The major symptoms of Tourette syndrome are motor and vocal tics, but Tourette syndrome is occasionally associated with cognitive alterations as well. Although Tourette syndrome does not affect the majority of cognitive functions, some of them improve. There is scarce evidence on the impairment of learning functions in patients with Tourette syndrome. The core symptoms of Tourette syndrome are related to dysfunction of the basal ganglia and the frontostriatal loops. Acquired equivalence learning is a kind of associative learning that is related to the basal ganglia and the hippocampi. The modified Rutgers Acquired Equivalence Test was used in the present study to observe the associative learning function of patients with Tourette syndrome. The cognitive learning task can be divided into two main phases: the acquisition and test phases. The latter is further divided into two parts: retrieval and generalization. The acquisition phase of the associative learning test, which mainly depends on the function of the basal ganglia, was affected in the entire patient group, which included patients with Tourette syndrome with attention deficit hyperactivity disorder, obsessive compulsive disorder, autism spectrum disorder, or no comorbidities. Patients with Tourette syndrome performed worse in building associations. However, the retrieval and generalization parts of the test phase, which primarily depend on the function of the hippocampus, were not worsened by Tourette syndrome.
The major symptoms of Tourette syndrome are motor and vocal tics, but Tourette syndrome is occasionally associated with cognitive alterations as well. Although Tourette syndrome does not affect the majority of cognitive functions, some of them improve. There is scarce evidence on the impairment of learning functions in patients with Tourette syndrome. The core symptoms of Tourette syndrome are related to dysfunction of the basal ganglia and the frontostriatal loops. Acquired equivalence learning is a kind of associative learning that is related to the basal ganglia and the hippocampi. The modified Rutgers Acquired Equivalence Test was used in the present study to observe the associative learning function of patients with Tourette syndrome. The cognitive learning task can be divided into two main phases: the acquisition and test phases. The latter is further divided into two parts: retrieval and generalization. The acquisition phase of the associative learning test, which mainly depends on the function of the basal ganglia, was affected in the entire patient group, which included patients with Tourette syndrome with attention deficit hyperactivity disorder, obsessive compulsive disorder, autism spectrum disorder, or no comorbidities. Patients with Tourette syndrome performed worse in building associations. However, the retrieval and generalization parts of the test phase, which primarily depend on the function of the hippocampus, were not worsened by Tourette syndrome.
Tourette syndrome (TS) is a disorder that presents before the age of 18 years, affecting 1% of school-aged children [1-4]. The most frequent symptoms are motor and vocal tics [1, 5], which significantly improve in many patients by young adulthood [6]. In addition to these primary symptoms, pure Tourette syndrome is associated with some mild alterations in cognitive functions, mainly in a few executive functions (i.e., verbal fluency, working memory, and Stroop effect), which extend into adulthood [7-9], and others, which disappear with age (i.e., deficits demonstrated by the Wisconsin Card Sorting Test [10]).The symptoms of Tourette syndrome are mainly related to dysfunction of the basal ganglia and the connected frontal lobe [11, 12]. Reduced left caudate nucleus volume [13], prefrontal hypertrophy, and structural changes have been described in Tourette syndrome [14-16]. The connection between the frontal lobe and the basal ganglia via parallel and overlapping frontostriatal circuits [5, 12, 17–22] is significantly weaker in Tourette syndrome [23].This frontostriatal system is responsible for motor functions and several cognitive functions [24]. However, significant impairment of cognitive functions has only been rarely described in patients with Tourette syndrome without any comorbidities [25], and the impairment often depends on the level of tic severity [26-28]. Most impairment has been reported in Tourette syndrome with its most frequent comorbidity, attention deficit hyperactivity disorder (ADHD) [29-31]. Previous studies have emphasized that most alterations of cognitive functions are primarily associated with concomitant ADHD and TS [32-36]. These results suggest that the cognitive performance of patients with TS + ADHD is more similar to that of patients with ADHD than that of patients with Tourette syndrome [33, 35, 37, 38]. Accordingly, Channon et al. did not find any impairment in explicit or implicit memory or learning processes in Tourette syndrome alone but did find these impairments in TS + ADHD [39]. In reinforcement learning, the results are conflicting, but most results show no difference between patients with Tourette syndrome and healthy controls [26, 40–43]. Patients with Tourette syndrome have intact motor sequence learning [44], but the procedural (habit) learning in a probabilistic classification learning, which is connected to the dorsal striatum [45] was significantly altered [46, 47]. However, hippocampus-related learning was not affected in patients with Tourette syndrome alone [47]. Another procedural learning type, implicit probabilistic sequence learning, was not affected or was even better in patients with Tourette syndrome [48, 49]. These learning functions function via frontostriatal loops as well as associative learning, which has not yet been investigated for Tourette syndrome.Associative learning, in which discrete and often different signals are linked together, is a type of conditioning. For example, when we remember a face, we record all the facial features, and the parts reinforce each other. This basic cognitive function is related to basal ganglia and hippocampus functions. The Rutgers Acquired Equivalence Test [35] investigates this specific learning ability. The primary advantage of this test is that each phase of the paradigm has well-described neural substrates. The acquisition phase, which primarily depends on the function of the basal ganglia [35, 50], tests the association of two different visual stimuli with the help of feedback about the correctness of the responses. In the test phase, which primarily depends on the function of the hippocampus and the mediotemporal lobe [35, 50], the previously learned associations are presented without any feedback (retrieval part), and previously not presented but predictable associations (generalization part) are shown. This learning function was previously investigated in adult patients with Parkinson’s disease, Alzheimer’s disease, schizophrenia, and migraine without aura [35, 51–53] but never in children with neurological or psychiatric disorders compared with healthy controls. Thus, the description of this learning ability in Tourette syndrome remains missing. Since Tourette syndrome is related to dysfunction of the basal ganglia and the frontostriatal loops, we hypothesized that the acquisition phase could be primarily affected in the Acquired Equivalence Test. Thus, the primary aim of the present study was to determine whether visually guided associative acquired equivalence learning is affected in children with Tourette syndrome. We also investigated whether similar to other cognitive deficits of patients with Tourette syndrome the ADHD is the primary reason for reduced associative learning ability in patients with Tourette syndrome.
Methods
Participants
Altogether, 46 children with Tourette syndrome participated in the present research. The children were recruited from Vadaskert Child Psychiatry Hospital in Budapest, Hungary. The children were diagnosed by both a licensed clinical psychologist and a board-certified child psychiatrist at the hospital according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) criteria [1]. A total of 21 patients were diagnosed with Tourette syndrome without any other neurological or psychiatric comorbidities (TS group); 15 were diagnosed with Tourette syndrome and comorbid ADHD (TS + ADHD group); and 10 were diagnosed with Tourette syndrome and some other comorbidity (obsessive compulsive disorder [OCD] or autism spectrum disorder [ASD]; TS + OCD/ASD group). In this study, we analyzed associative learning of patients in the TS, TS + ADHD, and TS + OCD/ASD groups in detail (32 boys and 14 girls, mean age: 11.64±2.38 years, age range: 8–17 years). Children with other neurodevelopmental or psychiatric comorbidities or learning disabilities were excluded. The mean Yale Global Tic Severity Scale (YGTSS) total tic score (TTS) was 20.7±6.4 (range: 8–33) [5, 54] in the whole patient group. Two participants showed minimal tic severity (TTS ≤ 10); 17 showed mild tic severity (score 11–20); and 19 showed moderate to severe tic severity (score > 20). There were no significant differences (Kruskal–Wallis ANOVA, p>0.05) among the patient subgroups according to age, IQ level, and tic severity. Twelve of the children involved in this study (3 from the TS group, 6 from the TS + ADHD group, and 3 from the TS + OCD/ASD group) were medicated because of the symptoms of their disorder. The TS group received dopamine 2 receptor antagonists (haloperidol and risperidone). The TS + ADHDpatients received a norepinephrine–dopamine reuptake inhibitor (methylphenidate), a dopamine 2 receptor antagonist (haloperidol), or a partial agonist of the dopamine 2 and serotonin 1A receptors (aripiprazole), a norepinephrine transporter and dopamine reuptake inhibitor (atomoxetine), or melatonin. The TS + OCD/ASD group received selective serotonin reuptake inhibitors (fluvoxamine and sertraline), a partial agonist of the dopamine 2 and serotonin 1A receptors (aripiprazole), a serotonin and dopamine antagonist (risperidone), or a norepinephrine-dopamine reuptake inhibitor (methylphenidate).The parents of all participants signed an informed consent form and did not receive financial compensation for their participation. The protocol of the study conformed to the tenets of the Declaration of Helsinki in all respects, and it was approved by the Ministry of Human Capacities in Budapest, Hungary (11818-6/2017/EÜIG).From our database of control children recruited from local schools, 46 control children (31 boys and 15 girls, mean age: 11.55±2.38 years, range: 8–17.5 years) were assorted and individually matched based on sex, age (differing in age by no more than six months), and IQ level to the patient groups. There were no significant differences (Kruskal–Wallis ANOVA, p>0.05) among the control subgroups according to age and IQ level. Table 1 shows the demographic data for the patient and control groups.
Table 1
Demographic parameters of the investigated groups.
TS: Tourette syndrome, ADHD: attention deficit hyperactivity disorder, OCD/ASD: obsessive compulsive disorder or autism spectrum disorder.The control group only included children without any known psychiatric, neurological, or neurodevelopmental disorders. All participants (patients and controls) had normal or corrected-to-normal vision and normal hearing. The intactness of color vision was tested by Ishihara plates prior to testing to exclude color blindness [55] both in the patient and control groups. Only patients and controls with normal color vision were analyzed in the present study. We estimated the IQ level with Raven’s Standard [56] and Colored [57] Progressive Matrices [58].
Visually guided associative learning paradigm
The principle of the visual learning paradigm is based on the Rutgers Acquired Equivalence Test [35]. The original visual associative learning test [35] written for iOS (Apple Inc.’s operating system) was slightly modified, translated to Hungarian, and rewritten in Assembly (for Windows) with the written permission of Prof. Catherine E. Myers (Rutgers University, NJ, USA). The test was run on a PC. The testing sessions occurred in a dark and quiet room with the participants sitting at a standard distance (114 cm) from the computer screen with comfortable visibility and legible brightness. The participants were asked to learn associations between antecedent stimuli (four faces: A1, A2, B1, and B2) and consequent stimuli (four fish with different colors: X1, X2, Y1, and Y2). The four possible faces were a male adult, a male child, a female adult, and a female child. The four colors were red, green, blue, and yellow. The antecedent-consequent pairings were randomly generated by the computer from these stimuli for each participant. The acquired equivalence paradigm was structured as follows (Fig 1).
Fig 1
Graphic overview of the visually guided acquired equivalence learning paradigm.
See details in Methods.
Graphic overview of the visually guided acquired equivalence learning paradigm.
See details in Methods.
Acquisition phase
During each trial of the task, participants saw a face and a pair of fish and had to learn through trial and error which of the fish matched which face. In the initial training stages, participants were expected to learn that when face A1 or A2 appears, the correct choice is fish X1 over fish Y1; when face B1 or B2 appears, the correct choice is fish Y1 over fish X1. If the associations are successfully learned, participants also learn that faces A1 and A2 are equivalent with respect to the associated fish (faces B1 and B2 are likewise equivalent with respect to the associated fish). Next, participants learned a new set of pairs: if presented with face A1, they had to choose fish X2 over Y2, and in the case of face B1, fish Y2 over X2. Altogether, six stimulus combinations were shown in the acquisition phase of the paradigm in which the computer provided feedback about the success of the acquisition after each trial. New associations were individually introduced during the acquisition stages. New associations were mixed with trials of previously learned associations. The participants had to achieve a certain number of consecutive correct responses after the presentation of each new association (4 after the presentation of the first association, and 4, 6, 8, 10, and 12 with the introduction of each new association, respectively) to be allowed to proceed. The number of trials in the acquisition phase was not constant. It depended on the performance of the participant in learning the associations.
Test phase (retrieval and generalization parts)
After successful acquisition, the participant continued with the test phase of the paradigm, in which no more feedback was provided about the correctness of the choices. The participant had to recall the six previously built associations (retrieval part) and had to make two new but predictable associations (generalization part). In the generalization part of the test, the participant was asked to choose fish X2 or Y2 when face A2 or B2 was presented. Having learned that faces A1 and A2 were equivalent in the acquisition phase, participants may generalize from learning that if A1 goes with X2, A2 also goes with X2; the same holds for B2 (equivalent to B1) and Y2 (associated with B1). In the test phase, the new associations were mixed with the previously learned associations. The test phase consistently contained 48 trials, including 36 previously built associations (retrieval part) and 12 new, previously not presented but predictable associations (generalization part). The participants’ task throughout the acquisition and testing phases was to indicate their choice in each trial by pressing one of two keyboard buttons labeled LEFT and RIGHT.Participants were tested individually without a time limit, so they could pay undivided attention to learning. No forced quick responses were expected. While the formal description may imply that the task was difficult, healthy children and intellectually disabled individuals reliably make these kinds of generalizations.
Data analysis
The number of trials in the acquisition phase and the response accuracy (error ratios) in the acquisition phase, the retrieval part of the test phase, and the generalization part of the test phase were analyzed. We registered the number of trials required to complete the acquisition phase (the number of acquisition trials [NAT]), the number of correct and incorrect choices during the acquisition phase, and the number of correct and incorrect responses for known and unknown associations during the retrieval and generalization parts of the test phase. Using these data, the error ratios were calculated by dividing the number of incorrect responses by the total number of responses provided. The proportion of the number of incorrect responses in the acquisition phase (the acquisition learning error ratio [ALER]), the number of incorrect responses divided by the total number of responses [36] in the retrieval part of the test phase (i.e., the retrieval error ratio [RER]), and the number of incorrect responses divided by the total number of responses [12] in the generalization part of the test phase (the generalization error ratio [GER]) were measured.
Statistical analysis
First, we tested the distribution of our data. If the data sets were not normally distributed according to the Shapiro–Wilk normality test, the comparisons between the performance of patients with Tourette syndrome and that of control children were performed with the Mann–Whitney rank test. A Kruskal–Wallis ANOVA was used to compare the performances of the TS, TS + ADHD, and TS + OCD/ASD groups and to compare the performances of the control subgroups, too. The median values and ranges are presented in the results section. If the data were normally distributed according to the Shapiro–Wilk test but the homogeneity of the variance test revealed different variance in the performances of patients with Tourette syndrome and that of healthy control children, Welch’s t-test was used to compare the two groups. The mean and SD values are presented in the results section. Statistical analyses were performed in Statistica 13.4.0.14 (1984–2018 TIBCO Software Inc., Palo Alto, CA, USA) and CogStat 1.8.0 and 1.9.0 (2012–2020 Attila Krajcsi).
Results
In this study, we present the performance of 46 pediatric patients with Tourette syndrome with and without comorbidities and 46 matched healthy control children. All of the participants completed the entire visually guided acquired equivalence learning paradigm.
The performances of the entire Tourette syndrome group with and without comorbidities versus healthy control children
In order to reduce the effect of multiple (twice in this case) application of the same data, the statistical results were evaluated after Bonferroni correction at a significance level of 0.025. The median NAT was 79.0 (range: 42–202, n = 46) in all patients with Tourette syndrome (with and without medication) and 62.0 (range: 46–124, n = 46) in the control group. The NAT values were significantly higher in patients with Tourette syndrome (Mann–Whitney rank test U = 636, p < 0.001). The median ALER was 0.102 (range: 0–0.325, n = 46) in all patients with Tourette syndrome and 0.085 (range: 0–0.186, n = 46) in the control group. The ALER values, similar to the NAT values, were significantly higher in patients with Tourette syndrome (Mann–Whitney rank test U = 690, p = 0.004). In the retrieval part of the test phase, there was no statistically significant difference (Mann–Whitney rank test U = 1.17e+0.3, p = 0.360) between the patients with Tourette syndrome (median: 0.056, range: 0–0.333, n = 46) and the control group (median: 0.083, range: 0–0.472, n = 46). In the generalization part of the test phase, similar to the retrieval part, there was no statistically significant difference (Mann–Whitney rank test U = 1.26e+0.3, p = 0.103) between the patients with Tourette syndrome (median: 0.125, range: 0–0.667, n = 46) and the control group (median: 0.167, range: 0–0.917, n = 46, Fig 2).
Fig 2
Performance of all patients with Tourette syndrome and healthy control children in the visually guided equivalence learning paradigm.
NAT denotes the number of the necessary trials in the acquisition phase of the paradigm. ALER shows the error ratios in the acquisition phase of the paradigm. Lower diagrams denote the error ratios in the retrieval (RER) and generalization (GER) parts of the test phase, respectively. In each panel, the first column (gray) shows the performance of all patients with Tourette syndrome, and the second column (white) denotes the performance of the control group. The lower margin of the boxes shows the 25th percentile; the line within the boxes marks the median; and the upper margin of the boxes indicates the 75th percentile. The error bars (whiskers) above and below the boxes indicate the 90th and 10th percentiles, respectively. The dots over and under the whiskers show the extreme outliers. The black stars indicate statistically significant differences (p < 0.05).
Performance of all patients with Tourette syndrome and healthy control children in the visually guided equivalence learning paradigm.
NAT denotes the number of the necessary trials in the acquisition phase of the paradigm. ALER shows the error ratios in the acquisition phase of the paradigm. Lower diagrams denote the error ratios in the retrieval (RER) and generalization (GER) parts of the test phase, respectively. In each panel, the first column (gray) shows the performance of all patients with Tourette syndrome, and the second column (white) denotes the performance of the control group. The lower margin of the boxes shows the 25th percentile; the line within the boxes marks the median; and the upper margin of the boxes indicates the 75th percentile. The error bars (whiskers) above and below the boxes indicate the 90th and 10th percentiles, respectively. The dots over and under the whiskers show the extreme outliers. The black stars indicate statistically significant differences (p < 0.05).
The effect of medication on the performances of patients with Tourette syndrome with and without comorbidities
To examine the effects of medications on the performances in the applied associative learning test, we compared the performances of the unmedicated patients (TS, TS + ADHD, and TS + OCD/ASD) and their matched healthy controls, the unmedicated patients with Tourette syndrome and all patients with TS, and the medicated and unmedicated patients with Tourette syndrome.
Unmedicated pediatric patients with Tourette syndrome versus healthy control children
In order to reduce the effect of multiple (twice in this case) application of the same data (first application was above in the comparison with the entire TS group), the statistical results were evaluated after Bonferroni correction at a significance level of 0.025. The median NAT was 78.5 (range: 42–202, n = 34) in all unmedicated patients and 60.5 (range: 46–124, n = 34) in the matched control group. The NAT values were significantly higher in patients with Tourette syndrome (Mann–Whitney rank test, U = 345, p = 0.004). The median ALER was 0.102 (range: 0–0.325, n = 34) in patients with Tourette syndrome and 0.086 (range: 0–0.186, n = 34) in the control group. The ALER values, similar to NAT values, were significant higher in patients with Tourette syndrome (Mann–Whitney rank test U = 392, p = 0.023). In the retrieval part of the test phase, there was no statistically significant difference (Mann–Whitney rank test U = 657, p = 0.330) between the TS group (median: 0.056, range: 0–0.333) and the control group (median: 0.083, range: 0–0.472). In the generalization part of the test phase, there was no statistically significant difference (Mann–Whitney rank test U = 734, p = 0.053) between the patients with Tourette syndrome (median: 0.083, range: 0–0.667) and the control group (median: 0.208, range: 0–0.917, Fig 3)
Fig 3
Performance of the unmedicated pediatric patients with Tourette syndrome versus that of healthy control children in the visually guided equivalence learning paradigm.
NAT denotes the number of the necessary trials in the acquisition phase of the paradigm. ALER shows the error ratios in the acquisition phase of the paradigm. Lower diagrams denote the error ratios in the retrieval (RER) and generalization (GER) parts of the test phase, respectively. In each panel, the first column (gray) shows the performance of all unmedicated patients with Tourette syndrome, and the second column (white) denotes the performance of the control group. The lower margin of the boxes shows the 25th percentile; the line within the boxes marks the median; and the upper margin of the boxes indicates the 75th percentile. The error bars (whiskers) above and below the boxes indicate the 90th and 10th percentiles, respectively. The dots over and under the whiskers show the extreme outliers. The black stars indicate statistically significant differences (p < 0.05).
Performance of the unmedicated pediatric patients with Tourette syndrome versus that of healthy control children in the visually guided equivalence learning paradigm.
NAT denotes the number of the necessary trials in the acquisition phase of the paradigm. ALER shows the error ratios in the acquisition phase of the paradigm. Lower diagrams denote the error ratios in the retrieval (RER) and generalization (GER) parts of the test phase, respectively. In each panel, the first column (gray) shows the performance of all unmedicated patients with Tourette syndrome, and the second column (white) denotes the performance of the control group. The lower margin of the boxes shows the 25th percentile; the line within the boxes marks the median; and the upper margin of the boxes indicates the 75th percentile. The error bars (whiskers) above and below the boxes indicate the 90th and 10th percentiles, respectively. The dots over and under the whiskers show the extreme outliers. The black stars indicate statistically significant differences (p < 0.05).
All pediatric patients with Tourette syndrome versus unmedicated patients with Tourette syndrome
Comparing the performances of the whole patient group (TS, TS + ADHD, and TS + OCD/ASD) with the unmedicated patient group (TS, TS + ADHD, and TS + OCD/ASD), we did not find any significant differences. The median NAT was 79.0 (range: 42–202, n = 46) in the whole patient group and 78.5 (range: 42–202, n = 34) in the unmedicated patient group. There was no significant difference in the NAT between these groups (Mann–Whitney rank test U = 763, p = 0.857). The median ALER was 0.102 (range: 0–0.325, n = 34) in the whole patient group and 0.102 (range: 0–0.325, n = 34) in the unmedicated patient group. The ALER values, similar to the NAT values, did not significantly differ (Mann–Whitney rank test U = 786, p = 0.969). In the retrieval part of the test phase, the median RER was 0.056 in the whole patient group (range: 0–0.333, n = 46) and 0.056 (range: 0–0.333, n = 34) in the unmedicated patient group, and this difference was not statistically significant (Mann–Whitney rank test U = 774, p = 0.937). In the generalization part of the test phase, the median GER was 0.125 in the whole patient group (range: 0–0.667, n = 46) and 0.083 (range: 0–0.667, n = 34) in the unmedicated patient group and this difference was not statistically significant (Mann–Whitney rank test U = 742, p = 0.698).
Medicated versus unmedicated pediatric patients with Tourette syndrome
The performance of the medicated patient group did not differ significantly from the performance of the unmedicated patient group. The median NAT was 79.0 (range: 68–101, n = 12) for the medicated patient group and 78.5 (range: 42–202, n = 34) for the unmedicated patient group. There was no statistically significant difference in the NAT between these groups (Mann–Whitney rank test U = 185, p = 0.643). The median ALER was 0.106 (range: 0.056–0.250, n = 12) in the medicated patient group and 0.102 (range: 0–0.325, n = 34) in the unmedicated patient group. The ALER values, similar to the NAT values, did not significantly differ (Mann–Whitney rank test U = 208, p = 0.920). In the retrieval part of the test phase, the median RER was 0.083 in the medicated patient group (range: 0–0.139, n = 12) and 0.056 (range: 0–0.333, n = 34) in the unmedicated patient group, and this difference was not statistically significant (Mann–Whitney U test U = 196, p = 0.840). In the generalization part of the test phase, the median GER was 0.208 in the medicated patient group (range: 0–0.667, n = 12) and 0.083 (range: 0–0.667, n = 34) in the unmedicated patient group, and the difference was not statistically significant (Mann–Whitney rank test U = 164, p = 0.319).
Comparison of the performances among the patients with TS, TS + ADHD, and TS + OCD/ASD
In the first step we have compared the performances in one multiple comparison of the three TS patient and the three control subgroups with Kruskal–Wallis ANOVA analysis. These results revealed significant differences among the six subgroups in NAT (χ2 (5, N = 92) = 14.1829, p = 0.0145) and ALER (χ2 (5, N = 92) = 11.7513, p = 0.0384) but not in RER (χ2 (5, N = 92) = 1.9133, p = 0.861) and GER (χ2 (5, N = 92) = 3.3317, p = 0.6490). In the next step we have compared the performances among the three TS patient subgroups. There were no significant differences in the performances of the three patient groups (TS, TS + ADHD, and TS + OCD/ASD with or without medication) for any of the investigated parameters. The results of the comparisons are shown in Table 2.
Table 2
The performances of the Tourette syndrome, Tourette syndrome and attention deficit hyperactivity disorder, and Tourette syndrome and obsessive compulsive disorder or autism spectrum disorder groups (with or without medication).
TS (n = 21)
TS + ADHD (n = 15)
TS + OCD/ASD (n = 10)
Kruskal–Wallis test
NAT
median: 79 range: 52–130
median: 78 range: 42–202
median:72 range: 46–169
χ2(2, N = 46) = 0.0498, p = 0.975
ALER
median: 0.101 range: 0.018–0.325
median: 0.120 range: 0–0.287
median: 0.106 range:0.043–0.172
χ2(2, N = 46) = 1.13, p = 0.568
RER
median: 0.056 range: 0–0.333
median: 0.056 range: 0.028–0.222
median: 0.097 range: 0.028–0.222
χ2(2, N = 46) = 1.1, p = 0.577
GER
median: 0.083 range: 0–0.667
median: 0.167 range: 0–0.667
median: 0.208 range: 0–0.583
χ2(2, N = 46) = 0.389 p = 0.823
TS: Tourette syndrome, ADHD: attention deficit hyperactivity disorder, OCD/ASD: obsessive compulsive disorder or autism spectrum disorder, NAT: the number of the necessary trials in the acquisition phase of the paradigm, ALER: the error ratios in the acquisition phase of the paradigm, RER: the error ratios in the retrieval part of the test phase, and GER: the error ratio in the generalization part of the test phase.
TS: Tourette syndrome, ADHD: attention deficit hyperactivity disorder, OCD/ASD: obsessive compulsive disorder or autism spectrum disorder, NAT: the number of the necessary trials in the acquisition phase of the paradigm, ALER: the error ratios in the acquisition phase of the paradigm, RER: the error ratios in the retrieval part of the test phase, and GER: the error ratio in the generalization part of the test phase.After the subtraction of the performances of the medicated patients from the analysis, there were no significant differences among the TS, TS + ADHD, and TS + OCD/ASD groups (Table 3).
Table 3
The performances of the three unmedicated patient groups.
TS (n = 18)
TS + ADHD (n = 9)
TS + OCD/ASD (n = 7)
Kruskal–Wallis test
NAT
median: 79,5 range: 52–130
median: 62 range: 42–202
median: 89 range: 46–169
χ2(2, N = 34) = 0.877, p = 0.645
ALER
median: 0.102 range: 0.018–0.325
median: 0.097 range: 0–0.287
median: 0.136 range: 0.043–0.172
χ2(2, N = 34) = 0.694, p = 0.707
RER
median: 0.056 range: 0–0.333
median: 0.056 range: 0.028–0.222
median: 0.028 range: 0.028–0.222
χ2(2, N = 34) = 0.535, p = 0.765
GER
median: 0.083 range: 0–0.667
median: 0.083 range: 0–0.161
median: 0.167 range: 0–0.583
χ2(2, N = 34) = 0.255, p = 0.880
TS: Tourette syndrome, ADHD: attention deficit hyperactivity disorder, OCD/ASD: obsessive compulsive disorder or autism spectrum disorder, NAT: the number of the necessary trials in the acquisition phase of the paradigm, ALER: the error ratios in the acquisition phase of the paradigm, RER: the error ratios in the retrieval part of the test phase, and GER: the error ratio in the generalization part of the test phase.
TS: Tourette syndrome, ADHD: attention deficit hyperactivity disorder, OCD/ASD: obsessive compulsive disorder or autism spectrum disorder, NAT: the number of the necessary trials in the acquisition phase of the paradigm, ALER: the error ratios in the acquisition phase of the paradigm, RER: the error ratios in the retrieval part of the test phase, and GER: the error ratio in the generalization part of the test phase.To avoid the significant effect of the different performances of the three different control subgroups we have compared the performances of the control subgroups, too. We have found no significant differences in each of the investigated values among the control subgroups (Kruskal–Wallis ANOVA, NAT: χ2 (2, N = 46) = 3.7562, p = 0.153; ALER: χ2 (2, N = 46) = 3.5641, p = 0.168; RER: χ2 (2, N = 46) = 0.7136, p = 0.965; GER: χ2 (2, N = 46) = 0.16242, p = 0.922).
Performance of the three TS groups versus their matched healthy control groups
To determine whether the significant findings described above originated in a similar manner for patients with Tourette syndrome without comorbidities and for patients with Tourette syndrome and comorbidities (TS + ADHD or TS + OCD/ASD) we separately compared the data of these three subpopulations with their matched healthy control groups.
Children with Tourette syndrome without any comorbidities versus healthy control children
We examined the difference between the performance of patients with Tourette syndrome and that of matched healthy controls. The median NAT was 79.0 (range: 52–130, n = 21) in the TS group and 60.0 (range: 46–124, n = 21) in the control group. The NAT was significantly higher in patients with Tourette syndrome (Mann–Whitney rank test U = 109, p = 0.005). The median ALER of patients with Tourette syndrome was 0.101 (range: 0.018–0.325, n = 21), and that of the healthy control group was 0.083 (range: 0–0.186, n = 21). The ALER values, similar to the NAT values, were higher in the TS group (Mann–Whitney rank test U = 142, p = 0.049). In the retrieval part of the test phase, the median RER in the TS group was 0.056, (range: 0–0.333, n = 21) and that in the matched healthy group was 0.083 (range: 0–0.361, n = 21). Although the RER was smaller in the Tourette syndrome group, this difference was not statistically significant (Mann–Whitney rank test U = 260, p = 0.327). In the generalization part of the test phase, the median GER was 0.083 (range: 0–0.667, n = 21) in the group of patients with Tourette syndrome and 0.167 (range: 0–0.917, n = 21) in the healthy control group. This difference was not statistically significant (Mann–Whitney rank test U = 270, p = 0.209, Fig 4).
Fig 4
Performance of the patients with Tourette syndrome without comorbidities versus that of matched healthy control children in the visually guided equivalence learning paradigm.
NAT denotes the number of the necessary trials in the acquisition phase of the paradigm. ALER shows the error ratios in the acquisition phase of the paradigm. Lower diagrams denote the error ratios in the retrieval (RER) and generalization (GER) parts of the test phase, respectively. In each panel, the first column (gray) shows the performance of the patients with Tourette syndrome without comorbidities, and the second column (white) denotes the performance of the control group. The lower margin of the boxes shows the 25th percentile; the line within the boxes marks the median; and the upper margin of the boxes indicates the 75th percentile. The error bars (whiskers) above and below the boxes indicate the 90th and 10th percentiles, respectively. The dots over and under the whiskers show the extreme outliers. The black stars indicate statistically significant differences (p < 0.05).
Performance of the patients with Tourette syndrome without comorbidities versus that of matched healthy control children in the visually guided equivalence learning paradigm.
NAT denotes the number of the necessary trials in the acquisition phase of the paradigm. ALER shows the error ratios in the acquisition phase of the paradigm. Lower diagrams denote the error ratios in the retrieval (RER) and generalization (GER) parts of the test phase, respectively. In each panel, the first column (gray) shows the performance of the patients with Tourette syndrome without comorbidities, and the second column (white) denotes the performance of the control group. The lower margin of the boxes shows the 25th percentile; the line within the boxes marks the median; and the upper margin of the boxes indicates the 75th percentile. The error bars (whiskers) above and below the boxes indicate the 90th and 10th percentiles, respectively. The dots over and under the whiskers show the extreme outliers. The black stars indicate statistically significant differences (p < 0.05).
Patients with TS + ADHD versus healthy controls
These comparisons revealed the same tendencies as those in the TS without any comorbidities and TS+OCD/ASD groups. The NAT and ALER values were higher in the TS + ADHD than in the control group, while the RER and GER values were lower in patients with TS+ADHD, but these differences did not significantly differ from those values of the matched control children. The median NAT was 78.0 (range: 42–202, n = 15) in the TS + ADHD group and 75.0 (range: 45–97, n = 15; Mann–Whitney rank test U = 89, p = 0.340) in the matched healthy control group. The median ALER was 0.120 (range: 0.0–0.287, n = 21) in the TS + ADHD group and 0.105 (range: 0.056–0.143, n = 15, Welch’s test t(22,2) = -1.56, p = 0.138) in the control group. In the retrieval part of the test phase, the median RER was 0.056 (range: 0.028–0.222, n = 15) in the TS + ADHD group and 0.083 (range: 0.0–0.472, n = 15, Mann–Whitney rank test U = 120, p = 0.784) in the control group. In the generalization part of the test phase, the median GER was 0.167 (range: 0–0.667, n = 15) in the TS + ADHD group and 0.167 (range: 0–0.917, n = 15, Mann–Whitney rank test U = 140, p = 0.255) in the matched healthy control group (Fig 5).
Fig 5
Performance of patients with concomitant Tourette syndrome and attention deficit hyperactivity disorder patients versus that in matched healthy control children in the visually guided equivalence learning paradigm.
NAT denotes the number of the necessary trials in the acquisition phase of the paradigm. ALER shows the error ratios in the acquisition phase of the paradigm. Lower diagrams denote the error ratios in the retrieval (RER) and generalization (GER) parts of the test phase, respectively. In each panel, the first column (gray) shows the performance of the patients with Tourette syndrome (TS) and attention deficit hyperactivity disorder (ADHD), and the second column (white) denotes the performance of the control group. The lower margin of the boxes shows the 25th percentile; the line within the boxes marks the median; and the upper margin of the boxes indicates the 75th percentile. The error bars (whiskers) above and below the boxes indicate the 90th and 10th percentiles, respectively. The dots over and under the whiskers show the extreme outliers. The black stars indicate statistically significant differences (p < 0.05).
Performance of patients with concomitant Tourette syndrome and attention deficit hyperactivity disorder patients versus that in matched healthy control children in the visually guided equivalence learning paradigm.
NAT denotes the number of the necessary trials in the acquisition phase of the paradigm. ALER shows the error ratios in the acquisition phase of the paradigm. Lower diagrams denote the error ratios in the retrieval (RER) and generalization (GER) parts of the test phase, respectively. In each panel, the first column (gray) shows the performance of the patients with Tourette syndrome (TS) and attention deficit hyperactivity disorder (ADHD), and the second column (white) denotes the performance of the control group. The lower margin of the boxes shows the 25th percentile; the line within the boxes marks the median; and the upper margin of the boxes indicates the 75th percentile. The error bars (whiskers) above and below the boxes indicate the 90th and 10th percentiles, respectively. The dots over and under the whiskers show the extreme outliers. The black stars indicate statistically significant differences (p < 0.05).
Patients with TS + OCD/ASD versus healthy controls
This comparison revealed the same significant differences as were demonstrated above by the patients with Tourette syndrome without any comorbidities. The NAT and ALER values were significantly higher in the TS + OCD/ASD group than in the control group, while the RER and GER values did not differ between the TS + OCD/ASD and control groups. The median NAT was 72.0 (range: 46–169, n = 10) in the TS + OCD/ASD group and 60.5 (range: 49–84, n = 10; independent samples t-test t(18) = -2.21, p = 0.041) in the matched healthy control group. The median ALER was 0.106 (range: 0.043–0.172, n = 10) in the TS + OCD/ASD group and 0.083 (range: 0.019–0.125, n = 10, independent samples t-test t(18) = -2.48, p = 0.023) in the control group. In the retrieval part of the test phase, the median RER was 0.097 (range: 0.028–0.222, n = 10) in the TS + OCD/ASD group and 0.083 (range: 0.027–0.250, n = 10, independent samples t-test t(18) = 0.335, p = 0.741) in the control group. In the generalization part of the test phase, the median GER was 0.208 (range: 0–0.583, n = 10) in the TS + OCD/ASD group and 0.208 (range: 0–0.750, n = 10, Mann–Whitney rank test U = 51.5, p = 0.939) in the matched healthy control group (Fig 6).
Fig 6
Performance of patients with concomitant Tourette syndrome and obsessive compulsive disorder or autism spectrum disorder versus that of matched healthy control children in the visually guided equivalence learning paradigm.
NAT denotes the number of the necessary trials in the acquisition phase of the paradigm. ALER shows the error ratios in the acquisition phase of the paradigm. Lower diagrams denote the error ratios in the retrieval (RER) and generalization (GER) parts of the test phase, respectively. In each panel, the first column (gray) shows the performance of the patients with Tourette syndrome (TS) and obsessive compulsive disorder (OCD) or autism spectrum disorder (ASD), and the second column (white) denotes the performance of the control group. The lower margin of the boxes shows the 25th percentile; the line within the boxes marks the median; and the upper margin of the boxes indicates the 75th percentile. The error bars (whiskers) above and below the boxes indicate the 90th and 10th percentiles, respectively. The dots over and under the whiskers show the extreme outliers. The black stars indicate statistically significant differences (p < 0.05).
Performance of patients with concomitant Tourette syndrome and obsessive compulsive disorder or autism spectrum disorder versus that of matched healthy control children in the visually guided equivalence learning paradigm.
NAT denotes the number of the necessary trials in the acquisition phase of the paradigm. ALER shows the error ratios in the acquisition phase of the paradigm. Lower diagrams denote the error ratios in the retrieval (RER) and generalization (GER) parts of the test phase, respectively. In each panel, the first column (gray) shows the performance of the patients with Tourette syndrome (TS) and obsessive compulsive disorder (OCD) or autism spectrum disorder (ASD), and the second column (white) denotes the performance of the control group. The lower margin of the boxes shows the 25th percentile; the line within the boxes marks the median; and the upper margin of the boxes indicates the 75th percentile. The error bars (whiskers) above and below the boxes indicate the 90th and 10th percentiles, respectively. The dots over and under the whiskers show the extreme outliers. The black stars indicate statistically significant differences (p < 0.05).
Discussion
The Rutgers Acquired Equivalence Test (face and fish test, [35]), which investigates visually guided associative learning in humans, has a well-defined neurological background. The acquisition phase, which primarily depends on the function of the basal ganglia [35, 50] tests the association between two different visual stimuli. The test phase, in which the previously learned associations (retrieval part) and new, but acquisition-based, predictable associations (generalization part) are evaluated, primarily depends on the hippocampi and the mediotemporal lobe [35, 50]. These cognitive functions were previously investigated in adult neurological and psychiatricpatients which were shown to be related to dysfunction of the basal ganglia and the hippocampi (i.e., Parkinson’s disease [34, 35], Alzheimer's disease [51], and migraine without aura [53]). However, the present study is the first to describe the alteration of visual associative learning in a group of children with Tourette syndrome with and without comorbidities. This finding is interesting because only in rare cases have significant impairments in any cognitive functions been described in Tourette syndrome. Tourette syndrome is strongly related to dysfunction of the basal ganglia and the frontal associative cortex. Because of the involvement of the basal ganglia in the pathogenesis of Tourette syndrome, the acquisition phase, which mainly depends on the basal ganglia, was primarily affected in the associative learning test. Based on our results, all patients with Tourette syndrome made the associations with less effectiveness than healthy control children. However, the retrieval and generalization parts of the test phase, which primarily depend on the function of the hippocampi, were not negatively affected by Tourette syndrome. Because of the compensation of the weaker acquisition building, even better performances were found in these phases of the paradigm, although these differences were not statistically significant [36, 47].Our results demonstrated that in the acquisition phase, the performance (NAT and ALER) of all patients (TS, TS + ADHD, and TS + OCD/ASD) was significantly weaker than in the sex, age, and IQ level-matched healthy control group. The question arises whether the alterations in equivalence learning in all patients with Tourette syndrome were primarily due to TS or its most common comorbidity, ADHD. In most cases, Tourette syndrome and ADHD, which seems to plays a major role, are jointly responsible for the alterations in cognitive functions [44, 59–61]. We compared the performances of the three patient groups and found no significant difference among their performances. This finding does not support the predominant role of ADHD in the described alterations in the acquisition phase of the associative learning task. The comparison of each patient group with its matched healthy control group revealed significantly increased NAT or ALER values in patients with Tourette syndrome without any comorbidities and TS + OCD/ASD but not in patients with TS + ADHD. These results together could suggest that concomitant ADHD and TS was not primarily responsible for the visual acquisition learning deficits in patients with Tourette syndrome. This is in contrast with previous findings that ADHD is primarily responsible for the alteration of cognitive functions in patients with TS + ADHD [33, 37, 38, 43]. Therefore, the visually guided acquired equivalence learning, similar to stimulus-response or habit learning [24, 45], which is mediated by the dorsal frontostriatal pathways, is more attributable to Tourette syndrome than ADHD, despite ADHD symptoms affecting the dorsolateral frontostriatal circuits [62].The volume of the hippocampi is significantly larger in patients with pure Tourette syndrome than that of their healthy counterparts [63], and no explicit memory (which is connected to the hippocampus) deficits were reported in children with Tourette syndrome [45, 47]. Our results are in line with these findings. The performance in the retrieval and generalization parts of the test phase, which are primarily related to the hippocampi was not worse in the entire group of patients with Tourette syndrome with and without comorbidities. Concerning the three investigated subpopulations of the patients with Tourette syndrome (TS without comorbidities, TS + ADHD, and TS + OCD/ASD), the RER and GER values did not differ from those of the matched healthy control children.Another question is the possible influence of medication on the performance of patients with Tourette syndrome with or without comorbidities. Because of the relatively low number of cases in the comorbid groups, we could not perform a valid comparison between the performance of medicated and unmedicated TS + ADHD and TS + OCD/ASD patients. Thus, we used the entire TS population (TS without comorbidities, TS + ADHD, and TS + OCD/ASD) to get information about the possible role of medication. The performances in the acquisition phase of the associative learning task in unmedicated TS pediatric patients, similar to the entire TS population, were significantly weaker than those of the matched healthy control children. The comparison of the performances of the entire and the unmedicated TS patient groups revealed no differences. Similarly, we found no differences between the performances of the entire population of medicated and unmedicated pediatric patients with Tourette syndrome. These findings collectively suggest that medication had no or only a weak influence on our results.In this study, we functionally confirmed the results of neuroimaging [14–16, 23] and functional studies that the dorsal frontostriatal circuits are strongly affected in Tourette syndrome, and these circuits are critical to the acquisition process of visually guided associative learning [46, 47]. The hippocampus mediated recall of previously learned associations, and the building of new but acquisition-based, predictable associations were not altered in Tourette syndrome.
The data of the psychophysical performances of 46 TS patients and the 46 matched controls, which were used in the present study.
TS: Tourette syndrome, ADHD: attention deficit hyperactivity disorder, OCD/ASD: obsessive compulsive disorder or autism spectrum disorder, NAT: the number of the necessary trials in the acquisition phase of the paradigm, ALER: the error ratios in the acquisition phase of the paradigm, RER: the error ratios in the retrieval part of the test phase, and GER: the error ratio in the generalization part of the test phase.(XLSX)Click here for additional data file.17 Feb 2020PONE-D-19-30158Impairment of visually guided associative learning in Tourette syndrome with and without ADHDPLOS ONEDear Dr Eördegh,Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.Please re-analyze the data incorporating the possible effects of medication into the analyzes. Please have the manuscript examined by a professional language editor.We would appreciate receiving your revised manuscript by Apr 02 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. 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Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.Reviewer #1: NoReviewer #2: Partly**********2. Has the statistical analysis been performed appropriately and rigorously?Reviewer #1: NoReviewer #2: No**********3. Have the authors made all data underlying the findings in their manuscript fully available?The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. 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(Please upload your review as an attachment if it exceeds 20,000 characters)Reviewer #1: This manuscript reports on original data determining the associative learning abilities in patients with Tourette syndrome with and without ADHD. This is informative to the field, but as written, the data do not support the conclusions and the statistical analyses are lacking in part (see Major Comments 3 and 7). Some ambiguity exists in description of the patient population and the study design (see Major Comments 1, 3-7).Major Comments1. A frequent inquiry in the literature is how behavior in Tourette syndrome differs by the presence of comorbidities, especially ADHD. Though the title indicates this as a consideration in this manuscript, ADHD is not discussed adequately as a factor in the Introduction. For example, the introduction on cognitive function does not indicate which references controlled for the presence of comorbid ADHD. Thus, the reader assumes any deficiencies listed are due to pure Tourette Syndrome, whereas some groups cited find them due to comorbid ADHD. This understanding of comorbid ADHD is expressed too late in line 80. Rather than introducing neuropsychological functions first and the impact of ADHD second, consider doing so in parallel.2. Many of the studies cited, especially on learning disabilities and executive functions, are from work prior to 2000. Recent studies should also be considered, as these more often include consideration of comorbid ADHD. (e.g., Jeter et al., 2015; Termine et al., 2016; Openneer et al., 2019).3. Please describe the patient sample more thoroughly. For example, the authors state patients with Tourette syndrome are usually of normal intelligence, yet those included in this cohort score a 2 (very high) on the intelligence scale used. Also, what is the average tic severity of the cohorts at the time of testing? The waxing and waning of symptoms may be an indicator of fronto-striato-cortical function, and perhaps cognitive function. Tic severity has been a considered factor in a variety of abilities in Tourette Syndrome (e.g., Burd et al., 2005; Jeter et al. 2015; Yaniv et al., 2018). Finally, what medications are the patients taking?4. It is not clear why the many neuropsychological functions are discussed in the Introduction. How, if at all, does associative learning relate to the many other neuropsychological functions listed? The underlying physiology of the task is explained and linked to a prediction of performance on the task. If, though, associative learning is related to one or more functions, how should we anticipate patients with Tourette syndrome to perform on this task of associative learning?5. The Methods report that 47 children with Tourette syndrome participated, yet data are presented for only 36. If data from the 11 children with Tourette syndrome and OCD are not included in this manuscript, do not mention them. If these children did complete the task, including their data in this manuscript produces a more complete understanding of associative learning in Tourette syndrome.6. Description of the task must be clearer. Divide description of the task into multiple paragraphs. Please revise the figure to include the colored fish not associated/selected. For example, show that faces A1 and A2 are first associated with X1 (yellow fish), and that it is Y1 (green fish) that is the wrong answer. How did the participant know when to abandon the first associations (with A1, A2) and develop new (with A1)? What are the correct answers in the generalization phase? The text explains that having learned A1 and A2 are equivalent; the participant will associate A2 with X2. Show in the figure that the alternative wrong fish is Y2 (blue).7. The authors must consider the impact of medications on patient performance. Many studies show the importance of controlling for this factor, preferably in the study design, but post hoc at a minimum. Contrary to most articles on neuropsychological functions, this study found that Tourette syndrome, not comorbid ADHD, contributed to deficits in associative learning. Yet, more patients with Tourette syndrome and ADHD were on medications (6/15=40%) than Tourette syndrome alone (3/21=14%), possibly masking the ill effects of ADHD on associative learning. Add analysis of patient performance by subtype, but only include those off medications. Discuss the findings in the Results and limitations in the Discussion.8. If associative learning deficits truly are attributed to Tourette Syndrome, and not comorbid conditions, discuss why this may be, particularly since it is the comorbid ADHD that is responsible for deficits in other neuropsychological functions. Link this to possible physiology.Minor Comments1. The Abstract (and Figure 1) describes the task as three main parts: acquisition, retrieval and generalization phases. Yet, the Introduction and Methods describe the task as having two parts: acquisition and test, with the latter having retrieval and generalization parts. Reconciling this language is important to conceptualizing the task.2. The Introduction describes Tourette syndrome as frequent, but most readers will not consider 1% prevalence as frequent.3. Please use the phrase, “patients with Tourette syndrome” rather than “Tourette Syndromepatients.” Some find the latter offensive, as it uses a disease as the descriptor of the person (i.e., the person is inseparable from the disease), rather than describing a person with a disease (i.e., the person has an identity apart from the disease). So, too, the phrase “mentally retarded” is now replaced with “intellectually disabled.”4. The Introduction states “only in rare cases…” Please be more specific, as this can be interpreted as “the rare child” or “the rare cognitive function.”5. The relevance of associative learning to daily life is not explained. Even simple statements about how a deficit in this domain can affect academic performance could help.6. Insert Table 1 after the explanation of how IQ is estimated.7. Define ADHD in Tables and captions.8. In defining NAT, RER, ALER, and GER, designate which are numerators, denominators in these ratios.9. On line 374, the hippocampi of patients with Tourette syndrome were larger than whose? TS+ADHD or controls?10. References 3 and 9 are the same article.Reviewer #2: The manuscript reports the results of a study comparing the associative learning performance of children with Tourette syndrome (TS) in the absence of any comorbidity (N=21) with children with TS and ADHD (N=15), on associative learning in a variant of the Rutgers Acquired Equivalence Test (adapted for use in Hungarian children). N=36 matched controls were also tested. Children with TS comorbid with ASD or OCD (N=11) are mentioned but I can’t see that these data have been included. These could well be publishable findings but I’m struggling to follow the conclusions in the present version of the manuscript.Points to be addressedAs is to be expected for this kind of work, the sample sizes are reasonable, but likely insufficient to take any differences attributable to medication into account. N=3 TS and N=6 TS+ADHDchildren were medicated and medication has previously been found to affect associative learning in both TS and ADHD. I’m not sure that the medication details have been provided and I can’t see that potentially confounded effects of medication have been discussed at all within the present manuscript.If the lack of difference in performance between TS and TS+ADHD groups suggests that the effects shown in Figure 2 (differences in NAT and ALER) are TS-mediated, should the same profile not also be shown in the 3rd TS group (comorbid with ASD or OCD)?The third TS group don’t seem to be shown in the figures, nor are the data considered with and without the exclusion of participants on medication?Ln 123-128 - I didn’t understand the rationale to categorise IQ scores: like age, IQ is a continuous variable and to categorise the participants’ scores into IQ ranges may result in a loss of statistical power. Please explain. It’s also not clear how we are to understand the categories which run from ‘extremely high’ through to ‘very low’ with no further definition of these categories.Ln 361-365 – I can’t see how this conclusion about the compensatory effect of ADHD follows. I thought the TS and TS+ADHD groups were not significantly different from each other? Now we’re getting a different comparison (each of the sub-groups with the controls) and the TS-ADHD group also happens to be smaller (N=15). Plus medication does not seem to have been taken into account.The writing is mostly understandable but the manuscript would benefit from further editing by a fluent English speaker, this is not really the job of the reviewer. For example, the Abstract which is most visible (and all some will read) could be better written (some specific suggestions below).Ln 21-22 - The first sentence is a little awkward.Ln22-23 – ‘the majority of the cognitive functions’ - ‘the majority of cognitive functions’Ln 23 - ‘only little evidence’ – suggest rephraseLn 26 – ‘The acquired equivalence learning…’ - ‘Acquired equivalence learning…’Ln 32 – ‘the entire patient group’ – please be more specific, presumably TS+ADHDLn 33 – ‘associations with lower effectiveness’ – please rephraseLn 36-37 – ‘parts of the test phase’ – plural so ‘depend…’ (and sentence seems to be missing a comma after hippocampus)Minor comments and typosLn 140 - iOS – should be defined?Ln 184 – misplaced (and uninformative) figure caption text.Ln 211-212 – Data availability statement and link will need updating. I’m not sure I see the point of providing the data for peer review only at the first revision if the data have not been provided at this point (for peer review prior to the point of being on a ‘revise and resubmit’ ticket)? Elsewhere (in the additional information boxes) it says all relevant data are within the manuscript and its Supporting Information files but I can’t see that the data has in fact been provided at this point. The Supporting Information files seem to be figures.Ln 238-248 – I think this para is the figure legend.Ln 272-277 – I think this para is the figure legend.Ln 297-302 – I think this para is the figure legend (ditto for other figures, why is the legend in the text?)Ln 579 – please make the figure caption self-explanatory rather than referring the reader back to the text.Ln 583 - are the data for TS and TS+ADHDparticipants in fact shown separately in Figure 2? (As implied by the figure header.) If we’re looking at all the TS data relative to matched controls why not also include TS+OCD/ASD?Ln 608 - ‘syndrom’ (typo)Ln 612 - please make the figure caption self-explanatory rather than referring the reader back to an earlier figure legend.**********6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.If you choose “no”, your identity will remain anonymous but your review may still be made public.Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.Reviewer #1: Yes: Cameron B. JeterReviewer #2: No[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.Submitted filename: PLoS One review due 13 Feb.pdfClick here for additional data file.17 Apr 2020First of all, we would like to express our gratitude for the scholarly and highly helpful criticism of both Referees, which helped us to improve the quality of our study. We accepted all suggestions of both Referees and made changes accordingly. The suggestions are answered below itemized; textual changes are marked in the final manuscript.Major Comments1. A frequent inquiry in the literature is how behavior in Tourette syndrome differs by the presence of comorbidities, especially ADHD. Though the title indicates this as a consideration in this manuscript, ADHD is not discussed adequately as a factor in the Introduction. For example, the introduction on cognitive function does not indicate which references controlled for the presence of comorbid ADHD. Thus, the reader assumes any deficiencies listed are due to pure Tourette Syndrome, whereas some groups cited find them due to comorbid ADHD. This understanding of comorbid ADHD is expressed too late in line 80. Rather than introducing neuropsychological functions first and the impact of ADHD second, consider doing so in parallel.Response: According to the suggestion of the reviewer we have restructured the Introduction part of the manuscript.2. Many of the studies cited, especially on learning disabilities and executive functions, are from work prior to 2000. Recent studies should also be considered, as these more often include consideration of comorbid ADHD. (e.g., Jeter et al., 2015; Termine et al., 2016; Openneer et al., 2019).Response: According to the suggestion we have removed the not obligatory references before 2000, and added the recommended new ones.3. Please describe the patient sample more thoroughly. For example, the authors state patients with Tourette syndrome are usually of normal intelligence, yet those included in this cohort score a 2 (very high) on the intelligence scale used. Also, what is the average tic severity of the cohorts at the time of testing? The waxing and waning of symptoms may be an indicator of fronto-striato-cortical function, and perhaps cognitive function. Tic severity has been a considered factor in a variety of abilities in Tourette Syndrome (e.g., Burd et al., 2005; Jeter et al. 2015; Yaniv et al., 2018). Finally, what medications are the patients taking?Response: We have deleted the IQ part of the Table 1. because of its low relevance to our study. Additionally, we have deleted the criticized sentence from the Introduction part of the manuscript. The difference from average IQ level in our cohort could arise from the higher educated parents, who have recognized the problem and bring their children to this special health care system. Another explanation could be that the Raven matrices are not as sensitive as the Wechsler intelligence test.We added the still missing tic severity data of the cohort.We described in detail the medication of the patient groups in Subjects subsection of methods.4. It is not clear why the many neuropsychological functions are discussed in the Introduction. How, if at all, does associative learning relate to the many other neuropsychological functions listed? The underlying physiology of the task is explained and linked to a prediction of performance on the task. If, though, associative learning is related to one or more functions, how should we anticipate patients with Tourette syndrome to perform on this task of associative learning?Response: We reduced the previous mentioned but to this manuscript not obligatory connected neuropsychological functions from the Introduction. We have described how the acquired equivalence learning can be connected to the above discussed neuropsychological functions. We have chosen a simple test (which could be done with success by the intellectually disabled individuals, too (de Rose JC, McIlvane WJ, Dube WV, Stoddard LT. Stimulus class formation and functional equivalence in moderately retarded individuals' conditional discrimination. Behav Processes. 1988;17(2):167-75.), which could be performed most probably with success by the Tourette syndromepatients, too. Our question was the effectivity in the applied learning paradigm.5. The Methods report that 47 children with Tourette syndrome participated, yet data are presented for only 36. If data from the 11 children with Tourette syndrome and OCD are not included in this manuscript, do not mention them. If these children did complete the task, including their data in this manuscript produces a more complete understanding of associative learning in Tourette syndrome.Response: In the Tourette syndrome and other (OCD and autism spectrum disorder, referred as to Tourette syndrome and OCD/ASD group) group ten of eleven children were able to complete the test (7 OCD and 3 ASD comorbid patient). We have involved this new group in the analysis. See new results of the manuscript). Thus the number of the participants increased to 46 in both patient and control groups, respectively. We also discussed these new results.6. Description of the task must be clearer. Divide description of the task into multiple paragraphs. Please revise the figure to include the colored fish not associated/selected. For example, show that faces A1 and A2 are first associated with X1 (yellow fish), and that it is Y1 (green fish) that is the wrong answer. How did the participant know when to abandon the first associations (with A1, A2) and develop new (with A1)? What are the correct answers in the generalization phase? The text explains that having learned A1 and A2 are equivalent; the participant will associate A2 with X2. Show in the figure that the alternative wrong fish is Y2 (blue).Response: In order to make the description of the paradigm more accurate we have introduced the suggested changes to the manuscript. Accordingly, we have prepared a new figure about the paradigm (see new Figure 1)7. The authors must consider the impact of medications on patient performance. Many studies show the importance of controlling for this factor, preferably in the study design, but post hoc at a minimum. Contrary to most articles on neuropsychological functions, this study found that Tourette syndrome, not comorbid ADHD, contributed to deficits in associative learning. Yet, more patients with Tourette syndrome and ADHD were on medications (6/15=40%) than Tourette syndrome alone (3/21=14%), possibly masking the ill effects of ADHD on associative learning. Add analysis of patient performance by subtype, but only include those off medications. Discuss the findings in the Results and limitations in the Discussion.Response: We analyzed the impact of medication on the performance in a new subsection in Results from three different aspects. These result support that the medication has no significant modulatory effects on the results. Thus the separate comparison of the performances of the entire three patient groups (TS, TS+ADHD, TS+OCD/ASD) with their matched control group we provided in the revised manuscript.The case number of the unmedicated TS+ADHD and TS+OCD/ASD groups would be under 10 and this calls into question the relevance of statistical analysis. However, we have performed the comparison of the unmedicated groups with their matched controls and we provide the results here in these tables. These results are basically same to the results of the entire (medicated and unmedicated together) patient subgroups. Thus we have decided to publish the results of the entire TS populations.TS (n=18) TS control (n=18) Mann-Whitney rank testNAT median: 79.5range: 52-130 median: 60range: 46-124 U=246,p = 0.009ALER median: 0.102rage: 0.018-0.325 median: 0.083range: 0-0.186 U=221,p = 0.064RER median: 0.056range: 0-0.333 median: 0.083range: 0-0.361 U=140,p = 0.482GER median: 0.083range: 0-0.667 median: 0.167range: 0-0.917 U=126p = 0.252Table 1 Performance of the unmedicated patient with Tourette syndrome group compared with matched healthy control groupTS means Tourette syndrome. NAT means the number of the necessary trials in the acquisition phase of the paradigm, ALER means the error ratios in the acquisition phase of the paradigm, RER means the error ratios in the retrieval and GER in the generalization parts of the test phase.TS+ADHD (n=9) TS+ADHD control (n=9) Mann-Whitney rank testNAT median: 62range: 42-202 median: 75range: 56-97 U=47.5,p = 0.565ALER median: 0.097rage: 0-0.287 median: 0.105range: 0.07-0.143 U=737,p = 0.480RER median: 0.056range: 0.028-0.222 median: 0.083range: 0.028-0.472 U=35.5,p = 0.687GER median: 0.083range: 0-0.5 median: 0.167range: 0-0.917 U=28,p = 0.280Table 2 Performance of the unmedicated patient with Tourette syndrome + ADHD group compared with matched healthy control groupTS means Tourette syndrome, ADHD means Attention Deficit Hyperactivity Disorder. NAT means the number of the necessary trials in the acquisition phase of the paradigm, ALER means the error ratios in the acquisition phase of the paradigm, RER means the error ratios in the retrieval and GER in the generalization parts of the test phase.TS+OCD/ASD (n=7) TS+OCD/ASD control (n=7) Statistical testNAT median: 89range: 46-169 median: 61range: 49-84 Welch test t(9.22)=2.08,p = 0.076ALER median: 0.136rage: 0.043-0.172 median: 0.072range: 0.019-0.125 t test t(12)=2.16,p = 0.052RER median: 0.028range: 0.028-0.222 median: 0.111range: 0.028-0.250 Mann-Whitney test U=20.5,p = 0.645GER median: 0.167range: 0-0.583 median: 0.250range: 0-0.750 t test t(12)=-0.822,p = 0.427Table 3 Performance of the unmedicated patient with Tourette syndrome + OCD/ASD group compared with matched healthy control groupTS means Tourette syndrome, OCD/ASD means the third patient group with OCD and ASD comorbidity. NAT means the number of the necessary trials in the acquisition phase of the paradigm, ALER means the error ratios in the acquisition phase of the paradigm, RER means the error ratios in the retrieval and GER in the generalization parts of the test phase.8. If associative learning deficits truly are attributed to Tourette Syndrome, and not comorbid conditions, discuss why this may be, particularly since it is the comorbid ADHD that is responsible for deficits in other neuropsychological functions. Link this to possible physiology.Response: We have deleted the speculations about the primary effect of the TS or the ADHD in the alterations of learning functions of the patients. We have modified the abstract accordingly. We have described in the discussion only, which seems to be clear based on our results that not the ADHD is alone/primarily responsible for the associative learning disabilities of the entire TS patient group.Minor Comments1. The Abstract (and Figure 1) describes the task as three main parts: acquisition, retrieval and generalization phases. Yet, the Introduction and Methods describe the task as having two parts: acquisition and test, with the latter having retrieval and generalization parts. Reconciling this language is important to conceptualizing the task.Response: We have made clearer the descriptions of the different parts of the learning task in each chapter of the manuscript.2. The Introduction describes Tourette syndrome as frequent, but most readers will not consider 1% prevalence as frequent.Response: We have deleted the word “frequent”.3. Please use the phrase, “patients with Tourette syndrome” rather than “Tourette Syndromepatients.” Some find the latter offensive, as it uses a disease as the descriptor of the person (i.e., the person is inseparable from the disease), rather than describing a person with a disease (i.e., the person has an identity apart from the disease). So, too, the phrase “mentally retarded” is now replaced with “intellectually disabled.”Response: We have changed the text according the suggestion of the reviewer.4. The Introduction states “only in rare cases…” Please be more specific, as this can be interpreted as “the rare child” or “the rare cognitive function.”Response: Done.5. The relevance of associative learning to daily life is not explained. Even simple statements about how a deficit in this domain can affect academic performance could help.Response: We added to the Introduction a typical application of the associative learning in the daily life.6. Insert Table 1 after the explanation of how IQ is estimated.Response: In the study, we used the Standard Progressive Matrices (SPM) at volunteers over 12 years of age and the Colored Progressive Matrices (CPM) below the age of 12 years. The Hungarian standard values of the two tests cannot be completely matched. The SPM values are in age-independent categories (7 levels), while the CPM values are in the Hungarian standard for age-dependent categories (8 levels, over 95, 90-95, 75-90, 50-75, 25-50, 10-25, 5-10, and bellow 5 centiles). This is the reason why CPM values cannot be compared to SPM values, since the same score for CPM falls in another IQ zone for a child aged 8 and 10 years. To eliminate this, we created a unified category system, combining the upper and lower two categories of CPM into the extremely high and very low categories, and merging the very low and extremely low of the SPM levels into the very low category. For the purposes of the study, IQ zones are only meaningful because of descriptive statistical characteristics, fitting based on the raw score obtained on the intelligence test for the same age. For the sake of clarity, we have removed the intelligence test values from the population characteristics. In the Methods section, we added two other references about the Hungarian standards. We deleted the corresponding part of Table 1. because of its low relevance to our results.7. Define ADHD in Tables and captions.Response: Done.8. In defining NAT, RER, ALER, and GER, designate which are numerators, denominators in these ratios.Response: In Data analysis section we have designated the ratios.9. On line 374, the hippocampi of patients with Tourette syndrome were larger than whose? TS+ADHD or controls?Response: We added to the manuscript: than that of the controls10. References 3 and 9 are the same article.Response: Thank you for the remark. We thought these are two separate article, because of they have different title (A personal 35 year perspective on Gilles de la Tourette syndrome: prevalence, phenomenology, comorbidities, and coexistent psychopathologies, and A personal 35 year perspective on Gilles de la Tourette syndrome: assessment, investigations, and management) and different page numbers (Lancet Psychiatry. 2015 Jan;2(1):68-87. and Lancet Psychiatry. 2015 Jan;2(1):88-104.)Reviewer #2:As is to be expected for this kind of work, the sample sizes are reasonable, but likely insufficient to take any differences attributable to medication into account. N=3 TS and N=6 TS+ADHDchildren were medicated and medication has previously been found to affect associative learning in both TS and ADHD. I’m not sure that the medication details have been provided and I can’t see that potentially confounded effects of medication have been discussed at all within the present manuscript.Response: We described in detail the medication of the patient groups in Participants subsection of Methods. We analyzed the impact of medication on the performance in a new subsection in Results from three different aspects. These result support that the medication has no significant modulatory effects on the results. Thus the separate comparison of the performances of the entire three patient groups (TS, TS+ADHD, TS+OCD/ASD) with their matched control group we provided in the revised manuscript. These new results were discussed, too.If the lack of difference in performance between TS and TS+ADHD groups suggests that the effects shown in Figure 2 (differences in NAT and ALER) are TS-mediated, should the same profile not also be shown in the 3rd TS group (comorbid with ASD or OCD)?Response: In the Tourette syndrome and other (OCD and autism spectrum disorder, termed Tourette syndrome + OCD/ASD) group ten of eleven children were able to complete the test (7 OCD and 3 ASD comorbid patient). We have made this new group and took into the analysis. Thus the number of the participants increased to 46 in patient and control groups, too. We also discussed the new results.The third TS group don’t seem to be shown in the figures, nor are the data considered with and without the exclusion of participants on medication?Response: We have shown the results of the third group (TS + OCD/ASD). We have reanalyzed the data with and without the exclusion of participants with medication.These result support that the medication has no significant modulatory effects on the results. Thus the separate comparison of the performances of the entire three patient groups (TS, TS+ADHD, TS+OCD/ASD) with their matched control group we provided in the revised manuscript. The case number of the unmedicated TS+ADHD and TS+OCD/ASD groups would be under 10 and this calls into question the relevance of statistical analysis. However, we have performed the comparison of the unmedicated groups with their matched controls and we provide the results here in these tables. These results are basically same to the results of the entire (medicated and unmedicated) patient subgroups. Thus we have decided to publish the results of the entire TS populations.TS (n=18) TS control (n=18) Mann-Whitney rank testNAT median: 79.5range: 52-130 median: 60range: 46-124 U=246,p = 0.009ALER median: 0.102rage: 0.018-0.325 median: 0.083range: 0-0.186 U=221,p = 0.064RER median: 0.056range: 0-0.333 median: 0.083range: 0-0.361 U=140,p = 0.482GER median: 0.083range: 0-0.667 median: 0.167range: 0-0.917 U=126p = 0.252Table 1 Performance of the unmedicated patient with Tourette syndrome group compared with matched healthy control groupTS means Tourette syndrome. NAT means the number of the necessary trials in the acquisition phase of the paradigm, ALER means the error ratios in the acquisition phase of the paradigm, RER means the error ratios in the retrieval and GER in the generalization parts of the test phase.TS+ADHD (n=9) TS+ADHD control (n=9) Mann-Whitney rank testNAT median: 62range: 42-202 median: 75range: 56-97 U=47.5,p = 0.565ALER median: 0.097rage: 0-0.287 median: 0.105range: 0.07-0.143 U=737,p = 0.480RER median: 0.056range: 0.028-0.222 median: 0.083range: 0.028-0.472 U=35.5,p = 0.687GER median: 0.083range: 0-0.5 median: 0.167range: 0-0.917 U=28,p = 0.280Table 2 Performance of the unmedicated patient with Tourette syndrome + ADHD group compared with matched healthy control groupTS means Tourette syndrome, ADHD means Attention Deficit Hyperactivity Disorder. NAT means the number of the necessary trials in the acquisition phase of the paradigm, ALER means the error ratios in the acquisition phase of the paradigm, RER means the error ratios in the retrieval and GER in the generalization parts of the test phase.TS+OCD/ASD (n=7) TS+OCD/ASD control (n=7) Statistical testNAT median: 89range: 46-169 median: 61range: 49-84 Welch test t(9.22)=2.08,p = 0.076ALER median: 0.136rage: 0.043-0.172 median: 0.072range: 0.019-0.125 t test t(12)=2.16,p = 0.052RER median: 0.028range: 0.028-0.222 median: 0.111range: 0.028-0.250 Mann-Whitney test U=20.5,p = 0.645GER median: 0.167range: 0-0.583 median: 0.250range: 0-0.750 t test t(12)=-0.822,p = 0.427Table 3 Performance of the unmedicated patient with Tourette syndrome + OCD/ASD group compared with matched healthy control groupTS means Tourette syndrome, OCD/ASD means the third patient group with OCD and ASD comorbidity. NAT means the number of the necessary trials in the acquisition phase of the paradigm, ALER means the error ratios in the acquisition phase of the paradigm, RER means the error ratios in the retrieval and GER in the generalization parts of the test phase.Ln 123-128 - I didn’t understand the rationale to categorize IQ scores: like age, IQ is a continuous variable and to categorize the participants’ scores into IQ ranges may result in a loss of statistical power. Please explain. It’s also not clear how we are to understand the categories which run from ‘extremely high’ through to ‘very low’ with no further definition of these categories.Response: In the study, we used the Standard Progressive Matrices (SPM) at volunteers over 12 years of age and the Colored Progressive Matrices (CPM) below the age of 12 years. The Hungarian standard values of the two tests cannot be completely matched. The SPM values are in age-independent categories (7 levels), while the CPM values are in the Hungarian standard for age-dependent categories (8 levels, over 95, 90-95, 75-90, 50-75, 25-50, 10-25, 5-10, and bellow 5 centiles). This is the reason why CPM values cannot be compared to SPM values, since the same score for CPM falls in another IQ zone for a child aged 8 and 10 years. To eliminate this, we created a unified category system, combining the upper and lower two categories of CPM into the extremely high and very low categories, and merging the very low and extremely low of the SPM levels into the very low category we use. For the purposes of the study, IQ zones are only meaningful because of descriptive statistical characteristics, fitting based on the raw score obtained on the intelligence test for the same age. For the sake of clarity, we have removed the intelligence test values from the population characteristics. In the Methods section, we added two other references about the Hungarian standards. In manuscript we deleted the connected part of Table 1. because of its low relevance to our results.Ln 361-365 – I can’t see how this conclusion about the compensatory effect of ADHD follows. I thought the TS and TS+ADHD groups were not significantly different from each other? Now we’re getting a different comparison (each of the sub-groups with the controls) and the TS-ADHD group also happens to be smaller (N=15). Plus medication does not seem to have been taken into account.Response: We have deleted the speculations about the primary effect of the TS or the ADHD in the alterations of learning functions of the patients. We have modified the abstract accordingly. We have described in the discussion only, which seems to be clear based on our results that not the ADHD is alone/primarily responsible for the associative learning disabilities of the entire TS patient group.The writing is mostly understandable but the manuscript would benefit from further editing by a fluent English speaker, this is not really the job of the reviewer. For example, the Abstract which is most visible (and all some will read) could be better written (some specific suggestions below).Response: Fluent English proofreading was done (see the attached certificate).Ln 21-22 - The first sentence is a little awkward.Ln22-23 – ‘the majority of the cognitive functions’ - ‘the majority of cognitive functions’Ln 23 - ‘only little evidence’ – suggest rephraseLn 26 – ‘The acquired equivalence learning…’ - ‘Acquired equivalence learning…’Ln 32 – ‘the entire patient group’ – please be more specific, presumably TS+ADHDLn 33 – ‘associations with lower effectiveness’ – please rephraseLn 36-37 – ‘parts of the test phase’ – plural so ‘depend…’ (and sentence seems to be missing a comma after hippocampus)Response: We accepted all of these suggestions and connected the manuscript accordingly.Minor comments and typosLn 140 - iOS – should be defined?Response: Done.Ln 184 – misplaced (and uninformative) figure caption text.Response: We have inserted this figure caption text immediately after the first paragraph in which the figure is cited according to the instruction for authors.Ln 211-212 – Data availability statement and link will need updating. I’m not sure I see the point of providing the data for peer review only at the first revision if the data have not been provided at this point (for peer review prior to the point of being on a ‘revise and resubmit’ ticket)? Elsewhere (in the additional information boxes) it says all relevant data are within the manuscript and its Supporting Information files but I can’t see that the data has in fact been provided at this point. The Supporting Information files seem to be figures.Response: We added in the supporting information an excel table about the psychophysical performances of 46 TS patients and the 46 matched controls, which were used in the present study (S1 Table).Ln 238-248 – I think this para is the figure legend.Ln 272-277 – I think this para is the figure legend.Ln 297-302 – I think this para is the figure legend (ditto for other figures, why is the legend in the text?)Response: According to the instruction for authors we had to put the figure captions within the text.Ln 579 – please make the figure caption self-explanatory rather than referring the reader back to the text.Response: We added the detailed explanation to each figure.Ln 583 - are the data for TS and TS+ADHDparticipants in fact shown separately in Figure 2? (As implied by the figure header.) If we’re looking at all the TS data relative to matched controls why not also include TS+OCD/ASD?Response: We have prepared a new figure including the data of TS+OCD/ASD group and its matched healthy control group.Ln 608 - ‘syndrom’ (typo)Response: Done, as well as in the caption of Figure 5.Ln 612 - please make the figure caption self-explanatory rather than referring the reader back to an earlier figure legend.Response: We added the detailed explanation to each figure.Submitted filename: Response to Reviewers.docxClick here for additional data file.14 May 2020PONE-D-19-30158R1Impairment of visually guided associative learning in children with Tourette syndromePLOS ONEDear Dr Eördegh,Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. 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If eligible, we will contact you to opt in or out.We look forward to receiving your revised manuscript.Kind regards,Alexandra Kavushansky, PhDAcademic EditorPLOS ONEAdditional Editor Comments (if provided):Thank you for the corrections performed to the original version of the submission. Most of the issues raised by the Reviewers were addressed; there is still a question of the statistical analyses (e.g. correction for multiple comparisons, when comparing different subgroups (with/no medication, without/with different comorbidities) with their controls), making it hard to solidly base the conclusions on the obtained results.[Note: HTML markup is below. Please do not edit.]Reviewers' comments:Reviewer's Responses to QuestionsComments to the Author1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.Reviewer #1: (No Response)**********2. Is the manuscript technically sound, and do the data support the conclusions?The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.Reviewer #1: No**********3. Has the statistical analysis been performed appropriately and rigorously?Reviewer #1: No**********4. Have the authors made all data underlying the findings in their manuscript fully available?The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.Reviewer #1: No**********5. Is the manuscript presented in an intelligible fashion and written in standard English?PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: Yes**********6. Review Comments to the AuthorPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)Reviewer #1: Thank you for the substantial revisions in response to Reviewer comments. Several additional comments are below.Major Comments:1. Does age differ significantly among subgroups? For example, is the nearly one-year age difference between the TS+ADHD and TS+OCD/ASD groups (patients or controls) significant?2. Does tic severity differ significantly among patient subgroups? Increased tic severity can accompany comorbid conditions.3. Does IQ differ significantly among patient subgroups? Of note, tic severity and IQ do not need to be included in Table 1, but a statement can be made that they do not differ among subgroups, if that is the case.4. Does performance differ significantly among control subgroups? A pitfall of enrolling one control per patient (rather than the same 10-20 controls used for all subgroups) is that the control subgroups may differ among themselves. Whereas age and gender appear to match, task performance varies. Specifically, the TS+ADHD controls had a median NAT of 75, whereas the other control subgroups had median NATs of 60.5 and 60, respectively. The TS+ADHD controls had a median ALER of 0.105, whereas the other control subgroups both had median ALER scores of 0.083. This potentially significant difference among control subgroups is critical, for it could be the reason the TS+ADHDpatient group does not differ from controls. This would change the interpretation of the data from ADHD not altering cognitive functions, to indeed altering visual acquisition.Minor Comments:1. On line 193, what is meant by “involuntary…attention”? Involuntary attention is to a unattended, unexpected stimulus that reflexively draws the subject’s gaze. “Undivided attention” sounds more like voluntary (albeit undivided) attention.2. The task description in the Methods is far more clear. Thank you.3. On line 233, reverse the order of words to read “with and without.”4. On line 306, please delete the word “After.”5. In Tables 2 and 3, add an “n” in “range” for the ALER of patients with TS.6. On line 369, what alterations are referenced? Perhaps “significant findings”?7. In the Results, please place the data of patients with TS+ADHD before that of TS+OCD to mirror all preceding text and tables.**********7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.If you choose “no”, your identity will remain anonymous but your review may still be made public.Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.Reviewer #1: Yes: Cameron B. Jeter[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.21 May 2020First of all, we would like to express our gratitude for the scholarly and highly helpful criticism of the Academic Editor and the Referees, which helped us to improve the quality of our study. We accepted all of the suggestions made changes accordingly. The suggestions are answered below itemized; textual changes are marked in the final re-revised manuscript.Reviewer #1: Thank you for the substantial revisions in response to Reviewer comments. Several additional comments are below.We can’t understand the concern of the reviewer about the data availability, because we have uploaded in the previous (revised) draft of the manuscript the entire xls table, which contains the psychophysical performances of all patients and controls in the supplementary materials of the manuscript.Major Comments:1. Does age differ significantly among subgroups? For example, is the nearly one-year age difference between the TS+ADHD and TS+OCD/ASD groups (patients or controls) significant?Response: The age was not different among the TS patient subgroups. We have added this statement to the manuscript. The age was not different among the control subgroups, too.2. Does tic severity differ significantly among patient subgroups? Increased tic severity can accompany comorbid conditions.Response: The tic severity was not different among the TS patient subgroups. We have added this statement to the manuscript.3. Does IQ differ significantly among patient subgroups? Of note, tic severity and IQ do not need to be included in Table 1, but a statement can be made that they do not differ among subgroups, if that is the case.Response: The IQ was not different among the TS patient subgroups. We have added this statement to the manuscript. The IQ was not different among the control subgroups, too.4. Does performance differ significantly among control subgroups? A pitfall of enrolling one control per patient (rather than the same 10-20 controls used for all subgroups) is that the control subgroups may differ among themselves. Whereas age and gender appear to match, task performance varies. Specifically, the TS+ADHD controls had a median NAT of 75, whereas the other control subgroups had median NATs of 60.5 and 60, respectively. The TS+ADHD controls had a median ALER of 0.105, whereas the other control subgroups both had median ALER scores of 0.083. This potentially significant difference among control subgroups is critical, for it could be the reason the TS+ADHDpatient group does not differ from controls. This would change the interpretation of the data from ADHD not altering cognitive functions, to indeed altering visual acquisition.Response: Thank You for this important question. None of the performances (NAT, ALEG, RER, GER) were different among the control subgroups. We added these results to the manuscript.Minor Comments:1. On line 193, what is meant by “involuntary…attention”? Involuntary attention is to a unattended, unexpected stimulus that reflexively draws the subject’s gaze. “Undivided attention” sounds more like voluntary (albeit undivided) attention.2. The task description in the Methods is far more clear. Thank you.3. On line 233, reverse the order of words to read “with and without.”4. On line 306, please delete the word “After.”5. In Tables 2 and 3, add an “n” in “range” for the ALER of patients with TS.6. On line 369, what alterations are referenced? Perhaps “significant findings”?7. In the Results, please place the data of patients with TS+ADHD before that of TS+OCD to mirror all preceding text and tables.Answer: We accepted all of these minor suggestions and corrected the manuscript accordingly.Submitted filename: Response to Reviewers2.docxClick here for additional data file.2 Jun 2020Impairment of visually guided associative learning in children with Tourette syndromePONE-D-19-30158R2Dear Dr. Eördegh,We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.An invoice for payment will follow shortly after the formal acceptance. 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Have the authors made all data underlying the findings in their manuscript fully available?The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.Reviewer #1: Yes**********5. Is the manuscript presented in an intelligible fashion and written in standard English?PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: Yes**********6. Review Comments to the AuthorPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)Reviewer #1: Thank you for addressing reviewer comments; the manuscript will make a nice publication.I had not previously seen the embedded link in the manuscript PDF to your uploaded data. It is there. Thanks.**********7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). 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