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Background: Children with Tourette syndrome (TS) often have comorbid disorders, particularly attention-deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). While subtle premorbid symptoms have been described in various psychiatric disorders, the presence of clinical precursors that may exist before the onset of tics is unknown. This longitudinal study aimed to find clinical precursors of tics by assessing a range of clinical characteristics prior to tic onset in comparison with children without onset of tics., Methods: A sample of 187 3- to 10-year-old first-degree unaffected relatives of children with TS were followed up to 7 years in the European Multicentre Tics in Children Study (EMTICS). We investigated whether clinical characteristics assessed at baseline predicted tic onset, comparing 126 children without tic onset to 61 children who developed tics. We used the least absolute shrinkage and selection operator (LASSO) method, a penalised logistic regression approach. We also explored sex differences and repeated our analyses in an age- and sex-matched subsample., Results: Children with tic onset were more frequently male (β = -0.36), had higher baseline severity of conduct problems (β = 0.23), autism spectrum disorder symptoms (ASD; β = 0.08), compulsions (β = 0.02) and emotional problems (β = 0.03) compared to children without tic onset. Conduct and ASD problems were male-specific predictors, whereas severity of compulsions and oppositional (β = 0.39) and emotional problems were female-specific predictors., Conclusion: This study supports the presence of clinical precursors prior to tic onset and highlights the need of sex-specific monitoring of children at risk of developing tics. This may aid in the earlier detection of tics, particularly in females. We moreover found that tics most often persisted one year after tic onset, in contrast to the common belief that tics are mostly transient., (© 2021 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Background: Methylphenidate may improve executive functioning in children with attention-deficit/hyperactivity disorder (ADHD). However, it is unclear if there are still acute effects of methylphenidate on executive functioning after long-term use., Methods: In a randomized double-blind, placebo-controlled discontinuation study, 94 children and adolescents (ages 8-18 years) who used methylphenidate beyond two years were either assigned to seven weeks of continued treatment with 36 or 54 mg of extended-release methylphenidate or to gradual withdrawal over three weeks to placebo for four weeks. Performance on neuropsychological tasks, measuring working memory, response inhibition, attentional flexibility and psychomotor speed was compared between both groups using mixed models for repeated measures. Additionally, we investigated within the discontinuation group if a deterioration on the investigator-rated Clinical Global Impressions Improvement scale after withdrawing to placebo was related to a worse performance on the neuropsychological tasks. This study was registered in the Netherlands Trial Register (www. Trialregister.nl) with identifier 5252., Results: After withdrawal of methylphenidate, the discontinuation group made more errors on working memory (β = -1.62, SD = 0.56, t = -2.88, p = .01, Cohen's f2 = .14), independent from reaction time compared to baseline, in contrast to the continuation group. We did not find differences in changes in response inhibition, attentional flexibility and psychomotor speed between the two groups. Also, there were no significant differences in task measures between the participants who deteriorated clinically and those who did not., Conclusions: Our study shows that methylphenidate has a beneficial effect on working memory after two years of use. Future studies should explore whether cognitive outcomes may aid clinical decision-making on the continued use of methylphenidate, given dissociation between cognitive and behavioural effects of stimulant medication., (© 2021 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Objectives: Tourette syndrome (TS) is characterised by the presence of sudden, rapid movements and vocalizations (tics). The nature of tics suggests impairments in inhibitory control. However, findings of impaired inhibitory control have so far been inconsistent, possibly due to small sample sizes, wide age ranges, or not taking medication use or attention-deficit/hyperactivity disorder (ADHD) comorbidity into account., Methods: We investigated group differences in response inhibition using an fMRI-based stop-signal task in 103 8 to 12-year-old children ( n  = 51 with TS, of whom n  = 28 without comorbid ADHD [TS - ADHD] and n  = 23 with comorbid ADHD [TS + ADHD]; and n  = 52 healthy controls), and related these measures to tic and ADHD severity., Results: We observed an impaired response inhibition performance in children with TS + ADHD, but not in those with TS - ADHD, relative to healthy controls, as evidenced by a slower stop-signal reaction time, slower mean reaction times, and larger variability of reaction times. Dimensional analyses implicated ADHD severity as the driving force in these findings. Neural activation during failed inhibition was stronger in the inferior frontal gyrus and temporal and parietal areas in TS + ADHD compared to healthy controls., Conclusions: Impaired inhibitory performance and increased neural activity in TS appear to manifest predominantly in relation to ADHD symptomatology.

Premonitory urges are uncomfortable physical sensations preceding tics that occur in most individuals with a chronic tic disorder. The Premonitory Urge for Tics Scale (PUTS) is the most frequently used self-report measure to assess the severity of premonitory urges. We aimed to evaluate the psychometric properties of the PUTS in the largest sample size to date (n = 656), in children aged 3-16 years, from the baseline measurement of the longitudinal European Multicenter Tics in Children Study (EMTICS). Our psychometric evaluation was done in three age-groups: children aged 3-7 years (n = 103), children between 8 and 10 years (n = 253), and children aged 11-16 years (n = 300). The PUTS exhibited good internal reliability in children and adolescents, also under the age of 10, which is younger than previously thought. We observed significant but small correlations between the severity of urges and severity of tics and obsessive-compulsive symptoms, and between severity of urges and ratings of attention-deficit/hyperactivity disorder and internalizing and externalizing behaviors, however, only in children of 8-10 years. Consistent with previous results, the 10th item of the PUTS correlated less with the rest of the scale compared to the other items and, therefore, should not be used as part of the questionnaire. We found a two-factor structure of the PUTS in children of 11 years and older, distinguishing between sensory phenomena related to tics, and mental phenomena as often found in obsessive-compulsive disorder. The age-related differences observed in this study may indicate the need for the development of an age-specific questionnaire to assess premonitory urges.

Little is known about the brain's functional organization during resting-state in children with Tourette syndrome (TS). We aimed to investigate this with a specific focus on the role of comorbid attention-deficit/hyperactivity disorder (ADHD). We applied graph theoretical analysis to resting-state functional magnetic resonance imaging data of 109 8-to-12-year-old children with TS (n = 46), ADHD without tics (n = 23), and healthy controls (n = 40). First, we compared these three groups, and in a second comparison four groups, distinguishing TS with (TS + ADHD, n = 19) and without comorbid ADHD (TS-ADHD, n = 27). Weighted brain graphs were constructed for both comparisons to investigate global efficiency, local efficiency, and clustering coefficient per acquired network. Local efficiency and clustering coefficient were significantly lower in children with TS-ADHD in the default mode network compared with healthy controls, and in the frontoparietal network compared with ADHD; we also found associations with higher tic severity. Our study supports a different functional brain network organization in children with TS-ADHD, compared with healthy controls and children with ADHD., Competing Interests: Declaration of Competing Interest Jan K. Buitelaar has been in the past 3 years a consultant to/member of advisory board of/and/or speaker for Janssen Cilag BV, Eli Lilly, Shire, Medice, Lundbeck, Roche, and Servier. He is not an employee nor a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents or royalties. The other authors have no conflict of interest to report., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Findings of executive functioning deficits in Tourette syndrome (TS) have so far been inconsistent, possibly due to methodological challenges of previous studies, such as the use of small sample sizes and not accounting for comorbid attention-deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), or medication use. We aimed to address these issues by examining several areas of executive functioning (response inhibition, attentional flexibility, cognitive control, and working memory) and psychomotor speed in 174 8-to-12-year-old children with TS [n = 34 without (TS-ADHD) and n = 26 with comorbid ADHD (TS+ADHD)], ADHD without tics (ADHD-TS; n = 54), and healthy controls (n = 60). We compared executive functioning measures and psychomotor speed between these groups and related these to ADHD severity across the whole sample, and tic severity across the TS groups. Children with TS+ADHD, but not TS-ADHD, made more errors on the cognitive control task than healthy children, while TS-ADHD had a slower psychomotor speed compared to healthy controls. The ADHD group showed impairment in cognitive control and working memory versus healthy controls. Moreover, higher ADHD severity was associated with poorer cognitive control and working memory across all groups; there was no relation between any of the executive functioning measures and tic severity. OCD severity or medication use did not influence our results. In conclusion, we found little evidence for executive function impairments inherent to TS. Executive function problems appear to manifest predominantly in relation to ADHD symptomatology, with both cross-disorder and unique features of neuropsychological functioning when cross-comparing TS and ADHD., Competing Interests: Declaration of Competing Interest Jan K. Buitelaar has been a consultant to/member of advisory board of/and/or speaker for Janssen Cilag BV, Eli Lilly, Lundbeck, Shire, Roche, Medice, Novartis, and Servier. He has received research support from Roche and Vifor. He is not an employee or a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, and royalties. The other authors have no conflict of interest to report., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Attention-deficit/hyperactivity disorder (ADHD) is the most common comorbidity in individuals with Tourette syndrome (TS). Yet, it is unclear to what extent TS and ADHD show overlapping or distinct neural abnormalities. ADHD has been associated with altered reward processing, but there are very few studies on reward processing in TS. This study assessed neural activation of basal ganglia and thalamus during reward anticipation and receipt in children with TS and/or ADHD. We analysed mean activations of a priori specified regions of interest during an fMRI monetary incentive delay task. Data was used from 124 children aged 8-12 years (TS n = 47, of which 29 had comorbid ADHD; ADHD n = 29; healthy controls n = 48). ADHD severity across ADHD and TS groups and healthy controls was marginally related to hypoactivation of the right nucleus accumbens during reward anticipation; this effect was not moderated by TS diagnosis. We detected no associations of neural activation with TS. The association between ADHD severity and hypoactivation of the right nucleus accumbens during reward anticipation, independent of the presence or absence of TS, is in line with the view of nucleus accumbens hypoactivation as a dimensional, neurofunctional marker of ADHD severity, transcending the boundaries of primary diagnosis., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Multi-modal imaging may improve our understanding of the relationship between cortical morphology and cytoarchitecture. To this end we integrated the analyses of several magnetic resonance imaging (MRI) and spectroscopy (MRS) metrics within the anterior cingulate cortex (ACC). Considering the ACCs role in neurodevelopmental disorders, we also investigated the association between neuropsychiatric symptoms and the various metrics. T1 and diffusion-weighted MRI and 1 H-MRS (ACC voxel) data along with phenotypic information were acquired from children (8-12 years) with various neurodevelopmental disorders (n=95) and healthy controls (n=50). From within the MRS voxel mean diffusivity (MD) of the grey matter fraction, intrinsic curvature (IC) of the surface and concentrations of creatine, choline, glutamate, N-acetylaspartate and myo-inositol were extracted. Linear models were used to investigate if the neurochemicals predicted MD and IC or if MD predicted IC. Finally, measures of various symptom severities were included to determine the influence of symptoms of neurodevelopmental disorders. All five neurochemicals inversely predicted MD (all p uncorrected <0.04, β=0.23-0.36). There was no association between IC and MD or IC and the neurochemicals (all p>0.05). Severity of autism symptoms related positively to MD (p uncorrected =0.002, β=0.39). Our findings support the notion that the neurochemicals relate to cytoarchitecture within the cortex. Additionally, we showed that autism symptoms across participants relate to the ACC cytoarchitecture., (Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.)

Background: Tourette's disorder and attention-deficit/hyperactivity disorder often co-occur and have both been associated with structural variation of the basal ganglia. However, findings are inconsistent and comorbidity is often neglected., Methods: T1-weighted magnetic resonance images from children (n = 141, 8 to 12 years) with Tourette's disorder and/or attention-deficit/hyperactivity disorder and controls were processed with the Oxford Centre for Functional MRI [Magnetic resonance imaging] of the Brain (FMRIB) integrated registration and segmentation tool to determine basal ganglia nuclei volume and shape. Across all participants, basal ganglia nuclei volume and shape were estimated in relation to Tourette's disorder (categorical), attention-deficit/hyperactivity disorder severity (continuous across all participants), and their interaction., Results: The analysis revealed no differences in basal ganglia nuclei volumes or shape between children with and without Tourette's disorder, no association with attention-deficit/hyperactivity disorder severity, and no interaction between the two., Conclusion: We found no evidence that Tourette's disorder, attention-deficit/hyperactivity disorder severity, or a combination thereof are associated with structural variation of the basal ganglia in 8- to 12-year-old patients. © 2016 International Parkinson and Movement Disorder Society., (© 2016 International Parkinson and Movement Disorder Society.)