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.

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.

Heterotopia in Individuals with 22q11.2 Deletion Syndrome.

BACKGROUND AND PURPOSE: MR imaging studies and neuropathologic findings in individuals with 22q11.2 deletion syndrome show anomalous early brain development. We aimed to retrospectively evaluate cerebral abnormalities, focusing on gray matter heterotopia, and to correlate these with subjects' neuropsychiatric impairments. MATERIALS AND METHODS: Three raters assessed gray matter heterotopia and other morphologic brain abnormalities on 3D T1WI and T2*WI in 75 individuals with 22q11.2 deletion syndrome (27 females, 15.5 [SD, 7.4] years of age) and 53 controls (24 females, 12.6 [SD, 4.7] years of age). We examined the association among the groups' most frequent morphologic findings, general cognitive performance, and comorbid neuropsychiatric conditions. RESULTS: Heterotopia in the white matter were the most frequent finding in individuals with 22q11.2 deletion syndrome (n = 29; controls, n = 0; between-group difference, P < .001), followed by cavum septi pellucidi and/or vergae (n = 20; controls, n = 0; P < .001), periventricular cysts (n = 10; controls, n = 0; P = .007), periventricular nodular heterotopia (n = 10; controls, n = 0; P = .007), and polymicrogyria (n = 3; controls, n = 0; P = .3). However, individuals with these morphologic brain abnormalities did not differ significantly from those without them in terms of general cognitive functioning and psychiatric comorbidities. CONCLUSIONS: Taken together, our findings, periventricular nodular heterotopia or heterotopia in the white matter (possibly related to interrupted Arc cells migration), persistent cavum septi pellucidi and/or vergae, and formation of periventricular cysts, give clues to the brain development disorder induced by the 22q11.2 deletion syndrome. There was no evidence that these morphologic findings were associated with differences in psychiatric or cognitive presentation of the 22q11.2 deletion syndrome.

The Neuroanatomy of Autism Spectrum Disorder Symptomatology in 22q11.2 Deletion Syndrome.

22q11.2 Deletion Syndrome (22q11.2DS) is a genetic condition associated with a high prevalence of neuropsychiatric conditions that include autism spectrum disorder (ASD). While evidence suggests that clinical phenotypes represent distinct neurodevelopmental outcomes, it remains unknown whether this translates to the level of neurobiology. To fractionate the 22q11.2DS phenotype on the level of neuroanatomy, we examined differences in vertex-wise estimates of cortical volume, surface area, and cortical thickness between 1) individuals with 22q11.2DS (n = 62) and neurotypical controls (n = 57) and 2) 22q11.2DS individuals with ASD symptomatology (n = 30) and those without (n = 25). We firstly observed significant differences in surface anatomy between 22q11.2DS individuals and controls for all 3 neuroanatomical features, predominantly in parietotemporal regions, cingulate and dorsolateral prefrontal cortices. We also established that 22q11.2DS individuals with ASD symptomatology were neuroanatomically distinct from 22q11.2DS individuals without ASD symptoms, particularly in brain regions that have previously been linked to ASD (e.g., dorsolateral prefrontal cortices and the entorhinal cortex). Our findings indicate that different clinical 22q11.2DS phenotypes, including those with ASD symptomatology, may represent different neurobiological subgroups. The spatially distributed patterns of neuroanatomical differences associated with ASD symptomatology in 22q11.2DS may thus provide useful information for patient stratification and the prediction of clinical outcomes.

Neurodevelopmental origins of abnormal cortical morphology in dissociative identity disorder.

OBJECTIVE: To examine the two constitutes of cortical volume (CV), that is, cortical thickness (CT) and surface area (SA), in individuals with dissociative identity disorder (DID) with the view of gaining important novel insights into the underlying neurobiological mechanisms mediating DID. METHODS: This study included 32 female patients with DID and 43 matched healthy controls. Between-group differences in CV, thickness, and SA, the degree of spatial overlap between differences in CT and SA, and their relative contribution to differences in regional CV were assessed using a novel spatially unbiased vertex-wise approach. Whole-brain correlation analyses were performed between measures of cortical anatomy and dissociative symptoms and traumatization. RESULTS: Individuals with DID differed from controls in CV, CT, and SA, with significantly decreased CT in the insula, anterior cingulate, and parietal regions and reduced cortical SA in temporal and orbitofrontal cortices. Abnormalities in CT and SA shared only about 3% of all significantly different cerebral surface locations and involved distinct contributions to the abnormality of CV in DID. Significant negative associations between abnormal brain morphology (SA and CV) and dissociative symptoms and early childhood traumatization (0 and 3 years of age) were found. CONCLUSIONS: In DID, neuroanatomical areas with decreased CT and SA are in different locations in the brain. As CT and SA have distinct genetic and developmental origins, our findings may indicate that different neurobiological mechanisms and environmental factors impact on cortical morphology in DID, such as early childhood traumatization.

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.

White-matter relaxation time and myelin water fraction differences in young adults with autism.

BACKGROUND: Increasing evidence suggests that autism is associated with abnormal white-matter (WM) anatomy and impaired brain 'connectivity'. While myelin plays a critical role in synchronized brain communication, its aetiological role in autistic symptoms has only been indirectly addressed by WM volumetric, relaxometry and diffusion tensor imaging studies. A potentially more specific measure of myelin content, termed myelin water fraction (MWF), could provide improved sensitivity to myelin alteration in autism. METHOD: We performed a cross-sectional imaging study that compared 14 individuals with autism and 14 age- and IQ-matched controls. T 1 relaxation times (T 1), T 2 relaxation times (T 2) and MWF values were compared between autistic subjects, diagnosed using the Autism Diagnostic Interview - Revised (ADI-R), with current symptoms assessed using the Autism Diagnostic Observation Schedule (ADOS) and typical healthy controls. Correlations between T 1, T 2 and MWF values with clinical measures [ADI-R, ADOS, and the Autism Quotient (AQ)] were also assessed. RESULTS: Individuals with autism showed widespread WM T 1 and MWF differences compared to typical controls. Within autistic individuals, worse current social interaction skill as measured by the ADOS was related to reduced MWF although not T 1. No significant differences or correlations with symptoms were observed with respect to T 2. CONCLUSIONS: Autistic individuals have significantly lower global MWF and higher T 1, suggesting widespread alteration in tissue microstructure and biochemistry. Areas of difference, including thalamic projections, cerebellum and cingulum, have previously been implicated in the disorder; however, this is the first study to specifically indicate myelin alteration in these regions.

The effect of age, diagnosis, and their interaction on vertex-based measures of cortical thickness and surface area in autism spectrum disorder.

Autism spectrum disorder (ASD) is a lifelong neurodevelopmental condition that is accompanied by an atypical development of brain maturation. So far, brain development has mainly been studied during early childhood in ASD, and using measures of total or lobular brain volume. However, cortical volumetric measures are a product of two distinct biological neuroanatomical features, cortical thickness, and surface area, which most likely also have different neurodevelopmental trajectories in ASD. Here, we therefore examined age-related differences in cortical thickness and surface area in a cross-sectional sample of 77 male individuals with ASD ranging from 7 to 25 years of age, and 77 male neurotypical controls matched for age and FSIQ. Surface-based measures were analyzed using a general linear model (GLM) including linear, quadratic, and cubic age terms, as well as their interactions with the main effect of group. When controlling for the effects of age, individuals with ASD had spatially distributed reductions in cortical thickness relative to controls, particularly in fronto-temporal regions, and also showed significantly reduced surface area in the prefrontal cortex and the anterior temporal lobe. We also observed significant group × age interactions for both measures. However, while cortical thickness was best predicted by a quadratic age term, the neurodevelopmental trajectory for measures of surface area was mostly linear. Our findings suggest that ASD is accompanied by age-related and region-specific reductions in cortical thickness and surface area during childhood and early adulthood. Thus, differences in the neurodevelopmental trajectory of maturation for both measures need to be taken into account when interpreting between-group differences overall.

Developing new pharmacotherapies for autism.

Developing new pharmacotherapies for autism spectrum disorder (ASD) is a challenge. ASD has a complex genetic architecture, several neurobiological phenotypes and multiple symptom domains. However, new opportunities are emerging that could lead to the development of 'targeted' and individualized pharmacological interventions. Here, first we review these important new insights into the aetiology and neurobiology of ASD with particular focus on (i) genetic variants mediating synaptic structure and functioning and (ii) differences in brain anatomy, chemistry and connectivity in this condition. The characterization of the genotypic and phenotypic differences underlying ASD might in the future be invaluable for stratifying the large range of different individuals on the autism spectrum into genetically and/or biologically homogeneous subgroups that might respond to similar targeted interventions. Secondly, we propose a strategic framework for the development of targeted pharmacotherapies for ASD, which comprises several different stages in which research findings are translated into clinical applications. The establishment of animal models and cellular assays is important for developing and testing new pharmacological targets before initiating large-scale clinical trials. Finally, we present the European Autism Interventions - A Multicentre Study for Developing New Medications (EU-AIMS) Initiative, which was set up in the context of the EU Innovative Medicines Initiative as the first European platform for integrated translational research in ASD. The EU-AIMS Initiative consists of academic and industrial partners working in collaboration to deliver a more 'personalized' approach to diagnosing and treating ASD in the future.

Disorder-specific functional abnormalities during sustained attention in youth with Attention Deficit Hyperactivity Disorder (ADHD) and with autism.

Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) are often comorbid and share behavioural-cognitive abnormalities in sustained attention. A key question is whether this shared cognitive phenotype is based on common or different underlying pathophysiologies. To elucidate this question, we compared 20 boys with ADHD to 20 age and IQ matched ASD and 20 healthy boys using functional magnetic resonance imaging (fMRI) during a parametrically modulated vigilance task with a progressively increasing load of sustained attention. ADHD and ASD boys had significantly reduced activation relative to controls in bilateral striato-thalamic regions, left dorsolateral prefrontal cortex (DLPFC) and superior parietal cortex. Both groups also displayed significantly increased precuneus activation relative to controls. Precuneus was negatively correlated with the DLPFC activation, and progressively more deactivated with increasing attention load in controls, but not patients, suggesting problems with deactivation of a task-related default mode network in both disorders. However, left DLPFC underactivation was significantly more pronounced in ADHD relative to ASD boys, which furthermore was associated with sustained performance measures that were only impaired in ADHD patients. ASD boys, on the other hand, had disorder-specific enhanced cerebellar activation relative to both ADHD and control boys, presumably reflecting compensation. The findings show that ADHD and ASD boys have both shared and disorder-specific abnormalities in brain function during sustained attention. Shared deficits were in fronto-striato-parietal activation and default mode suppression. Differences were a more severe DLPFC dysfunction in ADHD and a disorder-specific fronto-striato-cerebellar dysregulation in ASD.

Translational approaches to the biology of Autism: false dawn or a new era?

Discovering novel treatments for Autism Spectrum Disorders (ASD) is a challenge. Its etiology and pathology remain largely unknown, the condition shows wide clinical diversity, and case identification is still solely based on symptomatology. Hence clinical trials typically include samples of biologically and clinically heterogeneous individuals. 'Core deficits', that is, deficits common to all individuals with ASD, are thus inherently difficult to find. Nevertheless, recent reports suggest that new opportunities are emerging, which may help develop new treatments and biomarkers for the condition. Most important, several risk gene variants have now been identified that significantly contribute to ASD susceptibility, many linked to synaptic functioning, excitation-inhibition balance, and brain connectivity. Second, neuroimaging studies have advanced our understanding of the 'wider' neural systems underlying ASD; and significantly contributed to our knowledge of the complex neurobiology associated with the condition. Last, the recent development of powerful multivariate analytical techniques now enable us to use multi-modal information in order to develop complex 'biomarker systems', which may in the future be used to assist the behavioral diagnosis, aid patient stratification and predict response to treatment/intervention. The aim of this review is, therefore, to summarize some of these important new findings and highlight their potential significant translational value to the future of ASD research.

Anatomy and aging of the amygdala and hippocampus in autism spectrum disorder: an in vivo magnetic resonance imaging study of Asperger syndrome.

It has been proposed that people with autism spectrum disorder (ASD) have abnormal morphometry and development of the amygdala and hippocampus (AH). However, previous reports are inconsistent, perhaps because they included people of different ASD diagnoses, ages, and health. We compared, using magnetic resonance imaging, the in vivo anatomy of the AH in 32 healthy individuals with Asperger syndrome (12-47 years) and 32 healthy controls who did not differ significantly in age or IQ. We measured bulk (gray + white matter) volume of the AH using manual tracing (MEASURE). We first compared the volume of AH between individuals with Asperger syndrome and controls and then investigated age-related differences. We compared differences in anatomy before, and after, correcting for whole brain size. There was no significant between group differences in whole brain volume. However, individuals with Asperger syndrome had a significantly larger raw bulk volume of total (P<0.01), right (P<0.01), and left amygdala (P<0.05); and when corrected for overall brain size, total (P<0.05), and right amygdala (P<0.01). There was a significant group difference in aging of left amygdala; controls, but not individuals with Asperger syndrome, had a significant age-related increase in volume (r = 0.486, P<0.01, and r = 0.007, P = 0.97, z = 1.995). There were no significant group differences in volume or age-related effects in hippocampus. Individuals with Asperger syndrome have significant differences from controls in bulk volume and aging of the amygdala.

Migraine and motion sickness independently contribute to visual discomfort.

The objective of this study was to evaluate, in patients with migraine and healthy volunteers, with and without a history of motion sickness, the degree of discomfort elicited by drifting striped patterns. Eighteen healthy volunteers (HV) and 30 migraine patients participated in the study. Discomfort was greater in migraine patients than in HV, and in individuals with a history of motion sickness than in those without, but the effect of history of migraine was independent of history of motion sickness. Generalized Estimating Equations models for binary correlated data revealed that these differences did not depend on levels of duty cycle, spatial and temporal frequencies. Visual discomfort in migraine patients was associated with worse performance. There was a significant correlation between median degree of discomfort across conditions and number of migraine attacks in the past month. Discomfort to drifting striped patterns may be related to central sensitization in migraine patients.

Leucemia linfoide aguda a importancia do laboratorio de liquor para o sucesso do tratamento / Acute lymphoblastic leukemia: the importance of cerebrospinal fluid laboratory for successful treatament

A Leucemia Linfoide Aguda (LLA) e uma doenca caracterizada pelo acumulo de linfoblastos em numerosos orgaos e tecidos, notadamente na medula ossea. Entretanto as celulas malignas da LLA tem uma predisposicao de infiltrar o Sistema Nervoso Central (SNC) e os testiculos, sendo estes, considerados ¡°santuarios¡±. A importancia ao diagnostico da avaliacao citologica do liquido cefalorraqueano(Liquor) tornou-se fundamental para adequacao do tratamento, prognostico e para o monitoramento de eventuais recaidas. Citologicamente pode-se determinar um ¡°STATUS¡±, sendo que a avaliacao mais aceita atualmente ao diagnostico deve seguir os seguintes criterios: Status 1: puncao nao traumatica com ausencia de blastos apos citocentrifugacao. Status 2: puncao nao traumatica com presenca de blastos apos citocentrifugacao e leucocitos ¡Ü5/mm3. Status 3: puncao nao traumatica com presenca de blastosapos citocentrifugacao e leucocitos ¡Ý5/mm3 . A puncao traumatica deve ser classificada como risco, pois pode haver a infiltracao na hora da puncao. O objetivo deste trabalho e definir criteriosamente a importancia da atuacao do Farmaceutico Bioquimico no Laboratorio de Liquor auxiliando o clinico na avaliacao de conduta terapeutica baseado na avaliacao citologica do liquido cefalorraqueano.

Acute Lymphoblastic Leukemia (ALL) is an illness characterized for the accumulation of blasts in numerous organ and tissue, essential in the blone marrow. However the malignant cells of the ALL have a predisposition to infiltrate central nervous system(CNS) and the testicules, being been these, considered "sanctuaries". The importance to the diagnosis of the cytological evaluation of the cerebrospinal fluid (CSF), became basic for adequacy of the treatment, prognostic and for the involvement of eventual fallen again. Cytologically a "STATUS" can be determined, being most accepted currently to the diagnosis must follow the following criteria:CNS1 (puncture nontraumatic without leukemic blasts after ytocentrifugation), CNS2 (puncture nontraumatic, ¡Ü5 WBC/mm3 CSF with identifiable blasts after cytocentrifugation), CNS3 (puncture nontraumatic, ¡Ý5 WBC/mm3 CSF with identifiable blasts aftercytocentrifugation). TLP(+) ¨C puncture traumatic with blasts, and TLP(-) ¨C puncture traumatic without blasts. The traumatic puncture must be classified as risk therefore it can have infiltration in the hour puncture. The objective of this work is reintensification to define the importance of the performance of the Pharmaceutical Biochemist in the Cerebrospinal Fluid Laboratory assisting the physician in the based evaluation of therapeutical behavior in the cytological evaluation of the Cerebrospinal Fluid.

Genetic variation in the serotonin transporter modulates neural system-wide response to fearful faces.

A distributed, serotonergically innervated neural system comprising extrastriate cortex, amygdala and ventral prefrontal cortex is critical for identification of socially relevant emotive stimuli. The extent to which a genetic variation of serotonin transporter gene 5-HTTLPR impacts functional connectivity between the amygdala and the other components of this neural system remains little examined. In our study, neural activity was measured using event-related functional magnetic resonance imaging in 29 right-handed, white Caucasian healthy subjects as they viewed mild or prototypical fearful and neutral facial expressions. 5-HTTLPR genotype was classified as homozygous for the short allele (S/S), homozygous for the long allele (L/L) or heterozygous (S/L). S/S showed greater activity than L/L within right fusiform gyrus (FG) to prototypically fearful faces. To these fearful faces, S/S more than other genotype subgroups showed significantly greater positive functional connectivity between right amygdala and FG and between right FG and right ventrolateral prefrontal cortex (VLPFC). There was a positive association between measure of psychoticism and degree of functional connectivity between right FG and right VLPFC in response to prototypically fearful faces. Our data are the first to show that genotypic variation in 5-HTTLPR modulates both the amplitude within and the functional connectivity between different components of the visual object-processing neural system to emotionally salient stimuli. These effects may underlie the vulnerability to mood and anxiety disorders potentially triggered by socially salient, emotional cues in individuals with the S allele of 5-HTTLPR.

Neural responses to dynamic expressions of fear in schizophrenia.

Abnormalities in social functioning are a significant feature of schizophrenia. One critical aspect of these abnormalities is the difficulty these individuals have with the recognition of facial emotions, particularly negative expressions such as fear. The present work focuses on fear perception and its relationship to the paranoid symptoms of schizophrenia, specifically, how underlying limbic system structures (i.e. the amygdala) react when probed with dynamic fearful facial expressions. Seven paranoid and eight non-paranoid subjects (all males) with a diagnosis of schizophrenia took part in functional magnetic resonance imaging study (1.5T) examining neural responses to emerging fearful expressions contrasted with dissipating fearful expressions. Subjects viewed emerging and dissipating expressions while completing a gender discrimination task. Their brain activation was compared to that of 10 healthy male subjects. Increased hippocampal activation was seen in the non-paranoid group, while abnormalities in the bilateral amygdalae were observed only in the paranoid individuals. These patterns may represent trait-related hippocampal dysfunction, coupled with state (specifically paranoia) related amygdala abnormalities. The findings are discussed in light of models of paranoia in schizophrenia.

Blowing DNA bubbles.

We report here experimental observations which indicate that topologically or covalently formed polymer loops embedded in an ultrathin liquid film on a solid substrate can be "blown" into circular "bubbles" during scanning force microscopy (SFM) imaging. In particular, supercoiled vector DNA has been unraveled, moved, stretched, and overstretched to two times its B-form length and then torn apart. We attribute the blowing of the DNA bubbles to the interaction of the tapping SFM tip with the ultrathin liquid film.

The evaluation of sensory processing: a validity study using contrasting groups.

The purpose of this study was to examine the validity of a sensory history questionnaire using contrasting groups. Specifically, the goal was to identify items on the Evaluation of Sensory Processing that differentiate between parent ratings of children with sensory integrative dysfunction and parent ratings of typically developing children. Data were collected from 30 parents of children with sensory integrative dysfunction and 59 parents of typically developing children. Items were analyzed using a Wilcoxon signed rank test to detect the difference between the parent ratings for the 30 children with sensory integrative dysfunction and 30 of the typically developing children who were matched to the dysfunctional children on age, ethnicity, gender, geographic location, and socioeconomic status. Eighty-four of the 200 items significantly (p < .05) distinguished between parents' ratings of children with and without sensory integrative dysfunction.