Faculty Bibliography

BACKGROUND: Attention deficit/hyperactivity disorder (ADHD) is one of the most prevalent and commonly studied forms of psychopathology in children and adolescents. Causal models of ADHD have long implicated dysfunction in fronto-striatal and frontal-parietal networks supporting executive function, a hypothesis that can now be examined systematically using functional neuroimaging. The present work provides an objective, unbiased statistically-based meta-analysis of published functional neuroimaging studies of ADHD. METHODS: A recently developed voxel-wise quantitative meta-analytic technique known as activation likelihood estimation (ALE) was applied to 16 neuroimaging studies examining and contrasting patterns of neural activity in patients with ADHD and healthy controls. Voxel-wise results are reported using a statistical threshold of p < .05, corrected. Given the large number of studies examining response inhibition, additional meta-analyses focusing specifically on group differences in the neural correlates of inhibition were included. RESULTS: Across studies, significant patterns of frontal hypoactivity were detected in patients with ADHD, affecting anterior cingulate, dorsolateral prefrontal, and inferior prefrontal cortices, as well as related regions including basal ganglia, thalamus, and portions of parietal cortex. When focusing on studies of response inhibition alone, a more limited set of group differences were observed, including inferior prefrontal cortex, medial wall regions, and the precentral gyrus. In contrast, analyses focusing on studies of constructs other than response inhibition revealed a more extensive pattern of hypofunction in patients with ADHD than those of response inhibition. CONCLUSIONS: To date, the most consistent findings in the neuroimaging literature of ADHD are deficits in neural activity within fronto-striatal and fronto-parietal circuits. The distributed nature of these results fails to support models emphasizing dysfunction in any one frontal sub-region. While our findings are suggestive of the primacy of deficits in frontal-based neural circuitry underlying ADHD, we discuss potential biases in the literature that need to be addressed before such a conclusion can be fully embraced.

BACKGROUND: Maturation of prefrontal circuits during adolescence contributes to the development of cognitive processes such as decision-making. Recent theories suggest that these neural changes also play a role in the shift from generalized anxiety disorder (GAD) to depression that often occurs during this developmental period. Cognitive models of the development of GAD highlight the role of intolerance of uncertainty (IU), which can be characterized behaviorally by impairments in decision-making. The present study examines potential developmental differences in frontal regions associated with uncertain decision-making, and tests the impact of IU on these circuits. METHODS: Twelve healthy adults (ages 19-36) and 12 healthy adolescents (ages 13-17) completed a decision-making task with conditions of varied uncertainty while fMRI scans were acquired. They also completed measures of worry and IU, and a questionnaire about their levels of anxiety and certainty during the task. RESULTS: Combined group analyses demonstrated significant linear effects of uncertainty on activity within anterior cingulate cortex (ACC). Region of interest (ROI)-based analysis found a significant interaction of group and IU ratings in ACC. Increased IU was associated with robust linear increases in ACC activity only in adolescents. An ROI analysis of feedback-related processing found that adolescents demonstrated greater activation during incorrect trials relative to correct trials, while the adults showed no difference in neural activity associated with incorrect and correct feedback. CONCLUSIONS: This decision-making task was shown to be effective at eliciting uncertainty-related ACC activity in adults and adolescents. Further, IU impacts ACC activity in adolescents during uncertain decision-making, providing preliminary support for a developmental model of GAD.

Converging evidence from human and animal studies suggests that decision-making relies upon a distributed neural network based in the frontal lobes. In particular, models of decision-making emphasize the involvement of orbitofrontal cortices (OFC) and the medial wall. While decision-making has been studied broadly as a class of executive function, recent models have suggested the differentiation between risky and ambiguous decision-making. Given recent emphasis on the role of OFC in affectively laden 'hot' executive function and dorsolateral prefrontal cortex (DLPFC) in more purely cognitive 'cool' executive function, we hypothesize that the neural substrates of decision-making may differ depending on the nature of the decision required. To test this hypothesis, we used recently developed meta-analytic techniques to examine the existent functional neuroimaging literature. An initial meta-analysis of decision-making, both risky and ambiguous, found significantly elevated probabilities of activation in frontal and parietal regions, thalamus, and caudate. Ambiguous decision-making was associated with activity in DLPFC, regions of dorsal and subcallosal anterior cingulate cortex (ACC), and parietal cortex. Risky decision-making was associated with activity in OFC, rostral portions of the ACC, and parietal cortex. Direct statistical comparisons revealed significant differences between risky and ambiguous decision-making in frontal regions, including OFC, DLPFC, and ACC, that were consistent with study hypotheses. These findings provide evidence for the dissociation of neural circuits underlying risky and ambiguous decision-making, reflecting differential involvement of affective 'hot' and cognitive 'cool' processes

Attention-Deficit/Hyperactivity Disorder (ADHD) is characterized by excessive inattention, hyperactivity, and impulsivity, either alone or in combination. Neuropsychological findings suggest that these behaviors result from underlying deficits in response inhibition, delay aversion, and executive functioning which, in turn, are presumed to be linked to dysfunction of frontal-striatal-cerebellar circuits. Over the past decade, magnetic resonance imaging (MRI) has been used to examine anatomic differences in these regions between ADHD and control children. In addition to quantifying differences in total cerebral volume, specific areas of interest have been prefrontal regions, basal ganglia, the corpus callosum, and cerebellum. Differences in gray and white matter have also been examined. The ultimate goal of this research is to determine the underlying neurophysiology of ADHD and how specific phenotypes may be related to alterations in brain structure

ABSTRACT: BACKGROUND: Molecular genetic studies suggest the dopamine D1 receptor (D1R) may be implicated in attention-deficit/hyperactivity disorder (ADHD). As little is known about the potential motor role of D1R in ADHD, animal models may provide important insights into this issue. Methods: We investigated the effects of a full and selective D1R agonist, SKF-81297 (0.3, 3 and 10 mg/kg), on motor behaviour and expression of the plasticity-associated gene, c-fos, in habituated young adult male Spontaneously Hypertensive Rats (SHR), the most commonly used animal model of ADHD, and Wistar-Kyoto (WKY; the strain from which SHR were derived). Results: SHR rats were more behaviourally active than WKY rats after injection with vehicle. The 0.3 mg/kg dose of SKF-81297 increased motor behaviour (locomotion, sifting, rearing, and sniffing) in both SHR and WKY rats. Total grooming was also stimulated, but only in WKY rats. The same dose increased c-fos mRNA expression in the piriform cortex of both strains. The 3 mg/kg dose increased sifting and sniffing in both strains. Locomotion was also stimulated towards the end of the testing period. The intermediate dose decreased total rearing in both strains, and produced a significant increase in c-fos mRNA in the striatum, nucleus accumbens, olfactory tuberculum, and in the cingulate, agranular insular and piriform cortices. The 10 mg/kg dose of SKF-81297 produced a biphasic effect on locomotion, which was characterized by an initial decrease followed by later stimulation. The latter stimulatory effect was more pronounced in SHR than in WKY rats when compared to their respective vehicle-injected groups. The 10 mg/kg dose also stimulated sifting and sniffing in both strains. Both the 3 and 10 mg/kg doses had no effect on total grooming. The 10 mg/kg dose induced significantly higher levels of c-fos mRNA expression in the nucleus accumbens and adjacent cortical regions (but not striatum) of SHR when compared to WKY rats. CONCLUSION: The present results suggest a potential alteration in D1R neurotransmission within the frontal-striatal circuitry of SHR involved in motor control. These findings extend our understanding of the molecular alterations in SHR, a heuristically useful model of ADHD

CONTEXT: Data from a previous prospective study of lobar volumes in children with attention-deficit/hyperactivity disorder (ADHD) are reexamined using a measure of cortical thickness. OBJECTIVE: To determine whether regional differences in cortical thickness or cortical changes across time characterize ADHD and predict or reflect its clinical outcome. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal study of 163 children with ADHD (mean age at entry, 8.9 years) and 166 controls recruited mainly from a local community in Maryland. Participants were assessed with magnetic resonance imaging. Ninety-seven patients with ADHD (60%) had 2 or more images and baseline and follow-up clinical evaluations (mean follow-up, 5.7 years). MAIN OUTCOME MEASURES: Cortical thickness across the cerebrum. Patients with ADHD were divided into better and worse outcome groups on the basis of a mean split in scores on the Children's Global Assessment Scale and persistence/remission of DSM-IV-defined ADHD. RESULTS: Children with ADHD had global thinning of the cortex (mean reduction, -0.09 mm; P=.02), most prominently in the medial and superior prefrontal and precentral regions. Children with worse clinical outcome had a thinner left medial prefrontal cortex at baseline than the better outcome group (-0.38 mm; P=.003) and controls (-0.25 mm; P=.002). Cortical thickness developmental trajectories did not differ significantly between the ADHD and control groups throughout except in the right parietal cortex, where trajectories converged. This normalization of cortical thickness occurred only in the better outcome group. CONCLUSIONS: Children with ADHD show relative cortical thinning in regions important for attentional control. Children with a worse outcome have 'fixed' thinning of the left medial prefrontal cortex, which may compromise the anterior attentional network and encumber clinical improvement. Right parietal cortex thickness normalization in patients with a better outcome may represent compensatory cortical change

The hypothesis that Attention-Deficit/Hyperactivity Disorder (ADHD) reflects a primary inhibitory executive function deficit has spurred a substantial literature. However, empirical findings and methodological issues challenge the etiologic primacy of inhibitory and executive deficits in ADHD. Based on accumulating evidence of increased intra-individual variability in ADHD, we reconsider executive dysfunction in light of distinctions between 'hot' and 'cool' executive function measures. We propose an integrative model that incorporates new neuroanatomical findings and emphasizes the interactions between parallel processing pathways as potential loci for dysfunction. Such a reconceptualization provides a means to transcend the limits of current models of executive dysfunction in ADHD and suggests a plan for future research on cognition grounded in neurophysiological and developmental considerations

Children and adolescents with attention-deficit/hyperactivity disorder (ADHD) have smaller cerebellar volumes, particularly in the posterior-inferior cerebellar vermis (lobules VIII-X). Functional activation of the human cerebellar vermis following stimulant administration has also been repeatedly demonstrated. There is no well-characterized dopaminergic pathway that projects to the posterior-inferior cerebellar vermis, although the dopamine transporter (DAT) and tyrosine hydroxylase (TH) have been localized in the posterior-inferior vermis in the non-human primate by immunohistochemistry. We hypothesized that DA neurotransmission may occur in localized 'hot spots' in the cerebellar vermis, and if so, that differences in such neurotransmission might be relevant to the pathophysiology of ADHD. To investigate this hypothesis, cerebellar tissue was obtained from rats and non-human primates. Catecholamines were extracted and analyzed using HPLC with coulometric detection. A regional gradient of norepinephrine (NE) and DA was found throughout the cerebellum with NE levels always roughly 10-40-fold higher than DA in both rats and monkeys. In addition, in vivo microdialysis studies were performed in the rat posterior-inferior cerebellar vermis in anesthetized animals. Significant NE overflow was observed over baseline following reverse microdialysis induced release by potassium or d-amphetamine. DA overflow was not observed over baseline for potassium stimulation, but was significant for d-amphetamine stimulation. These studies refute the hypothesis that DA neurotransmission normally occurs in the rat cerebellar vermis, but highlight that vermal DA is released by d-amphetamine. The presence of DAT may therefore allow for enhanced regulation of NE and not regulation of released DA