Evaluation of data imputation strategies in complex, deeply-phenotyped data sets: the case of the EU-AIMS Longitudinal European Autism Project.

An increasing number of large-scale multi-modal research initiatives has been conducted in the typically developing population, e.g. Dev. Cogn. Neur. 32:43-54, 2018; PLoS Med. 12(3):e1001779, 2015; Elam and Van Essen, Enc. Comp. Neur., 2013, as well as in psychiatric cohorts, e.g. Trans. Psych. 10(1):100, 2020; Mol. Psych. 19:659-667, 2014; Mol. Aut. 8:24, 2017; Eur. Child and Adol. Psych. 24(3):265-281, 2015. Missing data is a common problem in such datasets due to the difficulty of assessing multiple measures on a large number of participants. The consequences of missing data accumulate when researchers aim to integrate relationships across multiple measures. Here we aim to evaluate different imputation strategies to fill in missing values in clinical data from a large (total N = 764) and deeply phenotyped (i.e. range of clinical and cognitive instruments administered) sample of N = 453 autistic individuals and N = 311 control individuals recruited as part of the EU-AIMS Longitudinal European Autism Project (LEAP) consortium. In particular, we consider a total of 160 clinical measures divided in 15 overlapping subsets of participants. We use two simple but common univariate strategies-mean and median imputation-as well as a Round Robin regression approach involving four independent multivariate regression models including Bayesian Ridge regression, as well as several non-linear models: Decision Trees (Extra Trees., and Nearest Neighbours regression. We evaluate the models using the traditional mean square error towards removed available data, and also consider the Kullback-Leibler divergence between the observed and the imputed distributions. We show that all of the multivariate approaches tested provide a substantial improvement compared to typical univariate approaches. Further, our analyses reveal that across all 15 data-subsets tested, an Extra Trees regression approach provided the best global results. This not only allows the selection of a unique model to impute missing data for the LEAP project and delivers a fixed set of imputed clinical data to be used by researchers working with the LEAP dataset in the future, but provides more general guidelines for data imputation in large scale epidemiological studies.

Fractal analysis highlights analogies in arenaceous tubes of Sabellaria alveolata (Metazoa, Polychaeta) and agglutinated tests of foraminifera (Protista).

Bioconstructions of Sabellaria alveolata (Polychaeta Sabellariidae) from southern Sicily (Central Mediterranean) were sampled and analysed through a multidisciplinary approach in order to unravel the construction pattern of arenaceous tubes and explore possible analogies existing between the worm tubes and the agglutinated tests of benthic foraminifera (Protista). Scanning Electron Microscopy and Energy Dispersive Spectroscopy analyses were carried out on entire tubes as well as sectioned ones. Results show that arenaceous tubes are built following a rigorous architectural framework, based on selection and methodical arrangement of the agglutinated grains, and show surprising analogies with the test microstructure previously observed in agglutinated foraminifera. The grain distribution detected in both model species bioconstructions was analysed using a fractal numerical model (Hausdorff fractal dimension). Collected data show that in both organisms the grains were distributed according to a fractal model, indicating that the evolutionary process may have led to finding the same optimal constructive strategy across organisms with an independent evolutionary history, notwithstanding different geometrical scales. Furthermore, in sectioned tubes we observed microplastic fragments agglutinated within the arenaceous wall and in the inter-tube area. This unexpected finding shows that marine animals can be affected by microplastic pollution not only in soft tissues, but also engineered hard structures, and suggests the problem is more pervasive than estimated so far.

Secondary hemophagocytic lymphohystiocytosis in a Rubinstein Taybi syndrome patient.

Rubinstein-Taybi syndrome (RSTS) is an autosomal dominant disorder, caused by variants in CREBBP or EP300. Affected individuals present with distinctive craniofacial features, broad thumbs and/or halluces, intellectual disability and immunodeficiency. Here we report on one RSTS patient who experienced hemophagocytic lymphohystiocytosis (HLH) and disseminated herpes virus 1 ( HSV-1) disease. The clinical picture of RSTS is expanding to include autoinflammatory, autoimmune, and infectious complications. Prompt treatment of HLH and disseminated HSV-1 can lower the mortality rate of these life-threatening conditions.

Preference for biological motion is reduced in ASD: implications for clinical trials and the search for biomarkers.

BACKGROUND: The neurocognitive mechanisms underlying autism spectrum disorder (ASD) remain unclear. Progress has been largely hampered by small sample sizes, variable age ranges and resulting inconsistent findings. There is a pressing need for large definitive studies to delineate the nature and extent of key case/control differences to direct research towards fruitful areas for future investigation. Here we focus on perception of biological motion, a promising index of social brain function which may be altered in ASD. In a large sample ranging from childhood to adulthood, we assess whether biological motion preference differs in ASD compared to neurotypical participants (NT), how differences are modulated by age and sex and whether they are associated with dimensional variation in concurrent or later symptomatology. METHODS: Eye-tracking data were collected from 486 6-to-30-year-old autistic (N = 282) and non-autistic control (N = 204) participants whilst they viewed 28 trials pairing biological (BM) and control (non-biological, CTRL) motion. Preference for the biological motion stimulus was calculated as (1) proportion looking time difference (BM-CTRL) and (2) peak look duration difference (BM-CTRL). RESULTS: The ASD group showed a present but weaker preference for biological motion than the NT group. The nature of the control stimulus modulated preference for biological motion in both groups. Biological motion preference did not vary with age, gender, or concurrent or prospective social communicative skill within the ASD group, although a lack of clear preference for either stimulus was associated with higher social-communicative symptoms at baseline. LIMITATIONS: The paired visual preference we used may underestimate preference for a stimulus in younger and lower IQ individuals. Our ASD group had a lower average IQ by approximately seven points. 18% of our sample was not analysed for various technical and behavioural reasons. CONCLUSIONS: Biological motion preference elicits small-to-medium-sized case-control effects, but individual differences do not strongly relate to core social autism associated symptomatology. We interpret this as an autistic difference (as opposed to a deficit) likely manifest in social brain regions. The extent to which this is an innate difference present from birth and central to the autistic phenotype, or the consequence of a life lived with ASD, is unclear.

Microstructural imaging of the human brain with a 'super-scanner': 10 key advantages of ultra-strong gradients for diffusion MRI.

The key component of a microstructural diffusion MRI 'super-scanner' is a dedicated high-strength gradient system that enables stronger diffusion weightings per unit time compared to conventional gradient designs. This can, in turn, drastically shorten the time needed for diffusion encoding, increase the signal-to-noise ratio, and facilitate measurements at shorter diffusion times. This review, written from the perspective of the UK National Facility for In Vivo MR Imaging of Human Tissue Microstructure, an initiative to establish a shared 300 mT/m-gradient facility amongst the microstructural imaging community, describes ten advantages of ultra-strong gradients for microstructural imaging. Specifically, we will discuss how the increase of the accessible measurement space compared to a lower-gradient systems (in terms of Δ, b-value, and TE) can accelerate developments in the areas of 1) axon diameter distribution mapping; 2) microstructural parameter estimation; 3) mapping micro-vs macroscopic anisotropy features with gradient waveforms beyond a single pair of pulsed-gradients; 4) multi-contrast experiments, e.g. diffusion-relaxometry; 5) tractography and high-resolution imaging in vivo and 6) post mortem; 7) diffusion-weighted spectroscopy of metabolites other than water; 8) tumour characterisation; 9) functional diffusion MRI; and 10) quality enhancement of images acquired on lower-gradient systems. We finally discuss practical barriers in the use of ultra-strong gradients, and provide an outlook on the next generation of 'super-scanners'.

Sex differences in frontal lobe connectivity in adults with autism spectrum conditions.

Autism spectrum conditions (ASC) are more prevalent in males than females. The biological basis of this difference remains unclear. It has been postulated that one of the primary causes of ASC is a partial disconnection of the frontal lobe from higher-order association areas during development (that is, a frontal 'disconnection syndrome'). Therefore, in the current study we investigated whether frontal connectivity differs between males and females with ASC. We recruited 98 adults with a confirmed high-functioning ASC diagnosis (61 males: aged 18-41 years; 37 females: aged 18-37 years) and 115 neurotypical controls (61 males: aged 18-45 years; 54 females: aged 18-52 years). Current ASC symptoms were evaluated using the Autism Diagnostic Observation Schedule (ADOS). Diffusion tensor imaging was performed and fractional anisotropy (FA) maps were created. Mean FA values were determined for five frontal fiber bundles and two non-frontal fiber tracts. Between-group differences in mean tract FA, as well as sex-by-diagnosis interactions were assessed. Additional analyses including ADOS scores informed us on the influence of current ASC symptom severity on frontal connectivity. We found that males with ASC had higher scores of current symptom severity than females, and had significantly lower mean FA values for all but one tract compared to controls. No differences were found between females with or without ASC. Significant sex-by-diagnosis effects were limited to the frontal tracts. Taking current ASC symptom severity scores into account did not alter the findings, although the observed power for these analyses varied. We suggest these findings of frontal connectivity abnormalities in males with ASC, but not in females with ASC, have the potential to inform us on some of the sex differences reported in the behavioral phenotype of ASC.

Relationship Between Cortical Gyrification, White Matter Connectivity, and Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition, which is accompanied by differences in gray matter neuroanatomy and white matter connectivity. However, it is unknown whether these differences are linked or reflect independent aetiologies. Using a multimodal neuroimaging approach, we therefore examined 51 male adults with ASD and 48 neurotypical controls to investigate the relationship between gray matter local gyrification (lGI) and white matter diffusivity in associated fiber tracts. First, ASD individuals had a significant increase in gyrification around the left pre- and post-central gyrus. Second, white matter fiber tracts originating and/or terminating in the cluster of increased lGI had a significant increase in axial diffusivity. This increase in diffusivity was predominantly observed in tracts in close proximity to the cortical sheet. Last, we demonstrate that the increase in lGI was significantly correlated with increased diffusivity of short tracts. This relationship was not significantly modulated by a main effect of group (i.e., ASD), which was more closely associated with gray matter gyrification than white matter diffusivity. Our findings suggest that differences in gray matter neuroanatomy and white matter connectivity are closely linked, and may reflect common rather than distinct aetiological pathways.

Atlasing the frontal lobe connections and their variability due to age and education: a spherical deconvolution tractography study.

In neuroscience, there is a growing consensus that higher cognitive functions may be supported by distributed networks involving different cerebral regions, rather than by single brain areas. Communication within these networks is mediated by white matter tracts and is particularly prominent in the frontal lobes for the control and integration of information. However, the detailed mapping of frontal connections remains incomplete, albeit crucial to an increased understanding of these cognitive functions. Based on 47 high-resolution diffusion-weighted imaging datasets (age range 22-71 years), we built a statistical normative atlas of the frontal lobe connections in stereotaxic space, using state-of-the-art spherical deconvolution tractography. We dissected 55 tracts including U-shaped fibers. We further characterized these tracts by measuring their correlation with age and education level. We reported age-related differences in the microstructural organization of several, specific frontal fiber tracts, but found no correlation with education level. Future voxel-based analyses, such as voxel-based morphometry or tract-based spatial statistics studies, may benefit from our atlas by identifying the tracts and networks involved in frontal functions. Our atlas will also build the capacity of clinicians to further understand the mechanisms involved in brain recovery and plasticity, as well as assist clinicians in the diagnosis of disconnection or abnormality within specific tracts of individual patients with various brain diseases.

Effect of high-potency cannabis on corpus callosum microstructure.

BACKGROUND: The use of cannabis with higher Δ9-tetrahydrocannabinol content has been associated with greater risk, and earlier onset, of psychosis. However, the effect of cannabis potency on brain morphology has never been explored. Here, we investigated whether cannabis potency and pattern of use are associated with changes in corpus callosum (CC) microstructural organization, in patients with first-episode psychosis (FEP) and individuals without psychosis, cannabis users and non-users. METHOD: The CC of 56 FEP (37 cannabis users) and 43 individuals without psychosis (22 cannabis users) was virtually dissected and segmented using diffusion tensor imaging tractography. The diffusion index of fractional anisotropy, mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity was calculated for each segment. RESULTS: Across the whole sample, users of high-potency cannabis had higher total CC MD and higher total CC AD than both low-potency users and those who never used (p = 0.005 and p = 0.004, respectively). Daily users also had higher total CC MD and higher total CC AD than both occasional users and those who never used (p = 0.001 and p < 0.001, respectively). However, there was no effect of group (patient/individuals without psychosis) or group x potency interaction for either potency or frequency of use. The within-group analysis showed in fact that the effects of potency and frequency were similar in FEP users and in users without psychosis. CONCLUSIONS: Frequent use of high-potency cannabis is associated with disturbed callosal microstructural organization in individuals with and without psychosis. Since high-potency preparations are now replacing traditional herbal drugs in many European countries, raising awareness about the risks of high-potency cannabis is crucial.

From Phineas Gage and Monsieur Leborgne to H.M.: Revisiting Disconnection Syndromes.

On the 50th anniversary of Norman Geschwind's seminal paper entitled 'Disconnexion syndrome in animal and man', we pay tribute to his ideas by applying contemporary tractography methods to understand white matter disconnection in 3 classic cases that made history in behavioral neurology. We first documented the locus and extent of the brain lesion from the computerized tomography of Phineas Gage's skull and the magnetic resonance images of Louis Victor Leborgne's brain, Broca's first patient, and Henry Gustave Molaison. We then applied the reconstructed lesions to an atlas of white matter connections obtained from diffusion tractography of 129 healthy adults. Our results showed that in all 3 patients, disruption extended to connections projecting to areas distant from the lesion. We confirmed that the damaged tracts link areas that in contemporary neuroscience are considered functionally engaged for tasks related to emotion and decision-making (Gage), language production (Leborgne), and declarative memory (Molaison). Our findings suggest that even historic cases should be reappraised within a disconnection framework whose principles were plainly established by the associationist schools in the last 2 centuries.

Using genetic, cognitive and multi-modal neuroimaging data to identify ultra-high-risk and first-episode psychosis at the individual level.

BACKGROUND: Group-level results suggest that relative to healthy controls (HCs), ultra-high-risk (UHR) and first-episode psychosis (FEP) subjects show alterations in neuroanatomy, neurofunction and cognition that may be mediated genetically. It is unclear, however, whether these groups can be differentiated at single-subject level, for instance using the machine learning analysis support vector machine (SVM). Here, we used a multimodal approach to examine the ability of structural magnetic resonance imaging (sMRI), functional MRI (fMRI), diffusion tensor neuroimaging (DTI), genetic and cognitive data to differentiate between UHR, FEP and HC subjects at the single-subject level using SVM. METHOD: Three age- and gender-matched SVM paired comparison groups were created comprising 19, 19 and 15 subject pairs for FEP versus HC, UHR versus HC and FEP versus UHR, respectively. Genetic, sMRI, DTI, fMRI and cognitive data were obtained for each participant and the ability of each to discriminate subjects at the individual level in conjunction with SVM was tested. RESULTS: Successful classification accuracies (p < 0.05) comprised FEP versus HC (genotype, 67.86%; DTI, 65.79%; fMRI, 65.79% and 68.42%; cognitive data, 73.69%), UHR versus HC (sMRI, 68.42%; DTI, 65.79%), and FEP versus UHR (sMRI, 76.67%; fMRI, 73.33%; cognitive data, 66.67%). CONCLUSIONS: The results suggest that FEP subjects are identifiable at the individual level using a range of biological and cognitive measures. Comparatively, only sMRI and DTI allowed discrimination of UHR from HC subjects. For the first time FEP and UHR subjects have been shown to be directly differentiable at the single-subject level using cognitive, sMRI and fMRI data. Preliminarily, the results support clinical development of SVM to help inform identification of FEP and UHR subjects, though future work is needed to provide enhanced levels of accuracy.

Frontotemporal white-matter microstructural abnormalities in adolescents with conduct disorder: a diffusion tensor imaging study.

BACKGROUND: Children with conduct disorder (CD) are at increased risk of developing antisocial personality disorder (ASPD) and psychopathy in adulthood. The biological basis for this is poorly understood. A preliminary diffusion tensor magnetic resonance imaging (DT-MRI) study of psychopathic antisocial adults reported significant differences from controls in the fractional anisotropy (FA) of the uncinate fasciculus (UF), a white-matter tract that connects the amygdala to the frontal lobe. However, it is unknown whether developmental abnormalities are present in the UF of younger individuals with CD. METHOD: We used DT-MRI tractography to investigate, for the first time, the microstructural integrity of the UF in adolescents with CD, and age-related differences in this tract. We compared FA and perpendicular diffusivity of the UF in 27 adolescents with CD and 16 healthy controls (12 to 19 years old) who did not differ significantly in age, IQ or substance use history. To confirm that these findings were specific to the UF, the same measurements were extracted from two non-limbic control tracts. Participants in the CD group had a history of serious aggressive and violent behaviour, including robbery, burglary, grievous bodily harm and sexual assault. RESULTS: Individuals with CD had a significantly increased FA (p = 0.006), and reduced perpendicular diffusivity (p = 0.002), in the left UF. Furthermore, there were significant age-related between-group differences in perpendicular diffusivity of the same tract (Z obs = 2.40, p = 0.01). Controls, but not those with CD, showed significant age-related maturation. There were no significant between-group differences in any measure within the control tracts. CONCLUSIONS: Adolescents with CD have significant differences in the 'connectivity' and maturation of UF.

Using deconvolution to improve PET spatial resolution in OSEM iterative reconstruction.

OBJECTIVES: A novel approach to the PET image reconstruction is presented, based on the inclusion of image deconvolution during conventional OSEM reconstruction. Deconvolution is here used to provide a recovered PET image to be included as "a priori" information to guide OSEM toward an improved solution. METHODS: Deconvolution was implemented using the Lucy-Richardson (LR) algorithm: Two different deconvolution schemes were tested, modifying the conventional OSEM iterative formulation: 1) We built a regularizing penalty function on the recovered PET image obtained by deconvolution and included it in the OSEM iteration. 2) After each conventional global OSEM iteration, we deconvolved the resulting PET image and used this "recovered" version as the initialization image for the next OSEM iteration. Tests were performed on both simulated and acquired data. RESULTS: Compared to the conventional OSEM, both these strategies, applied to simulated and acquired data, showed an improvement in image spatial resolution with better behavior in the second case. In this way, small lesions, present on data, could be better discriminated in terms of contrast. CONCLUSIONS: Application of this approach to both simulated and acquired data suggests its efficacy in obtaining PET images of enhanced quality.

A Deconvolution Approach Based on Multi-Tensor Model to Solve Fiber Crossing in Diffusion-MRI.

A deconvolution approach, based on a multi-tensor model, is presented to solve fiber crossing in diffusion MRI. In order to provide a direct physical interpretation of the signal generation process, we re-wrote the classical multi-tensor model, identifying a significant scalar parameter alpha to characterize the deconvolution process. Simulations show that, in presence of noise, the method is able to correctly separate fiber crossing. Application on in-vivo data highlights the ability of our approach to distinguish more than two fibers within the same voxel, suggesting its application in fiber tracking or connectivity studies even of complex brain structures.

Studies on the mechanism of action of mitomycin C.

The in vitro formation and properties of the molecular complex between mitomycin C and native DNA were examined by means of various experimental methods; the data obtained indicate that the complex is extremely weak and that the chromophoric moiety of the antibiotic is not involved in its formation. The alkylating activity of mitomycin C was also studied using 3H-mitomycin C; while monofunctional alkylation increases almost in parallel with the concentration of the antibiotic, the difunctional alkylation, causing inter-strand cross-linkages in DNA, rapidly reaches a maximum and then remains constant even when increasing the concentration of the antibiotic and monofunctional alkylation. On the basis of these results, the currently accepted molecular model of the mitomycin--DNA interaction must be revised; a new model of this interaction is presented, which is in better agreement with the properties of mitomycin C and with the latest findings on the subject.