Faculty Bibliography

While researchers have for decades considered the role of social factors, endocrinology, neural function, hippocampal integrity, and cognition in the development of schizophrenia, there has been a relative paucity of studies considering the participation of the stress cascade in the interplay of these elements. As described in this review, stressful exposures and stress sensitivity may plausibly be argued to play a role in the etiology, neurobiology, and course of schizophrenia and related psychotic disorders. Notably, research conducted over the last decade has made it increasingly clear that childhood traumatic experiences represent a prominent risk factor for the development of psychotic disorders, including schizophrenia. Accumulating evidence suggests that this relationship is mediated by the development of a neuropathological stress response, involving HPA axis dysregulation, aberrant functioning of different neurotransmitter systems, hippocampal damage, and memory deficits. However, it remains difficult to identify exact causal pathways linking early trauma to schizophrenia, including to the individual symptoms associated with the disorder. In addition to the strong association among early trauma, stress sensitization, and positive symptoms in schizophrenia, there is also evidence indicating that the negative and cognitive symptoms are related to these factors. However, the emergence of these symptoms may lie on a distinct and non-interacting pathway in relation to the development of the positive symptoms. The natural increases in stress sensitivity and HPA axis activity during adolescence may act on already maladaptive stress circuitry resulting from early trauma and/or a genetic predisposition to produce full blown stress sensitization and cause epigenetic effects, such as the altered methylation of different genes, that lead to schizophrenia or other psychiatric illnesses.

The objective of this study was to extend the probability of treatment benefit method by adding treatment condition as a stratifying variable, and illustrate this extension of the methodology using the Child and Adolescent Anxiety Multimodal Study data. The probability of treatment benefit method produces a simple and practical way to predict individualized treatment benefit based on pretreatment patient characteristics. Two pretreatment patient characteristics were selected in the production of the probability of treatment benefit charts: baseline anxiety severity, measured by the Pediatric Anxiety Rating Scale, and treatment condition (cognitive-behavioral therapy, sertraline, their combination, and placebo). We produced two charts as exemplars which provide individualized and probabilistic information for treatment response and outcome to treatments for child anxiety. We discuss the implications of the use of the probability of treatment benefit method, particularly with regard to patient-centered outcomes and individualized decision-making in psychology and psychiatry.

Human brain function undergoes complex transformations across the lifespan. We employed resting-state functional MRI and graph-theory approaches to systematically chart the lifespan trajectory of the topological organization of human whole-brain functional networks in 126 healthy individuals ranging in age from 7 to 85 years. Brain networks were constructed by computing Pearson's correlations in blood-oxygenation-level-dependent temporal fluctuations among 1024 parcellation units followed by graph-based network analyses. We observed that the human brain functional connectome exhibited highly preserved non-random modular and rich club organization over the entire age range studied. Further quantitative analyses revealed linear decreases in modularity and inverted-U shaped trajectories of local efficiency and rich club architecture. Regionally heterogeneous age effects were mainly located in several hubs (e.g., default network, dorsal attention regions). Finally, we observed inverse trajectories of long- and short-distance functional connections, indicating that the reorganization of connectivity concentrates and distributes the brain's functional networks. Our results demonstrate topological changes in the whole-brain functional connectome across nearly the entire human lifespan, providing insights into the neural substrates underlying individual variations in behavior and cognition. These results have important implications for disease connectomics because they provide a baseline for evaluating network impairments in age-related neuropsychiatric disorders.

Sulfur is required for the biosynthesis of cysteine, methionine and numerous other metabolites, and thus is critical for cellular metabolism and various growth and developmental processes. Plants are able to sense their physiological state with respect to sulfur availability, but the sensor remains to be identified. Here we report the isolation and characterization of two novel allelic mutants of Arabidopsis thaliana, sel1-15 and sel1-16, which show increased expression of a sulfur deficiency-activated gene beta-glucosidase 28 (BGLU28). The mutants, which represent two different missense alleles of SULTR1;2, which encodes a high-affinity sulfate transporter, are defective in sulfate transport and as a result have a lower cellular sulfate level. However, when treated with a very high dose of sulfate, sel1-15 and sel1-16 accumulated similar amounts of internal sulfate and its metabolite glutathione (GSH) to wild-type, but showed higher expression of BGLU28 and other sulfur deficiency-activated genes than wild-type. Reduced sensitivity to inhibition of gene expression was also observed in the sel1 mutants when fed with the sulfate metabolites Cys and GSH. In addition, a SULTR1;2 knockout allele also exhibits reduced inhibition in response to sulfate, Cys and GSH, consistent with the phenotype of sel1-15 and sel1-16. Taken together, the genetic evidence suggests that, in addition to its known function as a high-affinity sulfate transporter, SULTR1;2 may have a regulatory role in response to sulfur nutrient status. The possibility that SULTR1;2 may function as a sensor of sulfur status or a component of a sulfur sensory mechanism is discussed.

OBJECTIVE: To examine the role of 17beta-estradiol in the regulation of the autoantigen tripartite motif-containing protein 21 (TRIM-21) in patients with systemic lupus erythematosus (SLE). METHODS: Monocytes isolated from healthy control subjects and patients with SLE were stimulated with 17beta-estradiol and/or the estrogen receptor alpha (ERalpha) antagonist methyl-piperidino-pyrazole dihydrochloride. TRIM-21, ERalpha, and CREMalpha expression was determined by real-time polymerase chain reaction (PCR) analysis. MatInspector software was used to identify putative binding sites within the TRIM-21 promoter. ERalpha binding to the TRIM-21 gene promoter region in monocytes was analyzed by chromatin immunoprecipitation (ChIP) assay. TRIM-21 and interferon regulatory factor 3 protein levels were analyzed by Western blotting. RESULTS: Real-time PCR analysis demonstrated a role of estrogen in the regulation of TRIM-21 expression in monocytes, which correlated positively with ERalpha gene expression in patients with SLE. Investigations into the human TRIM-21 promoter revealed the presence of an estrogen response element, with ChIP assays confirming ERalpha binding to this site. Studies into estrogen-induced TRIM-21 expression revealed a hyperresponsiveness of SLE patients to 17beta-estradiol, which led to the enhanced levels of TRIM-21 observed in these individuals. CONCLUSION: Our results demonstrate a role of estrogen in the regulation of TRIM-21 expression through an ERalpha-dependent mechanism, a pathway that we observed to be overactive in SLE patients. Treatment of monocytes with an ERalpha antagonist abrogated estrogen-induced TRIM-21 expression and, as a consequence, decreased the expression of interleukin-23. These findings identify TRIM-21 as a novel ERalpha-regulated gene and provide novel insights into the link between estrogen and the molecular pathogenesis of SLE.

Quality indicators for programs integrating parent-delivered family support services for children's mental health have not been systematically developed. Increasing emphasis on accountability under the Affordable Care Act highlights the importance of quality-benchmarking efforts. Using a modified Delphi approach, quality indicators were developed for both program level and family support specialist level practices. These indicators were pilot tested with 21 community-based mental health programs. Psychometric properties of these indicators are reported; variations in program and family support specialist performance suggest the utility of these indicators as tools to guide policies and practices in organizations that integrate parent-delivered family support service components.

This study describes services provided by family support specialists (FSS), peer advocates in programs for children with serious psychiatric conditions, to delineate differences between recommended components of FSS services and services actually provided. An analysis of qualitative interview and observational data and quantitative survey data from 63 staff at 21 mental health programs in New York identified that FSS and other staff have generally similar ideas about FSS services, and that these perceptions of activities are generally congruent with what FSS actually did. Implications of findings are discussed in the context of developing competencies and quality indicators for FSS.