Topological state-space estimation of functional human brain networks.

We introduce an innovative, data-driven topological data analysis (TDA) technique for estimating the state spaces of dynamically changing functional human brain networks at rest. Our method utilizes the Wasserstein distance to measure topological differences, enabling the clustering of brain networks into distinct topological states. This technique outperforms the commonly used k-means clustering in identifying brain network state spaces by effectively incorporating the temporal dynamics of the data without the need for explicit model specification. We further investigate the genetic underpinnings of these topological features using a twin study design, examining the heritability of such state changes. Our findings suggest that the topology of brain networks, particularly in their dynamic state changes, may hold significant hidden genetic information.

White matter microstructure predicts individual differences in infant fear (But not anger and sadness).

We examine neural correlates of discrete expressions of negative emotionality in infants to determine whether the microstructure of white matter tracts at 1 month of age foreshadows the expression of specific negative emotions later in infancy. Infants (n = 103) underwent neuroimaging at 1-month, and mothers reported on infant fear, sadness, and anger at 6, 12, and 18 months using the Infant Behavior Questionnaire-Revised. Levels and developmental change in fear, sadness, and anger were estimated from mother reports. Relations between MRI and infant emotion indicated that 1-month white matter microstructure was differentially associated with level and change in infant fear, but not anger or sadness, in the left stria terminalis (p < 0.05, corrected), a tract that connects frontal and tempo-parietal regions and has been implicated in emerging psychopathology in adults. More relaxed constraints on significance (p < 0.10, corrected) revealed that fear was associated with lower white matter microstructure bilaterally in the inferior portion of the stria terminalis and regions within the sagittal stratum. Results suggest the neurobehavioral uniqueness of fear as early as 1 month of age in regions that are associated with potential longer-term outcomes. This work highlights the early neural precursors of fearfulness, adding to literature explaining the psychobiological accounts of affective development. HIGHLIGHTS: Expressions of infant fear and anger, but not sadness, increase from 6 to 18 months of age. Early neural architecture in the stria terminalis is related to higher initial levels and increasing fear in infancy. After accounting for fear, anger and sadness do not appear to be associated with differences in early white matter microstructure. This work identifies early neural precursors of fearfulness as early as 1-month of age.

Childhood inhibition predicts adolescent social anxiety: Findings from a longitudinal twin study.

An enduring issue in the study of mental health is identifying developmental processes that explain how childhood characteristics progress to maladaptive forms. We examine the role that behavioral inhibition (BI) has on social anxiety (SA) during adolescence in 868 families of twins assessed at ages 8, 13, and 15 years. Multimodal assessments of BI and SA were completed at each phase, with additional measures (e.g., parenting stress) for parents and twins. Analyses were conducted in several steps: first, we used a cross-lagged panel model to demonstrate bidirectional paths between BI and SA; second a biometric Cholesky decomposition showed that both genetic and environmental influences on childhood BI also affect adolescent SA; next, multilevel phenotypic models tested moderation effects between BI and SA. We tested seven potential moderators of the BI to SA prediction in individual models and included only those that emerged as significant in a final conditional model examining predictors of SA. Though several main effects emerged as significant, only parenting stress had a significant interaction with BI to predict SA, highlighting the importance of environmental moderators in models examining temperamental effects on later psychological symptoms. This comprehensive assessment continues to build the prototype for such developmental psychopathology models.

Elucidating the Links Between Mother and Father Alcohol Use Disorder and Adolescent Externalizing Psychopathology: A Test of Transmission Specificity Within Competing Factor Structures and Genetic and Environmental Liabilities.

Parental alcohol use disorder (AUD) is a substantiated risk factor for adolescent externalizing psychopathology; however, the level of specificity at which risk from parental AUD is transmitted to adolescent offspring should be interrogated further. The current study modeled competing factor structures of psychopathology in a sample of 502 adolescent twin pairs (Mage = 13.24 years) and tested associations with mother and father AUD. The bifactor model exhibited the best fit to the data when contrasted with correlated factors and general factor models. Paternal AUD predicted the externalizing and internalizing correlated factors, the adolescent P-factor but not the residual externalizing and internalizing factors, and the general factor. No significant associations with maternal AUD were noted. Lastly, the latent factors of adolescent psychopathology were all moderately heritable (h2 = 0.44-0.59) and influenced by the nonshared environment. Shared genetic factors primarily explained externalizing and internalizing covariance. Findings suggest that efforts to mitigate risk in offspring of fathers exhibiting AUD require broader approaches that address the full range of adolescent symptomology.

Longitudinal effects of family psychopathology and stress on pubertal maturation and hormone coupling in adolescent twins.

Adolescents experience profound neuroendocrine changes, including hormone "coupling" between cortisol, testosterone, and dehydroepiandrosterone. Emerging research has only begun to elucidate the role of hormone coupling, its genetic and environmental etiology, and the extent to which coupling is impacted by gender, puberty, and family context. We included measures on parent and child mental health, parenting stress, and family conflict of 444 twin pairs and their parents across two timepoints, when youth were on average 8 and 13 years old, respectively. Structural equation models examined the impact of family context effects on coupling during adolescence. Biometric twin models were then used to probe additive genetic, shared, and non-shared environmental effects on hormone coupling. Hormones were more tightly coupled for females than males, and coupling was sensitive to parental depression and co-twin psychopathology symptoms and stress exposure in females. The association between family context and coupling varied across specific neuroendocrine measures and was largely distinct from pubertal maturation. Biometric models revealed robust shared and non-shared environmental influences on coupling. We found that family antecedents modify the strength of coupling. Environmental influences account for much of the variation on coupling during puberty. Gender differences were found in genetic influences on coupling.

Observed Profiles of Infant Temperament: Stability, Heritability, and Associations With Parenting.

Profiles of infant temperament were derived from 990 infants at 6 and 12 months of age using observed measures from the Laboratory Temperament Assessment Battery. Mothers and fathers completed questionnaires measuring parent affect and stress. Four profiles emerged at each age (typical, low negative, withdrawn/inhibited, and positive/active or low reactive) using latent profile analysis. Temperament profiles show some evidence of stability and heritability, particularly for the withdrawn/inhibited group. In addition, profiles relate to parent affect and stress in different ways for mothers and fathers. Results highlight the utility of a person-centered approach to temperamental research and are discussed in relation to developmental patterns of infant temperament.

Attentional Control Explains Covariation Between Symptoms of Attention-Deficit/Hyperactivity Disorder and Anxiety During Adolescence.

Symptoms of attention-deficit/hyperactivity disorder (ADHD) and anxiety are common during adolescence and frequently co-occur. However, the genetic and environmental influences that underlie this co-occurrence are understudied. Using a large twin sample (N = 1,017), we examined cross-sectional genetic and environmental influences on ADHD and anxiety symptoms during childhood. We also explored whether these influences were shared with attentional control, a putative mechanism for symptom comorbidity. We found evidence for common genetic and nonshared environmental influences on the covariation among attentional control, ADHD, and anxiety symptoms, supporting the putative role of attentional control as a mechanism by which comorbid problems may develop. Genetic factors also accounted for symptom co-occurrence after controlling for covariation with attentional control, suggesting the presence of additional unmeasured mechanisms.

Wisconsin Twin Project Overview: Temperament and Affective Neuroscience.

The Wisconsin Twin Project encompasses nearly 30 years of longitudinal research that spans infancy to early adulthood. The twin sample was recruited from statewide birth records for birth cohorts 1989-2004. We summarize early recruitment, assessment, retention and recently completed twin neuroimaging studies. In addition to the focal twins, longitudinal data were also collected from two parents and nontwin siblings. Our adolescent and young adult neuroimaging sample (N = 600) completed several previous behavioral and environmental assessments, beginning shortly after birth. The extensive phenotyping is meant to support a range of empirical investigations with potentially differing theoretical perspectives.

Genetic associations with reflexive visual attention in infancy and childhood.

This study elucidates genetic influences on reflexive (as opposed to sustained) attention in children (aged 9-16 years; N = 332) who previously participated as infants in visual attention studies using orienting to a moving bar (Dannemiller, 2004). We investigated genetic associations with reflexive attention measures in infancy and childhood in the same group of children. The genetic markers (single nucleotide polymorphisms and variable number tandem repeats on the genes APOE, BDNF, CHRNA4, COMT, DRD4, HTR4, IGF2, MAOA, SLC5A7, SLC6A3, and SNAP25) are related to brain development and/or to the availability of neurotransmitters such as acetylcholine, dopamine, or serotonin. This study shows that typically developing children have differences in reflexive attention associated with their genes, as we found in adults (Lundwall, Guo & Dannemiller, 2012). This effort to extend our previous findings to outcomes in infancy and childhood was necessary because genetic influence may differ over the course of development. Although two of the genes that were tested in our adult study (Lundwall et al., 2012) were significant in either our infant study (SLC6A3) or child study (DRD4), the specific markers tested differed. Performance on the infant task was associated with SLC6A3. In addition, several genetic associations with an analogous child task occurred with markers on CHRNA4, COMT, and DRD4. Interestingly, the child version of the task involved an interaction such that which genotype group performed poorer on the child task depended on whether we were examining the higher or lower infant scoring group. These findings are discussed in terms of genetic influences on reflexive attention in infancy and childhood.

Infant stranger fear trajectories predict anxious behaviors and diurnal cortisol rhythm during childhood.

Although a robust literature has linked stable, high levels of fear across childhood to increased risk for anxiety problems, less is known about alternative pathways to anxiety. We tested two putatively normative developmental pathways of early fearfulness for their distinct associations with behavioral (anxiety-related behaviors and symptoms) and biological (diurnal cortisol) markers of anxiety risk in middle childhood in a community-based sample (n = 107). Steeper increases in fear from 6 to 36 months predicted more parent-reported anxiety symptoms at age 8 years. In addition, children who exhibited steep increases in fear during infancy were overrepresented among children with diagnoses of separation anxiety disorder at age 8 years. Finally, we showed that steeper increases in fearfulness in infancy predicted flatter slopes of diurnal cortisol at age 8 years for girls. Thus, differences in stranger fear across infancy may indicate varying degrees of risk for anxious behaviors in later childhood.

The Shared Etiology of Attentional Control and Anxiety: An Adolescent Twin Study.

We investigated the etiology of attentional control (AC) and four different anxiety symptom types (generalized, obsessive-compulsive, separation, and social) in an adolescent sample of over 400 twin pairs. Genetic factors contributed to 55% of the variance in AC and between 43 and 58% of the variance in anxiety. Negative phenotypic associations between AC and anxiety indicated that lower attentional ability is related to increased risk for all 4 anxiety categories. Genetic correlations between AC and anxiety phenotypes ranged from -.36 to -.47, with evidence of nonshared environmental covariance between AC and generalized and separation anxiety. Results suggest that AC is a phenotypic and genetic risk factor for anxiety in early adolescence, with somewhat differing levels of risk depending on symptomatology.

Partial replication of two rumination-related candidate gene studies.

Two recent papers associated candidate genes with brooding rumination, a possible cognitive endophenotype for depression, in children ages 8-14 years. Stone et al. reported that BDNF val66met polymorphism predicted brooding in adolescence. Woody et al. reported that children carrying at least one copy of a CRHR1 TAT haplotype reported less brooding than their peers in the presence of maternal depression. We attempted to replicate and extend these findings in a sample of twins aged 12-16 years. We analyzed the BDNF val66met (rs6265) polymorphism and two (rs242924 and rs7209436) out of three single nucleotide polymorphisms (SNPs) that Woody et al. used to create a CRHR1 haplotype. We controlled for maternal history of depression and clustering within families. Unlike Stone et al., we found higher brooding among BDNF Met carriers. This main effect was qualified by an interaction with pubertal status, with the effect driven by more physically mature participants. Similar to Woody et al., we found an interaction between CRHR1 SNPs and maternal depression, with the homozygous minor genotype acting as a protective factor against brooding in the presence of maternal depression. Findings provide partial support for the influence of candidate genes in two environmentally sensitive systems on brooding.

A Twin Factor Mixture Modeling Approach to Childhood Temperament: Differential Heritability.

Twin factor mixture modeling was used to identify temperament profiles while simultaneously estimating a latent factor model for each profile with a sample of 787 twin pairs (Mage  = 7.4 years, SD = .84; 49% female; 88.3% Caucasian), using mother- and father-reported temperament. A four-profile, one-factor model fit the data well. Profiles included "regulated, typical reactive," "well-regulated, positive reactive," "regulated, surgent," and "dysregulated, negative reactive." All profiles were heritable, with lower heritability and shared environment also contributing to membership in the "regulated, typical reactive" and "dysregulated, negative reactive" profiles.

Maternal negative affect during infancy is linked to disrupted patterns of diurnal cortisol and alpha asymmetry across contexts during childhood.

Maternal negative affect in the early environment is believed to sensitize long-term coping capacities in children. Yet, little work has identified physiological systems associated with coping responses, which may serve as mechanisms for links between early maternal negativity and child outcomes. Using a longitudinal twin sample (N=89), we found that high levels of maternal negative affect during infancy were associated with dysregulation of diurnal cortisol and electroencephalograph (EEG) asymmetry, two physiological systems that may support active approach-oriented coping when children are 7years old. Flattened slopes of diurnal cortisol were also associated with greater numbers of concurrent overanxious behaviors in children. A mediation analysis supported the role of dysregulated diurnal cortisol as a mediator of the link between maternal negative affect in the early environment and childhood risk for anxiety problems.

Context differences in delta beta coupling are associated with neuroendocrine reactivity in infants.

Although evidence suggests that delta-beta coupling may provide a useful index of trait level cortico-subcortical cross talk in baseline contexts, there has been little work done to clarify the role of delta-beta coupling across contexts and in association with other physiological markers of emotion processing. We examined whether individual differences in coupling were visible across both positive and negative emotion-eliciting episodes during infancy (age 6 months). We also tested the convergence between measures of delta-beta coupling and neuroendocrine reactivity, which is also believed to index emotion processing. Patterns of coupling across emotion-eliciting episodes differed based on infants' levels of cortisol reactivity. Low cortisol-reactive infants largely did not show differences in coupling across emotion contexts while high cortisol-reactive infants showed greater coupling in non-fear contexts during baseline and fear episodes. Moreover, high cortisol-reactive infants showed greater coupling than low-reactive infants in non-positive episodes.

Genetic and Environmental Contributions to Covariation Between DHEA and Testosterone in Adolescent Twins.

Although several studies have shown that pubertal tempo and timing are shaped by genetic and environmental factors, few studies consider to what extent endocrine triggers of puberty are shaped by genetic and environmental factors. Doing so moves the field from examining correlated developmentally-sensitive biomarkers toward understanding what drives those associations. Two puberty related hormones, dehydroepiandrosterone and testosterone, were assayed from salivary samples in 118 MZ (62 % female), 111 same sex DZ (46 % female) and 103 opposite-sex DZ twin pairs, aged 12-16 years (M = 13.1, SD = 1.3). Pubertal status was assessed with a composite of mother- and self-reports. We used biometric models to estimate the genetic and environmental influences on the variance and covariance in testosterone and DHEA, with and without controlling for their association with puberty, and to test for sex differences. In males, the variance in testosterone and pubertal status was due to shared and non-shared environmental factors; variation in DHEA was due to genetic and non-shared environmental factors. In females, variance in testosterone was due to genetic and non-shared environmental factors; genetic, shared, and non-shared environmental factors contributed equally to variation in DHEA. In males, the testosterone-DHEA covariance was primarily due to shared environmental factors that overlapped with puberty as well as shared and non-shared environmental covariation specific to testosterone and DHEA. In females, the testosterone-DHEA covariance was due to genetic factors overlapping with pubertal status, and shared and non-shared environmental covariation specific to testosterone and DHEA.

The Unique and Shared Genetic and Environmental Contributions to Fear, Anger, and Sadness in Childhood.

This study examined the extent to which subordinate dimensions of negative emotionality were genetically and environmentally distinct in a sample of 1,316 twins (51% female, 85.8% Caucasian, primarily middle class, Mage = 7.87 years, SD = .93), recruited from Wisconsin hospital birth records between 1989 and 2004. Cholesky, independent pathway, and common pathway models were fitted for mother report, father report, and in-home observation of temperament. Although findings support the use of negative emotionality, there were heritable aspects of anger and fear not explained by a common genetic factor, and shared environmental influences common to anger and sadness but not fear. Observed fear was independent from observed anger and sadness. Distinctions support specificity in measurement when considering implications for child development.

The development of stranger fear in infancy and toddlerhood: normative development, individual differences, antecedents, and outcomes.

Despite implications that stranger fear is an important aspect of developing behavioral inhibition, a known risk factor for anxiety, normative and atypical developmental trajectories of stranger fear across infancy and toddlerhood remain understudied. We used a large, longitudinal data set (N = 1285) including multi-trait, multi-method assessments of temperament to examine the normative course of development for stranger fear and to explore the possibility that individual differences exist in trajectories of stranger fear development between 6 and 36 months of age. A latent class growth analysis suggested four different trajectories of stranger fear during this period. Stable, high levels of stranger fear over time were associated with poorer RSA suppression at 6 months of age. Rates of concordance in trajectory-based class membership for identical (monozygotic) and fraternal (dizygotic) twins, along with associations between atypical stranger fear development and greater anxiety-related maternal characteristics, suggested that individual differences in developmental trajectories of stranger fear may be heritable. Importantly, trajectories of stranger fear during infancy and toddlerhood were linked to individual differences in behavioral inhibition, with chronically high levels of stranger fear and sharp increases in stranger fear over time related to greater levels of inhibition than other developmental trajectories.

Childhood temperament: passive gene-environment correlation, gene-environment interaction, and the hidden importance of the family environment.

Biological parents pass on genotypes to their children, as well as provide home environments that correlate with their genotypes; thus, the association between the home environment and children's temperament can be genetically (i.e., passive gene-environment correlation) or environmentally mediated. Furthermore, family environments may suppress or facilitate the heritability of children's temperament (i.e., gene-environment interaction). The sample comprised 807 twin pairs (mean age = 7.93 years) from the longitudinal Wisconsin Twin Project. Important passive gene-environment correlations emerged, such that home environments were less chaotic for children with high effortful control, and this association was genetically mediated. Children with high extraversion/surgency experienced more chaotic home environments, and this correlation was also genetically mediated. In addition, heritability of children's temperament was moderated by home environments, such that effortful control and extraversion/surgency were more heritable in chaotic homes, and negative affectivity was more heritable under crowded or unsafe home conditions. Modeling multiple types of gene-environment interplay uncovered the complex role of genetic factors and the hidden importance of the family environment for children's temperament and development more generally.

Wisconsin Twin Research: early development, childhood psychopathology, autism, and sensory over-responsivity.

The Wisconsin Twin Research Program comprises multiple longitudinal studies that utilize a panel recruited from statewide birth records for the years 1989 through 2004. Our research foci are the etiology and developmental course of early emotions, temperament, childhood anxiety and impulsivity, autism, sensory over-responsivity, and related topics. A signature feature of this research program is the breadth and depth of assessment during key periods of development. The assessments include extensive home- and laboratory-based behavioral batteries, recorded sibling and caregiver interactions, structured psychiatric interviews with caregivers and adolescents, observer ratings of child behavior, child self-report, cognitive testing, neuroendocrine measures, medical records, dermatoglyphics, genotyping, and neuroimaging. Across the various studies, testing occasions occurred between 3 months and 18 years of age. Data collection for some aspects of the research program has concluded and, for other aspects, longitudinal follow-ups are in progress.