Faculty Bibliography

Trisomy 21, or Down's syndrome (DS), is the most common genetic cause of intellectual disability. Altered neurotransmission in the brains of DS patients leads to hippocampus-dependent learning and memory deficiency. Although genetic mouse models have provided important insights into the genes and mechanisms responsible for DS-specific changes, the molecular mechanisms leading to memory deficits are not clear. We investigated whether the segmental trisomy model of DS, Ts[Rb(12.1716)]2Cje (Ts2), exhibits hippocampal glutamatergic transmission abnormalities and whether these alterations cause behavioral deficits. Behavioral assays demonstrated that Ts2 mice display a deficit in nest building behavior, a measure of hippocampus-dependent nonlearned behavior, as well as dysfunctional hippocampus-dependent spatial memory tested in the object-placement and the Y-maze spontaneous alternation tasks. Magnetic resonance spectra measured in the hippocampi revealed a significantly lower glutamate concentration in Ts2 as compared with normal disomic (2N) littermates. The glutamate deficit accompanied hippocampal NMDA receptor1 (NMDA-R1) mRNA and protein expression level downregulation in Ts2 compared with 2N mice. In concert with these alterations, paired-pulse analyses suggested enhanced synaptic inhibition and/or lack of facilitation in the dentate gyrus of Ts2 compared with 2N mice. Ts2 mice also exhibited disrupted synaptic plasticity in slice recordings of the hippocampal CA1 region. Collectively, these findings imply that deficits in glutamate and NMDA-R1 may be responsible for impairments in synaptic plasticity in the hippocampus associated with behavioral dysfunctions in Ts2 mice. Thus, these findings suggest that glutamatergic deficits have a significant role in causing intellectual disabilities in DS.

BACKGROUND:U.S. Child Welfare systems are involved in the lives of millions of children, and total spending exceeds $26 billion annually. Out-of-home foster care is a critical and expensive Child Welfare service, a major component of which is the maintenance rate paid to support housing and caring for a foster child. Maintenance rates vary widely across states and over time, but reasons for this variation are not well understood. As evidence-based programs are disseminated to state Child Welfare systems, it is important to understand what may be the important drivers in the uptake of these practices including state spending on core system areas. DATA AND METHODS/METHODS:We assembled a unique, longitudinal, state-level panel dataset (1990-2008) for all 50 states with annual data on foster care maintenance rates and measures of child population in need, poverty, employment, urbanicity, proportion minority, political party control of the state legislature and governorship, federal funding, and lawsuits involving state foster care systems. All monetary values were expressed in per-capita terms and inflation adjusted to 2008 dollars. We used longitudinal panel regressions with robust standard errors and state and year fixed effects to estimate the relationship between state foster care maintenance rates and the other factors in our dataset, lagging all factors by one year to mitigate the possibility that maintenance rates influenced their predictors. Exploratory analyses related maintenance rates to Child Welfare outcomes. FINDINGS/RESULTS:State foster care maintenance rates have increased in nominal terms, but in many states, have not kept pace with inflation, leading to lower real rates in 2008 compared to those in 1991 for 54% of states for 2 year-olds, 58% for 9 year-olds, and 65% for 16 year-olds. In multivariate analyses including socioeconomic, demographic, and political factors, monthly foster care maintenance rates declined $15 for each 1% increase in state unemployment and declined $40 if a state's governorship and legislature became Republican, though significance was marginal. In analyses also examining state revenue, federal funding, and legal challenges, maintenance rates increased as the federal share of maximum TANF payments increased. However, >50% of variation in foster care maintenance rates was explained by unobserved state-level factors as measured by state fixed effects. These factors did not appear to be strongly related to 2008 Child Welfare outcomes like foster care placement stability and maltreatment which were also not correlated with foster care maintenance rates. CONCLUSIONS:Despite being part of a social safety net, foster care maintenance rates have declined in real terms since 1991 in many states, and there is no strong evidence that they increase in response to harsher economic climates or to federal programs or legal reviews. State variation in maintenance rates was not related to Child Welfare outcomes, though further analysis of this important relationship is needed. Variability in state foster care maintenance rates appears highly idiosyncratic, an important contextual factor to consider when designing and disseminating evidence-based services.

The default network of the human brain has drawn much attention due to its relevance to various brain disorders, cognition, and behavior. However, its functional components and boundaries have not been precisely defined. There is no consensus as to whether the precuneus, a hub in the functional connectome, acts as part of the default network. This discrepancy is more critical for brain development and aging studies: it is not clear whether age has a stronger impact on the default network or precuneus, or both. We used Generalized Ranking and Averaging Independent Component Analysis by Reproducibility (gRAICAR) to investigate the lifespan trajectories of intrinsic functional networks. By estimating individual-specific spatial components and aligning them across subjects, gRAICAR measures the spatial variation of component maps across a population without constraining the same components to appear in every subject. In a cross-lifespan fMRI dataset (N=126, 7-85years old), we observed stronger age dependence in the spatial pattern of a precuneus-dorsal posterior cingulate cortex network compared to the default network, despite the fact that the two networks exhibit considerable spatial overlap and temporal correlation. These results remained even when analyses were restricted to a subpopulation with very similar head motion across age. Our analyses further showed that the two networks tend to merge with increasing age. Post-hoc analyses of functional connectivity confirmed the distinguishable cross-lifespan trajectories between the two networks. Based on these observations, we proposed a dynamic model of cross-lifespan functional segregation and integration between the two networks, suggesting that the precuneus network may have a different functional role than the default network, which declines with age. These findings have implications for understanding the functional roles of the default network, gaining insight into its dynamics throughout life, and guiding interpretation of alterations in brain disorders.

The purpose of the current study was to investigate differences in the frequency of stereotypic behavior (e.g., engaging in repetitive activities; repetitive body movements such as rocking, spinning, handflapping; repetition of words or sounds; and perseveration on specific topics) using a psychometrically sound measure, the Diagnostic Assessment for the Severely Handicapped, second edition (DASH-II). The sample investigated included 261 adults with severe or profound intellectual disability (ID), 51 of whom met criteria for ASD according to the DSM-5; 84 of whom met criteria for the DSM-IV-TR, but no longer qualify for an ASD diagnosis with the new criteria; and a control group of 126 adults who did not qualify for an ASD diagnosis according to either version of the DSM. The DSM-5 captured a more impaired population in terms of stereotypies, though a significant difference remains between those who no longer meet criteria and a control group with ID who did not meet criteria for ASD under either version of the DSM. Highlights. aEuro cent Approximately 38 % of adults with ID currently meeting criteria for autism under the DSM-IV-TR did not meet the DSM-5 criteria. aEuro cent Those who continued to meet criteria for ASD had higher scores on the DASH-II stereotypy subscale. aEuro cent People meeting DSM-IV but not DSM-5 criteria had significantly more stereotypic behavior than adults without ASD.

Background: The Third Universal Definition of Myocardial Infarction (MI) designates an increase in cardiac troponin concentration (cTn) > 99th percentile of a normal reference population as the decision level for MI diagnosis. The variability among hospitals in the lab-determined cTn level to diagnose MI [cTn decision level] relative to the assay manufacturer determined 99th percentile has not been well characterized. Methods: We surveyed 93 sites from 15 countries participating in the NHLBI ISCHEMIA trial to ascertain the cTn assay used at their hospital labs, its 99th percentile, as well as the cTn MI decision level. The ratio of cTn MI decision level to cTn 99th percentile was calculated for each lab. Results: Laboratories employed 32 unique cTn assays from 7 manufacturers; 77% used cTnI assays and 23% used cTnT assays. Highly sensitive assays were used in 18 labs (19.4%). The ratio of cTn MI decision level to cTn 99th percentile was <1 at 7 labs (7.5%), equal to 1 at 29 labs (31.2%) and >10 at 18 labs (19.4%) (Figure). Substantial variability was observed in cTn MI decision level even among labs using the same assay. Conclusion: Significant variability exists in the cTn MI decision level used by hospital laboratories relative to the assay cTn 99th percentile. Only one-third of labs follow the Third Universal Definition of MI. These data have important implications for the diagnosis of MI in clinical practice and adjudicating MI endpoints in clinical trials. (Figure Presented)

OBJECTIVE:To examine the extent to which child welfare agencies adopt new practices and to determine the barriers to and facilitators of adoption of new practices. METHODS:Data came from telephone interviews with the directors of the 92 public child welfare agencies that constituted the probability sample for the first National Survey of Child and Adolescent Well-being (NSCAWI). In a semi-structured 40 minute interview administered by a trained Research Associate, agency directors were asked about agency demographics, knowledge of evidence-based practices, use of technical assistance and actual use of evidence-based practices.. Of the 92 agencies, 83 or 90% agreed to be interviewed. RESULTS:Agencies reported that the majority of staff had a BA degree (53.45%) and that they either paid for (52.6%) or provided (80.7%) continuing education. Although agencies routinely collect standardized child outcomes (90%) they much less frequently collect measures of child functioning (30.9%). Almost all agencies (94%) had started a new program or practice but only 24.8% were evidence-based and strategies used to explore new programs or practices usually involved local or state contracts. Factors that were associated with program success included internal support for the innovation (27.3%), and an existing evidence base (23.5%). CONCLUSIONS:Directors of child welfare agencies frequently institute new programs or practices but they are not often evidence-based. Because virtually all agencies provide some continuing education adding discussions of evidence-based programs/practices may spur adaption. Reliance on local and state colleagues to explore new programs and practices suggests that developing well informed social networks may be a way to increase the spread of evidence0based practices.

PURPOSE/OBJECTIVE:To evaluate fetal cerebral venous blood oxygenation, Yv, using principles of MR susceptometry. MATERIALS AND METHODS/METHODS:A cohort of 19 pregnant subjects, with a mean gestational age of 31.6 ± 4.7 weeks were imaged using a modified susceptibility-weighted imaging (SWI) sequence. Data quality was first assessed for feasibility of oxygen saturation measurement, and data from five subjects (mean ± std gestational age of 33.7 ± 3.6 weeks) were then chosen for further quantitative analysis. SWI phase in the superior sagittal sinus was used to evaluate oxygen saturation using the principles of MR susceptometry. Systematic error in the measured Y(v) values was studied through simulations. RESULTS:Simulations showed that the systematic error in Yv depended upon the assumed angle of the vessel, θ, relative to the main magnetic field and the error in that vessel angle δθ. For the typical vessel angle of θ = 30° encountered in the fetal data analyzed, a δθ as large as ±20° led to an absolute error, δYv, of less than 11%. The measured mean oxygen saturation across the five fetuses was 66% ± 9.4%. This average cerebral venous blood oxygenation value is in close agreement with values in the published literature. CONCLUSION/CONCLUSIONS:We have reported the first in vivo measurement of human fetal cerebral venous oxygen saturation using MRI.

Touch plays a crucial role in social-emotional development. Slow, gentle touch applied to hairy skin is processed by C-tactile (CT) nerve fibers. Furthermore, 'social brain' regions, such as the posterior superior temporal sulcus (pSTS) have been shown to process CT-targeted touch. Research on the development of these neural mechanisms is scant, yet such knowledge may inform our understanding of the critical role of touch in development and its dysfunction in disorders involving sensory issues, such as autism. The aim of this study was to validate the ability of functional near-infrared spectroscopy (fNIRS), an imaging technique well-suited for use with infants, to measure temporal lobe responses to CT-targeted touch. Healthy adults received brushing to the right forearm (CT) and palm (non-CT) separately, in a block design procedure. We found significant activation in right pSTS and dorsolateral prefrontal cortex to arm > palm touch. In addition, individual differences in autistic traits were related to the magnitude of peak activation within pSTS. These findings demonstrate that fNIRS can detect brain responses to CT-targeted touch and lay the foundation for future work with infant populations that will characterize the development of brain mechanisms for processing CT-targeted touch in typical and atypical populations.

OBJECTIVE:To describe cumulative radiation exposure in a large single-center cohort of children with congenital heart disease (CHD) and identify risk factors for greater exposure. STUDY DESIGN/METHODS:A detailed medical radiation exposure history was collected retrospectively for patients aged <18 years who underwent surgery for CHD between January 1, 2001, and July 22, 2009. Cumulative per patient exposure was quantified as the effective dose in millisieverts (mSv) and annualized (mSv/year). RESULTS:A total of 4132 patients were subjected to 134,715 radiation examinations at a median follow-up of 4.3 years (range, 0-8.6 years). Exposure clustered around the time of surgery. The median exposure was 14 radiologic tests (the majority of which were plain film radiographs) at an effective dose of 0.96 mSv (the majority of which was from cardiac catheterization), although this distribution had a very wide range. Almost three-quarters (73.7%) were exposed to <3 mSv/year, and 5.3% were exposed to >20 mSv/year. Neonates, children with genetic syndromes, and children requiring surgery for cardiomyopathy, pulmonary valve, single ventricle, or tricuspid valve diseases were more likely to have higher exposure levels, and those requiring surgery for aortic arch anomalies or atrioventricular septal defects were more likely to have lower levels. CONCLUSION/CONCLUSIONS:Children with CHD requiring surgery are exposed to numerous medical forms of ionizing radiation. Although the majority of patients receive <3 mSv/year, there are identifiable risk factors for higher exposure levels. This may have important health implications as these patients age.