Distinct cerebellar networks underpin clinical improvement in adolescent Tourette disorder

Adolescence is frequently called the second period of brain maturation. In Tourette disorder (TD), the clinical trajectory of tics and associated psychiatric co-morbidities varies significantly across individuals during the transition from adolescence to adulthood. In this study, we aimed to identify patterns of resting-state functional connectivity that differentiate adolescents with Tourette disorder from their neurotypical peers, and to monitor symptom-specific functional changes over time. We employed a multivariate analysis based on a support vector machine (SVM) to predict patterns of resting-state functional connectivity in 64 adolescents with Tourette disorder and 61 sex- and age-matched healthy controls. Fifty-seven patients with Tourette disorder participated twice, with an interval of 15 months. Based on the results of the multivariate analysis, we implemented a general linear model to test 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. The SVM significantly discriminated Tourette disorder from healthy controls with above-chance accuracy, specificity and sensitivity. The most discriminative connections were prefrontal, striatal and cerebellar networks. Between the visits, adolescents with Tourette disorder showed decreased functional connectivity between vermis 3 and the bilateral supplementary motor area and between vermis 4, 5 and the occipital cortex. The correlation analysis revealed 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 (lobules 4, 5 and vermis 6) with the precuneus. Our findings support pathophysiological models of Tourette disorder, in which aberrant patterns of functional connectivity are associated with specific comorbidities that may evolve differently throughout adolescence. Resting-state functional connectivity may provide unique endophenotypes, with developmental changes potentially linked to modifications in the severity of comorbid conditions. Distinct regions of the cerebellum and their connectivity with various frontal cortical regions emerge as candidate biomarkers to monitor, and possibly predict, the clinical trajectory of Tourette disorder symptoms, offering insights into disorder pathogenesis and likely guiding clinical decision-making.