Functional and structural alterations in pediatric patients with Tourette and obsessive-compulsive disorder

Tourette syndrome (TS) is a frequent neuropsychiatric disorder characterized by multiple motor or phonic tics persistent for a year or more (American Psychiatric Association, 2013a). TS is accompanied by several comorbidities, predominantly obsessive-compulsive disorder (OCD) (Andrea Eugenio Cavanna et al., 2009; Hirschtritt et al., 2015). Independently from the co-occurrence in the context of TS, OCD may manifest alone as a disorder characterized by recurrent intrusive thoughts/urges and by compulsions, i.e., repetitive acts associated with the attempt by the individual to neutralize obsessions (James F. Leckman et al., 2010; Robbins et al., 2019). Repetitive, situation-inappropriate and distressful movements or behaviors are the hallmark of both TS and OCD. Particularly, in the case of TS+OCD patients are characterized by overlapping clinical features of the two disorders wherein the labeling of repetitive behaviors into complex tics or compulsions might be challenging (Mansueto & Keuler, 2005; Mathews & Grados, 2011a). In this context, patients with TS+OCD may either represent an intermediate phenotype underpinned by shared pathophysiological abnormalities of both TS and OCD or reflect a different pathophysiology altogether (Kloft et al., 2018). Addressing this issue our primary aim was to employ an exploratory/data-driven approach to directly compare resting-state functional connectivity patterns (rs-FC) in independent cohorts of TS without comorbidity (TSpure), TS with OCD comorbidity (TS+OCD), and pure OCD. This approach would further aid in clarifying whether TS+OCD patients are characterized by overlapping or independent FC changes when compared to TS pure or OCD patients. By examining functional connectivity (FC) patterns in seven resting-state networks of interest, we reported functional changes in the above cohorts in the basal ganglia, sensorimotor, default mode, frontoparietal and salience network. We also observed significant changes within the cerebellar network in all three patient cohorts. In particular, we reported that compared with Ctrls, all patient groups were characterized by increased cerebellar FC. While the rs-FC pattern was comparable in TSpure and TS+OCD, the OCD group had higher cerebellar connectivity than both the TS sub-cohorts. Moreover, the increased cerebellar connectivity correlated negatively with tic-severity in TS patients while a positive association was observed with compulsive scores in OCD. These correlations suggest a distinct functional role of cerebellum in the two neurodevelopmental disorders. In our sample the increased cerebellar FC changes in TS negatively correlated with tic severity indicating neuroplastic mechanisms involved in the modulation of tic expression. Contrastingly, in OCD the increased cerebellar FC positive correlated with compulsive scores reflecting maladaptive mechanism of neuroplasticity 6 possibly contributing to obsessive-compulsive symptom severity. These findings provided us with the necessary framework to fully investigate the involvement of cerebellum in the pathophysiology of TS and OCD. Cerebellum is involved in various motor functions and in several non-motor/emotion processing domains (Koziol et al., 2014; Van Overwalle et al., 2020) and only a handful of previous studies have postulated the involvement of cerebellum in TS and OCD (Sigurdsson et al., 2020; Tobe et al., 2010; Xu et al., 2019; H. Zhang et al., 2019). However, the precise role of the cerebellum in tics and compulsions has to be characterized in detail. Notably, to date direct comparisons contrasting cerebellar structural and functional changes in drug-naive children/adolescents with TSpure, TS+OCD, and pure OCD have not yet been explored. Therefore, to address this gap, and to better understand the potential contribution of the cerebellum and its afferent and efferent connections in the genesis of tics and compulsions we focused on exploring structural and functional connectivity of the cerebellum in our drug-naive pediatric cohorts. The structural analysis included the investigation of possible changes in cerebellar grey matter lobules as well as white matter (WM) fiber integrity of cerebellar peduncles. The functional analysis consisted of seed-based connectivity of deep cerebellar nuclei (i.e., dentate nucleus) with respect to whole brain (DN- FC). We specifically targeted the dentate nucleus in the cerebellum since it is the main cerebellar output pathway projecting its efferent fibers through the superior cerebellar peduncles (SCP) to the contralateral thalamus and various motor cortical and posterior associative areas. Hence the involvement of dentate in the neocerebellar functions is thought to subserve both motor and non-motor (cognitive) functions (Bernard et al., 2014; Bostan et al., 2013; Buckner, 2013). We anticipated to find alterations in the cerebellar grey matter lobules and white matter integrity of cerebellar peduncles. Additionally, we also hypothesized to find significant alterations in the cerebello-thalamo-cortical (CTC) circuit affecting both TS and OCD. Lastly, we expected to find possible correlations between significantly alerted cerebellar structural and functional connectivity and clinical severity scores. The pediatric nature of our cohorts enabled us to elucidate early pathophysiological changes in the cerebellum of children with TS and OCD. Also, the drug-free characteristic of our patients allowed us to demonstrate structural and functional cerebellar changes unrelated to chronic drug-treatments.