Faculty Bibliography

Although there are changes in gene expression and alterations in neuronal density and afferent inputs in the forebrain of trisomic mouse models of Down syndrome (DS) and Alzheimer's disease (AD), there is a lack of systematic assessments of gene expression and encoded proteins within individual vulnerable cell populations, precluding translational investigations at the molecular and cellular level. Further, no effective treatment exists to combat intellectual disability and basal forebrain cholinergic neurodegeneration seen in DS. To further our understanding of gene expression changes before and following cholinergic degeneration in a well-established mouse model of DS/AD, the Ts65Dn mouse, we assessed RNA expression levels from CA1 pyramidal neurons at two adult ages (∼6 months of age and ∼11 months of age) in both Ts65Dn and their normal disomic (2N) littermates. We further examined a viable therapeutic, maternal choline supplementation (MCS), which has been previously shown to lessen dysfunction in spatial cognition and attention, and have protective effects on the survival of basal forebrain cholinergic neurons (BFCNs) in the Ts65Dn mouse model. Results indicate that MCS normalized expression of several genes in key gene ontology categories, including synaptic plasticity, calcium signaling, and AD-associated neurodegeneration related to amyloid-beta peptide (Aβ) clearance. Specifically, normalized expression levels were found for endothelin converting enzyme-2 (Ece2), insulin degrading enzyme (Ide), Dyrk1a, and calcium/calmodulin-dependent protein kinase II (Camk2a), among other relevant genes. Single population expression profiling of vulnerable CA1 pyramidal neurons indicates that MCS is a viable therapeutic for long-term reprogramming of key transcripts involved in neuronal signaling that are dysregulated in the trisomic mouse brain which have translational potential for DS and AD.

OBJECTIVE:There is limited research on metabolic abnormalities in psychotropic-naïve patients with serious mental illness (SMI). Our study examined metabolic conditions in a large, ethnically diverse sample of psychotropic-naïve and non-naïve adults with SMI at an urban public hospital. METHODS:In this cross-sectional study of 923 subjects, the prevalences of hyperglycemia meeting criteria for type 2 diabetes mellitus (T2DM) based on fasting plasma glucose and obesity defined by BMI and abdominal girth were compared across duration of psychotropic medication exposure. Multiple logistic regression models used hyperglycemia and obesity as dependent variables and age, sex, race/ethnicity, and years on psychotropics as independent variables. RESULTS:Psychotropic-naïve patients, including both schizophrenia and non-psychotic subgroups, showed an elevated prevalence of hyperglycemia meeting criteria for T2DM and a decreased prevalence of obesity compared to the general population. Obesity rates significantly increased for those on psychotropic medications more than 5 years, particularly for patients without psychosis (BMI: aOR = 5.23 CI = 1.44-19.07; abdominal girth: aOR = 6.40 CI = 1.98-20.69). Women had a significantly higher obesity rate than men (BMI: aOR = 1.63 CI = 1.17-2.28; abdominal girth: aOR = 3.86 CI = 2.75-5.44). Asians had twice the prevalence of hyperglycemia as whites (aOR = 2.29 CI = 1.43-3.67), despite having significantly less obesity (BMI: aOR = .39 CI = .20-.76; abdominal girth: aOR = .34 CI = .20-.60). Hispanics had a higher rate of obesity by BMI than whites (aOR = 1.91 CI = 1.22-2.99). CONCLUSIONS:This study showed disparities between obesity and T2DM in psychotropic-naïve patients with SMI, suggesting separate risk pathways for these two metabolic conditions.

Massive galaxy clusters have been found that date to times as early as three billion years after the Big Bang, containing stars that formed at even earlier epochs^1-3. The high-redshift progenitors of these galaxy clusters-termed 'protoclusters'-can be identified in cosmological simulations that have the highest overdensities (greater-than-average densities) of dark matter^4-6. Protoclusters are expected to contain extremely massive galaxies that can be observed as luminous starbursts ⁷ . However, recent detections of possible protoclusters hosting such starbursts^8-11 do not support the kind of rapid cluster-core formation expected from simulations ¹² : the structures observed contain only a handful of starbursting galaxies spread throughout a broad region, with poor evidence for eventual collapse into a protocluster. Here we report observations of carbon monoxide and ionized carbon emission from the source SPT2349-56. We find that this source consists of at least 14 gas-rich galaxies, all lying at redshifts of 4.31. We demonstrate that each of these galaxies is forming stars between 50 and 1,000 times more quickly than our own Milky Way, and that all are located within a projected region that is only around 130 kiloparsecs in diameter. This galaxy surface density is more than ten times the average blank-field value (integrated over all redshifts), and more than 1,000 times the average field volume density. The velocity dispersion (approximately 410 kilometres per second) of these galaxies and the enormous gas and star-formation densities suggest that this system represents the core of a cluster of galaxies that was already at an advanced stage of formation when the Universe was only 1.4 billion years old. A comparison with other known protoclusters at high redshifts shows that SPT2349-56 could be building one of the most massive structures in the Universe today.

Limited access to evidence-based behavioral parent training (BPT) for addressing attention deficit/hyperactivity disorder (ADHD) has been a growing concern internationally. Models to improve access to BPT are needed, particularly those that can be readily implemented in community settings and that leverage the potential workforce to increase capacity to deliver BPT. The purpose of this study was to evaluate a BPT model which included oft-used content, methods, processes of BPT (common-elements), non-professionally delivered (task-shifted/shared) BPT intervention, and an efficient ancillary support system (training, fidelity, and supervision methods) for families of youth with parental concerns about ADHD. In a randomized controlled trial of 161 families of children (79% male; mean age 7.04 [1.55]), the Caring in Chaos (CiC) BPT model, delivered by community volunteers across 12 community-based sites in Denmark, was compared to a wait-list control condition on key child and parent outcomes at immediate post-treatment and 4-month follow-up assessment points. Results suggested that the CiC model led to significantly greater improvement in parenting behavior, parenting sense of competence, child functional impairment, parental stress and parental depressive symptoms compared to the wait list condition at immediate post-treatment, with maintenance of gains in most of these areas at follow-up assessment. No effect of intervention was found on ADHD symptoms. The results of this study suggest that developing efficient BPT intervention models, such as the CiC model, can result in readily implemented interventions by a variety of individuals in community settings. Such models are necessary to bend the curve on addressing unmet needs of families of youth with concerns about ADHD.

Executive function deficits are common in children and adolescents with epilepsy. Though the Wisconsin Card Sorting Task (WCST) is often considered the "gold standard" for executive function assessment, its sensitivity-particularly in the case of the 64-card version (WCST-64)-is insufficiently established in pediatric samples, including children and adolescents with epilepsy. The present investigation assesses the sensitivity of the WCST-64 in children and adolescents with epilepsy in comparison to another measure: the Tower of London - Drexel Version (TOL-DX). A total of 88 consecutively referred children and adolescents with epilepsy were administered both the WCST-64 and TOL-DX as part of a comprehensive neuropsychological evaluation. The sensitivity of WCST-64 and TOL-DX variables were established and relations with epilepsy severity measures and other executive function measures were assessed. Of the WCST-64 variables, Perseverative Responses is the most sensitive, but detected executive function impairment in only 19% of this clinically referred sample; in contrast, the TOL-DX Rule Violations detected executive function impairment in half of the sample. Further, TOL-DX performances are more strongly related to epilepsy severity variables and other executive function measures in comparison to the WCST-64. Despite its popularity amongst clinicians, the WCST-64 is not as sensitive to executive dysfunction in comparison to other measures of comparable administration time, such as the TOL-DX.

Advances in neuroimaging and network analyses have lead to discovery of highly connected regions, or hubs, in the connectional architecture of the human brain. Whether these hubs emerge in utero, has yet to be examined. The current study addresses this question and aims to determine the location of neural hubs in human fetuses. Fetal resting-state fMRI data (N = 105) was used to construct connectivity matrices for 197 discrete brain regions. We discovered that within the connectional functional organization of the human fetal brain key hubs are emerging. Consistent with prior reports in infants, visual and motor regions were identified as emerging hub areas, specifically in cerebellar areas. We also found evidence for network hubs in association cortex, including areas remarkably close to the adult fusiform facial and Wernicke areas. Functional significance of hub structure was confirmed by computationally deleting hub versus random nodes and observing that global efficiency decreased significantly more when hubs were removed (p < .001). Taken together, we conclude that both primary and association brain regions demonstrate centrality in network organization before birth. While fetal hubs may be important for facilitating network communication, they may also form potential points of vulnerability in fetal brain development.

Rigorously conducted meta-analyses provide evidence synthesis that has the potential to inform daily clinical decision making and development of clinical guidelines. In the past decade, there has been an increasing number of studies on pharmacologic and non-pharmacologic treatments for childhood and adolescent psychiatric disorders. Given this large body of research, busy clinicians might tend to rely on meta-analyses, rather than individual trials, to keep abreast of the evidence base supporting intervention strategies in child and adolescent psychiatry. Many meta-analyses focused on treatments for child and adolescent mental health problems have primarily addressed the question: Is treatment X more efficacious/effective (or safer) than the control condition? This is clearly an important starting point for clinicians when discussing with their patients and families the benefits and risks of treatment X, but clinicians need to know more. For instance, they might look for the evidence base to answer the following questions: Is treatment X the most efficacious and effective (or safest) option for my patient? When will treatment X likely start working? If the dose or intensity of the treatment does not seem to be effective, is it worthwhile to increase it? And if so, how?

The current study compares health care professionals' beliefs about vaccination statements with the beliefs of a sample of individuals from the general population. Students and faculty within a medical school (n = 58) and a sample from the general population in the United States (n = 177) were surveyed regarding their beliefs about vaccinations. Participants evaluated statements about vaccinations (both supporting and opposing), and indicated whether they thought the general population would agree with them. Overall, it was found that subjects in both populations agreed with statements supporting vaccination over opposing statements, but the general population was more likely to categorize the supporting statements as beliefs rather than facts. Additionally, there was little consensus within each population as to which statements were considered facts versus beliefs. Both groups underestimated the number of people that would agree with them; however, the medical affiliates showed the effect significantly more. Implications for medical education and health communication are discussed.