The deleterious effects of adversity are likely intergenerational, such that one generation’s adverse experiences can affect the next. Epidemiological studies link maternal adversity to offspring depression and anxiety, possibly via transmission mechanisms that influence offspring fronto-limbic connectivity. However, studies have not thoroughly disassociated postnatal exposure effects nor considered the role of offspring sex. We utilized infant neuroimaging to test the hypothesis that maternal childhood maltreatment (CM) would be associated with increased fronto-limbic connectivity in infancy and tested brain-behavior associations in childhood. Ninety-two dyads participated (32 mothers with CM, 60 without; 52 infant females, 40 infant males). Women reported on their experiences of CM and non-sedated sleeping infants underwent MRIs at 2.44 ± 2.74 weeks. Brain volumes were estimated via structural MRI and white matter structural connectivity (fiber counts) via diffusion MRI with probabilistic tractography. A subset of parents (n = 36) reported on children’s behaviors at age 5.17 ± 1.73 years. Males in the maltreatment group demonstrated greater intra-hemispheric fronto-limbic connectivity (b = 0.96, p= 0.008, [95%CI 0.25, 1.66]), no differences emerged for females. Fronto-limbic connectivity was related to somatic complaints in childhood only for males (r = 0.673, p = 0.006). Our findings suggest that CM could have intergenerational associations to offspring brain development, yet mechanistic studies are needed.

OBJECTIVES/GOALS: Maternal health and exposures during pregnancy play a major role in shaping the neurodevelopment of our offspring—one influence is maternal immune activation (MIA). Here we explore the association of MIA during pregnancy and the developing human connectome through analysis of 46 markers of activation. METHODS/STUDY POPULATION: 74 healthy women with singleton pregnancies underwent blood draws between 34-37 weeks gestation. 46 markers of maternal immune activation, both adaptive (e.g., IgG) and innate (e.g., cytokines and acute phase reactants), were collected. In addition, for preliminary analyses of MIA in relation to the newborn brain, we utilized 30 participants with MRIs between the ages of 0-6 months. RESULTS/ANTICIPATED RESULTS: Principal component analysis (PCA) identified the first 5 PCs explains ~68% of the variance and the first 10 explains ~83% (top PC is 42.1%). Using the top PC each edge in the connectome was correlated with the immune profiles. Several regions trended towards significance–one survived correction and included 359 edges, showing. The highest number of edges was observed in the inferior parietal lobe of the left hemisphere–a region associated with functions from basic attention toa social cognition, suggesting that deviations in fetal exposure to MIA can longitudinally impact offspring behavior in areas essential for human interaction. DISCUSSION/SIGNIFICANCE: This is the first study in understanding how interruptions (i.e., MIA) influence later development. Identification of alterations, and long-term outcomes could lead to the development of mechanism-based healthcare, facilitate timely referral for appropriate interventions and provide family support.

Childhood maltreatment (CM) is a known risk factor for adolescent pregnancy. Sleep disturbances and psychological distress, both common negative sequelae of CM, often co-occur during pregnancy, although directionality remains unclear. Furthermore, little is known about how CM affects sleep–distress associations during pregnancy. In pregnant adolescents, we examined: (a) whether there are significant predictive associations from CM to sleep quality and distress and (b) bidirectional influences of distress and sleep quality. Healthy pregnant adolescents (n = 204) were recruited before or during the 2nd trimester. CM was assessed at enrollment; sleep quality and distress were assessed in the 2nd and 3rd trimesters. Hypotheses were tested using path analysis. Findings revealed that CM was associated with worse 2nd trimester sleep quality and distress (β = .19, p < .05 for sleep; β = .30, p < .001 for distress). Higher levels of 2nd trimester distress were associated with lower 3rd trimester sleep quality (β = .19, p < .05). Findings provide novel information about (a) associations from CM to prenatal mood and sleep in pregnant adolescents, and (b) sleep–distress directionality over the course of pregnancy. These results have implications for better understanding the ways in which CM potentially exerts influences later in life, and for targeting interventions to address physical and mental health during pregnancy.

Experiments on the National Ignition Facility show that multi-dimensional effects currently dominate the implosion performance. Low mode implosion symmetry and hydrodynamic instabilities seeded by capsule mounting features appear to be two key limiting factors for implosion performance. One reason these factors have a large impact on the performance of inertial confinement fusion implosions is the high convergence required to achieve high fusion gains. To tackle these problems, a predictable implosion platform is needed meaning experiments must trade-off high gain for performance. LANL has adopted three main approaches to develop a one-dimensional (1D) implosion platform where 1D means measured yield over the 1D clean calculation. A high adiabat, low convergence platform is being developed using beryllium capsules enabling larger case-to-capsule ratios to improve symmetry. The second approach is liquid fuel layers using wetted foam targets. With liquid fuel layers, the implosion convergence can be controlled via the initial vapor pressure set by the target fielding temperature. The last method is double shell targets. For double shells, the smaller inner shell houses the DT fuel and the convergence of this cavity is relatively small compared to hot spot ignition. However, double shell targets have a different set of trade-off versus advantages. Details for each of these approaches are described.

In a variety of mammalian species, prenatal androgens organize brain structures and functions that are later activated by steroid hormones in postnatal life. In humans, studies of individuals with typical and atypical development suggest that sex differences in reproductive and nonreproductive behavior derive in part from similar prenatal and postnatal steroid effects on brain development. This paper provides a summary of research investigating hormonal influences on human behavior and describes how sex differences in the prevalences and natural histories of developmental psychopathologies may be consistent with these steroid effects. An association between patterns of sexual differentiation and specific forms of psychopathology suggests novel avenues for assessing the effects of sex steroids on brain structure and function, which may in turn improve our understanding of typical and atypical development in women and men.

Tourette syndrome (TS) is a complex neurobehavioral disorder principally characterized by motor and vocal tics. However, features of obsessive-compulsive and attention-deficit/hyperactivity disorders are often present. The basal ganglia and associated brain structures have been implicated in the pathophysiology of TS, as well as in these related conditions. Specifically, it is believed that the neuroanatomically and functionally defined basal ganglia thalamocortical loops are involved in TS. These loops are composed of a sequence of connections originating in the cortex and passing in series through the striatum (caudate and putamen), globus pallidus, and thalamus before returning to the cortical areas of origin. This review concentrates on the neuroimaging findings in Ts, particularly as they relate to alterations in components of the basal ganglia thalamocortical circuits. These neuroimaging data suggest that the major abnormalities in TS involve striatal or cortical dysfunction, as well as dysfunction of dopaminergic systems that regulate basas ganglia neurotransmission.

Functional imaging studies have reported with remarkable consistency hyperactivity in the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), and caudate nucleus of patients with obsessive–compulsive disorder (OCD). These findings have often been interpreted as evidence that abnormalities in cortico–basal ganglia–thalamo–cortical loops involving the OFC and ACC are causally related to OCD. This interpretation remains controversial, however, because such hyperactivity may represent either a cause or a consequence of the symptoms. This article analyzes the evidence for a causal role of these loops in producing OCD in children and adults. The article first reviews the strong evidence for anatomical abnormalities in these loops in patients with OCD. These findings are not sufficient to establish causality, however, because anatomical alterations may themselves be a consequence rather than a cause of the symptoms. The article then reviews three lines of evidence that, despite their own limitations, permit stronger causal inferences: the development of OCD following brain injury, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection, and neurosurgical lesions that attenuate OCD. Converging evidence from these various lines of research supports a causal role for the cortico–basal ganglia–thalamo–cortical loops that involve the OFC and ACC in the pathogenesis of OCD in children and adults.

The question of how to handle incidental findings (IFs) has sparked a heated debate among neuroimaging researchers and medical ethicists, a debate whose urgency stems largely from the recent explosion in the number of imaging studies being conducted and in the sheer volume of scans being acquired. Perhaps the point of greatest controversy within this debate is whether the magnetic resonance imaging (MRI) scans of all research participants should be reviewed in an active search for pathology and, moreover, whether this search should be performed by a radiologist. Resistance to routine readings performed by radiologists, as opposed to selective review of those scans on which investigators have spotted a possible IF, has been fueled in part by the obvious and enormous cost — financial and logistical — of engaging radiologists to read massive numbers of scans. This cost would be especially burdensome, even prohibitive, to investigators who are not affiliated with a medical center, because of their limited access to radiologists and other medical expertise.

The circumplex model of affect proposes that all affective states arise from cognitive interpretations of core neural sensations that are the product of two independent neurophysiological systems. This model stands in contrast to theories of basic emotions, which posit that a discrete and independent neural system subserves every emotion. We propose that basic emotion theories no longer explain adequately the vast number of empirical observations from studies in affective neuroscience, and we suggest that a conceptual shift is needed in the empirical approaches taken to the study of emotion and affective psychopathologies. The circumplex model of affect is more consistent with many recent findings from behavioral, cognitive neuroscience, neuroimaging, and developmental studies of affect. Moreover, the model offers new theoretical and empirical approaches to studying the development of affective disorders as well as the genetic and cognitive underpinnings of affective processing within the central nervous system.This work was supported in part by NIMH Grants MH01232, MH59139, MH36197, MHK02-74677, and MH068318; a grant from the National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD); NSF Grant BSC-0421702; and funding from the Thomas D. Klingenstein and Nancy D. Perlman Family Fund and the Suzanne Crosby Murphy Endowment at Columbia University.

The hypothesis that prenatal masculinization of the brain increases risk of tic disorders in postnatal life was tested by measuring gender and gender role behavior in 89 children and adults with a clinical diagnosis of Tourette syndrome or obsessive compulsive disorder and 67 healthy, unaffected children and adults. Consistent with this hypothesis, a tic disorder in females was associated with more gender dysphoria, increased masculine play preferences, and a more typically “masculine” pattern of performance on two sex-typed spatial tasks. Males with tic disorders reported increased masculine play preferences, and the strength of these preferences was positively associated with the severity of tic symptoms. In addition, unlike their female counterparts, males with tic disorders showed a relative impairment in mental rotation ability. These behavioral profiles are consistent with those of children who have verifiable elevations in prenatal androgen levels. These findings therefore support the hypothesis that an altered androgen-dependent process of sexual differentiation during prenatal life may contribute to the development of tic-related disorders.This work was supported by National Institutes of Health Grants MH01232 (B. P.) and MH59139 (B. P.) and the Suzanne Crosby Murphy endowment in Pediatric Neuropsychiatry, College of Physicians and Surgeons, Columbia University. The authors thank Amy Basile and Shibani Mukerji for their valuable assistance with behavioral testing.

Brain imaging studies in developmentally based psychopathologies most often use magnetic resonance imaging (MRI) to study regional volumes, task-related activity, neurometabolite concentrations, or the paths of fiber tracts within the brain. Methodological challenges for the use of MRI in studying these disorders include understanding the ultrastructural correlates of brain structure and function that are below the limits of resolution of this imaging modality and developing better methods for approximating the anatomical boundaries of the cytoarchitectonic units that are defined by those ultrastructural characteristics. Conceptual challenges include distinguishing findings that represent pathophysiologically central causes from compensatory and epiphenomenal effects, a difficulty that stems directly from the inherently correlational nature of imaging data. The promise of functional imaging studies must capitalize on the specificity of the cognitive and behavioral probes that are used to illuminate core features of the pathophysiology of developmental disorders, while recognizing the assumptions and limitations of the subtraction paradigms that are used to isolate the brain functions of interest. Statistical challenges include incorporating adequate statistical models for scaling effects within the brain, as well as modeling important demographic correlates that contribute to the substantial interindividual variability inherent in most imaging data. Statistical analyses need to consider the substantial intercorrelation of measures across the brain and the importance of correcting for multiple statistical comparisons, as well as the need for improved methods for brain warping and for assessing effective connectivity in functional imaging studies.