Granulocytic myeloid-derived suppressor cells (GR-MDSC) accumulate in cord blood of preterm infants and remain elevated during the neonatal period.

Preterm delivery is the leading cause of perinatal morbidity and mortality. Among the most important complications in preterm infants are peri- or postnatal infections. Myeloid-derived suppressor cells (MDSC) are myeloid cells with suppressive activity on other immune cells. Emerging evidence suggests that granulocytic MDSC (GR-MDSC) play a pivotal role in mediating maternal-fetal tolerance. The role of MDSC for postnatal immune-regulation in neonates is incompletely understood. Until the present time, nothing was known about expression of MDSC in preterm infants. In the present pilot study, we quantified GR-MDSC counts in cord blood and peripheral blood of preterm infants born between 23 + 0 and 36 + 6 weeks of gestation (WOG) during the first 3 months of life and analysed the effect of perinatal infections. We show that GR-MDSC are increased in cord blood independent of gestational age and remain elevated in peripheral blood of preterm infants during the neonatal period. After day 28 they drop to nearly adult levels. In case of perinatal or postnatal infection, GR-MDSC accumulate further and correlate with inflammatory markers C-reactive protein (CRP) and white blood cell counts (WBC). Our results point towards a role of GR-MDSC for immune-regulation in preterm infants and render them as a potential target for cell-based therapy of infections in these patients.

Low left amygdala volume is associated with a longer duration of unipolar depression.

The amygdala plays a crucial role in the pathogenesis of major depressive disorder (MDD). While robust findings support a negative impact of illness duration on hippocampal volume in MDD, morphometric studies of the amygdala have yielded inhomogeneous results. Considering the methodical problems of automatic segmentation methods, a standardized segmentation protocol with proven inter- and intra-rater reliability was employed using high-resolution magnetic resonance imaging. To identify the effect of MDD on amygdala morphometry, 23 unipolar depressed patients who responded to antidepressant medication and 30 age-matched healthy controls (HC) were enrolled. First, gray matter volumes (GMV) of the bilateral amygdala were delineated manually in 3D by three blinded experts using the MultiTracer. The whole brain GMV was determined by using voxel-based morphometry. Second, the differences of the whole brain and the bilateral amygdala GMV values between MDD and HC were calculated with t-statistics. The GMV of the whole brain and the amygdala did not differ between HC and MDD patients. Third, MDD characteristics were correlated with amygdala GMV. Within the normal range, the left amygdala GMV was larger in patients with later onset and smaller in cases of prolonged depression. In line with prior reports of depressed patients responding to antidepressant treatment, amygdala GMV was negatively related to illness duration, suggesting volume loss with disease progression. It remains unclear as to whether the association between illness duration and GMV reduced left amygdala volume indicates a neurotoxic effect of prolonged MDD or is rather a negative predictor of chronic depression.

Zoomed MRI Guided by Combined EEG/MEG Source Analysis: A Multimodal Approach for Optimizing Presurgical Epilepsy Work-up and its Application in a Multi-focal Epilepsy Patient Case Study.

In recent years, the use of source analysis based on electroencephalography (EEG) and magnetoencephalography (MEG) has gained considerable attention in presurgical epilepsy diagnosis. However, in many cases the source analysis alone is not used to tailor surgery unless the findings are confirmed by lesions, such as, e.g., cortical malformations in MRI. For many patients, the histology of tissue resected from MRI negative epilepsy shows small lesions, which indicates the need for more sensitive MR sequences. In this paper, we describe a technique to maximize the synergy between combined EEG/MEG (EMEG) source analysis and high resolution MRI. The procedure has three main steps: (1) construction of a detailed and calibrated finite element head model that considers the variation of individual skull conductivities and white matter anisotropy, (2) EMEG source analysis performed on averaged interictal epileptic discharges (IED), (3) high resolution (0.5 mm) zoomed MR imaging, limited to small areas centered at the EMEG source locations. The proposed new diagnosis procedure was then applied in a particularly challenging case of an epilepsy patient: EMEG analysis at the peak of the IED coincided with a right frontal focal cortical dysplasia (FCD), which had been detected at standard 1 mm resolution MRI. Of higher interest, zoomed MR imaging (applying parallel transmission, 'ZOOMit') guided by EMEG at the spike onset revealed a second, fairly subtle, FCD in the left fronto-central region. The evaluation revealed that this second FCD, which had not been detectable with standard 1 mm resolution, was the trigger of the seizures.

Effects of electroconvulsive therapy on amygdala function in major depression - a longitudinal functional magnetic resonance imaging study.

BACKGROUND: Electroconvulsive therapy (ECT) is one of the most effective treatments for severe depression. However, little is known regarding brain functional processes mediating ECT effects. METHOD: In a non-randomized prospective study, functional magnetic resonance imaging data during the automatic processing of subliminally presented emotional faces were obtained twice, about 6 weeks apart, in patients with major depressive disorder (MDD) before and after treatment with ECT (ECT, n = 24). Additionally, a control sample of MDD patients treated solely with pharmacotherapy (MED, n = 23) and a healthy control sample (HC, n = 22) were obtained. RESULTS: Before therapy, both patient groups equally showed elevated amygdala reactivity to sad faces compared with HC. After treatment, a decrease in amygdala activity to negative stimuli was discerned in both patient samples indicating a normalization of amygdala function, suggesting mechanisms potentially unspecific for ECT. Moreover, a decrease in amygdala activity to sad faces was associated with symptomatic improvements in the ECT sample (r spearman = -0.48, p = 0.044), and by tendency also for the MED sample (r spearman = -0.38, p = 0.098). However, we did not find any significant association between pre-treatment amygdala function to emotional stimuli and individual symptom improvement, neither for the ECT sample, nor for the MED sample. CONCLUSIONS: In sum, the present study provides first results regarding functional changes in emotion processing due to ECT treatment using a longitudinal design, thus validating and extending our knowledge gained from previous treatment studies. A limitation was that ECT patients received concurrent medication treatment.

Prefrontal gray matter volume mediates genetic risks for obesity.

Genetic and neuroimaging research has identified neurobiological correlates of obesity. However, evidence for an integrated model of genetic risk and brain structural alterations in the pathophysiology of obesity is still absent. Here we investigated the relationship between polygenic risk for obesity, gray matter structure and body mass index (BMI) by the use of univariate and multivariate analyses in two large, independent cohorts (n=330 and n=347). Higher BMI and higher polygenic risk for obesity were significantly associated with medial prefrontal gray matter decrease, and prefrontal gray matter was further shown to significantly mediate the effect of polygenic risk for obesity on BMI in both samples. Building on this, the successful individualized prediction of BMI by means of multivariate pattern classification algorithms trained on whole-brain imaging data and external validations in the second cohort points to potential clinical applications of this imaging trait marker.

Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group.

The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen's d effect sizes: -0.10 to -0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: -0.26 to -0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.

TNF receptors 1 and 2 exert distinct region-specific effects on striatal and hippocampal grey matter volumes (VBM) in healthy adults.

Tumour necrosis factor alpha (TNFα) has been implicated in the pathophysiology of neurodegenerative and neuropsychiatric disease, with research highlighting a role for TNFα in hippocampal and striatal regulation. TNFα signals are primarily transduced by TNF receptors 1 and 2 (TNFR1 and TNFR2), encoded by TNFRSF1A and TNFRSF1B, which exert opposing effects on cell survival (TNFR1, neurodegenerative; TNFR2, neuroprotective). We therefore sought to explore the respective roles of TNFR1 and TNFR2 in the regulation of hippocampal and striatal morphology in an imaging genetics study. Voxel-based morphometry was used to analyse the associations between TNFRSF1A (rs4149576 and rs4149577) and TNFRSF1B (rs1061624) genotypes and grey matter structure. The final samples comprised a total of 505 subjects (mean age = 33.29, SD = 11.55 years; 285 females and 220 males) for morphometric analyses of rs1061624 and rs4149576, and 493 subjects for rs4149577 (mean age = 33.20, SD = 11.56 years; 281 females and 212 males). Analyses of TNFRSF1A single nucleotide polymorphisms (SNPs) rs4149576 and rs4149577 showed highly significant genotypic associations with striatal volume but not the hippocampus. Specifically, for rs4149576, G homozygotes were associated with reduced caudate nucleus volumes relative to A homozygotes and heterozygotes, whereas for rs4149577, reduced caudate volumes were observed in C homozygotes relative to T homozygotes and heterozygotes. Analysis of the TNFRSF1B SNP rs1061624 yielded a significant association with hippocampal but not with striatal volume, whereby G homozygotes were associated with increased volumes relative to A homozygotes and heterozygotes. Our findings indicate a role for TNFR1 in regulating striatal but not hippocampal morphology, as well as a complementary role for TNFR2 in hippocampal but not in striatal morphology.

Differing brain structural correlates of familial and environmental risk for major depressive disorder revealed by a combined VBM/pattern recognition approach.

BACKGROUND: Neuroimaging traits of either familial or environmental risk for major depressive disorder (MDD) have been interpreted as possibly useful vulnerability markers. However, the simultaneous occurrence of familial and environmental risk might prove to be a major obstacle in the attempt of recent studies to confine the precise impact of each of these conditions on brain structure. Moreover, the exclusive use of group-level analyses does not permit prediction of individual illness risk which would be the basic requirement for the clinical application of imaging vulnerability markers. Hence, we aimed to distinguish between brain structural characteristics of familial predisposition and environmental stress by using both group- and individual-level analyses. METHOD: We investigated grey matter alterations between 20 healthy control subjects (HC) and 20 MDD patients; 16 healthy first-degree relatives of MDD patients (FH+) and 20 healthy subjects exposed to former childhood maltreatment (CM+) by using a combined VBM/pattern recognition approach. RESULTS: We found similar grey matter reductions in the insula and the orbitofrontal cortex in patients and FH+ subjects and in the hippocampus in patients and CM+ subjects. No direct overlap in grey matter alterations was found between FH+ and CM+ subjects. Pattern classification successfully detected subjects at risk for the disease even by strictly focusing on morphological traits of MDD. CONCLUSIONS: Familial and environmental risk factors for MDD are associated with differing morphometric anomalies. Pattern recognition might be a promising instrument in the search for and future application of vulnerability markers for MDD.

Multimodal imaging of a tescalcin (TESC)-regulating polymorphism (rs7294919)-specific effects on hippocampal gray matter structure.

In two large genome-wide association studies, an intergenic single-nucleotide polymorphism (SNP; rs7294919) involved in TESC gene regulation has been associated with hippocampus volume. Further characterization of neurobiological effects of the TESC gene is warranted using multimodal brain-wide structural and functional imaging. Voxel-based morphometry (VBM8) was used in two large, well-characterized samples of healthy individuals of West-European ancestry (Münster sample, N=503; SHIP-TREND, N=721) to analyze associations between rs7294919 and local gray matter volume. In subsamples, white matter fiber structure was investigated using diffusion tensor imaging (DTI) and limbic responsiveness was measured by means of functional magnetic resonance imaging (fMRI) during facial emotion processing (N=220 and N=264, respectively). Furthermore, gene x environment (G × E) interaction and gene x gene interaction with SNPs from genes previously found to be associated with hippocampal size (FKBP5, Reelin, IL-6, TNF-α, BDNF and 5-HTTLPR/rs25531) were explored. We demonstrated highly significant effects of rs7294919 on hippocampal gray matter volumes in both samples. In whole-brain analyses, no other brain areas except the hippocampal formation and adjacent temporal structures were associated with rs7294919. There were no genotype effects on DTI and fMRI results, including functional connectivity measures. No G × E interaction with childhood maltreatment was found in both samples. However, an interaction between rs7294919 and rs2299403 in the Reelin gene was found that withstood correction for multiple comparisons. We conclude that rs7294919 exerts highly robust and regionally specific effects on hippocampal gray matter structures, but not on other neuropsychiatrically relevant imaging markers. The biological interaction between TESC and RELN pointing to a neurodevelopmental origin of the observed findings warrants further mechanistic investigations.

Perception and pain thresholds for cutaneous heat and cold, and rectal distension: associations and disassociations.

BACKGROUND: Hypersensitivity to somatic or visceral pain has been reported in numerous clinical conditions such as fibromyalgia or the irritable bowel syndrome, and general hypersensitivity has been proposed to be the underlying mechanism. However, cross-modal relationships especially between somatic and visceral pain have rarely been investigated even in healthy volunteers. Furthermore, psychological influences on pain have rarely been characterized across modalities. METHODS: Sixty-one healthy participants underwent testing of perception and pain thresholds for cutaneous thermode heat and cold, as well as for rectal balloon distension. Psychological testing for anxiety, depression, and pain experience (including catastrophizing and coping) as well as cardiac interoception was performed. Measurement quality and the correlations between the different modalities were examined. KEY RESULTS: Significant correlations existed between the perception thresholds for cold/heat (τB  = -0.28, p = 0.002) and cold/distension (τB  = -0.21, p = 0.03) and for the pain thresholds for cold/heat (r = -0.61, p < 0.001) and heat/distension (r = 0.33, p = 0.01). No association was found between pain thresholds and anxiety, depression, psychological experience with and processing of pain, or cardiac interoception. Retest reliabilities for pain measurements were satisfying after short intertrial intervals (all intraclass correlation coefficients >0.8), but less so after longer intervals. The individuals contributing to the respective correlations differ between measurements. CONCLUSIONS & INFERENCES: Moderate associations were found for pain thresholds across modalities. The strength of the associations and their stability over time warrants further investigation and might serve to increase the understanding of conditions affecting multiple pain modalities.

Neutrophilic myeloid-derived suppressor cells in cord blood modulate innate and adaptive immune responses.

Neonates show an impaired anti-microbial host defence, but the underlying immune mechanisms are not understood fully. Myeloid-derived suppressor cells (MDSCs) represent an innate immune cell subset characterized by their capacity to suppress T cell immunity. In this study we demonstrate that a distinct MDSC subset with a neutrophilic/granulocytic phenotype (Gr-MDSCs) is highly increased in cord blood compared to peripheral blood of children and adults. Functionally, cord blood isolated Gr-MDSCs suppressed T cell proliferation efficiently as well as T helper type 1 (Th1), Th2 and Th17 cytokine secretion. Beyond T cells, cord blood Gr-MDSCs controlled natural killer (NK) cell cytotoxicity in a cell contact-dependent manner. These studies establish neutrophilic Gr-MDSCs as a novel immunosuppressive cell subset that controls innate (NK) and adaptive (T cell) immune responses in neonates. Increased MDSC activity in cord blood might serve as key fetomaternal immunosuppressive mechanism impairing neonatal host defence. Gr-MDSCs in cord blood might therefore represent a therapeutic target in neonatal infections.

Diffeomorphic susceptibility artifact correction of diffusion-weighted magnetic resonance images.

Diffusion-weighted magnetic resonance imaging is a key investigation technique in modern neuroscience. In clinical settings, diffusion-weighted imaging and its extension to diffusion tensor imaging (DTI) are usually performed applying the technique of echo-planar imaging (EPI). EPI is the commonly available ultrafast acquisition technique for single-shot acquisition with spatial encoding in a Cartesian system. A drawback of these sequences is their high sensitivity against small perturbations of the magnetic field, caused, e.g., by differences in magnetic susceptibility of soft tissue, bone and air. The resulting magnetic field inhomogeneities thus cause geometrical distortions and intensity modulations in diffusion-weighted images. This complicates the fusion with anatomical T1- or T2-weighted MR images obtained with conventional spin- or gradient-echo images and negligible distortion. In order to limit the degradation of diffusion-weighted MR data, we present here a variational approach based on a reference scan pair with reversed polarity of the phase- and frequency-encoding gradients and hence reversed distortion. The key novelty is a tailored nonlinear regularization functional to obtain smooth and diffeomorphic transformations. We incorporate the physical distortion model into a variational image registration framework and derive an accurate and fast correction algorithm. We evaluate the applicability of our approach to distorted DTI brain scans of six healthy volunteers. For all datasets, the automatic correction algorithm considerably reduced the image degradation. We show that, after correction, fusion with T1- or T2-weighted images can be obtained by a simple rigid registration. Furthermore, we demonstrate the improvement due to the novel regularization scheme. Most importantly, we show that it provides meaningful, i.e. diffeomorphic, geometric transformations, independent of the actual choice of the regularization parameters.

Techniques for the measurement of disruption halo currents in the National Spherical Torus Experiment.

This paper describes techniques for measuring halo currents, and their associated toroidal peaking, in the National Spherical Torus Experiments [M. Ono et al., Nucl. Fusion 40, 557 (2000)]. The measurements are based on three techniques: (1) measurement of the toroidal field created by the poloidal halo current, either with segmented Rogowski coils or discrete toroidal field sensors, (2) the direct measurement of halo currents into specially instrument tiles, and (3) small Rogowski coils placed on the mechanical supports of in-vessel components. For the segmented Rogowski coils and discrete toroidal field detectors, it is shown that the toroidal peaking factor inferred from the data is significantly less than the peaking factor of the underlying halo current distribution, and a simple model is developed to relate the two. For the array of discrete toroidal field detectors and small Rogowski sensors, the compensation steps that are used to isolate the halo current signal are described. The electrical and mechanical design of compact under-tile resistive shunts and mini-Rogowski coils is described. Example data from the various systems are shown.

Continuous improvement of H-mode discharge performance with progressively increasing lithium coatings in the National Spherical Torus Experiment.

Lithium wall coatings have been shown to reduce recycling, improve energy confinement, and suppress edge localized modes in the National Spherical Torus Experiment. Here, we show that these effects depend continuously on the amount of predischarge lithium evaporation. We observed a nearly monotonic reduction in recycling, decrease in electron transport, and modification of the edge profiles and stability with increasing lithium. These correlations challenge basic expectations, given that even the smallest coatings exceeded that needed for a nominal thickness of the order of the implantation range.

Multimodal imaging of functional networks and event-related potentials in performance monitoring.

The stop-signal task is a prototypical experiment to study cognitive processes that mediate successful performance in a rapidly changing environment. By means of simultaneous recording and combined analysis of electroencephalography and functional magnetic resonance imaging on single trial level, we provide a comprehensive view on brain responses related to performance monitoring in this task. Three types of event-related EEG components were analyzed: a go-related N2/P3-complex devoid of motor-inhibition, the stop-related N2/P3-complex and the error-related negativity with its consecutive error positivity. Relevant functional networks were identified by crossmodal correlation analyses in a parallel independent component analysis framework. Go-related potentials were associated with a midcingulate network known to participate in the processing of conflicts, a left-dominant somatosensory-motor network, and deactivations in visual cortices. Stop-related brain responses in association with the N2/P3-complex were seen with networks known to support motor and cognitive inhibition, including parts of the basal ganglia, the anterior midcingulate cortex and pre-supplementary motor area as well as the anterior insula. Error-related brain responses showed a similar constellation with additional recruitment of the posterior insula and the inferior frontal cortex. Our data clearly indicate that the pre-supplementary motor area is involved in inhibitory mechanisms but not in the processing of conflicts per se.

Neuropeptide S receptor gene -- converging evidence for a role in panic disorder.

Animal studies have suggested neuropeptide S (NPS) and its receptor (NPSR) to be involved in the pathogenesis of anxiety-related behavior. In this study, a multilevel approach was applied to further elucidate the role of NPS in the etiology of human anxiety. The functional NPSR A/T (Asn¹°7Ile) variant (rs324981) was investigated for association with (1) panic disorder with and without agoraphobia in two large, independent case-control studies, (2) dimensional anxiety traits, (3) autonomic arousal level during a behavioral avoidance test and (4) brain activation correlates of anxiety-related emotional processing in panic disorder. The more active NPSR rs324981 T allele was found to be associated with panic disorder in the female subgroup of patients in both samples as well as in a meta-analytic approach. The T risk allele was further related to elevated anxiety sensitivity, increased heart rate and higher symptom reports during a behavioral avoidance test as well as decreased activity in the dorsolateral prefrontal, lateral orbitofrontal and anterior cingulate cortex during processing of fearful faces in patients with panic disorder. The present results provide converging evidence for a female-dominant role of NPSR gene variation in panic disorder potentially through heightened autonomic arousal and distorted processing of anxiety-relevant emotional stimuli.

Neural correlates of trait anxiety in fear extinction.

BACKGROUND: Fear conditioning involves the amygdala as the main neural structure for learning fear responses whereas fear extinction mainly activates the inhibitory prefrontal cortex (PFC). In this study we investigated whether individual differences in trait anxiety affect amygdala and dorsal anterior cingulate cortex (dACC) activation during fear conditioning and extinction. METHOD: Thirty-two healthy subjects were investigated by functional magnetic resonance imaging (fMRI) at 3 T while performing a cued fear-conditioning task. All participants completed the trait version of the State-Trait Anxiety Inventory (STAI-T). Activations of the amygdala and the dACC were examined with respect to the effects of trait anxiety. RESULTS: Analysis of the fMRI data demonstrated enhanced activation in fear-related brain areas, such as the insula and the ACC, during both fear conditioning and extinction. Activation of the amygdala appeared only during the late acquisition phase whereas deactivation was observed during extinction. Regression analyses revealed that highly trait-anxious subjects exhibited sustained amygdala activation and reduced dACC involvement during the extinction of conditioned responses. CONCLUSIONS: This study reveals that high levels of trait anxiety are associated with both increased amygdala activation and reduced dACC recruitment during the extinction of conditioned fear. This hyper-responsivity of the amygdala and the deficient cognitive control during the extinction of conditioned fear in anxious subjects reflect an increased resistance to extinct fear responses and may thereby enhance the vulnerability to developing anxiety disorders.

Spectroscopic diagnostics for liquid lithium divertor studies on National Spherical Torus Experiment.

The use of lithium-coated plasma facing components for plasma density control is studied in the National Spherical Torus Experiment (NSTX). A recently installed liquid lithium divertor (LLD) module has a porous molybdenum surface, separated by a stainless steel liner from a heated copper substrate. Lithium is deposited on the LLD from two evaporators. Two new spectroscopic diagnostics are installed to study the plasma surface interactions on the LLD: (1) A 20-element absolute extreme ultraviolet (AXUV) diode array with a 6 nm bandpass filter centered at 121.6 nm (the Lyman-α transition) for spatially resolved divertor recycling rate measurements in the highly reflective LLD environment, and (2) an ultraviolet-visible-near infrared R=0.67 m imaging Czerny-Turner spectrometer for spatially resolved divertor D I, Li I-II, C I-IV, Mo I, D(2), LiD, CD emission and ion temperature on and around the LLD module. The use of photometrically calibrated measurements together with atomic physics factors enables studies of recycling and impurity particle fluxes as functions of LLD temperature, ion flux, and divertor geometry.