Dopamine transporter genotype is associated with a lateralized resistance to distraction during attention selection.

Although lateral asymmetries in orienting behavior are evident across species and have been linked to interhemispheric asymmetries in dopamine signaling, the relative contribution of attentional versus motoric processes remains unclear. Here we took a cognitive genetic approach to adjudicate between roles for dopamine in attentional versus response selection. A sample of nonclinical adult humans (N = 518) performed three cognitive tasks (spatial attentional competition, spatial cueing, and flanker tasks) that varied in the degree to which they required participants to resolve attentional or response competition. All participants were genotyped for two putatively functional tandem repeat polymorphisms of the dopamine transporter gene (DAT1; SLC6A3), which are argued to influence the level of available synaptic dopamine and confer risk to disorders of inattention. DAT1 genotype modulated the task-specific effects of the various task-irrelevant stimuli across both the spatial competition and spatial cueing but not flanker tasks. Specifically, compared with individuals carrying one or two copies of the 10-repeat DAT1 allele, individuals without this allele demonstrated an immunity to distraction, such that response times were unaffected by increases in the number of distractor stimuli, particularly when these were presented predominantly in the left hemifield. All three genotype groups exhibited uniform costs of resolving leftward response selection in a standard flanker task. None of these significant effects could be explained by speed-accuracy trade-offs, suggesting that participants without the 10-repeat allele of the DAT1 tandem repeat polymorphism possess an enhanced attentional ability to suppress task-irrelevant stimuli in the left hemifield.

An association between a dopamine transporter gene (SLC6A3) haplotype and ADHD symptom measures in nonclinical adults.

Previous genetic studies have postulated that attention deficit hyperactivity disorder (ADHD) should be regarded as the extreme end of a set of behavioural traits that can be continuously measured in the general population. The current study adopted a quantitative trait approach to examine the relationship between dopamine gene variants and self-reported ADHD symptoms in 517 nonclinical adults. Although genetic associations with variants of both the dopamine transporter (DAT1; SLC6A3) and D4 receptor (DRD4) genes have been reliably reported in children, results in adults are less consistent. We probed two potentially functional variable number of tandem repeat (VNTR) polymorphisms in the 3'UTR and intron 8 of DAT1, the 10-repeat and 6-repeat alleles of which respectively form a haplotype (10/6 DAT1 haplotype) that is associated with childhood ADHD. We also genotyped the exon 3 VNTR of DRD4, the 7-repeat allele of which is also an established risk factor for childhood ADHD. Permutation analysis showed an influence of the 10/6 DAT1 haplotype on both CAARS-G and CAARS-H (DSM-IV ADHD Symptoms Total and ADHD Index respectively), such that ADHD symptom scores increased with each additional copy of the 10/6 DAT1 haplotype. This result survived corrections for multiple comparisons both at the level of genotype and phenotype. A nominal association with CAARS-G was also found for the 7-repeat allele of the DRD4 VNTR however this did not survive multiple comparison correction. Our results provide further support for the influence of variation in the 10/6 DAT1 haplotype and individual differences in ADHD symptoms in adults.

Norepinephrine genes predict response time variability and methylphenidate-induced changes in neuropsychological function in attention deficit hyperactivity disorder.

Noradrenergic dysfunction may be associated with cognitive impairments in attention-deficit/hyperactivity disorder (ADHD), including increased response time variability, which has been proposed as a leading endophenotype for ADHD. The aim of this study was to examine the relationship between polymorphisms in the α-2A-adrenergic receptor (ADRA2A) and norepinephrine transporter (SLC6A2) genes and attentional performance in ADHD children before and after pharmacological treatment.One hundred one medication-naive ADHD children were included. All subjects were administered methylphenidate (MPH)-OROS for 12 weeks. The subjects underwent a computerized comprehensive attention test to measure the response time variability at baseline before MPH treatment and after 12 weeks. Additive regression analyses controlling for ADHD symptom severity, age, sex, IQ, and final dose of MPH examined the association between response time variability on the comprehensive attention test measures and allelic variations in single-nucleotide polymorphisms of the ADRA2A and SLC6A2 before and after MPH treatment.Increasing possession of an A allele at the G1287A polymorphism of SLC6A2 was significantly related to heightened response time variability at baseline in the sustained (P = 2.0 × 10) and auditory selective attention (P = 1.0 × 10) tasks. Response time variability at baseline increased additively with possession of the T allele at the DraI polymorphism of the ADRA2A gene in the auditory selective attention task (P = 2.0 × 10). After medication, increasing possession of a G allele at the MspI polymorphism of the ADRA2A gene was associated with increased MPH-related change in response time variability in the flanker task (P = 1.0 × 10).Our study suggested an association between norepinephrine gene variants and response time variability measured at baseline and after MPH treatment in children with ADHD. Our results add to a growing body of evidence, suggesting that response time variability is a viable endophenotype for ADHD and suggesting its utility as a surrogate end point for measuring stimulant response in pharmacogenetic studies.

The COMT Val158 allele is associated with impaired delayed-match-to-sample performance in ADHD.

BACKGROUND: This study explored the association between three measures of working memory ability and genetic variation in a range of catecholamine genes in a sample of children with ADHD. METHODS: One hundred and eighteen children with ADHD performed three working memory measures taken from the CANTAB battery (Spatial Span, Delayed-match-to-sample, and Spatial Working Memory). Associations between performance on working memory measures and allelic variation in catecholamine genes (including those for the noradrenaline transporter [NET1], the dopamine D4 and D2 receptor genes [DRD4; DRD2], the gene encoding dopamine beta hydroxylase [DBH] and catechol-O-methyl transferase [COMT]) were investigated using regression models that controlled for age, IQ, gender and medication status on the day of test. RESULTS: Significant associations were found between performance on the delayed-match-to-sample task and COMT genotype. More specifically, val/val homozygotes produced significantly more errors than did children who carried a least one met allele. There were no further associations between allelic variants and performance across the other working memory tasks. CONCLUSIONS: The working memory measures employed in the present study differed in the degree to which accurate task performance depended upon either the dynamic updating and/or manipulation of items in working memory, as in the spatial span and spatial working memory tasks, or upon the stable maintenance of representations, as in the delay-match-to-sample task. The results are interpreted as evidence of a relationship between tonic dopamine levels associated with the met COMT allele and the maintenance of stable working memory representations required to perform the delayed-match-to-sample-task.

Attentional asymmetries in a visual orienting task are related to temperament.

Spatial asymmetries are an intriguing feature of directed attention. Recent observations indicate an influence of temperament upon the direction of these asymmetries. It is unknown whether this influence generalises to visual orienting behaviour. The aim of the current study was therefore to explore the relationship between temperament and measures of spatial orienting as a function of target hemifield. An exogenous cueing task was administered to 92 healthy participants. Temperament was assessed using Carver and White's (1994) Behavioural Inhibition System and Behavioural Activation System (BIS/BAS) scales. Individuals with high sensitivity to punishment and low sensitivity to reward showed a leftward asymmetry of directed attention when there was no informative spatial cue provided. This asymmetry was not present when targets were preceded by spatial cues that were either valid or invalid. The findings support the notion that individual variations in temperament influence spatial asymmetries in visual orienting, but only when lateral targets are preceded by a non-directional (neutral) cue. The results are discussed in terms of hemispheric asymmetries and dopamine activity.

Val/Val genotype of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with a better response to OROS-MPH in Korean ADHD children.

Research on psychostimulants, analysis of animal models and genetic association studies all suggest that the brain-derived neurotrophic factor gene (BDNF) may be a good candidate for pharmacogenetic studies of attention deficit hyperactivity disorder (ADHD). Yet to date there have been no pharmacogenetic studies of BDNF in ADHD. A total of 102 drug-naive ADHD children (8.7±2.1 yr) were treated with osmotic release oral system-methylphenidate (OROS-MPH) for 12 wk, and four kinds of response criteria were applied, based first, on a combined threshold of the ADHD Rating Scale - IV (ARS) and the Clinical Global Impression - Improvement scale (CGI-I); second, on scores of 1 or 2 vs. 3-7 on the CGI - Severity scale; third, on a >50% reduction in ARS scores; and fourth, on satisfaction of all of the aforementioned criteria. The Val66Met polymorphism of BDNF and six single nucleotide polymorphisms from the SLC6A2, ADRA2A and NTF-3 genes were tested for association with each criterion. Relative to other genotypes, homozygosity for the Val allele of the BDNF Val66Met polymorphism was associated with a greater relative frequency of good response under all four response criteria (after controlling for baseline ARS score, age, gender, final dose (mg/kg) of OROS-MPH at 12 wk, and level of academic functioning). This association was significant at the uncorrected level for the first and third response criteria (p=0.013 and p=0.018, respectively) and significant at a Bonferroni-corrected level for the second and fourth response criteria (p=0.0002, p=0.0003, respectively). Our findings support an association between homozygosity for the Val allele of BDNF and better response to OROS-MPH in Korean ADHD children as assessed by four different response criteria.

Theta oscillations are affected by amnestic mild cognitive impairment and cognitive load.

Amnestic mild cognitive impairment (aMCI) is classified primarily via substantial episodic memory deficits in the absence of a dementia diagnosis. To investigate the potential neurophysiological correlates of such deficits we compared QEEG power between 12 participants with aMCI and 12 healthy matched controls. EEG was acquired during performance of a modified Sternberg word recognition task with low and high memory load conditions. While recognition accuracy of aMCI participants was lower than that of controls, this difference was not significant. Nevertheless the aMCI group demonstrated significantly lower theta power at a number of electrode sites and significant correlations were observed between power at these sites and neuropsychological assessment scores. Furthermore in the aMCI sample only, theta power was significantly lower under high versus low memory load. Given current interpretations of the neural generator(s), as well as the role(s), of theta oscillations in cognitive processes, the present data indicate that aMCI may be associated with disruptions in the operation of neurocognitive networks (e.g., MTL-neocortical), particularly under high cognitive load.

Allelic variation in dopamine D2 receptor gene is associated with attentional impulsiveness on the Barratt Impulsiveness Scale (BIS-11).

OBJECTIVES: Previous studies have postulated that noradrenergic and/or dopaminergic gene variations are likely to underlie individual differences in impulsiveness, however, few have shown this. The current study examined the relationship between catecholamine gene variants and self-reported impulsivity, as measured by the Barratt Impulsiveness Scale (Version 11; BIS-11) Methods: Six hundred and seventy-seven non-clinical adults completed the Barratt Impulsiveness Scale (BIS-11). DNA was analysed for a set of 142 single-nucleotide polymorphisms (SNPs) across 20 autosomal catecholamine genes. Association was tested using an additive regression model with permutation testing used to control for the influence of multiple comparison. RESULTS: Analysis revealed an influence of rs4245146 of the dopamine D2 receptor (DRD2) gene on the BIS-11 attention first-order factor, such that self-reported attentional impulsiveness increased in an additive fashion with each copy of the T allele. CONCLUSIONS: These findings provide preliminary evidence that allelic variation in DRD2 may influence impulsiveness by increasing the propensity for attentional lapses.

Theta power is reduced in healthy cognitive aging.

The effects of healthy cognitive aging on electroencephalographic (EEG) theta (4.9-6.8 Hz) power were examined during performance of a modified Sternberg, S., 1966. High-speed scanning in human memory. Science 153, 652-654.) word recognition task. In a sample of fourteen young (mean age 21.9 years, range=18-27) and fourteen older (mean age 68.4 years, range=60-80) participants, theta power was found to be significantly lower in older adults during both the retention and recognition intervals. This theta power difference was greatest at the fronto-central midline electrode and occurred in parallel with a small, non-significant decrease in recognition accuracy in the older sample. A significant decrease in older adults' mean theta power was also observed in resting EEG, however, it was of substantially smaller magnitude than the task-related theta difference. It is proposed that a neurophysiological measure(s), such as task-specific frontal midline theta (fmtheta) power, may be a more sensitive marker of cognitive aging than task performance measures. Furthermore, as recent research indicates that fmtheta is generated primarily in the anterior cingulate cortex, the current findings support evidence that the function of brain networks incorporating this structure may be affected in cognitive aging.

Cortical inhibitory deficits in premanifest and early Huntington's disease.

Although progress has been made towards understanding the gross cortical and subcortical pathology of Huntington's disease (HD), there remains little understanding of the progressive pathophysiological changes that occur in the brain circuits underlying the disease. Transcranial magnetic stimulation (TMS) enables investigation of the functional integrity of cortico-subcortical pathways, yet it has not been widely applied in HD research to date. This study sought to characterise profiles of cortical excitability, including inhibition and facilitation, in groups of premanifest and symptomatic HD participants via the use of TMS. We also investigated the clinical, neurocognitive and psychiatric correlates of cortical excitability to better understand the development of phenotypic heterogeneity. The sample comprised 16 premanifest HD, 12 early symptomatic HD and 17 healthy control participants. Single- and paired-pulse TMS protocols were administered to the left primary motor cortex, with surface electromyography recorded from the abductor pollicis brevis muscle. Short-interval cortical inhibition was significantly reduced in symptomatic HD, compared with premanifest HD and controls, and was significantly correlated with pathological burden and neurocognitive performance. There was also reduced long-interval cortical inhibition in both premanifest and symptomatic HD, compared with controls, which was associated with pathological burden and psychiatric disturbances. Motor thresholds, cortical silent periods and intracortical facilitation did not differ across groups. Our results provide important new insights into pathophysiological changes in cortico-subcortical circuits across disease stages in HD. We propose that neurophysiological measures obtained via TMS have potential utility as endophenotypic biomarkers in HD, given their association with both pathological burden and clinical phenotype.

A GABBR2 gene variant modifies pathophysiology in Huntington's disease.

Striatal degeneration in Huntington's disease (HD) causes changes in cortico-subcortical pathways. Transcranial magnetic stimulation (TMS) is a valuable tool for assessing pathophysiology within these pathways, yet has had limited application in HD. As cortico-subcortical pathways are largely mediated by GABA and dopamine receptor genes, understanding how these genes modulate neurophysiology in HD may provide new insights into how underlying pathology maps onto clinical phenotype. Twenty-nine participants with HD underwent motor cortex stimulation, while corticospinal excitability, cortical inhibition and intracortical facilitation were indexed via peripheral electromyography. Single-nucleotide polymorphism mapping was performed across six genes that are known to modulate cortico-subcortical pathways (GABRA2, GABBR1, GABBR2, DRD1, DRD2, DRD4). Genetic associations with six TMS measures and age at onset were investigated. Our hierarchical multiple regression analysis, controlling for CAG and age, revealed that a GABBR2 variant, predicted to be disease-causative, was significantly associated with corticospinal excitability at corrected levels. A subsequent uncorrected exploratory analysis revealed associations between GABBR2, GABRA2 and DRD2 variants with TMS measures of corticospinal excitability and cortical inhibition in HD, as well as with age at onset. Our findings support the notion that uncovering genetic associations with pathophysiological measures and age at onset is an important way forward in terms of generating meaningful biomarkers with diagnostic and prognostic sensitivity, and identifying novel human-validated targets for future clinical trials.

Cortical inhibitory deficits in Huntington's disease are not influenced by gender.

Huntington's disease (HD) affects GABA-mediated inhibitory circuitry in the cortex. As there is evidence that sex hormones affect GABAergic function, we investigated whether gender modulates GABA-related pathophysiological changes in HD. Fifteen premanifest HD, 11 symptomatic HD and 16 healthy control participants were assessed with paired-pulse transcranial magnetic stimulation applied to the primary motor cortex. Cortical inhibition was significantly reduced in symptomatic HD, compared with premanifest HD and controls. There was reduced inhibition in females overall, but no Group-by-Sex interaction. These findings suggest that sex hormones do not exert a direct influence on the mechanisms underpinning cortical inhibitory deficits in HD.

A Population Based Study of the Genetic Association between Catecholamine Gene Variants and Spontaneous Low-Frequency Fluctuations in Reaction Time.

The catecholamines dopamine and noradrenaline have been implicated in spontaneous low-frequency fluctuations in reaction time, which are associated with attention deficit hyperactivity disorder (ADHD) and subclinical attentional problems. The molecular genetic substrates of these behavioral phenotypes, which reflect frequency ranges of intrinsic neuronal oscillations (Slow-4: 0.027-0.073 Hz; Slow-5: 0.010-0.027 Hz), have not yet been investigated. In this study, we performed regression analyses with an additive model to examine associations between low-frequency fluctuations in reaction time during a sustained attention task and genetic markers across 23 autosomal catecholamine genes in a large young adult population cohort (n = 964), which yielded greater than 80% power to detect a small effect size (f(2) = 0.02) and 100% power to detect a small/medium effect size (f(2) = 0.15). At significance levels corrected for multiple comparisons, none of the gene variants were associated with the magnitude of low-frequency fluctuations. Given the study's strong statistical power and dense coverage of the catecholamine genes, this either indicates that associations between low-frequency fluctuation measures and catecholamine gene variants are absent or that they are of very small effect size. Nominally significant associations were observed between variations in the alpha-2A adrenergic receptor gene (ADRA2A) and the Slow-5 band. This is in line with previous reports of an association between ADRA2A gene variants and general reaction time variability during response selection tasks, but the specific association of these gene variants and low-frequency fluctuations requires further confirmation. Pharmacological challenge studies could in the future provide convergent evidence for the noradrenergic modulation of both general and time sensitive measures of intra-individual variability in reaction time.

Identification and functional characterisation of a novel dopamine beta hydroxylase gene variant associated with attention deficit hyperactivity disorder.

OBJECTIVES: Dysregulation in neurotransmitter signalling has been implicated in the aetiology of attention deficit hyperactivity disorder (ADHD). Polymorphisms of the gene encoding dopamine beta hydroxylase (DBH) have been reported to be associated with ADHD; however, small sample sizes have led to inconsistency. METHODS: We conducted transmission disequilibrium test analysis in 794 nuclear families to examine the relationship between DBH and ADHD. The effects of the ADHD-associated polymorphisms on gene expression were assessed by luciferase reporter assays in a human neuroblastoma cell line, SH-SY5Y. RESULTS: A SNP within the 3' untranslated region of DBH rs129882 showed a significant association with ADHD (χ(2) = 9.71, p = 0.0018, OR = 1.37). This association remained significant after Bonferroni correction for multiple testing (p = 0.02). Further, allelic variation in rs129882 significantly impacted luciferase expression. Specifically, the C allele of the ADHD-associated rs129882 SNP produced a 2-fold decrease (p < 0.001) in luciferase activity. CONCLUSIONS: These data demonstrate for the first time that a DBH gene variant, rs129882, which confers risk to ADHD is also associated with reduced in vitro gene expression. Reduced DBH expression would be consistent with decreased conversion of dopamine to noradrenaline and thus with a relative hypo-noradrenergic state in ADHD.

Evidence accumulation in decision making: unifying the "take the best" and the "rational" models.

An evidence accumulation model of forced-choice decision making is proposed to unify the fast and frugal take the best (TTB) model and the alternative rational (RAT) model with which it is usually contrasted. The basic idea is to treat the TTB model as a sequential-sampling process that terminates as soon as any evidence in favor of a decision is found and the rational approach as a sequential-sampling process that terminates only when all available information has been assessed. The unified TTB and RAT models were tested in an experiment in which participants learned to make correct judgments for a set of real-world stimuli on the basis of feedback, and were then asked to make additional judgments without feedback for cases in which the TTB and the rational models made different predictions. The results show that, in both experiments, there was strong intraparticipant consistency in the use of either the TTB or the rational model but large interparticipant differences in which model was used. The unified model is shown to be able to capture the differences in decision making across participants in an interpretable way and is preferred by the minimum description length model selection criterion.

Transcranial magnetic stimulation as a tool for understanding neurophysiology in Huntington's disease: a review.

Structural and functional magnetic resonance imaging modalities have been critical in advancing our understanding of the neuroanatomical and pathophysiological changes that emerge during the premanifest and symptomatic stages of Huntington's disease (HD). However, the relationship between underlying neuropathology and the motor, cognitive and behavioural changes associated with the disorder still remain poorly understood. Less conventional technologies, such as transcranial magnetic stimulation (TMS) and electroencephalography (EEG), provide a unique opportunity to further investigate the causal relationships between targeted neural circuits and objective neurophysiological responses together with overt behaviours. In this review, we discuss previous successful applications of TMS in other neurological disorders and its prospective use in HD. We also address the added value of multimodal TMS techniques, such as TMS-EEG, in investigating the integrity of neural networks in non-motor regions in HD. We conclude that neurophysiological outcome measures are likely to contribute towards characterising further the trajectory of decline across functional domains in HD, enhance understanding of underlying neural mechanisms, and offer new avenues for elucidating sensitive endophenotypic biomarkers of disease progression.

Norepinephrine transporter -3081(A/T) and alpha-2A-adrenergic receptor MspI polymorphisms are associated with cardiovascular side effects of OROS-methylphenidate treatment.

The purpose of this study was to investigate a possible association between norepinephrine genes and cardiovascular side effects of the Osmotic Controlled-Release Oral Delivery System-methylphenidate (OROS-MPH) in Korean children with attention-deficit/hyperactivity disorder (ADHD). One hundred and one children with ADHD (8.7 ± 1.7 years) were recruited from child psychiatric centers at six university hospitals in South Korea. All participants were drug-naive ADHD children treated with OROS-MPH for 12 weeks. During the treatment period the investigators titrated the OROS-MPH dosage on the basis of symptom severity and side effects. Resting heart rate (HR), diastolic blood pressure (DBP), and systolic blood pressure (SBP) were examined before and after treatment. The percentage change score (post-treatment - pretreatment/pretreatment × 100) of each parameter was calculated. Genotyping of SLC6A2 -3081(A/T) and G1287A, and alpha-2A-adrenergic receptor (ADRA2A) MspI and DraI polymorphisms was performed. Clinically significant changes were not found in cardiovascular monitoring during the course of treatment. An increase of HR after OROS-MPH treatment was found to be statistically significant (t = 3.54, p = 0.001). Changes in SBP and DBP were not significant and no specific change was found in the ECGs. However, an additive regression analysis demonstrated a significant association between SLC6A2 -3081(A/T) and percentage change in HR post-treatment (p = 0.01) after controlling for age, gender, dosage of MPH and response and baseline pulse rate. Children with ADHD having the T/T genotype of SLC6A2 showed a 12.5% increase in HR compared to baseline, whereas children with the A/T or A/A genotype showed a 3.5% and 2.5% increase after OROS-MPH treatment, respectively. There was also a significant association between the ADRA2A MspI genotype and percentage change of DBP post-treatment after controlling for age, gender, dosage of MPH and response and baseline DBP (p = 0.009). Children with ADHD having the C/C genotype of ADRA2A MspI showed an 18.5% increase in DBP compared to baseline, but children with the G/G or G/C genotype showed a 0.2% decrease after OROS-MPH treatment. The overall cardiovascular effects of OROS-MPH were modest. However, our findings show a positive association between norepinephrine-related gene polymorphisms and cardiovascular response induced by MPH in Korean children with ADHD. Consideration must be given to such children or adults with specific norepinephrine-related genotypes, especially if they show significant changes in HR or DBP after OROS-MPH administration.

Adolescent impulsivity phenotypes characterized by distinct brain networks.

The impulsive behavior that is often characteristic of adolescence may reflect underlying neurodevelopmental processes. Moreover, impulsivity is a multi-dimensional construct, and it is plausible that distinct brain networks contribute to its different cognitive, clinical and behavioral aspects. As these networks have not yet been described, we identified distinct cortical and subcortical networks underlying successful inhibitions and inhibition failures in a large sample (n = 1,896) of 14-year-old adolescents. Different networks were associated with drug use (n = 1,593) and attention-deficit hyperactivity disorder symptoms (n = 342). Hypofunctioning of a specific orbitofrontal cortical network was associated with likelihood of initiating drug use in early adolescence. Right inferior frontal activity was related to the speed of the inhibition process (n = 826) and use of illegal substances and associated with genetic variation in a norepinephrine transporter gene (n = 819). Our results indicate that both neural endophenotypes and genetic variation give rise to the various manifestations of impulsive behavior.

ERP measures indicate both attention and working memory encoding decrements in aging.

We investigated age-related attention and encoding deficits, and their possible interaction, by analyzing visual event-related potentials from young and older adults during a modified Sternberg word recognition task. Young adults performed more accurately, albeit not significantly so. P1 latency was shorter in young adults and correlated negatively with task accuracy (with age partialed out). These data support proposals that P1 indexes attentional suppression, which is less efficient in older adults. N1 was larger in older adults but did not correlate with accuracy. Young adults had higher P2 amplitudes and P2 latency correlated with accuracy (age partialed), supporting the view that semantic operations during encoding are affected by aging. These data indicate that attention (P1) and encoding (P2) decrements may contribute to memory or related cognitive decrements in aging, and P1 and P2 latency measures from appropriate paradigms may be salient ERP markers of these decrements.

Methylphenidate but not atomoxetine or citalopram modulates inhibitory control and response time variability.

BACKGROUND: Response inhibition is a prototypical executive function of considerable clinical relevance to psychiatry. Nevertheless, our understanding of its pharmacological modulation remains incomplete. METHODS: We used a randomized, double-blind, placebo-controlled, crossover design to examine the effect of an acute dose of methylphenidate (MPH) (30 mg), atomoxetine (ATM) (60 mg), citalopram (CIT) (30 mg), and placebo (PLAC) (dextrose) on the stop signal inhibition task in 24 healthy, right-handed men 18-35 years of age. Participants performed the task under each of the four drug conditions across four consecutive sessions. RESULTS: Methylphenidate led to a reduction in both response time variability and stop-signal reaction time (SSRT), indicating enhanced response inhibition compared with all other drug conditions. Crucially, the enhancement of response inhibition by MPH occurred without concomitant changes in overall response speed, arguing against a simple enhancement of processing speed. We found no significant differences between ATM and PLAC, CIT and PLAC, or ATM and CIT for either response time variability or SSRT. CONCLUSIONS: An acute dose of MPH but not ATM or CIT was able to improve SSRT and reduce response time variability in nonclinical participants. Improvements in response inhibition and response variability might underlie the reported clinical benefits of MPH in disorders such as attention-deficit/hyperactivity disorder.