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1.  Effects of smoking abstinence on impulsive behavior among smokers high and low in ADHD-like symptoms 
Psychopharmacology  2011;219(2):537-547.
Rationale
Impulsivity, a multifaceted construct that includes inhibitory control and heightened preference for immediate reward, is central to models of drug use and abuse. Within a self-medication framework, abstinence from smoking may lead to an increase in impulsive behavior and the likelihood of relapse, particularly among persons with disorders (e.g., attention-deficit/hyperactivity disorder, ADHD) and personality traits (e.g., impulsivity) linked to impulsive behavior.
Objectives
This study aimed to examine the effects of smoking abstinence on multiple measures of impulsivity among a non-clinical sample of adult smokers selected for high and low levels of ADHD symptoms.
Methods
In a within-subjects design, participants selected for high or low levels of self-reported ADHD symptoms (N=56) completed sessions following overnight abstinence and when smoking as usual (order counterbalanced). Measures of impulsive behavior included response inhibition (i.e., stop signal task), interference control (i.e., attentional modification of prepulse inhibition (PPI) of startle), and impulsive choice (i.e., hypothetical delay discounting).
Results
As hypothesized, abstinence decreased response inhibition and PPI. Although ADHD symptoms moderated abstinence effects on impulsive choice and response inhibition, the pattern was opposite to our predictions: the low-ADHD group responded more impulsively when abstinent, whereas the high-ADHD group was relatively unaffected by abstinence.
Conclusions
These findings highlight the importance of utilizing multiple laboratory measures to examine a multifactorial construct such as impulsive behavior and raise questions about how best to assess symptoms of ADHD and impulsivity among non-abstinent smokers.
doi:10.1007/s00213-011-2324-2
PMCID: PMC3184469  PMID: 21559802
Smoking; Abstinence; Impulsivity; Attention-deficit/hyperactivity disorder; Individual differences; Stop task; Delay discounting; Prepulse inhibition; Inhibitory control
2.  Behavioral models of impulsivity in relation to ADHD: Translation between clinical and preclinical studies 
Clinical Psychology Review  2006;26(4):379-395.
Impulsivity, broadly defined as action without foresight, is a component of numerous psychiatric illnesses including attention deficit/hyperactivity disorder (ADHD), mania and substance abuse. In order to investigate the mechanisms underpinning impulsive behavior, the nature of impulsivity itself needs to be defined in operational terms that can be used as the basis for empirical investigation. Due to the range of behaviors that the term impulsivity describes, it has been suggested that impulsivity is not a unitary construct, but encompasses a variety of related phenomena that may differ in their biological basis. Through fractionating impulsivity into these component parts, it has proved possible to devise different behavioral paradigms to measure various aspects of impulsivity in both humans and laboratory animals. This review describes and evaluates some of the current behavioral models of impulsivity developed for use with rodents based on human neuropsychological tests, focusing on the five-choice serial reaction time task, the stop-signal reaction time task and delay-discounting paradigms. Furthermore, the contributions made by preclinical studies using such methodology to improve our understanding of the neural and neurochemical basis of impulsivity and ADHD are discussed, with particular reference to the involvement of both the serotonergic and dopaminergic systems, and frontostriatal circuitry.
doi:10.1016/j.cpr.2006.01.001
PMCID: PMC1892795  PMID: 16504359
ADHD; Impulsivity; Frontal cortex; Inhibition; Serotonin; Dopamine
3.  Behavioral models of impulsivity in relation to ADHD: Translation between clinical and preclinical studies 
Clinical psychology review  2006;26(4):379-395.
Impulsivity, broadly defined as action without foresight, is a component of numerous psychiatric illnesses including attention deficit/hyperactivity disorder (ADHD), mania and substance abuse. In order to investigate the mechanisms underpinning impulsive behavior, the nature of impulsivity itself needs to be defined in operational terms that can be used as the basis for empirical investigation. Due to the range of behaviors that the term impulsivity describes, it has been suggested that impulsivity is not a unitary construct, but encompasses a variety of related phenomena that may differ in their biological basis. Through fractionating impulsivity into these component parts, it has proved possible to devise different behavioral paradigms to measure various aspects of impulsivity in both humans and laboratory animals. This review describes and evaluates some of the current behavioral models of impulsivity developed for use with rodents based on human neuropsychological tests, focusing on the five-choice serial reaction time task, the stop-signal reaction time task and delay-discounting paradigms. Furthermore, the contributions made by preclinical studies using such methodology to improve our understanding of the neural and neurochemical basis of impulsivity and ADHD are discussed, with particular reference to the involvement of both the serotonergic and dopaminergic systems, and frontostriatal circuitry.
doi:10.1016/j.cpr.2006.01.001
PMCID: PMC1892795  PMID: 16504359
ADHD; Impulsivity; Frontal cortex; Inhibition; Serotonin; Dopamine
4.  Separating Automatic and Intentional Inhibitory Mechanisms of Attention in Adults with Attention-Deficit/Hyperactivity Disorder 
Journal of abnormal psychology  2011;120(1):223-233.
Researchers in the cognitive sciences recognize a fundamental distinction between automatic and intentional mechanisms of inhibitory control. The use of eye-tracking tasks to assess selective attention has led to a better understanding of this distinction in specific populations such as children with attention-deficit/hyperactivity disorder (ADHD). This study examined automatic and intentional inhibitory control mechanisms in adults with ADHD using a saccadic interference (SI) task and a delayed ocular response (DOR) task. Thirty adults with ADHD were compared to 27 comparison adults on measures of inhibitory control. The DOR task showed that adults with ADHD were less able than comparison adults to inhibit a reflexive saccade towards the sudden appearance of a stimulus in the periphery. However, SI task performance showed that the ADHD group did not differ significantly from the comparison group on a measure of automatic inhibitory control. These findings suggest a dissociation between automatic and intentional inhibitory deficits in adults with ADHD.
doi:10.1037/a0021408
PMCID: PMC3065892  PMID: 21058752
ADHD; inhibition; automatic; intentional
5.  Impulsivity and response inhibition in alcohol dependence and problem gambling 
Psychopharmacology  2009;207(1):163-172.
Introduction
Impulsivity is a central feature of drug addiction and may arise as a result of impaired inhibitory control. The extent to which inhibitory deficits arise as a consequence of drug exposure or relate to pre-existing addiction vulnerability is unknown.
Materials and methods
This study compared measures of impulsivity in outpatients with alcohol dependence (n = 23) and problem gambling (n = 21), a putative behavioural addiction where direct effects of drug exposure may be minimal. Healthy controls (n = 27) were also tested, in a cross-sectional design. Subjects completed the stop-signal test as a neurocognitive probe of response inhibition, alongside self-report ratings of impulsivity, adult ADHD and OCD.
Results
On the stop-signal test, Go reaction time and stop-signal reaction time were significantly slower in the alcohol-dependent group, compared with healthy controls. Healthy controls slowed their responding after successful and failed stop trials. Slowing after failed stop trials was significantly attenuated in the alcohol-dependent subjects. Go reaction time and post-error slowing were correlated with chronicity and severity, respectively, in the alcohol-dependent subjects. Problem gamblers did not differ significantly from controls on the stop-signal test, despite trait elevations in impulsivity ratings.
Conclusion
Inhibitory control is impaired in alcohol dependence but occurs in the context of psychomotor slowing. In addition, alcohol-dependent individuals failed to show behavioral adjustment following failed stops. These deficits may represent direct effects of chronic alcohol administration on fronto-striatal circuitry.
doi:10.1007/s00213-009-1645-x
PMCID: PMC2764851  PMID: 19727677
Compulsivity; Executive function; Post-error adjustment; Pathological gambling; Alcoholism
6.  Neural substrates of impaired sensorimotor timing in adult attention-deficit/hyperactivity disorder 
Biological psychiatry  2010;68(4):359-367.
Background
Timing abilities are critical to the successful management of everyday activities and personal safety, and timing abnormalities have been argued to be fundamental to impulsiveness, a core symptom of attention-deficit/hyperactivity disorder (ADHD). Despite substantial evidence of timing deficits in ADHD youth, only two studies have explicitly examined timing in ADHD adults, and only at the supra-second time-scale. Also, the neural substrates of these deficits are largely unknown for both youth and adults with ADHD. The present study examined sub-second sensorimotor timing and its neural substrates in ADHD adults.
Methods
Using fMRI, we examined paced and unpaced finger tapping in a sample of 20 unmedicated adults with ADHD and 19 controls comparable on age, sex and estimated-IQ. The blood oxygenation level-dependent contrast response was used to estimate task-related neural activity.
Results
Behavioral data showed no between-group differences in mean tapping rates but greater within-subject variability in tap-to-tap intervals for ADHD adults relative to controls. Importantly, ADHD adults had greater clock rather than motor variability, consistent with a central timing locus for the atypical movements. The imaging results demonstrated that, relative to controls, ADHD adults showed less activity in a number of regions associated with sensorimotor timing, including prefrontal and precentral gyri, basal ganglia, cerebellum, inferior parietal lobule, superior temporal gyri and insula.
Conclusions
Our findings show that sub-second timing abnormalities in ADHD youth persist into adulthood and suggest that abnormalities in the temporal structure of behavior observed in ADHD adults result from atypical function of cortico-cerebellar and cortico-striatal timing systems.
doi:10.1016/j.biopsych.2010.05.012
PMCID: PMC2917236  PMID: 20619827
ADHD; fMRI; timing; cerebellum; frontal cortex; basal ganglia
7.  The influence of sex-linked genetic mechanisms on attention and impulsivity 
Biological Psychology  2012;89(1):1-13.
Highlights
► Attention and impulsivity are sexually dimorphic in healthy populations. ► Review how sex modulates the expression of disorders like ADHD and autism. ► Genetic mechanisms that underlie sex differences in attention/impulsivity discussed. ► Focus on candidate sex-linked genes likely to influence these cognitive processes.
It is now generally agreed that there are inherent sex differences in healthy individuals across a number of neurobiological domains (including brain structure, neurochemistry, and cognition). Moreover, there is a burgeoning body of evidence highlighting sex differences within neuropsychiatric populations (in terms of the rates of incidence, clinical features/progression, neurobiology and pathology). Here, we consider the extent to which attention and impulsivity are sexually dimorphic in healthy populations and the extent to which sex might modulate the expression of disorders characterised by abnormalities in attention and/or impulsivity such as attention deficit hyperactivity disorder (ADHD), autism and addiction. We then discuss general genetic mechanisms that might underlie sex differences in attention and impulsivity before focussing on specific positional and functional candidate sex-linked genes that are likely to influence these cognitive processes. Identifying novel sex-modulated molecular targets should ultimately enable us to develop more effective therapies in disorders associated with attentional/impulsive dysfunction.
doi:10.1016/j.biopsycho.2011.09.011
PMCID: PMC3245859  PMID: 21983394
Sexual dimorphism; Neuropsychiatric disorders; Attention; Impulsivity; Attention deficit hyperactivity disorder; Sex chromosomes; Autism; SRY; MAOA; Steroid sulfatase; Neurosteroids; Turner syndrome; COMT
8.  Event-related fMRI of inhibitory control in the Predominantly Inattentive and Combined Subtypes of AD/HD 
Background and Purpose
To examine the neurophysiological basis for the pronounced differences in hyperactivity and impulsiveness that distinguish the Predominantly Inattentive type of Attention-Deficit/Hyperactivity Disorder (ADHD-PI) from the combined type of the disorder (ADHD-C).
Methods
Event-related brain responses to a go/no-go test of inhibitory control were measured with functional magnetic resonance imaging (fMRI) in 11 children with ADHD-C and nine children with ADHD-PI, aged 7 to 13 years, who were matched for age, sex, and intelligence.
Results
There were no significant group differences in task performance. Children with ADHD-C and ADHD-PI activated overlapping regions of right inferior frontal gyrus, right superior temporal lobe, and left inferior parietal lobe during inhibitory control. However, the magnitude of the activation in the temporal and parietal regions, as well as in the bilateral middle frontal gyrus, was greater in children with ADHD-PI than those with ADHD-C. Conversely, children with ADHD-C activated bilateral medial occipital lobe to a greater extent than children with ADHD-PI.
Conclusions
The results provide preliminary evidence that phenotypic differences between the ADHD-C and ADHD-PI subtypes are associated with differential activation of regions that have previously been implicated in the pathophysiology of ADHD and are thought to mediate executive and attentional processes.
doi:10.1111/j.1552-6569.2008.00289.x
PMCID: PMC2711513  PMID: 19594667
9.  Cognitive-electrophysiological indices of attentional and inhibitory processing in adults with ADHD: familial effects 
Background
Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder that starts in childhood and frequently persists in adults. In a comparison of adults with ADHD and a matched control sample, we previously showed that abnormal inhibitory processing is typically preceded or accompanied by other processing deficits in adult ADHD. We now compare these data further to additional data from first-degree relatives (fathers) of children with ADHD to identify whether this pattern of abnormal processing shares familial influences with ADHD in adults.
Methods
Using a family design, we compared 20 fathers of children with the combined subtype of ADHD with 21 adults with ADHD combined subtype and 20 controls in event-related potential indices of preparatory states and subsequent response inhibition processing as elicited by a cued continuous performance task.
Results
Fathers of children with ADHD exhibited significantly weaker orienting attention to cues and inhibitory processing than the controls but not the ADHD sample.
Conclusions
These findings provide evidence for the familial association of attentional orienting and response inhibition processes with ADHD in adults and indicate a familial and neurobiological link between ADHD in children and adults.
doi:10.1186/1744-9081-7-26
PMCID: PMC3168399  PMID: 21752266
10.  MEG event-related desynchronization and synchronization deficits during basic somatosensory processing in individuals with ADHD 
Background
Attention-Deficit/Hyperactivity Disorder (ADHD) is a prevalent, complex disorder which is characterized by symptoms of inattention, hyperactivity, and impulsivity. Convergent evidence from neurobiological studies of ADHD identifies dysfunction in fronto-striatal-cerebellar circuitry as the source of behavioural deficits. Recent studies have shown that regions governing basic sensory processing, such as the somatosensory cortex, show abnormalities in those with ADHD suggesting that these processes may also be compromised.
Methods
We used event-related magnetoencephalography (MEG) to examine patterns of cortical rhythms in the primary (SI) and secondary (SII) somatosensory cortices in response to median nerve stimulation, in 9 adults with ADHD and 10 healthy controls. Stimuli were brief (0.2 ms) non-painful electrical pulses presented to the median nerve in two counterbalanced conditions: unpredictable and predictable stimulus presentation. We measured changes in strength, synchronicity, and frequency of cortical rhythms.
Results
Healthy comparison group showed strong event-related desynchrony and synchrony in SI and SII. By contrast, those with ADHD showed significantly weaker event-related desynchrony and event-related synchrony in the alpha (8–12 Hz) and beta (15–30 Hz) bands, respectively. This was most striking during random presentation of median nerve stimulation. Adults with ADHD showed significantly shorter duration of beta rebound in both SI and SII except for when the onset of the stimulus event could be predicted. In this case, the rhythmicity of SI (but not SII) in the ADHD group did not differ from that of controls.
Conclusion
Our findings suggest that somatosensory processing is altered in individuals with ADHD. MEG constitutes a promising approach to profiling patterns of neural activity during the processing of sensory input (e.g., detection of a tactile stimulus, stimulus predictability) and facilitating our understanding of how basic sensory processing may underlie and/or be influenced by more complex neural networks involved in higher order processing.
doi:10.1186/1744-9081-4-8
PMCID: PMC2266931  PMID: 18269747
11.  Sex differences in anterior cingulate cortex activation during impulse inhibition and behavioral correlates 
Psychiatry Research  2012;201(1):54-62.
Poor impulse inhibition is associated with behavioral problems including aggression and violence as well as clinical diagnoses such as attention deficit hyperactivity disorder (ADHD) and substance abuse, all of which are more prevalent in men than women. Studies have found that fronto-parietal and fronto-striatal-thalamic networks are critical for successful impulse inhibition. However, few studies have investigated neural differences in these networks between men and women. In this study, we use a well established behavioral task, the parametric Go/noGo task, to explore the relationships between brain regional activity during impulse control and impulsivity trait measures, as well as sex differences in these relationships. We found that males showed heightened activation of the rostral anterior cingulate, which correlated with ratings related to impulsivity. We also found that the activation/deactivation in males and females correlates with personality ratings in a sex-specific manner.
doi:10.1016/j.pscychresns.2011.05.008
PMCID: PMC3289751  PMID: 22285718
impulsivity; fMRI; impulsivity trait measure; Go/noGo task
12.  Individual Differences in Impulsivity Predict Anticipatory Eye Movements 
PLoS ONE  2011;6(10):e26699.
Impulsivity is the tendency to act without forethought. It is a personality trait commonly used in the diagnosis of many psychiatric diseases. In clinical practice, impulsivity is estimated using written questionnaires. However, answers to questions might be subject to personal biases and misinterpretations. In order to alleviate this problem, eye movements could be used to study differences in decision processes related to impulsivity. Therefore, we investigated correlations between impulsivity scores obtained with a questionnaire in healthy subjects and characteristics of their anticipatory eye movements in a simple smooth pursuit task. Healthy subjects were asked to answer the UPPS questionnaire (Urgency Premeditation Perseverance and Sensation seeking Impulsive Behavior scale), which distinguishes four independent dimensions of impulsivity: Urgency, lack of Premeditation, lack of Perseverance, and Sensation seeking. The same subjects took part in an oculomotor task that consisted of pursuing a target that moved in a predictable direction. This task reliably evoked anticipatory saccades and smooth eye movements. We found that eye movement characteristics such as latency and velocity were significantly correlated with UPPS scores. The specific correlations between distinct UPPS factors and oculomotor anticipation parameters support the validity of the UPPS construct and corroborate neurobiological explanations for impulsivity. We suggest that the oculomotor approach of impulsivity put forth in the present study could help bridge the gap between psychiatry and physiology.
doi:10.1371/journal.pone.0026699
PMCID: PMC3202566  PMID: 22046334
13.  Manipulation of Nicotinic Acetylcholine Receptors Differentially Affects Behavioral Inhibition in Human Subjects with and without Disordered Baseline Impulsivity 
Psychopharmacology  2011;220(2):331-340.
Rationale
Evidence for a relationship between cigarette smoking and Attention-Deficit/Hyperactivity Disorder (ADHD) has prompted investigations into nicotinic treatments for this disorder. Impulsivity is a hallmark of ADHD and is measured in the laboratory as behavioral inhibition (BI) using the Stop Signal Task (SST). Acute nicotine improves SST performance in adolescents and young adults with ADHD and impaired baseline SST performance, raising questions about the role of nicotinic acetylcholine receptor function in BI. The specificity of this effect to those with ADHD, the component processes of the SST affected by nicotine, and the effects of nicotinic antagonism are yet unknown.
Objectives
This study investigated the effects of both a nicotinic receptor agonist and antagonist on the SST and choice reaction time task (CRT) in highly impulsive (HI) and control (CTRL) subjects.
Methods
This was a within-subjects, double blind study of: 7 mg transdermal nicotine, 20 mg oral mecamylamine and placebo. Subjects were recruited into HI (n=11) and CTRL (n=14) groups based on both SST and clinical criteria.
Results
BI was significantly improved by nicotine compared to placebo in the HI group and impaired by mecamylamine in the CTRL group. Reaction time on the SST was improved by nicotine compared to placebo in the CTRL group and was unchanged in both groups on the CRT.
Conclusions
These findings demonstrate nicotinic modulation of BI in subjects with both normal and disordered baseline performance. The effects on BI are consistent with cholinergic enhancement of signal detection processes and/or modulation of noradrenaline by nicotine.
doi:10.1007/s00213-011-2476-0
PMCID: PMC3288699  PMID: 21969123
Cholinergic; nicotine; mecamylamine; ADHD; stop signal task; impulsivity; behavioral inhibition; reaction time; acetylcholine
14.  Impulsivity and alcohol consumption in young social drinkers 
Addictive behaviors  2011;37(2):217-220.
Impulsivity may have different facets that contribute to drinking patterns in young people. This research examined how aspects of impulse control, especially the ability to inhibit a response, predicted recent alcohol use patterns in young social drinkers. Participants (N = 109) between the ages of 18 and 21 performed a cued go/no-go task that required quick responses to go targets and the inhibition of responses to no-go targets. Participants also completed several questionnaires that assessed drinking habits (TLFB) and self-reported impulsivity (BIS-11). Regression analyses revealed that both the impulsivity questionnaire scores and the inhibitory failures observed on the behavioral task predicted various aspects of recent drinking. However, only the inhibitory failures from the behavioral task, and not the impulsivity questionnaire scores, predicted the highest number of drinks consumed on one occasion during the past month. These findings are consistent with the notion that impulsivity may have different components that may be contributing the drinking patterns, and this research suggests that the inability to withhold a response is a strong predictor of the binge use of alcohol.
doi:10.1016/j.addbeh.2011.09.013
PMCID: PMC3230724  PMID: 21981824
alcohol; binge drinking; impulsivity; behavioral control; reaction time
15.  Is there an inhibitory-response-control system in the rat? Evidence from anatomical and pharmacological studies of behavioral inhibition 
Many common psychiatric conditions, such as attention deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), Parkinson's disease, addiction and pathological gambling are linked by a failure in the mechanisms that control, or inhibit, inappropriate behavior. Models of rat behavioral inhibition permit us to study in detail the anatomical and pharmacological bases of inhibitory failure, using methods that translate directly with patient assessment in the clinic. This review updates current ideas relating to behavioral inhibition based on two significant lines of evidence from rat studies:
(1) To integrate new findings from the stop-signal task into existing models of behavioral inhibition, in particular relating to ‘impulsive action’ control. The stop-signal task has been used for a number of years to evaluate psychiatric conditions and has recently been translated for use in the rat, bringing a wealth of new information to behavioral inhibition research.
(2) To consider the importance of the subthalamic nucleus (STN) in the neural circuitry of behavioral inhibition. This function of this nucleus is central to a number of ‘disinhibitory’ disorders such as Parkinson's disease and OCD, and their therapies, but its role in behavioral inhibition is still undervalued, and often not considered in preclinical models of behavioral control.
Integration of these findings has pinpointed the orbitofrontal cortex (OF), dorsomedial striatum (DMStr) and STN within a network that normally inhibits many forms of behavior, including both impulsive and compulsive forms. However, there are distinct differences between behavioral subtypes in their neurochemical modulation.
This review brings new light to the classical view of the mechanisms that inhibit behavior, in particular suggesting a far more prominent role for the STN, a structure that is usually omitted from conventional behavioral-inhibition networks. The OF–DMStr–STN circuitry may form the basis of a control network that defines behavioral inhibition and that acts to suppress or countermand many forms of inappropriate or maladaptive behavior.
doi:10.1016/j.neubiorev.2009.07.003
PMCID: PMC2789250  PMID: 19615404
Dopamine; Serotonin; Noradrenaline; Atomoxetine; Orbitofrontal; Subthalamic nucleus; Dorsomedial striatum; Nucleus accumbens; SSRT; Premature response; Perseverative response
16.  Divergence by ADHD Subtype in Smoking Cessation Response to OROS-Methylphenidate 
Nicotine & Tobacco Research  2011;13(10):1003-1008.
Introduction:
Attention deficit hyperactivity disorder (ADHD) is a neuropsychiatric condition subclassified in DSM-IV according to its core symptoms domains as (a) predominantly inattentive (ADHD-IN), (b) predominantly hyperactive/impulsive (ADHD-H), and (c) combined inattentive and hyperactive/impulsive (ADHD-C). Whether these subtypes represent distinct clinical entities or points on a severity continuum is controversial. Divergence in treatment response is a potential indicator of qualitative heterogeneity. This study examined smoking cessation response by ADHD subtype to osmotic-release oral system methylphenidate (OROS-MPH).
Methods:
Male and female adult smokers (ADHD-C = 167 and ADHD-IN = 87) were randomized to receive OROS-MPH or placebo as augmentation treatment to nicotine patch and counseling. Logistic regression was conducted to test the effect of OROS-MPH versus placebo on prolonged smoking abstinence by ADHD subtype.
Results:
The subtypes were similar in baseline demographic, smoking, and psychiatric history but differed in smoking cessation response to OROS-MPH or placebo as a function of nicotine dependence level. The 3-way interaction was significant; χ2(1) = 8.22, p < .01. Among highly dependent smokers, the prolonged abstinence rates were greater with OROS-MPH than with placebo in the ADHD-C group (60% vs. 31.3%, respectively, p < .05) but higher with placebo than with OROS-MPH in the ADHD-IN group (60% vs. 11.8%, respectively, p < .01). Abstinence rates did not differ by subtype or treatment among smokers who were less nicotine dependent.
Conclusion:
Contrasting treatment response and divergence in the impact of nicotine dependence level support the hypothesis of ADHD subtypes as distinct clinical entities and may indicate the need and directions for personalized targeted treatments of smokers with ADHD.
doi:10.1093/ntr/ntr087
PMCID: PMC3179666  PMID: 21652734
17.  Self-Regulation in ADHD: The Role of Error Processing 
Clinical psychology review  2010;30(8):951-961.
Attention-deficit hyperactivity disorder (ADHD) is characterized by persistent and impairing developmentally inappropriate levels of inattention, hyperactivity, and impulsivity. Such behavioral dysregulation may be a consequence of deficits in self-monitoring or adaptive control, both of which are required for adaptive behavior. Processing of contextual demands, ongoing monitoring of one’s behavior to evaluate whether it is appropriate for a particular situation, and adjusting behavior when it is suboptimal are components of self-regulation. This review examines and integrates the emerging literature on error-processing and adaptive control as components of self-regulation into the prominent etiological theories of ADHD. Available data on error-processing, as reflected in event-related potentials (ERN and Pe) and behavioral performance, suggest that both early error detection and later error-evaluation may be diminished in ADHD, thereby interfering with adaptive control processes. However, variability in results limit broad conclusions, particularly for early error detection. A range of methodological issues, including ERP parameters and sample and task characteristics, likely contribute to this variability, and recommendations for future work are presented. The emerging literature on error-processing and adaptive control informs etiological theories of ADHD in general and may provide a method for testing self-regulation models in particular.
doi:10.1016/j.cpr.2010.06.010
PMCID: PMC2952677  PMID: 20659781
ADHD; self-regulation; error-processing; error-related brain activity; ERN; Pe
18.  The influence of serotonin- and other genes on impulsive behavioral aggression and cognitive impulsivity in children with attention-deficit/hyperactivity disorder (ADHD): Findings from a family-based association test (FBAT) analysis 
Background
Low serotonergic (5-HT) activity correlates with increased impulsive-aggressive behavior, while the opposite association may apply to cognitive impulsiveness. Both types of impulsivity are associated with attention-deficit/hyperactivity disorder (ADHD), and genes of functional significance for the 5-HT system are implicated in this disorder. Here we demonstrate the separation of aggressive and cognitive components of impulsivity from symptom ratings and test their association with 5-HT and functionally related genes using a family-based association test (FBAT-PC).
Methods
Our sample consisted of 1180 offspring from 607 families from the International Multicenter ADHD Genetics (IMAGE) study. Impulsive symptoms were assessed using the long forms of the Conners and the Strengths and Difficulties parent and teacher questionnaires. Factor analysis showed that the symptoms aggregated into parent- and teacher-rated behavioral and cognitive impulsivity. We then selected 582 single nucleotide polymorphisms (SNPs) from 14 genes directly or indirectly related to 5-HT function. Associations between these SNPs and the behavioral/cognitive groupings of impulsive symptoms were evaluated using the FBAT-PC approach.
Results
In the FBAT-PC analysis for cognitive impulsivity 2 SNPs from the gene encoding phenylethanolamine N-methyltransferase (PNMT, the rate-limiting enzyme for adrenalin synthesis) attained corrected gene-wide significance. Nominal significance was shown for 12 SNPs from BDNF, DRD1, HTR1E, HTR2A, HTR3B, DAT1/SLC6A3, and TPH2 genes replicating reported associations with ADHD. For overt aggressive impulsivity nominal significance was shown for 6 SNPs from BDNF, DRD4, HTR1E, PNMT, and TPH2 genes that have also been reported to be associated with ADHD. Associations for cognitive impulsivity with a SERT/SLC6A4 variant (STin2: 12 repeats) and aggressive behavioral impulsivity with a DRD4 variant (exon 3: 3 repeats) are also described.
Discussion
A genetic influence on monoaminergic involvement in impulsivity shown by children with ADHD was found. There were trends for separate and overlapping influences on impulsive-aggressive behavior and cognitive impulsivity, where an association with PNMT (and arousal mechanisms affected by its activity) was more clearly involved in the latter. Serotonergic and dopaminergic mechanisms were implicated in both forms of impulsivity with a wider range of serotonergic mechanisms (each with a small effect) potentially influencing cognitive impulsivity. These preliminary results should be followed up with an examination of environmental influences and associations with performance on tests of impulsivity in the laboratory.
doi:10.1186/1744-9081-4-48
PMCID: PMC2577091  PMID: 18937842
19.  Impulsiveness as a timing disturbance: neurocognitive abnormalities in attention-deficit hyperactivity disorder during temporal processes and normalization with methylphenidate 
We argue that impulsiveness is characterized by compromised timing functions such as premature motor timing, decreased tolerance to delays, poor temporal foresight and steeper temporal discounting. A model illustration for the association between impulsiveness and timing deficits is the impulsiveness disorder of attention-deficit hyperactivity disorder (ADHD). Children with ADHD have deficits in timing processes of several temporal domains and the neural substrates of these compromised timing functions are strikingly similar to the neuropathology of ADHD. We review our published and present novel functional magnetic resonance imaging data to demonstrate that ADHD children show dysfunctions in key timing regions of prefrontal, cingulate, striatal and cerebellar location during temporal processes of several time domains including time discrimination of milliseconds, motor timing to seconds and temporal discounting of longer time intervals. Given that impulsiveness, timing abnormalities and more specifically ADHD have been related to dopamine dysregulation, we tested for and demonstrated a normalization effect of all brain dysfunctions in ADHD children during time discrimination with the dopamine agonist and treatment of choice, methylphenidate. This review together with the new empirical findings demonstrates that neurocognitive dysfunctions in temporal processes are crucial to the impulsiveness disorder of ADHD and provides first evidence for normalization with a dopamine reuptake inhibitor.
doi:10.1098/rstb.2009.0014
PMCID: PMC2685816  PMID: 19487194
impulsiveness; timing; time perception; temporal discounting; attention-deficit hyperactivity disorder; methylphenidate
20.  Behavioral Components of Impulsivity Predict Alcohol Consumption in Adults with ADHD and Healthy Controls 
Drug and alcohol dependence  2010;113(2-3):139-146.
Background
The degree to which distinct behavioral components of impulsivity predict alcohol consumption is as yet not well-understood. Further, the possibility that this relation might be more pronounced in groups characterized by heightened impulsivity (i.e., individuals with ADHD) has not been tested.
Methods
The current study examined the degree to which three specific behavioral components of impulsivity (i.e., poor response inhibition, poor attentional inhibition, and increased risk-taking) were associated with quantity and frequency of alcohol consumption in a group of young adult social drinkers with ADHD (n = 33) and in a comparison control group (n = 21). Participants performed the delayed ocular return task (attentional inhibition), the cued go/no-go task (behavioral inhibition), and the Balloon Analogue Risk Task (risk-taking).
Results
Both poor behavioral inhibition and greater risk-taking were related to greater quantity of consumption in the entire sample, whereas poor attentional inhibition was related to greater quantity specifically among those with ADHD. By contrast, only risk-taking was associated with frequency of consumption, and this was found specifically in the control group.
Conclusions
These findings provide important information regarding the potential role of distinct behavioral components of impulsivity in drinking behavior, and highlight unique relevance of attentional impairments to drinking behavior in those with ADHD.
doi:10.1016/j.drugalcdep.2010.07.027
PMCID: PMC3010339  PMID: 20863628
behavioral impulsivity; alcohol consumption; ADHD
21.  Electrophysiological evidence for abnormal preparatory states and inhibitory processing in adult ADHD 
Background
Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder that starts in childhood and frequently persists in adults. Several theories postulate deficits in ADHD that have effects across many executive functions or in more narrowly defined aspects, such as response inhibition. Electrophysiological studies on children, however, indicate that ADHD is not associated with a core deficit of response inhibition, as abnormal inhibitory processing is typically preceded or accompanied by other processing deficits. It is not yet known if this pattern of abnormal processing is evident in adult ADHD.
Methods
The objective of this paper was to investigate event-related potential indices of preparatory states and subsequent response inhibition processing in adults with ADHD. Two cued continuous performance tasks were presented to 21 adults meeting current criteria for adult ADHD and combined type ADHD in childhood, and 20 controls.
Results
The ADHD group exhibited significantly weaker orienting attention to cues, cognitive preparation processes and inhibitory processing. In addition, we observed a strong correlation between the resources allocated to orienting to cues and the strength of the subsequent response strength control processes, suggesting that orienting deficits partly predict and determine response control deficits in ADHD.
Conclusions
These findings closely resemble those previously found in children with ADHD, which indicate that there is not a core response inhibition deficit in ADHD. These findings therefore suggest the possibility of developmental stability into adulthood of the underlying abnormal processes in ADHD.
doi:10.1186/1744-9081-6-66
PMCID: PMC2988695  PMID: 21029446
22.  Motorsports Involvement among Adolescents and Young Adults with Childhood ADHD 
Objective
Though children with attention-deficit/hyperactivity disorder (ADHD) are at risk for impulsive, health-endangering behavior, few studies have examined non-substance use-related risk-taking behaviors. This study examined whether adolescents and young adults with ADHD histories were more likely than those without ADHD histories to report frequent engagement in motorsports, a collection of risky driving-related activities associated with elevated rates of physical injury. Path analyses tested whether persistent impulsivity, comorbid conduct disorder or antisocial personality disorder (CD/ASP), and heavy alcohol use mediated this association. Analyses also explored whether frequent motorsporting was associated with unsafe and alcohol-influenced driving.
Method
Two-hundred and twenty-one adolescent and young adult males (16–25 years-old) diagnosed with ADHD in childhood and 139 demographically-similar males without ADHD histories reported their motorsports involvement. Persistent impulsivity, CD/ASP, heavy drinking, and hazardous driving were also measured in adolescence/young adulthood1
Results
Adolescents and young adults with ADHD histories were more likely to report frequent motorsports involvement than those without childhood ADHD. Impulsivity, CD/ASP and heavy drinking partially mediated this association, such that individuals with ADHD histories, who had persistent impulsivity or CD/ASP diagnoses, were more likely to engage in heavy drinking, which was positively associated with frequent motorsporting. Motorsports involvement was associated with more unsafe and alcohol-influenced driving, and this association was more often found among those with, than without, ADHD histories.
Conclusions
Adolescents and young adults with ADHD histories, especially those with persisting impulsivity, comorbid CD/ASP and heavy drinking tendencies, are more likely to engage in motorsports, which may heighten risk of injury.
doi:10.1080/15374416.2012.759227
PMCID: PMC3587661  PMID: 23347139
23.  Response Inhibition Impairment in High Functioning Autism and Attention Deficit Hyperactivity Disorder: Evidence from Near-Infrared Spectroscopy Data 
PLoS ONE  2012;7(10):e46569.
Background
Response inhibition, an important domain of executive function (EF), involves the ability to suppress irrelevant or interfering information and impulses. Previous studies have shown impairment of response inhibition in high functioning autism (HFA) and attention deficit hyperactivity disorder (ADHD), but more recent findings have been inconsistent. To date, almost no studies have been conducted using functional imaging techniques to directly compare inhibitory control between children with HFA and those with ADHD.
Method
Nineteen children with HFA, 16 age- and intelligence quotient (IQ)-matched children with ADHD, and 16 typically developing (TD) children were imaged using functional near-infrared spectroscopy (NIRS) while performing Go/No-go and Stroop tasks.
Results
Compared with the TD group, children in both the HFA and ADHD groups took more time to respond during the No-go blocks, with reaction time longest for HFA and shortest for TD. Children in the HFA and ADHD groups also made a greater number of reaction errors in the No-go blocks than those in the TD group. During the Stroop task, there were no significant differences between these three groups in reaction time and omission errors. Both the HFA and ADHD groups showed a higher level of inactivation in the right prefrontal cortex (PFC) during the No-go blocks, relative to the TD group. However, no significant differences were found between groups in the levels of oxyhemoglobin concentration in the PFC during the Stroop task.
Conclusion
Functional brain imaging using NIRS showed reduced activation in the right PFC in children with HFA or ADHD during an inhibition task, indicating that inhibitory dysfunction is a shared feature of both HFA and ADHD.
doi:10.1371/journal.pone.0046569
PMCID: PMC3467210  PMID: 23056348
24.  Non-pharmacological approaches for treating children with ADHD inattentive type 
The behavioral difficulties of children with attention-deficit/hyperactivity disorder (ADHD) inattentive type differ from those of children with ADHD combined or hyperactive/impulsive type. Existing evidence-based interventions primarily target the disruptive and impulsive behaviors exhibited by children with ADHD combined and hyperactive/impulsive type. A number of recent advances have been made in the non-pharmacological treatment of behavioral difficulties associated with ADHD inattentive type. Additional research using randomized controlled research designs and long-term follow-up evaluation is necessary before these interventions may be considered established evidence-based interventions for patients with ADHD inattentive type.
doi:10.3410/M1-16
PMCID: PMC2920695  PMID: 20948766
25.  Insight Into the Relationship Between Impulsivity and Substance Abuse From Studies Using Animal Models 
Drug use disorders are often accompanied by deficits in the capacity to efficiently process reward-related information and to monitor, suppress, or override reward-controlled behavior when goals are in conflict with aversive or immediate outcomes. This emerging deficit in behavioral flexibility and impulse control may be a central component of the progression to addiction, as behavior becomes increasingly driven by drugs and drug-associated cues at the expense of more advantageous activities. Understanding how neural mechanisms implicated in impulse control are affected by addictive drugs may therefore prove a useful strategy in the search for new treatment options. Animal models of impulsivity and addiction could make a significant contribution to this endeavor. Here, some of the more common behavioral paradigms used to measure different aspects of impulsivity across species are outlined, and the importance of the response to reward-paired cues in such paradigms is discussed. Naturally occurring differences in forms of impulsivity have been found to be predictive of future drug self-administration, but drug exposure can also increase impulsive responding. Such data are in keeping with the suggestion that impulsivity may contribute to multiple stages within the spiral of addiction. From a neurobiological perspective, converging evidence from rat, monkey, and human studies suggest that compromised functioning within the orbitofrontal cortex may critically contribute to the cognitive sequelae of drug abuse. Changes in gene transcription and protein expression within this region may provide insight into the mechanism underlying drug-induced cortical hypofunction, reflecting new molecular targets for the treatment of uncontrolled drug-seeking and drug-taking behavior.
doi:10.1111/j.1530-0277.2010.01215.x
PMCID: PMC3380443  PMID: 20491734
Orbitofrontal Cortex; Cocaine; Delay Discounting; Five-Choice Serial Reaction Time Task; Rat; Monkey

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