates this novel in-vivo measure may be a sensitive tool for detecting differences in soft-tissue mechanical properties. Greater variance in the C-M stiffness value in the older group may also demonstrate greater variability in cartilage mechanical properties with age. Further research will be conducted to validate the C-M constant methodology using a porcine joint model to inform future clinical research applications.

Blood biomarkers of expressed and inducible HIV-1.

To define the relationships between molecular measures of viral persistence in blood (i.e., plasma viremia, cellular HIV-1 DNA, and mRNA) and expressed or inducible virus from resting CD4 T cells of individuals on suppressive antiretroviral therapy. We compared molecular measurements of HIV-1 in plasma and in uncultured peripheral blood mononuclear cells (PBMCs) to the levels of virions produced by either unstimulated or phorbol myristate acetate and ionomycin (PMA/iono)-stimulated PBMC or resting CD4 T cells from 21 donors on suppressive antiretroviral therapy. We found that unstimulated virion release from cultured resting CD4 T cells was positively correlated with the levels of plasma viremia in vivo (Spearman rho = 0.67, P = 0.0017). We also found that levels of both cellular HIV-1 DNA and unspliced HIV-1 mRNA per million uncultured PBMC were positively correlated with the levels of inducible virion release from both PMA/iono-stimulated PBMC (total HIV-1 DNA: rho = 0.64, P = 0.0017; unspliced HIV-1 RNA: rho = 0.77, P < 0.001) and PMA/iono-stimulated resting CD4 T cells (total HIV-1 DNA: rho = 0.75, P < 0.001; unspliced HIV-1 RNA: rho = 0.75, P < 0.001). These results show for the first time that there are strong associations between in-vivo measures of HIV-1 persistence and ex-vivo measures of spontaneous and inducible virus production from cultured PBMC and resting CD4 T cells. Findings from this study provide insight into the biology of HIV-1 persistence and suggest methods to guide the evaluation of clinical strategies to reduce the size of the viral reservoir.

53: MRI measurements of abnormal placental oxygenation in pregnancies complicated by FGR

Antenatal identification of pathological growth restriction as opposed to small-for-gestational-age remains a significant challenge for clinicians. In-vivo measures of placental function may aid identification. Oxygen-Enhanced (OE) and Blood-Oxygen-Level Dependent (BOLD) MRI can measure changes in placental pO2 and oxygen saturation respectively. Our aim was to evaluate these placental parameters in normal pregnancies and those complicated by fetal growth restriction (FGR), as potential biomarkers of placental dysfunction. Ethical approval and informed consent were obtained for this case-control study. From October 2010-2015, 28 women with uncomplicated pregnancies (individualized birthweight ratio (IBR)>20th percentile and delivery>37 weeks) and 23 with FGR pregnancies (IBR<5th percentile and abnormal Doppler ultrasonography) underwent MRI. Differences in placental longitudinal R1 (1/T1) and transverse R2* (1/T2*) relaxation rates were quantified, breathing air and 100% oxygen. Data were acquired prospectively, with retrospective interpretation of group differences (unpaired t tests). Diagnostic models were developed by using logistic regression analysis with gestational age as a covariate. The mean baseline R1 and R2* for normal pregnancies (R1 0.59 ms, 95% CI 0.58-0.60; R2* 17 ms 95% CI 14-20) were significantly different from those of pregnancies complicated by FGR (R1 0.63 ms, 95% 0.62-0.65; R2* 26 ms, 95% CI 22-32) (P<0.0001). ΔR1 showed a significant negative association with gestational age (figure 1) (P<0.0001) in the combined cohort, with the FGR group having a ΔR1 that was generally 61.5% lower than that in the normal pregnancy group (P=0.003). The area under the receiver operating characteristic curve for the differentiation between pregnancy complicated by FGR and normal pregnancy using ΔR1, baseline R1, and baseline R2* was 0.91 (95% CI 0.82-0.99). R1, R2* and ΔR1 were significantly different between FGR and normal pregnancies. MR parameters have potential in identifying placental dysfunction associated with FGR and may have clinical utility in correctly identifying FGR amongst small for gestational age fetuses. A larger prospective study is needed to assess the incremental benefit beyond ultrasound.

Learned helplessness moderates the relationship between environmental concern and behavior

Many concerned individuals refrain from meaningful pro-environmental actions. We examined whether self-reported levels of trait learned helplessness moderates this concern–behavior relation. Results confirmed that learned helplessness moderated links between environmental concern and both self-reported and in-vivo measures of pro-environmental behavior, such that concern most strongly predicted behavior when learned helplessness scores were low. Results are reliable after controlling for gender as well as depression, anxiety, and stress symptoms. These findings suggest that learned helplessness acts as a barrier to pro-environmental behavior in the face of environmental concern.

Attentional bias mediates the effect of neurostimulation on emotional vulnerability

Transcranial direct current stimulation (tDCS) is a neuromodulatory technique which has garnered recent interest in the potential treatment for emotion-based psychopathology. While accumulating evidence suggests that tDCS may attenuate emotional vulnerability, critically, little is known about underlying mechanisms of this effect. The present study sought to clarify this by examining the possibility that tDCS may affect emotional vulnerability via its capacity to modulate attentional bias towards threatening information. Fifty healthy participants were randomly assigned to receive either anodal tDCS (2 mA/min) stimulation to the left dorsolateral prefrontal cortex (DLPFC), or sham. Participants were then eye tracked during a dual-video stressor task designed to elicit emotional reactivity, while providing a concurrent in-vivo measure of attentional bias. Greater attentional bias towards threatening information was associated with greater emotional reactivity to the stressor task. Furthermore, the active tDCS group showed reduced attentional bias to threat, compared to the sham group. Importantly, attentional bias was found to statistically mediate the effect of tDCS on emotional reactivity, while no direct effect of tDCS on emotional reactivity was observed. The findings are consistent with the notion that the effect of tDCS on emotional vulnerability may be mediated by changes in attentional bias, holding implications for the application of tDCS in emotion-based psychopathology. The findings also highlight the utility of in-vivo eye tracking measures in the examination of the mechanisms associated with DLPFC neuromodulation in emotional vulnerability.

Repeated dexamphetamine treatment alters the dopaminergic system and increases the phMRI response to methylphenidate.

Dexamphetamine (AMPH) is a psychostimulant drug that is used both recreationally and as medication for attention deficit hyperactivity disorder. Preclinical studies have demonstrated that repeated exposure to AMPH can induce damage to nerve terminals of dopamine (DA) neurons. We here assessed the underlying neurobiological changes in the DA system following repeated AMPH exposure and pre-treated rats with AMPH or saline (4 times 5 mg/kg s.c., 2 hours apart), followed by a 1-week washout period. We then used pharmacological MRI (phMRI) with a methylphenidate (MPH) challenge, as a sensitive and non-invasive in-vivo measure of DAergic function. We subsequently validated the DA-ergic changes post-mortem, using a.o. high-performance liquid chromatography (HPLC) and autoradiography. In the AMPH pre-treated group, we observed a significantly larger BOLD response to the MPH challenge, particularly in DA-ergic brain areas and their downstream projections. Subsequent autoradiography studies showed that AMPH pre-treatment significantly reduced DA transporter (DAT) density in the caudate-putamen (CPu) and nucleus accumbens, whereas HPLC analysis revealed increases in the DA metabolite homovanillic acid in the CPu. Our results suggest that AMPH pre-treatment alters DAergic responsivity, a change that can be detected with phMRI in rats. These phMRI changes likely reflect increased DA release together with reduced DAT binding. The ability to assess subtle synaptic changes using phMRI is promising for both preclinical studies of drug discovery, and for clinical studies where phMRI can be a useful tool to non-invasively investigate DA abnormalities, e.g. in neuropsychiatric disorders.

Alteration of gray matter microstructure in schizophrenia.

Neuroimaging studies demonstrate gray matter (GM) macrostructural abnormalities in patients with schizophrenia (SCZ). While ex-vivo and genetic studies suggest cellular pathology associated with abnormal neurodevelopmental processes in SCZ, few in-vivo measures have been proposed to target microstructural GM organization. Here, we use diffusion heterogeneity- to study GM microstructure in SCZ. Structural and diffusion magnetic resonance imaging (MRI) were acquired on a 3 Tesla scanner in 46 patients with SCZ and 37 matched healthy controls (HC). After correction for free water, diffusion heterogeneity as well as commonly used diffusion measures FA and MD and volume were calculated for the four cortical lobes on each hemisphere, and compared between groups. Patients with early course SCZ exhibited higher diffusion heterogeneity in the GM of the frontal lobes compared to controls. Diffusion heterogeneity of the frontal lobe showed excellent discrimination between patients and HC, while none of the commonly used diffusion measures such as FA or MD did. Higher diffusion heterogeneity in the frontal lobes in early SCZ may be due to abnormal brain maturation (migration, pruning) before and during adolescence and early adulthood. Further studies are needed to investigate the role of heterogeneity as potential biomarker for SCZ risk.