Distinct cerebellar networks underpin clinical improvement in adolescent Tourette disorder

Abstract Adolescence is frequently called the second brain maturation period. In Tourette disorder (TD), the clinical trajectory of tics and associated psychiatric co-morbidities vary significantly across individuals during the transition from adolescents to adulthood. In this study, we aimed to identify patterns of resting-state functional connectivity that differentiate adolescents with TD from their neurotypical peers, and to monitor symptom-specific functional changes over time. We employed multivariate analysis based on support vector machine (SVM) to predict patterns of resting-state functional connectivity in 64 adolescents with TD and 61 sex- and age-matched healthy controls (HC). 57 TD patients participated twice, at a time interval of 15 months. Based on the results of the multivariate analysis, we implemented a general linear model testing within-group differences in resting-state functional connectivity over time, as well as their correlation with changes in severity of tics, depressive, obsessive-compulsive (OCD) and attention deficit and hyperactivity (ADHD) symptoms. SVM significantly discriminated TD from HC with above-chance accuracy, specificity and sensitivity. The most discriminative connections were prefrontal, striatal and cerebellar networks. Between the visits, adolescents with TD showed decreased functional connectivity between the vermis 3 and the bilateral supplementary motor area, and between the vermis 4,5 and the occipital cortex. The correlation analysis evidenced that (i) an improvement between the visits in the severity of tics was associated with increased connectivity between the pre-supplementary motor cortex, anterior cingulate and inferior frontal gyrus; (ii) an improvement of ADHD was associated with decreased connectivity of the anterior cingulate cortex with the inferior temporal cortex; (iii) an improvement of OCD correlated with decreased cerebellar (lobule 8 and vermis 8, 9) connectivity with fronto-polar, superior temporal and superior frontal cortices, and increased cerebello-parietal connectivity, as well as fronto-parietal and fronto-frontal connectivity; and (iv) an improvement of depressive symptoms correlated with decreased connectivity of the cerebellum (lobule 4, 5 and vermis 6) with the precuneus. Our findings support pathophysiological models of TD in which aberrant patterns of functional connectivity are related to specific comorbidities, that may evolve differently throughout adolescence. Resting-state functional connectivity may provide unique endophenotypes with developmental changes potentially linked to the modification of severity of comorbid conditions. Distinct regions of the cerebellum and its connectivity with various frontal cortical regions emerge as candidate biomarkers to monitor, and possibly predict, the clinical trajectory of TD symptoms, offering insights into disorder pathogenesis and likely guide clinical decision-making.