Faculty Bibliography

OBJECTIVE: The purpose of this study was to assess the relative accuracies of the Conners' Brief Rating Scale, Parent Version, the Conners' Continuous Performance Test II (CPT II), and a novel interactive game called "Groundskeeper" to discriminate child psychiatric patients with and without attention-deficit/hyperactivity disorder (ADHD). METHODS: We administered the three assessments to 113 clinically referred ADHD and non-ADHD patients who had been diagnosed with the Kiddie-Schedule of Affective Disorders and Schizophrenia- Present and Lifetime (K-SADS-PL), Version 19. RESULTS: As measured by the area under the curve (AUC) statistic from receiver operating characteristic (ROC) analysis, the diagnostic accuracy of Groundskeeper (0.79) was as high as the accuracy of the Conners' parent rating of inattention (0.76) and better than the CPT II percent correct (0.62). Combining the three tests produced an AUC of 0.87. Correlations among the three measures were small and, mostly, not significant. CONCLUSIONS: Our finding of similar diagnostic accuracies between Groundskeeper and the Conners' inattention scale is especially remarkable given that the Conners' inattention scale shares method variance with the diagnostic process. Although our work is preliminary, it suggests that computer games may be useful in the diagnostic process. This provides an important direction for research, given the objectivity of such measures and the fact that computer games are well tolerated by youth.

OBJECTIVE: To assess activating and tranquilizing effects of second-generation antipsychotics (SGAs) in youth. METHODS: As part of the naturalistic inception cohort study, "Second-generation Antipsychotic Treatment Indication, Effectiveness and Tolerability in Youth (SATIETY)," subjective ratings of activating and tranquilizing symptoms were obtained monthly for 3 months from antipsychotic-naive youth initiating SGAs using the Treatment Emergent Symptoms Scale (TESS). Discontinuation rates, and TESS-reported symptom rates, and severity were related to clinical and treatment parameters. Two compound measures of TESS were defined: presence of any daytime activating (ACTIVATION+) and sedating symptoms (SEDATION+). RESULTS: In 327 antipsychotic-naive youth originally initiating the four studied SGAs, discontinuation due to sedation was marginally highest with quetiapine (13.0%) followed by olanzapine (7.3%), risperidone (4.2%), and aripiprazole (2.0%) (p = 0.056). Two hundred fifty-seven antipsychotic-naive youth (13.8 +/- 3.6 years, male = 57.8%) initiated aripiprazole (n = 40), olanzapine (n = 45), quetiapine (n = 36), or risperidone (n = 135) and completed >/=1 postbaseline follow-up visit. Baseline prevalence of ACTIVATION+ (39.9%) or SEDATION+ (54.1%) did not differ between SGAs. Rates of both compound measures changed significantly over time (decrease for ACTIVATION+, p = 0.0002; increase for SEDATION+, p < 0.0001) with slight differences between SGAs, explained by lower rates of ACTIVATION+ with olanzapine (p = 0.002) and slightly higher rates of ACTIVATION+ with aripiprazole (p = 0.018) during follow-up, and lower rates of SEDATION+ with aripiprazole (p = 0.018). All four SGAs reduced insomnia (p = 0.001) and increased hypersomnia (p < 0.001). Postbaseline prevalence of drowsiness, the most frequent, but mild TESS complaint was 85%, without SGA differences. Younger age was associated with activating symptoms, higher age with sedating symptoms, and lower baseline functioning increased both. Psychomotor retardation rates were high in subjects with schizophrenia-spectrum disorders, whereas stimulant comedication was associated with psychomotor activation, regardless of diagnosis. CONCLUSIONS: Although small SGA-specific differences in activating/sedating compound side effect measures were noted, independent predictors of single TESS ratings included clinical parameters, rather than specific SGAs, suggesting a need for carefully individualized treatment strategies.

Experience-induced replay of neuronal ensembles occurs during hippocampal high-frequency oscillations, or ripples. Post-learning increase in ripple rate is predictive of memory recall, while ripple disruption impairs learning. Ripples may thus present a fundamental component of a neurophysiological mechanism of memory consolidation. In addition to system-level local and cross-regional interactions, a consolidation mechanism involves stabilization of memory representations at the synaptic level. Synaptic plasticity within experience-activated neuronal networks is facilitated by noradrenaline release from the axon terminals of the locus coeruleus (LC). Here, to better understand interactions between the system and synaptic mechanisms underlying "off-line" consolidation, we examined the effects of ripple-associated LC activation on hippocampal and cortical activity and on spatial memory. Rats were trained on a radial maze; after each daily learning session neural activity was monitored for 1 h via implanted electrode arrays. Immediately following "on-line" detection of ripple, a brief train of electrical pulses (0.05 mA) was applied to LC. Low-frequency (20 Hz) stimulation had no effect on spatial learning, while higher-frequency (100 Hz) trains transiently blocked generation of ripple-associated cortical spindles and caused a reference memory deficit. Suppression of synchronous ripple/spindle events appears to interfere with hippocampal-cortical communication, thereby reducing the efficiency of "off-line" memory consolidation.

Although social cognition deficits have been associated with schizophrenia, social trait judgments - or first impressions - have rarely been studied. These first impressions, formed immediately after looking at a person's face, have significant social consequences. Eighty-one individuals with schizophrenia or schizoaffective disorder and 62 control subjects rated 30 neutral faces on 10 positive or negative traits: attractive, mean, trustworthy, intelligent, dominant, fun, sociable, aggressive, emotionally stable and weird. Compared to controls, patients gave higher ratings for positive traits as well as for negative traits. Patients also demonstrated more ambivalence in their ratings. Patients who were exhibiting paranoid symptoms assigned higher intensity ratings for positive social traits than non-paranoid patients. Social trait ratings were negatively correlated with everyday problem solving skills in patients. Although patients appeared to form impressions of others in a manner similar to controls, they tended to assign higher scores for both positive and negative traits. This may help explain the social deficits observed in schizophrenia: first impressions of higher degree are harder to correct, and ambivalent attitudes may impair the motivation to interact with others. Consistent with research on paranoia and self-esteem, actively-paranoid patients' positive social traits judgments were of higher intensity than non-paranoid patients'.

Organic acids, such as citrate and malate, are important contributors for the sensory traits of fleshy fruits. Although their biosynthesis has been illustrated, regulatory mechanisms of acid accumulation remain to be dissected. To provide transcriptional architecture and identify candidate genes for citrate accumulation in fruits, we have selected for transcriptome analysis four varieties of sweet orange (Citrus sinensis L. Osbeck) with varying fruit acidity, Succari (acidless), Bingtang (low acid), and Newhall and Xinhui (normal acid). Fruits of these varieties at 45 days post anthesis (DPA), which corresponds to Stage I (cell division), had similar acidity, but they displayed differential acid accumulation at 142 DPA (Stage II, cell expansion). Transcriptomes of fruits at 45 and 142 DPA were profiled using RNA sequencing and analyzed with three different algorithms (Pearson correlation, gene coexpression network and surrogate variable analysis). Our network analysis shows that the acid-correlated genes belong to three distinct network modules. Several of these candidate fruit acidity genes encode regulatory proteins involved in transport (such as AHA10), degradation (such as APD2) and transcription (such as AIL6) and act as hubs in the citrate accumulation gene networks. Taken together, our integrated systems biology analysis has provided new insights into the fruit citrate accumulation gene network and led to the identification of candidate genes likely associated with the fruit acidity control.

Epidemiological findings suggest that diabetic individuals are at a greater risk for developing Alzheimer's disease (AD). To examine the mechanisms by which diabetes mellitus (DM) may contribute to AD pathology in humans, we examined brain tissue from streptozotocin-treated type 1 diabetic adult male vervet monkeys receiving twice-daily exogenous insulin injections for 8-20 weeks. We found greater inhibitory phosphorylation of insulin receptor substrate 1 in each brain region examined of the diabetic monkeys when compared with controls, consistent with a pattern of brain insulin resistance that is similar to that reported in the human AD brain. Additionally, a widespread increase in phosphorylated tau was seen, including brain areas vulnerable in AD, as well as relatively spared structures, such as the cerebellum. An increase in active ERK1/2 was also detected, consistent with DM leading to changes in tau-kinase activity broadly within the brain. In contrast to these widespread changes, we found an increase in soluble amyloid-beta (Abeta) levels that was restricted to the temporal lobe, with the greatest increase seen in the hippocampus. Consistent with this localized Abeta increase, a hippocampus-restricted decrease in the protein and mRNA for the Abeta-degrading enzyme neprilysin (NEP) was found, whereas various Abeta-clearing and -degrading proteins were unchanged. Thus, we document multiple biochemical changes in the insulin-controlled DM monkey brain that can link DM with the risk of developing AD, including dysregulation of the insulin-signaling pathway, changes in tau phosphorylation, and a decrease in NEP expression in the hippocampus that is coupled with a localized increase in Abeta. SIGNIFICANCE STATEMENT: Given that diabetes mellitus (DM) appears to increase the risk of developing Alzheimer's disease (AD), understanding the mechanisms by which DM promotes AD is important. We report that DM in a nonhuman primate brain leads to changes in the levels or posttranslational processing of proteins central to AD pathobiology, including tau, amyloid-beta (Abeta), and the Abeta-degrading protease neprilysin. Additional evidence from this model suggests that alterations in brain insulin signaling occurred that are reminiscent of insulin signaling pathway changes seen in human AD. Thus, in anin vivomodel highly relevant to humans, we show multiple alterations in the brain resulting from DM that are mechanistically linked to AD risk.

Disruptive behavior disorders (DBDs) are chronic, impairing, and costly behavioral health conditions that are four times more prevalent among children of color living in impoverished communities as compared to the general population. This disparity is largely due to the increased exposure to stressors related to low socioeconomic status including community violence, unstable housing, under supported schools, substance abuse, and limited support systems. However, despite high rates and greater need, there is a considerably lower rate of mental health service utilization among these youth. Accordingly, the current study aims to describe a unique model of integrated health care for ethnically diverse youth living in a New York City borough. With an emphasis on addressing possible barriers to implementation, integrated models for children have the potential to prevent ongoing mental health problems through early detection and intervention.

Brain imaging efforts are being increasingly devoted to decode the functioning of the human brain. Among neuroimaging techniques, resting-state fMRI (R-fMRI) is currently expanding exponentially. Beyond the general neuroimaging analysis packages (e.g., SPM, AFNI and FSL), REST and DPARSF were developed to meet the increasing need of user-friendly toolboxes for R-fMRI data processing. To address recently identified methodological challenges of R-fMRI, we introduce the newly developed toolbox, DPABI, which was evolved from REST and DPARSF. DPABI incorporates recent research advances on head motion control and measurement standardization, thus allowing users to evaluate results using stringent control strategies. DPABI also emphasizes test-retest reliability and quality control of data processing. Furthermore, DPABI provides a user-friendly pipeline analysis toolkit for rat/monkey R-fMRI data analysis to reflect the rapid advances in animal imaging. In addition, DPABI includes preprocessing modules for task-based fMRI, voxel-based morphometry analysis, statistical analysis and results viewing. DPABI is designed to make data analysis require fewer manual operations, be less time-consuming, have a lower skill requirement, a smaller risk of inadvertent mistakes, and be more comparable across studies. We anticipate this open-source toolbox will assist novices and expert users alike and continue to support advancing R-fMRI methodology and its application to clinical translational studies.

One of the grand challenges faced by neuroscience is to delineate the determinants of interindividual variation in the comprehensive structural and functional connection matrices that comprise the human connectome. At present, this endeavor appears most tractable at the macroanatomic scale, where intrinsic brain activity exhibits robust patterns of synchrony that recapitulate core functional circuits at the individual level. Here, we use a classical twin study design to examine the heritability of intrinsic functional network properties in 101 twin pairs, including network activity (i.e., variance of a network's specific temporal fluctuations) and internetwork coherence (i.e., correlation between networks' specific temporal fluctuations). Five of 7 networks exhibited significantly heritable (23.3-65.2%) network activity, 6 of the 21 internetwork coherences were significantly heritable (25.6-42.0%), and 11 of the 21 internetwork coherences were significantly influenced by common environmental factors (18.0-47.1%). These results suggest that the source of interindividual variation in functional connectome has a modular architecture: individual modules represented by intrinsic connectivity networks are genetic controlled, while environmental factors influence the interplays between the modules. This work further provides network-specific hypotheses for discovery of the specific genetic and environmental factors influencing functional specialization and integration of the human brain.

OBJECTIVE: The objectives were to: assess the availability of on-site mental health professionals (MHP) in primary care; examine practice/pediatrician characteristics associated with on-site MHPs; and determine whether presence of on-site MHPs is related to pediatricians' co-managing or more frequently identifying, treat/managing or referring MH problems. METHODS: Analyses included AAP members who participated in an AAP Periodic Survey in 2013 and who practiced general pediatrics (N=321). Measures included socio-demographics, practice characteristics, questions on about on-site MHPs, co-management of MH problems and pediatricians' behaviors in response to 5 prevalent MH problems. Weighted univariate, bivariate and multivariable analyses were performed. RESULTS: Thirty-five percent reported on-site MHPs. Practice characteristics (medical schools/universities/HMOs, <100 visits/week, <80% of patients privately insured), and interactions of practice location (urban) with visits and patient insurance, were associated with on-site MHPs. There was no overall association between co-location and co-management or whether pediatricians usually identified, treat/managed or referred 5 common child MH problems. Among the subset of pediatricians who reported co-managing there was an association with co-management when the on-site MHP was a child psychiatrist, SA counselor, or social worker. CONCLUSIONS: On-site MHPs are more frequent in settings where low-income children are served and where pediatricians train. Pediatricians who co-manage MH problems are more likely to do so when the on-site MHP is a child psychiatrist, SA counselor, or social worker. Overall, on-site MHPs were not associated with co-management or increased likelihood of pediatricians identifying, treating/managing, or referring children with 5 common child MH problems.