Anxiety symptoms and puberty interactively predict lower cingulum microstructure in preadolescent Latina girls.

Preadolescence is a period of increased vulnerability for anxiety, especially among Latina girls. Reduced microstructure (fractional anisotropy; FA) of white matter tracts between limbic and prefrontal regions may underlie regulatory impairments in anxiety. However, developmental research on the association between anxiety and white matter microstructure is mixed, possibly due to interactive influences with puberty. In a sample of 39 Latina girls (8-13 years), we tested whether pubertal stage moderated the association between parent- and child-reported anxiety symptoms and FA in the cingulum and uncinate fasciculus. Parent- but not child-reported anxiety symptoms predicted lower cingulum FA, and this effect was moderated by pubertal stage, such that this association was only significant for prepubertal girls. Neither anxiety nor pubertal stage predicted uncinate fasciculus FA. These findings suggest that anxiety is associated with disruptions in girls' cingulum white matter microstructure and that this relationship undergoes maturational changes during puberty.

Paternal expressed emotion influences psychobiological indicators of threat and safety learning in daughters: A preliminary study.

This preliminary study examined the association of children's anxiety, paternal expressed emotion (EE), and their interaction with psychophysiological indices of children's threat and safety learning. Participants included 24 father-daughter dyads. Daughters (ages 8-13 years, 100% Latina) self-reported their anxiety levels and completed a differential threat conditioning and extinction paradigm, during which psychophysiological responding was collected. Fathers completed a Five-Minute Speech Sample, from which paternal EE (i.e., criticism, emotional overinvolvement) was assessed. Anxiety-dependent associations emerged between paternal EE and individual differences in daughters' psychophysiological responding to safety signals during threat conditioning. Paternal EE was positively associated with psychophysiological responding to safety in daughters with high and mean, but not low, levels of anxiety. Although previous work suggests that chronic harsh maternal parenting is a potential risk factor for children's general threat and safety learning, these preliminary findings implicate milder forms of negative parenting behavior in fathers, particularly for highly anxious children.

Social relevance modulates multivariate neural representations of threat generalization in children and adults.

Few studies have examined threat generalization across development and no developmental studies have compared the generalization of social versus nonsocial threat, making it difficult to identify contextual factors that contribute to threat learning across development. The present study assessed youth and adults' multivoxel neural representations of social versus nonsocial threat stimuli. Twenty adults (Mage  = 25.7 ± 4.9) and 16 youth (Mage  = 14.1 ± 1.7) completed two conditioning and extinction recall paradigms: one social and one nonsocial paradigm. Three weeks after conditioning, participants underwent a functional magnetic resonance imaging extinction recall task that presented the extinguished threat cue (CS+), a safety cue (CS-), and generalization stimuli (GS) consisting of CS-/CS+ blends. Across age groups, neural activity patterns and self-reported fear and memory ratings followed a linear generalization gradient for social threat stimuli and a quadratic generalization gradient for nonsocial threat stimuli, indicating enhanced threat/safety discrimination for social relative to nonsocial threat stimuli. The amygdala and ventromedial prefrontal cortex displayed the greatest neural pattern differentiation between the CS+ and GS/CS-, reinforcing their role in threat learning and extinction recall. Contrary to predictions, age did not influence threat representations. These findings highlight the importance of the social relevance of threat on generalization across development.

Social skills moderate the time-varying association between aggression and peer rejection among children with and without ADHD.

Although childhood aggression is typically associated with peer rejection, some children concurrently employ coercive and socially skilled behavior and successfully avoid negative peer outcomes. However, research on children's dual use of coercive and social behavior has largely employed cross-sectional designs with nonclinical populations and, as a result, little is known about the covariation of aggression with social skills, particularly among high-risk samples. We directly addressed this limitation by testing childhood aggression and social skills as separate time-varying predictors of prospective change in peer rejection in a sample of children with and without attention-deficit/hyperactivity disorder (ADHD). Two hundred and two 5-10-year-old children (M = 7.9 years, SD = 1.2) with and without ADHD were followed prospectively for 6 years. Key constructs, including children's overt aggression, social skills, and peer rejection, were collected at each of the three waves using multiple methods and informants. Controlling for demographic factors and time-varying ADHD symptoms, longitudinal change in child-, parent-, and teacher-reported aggression positively predicted prospective change in parent- and teacher-reported peer rejection. Importantly, predictions were moderated by parent- and teacher-reported social skills, such that aggression inversely predicted peer rejection for children with high social skills. These results demonstrate that social skills meaningfully alter trajectories of peer rejection predicted from cross-time variation in aggression. We discuss the theoretical and empirical implications of these findings within a developmental psychopathology framework, including recommendations for directions for future research.

Divergence in cortical representations of threat generalization in affective versus perceptual circuitry in childhood: Relations with anxiety.

Children at risk for anxiety display elevated threat sensitivity and may inaccurately classify safe stimuli as threatening, a process known as overgeneralization. Little is known about whether such overgeneralization might stem from altered sensory representations of stimuli resembling threat, especially in youth. Here we implement representational similarity analysis of fMRI data to examine the similarity of neural representations of threat versus ambiguous or safe stimuli in threat and perceptual neurocircuitry among children at varying levels of anxiety traits. Three weeks after completing threat conditioning and extinction, children underwent an fMRI extinction recall task, during which they viewed the extinguished threat cue (CS+), safety cue (CS-) and generalization stimuli (GS) consisting of CS-/CS+ blends. Multivoxel BOLD signal patterns were measured in seven regions of interest: four affective areas (ventromedial prefrontal cortex (vmPFC), anterior insular cortex (AIC), dorsomedial prefrontal cortex (dmPFC), and amygdala) and three perceptual areas (inferior temporal cortex (ITC) and visual areas V1 and V4). Compared to low anxious children, children with high trait anxiety evidenced less neural pattern differentiation between the CS+ and similar GS, particularly in the vmPFC. Together, these results demonstrate the utility of multivariate neuroimaging approaches in arbitrating the relative contributions of perceptual versus affective sources to threat generalization.

Resilience in mathematics after early brain injury: The roles of parental input and early plasticity.

Children with early focal unilateral brain injury show remarkable plasticity in language development. However, little is known about how early brain injury influences mathematical learning. Here, we examine early number understanding, comparing cardinal number knowledge of typically developing children (TD) and children with pre- and perinatal lesions (BI) between 42 and 50 months of age. We also examine how this knowledge relates to the number words children hear from their primary caregivers early in life. We find that children with BI, are, on average, slightly behind TD children in both cardinal number knowledge and later mathematical performance, and show slightly slower learning rates than TD children in cardinal number knowledge during the preschool years. We also find that parents' "number talk" to their toddlers predicts later mathematical ability for both TD children and children with BI. These findings suggest a relatively optimistic story in which neural plasticity is at play in children's mathematical development following early brain injury. Further, the effects of early number input suggest that intervening to enrich the number talk that children with BI hear during the preschool years could narrow the math achievement gap.

Clinical activity of gemcitabine plus pertuzumab in platinum-resistant ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

PURPOSE: Pertuzumab is a humanized monoclonal antibody that inhibits human epidermal growth factor receptor 2 (HER2) heterodimerization and has single-agent activity in recurrent epithelial ovarian cancer. The primary objective of this phase II study was to characterize the safety and estimate progression-free survival (PFS) of pertuzumab with gemcitabine in patients with platinum-resistant ovarian cancer. PATIENTS AND METHODS: Patients with advanced, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who had received a maximum of one prior treatment for recurrent cancer were randomly assigned to gemcitabine plus either pertuzumab or placebo. Collection of archival tissue was mandatory to permit exploration of biomarkers that would predict benefit from pertuzumab in this setting. RESULTS: One hundred thirty patients (65 per arm) were treated. Baseline characteristics were similar between arms. The adjusted hazard ratio (HR) for PFS was 0.66 (95% CI, 0.43 to 1.03; P = .07) in favor of gemcitabine + pertuzumab. The objective response rate was 13.8% in patients who received gemcitabine + pertuzumab compared with 4.6% in patients who received gemcitabine + placebo. In patients whose tumors had low HER3 mRNA expression (< median, n = 61), an increased treatment benefit was observed in the gemcitabine + pertuzumab arm compared with the gemcitabine alone arm (PFS HR = 0.32; 95% CI, 0.17 to 0.59; P = .0002). Grade 3 to 4 neutropenia, diarrhea, and back pain were increased in patients treated with gemcitabine + pertuzumab. Symptomatic congestive heart failure was reported in one patient in the gemcitabine + pertuzumab arm. CONCLUSION: Pertuzumab may add activity to gemcitabine for the treatment of platinum-resistant ovarian cancer. Low HER3 mRNA expression may predict pertuzumab clinical benefit and be a valuable prognostic marker.