Cognitive neuroscience studies of Attention Deficit Hyperactivity Disorder (ADHD) suggest multiple loci of pathology with respect to both cognitive domains and neural circuitry. Cognitive deficits extend beyond executive functioning to include spatial, temporal, and lower-level "nonexecutive" functions. Atypical functional anatomy extends beyond frontostriatal circuits to include posterior cortices, limbic regions, and the cerebellum. Pathophysiology includes dopaminergic as well as noradrenergic neurotransmitter systems. We review the major insights gained from functional brain imaging studies in ADHD and discuss working hypotheses regarding their neurochemical underpinnings.

Many researchers have noted that the functional architecture of the human brain is relatively invariant during task performance and the resting state. Indeed, intrinsic connectivity networks (ICNs) revealed by resting-state functional connectivity analyses are spatially similar to regions activated during cognitive tasks. This suggests that patterns of task-related activation in individual subjects may result from the engagement of one or more of these ICNs; however, this has not been tested. We used a novel analysis, spatial multiple regression, to test whether the patterns of activation during an N-back working memory task could be well described by a linear combination of ICNs delineated using Independent Components Analysis at rest. We found that across subjects, the cingulo-opercular Set Maintenance ICN, as well as right and left Frontoparietal Control ICNs, were reliably activated during working memory, while Default Mode and Visual ICNs were reliably deactivated. Further, involvement of Set Maintenance, Frontoparietal Control, and Dorsal Attention ICNs was sensitive to varying working memory load. Finally, the degree of left Frontoparietal Control network activation predicted response speed, while activation in both left Frontoparietal Control and Dorsal Attention networks predicted task accuracy. These results suggest that a close relationship between resting-state networks and task-evoked activation is functionally relevant for behavior, and that spatial multiple regression analysis is a suitable method for revealing that relationship.

Functional connectivity between brain regions can define large-scale neural networks and provide information about relationships between those networks. We examined how relationships within and across intrinsic connectivity networks were 1) sensitive to individual differences in dopaminergic function, 2) modulated by cognitive state, and 3) associated with executive behavioral traits. We found that regardless of cognitive state, connections between frontal, parietal, and striatal nodes of Task-Positive networks (TPNs) and Task-Negative networks (TNNs) showed higher functional connectivity in 10/10 homozygotes of the dopamine transporter gene, a polymorphism influencing synaptic dopamine, than in 9/10 heterozygotes. However, performance of a working memory task (a state requiring dopamine release) modulated genotype differences selectively, such that cross-network connectivity between TPNs and TNNs was higher in 10/10 than 9/10 subjects during working memory but not during rest. This increased cross-network connectivity was associated with increased self-reported measures of impulsivity and inattention traits. By linking a gene regulating synaptic dopamine to a phenotype characterized by inefficient executive function, these findings validate cross-network connectivity as an endophenotype of executive dysfunction.

No abstract

Implicit learning, the non-conscious acquisition of sequential and spatial environmental regularities, underlies skills such as language, social intuition, or detecting a target in a complex scene. We examined relationships between a variation of the dopamine transporter (DAT1) gene (SLC6A3), which influences dopamine transporter expression in the striatum, and two forms of implicit learning that differ in the regularity to be learned and in striatal involvement. Participants, grouped as 9-repeat carriers or 10/10 homozygotes, completed the Triplets Learning Task (TLT) and the Spatial Contextual Cueing Task (SCCT). The TLT assesses sequence learning, recruiting the striatal system, particularly as training continues. In contrast, the SCCT assesses spatial context learning, recruiting medial temporal brain networks. For both tasks, participants demonstrated learning in faster and/or more accurate responses to repeating patterns or spatial arrays. As predicted, TLT learning was greater for the 9-repeat carriers than the 10/10 group (despite equal overall accuracy and response speed) whereas there were no significant group differences in SCCT. Thus, presence of the DAT1 9-repeat allele was beneficial only for implicit sequence learning, indicating the influence of DAT1 genotype on one form of implicit learning and supporting evidence that implicit learning of sequential dependencies and spatial layouts recruit different neural systems.