Cortical thinning, functional connectivity, and mood-related impulsivity in schizophrenia: relationship to aggressive attitudes and behavior.

OBJECTIVE: Aggression in schizophrenia is a major societal issue, leading to physical harm, stigmatization, patient distress, and higher health care costs. Impulsivity is associated with aggression in schizophrenia, but it is multidetermined. The subconstruct of urgency is likely to play an important role in this aggression, with positive urgency referring to rash action in the context of positive emotion, and negative urgency referring to rash action in the context of negative emotion. METHOD: The authors examined urgency and its neural correlates in 33 patients with schizophrenia or schizoaffective disorder and 31 healthy comparison subjects. Urgency was measured using the Urgency, Premeditation, Perseverance, and Sensation-Seeking scale. Aggressive attitudes were measured using the Buss-Perry Aggression Questionnaire. RESULTS: Positive urgency, negative urgency, and aggressive attitudes were significantly and selectively elevated in schizophrenia patients (Cohen's d values, 1.21-1.50). Positive and negative urgency significantly correlated with the Aggression Questionnaire total score (r>0.48 in all cases) and each uniquely accounted for a significant portion of the variance in aggression over and above the effect of group. Urgency scores correlated with reduced cortical thickness in ventral prefrontal regions including the right frontal pole, the medial and lateral orbitofrontal gyrus and inferior frontal gyri, and the rostral anterior cingulate cortex. In patients, reduced resting-state functional connectivity in some of these regions was associated with higher urgency. CONCLUSIONS: These findings highlight the key role of urgency in aggressive attitudes in people with schizophrenia and suggest neural substrates of these behaviors. The results also suggest behavioral and neural targets for interventions to remediate urgency and aggression.

Decision-making and trait impulsivity in bipolar disorder are associated with reduced prefrontal regulation of striatal reward valuation.

Bipolar disorder is characterized by impaired decision-making captured in impulsivity and risk-taking. We sought to determine whether this is driven by a failure to effectively weight the lower-order goal of obtaining a strongly desired reward in relation to higher-order goals, and how this relates to trait impulsivity and risk-taking. We hypothesized that in bipolar disorder the weighting of valuation signals converging on ventromedial prefrontal cortex are more heavily weighted towards ventral striatum inputs (lower-order), with less weighting of dorsolateral prefrontal cortex inputs (higher-order). Twenty euthymic patients with bipolar disorder not in receipt of antipsychotic medication and 20 case-matched controls performed a roulette task during functional magnetic resonance imaging. Activity in response to high-probability ('safe') and low-probability ('risky') prospects was measured during both anticipation, and outcome. In control subjects, anticipatory and outcome-locked activity in dorsolateral prefrontal cortex was greater for safe than risky reward prospects. The bipolar disorder group showed the opposite pattern with preferential response to risky rewards. This group also showed increased anticipatory and outcome-locked activity in ventral striatum in response to rewards. In control subjects, however, ventromedial prefrontal activation was positively associated with both ventral striatum and dorsolateral prefrontal activity; patients evidenced a strong positive association with ventral striatum, but a negative association with dorsolateral prefrontal cortex. Response to high-probability rewards in dorsolateral prefrontal cortex was inversely associated with trait impulsivity and risk-taking in the bipolar disorder group. Our findings suggest that clinically impulsive and risky decision-making are related to subjective valuation that is biased towards lower-order preference, with diminished integration of higher-order goals. The findings extend a functional neuroanatomical account of disorders characterized by clinically impulsive decision-making, and provide targets for evaluating interventions that foster self-control.

Relationship between impulsivity, prefrontal anticipatory activation, and striatal dopamine release during rewarded task performance.

Impulsivity, and in particular the negative urgency aspect of this trait, is associated with poor inhibitory control when experiencing negative emotion. Individual differences in aspects of impulsivity have been correlated with striatal dopamine D2/D3 receptor availability and function. This multi-modal pilot study used both positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) to evaluate dopaminergic and neural activity, respectively, using modified versions of the monetary incentive delay task. Twelve healthy female subjects underwent both scans and completed the NEO Personality Inventory Revised to assess Impulsiveness (IMP). We examined the relationship between nucleus accumbens (NAcc) dopaminergic incentive/reward release, measured as a change in D2/D3 binding potential between neutral and incentive/reward conditions with [(11)C]raclopride PET, and blood oxygen level-dependent (BOLD) activation elicited during the anticipation of rewards, measured with fMRI. Left NAcc incentive/reward dopaminergic release correlated with anticipatory reward activation within the medial prefrontal cortex (mPFC), left angular gyrus, mammillary bodies, and left superior frontal cortex. Activation in the mPFC negatively correlated with IMP and mediated the relationship between IMP and incentive/reward dopaminergic release in left NAcc. The mPFC, with a regulatory role in learning and valuation, may influence dopamine incentive/reward release.

Trait impulsivity and impaired prefrontal impulse inhibition function in adolescents with internet gaming addiction revealed by a Go/No-Go fMRI study.

BACKGROUND: Recent studies suggest that Internet gaming addiction (IGA) is an impulse disorder, or is at least related to impulse control disorders. In the present study, we hypothesized that different facets of trait impulsivity may be specifically linked to the brain regions with impaired impulse inhibition function in IGA adolescents. METHODS: Seventeen adolescents with IGA and seventeen healthy controls were scanned during performance of a response-inhibition Go/No-Go task using a 3.0 T MRI scanner. The Barratt Impulsiveness Scale (BIS)-11 was used to assess impulsivity. RESULTS: There were no differences in the behavioral performance on the Go/No-Go task between the groups. However, the IGA group was significantly hyperactive during No-Go trials in the left superior medial frontal gyrus, right anterior cingulate cortex, right superior/middle frontal gyrus, left inferior parietal lobule, left precentral gyrus, and left precuneus and cuneus. Further, the bilateral middle temporal gyrus, bilateral inferior temporal gyrus, and right superior parietal lobule were significantly hypoactive during No-Go trials. Activation of the left superior medial frontal gyrus was positively associated with BIS-11 and Chen Internet Addiction Scale (CIAS) total score across IGA participants. CONCLUSIONS: Our data suggest that the prefrontal cortex may be involved in the circuit modulating impulsivity, while its impaired function may relate to high impulsivity in adolescents with IGA, which may contribute directly to the Internet addiction process.

[Therapeutic effects of exercise-based treatment programme on children with attention-deficit/hyperactivity disorder].

OBJECTIVE: To evaluate the effects of an exercise-based treatment programme (dyslexia, dyspraxia and attention-deficit treatment, DDAT) on various subtypes of attention-deficit/hyperactivity disorder (ADHD). METHOD: Ninety-one ADHD children with standing balance dysfunction (ADHD-I 43, ADHD-HI 15 and ADHD-C 33) were given DDAT for 6 months, the efficacy of DDAT was evaluated before DDAT, three, six months after the treatment and three month after end of the treatment according to SNAP-IV, before and after the treatment by balancing function test and Conners Parents Rating Scale. RESULT: Inattention subscale scores of ADHD-I, ADHD-HI and ADHD-C before and after the interventions were 1.99 ± 0.34, 0.96 ± 0.31, 2.17 ± 0.31and 1.19 ± 0.45, 0.81 ± 0.28, 1.32 ± 0.37, differences of ADHD-I and ADHD-C were significant (P < 0.05), hyperactivity subscale scores of three subtypes of ADHD were 0.81 ± 0.35, 2.01 ± 0.35, 1.96 ± 0.33 vs.0.45 ± 0.33, 0.79 ± 0.41, 1.10 ± 0.35, there were significant differences as well (P < 0.05). The score of hyperactivity symptom was reduced more compared to that of inattention symptom by the SNAP-IV scale parent forms. There were significant difference before and after the treatment based on Conners parent scale for conduct problem (1.11 ± 0.48 vs. 0.76 ± 0.44) , learning problem (1.97 ± 0.58 vs.1.60 ± 0.67), psychosomatic problems (0.61 ± 0.49 vs. 0.29 ± 0.35) , activity/ hyperactivity (1.46 ± 0.69 vs.1.09 ± 0.55) and anxiousness (1.05 ± 0.63 vs.0.62 ± 0.47) as well (P < 0.05); the standing balance dysfunction improved for most of the children, total effective rate was 87.9%, no significant difference was found among the three subtypes (P > 0.05). CONCLUSION: DDAT is a safe and efficient intervention for the ADHD children with standing balance dysfunction, the improvement on hyperactivity symptom was better than that on inattention symptom. This study shows that an exercise-based treatment programme for cerebellum function improves symptoms of ADHD and balance function.

Implementation intention and action planning interventions in health contexts: state of the research and proposals for the way forward.

The purpose of this paper is to provide an overview of the literature on two planning intervention techniques in health behaviour research, implementation intentions and action planning, and to develop evidence-based recommendations for effective future interventions and highlight priority areas for future research. We focused our review on four key areas: (1) definition and conceptualisation; (2) format and measurement; (3) mechanisms and processes; and (4) design issues. Overall, evidence supports the effectiveness of planning interventions in health behaviour with advantages including low cost and response burden. There is, however, considerable heterogeneity in the effects across studies and relatively few registered randomised trials that include objective behavioural measures. Optimally effective planning interventions should adopt "if-then" plans, account for salient and relevant cues, include examples of cues, be guided rather than user-defined, and include boosters. Future studies should adopt randomised controlled designs, report study protocols, include fidelity checks and relevant comparison groups, and adopt long-term behavioural follow-up measures. Priority areas for future research include the identification of the moderators and mediators of planning intervention effects. Future research also needs to adopt "best practice" components of planning interventions more consistently to elucidate the mechanisms and processes involved.

Selective serotonin reuptake inhibition modulates response inhibition in Parkinson's disease.

Impulsivity is common in Parkinson's disease even in the absence of impulse control disorders. It is likely to be multifactorial, including a dopaminergic 'overdose' and structural changes in the frontostriatal circuits for motor control. In addition, we proposed that changes in serotonergic projections to the forebrain also contribute to response inhibition in Parkinson's disease, based on preclinical animal and human studies. We therefore examined whether the selective serotonin reuptake inhibitor citalopram improves response inhibition, in terms of both behaviour and the efficiency of underlying neural mechanisms. This multimodal magnetic resonance imaging study used a double-blind randomized placebo-controlled crossover design with an integrated Stop-Signal and NoGo paradigm. Twenty-one patients with idiopathic Parkinson's disease (46-76 years old, 11 male, Hoehn and Yahr stage 1.5-3) received 30 mg citalopram or placebo in addition to their usual dopaminergic medication in two separate sessions. Twenty matched healthy control subjects (54-74 years old, 12 male) were tested without medication. The effects of disease and drug on behavioural performance and regional brain activity were analysed using general linear models. In addition, anatomical connectivity was examined using diffusion tensor imaging and tract-based spatial statistics. We confirmed that Parkinson's disease caused impairment in response inhibition, with longer Stop-Signal Reaction Time and more NoGo errors under placebo compared with controls, without affecting Go reaction times. This was associated with less stop-specific activation in the right inferior frontal cortex, but no significant difference in NoGo-related activation. Although there was no beneficial main effect of citalopram, it reduced Stop-Signal Reaction Time and NoGo errors, and enhanced inferior frontal activation, in patients with relatively more severe disease (higher Unified Parkinson's Disease Rating Scale motor score). The behavioural effect correlated with the citalopram-induced enhancement of prefrontal activation and the strength of preserved structural connectivity between the frontal and striatal regions. In conclusion, the behavioural effect of citalopram on response inhibition depends on individual differences in prefrontal cortical activation and frontostriatal connectivity. The correlation between disease severity and the effect of citalopram on response inhibition may be due to the progressive loss of forebrain serotonergic projections. These results contribute to a broader understanding of the critical roles of serotonin in regulating cognitive and behavioural control, as well as new strategies for patient stratification in clinical trials of serotonergic treatments in Parkinson's disease.

Ventral medial prefrontal cortex inactivation impairs impulse control but does not affect delay-discounting in rats.

Maladaptive levels of impulsivity are found in several neuropsychiatric disorders, such as ADHD, addiction, aggression and schizophrenia. Intolerance to delay-of-gratification, or delay-discounting, and deficits in impulse control are dissociable forms of impulsivity top-down controlled by the prefrontal cortex, with the ventral medial prefrontal cortex (vmPFC) suggested to be critically involved. The present study used transient inactivation of the rats' vmPFC via bilateral microinfusion of the GABAA receptor agonist muscimol (0.05, 0.5 µg/0.3 µl) to analyse its relevance for impulse control in a 5-choice serial reaction time task (5-CSRTT) and delay-discounting in a Skinner box. Intra-vmPFC injection of low-dose muscimol impaired impulse control indicated by enhanced premature responding in the 5-CSRTT, while flattening the delay-dependent shift in the preference of the large reward in the delay-discounting task. Likewise, high-dose muscimol did not affect delay-discounting, though raising the rate of omissions. On the contrary, 5-CSRTT performance was characterised by deficits in impulse and attentional control. These data support the behavioural distinction of delay-discounting and impulse control on the level of the vmPFC in rats. Reversible inactivation with muscimol revealed an obvious implication of the vmPFC in the modulation of impulse control in the 5-CSRTT. By contrast, delay-discounting processes seem to be regulated by other neuronal pathways, with the vmPFC playing, if at all, a minor role.

Multiple modes of impulsivity in Parkinson's disease.

Cognitive problems are a major factor determining quality of life of patients with Parkinson's disease. These include deficits in inhibitory control, ranging from subclinical alterations in decision-making to severe impulse control disorders. Based on preclinical studies, we proposed that Parkinson's disease does not cause a unified disorder of inhibitory control, but rather a set of impulsivity factors with distinct psychological profiles, anatomy and pharmacology. We assessed a broad set of measures of the cognitive, behavioural and temperamental/trait aspects of impulsivity. Sixty adults, including 30 idiopathic Parkinson's disease patients (Hoehn and Yahr stage I-III) and 30 healthy controls, completed a neuropsychological battery, objective behavioural measures and self-report questionnaires. Univariate analyses of variance confirmed group differences in nine out of eleven metrics. We then used factor analysis (principal components method) to identify the structure of impulsivity in Parkinson's disease. Four principal factors were identified, consistent with four different mechanisms of impulsivity, explaining 60% of variance. The factors were related to (1) tests of response conflict, interference and self assessment of impulsive behaviours on the Barrett Impulsivity Scale, (2) tests of motor inhibitory control, and the self-report behavioural approach system, (3) time estimation and delay aversion, and (4) reflection in hypothetical scenarios including temporal discounting. The different test profiles of these four factors were consistent with human and comparative studies of the pharmacology and functional anatomy of impulsivity. Relationships between each factor and clinical and demographic features were examined by regression against factor loadings. Levodopa dose equivalent was associated only with factors (2) and (3). The results confirm that impulsivity is common in Parkinson's disease, even in the absence of impulse control disorders, and that it is not a unitary phenomenon. A better understanding of the structure of impulsivity in Parkinson's disease will support more evidence-based and effective strategies to treat impulsivity.

Brain circuitry of compulsivity and impulsivity.

Impulsivity and compulsivity have been considered opposite poles of a continuous spectrum, but their relationship appears to be more complex. Disorders characterized by impulsivity often have features of compulsivity and vice versa. The overlaps of the constructs of compulsivity and impulsivity warrant additional investigation, not only to identify the similarities and differences, but also to examine the implications for prevention and treatment strategies of both compulsive and impulsive behaviors.

The role of trait impulsivity in response inhibition: event-related potentials in a stop-signal task.

The study examined the relation between self-reported impulsivity and inhibitory control in normal individuals. We compared stopping performance and neural correlates of stopping on stop-signal task between participants who scored in the top (n=12) and bottom 25% (n=12) on Impulsivity Scale from a sample of 305 male adults. Participants scoring high on impulsivity did not show impaired inhibitory control. However, it seems that the high impulsive tended to make more errors of commission and omission. Enhanced N1 amplitudes were found in successful than failed inhibition trials. The high impulsive group had smaller P3 amplitude than the low impulsive group. It appears that the high impulsive group may have a less efficient inhibitory control. Impulsivity Scale non-planning impulsiveness score and inattention score of Adult ADHD Self-Report Scale (ASRS) were negatively correlated with P3 amplitudes on successful inhibition trails, suggesting that impulsivity could have the potential influence on inhibitory control.

Neuroimaging studies of factors related to exercise: rationale and design of a 9 month trial.

The prevalence of obesity is high resulting from chronic imbalances between energy intake and expenditure. On the expenditure side, regular exercise is associated with health benefits, including enhanced brain function. The benefits of exercise are not immediate and require persistence to be realized. Brain regions associated with health-related decisions, such as whether or not to exercise or controlling the impulse to engage in immediately rewarding activities (e.g., sedentary behavior), include reward processing and cognitive control regions. A 9 month aerobic exercise study will be conducted in 180 sedentary adults (n = 90 healthy weight [BMI = 18.5 to 26.0 kg/m(2)]; n = 90 obese [BMI = 29.0 to 41.0 kg/m(2)) to examine the brain processes underlying reward processing and impulse control that may affect adherence in a new exercise regimen. The primary aim is to use functional magnetic resonance imaging (fMRI) to examine reward processing and impulse control among participants that adhere (exercise >80% of sessions) and those that do not adhere to a nine-month exercise intervention with secondary analyses comparing sedentary obese and sedentary healthy weight participants. Our results will provide valuable information characterizing brain activation underlying reward processing and impulse control in sedentary obese and healthy weight individuals. In addition, our results may identify brain activation predictors of adherence and success in the exercise program along with measuring the effects of exercise and improved fitness on brain activation.

Evaluation of neurofeedback in ADHD: the long and winding road.

Among the clinical applications of neurofeedback, most research has been conducted in ADHD. As an introduction a short overview of the general history of neurofeedback will be given, while the main part of the paper deals with a review of the current state of neurofeedback in ADHD. A meta-analysis on neurofeedback from 2009 found large effect sizes for inattention and impulsivity and medium effects sizes for hyperactivity. Since 2009 several new studies, including 4 placebo-controlled studies, have been published. These latest studies are reviewed and discussed in more detail. The review focuses on studies employing (1) semi-active, (2) active, and (3) placebo-control groups. The assessment of specificity of neurofeedback treatment in ADHD is discussed and it is concluded that standard protocols such as theta/beta, SMR and slow cortical potentials neurofeedback are well investigated and have demonstrated specificity. The paper ends with an outlook on future questions and tasks. It is concluded that future controlled clinical trials should, in a next step, focus on such known protocols, and be designed along the lines of learning theory.

Selective involvement by the medial orbitofrontal cortex in biasing risky, but not impulsive, choice.

Separate regions of the orbitofrontal cortex (OFC) have been implicated in mediating different aspects of cost-benefit decision-making in humans and animals. Anatomical and functional imaging studies indicate that the medial (mOFC) and lateral OFC may subserve dissociable functions related to reward and decision-making processes, yet the majority of studies in rodents have focused on the lateral OFC. The present study investigated the contribution of the rat mOFC to risk and delay-based decision-making, assessed with probabilistic and delay-discounting tasks. In well-trained rats, reversible inactivation of the mOFC increase a risky choice on the probabilistic discounting task, irrespective of whether the odds of obtaining a larger/risky reward decreased (100-12.5%) or increased (12.5-100%) over the course of a session. The increase in risky choice was associated with enhanced win-stay behavior, wherein rats showed an increased tendency to choose the risky option after being rewarded for the risky choice on a preceding trial. In contrast, mOFC inactivation did not alter delay discounting. These findings suggest that the mOFC plays a selective role in decisions involving reward uncertainty, mitigating the impact that larger, probabilistic rewards exert on subsequent choice behavior. This function may promote the exploration of novel options when reward contingencies change.

Long-term temporal stability of measured inattention and impulsivity in typical and referred children.

OBJECTIVE: This study investigates the stability of measured inattention and impulsivity in children. METHOD: The Gordon Diagnostic System (GDS) assesses inattention and impulsivity and has been administered in the same manner since its 1983 publication. GDS scores were compared between the 1983 standardization sample and a recent typical sample of 445 children, 562 children with ADHD-Combined (ADHD-C) type, 235 with ADHD-Inattentive (ADHD-I) type, and 231 with autism. RESULTS: Typical children earned a GDS composite standard score of 100, consistent with the normal mean of 100 in the 1983 standardization sample. Means for children with ADHD-C, ADHD-I, and autism were 70, 78, and 76, respectively, approximately two standard deviations below the normal mean. CONCLUSION: As measured by the GDS, children are no more or less inattentive and impulsive today than in 1983, suggesting that inattention and impulsivity are stable neurobiological traits largely unaffected by cultural, educational, and environmental factors.

Impulsivity is associated with uric acid: evidence from humans and mice.

BACKGROUND: The ability to control impulses varies greatly, and difficulty with impulse control can have severe consequences; in the extreme, it is the defining feature of many psychiatric disorders. Evidence from disparate lines of research suggests that uric acid is elevated in psychiatric disorders characterized by high impulsivity, such as attention-deficit/hyperactivity disorder and bipolar disorder. The present research tests the hypothesis that impulsivity is associated with higher uric acid in humans and mice. METHODS: Using two longitudinal, nonclinical community samples (total n = 6883), we tested whether there is an association between uric acid and normal variation in trait impulsivity measured with the Revised NEO Personality Inventory. We also examined the effect of uric acid on behavior by comparing wild-type mice, which naturally have low levels of uric acid, with mice genetically modified to accumulate high levels of uric acid. RESULTS: In both human samples, the emotional aspects of trait impulsivity, specifically impulsiveness and excitement seeking, were associated with higher levels of uric acid concurrently and when uric acid was measured 3 to 5 years later. Consistent with the human data, the genetically modified mice displayed significantly more exploratory and novelty-seeking behavior than the wild-type mice. CONCLUSIONS: Higher uric acid was associated with impulsivity in both humans and mice. The identification of biological markers of impulsivity may lead to a better understanding of the physiological mechanisms involved in impulsivity and may suggest potential targets for therapeutic intervention.

Error processing in current and former cocaine users.

Deficits in response inhibition and error processing can result in maladaptive behavior, including failure to use past mistakes to inform present decisions. A specific deficit in inhibiting a prepotent response represents one aspect of impulsivity and is a prominent feature of addictive behaviors in general, including cocaine abuse/dependence. Brain regions implicated in cognitive control exhibit reduced activation in cocaine abusers. The purposes of the present investigation were (1) to identify neural differences associated with error processing in current and former cocaine-dependent individuals compared to healthy controls and (2) to determine whether former, long-term abstinent cocaine users showed similar differences compared with current users. The present study used an fMRI Go/No-Go task to investigate differences in BOLD response to correct rejections and false alarms between current cocaine users (n = 30), former cocaine users (n = 29), and healthy controls (n = 35). Impulsivity trait measures were also assessed and compared with BOLD activity. Nineteen regions of interest previously implicated in errors of disinhibition were queried. There were no group differences in the correct rejections condition, but both current and former users exhibited increased BOLD response relative to controls for false alarms. In current users, the pregenual cingulate gyrus and left angular/supramarginal gyri overactivated. In former users, the right middle frontal/precentral gyri, right inferior parietal lobule, and left angular/supramarginal gyri overactivated. Overall, our results support a hypothesis that neural activity in former users differs more from healthy controls than that of current users due to cognitive compensation that facilitates abstinence.

Ventral-striatal responsiveness during reward anticipation in ADHD and its relation to trait impulsivity in the healthy population: a meta-analytic review of the fMRI literature.

A review of the existing functional magnetic resonance imaging (fMRI) studies on reward anticipation in patients with attention-deficit/hyperactivity disorder (ADHD) is provided. Meta-analysis showed a significant medium effect size (Cohen's d=0.48-0.58) in terms of ventral-striatal (VS)-hyporesponsiveness in ADHD. Studies on VS-responsiveness and trait impulsivity in the healthy population demonstrate the opposite relationship, i.e. impulsivity-scores positively correlated with VS activation during reward processing. Against the background that ADHD may represent an extreme on a continuum of normal variability, the question arises as to how these contrasting findings can be integrated. We discuss three theoretical approaches, each of which integrates the opposing findings: (1) an inverted-u-shape model; (2) a (genetic) moderator model; and (3) the "unrelated model". We conclude that at the present stage the number of existing studies in the healthy population as well as in ADHD groups is too small for a final answer. Therefore, our presented integrative approaches should be understood as an attempt to frame future research directions by generating testable hypotheses and giving practical suggestions for future studies.

Impulsivity, irritability, and depression: antidepressants.

Definitional and conceptual issues related to the symptoms of impulsivity, irritability, and depression are described. A brief overview of the relevant neurobiology of each symptom is then provided. General psychopharmacologic strategies to address these symptoms are explored. Finally, brief clinical vignettes are described along with specific pharmacologic information on commonly used agents.

Attention deficits and hyperactivity-impulsivity: what have we learned, what next?

The domains of self-regulation, self-control, executive function, inattention, and impulsivity cut across broad swathes of normal and abnormal development. Attention-deficit/hyperactivity disorder is a common syndrome that encompasses a portion of these domains. In the past 25 years research on attention-deficit/hyperactivity disorder has been characterized by dramatic advances in genetic, neural, and neuropsychological description of the syndrome as well as clarification of its multidimensional phenotypic structure. The limited clinical applicability of these research findings poses the primary challenge for the next generation. It is likely that clinical breakthroughs will require further refinement in describing heterogeneity or clinical/biological subgroups, renewed focus on the environment in the form of etiological events as well as psychosocial contexts of development, and integration of both with biological understanding.