Tourette syndrome (TS) is a neurodevelopmental disorder of childhood onset characterized by chronic motor and vocal tics. Although its etiology and pathophysiology are still unknown, there is increasing evidence for disruptions in the structure and function of cortico-striatal-thalamic-cortico (CSTC) neural circuitry. This altered functioning of CSTC circuitry including the prefrontal cortex might be associated with general problems of inhibitory control, not only of motor function, but also of cognitive and emotional regulation 1. Unfortunately, the large number of neuropsychological studies addressing inhibition in TS could not draw a clear picture (for a review see 12).

First, it has to be taken into consideration that there are separable types of inhibition, probably all with different neural substrates 3. However, there were inconsistencies between studies in TS even when they used the same task for measuring inhibitory control. For example, a flanker task did not show deficits in response inhibition in adults 4, but in children with 'pure' TS compared to a control group 5. Two studies using another test of response inhibition, an A-X version of the continuous performance task (CPT) revealed divergent findings in children with TS compared to healthy controls. One study found differences 6, the other not 7.

Second, all these inconsistencies might be attributable to several confounders. The uncontrolled psychiatric symptomatology often comorbid to TS like attention-deficit/hyperactivity disorder (ADHD) is thought to contribute mainly to found inhibitory deficits 8. Additionally, previous and actual medication as well as short- and long-term compensatory mechanisms due to voluntary tic-suppression might have confounded previous findings on response inhibition performance in TS.

Hence, there is consensus that response inhibition in TS merits a more thorough investigation of less heterogeneous samples to come to firmer conclusions 4. Because the a priori exclusion of confounders is the less biased method compared to post hoc statistical adjustment 9, we chose this approach to have the best ability to detect response inhibition deficits specific for TS per se. We applied a Go/Nogo task as one of the most common neuropsychological paradigms to investigate response inhibition in the motor domain 1011.

Normal performance in the Go/Nogo task has been found in children with TS without comorbid conditions 12 as well as in adults with TS (some of them with comorbid ADHD and/or OCD) 13. This is surprising as there are quite prominent differences between both versions of the Go/Nogo task applied.

For example in the task of Ozonoff et al. 12 the ratio of Go to Nogo stimuli is 50:50, whereas it is 83:17 in that of Hershey et al. 13. Frequent Go stimuli are needed to ensure a prepotent tendency to respond that must then be inhibited for Nogo stimuli. But relatively rare Nogo stimuli entail the problem that novelty effects of increased arousal and orientation could not be distinguished from inhibitory requirements 14. Hence, on the one hand a task with rare Nogo stimuli is needed to ensure that responses are prepotent and response inhibition is difficult, but on the other hand it has to control for the effects of stimulus probability 15. This is even more important in TS as patients were found to be impaired on tasks requiring the processing of novel stimuli 1617.

Hence, we progress the field of inhibitory control in TS in two points. First, we applied a more demanding Go/Nogo task than Ozonoff et al. 12 to detect inhibitory deficits that could possibly not be detected by their task. Additionally, the present Go/Nogo task controlled for the first time in TS research for the important confounding of novelty. Second, we included only medication naïve boys with 'pure' TS to avoid confounding effects of medication and psychopathology other than TS. To minimize the extent of compensatory mechanisms we included boys with a short history of tics. In accordance with previous studies on inhibitory control we expected impaired performance of the subjects suffering from TS compared to healthy controls in our highly demanding Go/Nogo task.

Success rate was different for the letters presented ("Letter" F_(2,66) = 247.3, ε = .51, p < .01), with lower success rates for Nogo compared to both Go stimuli (see Table 2). Neither time on task effects as reflected by the factor "Run" or group-differences, nor any interactions were found.

RTs of correct responses were slower for "A" compared to "X" ("Letter" F_(1,33) = 66.8, p < .01). Again, no effects of time on task or "Group" or any interactions reached significance.

Reaction-times of Nogo errors were faster than correct responses to novel Go stimuli (F_(1,33) = 10.8, p < .01), but did not differ between groups (F_(1,33) = 0.6, p = .42) nor show an interaction "Letter*Group" (F_(1,33) = 0.1, p = .90).

Intra-individual RT-SD of correct responses was lower on letters "X" compared to "A" ("Letter" F_(1,33) = 13.2, p < .01), but there were also an interaction "Run*Letter" (F_(2,66) = 3.2, ε = .99, p = .05) and a trend for an interaction "Run*Group" (F_(1,33) = 2.8, ε = .96, p = .07). The latter trend was disentangled by considering confidence intervals at p < .10. In the first run controls displayed higher RT-SD than boys with TS which reversed in the third block where subjects suffering from TS showed higher RT-SD; in the second run no group differences were found. No general main effects of "Group" were found (F_(1,33) = 0.1, p = .86). Separate repeated measure ANOVAs for each Go stimulus revealed no effects for letter "A", but an interaction "Run*Group" for letter "X" (F_(2,66) = 4.5, ε = .99, p = .02) that was accompanied by a trend for higher RT-SD for subjects suffering from TS in the last run only. All these results remained stable also after entering age as a covariate to test for developmental effects.

Using a Go/Nogo task we found no differences in response inhibition between drug naïve boys suffering from TS without any comorbid disorder and healthy controls of same age, gender and IQ. The high demanding Go/Nogo task applied here following Tamm et al. 25 controlled for the first time in TS research for novelty effects in the Go/Nogo task. Additionally, the inclusion of only boys with 'pure' TS who had never taken psychotropic medication is a further methodological progress of previous work 12. The higher scores in some of the SDQ scales of the boys with TS have no relevance since all are in the lower normal range. This indicates that there are no comorbid symptoms or diagnoses. This in turn raises the question if studying the minority of patients with 'pure' TS also allows conclusions concerning TS in general, because TS is frequently (up to 90%) co-existing with further psychiatric problems 26. In terms of the most frequently comorbid condition in TS, i.e. ADHD several studies on different domains (psychopathology, neuropsychology etc.) have shown that TS and ADHD co-occur in an additive manner 82728. Hence, it seems likely that 'pure' TS and TS comorbid with other conditions are very similar if not identical.

The fact that RTs to the infrequent Go stimuli "A" were slower than to the frequent Go stimuli "X" highlights the importance of controlling for novelty effects. Furthermore, the task used in this study is highly demanding as reflected by the higher percentage of false alarms (~60%) compared to that of the tasks in the studies of Ozonoff (~15%; 12) and Hershey et al. (~20%; 13). Nevertheless, the present results based on a TS sample excluding possible confounders like gender, medication and comorbidity are in line with previous less controlled studies which reported no group differences in Go/Nogo performance of children 12 and adults with TS 13. Thus they add evidence to the increasing base of knowledge that in 'pure' TS no deviances in neuropsychological task performance can be found except some few specific deficits. One of the latter might be a deficit of patients with TS in tasks requiring higher inhibition capacities 29. Another one might be indicated in the present study by a trend for group differences in time on task effects for RT-SD. However, these exploratory findings of time on task effects require replication by more appropriate task designs to allow interpretation.

However, it has to be noted that the severity of TS was moderate in our group as indicated by the TSSS 19 and SDQ parent- and self-rated scores 18. Hence, assuming a correlation between tic severity and inhibitory deficits one could speculate that patients with more severe tics might show performance deficits in inhibitory tasks. But this speculation is questioned by the findings of Mueller et al. 30 who showed that chronic suppression of tics results in an enhancement of the executive processes involved in inhibitory control. Hence, the question arises if more severe tics would result in a more efficiently trained inhibitory control than milder tics.

However, the absence of performance differences in a Stop-task between a group with TS and healthy controls seems to be in contrast to the differences in co-registered neurophysiological parameters between these groups during the same experiment. The process of response inhibition was related to an enhanced frontal brain electrical negativity and a more anterior scalp distribution of the Nogo-anteriorization component in TS 31. Similarly, Serrien et al. 32 interpreted an elevated frontomesial electroencephalographic coherence in TS as serving to compensate for diminished inhibitory control in a special Go/Nogo task.

Hence, compensatory mechanisms in TS to control for tics might lead to neurophysiological deviances but yield normal findings in neuropsychological performance on response inhibition in TS. To better understand the relationship between neuronal mechanisms of response inhibition and its neuropsychological performance in TS further studies combining neuropsychological and neurophysiological methods (e.g. electroencephalography, fMRI) using the same strictly controlled design along the whole range of development and tic severity are recommended.

The authors declare that they have no competing interests.

VR designed and coordinated the study and drafted the manuscript. BA has been responsible for the data analysis and contributed to the interpretation of the results. PD, JB participated in the acquisition of data, discussions about the data analyses and commented on the written drafts of the manuscript. AR participated in the overall conceptualization and supervision of project, including the design and interpretation of the results. All authors have read and approved the final manuscript.