Daniel von Rhein

Increased Neural Responses to Reward in Adolescents and Young Adults With Attention-Deficit/Hyperactivity Disorder and Their Unaffected Siblings

OBJECTIVE Attention-deficit/hyperactivity disorder (ADHD) is a heritable neuropsychiatric disorder associated with abnormal reward processing. Limited and inconsistent data exist about the neural mechanisms underlying this abnormality. Furthermore, it is not known whether reward processing is abnormal in unaffected siblings of participants with ADHD. METHOD We used event-related functional magnetic resonance imaging (fMRI) to investigate brain responses during reward anticipation and receipt with an adapted monetary incentive delay task in a large sample of adolescents and young adults with ADHD (n = 150), their unaffected siblings (n = 92), and control participants (n = 108), all of the same age. RESULTS Participants with ADHD showed, relative to control participants, increased responses in the anterior cingulate, anterior frontal cortex, and cerebellum during reward anticipation, and in the orbitofrontal, occipital cortex and ventral striatum. Responses of unaffected siblings were increased in these regions as well, except for the cerebellum during anticipation and ventral striatum during receipt. CONCLUSION ADHD in adolescents and young adults is associated with enhanced neural responses in frontostriatal circuitry to anticipation and receipt of reward. The findings support models emphasizing aberrant reward processing in ADHD, and suggest that processing of reward is subject to familial influences. Future studies using standard monetary incentive delay task parameters are needed to replicate our findings.

Distinguishing Adolescents With ADHD From Their Unaffected Siblings and Healthy Comparison Subjects by Neural Activation Patterns During Response Inhibition

OBJECTIVE Dysfunctional response inhibition is a key executive function impairment in attention deficit hyperactivity disorder (ADHD). Still, behavioral response inhibition measures do not consistently differentiate affected from unaffected individuals. The authors therefore investigated neural correlates of response inhibition and the familial nature of these neural correlates. METHODS Functional MRI measurements of neural activation during the stop-signal task and behavioral measures of response inhibition were obtained in adolescents and young adults with ADHD (N=185), their unaffected siblings (N=111), and healthy comparison subjects (N=124). RESULTS Stop-signal task reaction times were longer and error rates were higher in participants with ADHD, but not in their unaffected siblings, while reaction time variability was higher in both groups than in comparison subjects. Relative to comparison subjects, participants with ADHD and unaffected siblings had neural hypoactivation in frontal-striatal and frontal-parietal networks, whereby activation in inferior frontal and temporal/parietal nodes in unaffected siblings was intermediate between levels of participants with ADHD and comparison subjects. Furthermore, neural activation in inferior frontal nodes correlated with stop-signal reaction times, and activation in both inferior frontal and temporal/parietal nodes correlated with ADHD severity. CONCLUSIONS Neural activation alterations in ADHD are more robust than behavioral response inhibition deficits and explain variance in response inhibition and ADHD severity. Although only affected participants with ADHD have deficient response inhibition, hypoactivation in inferior frontal and temporal-parietal nodes in unaffected siblings supports the familial nature of the underlying neural process. Activation deficits in these nodes may be useful as endophenotypes that extend beyond the affected individuals in the family.

Is your error my concern? An event-related potential study on own and observed error detection in cooperation and competition.

For successful goal-directed behavior it is essential for humans to continuously monitor one’s actions and detect errors as fast as possible. EEG studies have identified an error-related ERP component known as the error-related negativity or ERN. Theories on error monitoring propose a direct relation to reward processing. Whenever an error is made, the outcome of an action turns out to be worse than expected, resulting in a loss of reward and hence eliciting the ERN. However, as own errors are always associated with a loss of reward, disentangling whether the ERN is error- or reward-dependent has proven to be an extremely difficult endeavor. Recently, an ERN has also been demonstrated following the observation of other’s errors. An important difference with own errors is that other people’s errors can be associated with loss or gain depending on the cooperative or competitive context in which they are made. We conducted an ERP study to disentangle whether performance monitoring is error- or reward-dependent. Twelve pairs (N=24) of participants performed and observed a speeded-choice reaction task in two contexts. Own errors were always associated with a loss of reward. Observed errors in the cooperative context also yielded a loss of reward, but observed errors in the competitive context resulted in a gain. The results showed that the ERN was present following all types of errors independent of who made the error and the outcome of the action. Consequently, the current study demonstrates that performance monitoring as reflected by the ERN is error-specific and not directly dependent on reward.

Similar Subgroups Based on Cognitive Performance Parse Heterogeneity in Adults With ADHD and Healthy Controls

Objective: To characterize heterogeneity in adults with ADHD we aimed to identify subgroups within the adult ADHD spectrum, which differ in their cognitive profile. Method: Neuropsychological data from adults with ADHD (n = 133) and healthy control participants (n = 132) were used in a confirmatory factor analysis. The resulting six cognitive factors were correlated across participants to form networks. We used a community detection algorithm to cluster these networks into subgroups. Results: Both the ADHD and control group separated into three profiles that differed in cognitive performance. Profile 1 was characterized by aberrant attention and inhibition, profile 2 by increased delay discounting, and profile 3 by atypical working memory and verbal fluency. Conclusion: Our findings suggest that qualitative differences in neuropsychological performance exist in both control and ADHD adult individuals. This extends prior findings in children with and without ADHD and provides a framework to parse participants into well-defined subgroups.

Network-Level Assessment of Reward-Related Activation in Patients with ADHD and Healthy Individuals

Reward processing is a key aspect of cognitive control processes, putatively instantiated by mesolimbic and mesocortical brain circuits. Deficient signaling within these circuits has been associated with psychopathology. We applied a network discovery approach to assess specific functional networks associated with reward processing in participants with attention‐deficit/hyperactivity disorder (ADHD).

Variation in serotonin neurotransmission genes affects neural activation during response inhibition in adolescents and young adults with ADHD and healthy controls

Objectives. Deficits in response inhibition have been associated with attention-deficit/hyperactivity disorder (ADHD). Given the role of serotonin in ADHD and impulsivity, we postulated that genetic variants within the serotonin pathway might influence response inhibition. Methods. We measured neural activation during stop-signal task performance in adolescents with ADHD (N = 185), their unaffected siblings (N = 111), and healthy controls (N = 124), and investigated the relationship of two serotonin gene polymorphisms (the rs6296 SNP of the HTR1B gene and HTTLPR variants of the 5-HTT gene) with the neural correlates of response inhibition. Results. The whole-brain analyses demonstrated large scale neural activation differences in the inferior and medial frontal and temporal/parietal regions of the response inhibition network between the different variants of both the HTR1B and 5HTT genes. Activation in these regions was significantly associated with stop-task performance, but not with ADHD diagnosis or severity. No associations were found between HTR1B and 5HTT variants and ADHD or ADHD-related neural activation. Conclusions. These results provide novel evidence that serotonin may play an important role in the neurobiology of response inhibition. Although response inhibition is strongly linked to ADHD, serotonin linked genetic variants associated with response inhibition and its neural correlates do not explain variance of the ADHD phenotype.

The link between callous-unemotional traits and neural mechanisms of reward processing: An fMRI study

Callous-unemotional (CU) traits, i.e., unconcernedness and lack of prosocial feelings, may manifest in Conduct Disorder (CD), but also in Oppositional Defiant Disorder (ODD) and Attention Deficit Hyperactivity Disorder (ADHD). These disorders have been associated with aberrant reward processing, while the influence of CU traits is unclear. Using functional Magnetic Resonance Imaging (fMRI), we examined whether CU traits affect the neural circuit for reward. A Monetary Incentive Delay (MID) task was administered to 328 adolescents and young adults with varying levels of CU traits: 40 participants with ODD/CD plus ADHD, 101 participants with ADHD only, 84 siblings of probands with ADHD and 103 typically developing (TD) individuals. During reward anticipation, CU traits related negatively to medial prefrontal cortex (mPFC) activity, independent of ADHD symptoms and ODD/CD diagnosis. Our results indicate that CU traits are a valuable dimension for assessing the neural basis of reward processing.

Handling hybrid and missing data in constraint-based causal discovery to study the etiology of ADHD

Causal discovery is an increasingly important method for data analysis in the field of medical research. In this paper, we consider two challenges in causal discovery that occur very often when working with medical data: a mixture of discrete and continuous variables and a substantial amount of missing values. To the best of our knowledge, there are no methods that can handle both challenges at the same time. In this paper, we develop a new method that can handle these challenges based on the assumption that data are missing at random and that continuous variables obey a non-paranormal distribution. We demonstrate the validity of our approach for causal discovery on simulated data as well as on two real-world data sets from a monetary incentive delay task and a reversal learning task. Our results help in the understanding of the etiology of attention-deficit/hyperactivity disorder (ADHD).

Stimulant Treatment Trajectories Are Associated With Neural Reward Processing in Attention-Deficit/Hyperactivity Disorder

OBJECTIVE The past decades have seen a surge in stimulant prescriptions for the treatment of attention-deficit/hyperactivity disorder (ADHD). Stimulants acutely alleviate symptoms and cognitive deficits associated with ADHD by modulating striatal dopamine neurotransmission and induce therapeutic changes in brain activation patterns. Long-term functional changes after treatment are unknown, as long-term studies are scarce and have focused on brain structure. In this observational study (2009-2012), we investigated associations between lifetime stimulant treatment history and neural activity during reward processing. METHODS Participants fulfilling DSM-5 criteria for ADHD (N = 269) were classified according to stimulant treatment trajectory. Of those, 124 performed a monetary incentive delay task during magnetic resonance imaging, all in their nonmedicated state (nEARLY&INTENSE = 51; nLATE&MODERATE = 49; nEARLY&MODERATE = 9; nNAIVE = 15; mean age = 17.4 years; range, 10-26 years). Whole-brain analyses were performed with additional focus on the striatum, concentrating on the 2 largest treatment groups. RESULTS Compared to the late-and-moderate treatment group, the early-and-intense treatment group showed more activation in the supplementary motor area and dorsal anterior cingulate cortex (SMA/dACC) during reward outcome (cluster size = 8,696 mm³; PCLUSTER < .001). SMA/dACC activation of the control group fell in between the 2 treatment groups. Treatment history was not associated with striatal activation during reward processing. CONCLUSIONS Our findings are compatible with previous reports of acute increases of SMA/dACC activity in individuals with ADHD after stimulant administration. Higher SMA/dACC activity may indicate that patients with a history of intensive stimulant treatment, but currently off medication, recruit brain regions for cognitive control and/or decision-making upon being rewarded. No striatal or structural changes were found.

Causal Discovery from Medical Data: Dealing with Missing Values and a Mixture of Discrete and Continuous Data

Causal discovery is an increasingly popular method for data analysis in the field of medical research. In this paper we consider two challenges in causal discovery that occur very often when working with medical data: a mixture of discrete and continuous variables and a substantial amount of missing values. To the best of our knowledge there are no methods that can handle both challenges at the same time. In this paper we develop a new method that can handle these challenges based on the assumption that data is missing completely at random and that variables obey a non-paranormal distribution. We demonstrate the validity of our approach for causal discovery for empiric data from a monetary incentive delay task. Our results may help to better understand the etiology of attention deficit-hyperactivity disorder (ADHD).