Differences in the right inferior longitudinal fasciculus but no general disruption of white matter tracts in children with autism spectrum disorder

One of the most widely cited features of the neural phenotype of autism is reduced “integrity” of long-range white matter tracts, a claim based primarily on diffusion imaging studies. However, many prior studies have small sample sizes and/or fail to address differences in data quality between those with autism spectrum disorder (ASD) and typical participants, and there is little consensus on which tracts are affected. To overcome these problems, we scanned a large sample of children with autism (n = 52) and typically developing children (n = 73). Data quality was variable, and worse in the ASD group, with some scans unusable because of head motion artifacts. When we follow standard data analysis practices (i.e., without matching head motion between groups), we replicate the finding of lower fractional anisotropy (FA) in multiple white matter tracts. However, when we carefully match data quality between groups, all these effects disappear except in one tract, the right inferior longitudinal fasciculus (ILF). Additional analyses showed the expected developmental increases in the FA of fiber tracts within ASD and typical groups individually, demonstrating that we had sufficient statistical power to detect known group differences. Our data challenge the widely claimed general disruption of white matter tracts in autism, instead implicating only one tract, the right ILF, in the ASD phenotype.What is the key difference in the brains of individuals with autism that accounts for the distinctive cognitive profile of this disorder? One of the most widely claimed brain signatures of autism spectrum disorder (ASD), reported in dozens of papers that used diffusion-weighted imaging (DWI), is reduced integrity of long-range fiber tracts (1). This finding has been taken as evidence that autism is fundamentally a “disconnection” syndrome, in which the core cognitive deficits result from reduced integration of information at the neural and cognitive levels (2–5). For example, it has been argued that the characteristic deficits in social cognition and language arise because these functions require rapid integration of information across spatially distant brain areas (3, 6, 7), which would likely be affected if major white matter tracts are compromised.Evidence for a general reduction in the “integrity”^* of white matter in autism has come primarily from diffusion imaging studies that report reduced directionality of the diffusion of water molecules, or fractional anisotropy (FA), and increased speed of diffusion, or mean diffusivity (MD) of many major fiber bundles. However, the literature reveals little actual agreement on the existence and direction of group differences in diffusion parameters (reviewed in ref. 1). White-matter differences have been reported in various brain regions in positive and negative directions. Possible reasons for these inconsistent findings include small sample sizes [mean of ∼20 in each group, with 40% of studies scanning 15 or fewer participants with ASD (1)], the heterogeneity of ASD itself, variations across studies in the age of the cohort tested, and the type of DTI analysis performed. Another potential problem that few diffusion studies of autism address or even mention is data quality. Indeed, to our knowledge, only two studies (9, 10) report quantitative analyses of the amount of motion in their DWI data. Group differences in head motion could be a serious confounding factor, given that head motion is likely to be greater in children with autism, and group differences in head motion can lead artifactually to just the effects most often reported: reduced FA in white matter tracts in ASD (11).To address these concerns, we scanned a relatively large sample of children with and without ASD, and evaluated data quality from each participant by visual inspection of the data and quantification of head motion (11). We then excluded scans that did not reach our data quality criterion, and matched the remaining participants across groups for data quality. These data were used to determine whether people with autism do in fact show widespread differences in the known white matter tracts in ASD. We further tested the specific hypothesis that individuals with ASD show changes in one particular tract, the inferior longitudinal fasciculus (ILF), a white matter tract important for face recognition (12, 13), a mental function selectively disrupted in ASD (ref. 14; but see ref. 15).     

Inhibition of the liver expression of arylalkylamine N-acetyltransferase increases the expression of angiogenic factors in cholangiocytes

Background and aims

Reduction of biliary serotonin N-acetyltransferase (AANAT) expression and melatonin administration/secretion in cholangiocytes increases biliary proliferation and the expression of SR, CFTR and Cl^–/HCO₃^– AE2. The balance between biliary proliferation/damage is regulated by several autocrine neuroendocrine factors including vascular endothelial growth factor-A/C (VEGF-A/C). VEGFs are secreted by several epithelia, where they modulate cell growth by autocrine and paracrine mechanisms. No data exists regarding the effect of AANAT modulation on the expressions of VEGFs by cholangiocytes.

Methods

In this study, we evaluated the effect of local modulation of biliary AANAT expression on the cholangiocytes synthesis of VEGF-A/C.

Results

The decrease in AANAT expression and subsequent lower melatonin secretion by cholangiocytes was associated with increased expression of VEGF-A/C. Overexpression of AANAT in cholangiocyte lines decreased the expression of VEGF-A/C.

Conclusions

Modulation of melatonin synthesis may affect the expression of VEGF-A/C by cholangiocytes and may modulate the hepatic microvascularization through the regulation of VEGF-A/C expression regulating biliary functions.     

Do patient and ward-related characteristics influence the use of coercive measures? Results from the EUNOMIA international study

Purpose

This study aims to identify whether selected patient and ward-related factors are associated with the use of coercive measures. Data were collected as part of the EUNOMIA international collaborative study on the use of coercive measures in ten European countries.

Methods

Involuntarily admitted patients (N = 2,027) were divided into two groups. The first group (N = 770) included patients that had been subject to at least one of these coercive measures during hospitalization: restraint, and/or seclusion, and/or forced medication; the other group (N = 1,257) included patients who had not received any coercive measure during hospitalization. To identify predictors of use of coercive measures, both patients’ sociodemographic and clinical characteristics and centre-related characteristics were tested in a multivariate logistic regression model, controlled for countries’ effect.

Results

The frequency of the use of coercive measures varied significantly across countries, being higher in Poland, Italy and Greece. Patients who received coercive measures were more frequently male and with a diagnosis of psychotic disorder (F20–F29). According to the regression model, patients with higher levels of psychotic and hostility symptoms, and of perceived coercion had a higher risk to be coerced at admission. Controlling for countries’ effect, the risk of being coerced was higher in Poland. Patients’ sociodemographic characteristics and ward-related factors were not identifying as possible predictors because they did not enter the model.

Conclusions

The use of coercive measures varied significantly in the participating countries. Clinical factors, such as high levels of psychotic symptoms and high levels of perceived coercion at admission were associated with the use of coercive measures, when controlling for countries’ effect. These factors should be taken into consideration by programs aimed at reducing the use of coercive measures in psychiatric wards.     

Differential developmental trajectories of magnetic susceptibility in human brain gray and white matter over the lifespan

As indicated by several recent studies, magnetic susceptibility of the brain is influenced mainly by myelin in the white matter and by iron deposits in the deep nuclei. Myelination and iron deposition in the brain evolve both spatially and temporally. This evolution reflects an important characteristic of normal brain development and ageing. In this study, we assessed the changes of regional susceptibility in the human brain in vivo by examining the developmental and ageing process from 1 to 83 years of age. The evolution of magnetic susceptibility over this lifespan was found to display differential trajectories between the gray and the white matter. In both cortical and subcortical white matter, an initial decrease followed by a subsequent increase in magnetic susceptibility was observed, which could be fitted by a Poisson curve. In the gray matter, including the cortical gray matter and the iron‐rich deep nuclei, magnetic susceptibility displayed a monotonic increase that can be described by an exponential growth. The rate of change varied according to functional and anatomical regions of the brain. For the brain nuclei, the age‐related changes of susceptibility were in good agreement with the findings from R2^* measurement. Our results suggest that magnetic susceptibility may provide valuable information regarding the spatial and temporal patterns of brain myelination and iron deposition during brain maturation and ageing. Hum Brain Mapp 35:2698–2713, 2014. © 2013 Wiley Periodicals, Inc .     

The lumbar spine has an intrinsic shape specific to each individual that remains a characteristic throughout flexion and extension

Purpose

We have previously shown that the lumbar spine has an intrinsic shape specific to the individual and characteristic of sitting, standing and supine postures. The purpose of this study was to test the hypothesis that this intrinsic shape is detectable throughout a range of postures from extension to full flexion in healthy adults.

Methods

Sagittal images of the lumbar spine were taken using a positional MRI with participants (n = 30) adopting six postures: seated extension, neutral standing, standing with 30, 45 and 60° and full flexion. Active shape modelling (ASM) was used to identify and quantify ‘modes’ of variation in the shape of the lumbar spine.

Results

ASM showed that 89.5 % of the variation in the shape of the spine could be explained by the first two modes; describing the overall curvature and the distribution of curvature of the spine. Mode scores were significantly correlated between all six postures (modes 1–9, r = 0.4–0.97, P < 0.05), showing that an element of intrinsic shape was maintained when changing postures. The spine was most even in seated extension (P < 0.001) and most uneven between 35 and 45° flexion (P < 0.05).

Conclusions

This study shows that an individual’s intrinsic lumbar spine shape is quantifiable and detectable throughout lumbar flexion and extension. These findings will enable the role of lumbar curvature in injury and low back pain to be assessed in the clinic and in the working and recreational environments.

     

Does Epidural Morphine Loading in Addition to Thoracic Epidural Analgesia Benefit the Postoperative Management of Morbidly Obese Patients Undergoing Open Bariatric Surgery? A Pilot Study

Background

Insufficient data exist regarding postoperative thoracic epidural analgesia for morbidly obese patients undergoing open bariatric surgery. This study evaluated the effectiveness of morphine loading in a postoperative thoracic epidural analgesic regimen of patient-controlled epidural analgesia (PCEA) with levobupivacaine combined with continuously administered epidural morphine in this patient group.

Methods

In this prospective randomized controlled trial, 48 superobese patients (body mass index of ≥50 kg/m²) undergoing open bariatric surgery were randomly allocated to three groups of 16 patients each. Postoperatively, all groups received a continuous epidural morphine infusion of 0.2 mg/h with 0.1 % levobupivacaine via PCEA. Group A did not receive intraoperative epidural morphine loading, while groups B and C received an intraoperative 1- and 2-mg morphine bolus, respectively. Levobupivacaine consumption via PCEA (primary outcome), pain scores at rest and on cough, the time to return of bowel function and ambulation, and arterial blood gas levels (secondary outcomes) were recorded.

Results

The increase in perioperative morphine administration (groups B and C) led to a significantly prolonged return to normal bowel function and delayed ambulation (P?Conclusions Thoracic PCEA with 0.1 % levobupivacaine combined with continuous epidural morphine administration of 0.2 mg/h without morphine loading is an effective postoperative analgesic regimen that provides adequate pain control, early ambulation, and early return of bowel function in superobese patients, particularly those with OSA.     

Whole-Genome Analysis of Exserohilum rostratum from an Outbreak of Fungal Meningitis and Other Infections

Exserohilum rostratum was the cause of most cases of fungal meningitis and other infections associated with the injection of contaminated methylprednisolone acetate produced by the New England Compounding Center (NECC). Until this outbreak, very few human cases of Exserohilum infection had been reported, and very little was known about this dematiaceous fungus, which usually infects plants. Here, we report using whole-genome sequencing (WGS) for the detection of single nucleotide polymorphisms (SNPs) and phylogenetic analysis to investigate the molecular origin of the outbreak using 22 isolates of E. rostratum retrieved from 19 case patients with meningitis or epidural/spinal abscesses, 6 isolates from contaminated NECC vials, and 7 isolates unrelated to the outbreak. Our analysis indicates that all 28 isolates associated with the outbreak had nearly identical genomes of 33.8 Mb. A total of 8 SNPs were detected among the outbreak genomes, with no more than 2 SNPs separating any 2 of the 28 genomes. The outbreak genomes were separated from the next most closely related control strain by ∼136,000 SNPs. We also observed significant genomic variability among strains unrelated to the outbreak, which may suggest the possibility of cryptic speciation in E. rostratum.