Faculty Bibliography

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a prevalent neuropsychiatric disorder in childhood with established problems in cognitive control and associated fronto-striatal circuitry. More recently, fronto-cerebellar circuits have been implicated in this disorder. Both of these circuits are important in predicting the occurrence and timing of behaviorally relevant events and in detecting violations of these predictions. Therefore, we hypothesized that the ability to predict the occurrence of frequent events would be compromised in ADHD, as well as the ability to adapt behavior when expectancy was violated. METHODS: We used rapid, mixed-trial, event-related functional magnetic resonance imaging (fMRI) to examine cognitive and neural processes in two independent samples of children and adolescents with ADHD and matched controls. Subjects performed a variation of a go-no/go task where the predictability of stimulus identity (what) and timing (when) was manipulated. RESULTS: Behaviorally, children and adolescents with ADHD had increased variability in reaction times, and decreased benefit in reaction time when events were predictable. Differences in accuracy between groups were most reliable for temporally unpredictable trials. Functional imaging results from both samples showed that relative to the control children and adolescents, individuals with ADHD had diminished cerebellar activity to violations of stimulus timing and diminished ventral prefrontal and anterior cingulate activity to violations in stimulus timing and identity. CONCLUSIONS: These findings are consistent with the view that disruptive behaviors in inappropriate contexts, a major criterion in diagnosing ADHD, may be related to an impaired ability to predict temporal and contextual cues in the environment, thus hindering the ability to alter behavior when they change. This ability requires intact fronto-cerebellar, as well as fronto-striatal circuitry.

Anterior cingulate cortex (ACC) is a nexus of information processing and regulation in the brain. Reflecting this central role, ACC is structurally and functionally heterogeneous, a fact long appreciated in studies of non-human primates. Human neuroimaging studies also recognize this functional heterogeneity, with meta-analyses and task-based studies demonstrating the existence of motor, cognitive and affective subdivisions. In contrast to task-based approaches, examinations of resting-state functional connectivity enable the characterization of task-independent patterns of correlated activity. In a novel approach to understanding ACC functional segregation, we systematically mapped ACC functional connectivity during rest. We examined patterns of functional connectivity for 16 seed ROIs systematically placed throughout caudal, rostral, and subgenual ACC in each hemisphere. First, our data support the commonly observed rostral/caudal distinction, but also suggest the existence of a dorsal/ventral functional distinction. For each of these distinctions, more fine-grained patterns of differentiation were observed than commonly appreciated in human imaging studies. Second, we demonstrate the presence of negatively predicted relationships between distinct ACC functional networks. In particular, we highlight negative relationships between rostral ACC-based affective networks (including the 'default mode network') and dorsal-caudal ACC-based frontoparietal attention networks. Finally, interhemispheric activations were more strongly correlated between homologous regions than in non-homologous regions. We discuss the implications of our work for understanding ACC function and potential applications to clinical populations

CONTEXT: Attention-deficit/hyperactivity disorder (ADHD) is one of the most heritable neuropsychiatric disorders, and a polymorphism within the dopamine D4 receptor (DRD4) gene has been frequently implicated in its pathogenesis. OBJECTIVE: To examine the effects of the 7-repeat microsatellite in the DRD4 gene on clinical outcome and cortical development in ADHD. We drew comparisons with a single nucleotide polymorphism in the dopamine D1 receptor (DRD1) gene, which was associated with ADHD within our cohort, and a polymorphism within the dopamine transporter (DAT1) gene, reported to have additive effects with the DRD4 7-repeat allele. DESIGN: Longitudinal cohort study. SETTING: National Institutes of Health, Bethesda, Maryland. PARTICIPANTS: One hundred five children (with 222 neuroanatomical magnetic resonance images) with ADHD (mean age at entry, 10.1 years) and 103 healthy controls (total of 220 magnetic resonance images). Sixty-seven subjects with ADHD (64%) had follow-up clinical evaluations (mean follow-up, 6 years). MAIN OUTCOME MEASURES: Cortical thickness across the cerebrum and presence of DSM-IV-defined ADHD at follow-up. RESULTS: Possession of the DRD4 7-repeat allele was associated with a thinner right orbitofrontal/inferior prefrontal and posterior parietal cortex. This overlapped with regions that were generally thinner in subjects with ADHD compared with controls. Participants with ADHD carrying the DRD4 7-repeat allele had a better clinical outcome and a distinct trajectory of cortical development. This group showed normalization of the right parietal cortical region, a pattern that we have previously linked with better clinical outcome. By contrast, there were no significant effects of the DRD1 or DAT1 polymorphisms on clinical outcome or cortical development. CONCLUSIONS: The DRD4 7-repeat allele, which is widely associated with a diagnosis of ADHD, and in our cohort with better clinical outcome, is associated with cortical thinning in regions important in attentional control. This regional thinning is most apparent in childhood and largely resolves during adolescence

BACKGROUND: Calcyon is a single transmembrane protein predominantly expressed in the brain. Very recently, calcyon has been implicated in clathrin mediated endocytosis, a critical component of synaptic plasticity. At the genetic level, preliminary evidence supports an association between attention-deficit/hyperactivity disorder (ADHD) and polymorphisms in the calcyon gene. As little is known about the potential role of calcyon in ADHD, animal models may provide important insights into this issue. METHODS: We examined calcyon mRNA expression in the frontal-striatal circuitry of three-, five-, and ten-week-old Spontaneously Hypertensive Rats (SHR), the most commonly used animal model of ADHD, and Wistar-Kyoto (WKY; the strain from which SHR were derived). As a complement, we performed a co-expression network analysis using a database of mRNA gene expression profiles of multiple brain regions in order to explore potential functional links of calcyon to other genes. RESULTS: In all age groups, SHR expressed significantly more calcyon mRNA in the medial prefrontal and orbital frontal cortices than WKY rats. In contrast, in the motor cortex, dorsal striatum and nucleus accumbens, calcyon mRNA expression was only significantly elevated in SHR in younger animals. In both strains, calcyon mRNA levels decreased significantly with age in all regions studied. In the co-expression network analysis, we found a cluster of genes (many of them poorly studied so far) strongly connected to calcyon, which may help elucidate its role in the brain. The pair-wise relations of calcyon with other genes support its involvement in clathrin mediated endocytosis and, potentially, some other membrane/vesicular processes. Interestingly, no link was found between calcyon and the dopamine D1 receptor, which was previously shown to interact with the C-terminal of calcyon. CONCLUSION: The results indicate an alteration in calcyon expression within the frontal-striatal circuitry of SHR, especially in areas involved in cognitive processes. These findings extend our understanding of the molecular alterations in SHR, a heuristically useful model of ADHD

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) comorbid with oppositional defiant disorder (ODD) or conduct disorder (CD) and substance abuse/dependence seems to represent a specific subset within the phenotypic ADHD spectrum. METHODS: We applied complex segregation and linkage analyses in a set of multigenerational families densely segregating ADHD comorbid with ODD, CD, alcohol abuse/dependence, and nicotine dependence. RESULTS: Our data suggest that ADHD cosegregates with disruptive behaviors as a unique, phenotypically variable trait as evidenced by highly significant pair-wise linkages among: ADHD and ODD (logarithm of odds [LOD]=14.19), ADHD and CD (LOD=5.34), ODD and CD (LOD=6.68), and CD and alcohol abuse/dependence (LOD=3.98). In addition to previously reported ADHD susceptibility loci, we found evidence of linkage for comorbid ADHD phenotypes to loci at 8q24, 2p21-22.3, 5p13.1-p13.3, 12p11.23-13.3, 8q15, and 14q21.1-22.2. These results were replicated with an affected status phenotype derived from latent class clusters. CONCLUSIONS: Patterns of cosegregation of ADHD with comorbidities can inform our understanding of the inheritance patterns not only of ADHD but also of disruptive behavioral disorders and alcohol abuse/dependence. Refining the comorbid ADHD phenotype by determining the cosegregation profile of specific comorbidities might be a powerful tool for defining significant regions of linkage

Polymorphisms of the dopamine receptor D4 gene DRD4, 11p15.5, have previously been associated with attention-deficit/hyperactivity disorder (ADHD) [Bobb et al., 2005; Am J Med Genet B Neuropsychiatr Genet 132:109-125; Faraone et al., 2005; Biol Psychiatry 57:1313-1323; Thapar et al., 2005; Hum Mol Genet 14 Spec No. 2:R275-R282]. As a follow up to a pilot study [see Castellanos et al., 1998; Mol Psychiatry 3:431-434] consisting of 41 probands and 56 controls which found no significant association between the DRD4 7-repeat allele in exon 3 and ADHD, a greatly expanded study sample (cases n = 166 and controls n = 282) and long term follow-up (n = 107, baseline mean age n = 9, follow-up mean age of n = 15) prompted reexamination of this gene. The DRD4 7-repeat allele was significantly more frequent in ADHD cases than controls (OR = 1.2; P = 0.028). Further, within the ADHD group, the 7-repeat allele was associated with better cognitive performance (measured by the WISC-III) (P = 0.013-0.07) as well as a trend for association with better long-term outcome. This provides further evidence of the role of the DRD4 7-repeat allele in the etiology of ADHD and suggests that this allele may be associated with a more benign form of the disorder

BACKGROUND: Although abnormalities in reward processing have been proposed to underlie attention-deficit/hyperactivity disorder (ADHD), this link has not been tested explicitly with neural probes. METHODS: This hypothesis was tested by using fMRI to compare neural activity within the striatum in individuals with ADHD and healthy controls during a reward-anticipation task that has been shown previously to produce reliable increases in ventral striatum activity in healthy adults and healthy adolescents. Eleven adolescents with ADHD (5 off medication and 6 medication-naive) and 11 healthy controls (ages 12-17 y) were included. Groups were matched for age, gender, and intelligence quotient. RESULTS: We found reduced ventral striatal activation in adolescents with ADHD during reward anticipation, relative to healthy controls. Moreover, ventral striatal activation was negatively correlated with parent-rated hyperactive/impulsive symptoms across the entire sample. CONCLUSIONS: These findings provide neural evidence that symptoms of ADHD, and impulsivity or hyperactivity in particular, may involve diminished reward anticipation, in addition to commonly observed executive dysfunction

Multiple theories of Attention-Deficit/Hyper-activity Disorder (ADHD) have been proposed, but one that has stood the test of time is the dopamine deficit theory. We review the narrow literature from recent brain imaging and molecular genetic studies that has improved our understanding of the role of dopamine in manifestation of symptoms of ADHD, performance deficits on neuropsychological tasks, and response to stimulant medication that constitutes the most common treatment of this disorder. First, we consider evidence of the presence of dopamine deficits based on the recent literature that (1) confirms abnormalities in dopamine-modulated frontal-striatal circuits, reflected by size (smaller-than-average components) and function (hypoactivation); (2) clarifies the agonist effects of stimulant medication on dopaminergic mechanisms at the synaptic and circuit level of analysis; and (3) challenges the most-widely accepted ADHD-related neural abnormality in the dopamine system (higher-than-normal dopamine transporter [DAT] density). Second, we discuss possible genetic etiologies of dopamine deficits based on recent molecular genetic literature, including (1) multiple replications that confirm the association of ADHD with candidate genes related to the dopamine receptor D4 (DRD4) and the DAT; (2) replication of differences in performance of neuropsychological tasks as a function of the DRD4 genotype; and (3) multiple genome-wide linkage scans that demonstrate the limitations of this method when applied to complex disorders but implicate additional genes that may contribute to the genetic basis of ADHD. Third, we review possible environmental etiologies of dopamine deficits based on recent studies of (1) toxic substances that may affect the dopamine system in early development and contribute substantially to the etiology of ADHD; (2) fetal adaptations in dopamine systems in response to stress that may alter early development with lasting effects, as proposed by the developmental origins of health and disease hypothesis; and (3) gene-environment interactions that may moderate selective damage or adaptation of dopamine neurons. Based on these reviews, we identify critical issues about etiologic subtypes of ADHD that may involve dopamine, discuss methods that could be used to address these issues, and review old and new theories that may direct research in this area in the future

In traditional accounts, fluctuations in sustained and focused attention and associated attentional lapses during task performance are regarded as the result of failures of top-down and effortful higher order processes. The current paper reviews an alternative hypothesis: that spontaneous patterns of very low frequency (<0.1 Hz) coherence within a specific brain network ('default-mode network') thought to support a pattern of generalized task-non-specific cognition during rest, can persist or intrude into periods of active task-specific processing, producing periodic fluctuations in attention that compete with goal-directed activity. We review recent studies supporting the existence of the resting state default network, examine the mechanism underpinning it, describe the consequent temporally distinctive effects on cognition and behaviour of default-mode interference into active processing periods, and suggest some factors that might predispose to it. Finally, we explore the putative role of default-mode interference as a cause of performance variability in attention deficit/hyperactivity disorder