Large-scale analysis of structural brain asymmetries during neurodevelopment: Associations with age and sex in 4265 children and adolescents.

Only a small number of studies have assessed structural differences between the two hemispheres during childhood and adolescence. However, the existing findings lack consistency or are restricted to a particular brain region, a specific brain feature, or a relatively narrow age range. Here, we investigated associations between brain asymmetry and age as well as sex in one of the largest pediatric samples to date (n = 4265), aged 1-18 years, scanned at 69 sites participating in the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) consortium. Our study revealed that significant brain asymmetries already exist in childhood, but their magnitude and direction depend on the brain region examined and the morphometric measurement used (cortical volume or thickness, regional surface area, or subcortical volume). With respect to effects of age, some asymmetries became weaker over time while others became stronger; sometimes they even reversed direction. With respect to sex differences, the total number of regions exhibiting significant asymmetries was larger in females than in males, while the total number of measurements indicating significant asymmetries was larger in males (as we obtained more than one measurement per cortical region). The magnitude of the significant asymmetries was also greater in males. However, effect sizes for both age effects and sex differences were small. Taken together, these findings suggest that cerebral asymmetries are an inherent organizational pattern of the brain that manifests early in life. Overall, brain asymmetry appears to be relatively stable throughout childhood and adolescence, with some differential effects in males and females.

Subtyping cognitive profiles in Autism Spectrum Disorder using a Functional Random Forest algorithm.

DSM-5 Autism Spectrum Disorder (ASD) comprises a set of neurodevelopmental disorders characterized by deficits in social communication and interaction and repetitive behaviors or restricted interests, and may both affect and be affected by multiple cognitive mechanisms. This study attempts to identify and characterize cognitive subtypes within the ASD population using our Functional Random Forest (FRF) machine learning classification model. This model trained a traditional random forest model on measures from seven tasks that reflect multiple levels of information processing. 47 ASD diagnosed and 58 typically developing (TD) children between the ages of 9 and 13 participated in this study. Our RF model was 72.7% accurate, with 80.7% specificity and 63.1% sensitivity. Using the random forest model, the FRF then measures the proximity of each subject to every other subject, generating a distance matrix between participants. This matrix is then used in a community detection algorithm to identify subgroups within the ASD and TD groups, and revealed 3 ASD and 4 TD putative subgroups with unique behavioral profiles. We then examined differences in functional brain systems between diagnostic groups and putative subgroups using resting-state functional connectivity magnetic resonance imaging (rsfcMRI). Chi-square tests revealed a significantly greater number of between group differences (p < .05) within the cingulo-opercular, visual, and default systems as well as differences in inter-system connections in the somato-motor, dorsal attention, and subcortical systems. Many of these differences were primarily driven by specific subgroups suggesting that our method could potentially parse the variation in brain mechanisms affected by ASD.

Identification of the cleavage sites of the RNA2-encoded polyproteins for two members of the genus Torradovirus by N-terminal sequencing of the virion capsid proteins.

Torradoviruses, family Secoviridae, are emergent bipartite RNA plant viruses. RNA1 is ca. 7kb and has one open reading frame (ORF) encoding for the protease, helicase and RNA-dependent RNA polymerase (RdRp). RNA2 is ca. 5kb and has two ORFs. RNA2-ORF1 encodes for a putative protein with unknown function(s). RNA2-ORF2 encodes for a putative movement protein and three capsid proteins. Little is known about the replication and polyprotein processing strategies of torradoviruses. Here, the cleavage sites in the RNA2-ORF2-encoded polyproteins of two torradoviruses, Tomato marchitez virus isolate M (ToMarV-M) and tomato chocolate spot virus, were determined by N-terminal sequencing, revealing that the amino acid (aa) at the -1 position of the cleavage sites is a glutamine. Multiple aa sequence comparison confirmed that this glutamine is conserved among other torradoviruses. Finally, site-directed mutagenesis of conserved aas in the ToMarV-M RdRp and protease prevented substantial accumulation of viral coat proteins or RNAs.

The effects of circulating testosterone and pubertal maturation on risk for disordered eating symptoms in adolescent males.

BACKGROUND: Testosterone may be a biological factor that protects males against eating disorders. Elevated prenatal testosterone exposure is linked to lower levels of disordered eating symptoms, but effects emerge only after mid-puberty. Whether circulating levels of testosterone account for decreased risk for disordered eating in boys after mid-puberty is currently unknown; however, animal data support this possibility. In rodents, prenatal testosterone's masculinizing effects on sex-differentiated behaviors emerge during puberty when circulating levels of testosterone increase and 'activate' the expression of masculinized phenotypes. This study investigated whether higher levels of circulating testosterone predict lower levels of disordered eating symptoms in adolescent boys, and in particular whether effects are associated with advancing pubertal maturation. METHOD: Participants were 213 male twins from the Michigan State University Twin Registry. The Minnesota Eating Behavior Survey and Eating Disorder Examination Questionnaire assessed several disordered eating symptoms. The Pubertal Development Scale assessed pubertal status. Afternoon saliva samples were assayed for testosterone using enzyme immunoassays. RESULTS: Consistent with animal data, higher levels of circulating testosterone predicted lower levels of disordered eating symptoms in adolescent boys and effects emerged with advancing puberty. Results were not accounted for by several important covariates, including age, adiposity, or mood/anxiety symptoms. CONCLUSIONS: Findings suggest that elevated circulating testosterone may be protective and underlie decreased risk for eating pathology in males during/after puberty, whereas lower levels of testosterone may increase risk and explain why some, albeit relatively few, males develop eating disorders.

The autism brain imaging data exchange: towards a large-scale evaluation of the intrinsic brain architecture in autism.

Autism spectrum disorders (ASDs) represent a formidable challenge for psychiatry and neuroscience because of their high prevalence, lifelong nature, complexity and substantial heterogeneity. Facing these obstacles requires large-scale multidisciplinary efforts. Although the field of genetics has pioneered data sharing for these reasons, neuroimaging had not kept pace. In response, we introduce the Autism Brain Imaging Data Exchange (ABIDE)-a grassroots consortium aggregating and openly sharing 1112 existing resting-state functional magnetic resonance imaging (R-fMRI) data sets with corresponding structural MRI and phenotypic information from 539 individuals with ASDs and 573 age-matched typical controls (TCs; 7-64 years) (http://fcon_1000.projects.nitrc.org/indi/abide/). Here, we present this resource and demonstrate its suitability for advancing knowledge of ASD neurobiology based on analyses of 360 male subjects with ASDs and 403 male age-matched TCs. We focused on whole-brain intrinsic functional connectivity and also survey a range of voxel-wise measures of intrinsic functional brain architecture. Whole-brain analyses reconciled seemingly disparate themes of both hypo- and hyperconnectivity in the ASD literature; both were detected, although hypoconnectivity dominated, particularly for corticocortical and interhemispheric functional connectivity. Exploratory analyses using an array of regional metrics of intrinsic brain function converged on common loci of dysfunction in ASDs (mid- and posterior insula and posterior cingulate cortex), and highlighted less commonly explored regions such as the thalamus. The survey of the ABIDE R-fMRI data sets provides unprecedented demonstrations of both replication and novel discovery. By pooling multiple international data sets, ABIDE is expected to accelerate the pace of discovery setting the stage for the next generation of ASD studies.

The effects of puberty on genetic risk for disordered eating: evidence for a sex difference.

BACKGROUND: Differences in genetic influences on disordered eating are present across puberty in girls. Heritability is 0% before puberty, but over 50% during and after puberty. Emerging data suggest that these developmental differences may be due to pubertal increases in ovarian hormones. However, a critical piece of evidence is lacking, namely, knowledge of genetic influences on disordered eating across puberty in boys. Boys do not experience increases in ovarian hormones during puberty. Thus, if pubertal increases in genetic effects are present in boys, then factors in addition to ovarian hormones may drive increases in heritability in girls. The current study was the first to examine this possibility in a sample of 1006 male and female twins from the Michigan State University Twin Registry. METHOD: Disordered eating was assessed with the Minnesota Eating Behavior Survey. Pubertal development was assessed with the Pubertal Development Scale. RESULTS: No significant differences in genetic influences on disordered eating were observed in males across any developmental stage. Heritability was 51% in boys during pre-puberty, puberty and young adulthood. By contrast, in girls, genetic factors accounted for 0% of the variance in pre-puberty, but 51% of the variance during puberty and beyond. Sex differences in genetic effects were only significant during pre-puberty, as the best-fitting models constrained heritability to be equal across all males, pubertal females and young adult females. CONCLUSIONS: The results highlight sex-specific effects of puberty on genetic risk for disordered eating and provide indirect evidence of a role for ovarian hormones and/or other female-specific factors.

Change in teachers' ratings of attention problems and subsequent change in academic achievement: a prospective analysis.

BACKGROUND: Recent research has documented a link between attention problems at school entry and later academic achievement. Little is known about the association of change in attention problems during the early school years with subsequent change in academic achievement. METHOD: A community-based cohort was followed up and assessed for attention problems at ages 6 and 11 (Teacher Report Form; TRF) and for academic achievement in math and reading at ages 11 and 17 (Woodcock-Johnson Psycho-Educational Battery). Complete data were available on 590 children (72% of the initial sample). Ordinary least squares regressions were used to estimate change in academic achievement from age 11 to age 17 in relation to change in TRF-attention problems from age 6 to age 11. Children's IQ and family factors were statistically controlled. RESULTS: Change in teachers' ratings of attention problems from age 6 to age 11 was negatively associated with change in math and reading from age 11 to age 17, controlling for children's IQ and family factors. Externalizing problems had no significant association with change in math or reading, when added to the multivariable model. CONCLUSIONS: Increases in teacher-rated attention problems from age 6 to age 11 were followed by declines in academic achievement from age 11 to age 17; decreases were followed by gains. The results underscore the need for research on the course of attention problems, the testing of interventions to address children's early attention problems and the evaluation of their effects on subsequent academic achievement.

Association and linkage of alpha-2A adrenergic receptor gene polymorphisms with childhood ADHD.

Attention-deficit hyperactivity disorder (ADHD) is a heritable disorder, prevalent from childhood through adulthood. Although the noradrenergic (NA) system is thought to mediate a portion of the pathophysiology of ADHD, genes in this pathway have not been investigated as frequently as those in the dopaminergic system. Previous association studies of one candidate gene in the NA system, ADRA2A, showed inconsistent results with regard to an MspI polymorphism. In the current study, two nearby single-nucleotide polymorphisms, which define HhaI and DraI restriction fragment length polymorphisms, were also genotyped and were in significant linkage disequilibrium with the MspI RFLP. Transmission disequilibrium tests (TDTs) in a sample of 177 nuclear families showed significant association and linkage of the DraI polymorphism with the ADHD combined subtype (P=0.03), and the quantitative TDT showed association of this polymorphism with the inattentive (P=0.003) and hyperactive-impulsive (P=0.015) symptom dimensions. The haplotype that contained the less common allele of the DraI polymorphism likewise showed a strong relationship with the inattentive (P=0.001) and hyperactive-impulsive (P=0.004) symptom dimensions. This study supports the hypothesis that an allele of the ADRA2A gene is associated and linked with the ADHD combined subtype and suggests that the DraI polymorphism of ADRA2A is linked to a causative polymorphism.

Parent stress and coping in relation to child ADHD severity and associated child disruptive behavior problems.

Examined parent role distress and coping in relation to childhood attention deficit hyperactivity disorder (ADHD) in mothers and fathers of 66 children age 7 to 11 (42 boys, 24 girls; mean age = 10.2). Parents of children with ADHD combined and inattentive subtypes expressed more role dissatisfaction than parents of control children. Parents of ADHD combined and inattentive type children did not differ significantly in levels of distress. For mothers, child inattention and oppositional-conduct problems but not hyperactivity contributed uniquely to role distress (dissatisfaction related to parenting or parenting performance). For fathers, parenting role distress was associated uniquely with child oppositional or aggressive behaviors but not with ADHD symptom severity. Parent coping by more use of positive reframing (thinking about problems as challenges that might be overcome) was associated with higher role satisfaction for both mothers and fathers. Community supports were associated with higher distress for mothers only.

Is ADHD a disinhibitory disorder?

Attention deficit hyperactivity disorder (ADHD) is widely theorized to stem from dysfunctional inhibitory processes. However, the definition of inhibition is imprecisely distinguished across theories. To clarify the evidence for this conception, the author relies on a heuristic distinction between inhibition that is under executive control and inhibition that is under motivational control (anxiety or fear). It is argued that ADHD is unlikely to be due to a motivational inhibitory control deficit, although suggestions are made for additional studies that could overturn that conclusion. Evidence for a deficit in an executive motor inhibition process for the ADHD combined type is more compelling but is not equally strong for all forms of executive inhibitory control. Remaining issues include specificity to ADHD, whether inhibitory problems are primary or secondary in causing ADHD, role of comorbid anxiety and conduct disorder, and functional deficits in the inattentive ADHD subtype.

On inhibition/disinhibition in developmental psychopathology: views from cognitive and personality psychology and a working inhibition taxonomy.

Disinhibition is a common focus in psychopathology research. However, use of inhibition models often is piecemeal, lacking an overarching taxonomy of inhibitory processes. The author organizes key concepts and models pertaining to different kinds of inhibitory control from the cognitive and temperament/personality literatures. Within the rubrics of executive inhibitory processes, motivational inhibitory processes, and automatic attentional inhibition processes, 8 kinds of inhibition are distinguished. Three basic temperament traits may address key executive and motivational inhibitory processes. Future developmental psychopathology research should be based on a systematic conceptual taxonomy of the kinds of inhibitory function relevant to a given disorder. Such an approach can clarify which inhibition distinctions are correct and which inhibition deficits go with which disorders.

The ADHD response-inhibition deficit as measured by the stop task: replication with DSM-IV combined type, extension, and qualification.

Although response inhibition has been proposed as a core element of child attention-deficit hyperactivity disorder (ADHD), the literature is heavily reliant on studies using DSM-III-R diagnostic criteria, older methods of measuring response inhibition, samples of boys, and failing to control thoroughly for comorbid problems--both as diagnoses and as subclinical variation. The present study replicated a deficit in response inhibition in the ADHD combined type (DSM-IV, American Psychiatric Association, 1994) using samples matched on age and sex. The study replicated an effect size of approximately d = .6 in boys with ADHD, and observed an even larger effect size for girls, although the Sex x Group interaction was nonsignificant. Children with ADHD also had problems with response output, shown by variable responding. Excluding comorbid conduct disorder, reading disorder, generalized anxiety disorder, obsessive-compulsive disorder, major depression, and posttraumatic stress disorder from the sample did not alter the results. Correlations indicated that response inhibition was associated with both attentional problems and reading level. Covarying for reading problems did not eliminate the ADHD group effect, but the association of response inhibition with reading clearly requires further examination. Overall, the study supported the role of response inhibition in the DSM-IV ADHD combined type, but with key qualifications as to degree of specificity in reference both to comorbid problems and other executive functions.

A two-year longitudinal study of neuropsychological and cognitive performance in relation to behavioral problems and competencies in elementary school children.

Despite interest in early neuropsychological status as a possible contributor to children's behavioral development, prospective longitudinal investigations of neuropsychological measures in relation to later behavioral outcomes in childhood are few. A 2-year longitudinal study in a nonselected childhood sample is reported. The study tested the influence of early neuropsychological performance (verbal fluency, mental inhibitory control, and visual spatial ability) on later childhood behavioral problems and social competency. Regular education children (n = 235) were assessed at three time points 1 year apart. To control for autocorrelation of outcome measures, Time 1 behavior was partialed while testing the effects of Time 1 neuropsychological scores on Time 3 outcome. To control for autocorrelation of neuropsychological scores, Time 2 scores were partialed while testing the predictive effect of Time 1 scores on Time 3 outcome. Both sets of regression models suggested modest but statistically significant effects for inhibitory control and verbal fluency, but not IQ, reading, or visual spatial ability, on behavioral outcome. Study results are consistent with a modest causal effect of selected neuropsychological skills on later behavioral adjustment. The findings support theories that implicate subtle neuropsychological dysfunction in the development of behavioral problems in childhood.

Parent personality traits and psychopathology associated with antisocial behaviors in childhood attention-deficit hyperactivity disorder.

Although a role for family and parent factors in the development of behavioral problems in childhood is often acknowledged, the roles of specific parental characteristics in relation to specific child actions need further elucidation. We studied parental "Big Five" personality traits and psychiatric diagnoses in relation to their children's antisocial diagnoses and naturalistically observed antisocial behaviors, in boys with and without the diagnosis of Attention-Deficit Hyperactivity Disorder (ADHD). First, regardless of comorbid antisocial diagnosis, boys with ADHD, more often than comparison boys, had mothers with a major depressive episode and/or marked anxiety symptoms in the past year, and fathers with a childhood history of ADHD. Second, compared to the nondiagnosed group, boys with comorbid ADHD + Oppositional Defiant or Conduct Disorder (ODD/CD) had fathers with lower Agreeableness, higher Neuroticism, and more likelihood of having Generalized Anxiety Disorder. Third, regarding linkages between parental characteristics and child externalizing behaviors, higher rates of child overt antisocial behaviors observed in a naturalistic summer program were associated primarily with maternal characteristics, including higher Neuroticism, lower Conscientiousness, presence of Major Depression, and absence of Generalized Anxiety Disorder. The association of maternal Neuroticism with child aggression was larger in the ADHD than in the comparison group. In contrast, higher rates of observed child covert antisocial behaviors were associated solely with paternal characteristics, including history of substance abuse and higher Openness. Results provide external validation in parent data for a distinction between overt and covert antisocial behaviors and support inclusion of parent personality traits in family studies. The interaction of maternal Neuroticism and child ADHD in predicting child aggression is interpreted in regard to a conceptualization of child by parent "fit."

Developmental psychopathology, personality, and temperament: reflections on recent behavioral genetics research.

Personality, temperament, and psychopathology were until recently largely distinct areas of study, each of which emphasized partitioning of heritable and environmental variance. The emergence of the paradigm of developmental psychopathology along with application of multivariate biometric models to behavioral genetic data has defined a second phase of research in these domains. Integrated research has begun to map dimensional liability-threshold models of psychopathology and to evaluate empirically the categorical versus dimensional etiology of traits and disorders. An interesting pattern in the data is that psychopathology is probably not merely an extreme of temperament or personality in many cases. Variations in temperament and personality are now known to be heavily influenced by additive genetic and nonshared environmental factors and to exhibit stable or increasing heritability across development. This pattern holds for some measures of psychopathology but not for others. For example, shared environment effects and decreasing heritability influence much adolescent psychopathology, and comorbid problems in young children appear to be due in part to shared environment effects. Other recent biometric work on the central problem of comorbidity in psychopathology suggests that shared genetic covariation accounts for some specific comorbidities but not others. A third phase of research is now underway, featuring study of specific molecular gene mechanisms by means of linkage and association studies in relation to behavioral phenotypes. Complementary integration of discoveries from biometric behavioral studies and molecular studies is expected to be the norm for the near future.

Covert visual spatial attention in boys with attention deficit hyperactivity disorder: lateral effects, methylphenidate response and results for parents.

We report three related studies of covert visual spatial orienting in child attention deficit hyperactivity disorder (ADHD). In Study 1, we examined covert visual spatial orienting in ADHD and comparison boys, Study 2 comprised a dose-response study of methylphenidate for the ADHD group, and Study 3 was an investigation of biological and adoptive parents. In contrast with comparison subjects (n = 17). ADHD boys aged 6-12 (n = 27) showed both slower reaction times overall and within-condition (lateral) asymmetries in reaction times. Specifically, boys with ADHD reacted more slowly to uncued targets in the left visual field than in the right visual field. Responses to stimuli in the two visual fields were differentially affected by methylphenidate for the ADHD group. Medication equalized visual field responses to the uncued targets, resulting in a significant cue x dose x visual field interaction. Further, medication altered the relative cue responsivity in the two visual fields, resulting in a significant dose x visual field interaction for the Validity Effect. Biological parents of ADHD boys (n = 16) also showed slower reaction times to uncued left visual field targets than to right visual field targets; in addition they showed slower response to invalidity cued targets in the right visual field. These literal effects were not observed in adoptive parents of ADHD boys (n = 12) or biological parents of comparison boys (n = 14). Possible abnormal hemispheric asymmetry of attention functions in boys with ADHD and their biological parents is discussed.

Neuropsychological functioning, motor speed, and language processing in boys with and without ADHD.

We administered a neuropsychological battery to boys aged 6 to 12 years old diagnosed with attention-deficit hyperactivity disorder (ADHD; n = 51) and to comparison boys of the same age range (n = 31). Boys with ADHD had greater difficulty than comparison youngsters on nonautomated language and motor tasks administered with a fast instructional set and on one of two traditional frontal executive measures (Porteus mazes). When tasks requiring automatic processing were paired with similar tasks requiring greater use of selective attention processes, the latter, controlled processing tasks differentiated groups better than did automated tasks. This differential effect of otherwise similar tasks is interpreted in terms of an output deficit mediated by response organization as detailed in the information processing literature. The ADHD group also exhibited slow gross motor output, measured independently of verbal output. The findings are evaluated in terms of both Luria's (1973) tripartite model of neurocognitive organization and frontal striatal models, with an emphasis on output processes. The observed language deficits could represent frontal lobe processes intricately related to self-monitoring and planning. The utility of controlled processing, self-paced tasks with fast instructional sets in assessing language and motor skills in ADHD is highlighted.

Genetics of personality disorders: perspectives from personality and psychopathology research.

Although the field is young, studies pertinent to genetic hypotheses have accumulated for several personality disorders. Genetic links to personality disorders from the domains of normal personality and Axis I disorders are reviewed. Evidence of a link to schizophrenia is clearest for schizotypal and less conclusive for paranoid and schizoid personality disorders. A genetic association between borderline personality disorder and affective disorders has not been clearly supported, but there may be a subtype genetically linked to affective disorders. Evidence of genetic influence is mixed for obsessive-compulsive personality disorder. In general, greater attention to dimensional phenotypic measures and multivariate designs can yield more definitive answers regarding the correct subtyping and probable etiology of personality disorders.

A paradigm for single-case research: the time series study of a long-term psychotherapy for depression.

This study articulates a paradigm for single-case research in psychotherapy. A patient diagnosed as having major depressive disorder was seen in an intensive, twice-weekly psychodynamic psychotherapy for 2 1/2 years. Each session was videotaped, and assessment of patient change were obtained at regular intervals. A time-series analysis was used to model fluctuations in the therapy process to take into account time and the effect of previous events on subsequent changes, thereby preserving the context-determined meaning for therapist and patient actions. A bidirectional analysis of casual effects shows that the influence processes between therapist and patient are mutual and reciprocal and suggests that the effect of the patient on the therapist and on the process has not been made sufficiently explicit in previous models of process and change. The potential of intensive single-case designs for uncovering causal effects in psychotherapy is demonstrated.

Malevolence, splitting, and parental ratings by borderlines.

Malevolent object relations as well as splitting have long been considered by psychodynamic theorists as central features of borderline personality disorder. We tested the hypotheses that borderlines would a) perceive their parents more negatively than both nonborderline major depressive patients and nonpatient normal controls, and b) split their representations of their parents into opposites more than the comparison subjects. Borderlines (N = 31), who were identified by the Diagnostic Interview for Borderlines, Research Diagnostic Criteria major depressives (N = 15), and nonpatient controls (N = 14) were asked to rate each parent on the Adjective Check List (ACL; Gough and Heilbrun, 1983). Seven ACL scales were studied: Favorable, Unfavorable, Critical Parent, Nurturing Parent, Nurturance, Aggression, and Dominance. Correlations were performed between scores for mother and father on the various scales for each of the three cohorts. Analysis of variance and one-way t-tests with Bonferroni correction were used to test group differences. Borderlines rated their parents, especially their fathers, not only as more unfavorable on negative scales than depressives or normals, but as less favorable on positive scales than the comparison groups. Analysis of covariance revealed that a significant portion of the variance in father scores, but not in mother scores, was related to age of respondent and history of sexual abuse. While borderlines did not appear to split their parents into one good and one bad parent, they did show significantly less correlation between parents on the Favorable scale when compared with either depressives or normal subjects. The results imply that borderlines have a greater tendency to view the world in negative, malevolent ways than to split their object representations.