Faculty Bibliography

BACKGROUND: The recent upsurge in interest about pediatric bipolar disorder (BD) has spurred the need for greater understanding of its neurobiology. Structural and functional magnetic resonance imaging studies have implicated fronto-temporal dysfunction in pediatric BD. However, recent data suggest that task-dependent neural changes account for a small fraction of the brain's energy consumption. We now report the first use of task-independent spontaneous resting state functional connectivity (RSFC) to study the neural underpinnings of pediatric BD. METHODS: We acquired task-independent RSFC blood oxygen level-dependent functional magnetic resonance imaging scans while participants were at rest and also a high-resolution anatomical image (both at three Tesla) in BD and control youths (n = 15 of each). We focused, on the basis of prior research, on the left dorsolateral prefrontal cortex (DLPFC), amygdala, and accumbens. Image processing and group-level analyses followed that of prior work. RESULTS: Our primary analysis showed that pediatric BD participants had significantly greater negative RSFC between the left DLPFC and the right superior temporal gyrus versus control subjects. Secondary analyses using partial correlation showed that BD and control youths had opposite phase relationships between spontaneous RSFC fluctuations in the left DLPFC and right superior temporal gyrus. CONCLUSIONS: Our data indicate that pediatric BD is characterized by altered task-independent functional connectivity in a fronto-temporal circuit that is also implicated in working memory and learning. Further study is warranted to determine the effects of age, gender, development, and treatment on this circuit in pediatric BD

African American adolescent boys underutilize mental health service due to stigma associated with depression. Gaining an increased understanding of how depressed, African American adolescent boys perceive their mental health needs and engage in help-seeking behaviors might play an essential role in efforts to improve their symptoms and access to care. Using a mixed-methods design, this study examined the influence of mental health stigma and social support on depressive symptoms among African American adolescent boys. Findings indicated the protective effects of social support in decreasing depressive symptoms, especially when participants experienced mental health stigma. Results also revealed the pivotal role of family social support over both professional and peer support for participants who struggled with depressive symptoms. The primacy of family support among the sample, combined with the frequent distrust of professionals and peer networks, would indicate that working with families may improve initial identification of depression among African American adolescent boys and decrease their barriers to care.

There exists a divide between findings from integrative neuroscience and clinical research focused on mechanisms of psychopathology. Specifically, a clear correspondence does not emerge between clusters of complex clinical symptoms and dysregulated neurobiological systems, with many apparent redundancies. For instance, many mental disorders involve multiple disruptions in putative mechanistic factors (e.g., excessive fear, deficient impulse control), and different disrupted mechanisms appear to play major roles in many disorders. The Research Domain Criteria (RDoC) framework is a heuristic to facilitate the incorporation of behavioral neuroscience in the study of psychopathology. Such integration might be achieved by shifting the central research focus of the field away from clinical description to more squarely examine aberrant mechanisms. RDoC first aims to identify reliable and valid psychological and biological mechanisms and their disruptions, with an eventual goal of understanding how anomalies in these mechanisms drive psychiatric symptoms. This approach will require new methods to ascertain samples, relying on hypothesized psychopathological mechanisms to define experimental groups instead of traditional diagnostic categories. RDoC, by design, uncouples research efforts from clinically familiar categories to focus directly on fundamental mechanisms of psychopathology. RDoC proposes a matrix of domains and levels of analyses and invites the field to test and refine the framework. If RDoC is successful, the domains will ultimately relate to familiar psychopathologies in ways that promote new knowledge regarding etiology and more efficient development of new preventive and treatment interventions.

CONTEXT: Controversy exists about the appropriate criteria for a diagnosis of adult attention-deficit/hyperactivity disorder (ADHD). OBJECTIVE: To examine the structure and symptoms most predictive of DSM-IV adult ADHD. DESIGN: The data are from clinical interviews in enriched subsamples of the National Comorbidity Survey Replication (n = 131) and a survey of a large managed health care plan (n = 214). The physician-administered Adult ADHD Clinical Diagnostic Scale (ACDS) was used to assess childhood ADHD and expanded symptoms of current adult ADHD. Analyses examined the stability of symptoms from childhood to adulthood, the structure of adult ADHD, and the adult symptoms most predictive of current clinical diagnoses. SETTING: The ACDS was administered telephonically by clinical research interviewers with extensive experience in the diagnosis and treatment of adult ADHD. PARTICIPANTS: An enriched sample of community respondents. MAIN OUTCOME MEASURE: Diagnoses of DSM-IV /ACDS adult ADHD. RESULTS: Almost half of the respondents (45.7%) who had childhood ADHD continued to meet the full DSM-IV criteria for current adult ADHD, with 94.9% of these patients having current attention-deficit disorder and 34.6% having current hyperactivity disorder. Adult persistence was much greater for inattention than for hyperactivity/impulsivity. Additional respondents met the full criteria for current adult ADHD despite not having met the full childhood criteria. A 3-factor structure of adult symptoms included executive functioning (EF), inattention/hyperactivity, and impulsivity. Stepwise logistic regression found EF problems to be the most consistent and discriminating predictors of adult DSM-IV /ACDS ADHD. CONCLUSIONS: These findings document the greater persistence of inattentive than of hyperactive/impulsive childhood symptoms of ADHD in adulthood but also show that inattention is not specific to ADHD because it is strongly associated with other adult mental disorders. In comparison, EF problems are more specific and consistently important predictors of DSM-IV adult ADHD despite not being in the DSM-IV, suggesting that the number of EF symptoms should be increased in the DSM-V/ICD-11

OBJECTIVE: To compare objective polysomnographic parameters between 3 cohorts: children with autism, typical development, and developmental delay without autism. DESIGN: Overnight polysomnographic recordings were scored for sleep architecture according to American Academy of Sleep Medicine criteria by a board-certified sleep medicine specialist blind to diagnosis for studies collected between July 2006 and September 2009. SETTING: Subjects were evaluated in the pediatric ward in the Clinical Research Center of the National Institutes of Health. PARTICIPANTS: First 60 consecutive children with autism, 15 with typical development, and 13 with developmental delay matched for nonverbal IQ to the autism group, ranging in age from 2 to 13 years, selected without regard to the presence or absence of sleep problem behavior. MAIN OUTCOME MEASURES: Total sleep time, latencies to non-rapid eye movement (REM) and REM sleep, and percentages of total sleep time for stages 1 and 2 sleep, slow-wave sleep, and REM sleep. RESULTS: There were no differences between the typical vs developmental delay groups. Comparison of children with autism vs typical children revealed shorter total sleep time (P = .004), greater slow-wave sleep percentage (P = .001), and much smaller REM sleep percentage (14.5% vs 22.6%; P < .001). Comparison of children with autism vs children with developmental delay revealed shorter total sleep time (P = .001), greater stage 1 sleep percentage (P < .001), greater slow-wave sleep percentage (P < .001), and much less REM sleep percentage (14.5% v 25%; P < .001). CONCLUSION: A relative deficiency of REM sleep may indicate an abnormality in neural organization in young children with autism that is not directly associated with or related to inherent intellectual disability but may serve as a window into understanding core neurotransmitter abnormalities unique to this disorder

Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting that about 80% of phenotypic variance is due to genetic factors. We used the integration of statistical and functional approaches to discover a novel gene that contributes to ADHD. For our statistical approach, we started with a linkage study based on large multigenerational families in a population isolate, followed by fine mapping of targeted regions using a family-based design. Family- and population-based association studies in five samples from disparate regions of the world were used for replication. Brain imaging studies were performed to evaluate gene function. The linkage study discovered a genome region harbored in the Latrophilin 3 gene (LPHN3). In the world-wide samples (total n=6360, with 2627 ADHD cases and 2531 controls) statistical association of LPHN3 and ADHD was confirmed. Functional studies revealed that LPHN3 variants are expressed in key brain regions related to attention and activity, affect metabolism in neural circuits implicated in ADHD, and are associated with response to stimulant medication. Linkage and replicated association of ADHD with a novel non-candidate gene (LPHN3) provide new insights into the genetics, neurobiology, and treatment of ADHD

Resting-state functional connectivity (RSFC) approaches offer a novel tool to delineate distinct functional networks in the brain. In the present functional magnetic resonance imaging (fMRI) study, we elucidated patterns of RSFC associated with 6 regions of interest selected primarily from a meta-analysis on word reading (Bolger DJ, Perfetti CA, Schneider W. 2005. Cross-cultural effect on the brain revisited: universal structures plus writing system variation. Hum Brain Mapp. 25: 92-104). In 25 native adult readers of English, patterns of positive RSFC were consistent with patterns of task-based activity and functional connectivity associated with word reading. Moreover, conjunction analyses highlighted the posterior left inferior frontal gyrus and the posterior left middle temporal gyrus (post-LMTG) as potentially important loci of functional interaction among 5 of the 6 reading networks. The significance of the post-LMTG has typically been unappreciated in task-based studies on unimpaired readers but is frequently reported to be a locus of hypoactivity in dyslexic readers and exhibits intervention-induced changes of activity in dyslexic children. Finally, patterns of negative RSFC included not only regions of the so-called default mode network but also regions involved in effortful controlled processes, which may not be required once reading becomes automatized. In conclusion, the current study supports the utility of resting-state fMRI for investigating reading networks and has direct relevance for the understanding of reading disorders such as dyslexia

OBJECTIVE: To describe the design of a longitudinal study of youth with elevated symptoms of mania (ESM), as well as the prevalence and correlates of manic symptoms. Bipolar disorder in youth is serious and is surrounded by controversy about its phenomenology, course, and treatment. Yet, there are no longitudinal studies of youth selected only for ESM, the phenomenological hallmark. The study's objective is to document the rate and sociodemographic correlates of ESM in children attending outpatient psychiatric clinics. METHOD: Parents of 3,329 children aged 6-12 years visiting 10 outpatient clinics were asked to complete the Parent General Behavior Inventory 10-Item Mania Scale (PGBI-10M). Children with PGBI-10M scores >/= 12 (ESM positive-screen [ESM+]) and a matched sample of ESM screen-negative (ESM-) children were invited to enroll in the longitudinal study. The sample was accrued from November 14, 2005, to November 28, 2008. RESULTS: Most of the children whose parents filled out the PGBI-10M (N = 2,622, 78.8%) participated in the study. Nonparticipants were slightly younger (mean age = 9.1 years [SD = 2.0 years] versus 9.4 years [SD = 2.0 years] for participants; t3327 = 4.42, P < .001). Nearly half of the participants (43%) were ESM+; these were more likely to be Latino (4.2% versus 2.5% for ESM-; chi(2)1 = 5.45, P = .02), younger (mean age = 9.3 years [SD = 2.0 years] versus 9.6 years [SD = 1.9 years] for ESM-; t2620 = 3.8, P < .001), and insured by Medicaid (48.4% versus 35.4% for ESM-; chi(2)1 = 45.00, P < .001). There were no sociodemographic differences between those who did versus did not agree to enroll in the longitudinal portion (yes to enrollment: n = 621, 55.2%; no to enrollment: n = 503, 44.8%). Four items best discriminated ESM+ children from ESM- children. Three of the 4 items were not the most commonly endorsed items, but all were indicative of behavioral extremes. CONCLUSIONS: Data suggest that ESM+ is not rare in 6- to 12-year-olds. Children who are ESM+ show behavioral extremes, including rapid mood shifts, compared to ESM- children.

This study examines the perceptions of health, health seeking behavior, access to information and resources, work related hazards, substance abuse, and social support of emancipated migrant youth (EMY) who come to the United States without their families to work. METHODS: Semi-structured interviews were performed with EMY living without their families in Santa Clara County, California. Interviews were digitally recorded in Spanish, transcribed, translated into English, and analyzed by a five-person analysis team. RESULTS: Eleven interviews were conducted with 29 participants. Work was identified as the overarching priority of the EMY Their greatest concern was becoming sick and unable to work. They described their work environment as demanding and stressful, but felt obliged to work regardless of conditions. Alcohol and drug abuse were reported as prevalent problems. CONCLUSION: Emancipated migrant youth are a vulnerable population who have significant occupational stress, hazardous environmental exposures, social isolation, and drug/alcohol abuse.

BACKGROUND: Psychosis has been repeatedly suggested to be affected by increases in stress and arousal. However, there is a dearth of evidence supporting the temporal link between stress, arousal, and psychosis during 'real-world' functioning. This paucity of evidence may stem from limitations of current research methodologies. Our aim is to the test the feasibility and validity of a novel methodology designed to measure concurrent stress and arousal in individuals with psychosis during 'real-world' daily functioning. METHOD: Twenty patients with psychosis completed a 36-hour ambulatory assessment of stress and arousal. We used experience sampling method with palm computers to assess stress (10 times per day, 10 AM --> 10 PM) along with concurrent ambulatory measurement of cardiac autonomic regulation using a Holter monitor. The clocks of the palm computer and Holter monitor were synchronized, allowing the temporal linking of the stress and arousal data. We used power spectral analysis to determine the parasympathetic contributions to autonomic regulation and sympathovagal balance during 5 minutes before and after each experience sample. RESULTS: Patients completed 79% of the experience samples (75% with a valid concurrent arousal data). Momentary increases in stress had inverse correlation with concurrent parasympathetic activity (rho = -.27, P < .0001) and positive correlation with sympathovagal balance (rho = .19, P = .0008). Stress and heart rate were not significantly related (rho = -.05, P = .3875). CONCLUSION: The findings support the feasibility and validity of our methodology in individuals with psychosis. The methodology offers a novel way to study in high time resolution the concurrent, 'real-world' interactions between stress, arousal, and psychosis. The authors discuss the methodology's potential applications and future research directions