Faculty Bibliography

OBJECTIVE: To understand disorder-unique and common pathophysiology, studies in multiple patient groups with overlapping symptoms are needed. Deficits in emotion processing and hyperarousal symptoms are prominent features of bipolar disorder, attention deficit hyperactivity disorder (ADHD), and severe mood dysregulation. The authors compared amygdala response during emotional and nonemotional ratings of neutral faces in youths with these disorders as well as a group of healthy comparison youths. METHOD: Blood-oxygen-level-dependent (BOLD) signal in the amygdala was examined in children with bipolar disorder (N=43), ADHD (N=18), and severe mood dysregulation (N=29) and healthy comparison subjects (N=37). During functional magnetic resonance imaging (fMRI), participants attended to emotional and nonemotional aspects of neutral faces. RESULTS: While rating subjective fear of neutral faces, youths with ADHD demonstrated left amygdala hyperactivity relative to the other three groups, whereas youths with severe mood dysregulation demonstrated hypoactivity. CONCLUSIONS: These findings support the role of unique neural correlates in face-emotion processing among youths with bipolar disorder, ADHD, and severe mood dysregulation.

This study examined relations among family environment, cortisol response, and behavior in the context of a randomized controlled trial with 92 children (M = 48 months) at risk for antisocial behavior. Previously, researchers reported an intervention effect on cortisol response in anticipation of a social challenge. The current study examined whether changes in cortisol response were related to later child aggression. Among lower warmth families, the intervention effect on aggression was largely mediated by the intervention effect on cortisol response. Although the intervention also resulted in significant benefits on child engaging behavior, cortisol response did not mediate this effect. These findings demonstrate meaningful associations between cortisol response and aggression among children at familial risk for antisocial behavior

How do infants learn to perceive the backs of objects that they see only from a limited viewpoint? Infants' 3-dimensional object completion abilities emerge in conjunction with developing motor skills--independent sitting and visual-manual exploration. Infants at 4.5 to 7.5 months of age (n = 28) were habituated to a limited-view object and tested with volumetrically complete and incomplete (hollow) versions of the same object. Parents reported infants' sitting experience, and infants' visual-manual exploration of objects was observed in a structured play session. Infants' self-sitting experience and visual-manual exploratory skills predicted looking at the novel, incomplete object on the habituation task. Further analyses revealed that self-sitting facilitated infants' visual inspection of objects while they manipulated them. The results are framed within a developmental systems approach, wherein infants' sitting skill, multimodal object exploration, and object knowledge are linked in developmental time.

OBJECTIVES: Administration to rats of mood stabilizers approved for bipolar disorder (BD) downregulates markers of the brain arachidonic acid (AA, 20:4n-6) metabolic cascade, including phospholipase A(2) (PLA(2)) and cyclooxygenase (COX) expression. We hypothesized that other agents that target the brain AA cascade, nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids, also would ameliorate BD symptoms. METHODS: Medication histories on subjects who had been prescribed lithium were collected from the Netherlands PHARMO Record Linkage System. Data were stratified according to drug classes that inhibit PLA(2) and/or COX enzymes, and duration of use. Incidence density (ID) of medication events (dose increase or substance change) was used as a proxy for clinical worsening. ID ratios in patients with the inhibitors plus lithium were compared to ratios in patients using lithium alone. RESULTS: Low-dose acetylsalicylic acid (aspirin) significantly reduced the ID ratio of medication events, independent of use duration. The ID ratios of NSAIDs and glucocorticoids did not differ significantly from 1.0 if prescribed for > or =180 or > or =90 days, but exceeded 1.0 with shorter use. Selective COX-2 inhibitors had no significant effect and multiagent administration increased the ID ratio above 1.0. CONCLUSIONS: Low-dose aspirin produced a statistically significant duration-independent reduction in the relative risk of clinical deterioration in subjects on lithium, whereas other NSAIDs and glucocorticoids did not. These tentative findings could be tested on larger databases containing detailed information about diagnosis and disease course, as well as by controlled clinical trials.

The metabolic effects of stress are known to have significant health effects in both humans and animals. Most of these effects are mediated by the major stress hormonal axis in the body, the hypothalamic-pituitary-adrenal (HPA) axis. Within the central nervous system (CNS), the hippocampus, the amygdala and the prefrontal cortex as part of the limbic system are believed to play important roles in the regulation of the HPA axis. With the advent of structural and functional neuroimaging techniques, the role of different CNS structures in the regulation of the HPA axis can be investigated more directly. In the current paper, we summarize the findings obtained in our laboratory in the context of stress and HPA axis regulation. Our laboratory has developed and contributed to the development of manual and automated segmentation protocols from structural magnetic resonance imaging (MRI) scans for assessment of hippocampus, amygdala, medial temporal lobe and frontal lobe structures. Employing these protocols, we could show significant age-related changes in HC volumes, which were different between men and women, with pre-menopausal women showing smaller age-related volume decline compared to men. We could recently extent these findings by showing how estrogen therapy after menopause leads to higher volumes in the HC. Investigating possible neurotoxicity effects of steroids, we showed effects of long-term steroid exposure on HC volumes, and investigated variability of HC volumes in relation to HPA axis regulation in young and elderly populations. Here, we were able to follow-up from non-imaging studies showing that subjects low in self-esteem have higher cortisol stress responses, and the HC emerged as the critical link between these variables. Recently, we have made two more important discoveries with regard to HC volume: we could show that HC volume is as variable in young as it is in older adults, in subjects ranging in age from 18 to 80 years. Also, we have linked birth weight and maternal care to HC volumes in young adults, demonstrating the effects of variations in maternal care on the integrity of the CNS. Besides structural assessments, there is increasing interest in functional techniques to investigate possible links between CNS activity and HPA axis regulation. These two approaches complement each other; some aspects of HPA axis regulation might be linked to the integrity of a specific CNS structure, while other aspects might be linked to the function of a specific structure with no involvement of CNS morphology. Thus, we have developed a mental arithmetic stress task that can be employed in functional neuroimaging studies, and have used it in a number of functional neuroimaging studies. Employing positron emission tomography (PET), we were able to demonstrate that stress causes dopamine release if subjects reported low maternal care early in life. Finally, employing the task in functional magnetic resonance imaging (fMRI), we could show how exposure to stress and activation of the HPA axis are associated with decreased activity in major portions of the limbic system, a result that allows to speculate on the effects of stress on cognitive and emotional regulation in the brain. Taken together, the use of neuroimaging techniques in Psychoneuroendocrinology opens exciting new possibilities for the investigation of stress effects in the central nervous system

There is increasing consensus that disruptive behavior disorders and syndromes (DBDs) are identifiable in preschool children. There is also concomitant recognition of the limitations of the current DBD nosology for distinguishing disruptive behavior symptoms from the normative misbehavior of early childhood. In particular, there appears to be substantial insensitivity to heterotypic manifestations of this developmental period and problems in identifying meaningful heterogeneity. As a result, the developmental basis for much of the current nosology may be called into question. To address these and other critical issues, this paper reviews the foundational elements of clinical and developmental science pertinent to developmental differentiation of disruptive behavior in the preschool period as paradigmatic for developmental specification across the lifespan and generates an agenda for future research. We begin by reviewing evidence of the validity of DBDs in preschool children. This is followed by an outline of key developmental concepts and a review of the corollary evidence from developmental science. These provide a basis for conceptualizing disruptive behavior in reference to developmental deviation in four core dimensions hypothesized to mark the core features of disruptive behavior syndromes. Finally, we propose a program of research to establish an empirical basis for determining the incremental utility of a developmentally specified nosology. Central to this approach is a contention that the benefits of developmental specification are extensive and outweigh any disadvantages. This is because a developmentally specified approach holds substantial promise for increasing sensitivity and specificity for differentiating disruptive behavior from normative misbehavior and from other related syndromes as well as for improving prediction. Further, more precisely defined, developmentally based phenotypes are likely to elucidate distinct mechanisms within translational studies and to serve as a catalyst for the generation of novel treatments

OBJECTIVES: Adult studies of celiac disease (CD) have shown that duodenal mucosal histopathological changes may be patchy, and the diagnostic utility of duodenal bulb biopsies is believed to be limited. Few related pediatric data exist. METHODS: We assessed the prevalence of variable biopsy findings and duodenal bulb involvement in children with CD, as well as its association with clinical parameters. A total of 198 consecutive cases of CD diagnosed at the Children's Hospital during 2001-2005 were analyzed. All biopsies were scored by a pathologist blinded to the clinical data using the Marsh criteria. Mucosal changes were classified as focal if changes consistent with CD and normal mucosa were found within a single biopsy fragment. Patchiness was defined as variation of at least one Marsh grade between separate fragments in a biopsy set. RESULTS: The median age was 9.3 years; 62% were female. An average of 3.6 biopsy samples was obtained per case. In 101 cases, biopsy samples were obtained from the duodenal bulb and the second portion of the duodenum. Focality was present in biopsy samples collected from 36 (18%) cases. Patchiness was found in 105 (53%) cases, and at least 1 normal biopsy fragment was present in 71 (36%) cases. In 10 cases, only the bulb biopsies were diagnostic of CD. There was no association with the clinical features examined. CONCLUSIONS: Duodenal involvement in pediatric CD is frequently patchy and may show variable severity even within a single biopsy fragment. Variability cannot be predicted by clinical characteristics. Multiple endoscopic biopsies, including the duodenal bulb, should be obtained in suspected pediatric CD cases to maximize diagnostic yield.

The purpose of this preliminary study is to evaluate if there is a difference between the intelligence quotient (IQ) of 27 adolescent defendants referred to the Bellevue Hospital Center Forensic Psychiatry Clinic after committing violent crimes, and those adolescents in the same age group in the general population of the United States, as defined by the norms of the psychometric testing instrument Wechsler Intelligence Scale for Children, 4th edition (WISC-IV). The IQ scores and sub-scores were compared to IQ scores of the general population (mean = 100, SD = 15) using a Z-test. The mean for the Full Scale IQ was 82.93. The means for the subtests which include Processing Speed Index, Perceptual Reasoning Index, Verbal Comprehension Index, and Working Memory Index, were: 78.48, 87.78, 86.70 (p < 0.05), and 90.78 (p = 0.09) respectively. There is a statistically significant difference in the IQ scores of the violent juveniles studied when compared to the general population

Brain derived neurotrophic factor (BDNF), a member of the neurotrophin family of structurally related proteins that promote neuronal differentiation and survival during development, is a potent modulator of synaptic plasticity. Changes in BDNF expression, release and neuromodulatory activity, mediated by both epigenetic and post-translational mechanisms, have been associated with many pathological conditions and developmental experiences, such as maternal deprivation and environmental enrichment. Much effort has been devoted to studying plasticity in the hippocampus, a structure traditionally associated with learning and memory, yet there is increasing empirical support for the contribution of another structure--the amygdala--to BDNF-induced changes. Because the amygdala is a critical site for emotional memory formation, and many emotional and neurodevelopmental pathologies have been linked to amygdala-based abnormalities, considerable efforts have been devoted to the characterization of its circuitry. Here we review the role of BDNF as a biochemical integrator of convergent cellular signals, and as a central driver of neural plasticity. We conclude by emphasizing the importance of characterizing BDNF signaling cascades in behaviorally-relevant networks, to identify potential drug targets for novel therapeutic interventions

Adults produce left-lateralized N170 responses to visual words relative to control stimuli, even within tasks that do not require active reading. This specialization begins in preschoolers as a right-lateralized N170 effect. We investigated whether this developmental shift reflects an early learning phenomenon, such as attaining visual familiarity with a script, by training adults in an artificial script and measuring N170 responses before and afterward. Training enhanced the N170 response, especially over the right hemisphere. This suggests N170 sensitivity to visual familiarity with a script emerges before reading becomes sufficiently automatic to drive left-lateralized effects in a shallow encoding task.