Faculty Bibliography

BACKGROUND: Current theories suggest a role for frontal-striatal circuits in the pathogenesis of attention-deficit/hyperactivity disorder (ADHD). METHODS: We used magnetoencephalography (MEG) to measure event-related brain activity during a simplified version of the Wisconsin Card Sorting Test in children with DSM-IV combined type ADHD (ADHD-C) or predominantly inattentive type ADHD (ADHD-PI) and in age- and intelligence-matched control children. RESULTS: In control children, set-shifting cues evoked a higher degree of activation in the medial temporal lobe (MTL) between 200 and 300 msec than non-shifting cues, with MTL activation predicting later activity in left anterior cingulate cortex (ACC) (at 400-500 msec). This MTL-ACC response pattern was diminished in children with ADHD. By contrast, children with ADHD showed early activity in regions barely activated in control children, such as left inferior parietal lobe and posterior superior temporal gyrus. CONCLUSIONS: These preliminary data support theories of frontal dysfunction in ADHD but also suggest that deficits in higher-level functions might be secondary to disruptions in earlier limbic processes

This study investigated whether age and ADHD symptoms affected choice preferences in children and adolescents when they chose between (1) small immediate rewards and larger delayed rewards and (2) small certain rewards and larger probabilistic uncertain rewards. A temporal discounting (TD) task and a probabilistic discounting (PD) task were used to measure the degree to which the subjective value of a large reward decreased as one had to wait longer for it (TD), and as the probability of obtaining it decreased (PD). Rewards used were small amounts of money. In the TD task, the large reward (10 cents) was delayed by between 0 and 30s, and the immediate reward varied in magnitude (0-10 cents). In the PD task, receipt of the large reward (10 cents) varied in likelihood, with probabilities of 0, 0.25, 0.5, 0.75, and 1.0 used, and the certain reward varied in magnitude (0-10 cents). Age and diagnostic group did not affect the degree of PD of rewards: All participants made choices so that total gains were maximized. As predicted, young children, aged 6-11 years (n=25) demonstrated steeper TD of rewards than adolescents, aged 12-17 years (n=21). This effect remained significant even when choosing the immediate reward did not shorten overall task duration. This, together with the lack of interaction between TD task version and age, suggests that steeper discounting in young children is driven by reward immediacy and not by delay aversion. Contrary to our predictions, participants with ADHD (n=22) did not demonstrate steeper TD of rewards than controls (n=24). These results raise the possibility that strong preferences for small immediate rewards in ADHD, as found in previous research, depend on factors such as total maximum gain and the use of fixed versus varied delay durations. The decrease in TD as observed in adolescents compared to children may be related to developmental changes in the (dorsolateral) prefrontal cortex. Future research needs to investigate these possibilities

Attention deficit hyperactivity disorder (ADHD) is highly heritable but is likely a complex disorder involving multiple genes of moderate effect (Smalley [1997: Am J Hum Genet 60:1276-1282]). Over 100 studies have examined the genetics of ADHD by linkage or association, though no article has presented a comprehensive overview of all published reports. We reviewed all ADHD studies, including 3 genome-wide linkage studies, and association studies of 94 polymorphisms in 33 candidate genes. To simplify comparisons across heterogeneous articles, demographics and comorbidity were ignored; analyses of subtype and haplotypes were excluded; and only the most positive finding for each polymorphism in a study was reported. Thirty-six percent of all findings were positive (P < 0.05), 17% were trends (0.05 < P < 0.15), and 47% were negative (P > 0.15). Studies utilizing dimensional measures of ADHD tended to result in higher rates of positive findings than those using categorical diagnoses (chi2 = 5.6, P = 0.018), and case-control studies tended to result in higher rates of positive findings than family-based studies (chi2 = 18.8, P < 0.001). However, for either dichotomy, no significant difference remained when analyzing only studies using both methods within the same population and polymorphism. Evidence for association exists for four genes in ADHD: the dopamine D4 and D5 receptors, and the dopamine and serotonin transporters; others are promising but need further replication, including the dopamine D2 and serotonin 2A receptors. All candidate gene approaches continue to face the problem of relatively low power, given modest odds ratios for even the best replicated genes.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BPD) are frequently comorbid and overlapping diagnoses. To move beyond diagnosis toward unique pathophysiology, we evaluated both ADHD and BPD children for neurologic examination abnormalities (NEAs) in comparison with normal control (NC) children. METHODS: We performed the Revised Physical and Neurological Examination for Soft Signs in three groups (ADHD, BPD, NC). Then, a rater blind to diagnosis evaluated their motor performance. Results were analyzed with a multiple analysis of covariance. RESULTS: Subjects with ADHD were impaired on repetitive task reaction time. In contrast, pediatric BPD subjects, both with and without comorbid ADHD, were impaired on sequential task reaction time. CONCLUSIONS: This differential pattern of NEAs by diagnosis suggests pathophysiologic differences between ADHD and BPD in children. Repetitive motor performance requires inhibition of nonrelevant movements; ADHD subjects' impairment in this domain supports the hypothesis that ADHD involves a core deficit of fronto-striato-basal ganglia neurocircuitry. In contrast, BPD subjects' impaired sequential motor performance is consistent with behavioral data showing impaired attentional set-shifting and reversal learning in BPD subjects. Further study, going beyond symptom description to determine pathophysiologic differences, is required to refine neuronal models of these often comorbid diagnoses

Pediatric major depressive disorder (MDD) is a common disease associated with significant morbidity and mortality. Newly available noninvasive neuroimaging techniques provide unique opportunities to illuminate the underlying neurobiological factors of MDD. This article reviews structural and functional neuroimaging data in pediatric MDD. In general, neuroimaging studies in pediatric MDD tend to confirm findings in adult depression implicating the prefrontal cortex, amygdala, and hippocampus. These brain regions are linked and believed to be critical in modulating emotional responses. However, neuroimaging research in pediatric MDD is still in its infancy, and inconsistencies are rife. These inconsistencies are largely due to the small samples and lack of agreement regarding methodology in ascertainment as well as in imaging. Greater focus on careful delineation of clinically and neurobiologically defined subgroups will likely lead to improved understanding of the pathophysiology of MDD. (journal abstract)

OBJECTIVE: Characterize maturation of transcallosal inhibition (ipsilateral silent period [iSP]) in attention deficit/hyperactivity disorder (ADHD) using transcranial magnetic stimulation (TMS). BACKGROUND: Maturation of the iSP is related to acquisition of fine motor skills in typically developing children suggesting that dexterous fine motor skills depend upon mature interhemispheric interactions. Since neuromotor maturation is abnormal in boys with ADHD we hypothesized that iSP maturation in these children would be abnormal. We studied iSP maturation in 12 boys with ADHD and 12 age-matched, typically developing boys, 7-13 years of age. METHODS: Surface electromyographic activity was recorded from right first dorsal interosseus (FDI). During background activation, focal TMS was delivered at maximal stimulator output over the ipsilateral motor cortex. RESULTS: Maturation of finger speed in boys with ADHD was significantly slower than that in the control group. The iSP latency decreased with age in the control group but not in the ADHD group. CONCLUSIONS: These findings suggest the presence of a complex relationship between abnormalities of certain interhemispheric interactions (as represented by iSP latency) and delayed maturation of neuromotor skills in boys with ADHD. SIGNIFICANCE: These data provide preliminary physiologic evidence supporting delayed or abnormal development of interhemispheric interactions in boys with ADHD

OBJECTIVE: The pattern of dopamine antagonism by metoclopramide suggests benefits in the treatment of tic disorders. The purpose of this study was to examine the efficacy and safety of metoclopramide in the treatment of children and adolescents with tic disorders. METHOD: Twenty-seven medication-free patients (age 11.9 +/- 2.7 years) with Tourette's disorder or a chronic tic disorder participated in an 8-week double-blind, randomized, placebo-controlled trial of metoclopramide. Metoclopramide was started at 5 mg daily and titrated as needed to a maximum dose of 40 mg daily. Tics were rated every 2 weeks, and adverse effects, including weight, cardiac, and laboratory measures, were monitored. RESULTS: After 8 weeks of treatment, subjects receiving metoclopramide showed a 39% reduction in their total tic score on the Yale Global Tic Severity Scale, while subjects receiving placebo showed only a 13% reduction in tic severity (p = .001). Metoclopramide was well tolerated with no significant laboratory or cardiac changes noted other than an increase in serum prolactin. CONCLUSIONS: The results of this small controlled study suggest that metoclopramide is an effective and well-tolerated treatment for children and adolescents with tic disorders. Further trials are needed to confirm its efficacy and safety in pediatric patients and adults

Intra-individual variability in behavior and functioning is ubiquitous among children with attention-deficit/hyperactivity disorder (ADHD), but it has not been systematically examined or integrated within causal models. This article seeks to provide a conceptual, methodologic, and analytic framework as a foundation for future research. We first identify five key research questions and methodologic issues. For illustration, we examine the periodic structure of Eriksen Flanker task reaction time (RT) data obtained from 24 boys with ADHD and 18 age-matched comparison boys. Reaction time variability in ADHD differed quantitatively from control subjects, particularly at a modal frequency around .05 Hz (cycle length approximately 20 sec). These oscillations in RT were unaffected by double-blind placebo and were suppressed by double-blind methylphenidate. Together with converging lines of basic and clinical evidence, these secondary data analyses support the speculative hypothesis that the increased power of multisecond oscillations in ADHD RT data, and by inference, in attentional performance, represents a catecholaminergic deficit in the ability to appropriately modulate such oscillations in neuronal activity. These results highlight the importance of retaining time-series data and quantitatively examining intra-subject measures of variability as a putative endophenotype for ADHD

The reinforcernent/extinction disorder hypothesis (Sagvolden et al.) is an important counterweight to the executive dysfunction model of attention-deficit/hyperactivity disorder (ADHD). However, like that model, it conceptualises ADHD as pathophysiologically homogeneous, resulting from a common core dysfunction. Recent studies reporting neuropsychological heterogeneity suggest that this common core dysfunction may be the scientific equivalent of a red herring