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.

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.

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.

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.

Structural Brain Correlates of Childhood Inhibited Temperament: An ENIGMA-Anxiety Mega-analysis.

Temperament involves stable behavioral and emotional tendencies that differ between individuals, which can be first observed in infancy or early childhood and relate to behavior in many contexts and over many years.1 One of the most rigorously characterized temperament classifications relates to the tendency of individuals to avoid the unfamiliar and to withdraw from unfamiliar people, objects, and unexpected events. This temperament is referred to as behavioral inhibition or inhibited temperament (IT).2 IT is a moderately heritable trait1 that can be measured in multiple species.3 In humans, levels of IT can be quantified from the first year of life through direct behavioral observations or reports by caregivers or teachers. Similar approaches as well as self-report questionnaires on current and/or retrospective levels of IT1 can be used later in life.

Pediatric assessment of Research Domain Criteria positive and negative valence systems: Partial genetic mediation of links to problem behaviors.

We use the highly structured Laboratory-Temperament Assessment Battery to measure behaviors that map onto the Research Domain Criteria (RDoC) positive and negative valence systems. Using a birth record-based sample (N = 1374 individual twins; mean age 7.7 years), we created composites of observed behavior reflecting the RDoC constructs Reward Responsiveness, Frustrative Nonreward, Loss, and Fear. Next, we related the RDoC constructs concurrently and longitudinally to problem behaviors, measured using parent-report on the Health Behavior Questionnaire and symptom counts from the Diagnostic Interview Schedule for Children, Version IV (DISC-IV; reflecting DSM-IV). The four pediatric RDoC positive and negative valence system measures, especially Reward Responsiveness, Frustrative Nonreward, and Loss, were heritable and modestly but plausibly related to traditional DSM-based measures in a transdiagnostic manner. The modest predictions from RDoC measures to DSM-based measures were largely genetically mediated, although relationships with aggressive and oppositional behaviors were also influenced by common environmental factors. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Reduction of Motion Artifacts in Functional Connectivity Resulting from Infrequent Large Motion.

Introduction: Subject head motion is an ongoing challenge in functional magnetic resonance imaging, particularly in the estimation of functional connectivity. Infants (1-month old) scanned during nonsedated sleep often have occasional but large movements of several millimeters separated by periods with relatively little movement. This results in residual signal changes even after image realignment and can distort estimates of functional connectivity. A new motion correction technique, JumpCor, is introduced to reduce the effects of this motion and compared to other existing techniques. Methods: Different approaches for reducing residual motion artifacts after image realignment were compared both in actual and simulated data: JumpCor, regressing out the estimated subject motion, and regressing out the average white matter, cerebrospinal fluid (CSF), and global signals and their temporal derivatives. Results: Motion-related signal changes resulting from infrequent large motion were significantly reduced both by regressing out the estimated motion parameters and by JumpCor. Furthermore, JumpCor significantly reduced artifacts and improved the quality of functional connectivity estimates when combined with typical preprocessing approaches. Discussion: Motion-related signal changes resulting from occasional large motion can be effectively corrected using JumpCor and to a certain extent also by regressing out the estimated motion. This technique should reduce the data loss in studies where participants exhibit this type of motion, such as sleeping infants.

Genetic and environmental influences of variation in diffusion MRI measures of white matter microstructure.

Quantitative neuroimaging studies in twin samples can investigate genetic contributions to brain structure and microstructure. Diffusion tensor imaging (DTI) studies with twin samples have shown moderate to high heritability in white matter microstructure. This study investigates the genetic and environmental contributions of another widely used diffusion MRI model not yet applied to twin studies, neurite orientation dispersion and density imaging (NODDI). The NODDI model is a multicompartment model of the diffusion-weighted MRI signal, providing estimates of neurite density (ND) and the orientation dispersion index (ODI). A cohort of monozygotic (MZ) and same-sex dizygotic (DZ) twins (N = 460 individuals) between 13 and 24 years of age were scanned with a multi-shell diffusion weighted imaging protocol. Select white matter (WM) regions of interest (ROI) were extracted. Biometric structural equation modeling estimated the relative contributions from additive genetic (A) and common (C) and unique environmental (E) factors. Genetic factors for the NODDI measures accounted for 91% and 65% of the variation of global ND and ODI, respectively, compared with 83% for FA. We observed higher heritability for ND than both FA and ODI in 25 of 30 discrete white matter regions that we examined, suggesting ND may be more sensitive to underlying genetic sources of variation. This study demonstrated that genetic factors play a key role in the development of white matter microstructure using both DTI and NODDI.

Cord blood DNA methylation modifications in infants are associated with white matter microstructure in the context of prenatal maternal depression and anxiety.

Maternal and environmental factors influence brain networks and architecture via both physiological pathways and epigenetic modifications. In particular, prenatal maternal depression and anxiety symptoms appear to impact infant white matter (WM) microstructure, leading us to investigate whether epigenetic modifications (i.e., DNA methylation) contribute to these WM differences. To determine if infants of women with depression and anxiety symptoms exhibit epigenetic modifications linked to neurodevelopmental changes, 52 umbilical cord bloods (CBs) were profiled. We observed 219 differentially methylated genomic positions (DMPs; FDR p < 0.05) in CB that were associated with magnetic resonance imaging measures of WM microstructure at 1 month of age and in regions previously described to be related to maternal depression and anxiety symptoms. Genomic characterization of these associated DMPs revealed 143 unique genes with significant relationships to processes involved in neurodevelopment, GTPase activity, or the canonical Wnt signaling pathway. Separate regression models for female (n = 24) and male (n = 28) infants found 142 associated DMPs in females and 116 associated DMPs in males (nominal p value < 0.001, R > 0.5), which were annotated to 98 and 81 genes, respectively. Together, these findings suggest that umbilical CB DNA methylation levels at birth are associated with 1-month WM microstructure.

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.

Persistence During Childhood Problem-Solving as a Predictor of Active Suicidal Ideation During Adolescence.

Clarifying longitudinal, behavioral predictors for adolescent suicidality could enhance prediction and treatment efforts. We examined whether childhood attentional focusing, persistence, and problem-solving behavior are associated with risk for adolescent suicidal ideation. Participants were 116 twins, 40 of whom endorsed active suicidal ideation (i.e., probands), probands' cotwins, and matched controls. Higher scores on a composite measure derived at mean age 7.7 years of (1) effort and work duration during two childhood problem-solving tasks (untangling yarn and attempting to solve an unsolvable puzzle), (2) mother reported attentional focusing, and (3) observer reported persistence predicted decreased risk for suicidal ideation at mean age 14.4 years. This prediction held when comparing probands with controls (B = -1.01, SE = 0.38, p = 0.01, OR = 0.37) and with their cotwins (B = -0.86, SE = 0.38, p = 0.02, OR = 0.42). Our findings indicate that childhood problem-solving behavior relates meaningfully to risk for suicidal thoughts approximately 7 years later, on average. These results underscore how longitudinal behavioral risk factors could enhance prediction and treatment of adolescent suicidal ideation.

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.

Sex Differences in the Relationship Between Childhood Self-Regulation and Adolescent Adiposity.

OBJECTIVE: Research suggests that higher childhood self-regulation (CSR) predicts lower adiposity in adolescence. However, it is unclear whether this relationship differs by sex or by baseline weight status. Thus, this study investigated these questions in a longitudinal, community-based cohort. METHODS: The cohort included 221 girls and 214 boys. At age 9, CSR was assessed via parent/teacher reports of effortful control, and childhood BMI z scores (BMIz) were calculated from staff measurements. Late-adolescent waist-to-height ratio was based on staff measurements at age 18. RESULTS: CSR has a small inverse correlation with concurrent childhood BMIz in girls, but not in boys. Prospectively, however, CSR has a small inverse association with late-adolescent weight-to-height ratio in both sexes, after adjusting for childhood BMIz and other childhood predictors. This prospective association is marginally stronger for girls with higher (vs. lower) childhood BMIz. CONCLUSIONS: CSR inversely predicts changes in adiposity across adolescence in both sexes, with some evidence that this association is stronger for girls with higher (vs. lower) childhood adiposity. However, this inverse association between CSR and adiposity may emerge earlier in girls. Future research should examine the causal status of CSR and its relationship to behaviors (e.g., diet).

Early microstructure of white matter associated with infant attention.

Early infancy is characterized by rapid brain development that occurs alongside, and in response to, the development of cognitive and behavioral functions, including attention. Infants' ability to orient and sustain attention to stimuli develops in concert with refinement of the orienting network in frontoparietal regions of the brain. Infants (n = 97) underwent magnetic resonance imaging at one-month of age and data were fit to a diffusion tensor imaging model to calculate fractional anisotropy (FA) and radial diffusivity (RD), as well as to a neurite orientation dispersion and density imaging model to calculate intracellular volume fraction (νic). Infant attention was assessed at six months of age using a dynamic puppet task (Cuevas and Bell, 2014). Infants with higher FA in the corpus callosum and anterior cingulum showed increased orienting behaviors. Our findings indicate that increased microstructure of the white matter tracts in the orienting network may play a role in the early neurodevelopment of attentional orienting behaviors.

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.

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.

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.

Optimizing the intrinsic parallel diffusivity in NODDI: An extensive empirical evaluation.

PURPOSE: NODDI is widely used in parameterizing microstructural brain properties. The model includes three signal compartments: intracellular, extracellular, and free water. The neurite compartment intrinsic parallel diffusivity (d∥) is set to 1.7 µm2⋅ms-1, though the effects of this assumption have not been extensively explored. This work investigates the optimality of d∥ = 1.7 µm2⋅ms-1 under varying imaging protocol, age groups, sex, and tissue type in comparison to other biologically plausible values of d∥. METHODS: Model residuals were used as the optimality criterion. The model residuals were evaluated in function of d∥ over the range from 0.5 to 3.0 µm2⋅ms-1. This was done with respect to tissue type (i.e., white matter versus gray matter), sex, age (infancy to late adulthood), and diffusion-weighting protocol (maximum b-value). Variation in the estimated parameters with respect to d∥ was also explored. RESULTS: Results show d∥ = 1.7 µm2⋅ms-1 is appropriate for adult brain white matter but it is suboptimal for gray matter with optimal values being significantly lower. d∥ = 1.7 µm2⋅ms-1 was also suboptimal in the infant brain for both white and gray matter with optimal values being significantly lower. Minor optimum d∥ differences were observed versus diffusion protocol. No significant sex effects were observed. Additionally, changes in d∥ resulted in significant changes to the estimated NODDI parameters. CONCLUSION: The default (d∥) of 1.7 µm2⋅ms-1 is suboptimal in gray matter and infant brains.