Urge-tic associations in children and adolescents with Tourette syndrome

In this study, for the first time, urge-tic relationships were investigated using fine-grained, temporally specific methods in children and adolescents with GTS using the real-time urge monitor. At the group level, our analyses confirm an association between urges and tics, extending previous findings from adults12,24 to a developmental sample. As previously found in adults, inter-individual variability of urge-tic association patterns was high, with less than half of the participants showing a positive urge-tic association at the individual level. Across participants, higher tic intensities were associated with more pronounced urge-tic relationships, suggesting that anticipation of tics might be facilitated by more “prominent” tics. Compared to an adult sample24, the temporal association between urge and instantaneous tic intensity was found to be reduced in children and adolescents. This is consistent with the hypothesis that urges develop over time, presumably as an adaptation to tics, rather than being the direct cause of tics. However, this latter finding needs to be interpreted with caution as the group difference was only present in one of the three measures of urge-tic association.

In line with previous results in adult patients with GTS12,24, we found a positive association between urges and tics in children at the group level: stronger urges were associated with a greater likelihood to tic, urges were elevated around tic occurrence, and tic intensity correlated with urge. These results are consistent with the reported clinical phenomenology of premonitory urges in relation to tic execution16,19,20,26 and, at first sight, could be interpreted as support for the notion of urges causing tics. However, this interpretation is weakened by the high variability of individual urge-tic associations.

In fact, examining individual data, only between ten and twelve (40–48%; depending on the measure) children/adolescents showed a positive association between urge and tics while in eleven to 13 children/adolescents (44–52%), no significant correlation could be detected. In two (8%) patients, even a negative correlation was found. This heterogeneity is qualitatively and quantitatively comparable to previous findings in adult patients with GTS24, and as discussed there, is at odds with the notion of tics being directly caused by urges. Moreover, as argued in the introduction, assuming a causal relationship from urges to tics would also lead to the developmental prediction of more “pure” (pronounced and consistent) urge-tic associations, presumably less mitigated by voluntary tic suppression, in children and adolescents compared to adults. This prediction is incompatible with our finding of substantial heterogeneity in urge-tic associations in children and adolescents.

Comparison to data from a previously reported adult sample, using the same research methodology24, indicated weaker urge-tic associations in children and adolescents according to one of the three measures of urge-tic association (taking into account tic intensity). While the statistical strength of this result is limited, it is nevertheless informative with respect to the two opposing views concerning the nature of the relationship between urges and tics: as discussed in the introduction, tics in GTS are usually most severe during childhood2,10,38 and likely less influenced by voluntary suppression compared to adults. If tics were caused by urges, this would lead to the prediction of stronger, more “pure” urge-tic associations in childhood and adolescence compared to adults. In contrast, as we propose in the Introduction, if tics are the primary clinical phenomenon and urges develop as an adaptation to tics, for instance to better anticipate and possibly control one’s tics, urge-tic associations should become more pronounced during development. Our findings from the comparison to the adult sample do not support the first view but are, at least partially, consistent with the hypothesis of urges as an adaptation to tics.

Considering inter-individual differences in children and adolescents with GTS and the relation to clinical measures, we found a positive relation between tic frequency (tics/min) during a standardized video-based assessment (RUSH video protocol) and tic frequency (%) during the urge monitor recording. This result confirms good reliability and objectivity of the tic ratings. Consistent with prior findings, we also found a positive correlation between reported urge intensity in the urge monitor and total scores of the Premonitory Urge for Tics Scale (PUTS)12,39, documenting convergent validity with respect to the different urge measurements.

Similar to adults24, measures of the strength of urge-tic association did not show correlations with clinical scores, in particular not the Premonitory Urge to Tic Scale (PUTS)40. However, unlike adults24, each of the three measures of urge-tic association showed a significant positive correlation with mean tic intensity during the urge monitor. Higher tic intensities were associated with more pronounced positive urge-tic relationships, suggesting that anticipation of tics is facilitated by more “prominent” tics. This is consistent with the hypothesis that urges develop as an adaptation to tics: patients with stronger tics may be more likely to develop tic awareness as well as tic anticipation behavior, resulting in more pronounced urge-tic associations. Importantly (and as in the adult sample), measures of urge-tic associations did not correlate with mean or range (SD) of urge during the urge monitor, emphasizing that the detection of urge-tic associations was not confounded with participants’ use of the available urge scale.

Nine participants of the current sample indicated not experiencing premonitory urges in the clinical assessment. We decided not to exclude these participants from the study as the instructions of the urge monitor appeared to make sense to each of them and the urge monitor may provide additional, possibly more fine-grained information about participants’ premonitory sensations than a clinical questionnaire (PUTS). Of note, all of these nine participants indicated varying urge levels in the urge monitor and, importantly, most of them showed significant urge-tic associations for at least some of the measures of urge-tic association. Moreover, restricting the group-level analyses to these nine participants revealed significant urge-tic associations for two of the three analyses. This indicates that these patients, despite not reporting urges in the clinical interview, were able to indicate apparently meaningful urge levels in the urge monitor. A possible explanation of this mismatch could be a missing ability to verbally express or describe feelings of urges at young age although they are present40,41,42. Using a non-verbal outcome measure, as in the urge monitor, may facilitate the expression of subtle or vague premonitory sensations. This suggests that, also in epidemiological and in particular developmental studies, the assessment of premonitory urges should be based on multiple measurement instruments, ideally minimizing demands to verbally express one’s urges.

Considering neural mechanism, it appears that urges and tics emerge from distinct functional systems43,44. Cortico-basal ganglia-thalamo-cortical circuits and connected regions, particularly the basal ganglia, the primary motor cortex (M1) and medial frontal areas play a crucial role in tic generation and tic execution43,45,46,47,48. In contrast, primarily sensory regions including the primary and secondary somatosensory cortices have been implicated in the generation of urges43,44,45,48,49,50. These regions strongly project to the insula playing an important role in the integration of somatosensory, visceral and emotional information and interoception45,50. Both networks, i.e., tic generation circuits and loops generating urges are connected through pathways linking the insula, the supplementary motor area and the cingulate motor area, which in turn project to M1 and descending motor pathways45,47,50. These data suggest that urges and tic emerge from separate but interconnected neuronal networks. Interestingly, in a resting state functional connectivity MRI study it was found that in some of the connections between urge and tic networks physiological maturation including decreases in connectivity was delayed in patients with GTS patients, implying some degree of immaturity of these pathways in GTS44. These data could be interpreted such that supra-physiological connectivity between these areas leads to increased bodily awareness creating urges as a “byproduct” in GTS.

Limitations of the present study include the sample size and challenges of disambiguating tics from physiological movements. Based on established criteria, our current sample size is appropriate for detecting moderate to strong correlations and, in the comparison to the adult sample, allowed detecting large effect sizes. A larger sample size may have allowed detecting weaker or multi-factorial associations and group differences. As in the previously reported adult sample24, the heterogeneity in urge-tic associations provides evidence against a straightforward causal relation between urges and tics. However, performing the urge monitor depends on the capability of individuals to report their current urge level, making the task inherently variable. Thus, inter-individual variability in urge-tic associations may be partly explained by inter-individual differences in the ability to accurately sense and indicate their subjective urge intensity.

The ambiguity of tics within a spectrum of physiological movements51 results in a certain degree of uncertainty with respect to tic ratings, especially in children and adolescents, where distraction, “playing” or more generally the presence of “surplus movements” may render the distinction between tics and non-tic movements more difficult. This was addressed by preliminary viewing and agreement on non-tic-movements between the two raters prior to the detailed video rating (see Sect. 2.3 Video-based tic ratings). Moreover, urge-tic associations may be underestimated due to the fact that tics were only recorded and rated from the upper body while participants reported overall urge intensities which may also be related to tics occurring at the lower body12. Yet, inter-rater reliability scores and agreement with tic ratings during the RUSH protocol indicate good reliability and objectivity of the tic measures.

To minimize systematic differences between age groups, the raters for the present study were trained and supervised by the raters of the previously acquired adult sample24 until high inter-rater reliability was achieved between all four raters. Moreover, while the rating scheme of the present study is a subset of the rating scheme used in the adult study (which also included information on body region and tic onset), it does include all the relevant information used in the analysis of the adult sample (tic presence/absence and tic intensity). The validity of the measures from the urge monitor task might be different for adults as compared to children (e.g., children might be more prone to distraction). Before conducting the task, the importance of not “playing” but indicating the real current urge feeling was explained to the patients age-appropriately. All videos and data from the urge monitor task were checked for any indications of not executing the task properly. This led to the exclusion of one patient. In the data of the remaining patients there were no signs of not performing the instructed task.

Using an established self-report tool, the urge monitor, to capture premonitory urge intensities and determine urge-tic associations in GTS, our results confirm significant positive correlations between premonitory urges and tics also in children and adolescents with GTS. Substantial inter-individual variability in urge-tic associations as well as some evidence for weaker urge-tic associations in the present compared to a previous adult sample are incompatible with the notion of tics solely being a consequence of elevated urge but are consistent with the hypothesis of urges developing as an adaptation to tics, for instance to anticipate and control tic expression. These findings are of considerable importance for the understanding of GTS and are potentially also relevant for therapy. Existing behavioral treatments, such as the Comprehensive Behavioral Intervention for Tics (CBIT), train participants to perform competing (non-tic) actions when they feel the urge to execute a tic e.g., Ref.52. In children and adolescents without urges or only weak urge-tic associations, alternative strategies, e.g., attention training techniques, might be more appropriate53. Investigations of urge-tic relations may thus become useful for personalized treatment approached in this common neuropsychiatric disorder.

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