Faculty Bibliography

In this study, we attempted to clarify whether distractibility in ADHD might arise from increased sensory-driven interference or from inefficient top-down control. We employed an attentional filtering paradigm in which discrimination difficulty and distractor salience (amount of image "graying") were parametrically manipulated. Increased discrimination difficulty should add to the load of top-down processes, whereas increased distractor salience should produce stronger sensory interference. We found an unexpected interaction of discrimination difficulty and distractor salience. For difficult discriminations, ADHD children filtered distractors as efficiently as healthy children and adults; as expected, all three groups were slower to respond with high vs. low salience distractors. In contrast, for easy discriminations, robust between-group differences emerged: ADHD children were much slower and made more errors than either healthy children or adults. For easy discriminations, healthy children and adults filtered out high salience distractors as easily as low salience distractors, but ADHD children were slower to respond on trials with low salience distractors than they did on trials with high salience distractors. These initial results from a small sample of ADHD children have implications for models of attentional control, and ways in which it can malfunction. The fact that ADHD children exhibited efficient attentional filtering when task demands were high, but showed deficient and atypical distractor filtering under low task demands suggests that attention deficits in ADHD may stem from a failure to efficiently engage top-down control rather than an inability to implement filtering in sensory processing regions.

Early intervention approaches have rarely been implemented for the prevention of attention deficit/hyperactivity disorder (ADHD). In this paper we explore whether such an approach may represent an important new direction for therapeutic innovation. We propose that such an approach is most likely to be of value when grounded in and informed by developmental models of the dynamic, complex and heterogeneous nature of the condition. First, we set out a rationale for early intervention grounded in the science of ADHD viewed through developmental models. Second, we re-examine the concept of disorder-onset from the perspective of developmental trajectories and phenotypes. Third, we examine potential causal pathways to ADHD with regard to originating risk, pathophysiological mediators, environmental moderators and developmental continuities. Finally, we explore the potential value of strategies for identifying young children at risk for ADHD, and implementing interventions in ways that can target these underlying pathogenic processes. The utility of such an approach represents an important area for future research but still requires 'proof of concept'. Therefore prior to widespread clinical implementation, far greater knowledge is required of (i) developmental pathways into ADHD, (ii) the value of identifying neuropsychological mediators of these pathways, and (iii) the extent to which targeting mediating mechanisms will improve treatment outcomes for children with ADHD

Throughout this monograph, there has been frequent reference to levels of risk, inference of causation, testing for mediating variables, and the need to consider possible moderating influences. In this chapter, we review what is meant by these concepts, and then seek to pull together the findings from the English and Romanian Adoptee (ERA) studies that were relevant for these issues. When the findings have been presented in detail in earlier chapters, we simply summarize the main salient points. However, with respect to possible genetic moderation of the effects of institutional deprivation, we present new data because these were not considered in earlier chapters. There was a time when most developmental research, particularly that dealing with social development, moved blithely ahead using cross-sectional studies to investigate developmental processes without consideration of the multiple complex ways in which these processes may work together or separately. That is no longer acceptable (Kraemer et al., 1997; Kraemer, Stice, Kazdin, Offord, & Kupfer, 2001; Murray, Farrington, & Eisner, 2009; Rutter, 1988, 2009). Not only must the various processes, and their interplay, be clearly conceptualized, but also it will be essential to pit different refutable causal hypotheses against each other (Lahey, D'Onofrio, & Waldman, 2009; Rutter, 2003, 2006b)

BACKGROUND AND OBJECTIVE: Periodontal disease is characterized by increased expression and activity of matrix metalloproteinases (MMPs) and insufficient expression/activity of their inhibitors, tissue inhibitors of matrix metalloproteinases (TIMPs). This altered MMP-TIMP balance results in progressive destruction of gingival and periodontal extracellular matrix. Enamel matrix derivative (EMD), clinically used for periodontal regeneration in a device called Emdogain, has been suggested to enhance gingival healing following periodontal procedures in humans. We previously showed that EMD increases the proliferation of human and rat gingival fibroblasts and protects them from tumor necrosis factor-induced apoptosis. In the present study, the modulation of MMP and TIMP expression by EMD was investigated. MATERIAL AND METHODS: Primary human gingival fibroblasts were treated in vitro with tumor necrosis factor, EMD or both in serum-free conditions, and RNA was analyzed with an extracellular matrix-focused microarray and quantitative real-time polymerase chain reaction. RESULTS: Microarray analysis showed detectable expression of MMP-1, MMP-2, MMP-3, MMP-7 and MMP-13, as well as TIMP-1 and TIMP-3 in untreated cells. There was no apparent regulation of the expression of MMP-2, MMP-7, MMP-13 and TIMP-1 by either tumor necrosis factor or EMD. In contrast, tumor necrosis factor significantly increased MMP-1 expression, and EMD reduced it when both agents were present. Also, EMD significantly induced TIMP-3 expression, an effect which was dependent on activation of extracellular signal-regulated kinase 1/2, since it was totally abolished by a selective extracellular signal-regulated kinase pathway inhibitor. CONCLUSION: These data suggest that EMD may affect gingival health by ways other than cell proliferation/survival, i.e. by stimulation of TIMP-3 production, which could improve the MMP-TIMP balance in gingival tissue and curb extracellular matrix destruction.

Sensory processing is often regarded as a passive process in which biological receptors like photoreceptors and mechanoreceptors transduce physical energy into a neural code. Recent findings, however, suggest that: first, most sensory processing is active, and largely determined by motor/attentional sampling routines; second, owing to rhythmicity in the motor routine, as well as to its entrainment of ambient rhythms in sensory regions, sensory inflow tends to be rhythmic; third, attentional manipulation of rhythms in sensory pathways is instrumental to perceptual selection. These observations outline the essentials of an Active Sensing paradigm, and argue for increased emphasis on the study of sensory processes as specific to the dynamic motor/attentional context in which inputs are acquired

OBJECTIVE: Generalized anxiety disorder (GAD) is a prevalent and debilitating psychiatric condition of adolescence. Two effective forms of treatment are cognitive behavioral therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs). This pilot study examined changes in brain function following each type of treatment in GAD. METHOD: Subjects were 14 youths with GAD (7 had CBT, 7 received fluoxetine) and 10 age- and gender-matched healthy peers. Functional magnetic resonance imaging (fMRI) scans were acquired before and after treatment for patients and over two comparable time points for controls. During fMRI acquisition, a probe detection task with emotional (angry, happy) and neutral faces allowed for assessment of neural response to threat. Following previous research, region of interest analyses were performed in the right ventrolateral prefrontal cortex (VLPFC). RESULTS: fMRI results showed increased right VLPFC activation, relative to controls, in the medication (t(15) = 3.01, p < 0.01) and CBT (t(15) = 3.22, p < 0.01) groups following treatment. CONCLUSIONS: This study shows significant increase in right VLPFC activation in response to angry faces following treatment with CBT or fluoxetine for GAD. This is consistent with previous research indicating that the VLPFC may facilitate effective responding to underlying neural correlates of anxiety in other brain regions, such as the amygdala.

In this monograph, we have brought the findings of the English and Romanian Adoptee (ERA) study up to age 15 years and, in so doing, have focused especially on the question of whether there are deprivation-specific psychological patterns (DSPs) that differ meaningfully from other forms of psychopathology. For this purpose, our main analytic strategy was to compare the subgroup of young people who had received institutional care in Romania that persisted up to at least the age of 6 months and a pooled comparison group that comprised the remainder of the sample. In chapter II, we presented the evidence that there were no significant variations among the three subgroups that made up the pooled comparison group. A large proportion of this pooled comparison group came from the 52 individuals adopted before the age of 6 months from within the United Kingdom, who had not experienced institutional care or other major deprivation experiences. In addition, there were 45 children who had experienced institutional care that had ceased before the age of 6 months. Finally, there was a small group of 21 Romanian individuals who had come from a severely deprived background but who had not experienced institutional care. In the young people who experienced institutional deprivation, we found that a cut-off at 6 months marked the division between those without appreciable sequelae and those with a substantial proportion of persisting deficits. Because we found that the rate of deficits in the group who had experienced institutional care for 46 months did not vary according to the duration of institutional care, we pooled the entire group of individuals experiencing institutional care up to at least the age of 6 months. We found that these two pooled groups differed substantially and significantly in the rate of maladaptive outcomes. The details of the evidence justifying this pooling and a two-way comparison are provided in chapter II. Because of our interest in exploring the possibility of DSPs, our main subdivision within the above 6-month group was between those individuals showing the putative DSPs and those showing other forms of psychopathology or not showing deficits at all