Incidental Findings from 16,400 Brain MRI Examinations of Research Volunteers.

BACKGROUND AND PURPOSE: Incidental findings are discovered in neuroimaging research, ranging from trivial to life-threatening. We describe the prevalence and characteristics of incidental findings from 16,400 research brain MRIs, comparing spontaneous detection by nonradiology scanning staff versus formal neuroradiologist interpretation. MATERIALS AND METHODS: We prospectively collected 16,400 brain MRIs (7782 males, 8618 females; younger than 1 to 94 years of age; median age, 38 years) under an institutional review board directive intended to identify clinically relevant incidental findings. The study population included 13,150 presumed healthy volunteers and 3250 individuals with known neurologic diagnoses. Scanning staff were asked to flag concerning imaging findings seen during the scan session, and neuroradiologists produced structured reports after reviewing every scan. RESULTS: Neuroradiologists reported 13,593/16,400 (83%) scans as having normal findings, 2193/16,400 (13.3%) with abnormal findings without follow-up recommended, and 614/16,400 (3.7%) with "abnormal findings with follow-up recommended." The most common abnormalities prompting follow-up were vascular (263/614, 43%), neoplastic (130/614, 21%), and congenital (92/614, 15%). Volunteers older than 65 years of age were significantly more likely to have scans with abnormal findings (P < .001); however, among all volunteers with incidental findings, those younger than 65 years of age were more likely to be recommended for follow-up. Nonradiologists flagged <1% of MRIs containing at least 1 abnormality reported by the neuroradiologists to be concerning enough to warrant further evaluation. CONCLUSIONS: Four percent of individuals who undergo research brain MRIs have an incidental, potentially clinically significant finding. Routine neuroradiologist review of all scans yields a much higher rate of significant lesion detection than selective referral from nonradiologists who perform the examinations. Workflow and scan review processes need to be carefully considered when designing research protocols.

Leveraging latent profile analysis to synthesize childhood and adolescent risk factors for suicidal ideation.

Person-centered typologies identified with latent profile analysis can clarify patterns of chronic and acute risk factors for suicidal ideation. We derived five profiles of individuals using cognitive, behavioral, and familial factors relating to suicidal ideation risk factors. Participants (n = 1,142) were assessed at age 8 using the Laboratory Temperament Assessment Battery and mother-reported parenting measures and at age 14 using interviews about clinical symptoms and suicidal ideation. The best-fitting model included five profiles: typical, elevated adolescent symptomology, mildly elevated typical, low childhood persistence, and very low childhood persistence/mixed symptoms. Participants in the elevated adolescent symptomology and very low childhood persistence/mixed symptoms profiles were 2.6 and 5.3 times more likely to report suicidal ideation compared with the typical profile. Overall, our results underscore how using a person-centered pattern recognition approach and incorporating facets of childhood behavior may enhance conceptualizations of adolescent suicidal ideation risk.

Longitudinal Research at the Interface of Affective Neuroscience, Developmental Psychopathology, Health and Behavioral Genetics: Findings from the Wisconsin Twin Project.

The Wisconsin Twin Project comprises multiple longitudinal studies that span infancy to early adulthood. We summarize recent papers that show how twin designs with deep phenotyping, including biological measures, can inform questions about phenotypic structure, etiology, comorbidity, heterogeneity, and gene-environment interplay of temperamental constructs and mental and physical health conditions of children and adolescents. The general framework for investigations begins with rich characterization of early temperament and follows with study of experiences and exposures across childhood and adolescence. Many studies incorporate neuroimaging and hormone assays.

Correction to: Investigation of brain structure in the 1-month infant.

The authors regret that, in this article, there was an error in the analyses comparing infant male and female regional brain volume differences.

Investigation of brain structure in the 1-month infant.

The developing brain undergoes systematic changes that occur at successive stages of maturation. Deviations from the typical neurodevelopmental trajectory are hypothesized to underlie many early childhood disorders; thus, characterizing the earliest patterns of normative brain development is essential. Recent neuroimaging research provides insight into brain structure during late childhood and adolescence; however, few studies have examined the infant brain, particularly in infants under 3 months of age. Using high-resolution structural MRI, we measured subcortical gray and white matter brain volumes in a cohort (N = 143) of 1-month infants and examined characteristics of these volumetric measures throughout this early period of neurodevelopment. We show that brain volumes undergo age-related changes during the first month of life, with the corresponding patterns of regional asymmetry and sexual dimorphism. Specifically, males have larger total brain volume and volumes differ by sex in regionally specific brain regions, after correcting for total brain volume. Consistent with findings from studies of later childhood and adolescence, subcortical regions appear more rightward asymmetric. Neither sex differences nor regional asymmetries changed with gestation-corrected age. Our results complement a growing body of work investigating the earliest neurobiological changes associated with development and suggest that asymmetry and sexual dimorphism are present at birth.

Childhood inhibitory control and adolescent impulsivity and novelty seeking as differential predictors of relational and overt aggression.

Impulsivity is commonly conflated with novelty seeking, but these traits are conceptually independent and hold different predictive implications. Using a multi-informant, longitudinal design, we examined childhood inhibitory control, as well as adolescent impulsivity and novelty seeking, as predictors of aggression in a sample of 976 twins. Lower childhood inhibitory control and higher adolescent impulsivity predicted both overt and relational aggression in regression analyses that accounted for sex, puberty status, age, and socioeconomic status. As predicted, novelty seeking did not predict aggression, a finding that supports its independence from impulsivity.

Mapping White Matter Microstructure in the One Month Human Brain.

White matter microstructure, essential for efficient and coordinated transmission of neural communications, undergoes pronounced development during the first years of life, while deviations to this neurodevelopmental trajectory likely result in alterations of brain connectivity relevant to behavior. Hence, systematic evaluation of white matter microstructure in the normative brain is critical for a neuroscientific approach to both typical and atypical early behavioral development. However, few studies have examined the infant brain in detail, particularly in infants under 3 months of age. Here, we utilize quantitative techniques of diffusion tensor imaging and neurite orientation dispersion and density imaging to investigate neonatal white matter microstructure in 104 infants. An optimized multiple b-value diffusion protocol was developed to allow for successful acquisition during non-sedated sleep. Associations between white matter microstructure measures and gestation corrected age, regional asymmetries, infant sex, as well as newborn growth measures were assessed. Results highlight changes of white matter microstructure during the earliest periods of development and demonstrate differential timing of developing regions and regional asymmetries. Our results contribute to a growing body of research investigating the neurobiological changes associated with neurodevelopment and suggest that characteristics of white matter microstructure are already underway in the weeks immediately following birth.

Genetic and environmental influences on socio-emotional behavior in toddlers: an initial twin study of the infant-toddler social and emotional assessment.

BACKGROUND: Relatively little is known about the genetic architecture of childhood behavioral disorders in very young children. METHOD: In this study, parents completed the Infant-Toddler Social and Emotional Assessment, a questionnaire that assesses symptoms of childhood disorders, as well as socio-emotional competencies, for 822 twin pairs (49.3% female; age 17-48 months) participating in the Wisconsin Twin Project. Psychometric, rater bias, and sex-limitation models explored the role of genetic and environmental influences on (1) externalizing and internalizing behavior; (2) less commonly assessed behaviors pertaining to physical and emotional dysregulation, general competencies, social relatedness; and (3) infrequent behaviors such as those associated with pervasive developmental delays. RESULTS: Heritable influences accounted for the majority (56% or more) of variation in behavior that was commonly observed by both parents. The remaining variance was associated with non-shared environmental factors, with the exception of competency and atypical behavior, which were also influenced by shared environmental factors. In contrast, for most behaviors, the variation unique to mother and father ratings was split between variation due to shared environment or rater biases and to measurement error. Little evidence emerged for sex differences in the underlying causes of variation.

Assessing internalizing, externalizing, and attention problems in young children: validation of the MacArthur HBQ.

OBJECTIVE: To test the validity of the MacArthur Health and Behavior Questionnaire (HBQ) using receiver operating characteristic (ROC) analysis to determine optimal thresholds for the HBQ in predicting Diagnostic Interview Schedule for Children Version-IV (DISC-IV) diagnoses. The roles of child sex, level of impairment, and physical health in understanding of psychopathology were also considered. METHOD: A sample of 814 8-year-old twin children was recruited from birth records. Mothers were interviewed over the telephone using the HBQ and were also interviewed in person using the DISC-IV. Fathers also completed the HBQ; children completed the parallel module of the Berkeley Puppet Interview. RESULTS: The HBQ identified more cases overall than the DISC-IV. Sex did not contribute to prediction of diagnosis. Impairment, DISC-IV symptom counts, father HBQ, child Berkeley Puppet Interview, and physical health significantly distinguished the HBQ low and high symptom groups. CONCLUSIONS: The HBQ is a valid new screening measure of psychopathology for use with children under 9 years of age. It is sensitive to internalizing disorders, which may aid the understanding of depression and anxiety disorders that are often underappreciated in young children.

A population-based twin study of parentally reported tactile and auditory defensiveness in young children.

Some adults and children exhibit defensive behaviors to tactile or auditory stimulation. These symptoms occur not only in subsets of children with ADHD, autism, and Fragile X syndrome, but also in the apparent absence of accompanying disorders. Relatively little research explores the correlates and antecedents of sensory defensiveness. Using a population-based sample of 1,394 toddler-aged twins, mothers reported on tactile and auditory defensiveness, temperament, and behavior problems. The incidence of defensive symptoms was widely distributed, with some accumulation of cases in the extreme range. Girls were overrepresented in the extreme tactile defensiveness group. Both auditory and tactile defensiveness were modestly associated with fearful temperament and anxiety, but they were relatively distinct from other common dimensions of childhood behavioral dysfunction. Twin correlations for the full range of scores and concordance rates for the extremes suggested moderate genetic influences, with some indication that the tactile domain might be more heritable than the auditory domain.

Gaze fixation and the neural circuitry of face processing in autism.

Diminished gaze fixation is one of the core features of autism and has been proposed to be associated with abnormalities in the neural circuitry of affect. We tested this hypothesis in two separate studies using eye tracking while measuring functional brain activity during facial discrimination tasks in individuals with autism and in typically developing individuals. Activation in the fusiform gyrus and amygdala was strongly and positively correlated with the time spent fixating the eyes in the autistic group in both studies, suggesting that diminished gaze fixation may account for the fusiform hypoactivation to faces commonly reported in autism. In addition, variation in eye fixation within autistic individuals was strongly and positively associated with amygdala activation across both studies, suggesting a heightened emotional response associated with gaze fixation in autism.

Genetic, environmental, and gender effects on individual differences in toddler expressive language.

In this article, the authors examined the genetic and environmental factors influencing expressive language development in a sample of 386 toddler twin pairs participating in the Wisconsin Twin Project. Expressive language was assessed using 2 measures from the MacArthur Communicative Development Inventories-Short Form: Total Vocabulary and Two-Word Combination Use (L. Fenson et al., 2000). A sex-limitation structural equation model estimated the contribution of genetics, shared environment, and nonshared environment to individual variation. For vocabulary, heritability was higher for boys than for girls (20% vs. 8%). For word combination use, heritability was higher for girls (28% vs. 10%). However, the majority of individual variation in both boys and girls could be attributed to shared environment (54%-78%).

Disambiguating the components of emotion regulation.

Affective neuroscience and cognitive science approaches are useful for understanding the components of emotion regulation; several examples from current research are provided. Individual differences in emotion regulation and a focus on the context of emotion experience and expression provide additional tools to study emotion regulation, and its development, from a biobehavioral perspective.

Children's temperament and behavior problems predict their employed mothers' work functioning.

Numerous studies have been conducted on the impact of dual-earner parents' employment on their children, yet the reverse process-the impact of children and their behavior on the work functioning of their parents-has been ignored. This study investigated spillover from the mother role to the work role in a sample of more than 300 families. At 4 months, 12 months, 3.5 years, and 4.5 years of age, child's difficult temperament was significantly associated with mother's work outcomes, including work role quality and rewards from combining work and family. The evidence was consistent with a structural model in which maternal sense of parenting competence and maternal depressed affect mediated these effects.

Continuity and change in inhibited and uninhibited children.

After screening 368 toddlers and selecting 77 into extremely inhibited, extremely uninhibited, and intermediate groups, 63 children (82%) were followed up at 4 and 7 years. Minority subgroups of both the inhibited and uninhibited children showed continuity on outcomes consisting of questionnaire measures of shyness, inhibitory control, and impulsivity, as well as multiepisode observational measures of behavioral inhibition and exuberance. Change from both inhibited and uninhibited status from the toddler age was more common than remaining extremely inhibited or uninhibited, but that change was largely constrained to the middle of the distribution.

Salivary cortisol as a predictor of socioemotional adjustment during kindergarten: a prospective study.

This study, based on a sample of 172 children, examined the relation between average afternoon salivary cortisol levels measured at home at age 4.5 years and socioemotional adjustment a year and a half later, as reported by mothers, fathers, and teachers. Cortisol levels were hypothesized to be positively associated with withdrawal-type behaviors (e.g., internalizing, social wariness) and inversely related to approach-type behaviors, both negative and positive (e.g., externalizing, school engagement). Higher cortisol levels at age 4.5 predicted more internalizing behavior and social wariness as reported by teachers and mothers, although child gender moderated the relation between cortisol and mother report measures. An inverse relation was found between boys' cortisol levels and father report of externalizing behavior. A marginal inverse relation was found between child cortisol levels and teacher report of school engagement. Behavior assessed concurrently with cortisol collection did not account for the prospective relations observed,suggesting that cortisol adds uniquely to an understanding of behavioral development.

Linking temperamental fearfulness and anxiety symptoms: a behavior-genetic perspective.

Research on mood and anxiety disorders has historically proceeded without sufficient reference to the growing body of work on the nature of typical emotional development and temperament. Reviewing data from several studies, we consider experiential, biological, and genetic factors as providing causal input to typical developmental variation in fearfulness and anxiety during infancy and early childhood. Longitudinal behavioral methods, psychophysiologic measures, and a behavior-genetic framework are used to approach these issues. Results from twin studies implicate moderately strong genetic influences on different facets of temperamental fearfulness, as well as childhood anxiety symptoms. Then, we consider the distinction between normal range temperament and overt anxiety symptoms from a quantitative genetic perspective. Biological correlates (cortisol, asymmetric frontal EEG activation, cardiac reactivity) of inhibited behavior are considered as related endophenotypes for anxiety. In a nongenetic analysis, we report the prediction of internalizing problems during kindergarten from earlier temperament and earlier basal cortisol measures. Our review highlights connections between behavioral indicators and various putative endophenotypes and the fuzzy boundary between normal-range temperament and anxiety disorders.

Derivation and prediction of temperamental types among preschoolers.

The number and nature of temperamental types in 488 children aged 3 years 6 months was examined on the basis of a broad set of temperamental characteristics, including positive and negative emotionality and the attentional and behavioral control domains. Configural frequency analysis methods showed clear support for two temperament types: controlled-nonexpressive and noncontrolled-expressive. These types showed meaningful differences against external criteria related to a wide range of problem behaviors from the emotional, social, and attentional domains. The reports of problem behaviors were obtained contemporaneously from fathers and caregivers. These findings replicated a year later when children were aged 4 years 6 months. Furthermore, the findings showed that infant and toddler-age temperamental characteristics differentiated these preschool-aged types. The authors discuss the implications of the results for a categorical view of temperament-personality.

Genetic analyses of focal aspects of infant temperament.

The authors explored the genetic and environmental underpinnings of individual differences in temperament with a sample of 604 3- to 16-month-old infant twins and their parents. Mothers completed Rothbart's Infant Behavior Questionnaire (IBQ), and a subsample of 140 9-month-old twins participated in behavioral assessment of temperament in the laboratory as well. For IBQ Smiling and Laughter and Duration of Orienting, both additive genetic and shared environmental effects were needed to best represent the data. Shared environmental effects fully accounted for cotwin similarity for IBQ Soothability, and conversely, additive genetic effects fully accounted for cotwin similarity for the IBQ Distress to Limitations, Distress to Novelty, and Activity Level scales. With the subsample, the authors fit a multivariate model to mother report, father report, and lab measures of stranger distress and found that genetic influences were most important for the covariation among these measures.