Faculty Bibliography

We sought to determine whether functional connectivity streams that link sensory, attentional, and higher-order cognitive circuits are atypical in attention-deficit/hyperactivity disorder (ADHD). We applied a graph-theory method to the resting-state functional magnetic resonance imaging data of 120 children with ADHD and 120 age-matched typically developing children (TDC). Starting in unimodal primary cortex-visual, auditory, and somatosensory-we used stepwise functional connectivity to calculate functional connectivity paths at discrete numbers of relay stations (or link-step distances). First, we characterized the functional connectivity streams that link sensory, attentional, and higher-order cognitive circuits in TDC and found that systems do not reach the level of integration achieved by adults. Second, we searched for stepwise functional connectivity differences between children with ADHD and TDC. We found that, at the initial steps of sensory functional connectivity streams, patients display significant enhancements of connectivity degree within neighboring areas of primary cortex, while connectivity to attention-regulatory areas is reduced. Third, at subsequent link-step distances from primary sensory cortex, children with ADHD show decreased connectivity to executive processing areas and increased degree of connections to default mode regions. Fourth, in examining medication histories in children with ADHD, we found that children medicated with psychostimulants present functional connectivity streams with higher degree of connectivity to regions subserving attentional and executive processes compared to medication-naive children. We conclude that predominance of local sensory processing and lesser influx of information to attentional and executive regions may reduce the ability to organize and control the balance between external and internal sources of information in ADHD. Hum Brain Mapp 36:2544-2557, 2015. (c) 2015 Wiley Periodicals, Inc.

BACKGROUND: The consumption of sweetened beverages, refined foods, and pastries has been shown to be associated with an increased risk of depression in longitudinal studies. However, any influence that refined carbohydrates has on mood could be commensurate with their proportion in the overall diet; studies are therefore needed that measure overall intakes of carbohydrate and sugar, glycemic index (GI), and glycemic load. OBJECTIVE: We hypothesized that higher dietary GI and glycemic load would be associated with greater odds of the prevalence and incidence of depression. DESIGN: This was a prospective cohort study to investigate the relations between dietary GI, glycemic load, and other carbohydrate measures (added sugars, total sugars, glucose, sucrose, lactose, fructose, starch, carbohydrate) and depression in postmenopausal women who participated in the Women's Health Initiative Observational Study at baseline between 1994 and 1998 (n = 87,618) and at the 3-y follow-up (n = 69,954). RESULTS: We found a progressively higher dietary GI to be associated with increasing odds of incident depression in fully adjusted models (OR for the fifth vs. first quintile: 1.22; 95% CI: 1.09, 1.37), with the trend being statistically significant (P = 0.0032). Progressively higher consumption of dietary added sugars was also associated with increasing odds of incident depression (OR for the fifth vs. first quintile: 1.23; 95% CI: 1.07, 1.41; P-trend = 0.0029). Higher consumption of lactose, fiber, nonjuice fruit, and vegetables was significantly associated with lower odds of incident depression, and nonwhole/refined grain consumption was associated with increased odds of depression. CONCLUSIONS: The results from this study suggest that high-GI diets could be a risk factor for depression in postmenopausal women. Randomized trials should be undertaken to examine the question of whether diets rich in low-GI foods could serve as treatments and primary preventive measures for depression in postmenopausal women. The Women's Health Initiative is registered at clinicaltrials.gov as NCT00000611.

Attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BD) are neurodevelopmental disorders with onset in childhood and early adolescence, and common persistence in adulthood. Both disorders are often undiagnosed, misdiagnosed, and sometimes over diagnosed, leading to high rates of morbidity and disability. The differentiation of these conditions is based on their clinical features, comorbidity, psychiatric family history course of illness, and response to treatment. We review recent relevant findings and highlight epidemiological, clinical, family history, course, and treatment-response differences that can aid the differential diagnosis of these conditions in an outpatient pediatric setting.

BACKGROUND: Preschool hyperactivity is an early risk factor for adult mental health problems and criminality. Little is known about; (a) the patterns of long-term service costs associated with this behavioural marker in the general population and (b) the specific factors predicting hyperactivity-related costs. We undertook a prospective study investigating associations between preschool hyperactivity and average individual annual service costs up to late adolescent and young adulthood. METHODS: One-hundred and seventy individuals rated as hyperactive by their parents and 88 nonhyperactive controls were identified from a community sample of 4,215 three years olds. Baseline information about behaviour/emotional problems and background characteristics were collected. At follow-up (when individuals were aged between 14 and 25 years) information was obtained on service use, and associated costs since the age of three. Based on this information we calculated the average cost per annum incurred by each individual. RESULTS: Compared to controls, preschoolers with hyperactivity had 17.6 times higher average costs per annum across domains (apart from nonmental health costs). These were pound562 for each hyperactive individual compared with pound30 for controls. Average annual costs decreased as a function of age, with higher costs incurred at younger ages. The effects of hyperactivity remained significant when other baseline factors were added to the model. Effects were fully mediated by later psychiatric morbidity. When the hyperactive group were examined separately, costs were consistently predicted by male gender and, for some cost codes, by conduct problems. CONCLUSIONS: Preventative approaches targeting early hyperactivity may be of value. Services should be targeted towards high-risk individuals with careful consideration given to the cost-to-benefit trade-off of early intervention strategies.

Risky decision-making, particularly in the context of reward-seeking behavior, is strongly associated with the presence of substance use disorders (SUDs). However, there has been little research on the neural substrates underlying reward-related decision-making in drug-naive youth who are at elevated risk for SUDs. Participants comprised 23 high-risk (HR) youth with a well-established SUD risk phenotype and 27 low-risk healthy comparison (HC) youth, aged 10-14. Participants completed the balloon analog risk task (BART), a task designed to examine risky decision-making, during functional magnetic resonance imaging. The HR group had faster reaction times, but otherwise showed no behavioral differences from the HC group. HR youth experienced greater activation when processing outcome, as the chances of balloon explosion increased, relative to HC youth, in ventromedial prefrontal cortex (vmPFC). As explosion probability increased, group-by-condition interactions in the ventral striatum/anterior cingulate and the anterior insula showed increasing activation in HR youth, specifically on trials when explosions occurred. Thus, atypical activation increased with increasing risk of negative outcome (i.e., balloon explosion) in a cortico-striatal network in the HR group. These findings identify candidate neurobiological markers of addiction risk in youth at high familial and phenotypic risk for SUDs.

OBJECTIVE: To describe the long-term psychopharmacological treatment of children first diagnosed with attention-deficit/hyperactivity disorder (ADHD) as preschoolers. METHOD: In a systematic, prospective, naturalistic follow-up, 206 (68.0%) of the 303 children who participated in the Preschool ADHD Treatment Study (PATS) were reassessed 3 years (mean age 7.4 years) and 179 (59.1%) were reassessed 6 years (mean age 10.4 years) after completion of the controlled study. Pharmacotherapy and clinical data were obtained from the parents. Pharmacotherapy was defined as use of a specific class of medication for at least 50% of the days in the previous 6 months. RESULTS: At year 3, a total of 34.0% of the participants were on no pharmacotherapy, 41.3% were on stimulant monotherapy, 9.2% were on atomoxetine alone or with a stimulant, 8.3% were on an antipsychotic usually together with a stimulant, and the remaining 7.2% were on other pharmacotherapy; overall, 65.0% were on an indicated ADHD medication. At year 6, a total of 26.8% of the participants were on no pharmacotherapy, 40.2% were on stimulant monotherapy, 4.5% were on atomoxetine alone or with a stimulant, 13.4% were on an antipsychotic, and 15.1% were on other pharmacotherapy; overall, 70.9% were on an indicated ADHD medication. Antipsychotic treatment was associated with more comorbidity, in particular disruptive behavior disorders and pervasive development disorders, and a lower level of functioning. CONCLUSION: In this study, the long-term pharmacotherapy of preschoolers with ADHD was heterogeneous. Although stimulant medication continued to be used by most children, about 1 child in 4 was off medication, and about 1 in 10 was on an antipsychotic.

Schizophrenia is a debilitating syndrome with high heritability. Genomic studies reveal more than a hundred genetic variants, largely nonspecific and of small effect size, and not accounting for its high heritability. De novo mutations are one mechanism whereby disease related alleles may be introduced into the population, although these have not been leveraged to explore the disease in general samples. This paper describes a framework to find high impact genes for schizophrenia. This study consists of two different datasets. First, whole exome sequencing was conducted to identify disruptive de novo mutations in 14 complete parent-offspring trios with sporadic schizophrenia from Jerusalem, which identified 5 sporadic cases with de novo gene mutations in 5 different genes (PTPRG, TGM5, SLC39A13, BTK, CDKN3). Next, targeted exome capture of these genes was conducted in 48 well-characterized, unrelated, ethnically diverse schizophrenia cases, recruited and characterized by the same research team in New York (NY sample), which demonstrated extremely rare and potentially damaging variants in three of the five genes (MAF<0.01) in 12/48 cases (25%); including PTPRG (5 cases), SCL39A13 (4 cases) and TGM5 (4 cases), a higher number than usually identified by whole exome sequencing. Cases differed in cognition and illness features based on which mutation-enriched gene they carried. Functional de novo mutations in protein-interaction domains in sporadic schizophrenia can illuminate risk genes that increase the propensity to develop schizophrenia across ethnicities.

Background. Major depressive disorder (MDD) is highly comorbid with diabetes, a relationship underappreciated by clinicians. Purpose. Examine the proportion of nonpregnant individuals >/=20 years with MDD and elevated glucose and the demographic and clinical characteristics associated with unrecognized elevated glucose. Methods. 14,373 subjects who participated in the National Health and Nutrition Examination Survey (2007-2012) completed the PHQ-9 depression screen and had hemoglobin A1C (HbA1c) measured. PHQ-9 scores >/=10 and HbA1c scores >/=5.7% were defined as MDD and elevated HbA1c, respectively. Data were analyzed using complex survey sampling software. Results. 38.4% of the sample with MDD had elevated HbA1c readings. Compared with nondepressed subjects, they were significantly more likely to have elevated glucose readings (P = 0.003) and to be aware of their elevated glucose levels if they had a higher body mass index, family history of diabetes, more doctor visits in the past year, a usual care source, health insurance, or were taking hypertension or hypercholesterolemia medications. Conclusions. Many adults with MDD have elevated HbA1c levels, have never been advised of elevated HbA1c, have not received diabetes screening, and have minimal contact with a healthcare provider. Additional opportunities for diabetes risk screening in people with MDD are needed.

Game-based cognitive-behavioral therapy group model for nonoffending caregivers utilizes structured therapeutic games to assist parents following child sexual abuse. Game-based cognitive-behavioral therapy group model is a manualized group treatment approach that integrates evidence-based cognitive-behavioral therapy components with structured play therapy to teach parenting and coping skills, provide psychoeducation, and process trauma. Structured therapeutic games were designed to allow nonoffending caregivers to process their children's abuse experiences and learn skills necessary to overcome trauma in a nonthreatening, fun, and engaging manner. The implementation of these techniques allow clinicians to address a variety of psychosocial difficulties that are commonly found among nonoffending caregivers of children who have experienced sexual abuse. In addition, structured therapeutic games help caregivers develop strengths and abilities that they can use to help their children cope with abuse and trauma and facilitates the development of positive posttraumatic growth. Techniques and procedures for treatment delivery along with a description of core components and therapeutic modules are discussed. An illustrative case study is provided.