Improvement in Tics and Motor Impulsivity Is Associated with Functional and Receptor-Enriched Connectivity changes in Adolescents with Tourette Disorder

BACKGROUND: In Tourette Disorder (TD), tics are frequently associated with impulsivity, yet the mechanisms linking these dimensions and their evolution during adolescence remain unclear. We combined behavioral, clinical, and receptor-enriched by target (REACT) functional connectivity imaging to examine tic severity and impulsivity over time in TD adolescents. METHODS: 64 TD adolescents and 56 healthy controls completed a saccadic motor waiting impulsivity (WI) task and resting-state fMRI at baseline. TD participants were reassessed 15 months later. REACT was used to examine dopamine transporter (DAT) - and serotonin 1B receptor (5-HT1B)-weighted functional connectivity within fronto-striatal motor and limbic networks. Longitudinal analyses focused on within-TD changes and their associations with clinical measures. RESULTS: Behaviorally, no differences emerged between groups, but within TD, higher WI was associated with greater global tic severity (YGTSS/100). Longitudinally, both tics (YGTSS/50 and /100) and WI improved significantly. Compared to controls, TD showed a higher functional connectivity between caudate and anterior cingulate cortex (ACC) on the left. Longitudinally, tic reduction (YGTSS/50) was linked to increased connectivity between nucleus accumbens (NAcc) - ventral tegmental area on the left; reduced WI correlated with a higher left caudate - subgenual ACC and bilateral putamen-supplementary motor area (SMA) connectivity. In TD versus controls, REACT showed elevated both DAT-weighted connectivity between the NAcc-SMA and 5-HT1B-weighted connectivity between the raphe-SMA. Longitudinally in TD, while 5-HT1B-weighted connectivity declined DAT-weighted connectivity remained stable. CONCLUSIONS: Changes in motor and limbic fronto-striatal functional connectivity were associated with longitudinal improvements in tics and WI in TD adolescents.