Shifting uncertainty intolerance: methylphenidate and attention-deficit hyperactivity disorder.

Risk evaluation is a critical component of decision making. Risk tolerance is relevant in both daily decisions and pathological disorders such as attention-deficit hyperactivity disorder (ADHD), where impulsivity is a cardinal symptom. Methylphenidate, a commonly prescribed drug in ADHD, improves attention but has mixed reports on risk-based decision making. Using a double-blinded placebo protocol, we studied the risk attitudes of ADHD patients and age-matched healthy volunteers while performing the 2-step sequential learning task and examined the effect of methylphenidate on their choices. We then applied a novel computational analysis using the hierarchical drift-diffusion model to extract parameters such as threshold ('a'-amount of evidence accumulated before making a decision), drift rate ('v'-information processing speed) and response bias ('z' apriori bias towards a specific choice) focusing specifically on risky choice preference. Critically, we show that ADHD patients on placebo have an apriori bias towards risky choices compared to controls. Furthermore, methylphenidate enhanced preference towards risky choices (higher apriori bias) in both groups but had a significantly greater effect in the patient population independent of clinical scores. Thus, methylphenidate appears to shift tolerance towards risky uncertain choices possibly mediated by prefrontal dopaminergic and noradrenergic modulation. We emphasise the utility of computational models in detecting underlying processes. Our findings have implications for subtle yet differential effects of methylphenidate on ADHD compared to healthy population.Wellcome Trust Intermediate Fellowship (093881/Z/10/Z) to Dr. Harrison, Brighton and Sussex Medical School and the Dr. Mortimer and Dame Theresa Sackler Foundation. Dr. Voon is supported by a Medical Research Council Senior Clinical Fellowship (MR/P008747/1)

A neurocomputational account of reward and novelty processing and effects of psychostimulants in attention deficit hyperactivity disorder.

Computational models of reinforcement learning have helped dissect discrete components of reward-related function and characterize neurocognitive deficits in psychiatric illnesses. Stimulus novelty biases decision-making, even when unrelated to choice outcome, acting as if possessing intrinsic reward value to guide decisions toward uncertain options. Heightened novelty seeking is characteristic of attention deficit hyperactivity disorder, yet how this influences reward-related decision-making is computationally encoded, or is altered by stimulant medication, is currently uncertain. Here we used an established reinforcement-learning task to model effects of novelty on reward-related behaviour during functional MRI in 30 adults with attention deficit hyperactivity disorder and 30 age-, sex- and IQ-matched control subjects. Each participant was tested on two separate occasions, once ON and once OFF stimulant medication. OFF medication, patients with attention deficit hyperactivity disorder showed significantly impaired task performance (P = 0.027), and greater selection of novel options (P = 0.004). Moreover, persistence in selecting novel options predicted impaired task performance (P = 0.025). These behavioural deficits were accompanied by a significantly lower learning rate (P = 0.011) and heightened novelty signalling within the substantia nigra/ventral tegmental area (family-wise error corrected P < 0.05). Compared to effects in controls, stimulant medication improved attention deficit hyperactivity disorder participants' overall task performance (P = 0.011), increased reward-learning rates (P = 0.046) and enhanced their ability to differentiate optimal from non-optimal novel choices (P = 0.032). It also reduced substantia nigra/ventral tegmental area responses to novelty. Preliminary cross-sectional evidence additionally suggested an association between long-term stimulant treatment and a reduction in the rewarding value of novelty. These data suggest that aberrant substantia nigra/ventral tegmental area novelty processing plays an important role in the suboptimal reward-related decision-making characteristic of attention deficit hyperactivity disorder. Compared to effects in controls, abnormalities in novelty processing and reward-related learning were improved by stimulant medication, suggesting that they may be disorder-specific targets for the pharmacological management of attention deficit hyperactivity disorder symptoms

Comparing resting state fMRI de-noising approaches using multi- and single-echo acquisitions

Artifact removal in resting state fMRI (rfMRI) data remains a serious challenge, with even subtle head motion undermining reliability and reproducibility. Here we compared some of the most popular single-echo de-noising methodsÐregression of Motion parameters, White matter and Cerebrospinal fluid signals (MWC method), FMRIB's ICA-based X-noiseifier (FIX) and ICA-based Automatic Removal Of motion Artifacts (ICA-AROMA)Ðwith a multiecho approach (ME-ICA) that exploits the linear dependency of BOLD on the echo time. Data were acquired using a clinical scanner and included 30 young, healthy participants (minimal head motion) and 30 Attention Deficit Hyperactivity Disorder patients (greater head motion). De-noising effectiveness was assessed in terms of data quality after each cleanup procedure, ability to uncouple BOLD signal and motion and preservation of default mode network (DMN) functional connectivity. Most cleaning methods showed a positive impact on data quality. However, based on the investigated metrics, ME-ICA was the most robust. It minimized the impact of motion on FC even for high motion participants and preserved DMN functional connectivity structure. The high-quality results obtained using ME-ICA suggest that using a multi-echo EPI sequence, reliable rfMRI data can be obtained in a clinical setting

Shifting uncertainty intolerance: methylphenidate and attention-deficit hyperactivity disorder

Abstract: Risk evaluation is a critical component of decision making. Risk tolerance is relevant in both daily decisions and pathological disorders such as attention-deficit hyperactivity disorder (ADHD), where impulsivity is a cardinal symptom. Methylphenidate, a commonly prescribed drug in ADHD, improves attention but has mixed reports on risk-based decision making. Using a double-blinded placebo protocol, we studied the risk attitudes of ADHD patients and age-matched healthy volunteers while performing the 2-step sequential learning task and examined the effect of methylphenidate on their choices. We then applied a novel computational analysis using the hierarchical drift–diffusion model to extract parameters such as threshold (‘a’—amount of evidence accumulated before making a decision), drift rate (‘v’—information processing speed) and response bias (‘z’ apriori bias towards a specific choice) focusing specifically on risky choice preference. Critically, we show that ADHD patients on placebo have an apriori bias towards risky choices compared to controls. Furthermore, methylphenidate enhanced preference towards risky choices (higher apriori bias) in both groups but had a significantly greater effect in the patient population independent of clinical scores. Thus, methylphenidate appears to shift tolerance towards risky uncertain choices possibly mediated by prefrontal dopaminergic and noradrenergic modulation. We emphasise the utility of computational models in detecting underlying processes. Our findings have implications for subtle yet differential effects of methylphenidate on ADHD compared to healthy population

Waiting Impulsivity: The Influence of Acute Methylphenidate and Feedback.

BACKGROUND: The ability to wait and to weigh evidence is critical to behavioral regulation. These behaviors are known as waiting and reflection impulsivity. In Study 1, we examined the effects of methylphenidate, a dopamine and norepinephrine reuptake inhibitor, on waiting and reflection impulsivity in healthy young individuals. In study 2, we assessed the role of learning from feedback in disorders of addiction. METHODS: We used the recently developed 4-Choice Serial Reaction Time task and the Beads task. Twenty-eight healthy volunteers were tested twice in a randomized, double-blind, placebo-controlled cross-over trial with 20mg methylphenidate. In the second study, we analyzed premature responses as a function of prior feedback in disorders of addiction. RESULTS: Study 1: Methylphenidate was associated with greater waiting impulsivity to a cue predicting reward along with faster responding to target onset without a generalized effect on reaction time or attention. Methylphenidate influenced reflection impulsivity based on baseline impulsivity. Study 2: More premature responses occurred after premature responses in stimulant-dependent subjects. CONCLUSIONS: We show that methylphenidate has dissociable effects on waiting and reflection impulsivity. Chronic stimulant exposure impairs learning from prior premature responses, suggesting a failure to learn that premature responding is suboptimal. These findings provide a greater mechanistic understanding of waiting impulsivity.VV and NAH are Wellcome Trust (WT) intermediate Clinical Fellows. LSM is an MRC student. The BCNI is supported by a WT and MRC grant. The authors report no conflicts of interest. TWR consults for Cambridge Cognition, Lundbeck, Teva, Shire Pharmaceuticals, Otsuka, has research grants from Lundbeck, GSK. Royalties Cambridge Cognition and receives editorial honoraria from Springer, Elsevier.This is the final version of the article. It first appeared from Oxford University Press via http://dx.doi.org/10.1093/ijnp/pyv07

Rapid white matter changes in children with conduct problems during a parenting intervention

Studies report that the microstructural integrity of the uncinate fasciculus (UF; connecting the anterior temporal lobe to the orbitofrontal cortex) is abnormal in adults with psychopathy and children with conduct problems (CP), especially those with high callous-unemotional (CU) traits. However, it is unknown if these abnormalities are 'fixed' or 'reversible'. Therefore, we tested the hypothesis that a reduction in CP symptoms, following a parenting intervention, would be associated with altered microstructural integrity in the UF. Using diffusion tensor imaging tractography we studied microstructural differences (mean diffusivity (MD) and radial diffusivity (RD)) in the UF of 43 typically developing (TD) and 67 boys with CP before and after a 14-week parenting intervention. We also assessed whether clinical response in CP symptoms or CU traits explained changes in microstructure following the intervention. Prior to intervention, measures of MD and RD in the UF were increased in CP compared to TD boys. Following intervention, we found that the CP group had a significant reduction in RD and MD. Further, these microstructural changes were driven by the group of children whose CU traits improved (but not CP symptoms as hypothesized). No significant microstructural changes were observed in the TD group. Our findings suggest, for the first time, that microstructural abnormalities in the brains of children with CP may be reversible following parenting intervention

Unravelling the effects of methylphenidate on the dopaminergic and noradrenergic functional circuits

Functional magnetic resonance imaging (fMRI) can be combined with drugs to investigate the system-level functional responses in the brain to such challenges. However, most psychoactive agents act on multiple neurotransmitters, limiting the ability of fMRI to identify functional effects related to actions on discrete pharmacological targets. We recently introduced a multimodal approach, REACT (Receptor-Enriched Analysis of functional Connectivity by Targets), which offers the opportunity to disentangle effects of drugs on different neurotransmitters and clarify the biological mechanisms driving clinical efficacy and side effects of a compound. Here, we focus on methylphenidate (MPH), which binds to the dopamine transporter (DAT) and the norepinephrine transporter (NET), to unravel its effects on dopaminergic and noradrenergic functional circuits in the healthy brain at rest. We then explored the relationship between these target-enriched resting state functional connectivity (FC) maps and inter-individual variability in behavioural responses to a reinforcement-learning task encompassing a novelty manipulation to disentangle the molecular systems underlying specific cognitive/behavioural effects. Our main analysis showed a significant MPH-induced FC increase in sensorimotor areas in the functional circuit associated with DAT. In our exploratory analysis, we found that MPH-induced regional variations in the DAT and NET-enriched FC maps were significantly correlated with some of the inter-individual differences on key behavioural responses associated with the reinforcement-learning task. Our findings show that main MPH-related FC changes at rest can be understood through the distribution of DAT in the brain. Furthermore, they suggest that when compounds have mixed pharmacological profiles, REACT may be able to capture regional functional effects that are underpinned by the same cognitive mechanism but are related to engagement of distinct molecular targets

Emotion recognition profiles in clusters of youth based on levels of callous-unemotional traits and reactive and proactive aggression

Youth with disruptive behavior showing high callous-unemotional (CU) traits and proactive aggression are often assumed to exhibit distinct impairments in emotion recognition from those showing mainly reactive aggression. Yet, reactive and proactive aggression and CU traits may co-occur to varying degrees across individuals. We aimed to investigate emotion recognition in more homogeneous clusters based on these three dimensions. In a sample of 243 youth (149 with disruptive behavior problems and 94 controls) aged 8-18 years, we used model-based clustering on self-report measures of CU traits and reactive and proactive aggression and compared the resulting clusters on emotion recognition (accuracy and response bias) and working memory. In addition to a Low and Low-Moderate symptom cluster, we identified two high CU clusters. The CU-Reactive cluster showed high reactive and low-to-medium proactive aggression; the CU-Mixed cluster showed high reactive and proactive aggression. Both CU clusters showed impaired fear recognition and working memory, whereas the CU-Reactive cluster also showed impaired recognition of disgust and sadness, partly explained by poor working memory, as well as a response bias for anger and happiness. Our results confirm the importance of CU traits as a core dimension along which youth with disruptive behavior may be characterized, yet challenge the view that high CU traits are closely linked to high proactive aggression per se. Notably, distinct neurocognitive processes may play a role in youth with high CU traits and reactive aggression with lower versus higher proactive aggression. Keywords: Callous-unemotional traits; Disruptive behavior problems; Emotion recognition; Proactive aggression; Reactive aggressio

Executive functioning and emotion recognition in youth with oppositional defiant disorder and/or conduct disorder

Objectives: Executive functioning and emotion recognition may be impaired in disruptive youth, yet findings in oppositional defiant disorder (ODD) and conduct disorder (CD) are inconsistent. We examined these functions related to ODD and CD, accounting for comorbid attention-deficit/hyperactivity disorder (ADHD) and internalising symptoms.Methods: We compared executive functioning (visual working memory, visual attention, inhibitory control) and emotion recognition between youth (8-18 years old, 123 boys, 55 girls) with ODD (n = 44) or CD (with/without ODD, n = 48), and healthy controls (n = 86). We also related ODD, CD, and ADHD symptom counts and internalising symptomatology to all outcome measures, as well as executive functioning to emotion recognition.Results: Visual working memory and inhibitory control were impaired in the ODD and CD groups versus healthy controls. Anger, disgust, fear, happiness, and sadness recognition were impaired in the CD group; only anger recognition was impaired in the ODD group. Deficits were not explained by comorbid ADHD or internalising symptoms. Visual working memory was associated with recognition of all basic emotions.Conclusions: Our findings challenge the view that neuropsychological impairments in youth with ODD/CD are driven by comorbid ADHD and suggest possible distinct neurocognitive mechanisms in CD versus ODD