Motor cortex modulation and reward in children with attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder, the most prevalent developmental disorder in childhood, is a biologically heterogenous condition characterized by impaired attention and impulse control as well as motoric hyperactivity and anomalous motor skill development. Neuropsychological testing often demonstrates impairments in motivation and reward-related decision making in attention-deficit/hyperactivity disorder, believed to indicate dysfunction of the dopamine reward pathway. Development of reliable, non-invasive, easily obtained and quantitative biomarkers correlating with the presence and severity of clinical symptoms and impaired domains of function could aid in identifying meaningful attention-deficit/hyperactivity disorder subgroups and targeting appropriate treatments. To this end, 55 (37 male) 8-12-year-old children with attention-deficit/hyperactivity disorder and 50 (32 male) age-matched, typically-developing controls were enrolled in a transcranial magnetic stimulation protocol-used previously to quantify cortical disinhibition in both attention-deficit/hyperactivity disorder and Parkinson's Disease-with a child-friendly reward motivation task. The primary outcomes were reward task-induced changes in short interval cortical inhibition and up-modulation of motor evoked potential amplitudes, evaluated using mixed model, repeated measure regression. Our results show that both reward cues and reward receipt reduce short-interval cortical inhibition, and that baseline differences by diagnosis (less inhibition in attention-deficit/hyperactivity disorder) were no longer present when reward was cued or received. Similarly, both reward cues and reward receipt up-modulated motor evoked potential amplitudes, but, differentiating the two groups, this Task-Related-Up-Modulation was decreased in children with attention-deficit/hyperactivity disorder. Furthermore, more severe hyperactive/impulsive symptoms correlated significantly with less up-modulation with success in obtaining reward. These results suggest that in children with attention-deficit/hyperactivity disorder, short interval cortical inhibition may reflect baseline deficiencies as well as processes that normalize performance under rewarded conditions. Task-Related-Up-Modulation may reflect general hypo-responsiveness in attention-deficit/hyperactivity disorder to both reward cue and, especially in more hyperactive/impulsive children, to successful reward receipt. These findings support transcranial magnetic stimulation evoked cortical inhibition and task-induced excitability as biomarkers of clinically relevant domains of dysfunction in childhood attention-deficit/hyperactivity disorder.

Predicted DRD4 prefrontal gene expression moderates snack intake and stress perception in response to the environment in adolescents.

Body weight is substantially determined by eating behaviors, which are themselves driven by biological factors interacting with the environment. Previous studies in young children suggest that genetic influences on dopamine function may confer differential susceptibility to the environment in such a way that increases behavioral obesity risk in a lower socioeconomic status (SES) environment but decreases it in a higher SES environment. We aimed to test if this pattern of effect could also be observed in adolescence, another critical period for development in brain and behavior, using a novel measure of predicted expression of the dopamine receptor 4 (DRD4) gene in prefrontal cortex. In a sample of 76 adolescents (37 boys and 39 girls from Baltimore, Maryland/US, aged 14-18y), we estimated individual levels of DRD4 gene expression (PredDRD4) in prefrontal cortex from individual genomic data using PrediXcan, and tested interactions with a composite SES score derived from their annual household income, maternal education, food insecurity, perceived resource availability, and receipt of public assistance. Primary outcomes were snack intake during a multi-item ad libitum meal test, and food-related impulsivity assessed using a food-adapted go/no-go task. A linear regression model adjusted for sex, BMI z-score, and genetic ethnicity demonstrated a PredDRD4 by composite SES score interaction for snack intake (p = 0.009), such that adolescents who had lower PredDRD4 levels exhibited greater snack intake in the lower SES group, but lesser snack intake in the higher SES group. Exploratory analysis revealed a similar pattern for scores on the Perceived Stress Scale (p = 0.001) such that the low PredDRD4 group reported higher stress in the lower SES group, but less stress in the higher SES group, suggesting that PredDRD4 may act in part by affecting perceptions of the environment. These results are consistent with a differential susceptibility model in which genes influencing environmental responsiveness interact with environments varying in obesogenicity to confer behavioral obesity risk in a less favorable environment, but behavioral obesity protection in a favorable one.

Development of the frontal lobe.

Development of the frontal lobe is critical to acquisition, execution, and control of a wide range of functions, from basic motor response to complex decision-making. These functions are influenced by contingency-based (e.g., reward and response-cost/punishment) feedback that is mediated through the adaptive integration of fronto-subcortical neural circuitry. The frontal lobe manages incoming information and chooses the appropriate action based on one's goals in a particular context. This aspect of frontal function, while only one component, is crucial to development and maintenance of approach and avoidance behavior central to all human (and animal) behavior. Furthermore, disruptions in fronto-subcortical circuitry governing motivated behavior appear to contribute to a range of developmental disorders, including attention-deficit/hyperactivity disorder (ADHD), and confer vulnerability for psychopathology more broadly. The particular deficits that manifest in altered behavior depend upon the specific circuitry that is compromised due to the functional specificity of distinct regions of the frontal lobe and its interconnections with subcortical structures. Neurobiologic models of motivated behavior provide a valuable framework for characterizing developmental disorders from a transdiagnostic dimensional systems perspective. Improved characterization of approach and avoidance motivation across neurodevelopmental disorders has the potential to inform the development of novel interventions and personalized medicine.

The effects of performance-based rewards on neurophysiological correlates of stimulus, error, and feedback processing in children with ADHD.

Rewards have been shown to improve behavior and cognitive processes implicated in attention-deficit hyperactivity disorder (ADHD), but the information-processing mechanisms by which these improvements occur remain unclear. We examined the effect of performance-based rewards on ERPs related to processing of the primary task stimuli, errors, and feedback in children with ADHD and typically developing controls. Participants completed a flanker task containing blocks with and without performance-based rewards. Children with ADHD showed reduced amplitude of ERPs associated with processing of the flanker stimuli (P3) and errors (ERN, Pe), but did not differ in feedback-processing (FRN). Rewards enhanced flanker-related P3 amplitude similarly across groups and error-related Pe amplitude differentially for children with ADHD. These findings suggest that rewards may improve cognitive deficits in children with ADHD through enhanced processing of relevant stimuli and increased error evaluation.