Anna Costa

Reliability and plasticity of response inhibition and interference control

This study investigated the internal reliability, temporal stability and plasticity of commonly used measures of inhibition-related functions. Stop-signal, go/no-go, antisaccade, Simon, Eriksen flanker, Stroop and Continuous Performance tasks were administered twice to 23 healthy participants over a period of approximately 11 weeks in order to assess test-retest correlations, internal consistency (Cronbachs alpha), and systematic between as well as within session performance changes. Most of the inhibition-related measures showed good test-retest reliabilities and internal consistencies, with the exception of the stop-signal reaction time measure, which showed poor reliability. Generally no systematic performance changes were observed across the two assessments with the exception of four variables of the Eriksen flanker, Simon and Stroop task which showed reduced variability of reaction time and an improvement in the response time for incongruent trials at second assessment. Predominantly stable performance within one test session was shown for most measures. Overall, these results are informative for studies with designs requiring temporally stable parameters e.g. genetic or longitudinal treatment studies.

Associations between trait impulsivity and prepotent response inhibition.

This study addresses the relationship between trait impulsivity and inhibitory control, two features known to be impaired in a number of psychiatric conditions. While impulsivity is often measured using psychometric self-report questionnaires, the inhibition of inappropriate, impulsive motor responses is typically measured using experimental laboratory tasks. It remains unclear, however, whether psychometrically assessed impulsivity and experimentally operationalized inhibitory performance are related to each other. Therefore, we investigated the relationship between these two traits in a large sample using correlative and latent variable analysis. A total of 504 healthy individuals completed the Barratt Impulsiveness Scale (BIS-11) and a battery of four prepotent response inhibition paradigms: the antisaccade, Stroop, stop-signal, and go/no-go tasks. We found significant associations of BIS impulsivity with commission errors on the go/no-go task and directional errors on the antisaccade task, over and above effects of age, gender, and intelligence. Latent variable analysis (a) supported the idea that all four inhibitory measures load on the same underlying construct termed “prepotent response inhibition” and (b) revealed that 12% of variance of the prepotent response inhibition construct could be explained by BIS impulsivity. Overall, the magnitude of associations observed was small, indicating that while a portion of variance in prepotent response inhibition can be explained by psychometric trait impulsivity, the majority of variance remains unexplained. Thus, these findings suggest that prepotent response inhibition paradigms can account for psychometric trait impulsivity only to a limited extent. Implications for studies of patient populations with symptoms of impulsivity are discussed.

Relationship between SLC6A3 genotype and striatal dopamine transporter availability: A meta‐analysis of human single photon emission computed tomography studies

The human dopamine transporter (DAT) gene (SLC6A3) contains a 40‐bp variable number of tandem repeats (VNTR) polymorphism. A number of studies have investigated the association of this VNTR with striatal DAT availability in humans using single photon emission computed tomography (SPECT). However, the results are not consistent. Therefore, we carried out a meta‐analysis of the association between the SLC6A3 VNTR and striatal DAT binding measured in human SPECT studies. The meta‐analysis of five samples of healthy individuals failed to find a significant difference in DAT availability between SLC6A3 9‐repeat carriers and 10‐repeat homozygotes (P = 0.22) although the 9R carriers had nominally higher striatal DAT levels (g = 0.66). The results remained nonsignificant after the inclusion of patient samples, namely schizophrenia, attention deficit hyperactivity disorder, and Parkinsons disease (four samples; all P > 0.18). To conclude, this meta‐analysis provides no evidence to support the hypothesis that the SLC6A3 VNTR is significantly associated with interindividual differences in DAT availability in the human striatum. Further work is needed to clarify the molecular mechanisms by which this polymorphism may affect cognition and psychiatric disorders, if not through altered expression as measured by molecular imaging. Synapse, 2011.

Methylphenidate Effects on Neural Activity During Response Inhibition in Healthy Humans

Methylphenidate (MPH) is a catecholamine transporter blocker, with dopamine agonistic effects in the basal ganglia. Response inhibition, error detection, and its mediating frontostriatal brain activation are improved by MPH in patients with attention-deficit/hyperactivity disorder. However, little is known about the effects of MPH on response inhibition and error processing or its underlying brain function in healthy individuals. Therefore, this study employed functional magnetic resonance imaging (fMRI) and 2 response inhibition tasks in 52 healthy males. Subjects underwent fMRI during a go/no-go task and a tracking stop-signal task after administration of 40 mg MPH and placebo in a double-blind, placebo-controlled, repeated-measures design. Results revealed task- and condition-specific neural effects of MPH: it increased activation in the putamen only during inhibition errors but not during successful inhibition and only in the go/no-go task. We speculate that task specificity of the effect might be due to differences in the degree of error saliency in the 2 task designs, whereas errors were few in the go/no-go task and thus had high saliency and the stop-signal task was designed to elicit 50% of errors in all subjects, diminishing the error saliency effect. The findings suggest that neural MPH effects interact with the saliency of the behavior under investigation.

Attentional and sensory effects of lowered levels of intrinsic alertness

Low levels of intrinsic alertness are associated with lateralized performance in visual tasks, similar to neglect of the left (ipsilesional) visual hemi-field. However, it is unclear whether reduced alertness produces a specific lateralization of spatial-attentional processes in terms of the prioritization of right- over left-side stimuli, or whether it affects more basic functions of visuo-sensory coding, and/or higher function of the top-down control of selection, of stimuli on the left side. To decide between these alternatives, the present study examined the effects of lowered alertness, induced by a 50-min vigilance task, in a partial-report paradigm of briefly presented letter displays. With only one (unilateral) stimulus in display, no specific hemi-field effects were found under low-alertness conditions, indicating that reduced alertness impairs neither sensory effectiveness nor the top-town control of selection. However, with dual, bilateral stimuli, report accuracy was specifically affected for left-side targets (in subjects who showed comparable performance for both sides under normal-alertness conditions). This pattern can be interpreted in terms of a specific bias in spatial-attentional weighting, where prioritization of stimuli on the right leads to (mild) extinction of targets on the left. Moreover, participants who had a lower general level of alertness also showed a more pronounced re-distribution of weights, evidenced by a more severe imbalance in report accuracy, in a low compared to a normal state of alertness. This suggests that a low general level of intrinsic alertness engenders a specific vulnerability to neglect-like performance with a (mild) left-side extinction.

The effects of methylphenidate on whole brain intrinsic functional connectivity

Methylphenidate (MPH) is an indirect dopaminergic and noradrenergic agonist that is used to treat attention deficit hyperactivity disorder and that has shown therapeutic potential in neuropsychiatric diseases such as depression, dementia, and Parkinsons disease. While effects of MPH on task‐induced brain activation have been investigated, little is known about how MPH influences the resting brain. To investigate the effects of 40 mg of oral MPH on intrinsic functional connectivity, we used resting state fMRI in 54 healthy male subjects in a double‐blind, randomized, placebo‐controlled study. Functional connectivity analysis employing ICA revealed seven resting state networks (RSN) of interest. Connectivity strength between the dorsal attention network and the thalamus was increased after MPH intake. Other RSN located in association cortex areas, such as the left and right frontoparietal networks and the executive control network, showed MPH‐induced connectivity increase to sensory‐motor and visual cortex regions and connectivity decrease to cortical and subcortical components of cortico‐striato‐thalamo‐cortical circuits (CST). RSN located in sensory‐motor cortex areas showed the opposite pattern with MPH‐induced connectivity increase to CST components and connectivity decrease to sensory‐motor and visual cortex regions. Our results provide evidence that MPH does not only alter intrinsic connectivity between brain areas involved in sustained attention, but that it also induces significant changes in the cortico‐cortical and cortico‐subcortical connectivity of many other cognitive and sensory‐motor RSN. Hum Brain Mapp 35:5379–5388, 2014.

Impulsivity is related to striatal dopamine transporter availability in healthy males

Impulsivity characterises various psychiatric disorders, particularly attention-deficit/hyperactivity disorder (ADHD). Evidence shows that ADHD symptoms are associated with dopamine dysfunction and alleviated with methylphenidate, a drug that reduces dopamine transporter availability. ADHD-like symptoms and impulsive traits are continuously distributed across the general population. Here, we aimed to investigate the dopaminergic basis of impulsivity and other ADHD-related traits in healthy individuals by studying the association of these traits with striatal dopamine transporter availability. Single-photon emission computed tomography with [(123)I] FP-CIT was performed on 38 healthy males. Impulsivity was measured using the Barratt Impulsiveness Scale (BIS) and hyperactivity-impulsivity and inattention using the Adult ADHD Self-Report Scale (ASRS). We found that greater dopamine transporter availability was associated with higher BIS impulsivity but not with ADHD-related traits. The association with BIS was significant after accounting for individual differences in age and neuroticism. These results suggest that individual differences in the dopamine system may be a neural correlate of trait impulsivity in healthy individuals.

Methylphenidate Effects on Brain Activity as a Function of SLC6A3 Genotype and Striatal Dopamine Transporter Availability

We pharmacologically challenged catecholamine reuptake, using methylphenidate, to investigate its effects on brain activity during a motor response inhibition task as a function of the 3′-UTR variable number of tandem repeats (VNTR) polymorphism of the dopamine transporter (DAT) gene (SLC6A3) and the availability of DATs in the striatum. We measured the cerebral hemodynamic response of 50 healthy males during a Go/No-Go task, a measure of cognitive control, under the influence of 40u2009mg methylphenidate and placebo using 3T functional magnetic resonance imaging. Subjects were grouped into 9-repeat (9R) carriers and 10/10 homozygotes on the basis of the SLC6A3 VNTR. During successful no-go trials compared with oddball trials, methylphenidate induced an increase of blood oxygen level-dependent (BOLD) signal for carriers of the SLC6A3 9R allele but a decrease in 10/10 homozygotes in a thalamocortical network. The same pattern was observed in caudate and inferior frontal gyrus when successful no-go trials were compared with successful go trials. We additionally investigated in a subset of 35 participants whether baseline striatal DAT availability, ascertained with 123I-FP-CIT single photon emission computed tomography, predicted the amount of methylphenidate-induced change in hemodynamic response or behavior. Striatal DAT availability was nominally greater in 9R carriers compared with 10/10 homozygotes (d=0.40), in line with meta-analyses, but did not predict BOLD or behavioral changes following MPH administration. We conclude that the effects of acute MPH administration on brain activation are dependent on DAT genotype, with 9R carriers showing enhanced BOLD following administration of a prodopaminergic compound.

Schizotypy and Behavioural Adjustment and the Role of Neuroticism

Objective In the present study the relationship between behavioural adjustment following cognitive conflict and schizotypy was investigated using a Stroop colour naming paradigm. Previous research has found deficits with behavioural adjustment in schizophrenia patients. Based on these findings, we hypothesized that individual differences in schizotypy, a personality trait reflecting the subclinical expression of the schizophrenia phenotype, would be associated with behavioural adjustment. Additionally, we investigated whether such a relationship would be explained by individual differences in neuroticism, a non-specific measure of negative trait emotionality known to be correlated with schizotypy. Methods 106 healthy volunteers (mean age: 25.1, 60% females) took part. Post-conflict adjustment was measured in a computer-based version of the Stroop paradigm. Schizotypy was assessed using the Schizotypal Personality Questionnaire (SPQ) and Neuroticism using the NEO-FFI. Results We found a negative correlation between schizotypy and post-conflict adjustment (ru200a=u200a−.30, p<.01); this relationship remained significant when controlling for effects of neuroticism. Regression analysis revealed that particularly the subscale No Close Friends drove the effect. Conclusion Previous findings of deficits in cognitive control in schizophrenia patients were extended to the subclinical personality expression of the schizophrenia phenotype and found to be specific to schizotypal traits over and above the effects of negative emotionality.

Gently restless: association of ADHD-like traits with response inhibition and interference control

AbstractnImpairment of inhibition-related functions is one of the most pronounced cognitive deficits found in attention-deficit/hyperactivity disorder (ADHD). Compelling evidence from studies of unaffected relatives of patients with ADHD and of ADHD-like traits in healthy subjects suggest the continuous distribution of ADHD symptoms in the population. A more subtle inhibitory deficit can also be found in healthy relatives of patients and in subjects with high ADHD-like traits. Here, we examined the relationship between inhibitory performance and ADHD-like traits, for the first time, in a large sample of healthy adults by applying multiple, widely used tests of inhibition-related functions. ADHD-like traits, in general, were independently predicted by Stroop interference score and, at trend level, by go/no-go commission error rate while controlling for socio-demographic factors, verbal intelligence and neuroticism. Additionally, higher inattentive traits were related to worse Stroop performance at trend level, and higher hyperactive/impulsive traits were significantly associated with more go/no-go commission errors. ADHD-like traits were strongly related to neuroticism. The study shows that individual differences in ADHD-like traits are related to variance in fundamental inhibition-related functions over and above effects of negative affect regulation, but the relationships tend to be small. The results suggest the quasi-dimensionality of ADHD and raise further questions about the relationship between genetic factors and the deficit of inhibition-related functions in the ADHD spectrum.