Faculty Bibliography

Pattern separation plays an important role in perception and memory. In olfaction, pattern separation is critical component of piriform cortical odor processing contributing to behavioral perception of overlapping odor mixtures. Previous work has demonstrated that odor discrimination ability is modulated by acetylcholine. Here, we extended this previous work by using a distinct, well characterized complex odor stimulus set that has been shown to differentially involve pattern separation processes within piriform cortex. We find that the cholinergic muscarinic receptor agonist oxotremorine facilitates the acquisition of odor discrimination. Furthermore, the muscarinic receptor antagonist scopolamine impairs acquisition of odor discrimination even if the antagonist is limited to the piriform cortex. Finally, acetylcholine effects are most robust during discrimination acquisition, with minimal effects during expression.

BACKGROUND:22q13 deletion syndrome, also known as Phelan-McDermid syndrome, is a neurodevelopmental disorder characterized by intellectual disability, hypotonia, delayed or absent speech, and autistic features. SHANK3 has been identified as the critical gene in the neurological and behavioral aspects of this syndrome. The phenotype of SHANK3 deficiency has been described primarily from case studies, with limited evaluation of behavioral and cognitive deficits. The present study used a prospective design and inter-disciplinary clinical evaluations to assess patients with SHANK3 deficiency, with the goal of providing a comprehensive picture of the medical and behavioral profile of the syndrome. METHODS:A serially ascertained sample of patients with SHANK3 deficiency (n = 32) was evaluated by a team of child psychiatrists, neurologists, clinical geneticists, molecular geneticists and psychologists. Patients were evaluated for autism spectrum disorder using the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule-G. RESULTS:Thirty participants with 22q13.3 deletions ranging in size from 101 kb to 8.45 Mb and two participants with de novo SHANK3 mutations were included. The sample was characterized by high rates of autism spectrum disorder: 27 (84%) met criteria for autism spectrum disorder and 24 (75%) for autistic disorder. Most patients (77%) exhibited severe to profound intellectual disability and only five (19%) used some words spontaneously to communicate. Dysmorphic features, hypotonia, gait disturbance, recurring upper respiratory tract infections, gastroesophageal reflux and seizures were also common. Analysis of genotype-phenotype correlations indicated that larger deletions were associated with increased levels of dysmorphic features, medical comorbidities and social communication impairments related to autism. Analyses of individuals with small deletions or point mutations identified features related to SHANK3 haploinsufficiency, including ASD, seizures and abnormal EEG, hypotonia, sleep disturbances, abnormal brain MRI, gastroesophageal reflux, and certain dysmorphic features. CONCLUSIONS:This study supports findings from previous research on the severity of intellectual, motor, and speech impairments seen in SHANK3 deficiency, and highlights the prominence of autism spectrum disorder in the syndrome. Limitations of existing evaluation tools are discussed, along with the need for natural history studies to inform clinical monitoring and treatment development in SHANK3 deficiency.

The neurotrophin BDNF and the steroid hormone estrogen exhibit potent effects on hippocampal neurons during development and in adulthood. BDNF and estrogen have also been implicated in the etiology of diverse types of neurological disorders or psychiatric illnesses, or have been discussed as potentially important in treatment. Although both are typically studied independently, it has been suggested that BDNF mediates several of the effects of estrogen in hippocampus, and that these interactions play a role in the normal brain as well as disease. Here we focus on the mossy fiber (MF) pathway of the hippocampus, a critical pathway in normal hippocampal function, and a prime example of a location where numerous studies support an interaction between BDNF and estrogen in the rodent brain. We first review the temporal and spatially-regulated expression of BDNF and estrogen in the MFs, as well as their receptors. Then we consider the results of studies that suggest that 17beta-estradiol alters hippocampal function by its influence on BDNF expression in the MF pathway. We also address the hypothesis that estrogen influences hippocampus by mechanisms related not only to the mature form of BDNF, acting at trkB receptors, but also by regulating the precursor, proBDNF, acting at p75NTR. We suggest that the interactions between BDNF and 17beta-estradiol in the MFs are potentially important in the normal function of the hippocampus, and have implications for sex differences in functions that depend on the MFs and in diseases where MF plasticity has been suggested to play an important role, Alzheimer's disease, epilepsy and addiction.

BACKGROUND: Like fear conditioning, the acquisition phase of extinction involves new learning that is mediated by the amygdala. During extinction training, the conditioned stimulus is repeatedly presented in the absence of the unconditioned stimulus, and the expression of previously learned fear gradually becomes suppressed. Our previous study revealed that chronic treatment with a selective serotonin reuptake inhibitor (SSRI) impairs the acquisition of auditory fear conditioning. To gain further insight into how SSRIs affect fear learning, we tested the effects of chronic SSRI treatment on the acquisition of extinction. METHODS: Rats were treated chronically (22 days) or subchronically (9 days) with the SSRI citalopram (10 mg/kg/day) before extinction training. The results were compared with those after chronic and subchronic treatment with tianeptine (10 mg/kg/day), an antidepressant with a different method of action. The expression of the NR2B subunit of the N-methyl-D-aspartate receptor in the amygdala was examined after behavioral testing. RESULTS: Chronic but not subchronic administration of citalopram impaired the acquisition of extinction and downregulated the NR2B subunit of the N-methyl-D-aspartate receptor in the lateral and basal nuclei of the amygdala. Similar behavioral and molecular changes were found with tianeptine treatment. CONCLUSIONS: These results provide further evidence that chronic antidepressant treatment can impair amygdala-dependent learning. Our findings are consistent with a role for glutamatergic neurotransmission in the final common pathway of antidepressant treatment.

OBJECTIVE: To compare BMI and obesity rates in fully grown men with and without childhood attention-deficit/hyperactivity disorder (ADHD). We predicted higher BMI and obesity rates in: (1) men with, versus men without, childhood ADHD; (2) men with persistent, versus men with remitted, ADHD; and (3) men with persistent or remitted ADHD versus those without childhood ADHD. METHODS: Men with childhood ADHD were from a cohort of 207 white boys (referred at a mean age of 8.3 years), interviewed blindly at mean ages 18 (FU18), 25 (FU25), and 41 years (FU41). At FU18, 178 boys without ADHD were recruited. At FU41, 111 men with childhood ADHD and 111 men without childhood ADHD self-reported their weight and height. RESULTS: Men with childhood ADHD had significantly higher BMI (30.1 +/- 6.3 vs 27.6 +/- 3.9; P = .001) and obesity rates (41.4% vs 21.6%; P = .001) than men without childhood ADHD. Group differences remained significant after adjustment for socioeconomic status and lifetime mental disorders. Men with persistent (n = 24) and remitted (n = 87) ADHD did not differ significantly in BMI or obesity rates. Even after adjustment, men with remitted (but not persistent) ADHD had significantly higher BMI (B: 2.86 [95% CI: 1.22 to 4.50]) and obesity rates (odds ratio: 2.99 [95% CI: 1.55 to 5.77]) than those without childhood ADHD. CONCLUSIONS: Children with ADHD are at increased risk of obesity as adults. Findings of elevated BMI and obesity rates in men with remitted ADHD require replication.

Conventional group analysis is usually performed with Student-type t-test, regression, or standard AN(C)OVA in which the variance-covariance matrix is presumed to have a simple structure. Some correction approaches are adopted when assumptions about the covariance structure is violated. However, as experiments are designed with different degrees of sophistication, these traditional methods can become cumbersome, or even be unable to handle the situation at hand. For example, most current FMRI software packages have difficulty analyzing the following scenarios at group level: (1) taking within-subject variability into account when there are effect estimates from multiple runs or sessions; (2) continuous explanatory variables (covariates) modeling in the presence of a within-subject (repeated measures) factor, multiple subject-grouping (between-subjects) factors, or the mixture of both; (3) subject-specific adjustments in covariate modeling; (4) group analysis with estimation of hemodynamic response (HDR) function by multiple basis functions; (5) various cases of missing data in longitudinal studies; and (6) group studies involving family members or twins. Here we present a linear mixed-effects modeling (LME) methodology that extends the conventional group analysis approach to analyze many complicated cases, including the six prototypes delineated above, whose analyses would be otherwise either difficult or unfeasible under traditional frameworks such as AN(C)OVA and general linear model (GLM). In addition, the strength of the LME framework lies in its flexibility to model and estimate the variance-covariance structures for both random effects and residuals. The intraclass correlation (ICC) values can be easily obtained with an LME model with crossed random effects, even at the presence of confounding fixed effects. The simulations of one prototypical scenario indicate that the LME modeling keeps a balance between the control for false positives and the sensitivity for activation detection. The importance of hypothesis formulation is also illustrated in the simulations. Comparisons with alternative group analysis approaches and the limitations of LME are discussed in details.

Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P<5 x 10(-8)); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P=1.85 x 10(-6)). A secondary analysis including an additional 211 cases and 285 controls from two closely related Latin American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (P=3.6 x 10(-7) for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.

CONTEXT: In response to national efforts to improve quality of care, policymakers and health care leaders have increasingly turned to quality improvement collaboratives (QICs) as an efficient approach to improving provider practices and patient outcomes through the dissemination of evidence-based practices. This article presents findings from a systematic review of the literature on QICs, focusing on the identification of common components of QICs in health care and exploring, when possible, relations between QIC components and outcomes at the patient or provider level. METHODS: A systematic search of five major health care databases generated 294 unique articles, twenty-four of which met our criteria for inclusion in our final analysis. These articles pertained to either randomized controlled trials or quasi-experimental studies with comparison groups, and they reported the findings from twenty different studies of QICs in health care. We coded the articles to identify the components reported for each collaborative. FINDINGS: We found fourteen crosscutting components as common ingredients in health care QICs (e.g., in-person learning sessions, phone meetings, data reporting, leadership involvement, and training in QI methods). The collaboratives reported included, on average, six to seven of these components. The most common were in-person learning sessions, plan-do-study-act (PDSA) cycles, multidisciplinary QI teams, and data collection for QI. The outcomes data from these studies indicate the greatest impact of QICs at the provider level; patient-level findings were less robust. CONCLUSIONS: Reporting on specific components of the collaborative was imprecise across articles, rendering it impossible to identify active QIC ingredients linked to improved care. Although QICs appear to have some promise in improving the process of care, there is great need for further controlled research examining the core components of these collaboratives related to patient- and provider-level outcomes.