The clinical presentation, neurcognition and neural correlates of children with a tic disorder
Openneer, Thaïra
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10.33612/diss.173528953
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Openneer, T. (2021). The clinical presentation, neurcognition and neural correlates of children with a tic disorder. University of Groningen. https://doi.org/10.33612/diss.173528953
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Summary and general discussion
Chapter 7
SUMMARY AND
The overall goal of this thesis was to increase our understanding of TS, by investigating various aspects of its clinical presentation, neurocognition and neural correlates, in particular the influence of comorbid ADHD in TS while also comparing it to children with ADHD without tics and healthy controls. I aimed to extend our knowledge by overcoming several methodological challenges that have hampered existing studies, that is, by using prospectively gathered data, using larger sample sizes, taking comorbid ADHD into account, and controlling for comorbid OCD and current medication use. In the discussion to follow I will first shortly summarize each chapter and subsequently interpret the findings within the relevant literature and theoretical frameworks. Additionally, I will shortly investigate the clinical applications and future research directions.
Summary of the chapters
The aim of the first part of this thesis was to extend our knowledge regarding the clinical presentation of TS. I focused on two under-investigated clinical topics in TS: precursors of tics and premonitory urges. In Chapter 2 I focused on precursors of tic onset by assessing a range
of dimensional clinical symptom scales and a quality-of-life score prior to tic onset in comparison with children without onset of tics. I observed a distinct clinical profile prior to tic onset compared to those without a tic onset. Participants with a tic onset were more frequently male, had higher baseline severity of conduct and emotional problems, compulsions and ASD symptoms compared to children without a tic onset. Furthermore, this clinical profile prior to tic onset appeared sex-specific, with conduct and ASD problems being male-specific predictors, and severity of compulsions, oppositional and emotional problems being female-specific predictors. I moreover found that tics most often persisted one year after tic onset, in contrast to common belief that tics are mostly transient. I concluded that high-risk children should be monitored from a young age onwards, while taking sex differences into account.
In Chapter 3 I focused on premonitory urges in children and adolescents (aged 3-16
years), by investigating the psychometric properties of the widely used Premonitory Urge for Tics Scale, using the largest pediatric sample size to date (656 children and adolescents). I found that premonitory urges are present in a large number of children, also in very young children (< 7 years of age), which was contrary to the general belief that premonitory urges have not been yet developed in young children. Additionally, I found weak correlations between premonitory urges and tic severity and OCD severity in children between 8 - 10 years
of age, and not in younger or older children. My results indicated that the development of age-appropriate questionnaires may be necessary.
In the second part of this thesis, I aimed to investigate the influence of comorbid ADHD in children with TS on executive function and neural activity. In Chapter 4 I set out
to extend the current knowledge by investigating the influence of comorbid ADHD on executive function (response inhibition, attentional flexibility, cognitive control, and working memory) and psychomotor speed in 8-to-12-year-old children with TS, and in relation to ADHD without tics. I found executive function impairments (cognitive control and working memory) in TS in relation to ADHD symptoms; this was independent from comorbid OCD and medication use. I concluded that executive function impairments are not inherent to TS, but related to ADHD symptomatology.
The influence of comorbid ADHD in children with TS has been further examined in
Chapter 5, where I investigated group differences in response inhibition using an
fMRI-based stop-signal task. This is one of the few studies to investigate response inhibition in TS with and without comorbid ADHD compared to healthy controls, on a behavioral and neural level, using the largest sample size to date. I observed a specific response inhibition deficit and broader cognitive impairments in children with TS, which largely related to comorbid ADHD symptoms; this was independent from comorbid OCD and current medication use. Furthermore, increased brain activation was observed during failed inhibition in the right inferior frontal gyrus and left insula in children with TS and comorbid ADHD compared with healthy controls. Similar to Chapter 4, I concluded that response inhibition deficits and
enhanced brain activity during a response inhibition task are not inherent to TS, but related predominantly to ADHD symptomatology.
Finally, in Chapter 6, I aimed to investigate the functional brain organization during
rest in children with TS with and without comorbid ADHD, ADHD without tics, and healthy controls, using a graph theoretical analysis approach. Due to the paucity of previous studies, I did not restrict my analyses to particular brain regions, but adopted a data-driven, whole-brain approach, using one of the largest sample sizes in a pediatric population to date. I observed a suboptimal functional topological brain organization in TS without comorbid ADHD, specifically a lower local efficiency and clustering in the fronto-parietal network and in the default-mode network. I also found associations with higher tic severity. The results of this study suggested that a different functional brain network organization is inherent to TS, and not due to comorbid ADHD symptomatology.
Interpretation in the context of the existing literature
Precursors of tic onset
In Part 1 I started with a study on precursors of tic onset. Little was known about the onset of tics, as most studies were retrospectively designed resulting in difficulties in reporting or recall, and were often comprised of low sample sizes. With EMTICS, one of the largest prospective studies to date, I investigated high-risk as of yet tic-free siblings of children with tics who were followed for up to seven years, to investigate factors associated with a possible onset of tics (ONSET study; please see for more information about study procedures Schrag et al., 2019). In recent years, a body of research has focused on identifying early-life clinical characteristics that precede the onset of psychiatric disorders to aid in timely detection, early intervention, and possible prevention (Möricke et al., 2019; Hafeman et al., 2017; Bolton et al., 2012). However, it was not yet known whether early clinical characteristics precede the onset of tics. In line with my expectations, in Chapter 2, I observed several precursors prior to tic onset: children with
a tic onset were more frequently male, had a higher severity of conduct problems, compulsivity, ASD symptoms and emotional problems (anxiety and depression) compared to those without an onset of tics. Moreover, during follow-up one year after tic onset, I confirmed the presence of a chronic tic disorder in the majority (66%) of children, while 32% were diagnosed with transient tics lasting less than 12 months. This supports new insights that the persistence of tics is more often the rule than the exception (Kim et al., 2019), in contrast to common belief that tics in children are mostly transient.
In the medical practice, risk prediction models are often used to predict an individual’s risk of developing a condition (Tripepi et al., 2013). Although risk prediction models are still relatively nascent in psychiatry, it is increasingly used, for example in depression, anxiety disorder and bipolar disorder (see for review Bernardini et al., 2017). Although my method of analysis did not permit to calculate a risk profile of a child to develop tics, my results did point to several factors that are precursors of tic onset, which may aid in the future development of a risk prediction model. Future studies may investigate if other factors often seen in children with TS are also associated with tic onset, to identify the optimal set of risk factors, such as rage attacks, sleep problems, and learning disabilities (Kumar et al., 2016). Overall, my results highlight the need of regular monitoring of high-risk children from a young age onwards, which may aid in early detection of tics.
Sex differences in TS
In Chapter 2, I also investigated sex-differences in clinical precursors prior to tic onset. I
observed that conduct problems and ASD were predictors of tics in boys, whereas OCD, emotional problems, and ODD were female-specific predictors of tic onset. This may not be surprising as the co-occurring disorders in TS generally have a strong sex distribution. Indeed, similar to tic disorders, ADHD, CD and ASD have generally a male preponderance, whereas OCD and internalizing disorders (e.g., emotional problems such as anxiety/depression) occur in general more in females, especially from puberty onwards (Hirschtritt et al., 2015; Steinhausen & Jakobsen, 2019). However, the basis for sex differences in psychiatric disorders is poorly understood. Some theories have suggested that males and females may be differentially exposed to biological risk factors (e.g., prenatal testosterone exposure; Baron-Cohen, 2002), differentially susceptible to environmental factors (e.g., Hinshaw et al., 2006), or exhibit distinct psychological risk factors (e.g., Nolen-Hoeksema & Girgus, 1994). So far, only a few studies have investigated sex differences in TS. For example, a recent study of adults with TS using a latent class approach suggested that females may exhibit a behavioral phenotype characterized by more prominent OCD, phobias and panic attack (Rodgers et al., 2014). In line with this, Lewin et al. (2012) observed that females with tics had a higher life-time prevalence of comorbid OCD and non-OCD anxiety, and more likely to report that tics may have precipitated depression or anxiety. An older study found that males experienced more aggression and anger (‘rage’) during the onset of tics, which correlates with a higher prevalence of externalizing disorders (ADHD/conduct problems), whereas onset for females was associated with compulsive tics (Santangelo et al., 1994). The results of my study extend our knowledge regarding sex-differences in TS, largely showing that symptoms of internalizing behaviors (OCD, emotional problems, and the affective domain within ODD) are present prior to tic onset in females, whereas symptoms of externalizing behaviors (conduct problems) largely predicted male tic onset. Nonetheless, sex-related differences in TS are still insufficiently studied and poorly understood. Better knowledge of the mechanisms of sex differences in brain structure and function is likely to aid diagnosis and prognosis, differentiation of phenotypes, and development of new therapeutic options to treat and possibly modify the progression of TS.
Premonitory urges
Premonitory urges were the second feature that I focused on, by investigating the psychometric properties of the Premonitory Urge for Tics Scale (PUTS; Woods et al., 2005), using 656
children from EMTICS who were enrolled in the study with a diagnosis of a tic disorder (COURSE study; Schrag et al., 2019). Traditionally it has been thought that young children develop premonitory urges on average a few years after the onset of tics (Leckman et al., 1993). Thus, it has been generally believed that children under the age of 10 do not experience premonitory urges or are not aware of them (Banaschewski & Rothenberger, 2003; Raines et al., 2017). In contrast to this general belief, I observed in Chapter 3 that premonitory urges
are present to some extent in 81% - 95% of children between 3 - 10 years of age. However, it
remains questionable to what extent very young children were able to reliably fill in a self-report questionnaire, even though there are self-reports of 5-year-olds reliably filling in age-appropriate health-related questionnaires (Varni et al., 2007). More research is warranted to further explore the possible existence and reporting of premonitory urges in very young children.
In contrast to my expectations, I observed overall weak associations between premonitory urges and tic severity in Chapter 3. It has been thought that premonitory urges
maintain tics as a result of a negative reinforcement cycle (Capriotti et al., 2014; Himle et al., 2007). As premonitory urges are experienced as highly unpleasant sensations (Eddy & Cavanna, 2013), and patients execute tics to avoid these sensations, tics become rewarding as they relief these unpleasant sensations (Brandt et al., 2016). The assumption under which premonitory urges are usually studied is that these urges increase prior to tics and decrease after tics are executed. Interestingly, however, recent studies also indicated that urges may not be necessary for the ability to suppress tics (Banaschewski & Rothenberger, 2003; Ganos et al., 2012). For example, Ganos et al. (2012) suggested distinct neurological pathways for urge and tic generation, and tic suppression. A similar distinction has been mentioned by Brandt et al. (2016), showing only a weak relationship between premonitory urges and tic frequency during tic suppression, suggesting a decoupling of urges and tics during tic suppression. Although these results indicate that premonitory urges are not necessary prerequisites for tic suppression, a tight link between premonitory urges and tic execution is still assumed, also confirmed by the efficacy of behavioral therapies such as habit reversal training (Dutta & Cavanna, 2013). Yet, the results regarding the association between tic severity and premonitory urges are mixed: some authors observed an association between premonitory urges and more severe tics (Woods et al., 2005; Kano et al., 2015), whereas others did not confirm this relationship (Steinberg et al., 2010; Gulisano et al., 2015), similar to my results in Chapter 3.
One possible explanation for the discrepant results may be that the PUTS does not optimally assess premonitory urges, as it was originally designed as a unitary construct (Woods et al.,
2005), whereas the inconsistent findings of recent studies shows that there are different underlying urge dimensions which may differ between age groups and/or comorbidities (Brandt et al., 2016; Matsuda et al., 2020; Raines et al., 2018; Chapter 3). In the last years,
several new questionnaires have been developed that recognizes that the PUTS is not a unitary construct, such as the revised PUTS (Baumung et al., 2020), the Rumination and Awareness Scale for tic-associated sensations (Matsuda et al., 2020) and the individualized PUTS (McGuire et al., 2016). However, more research is warranted to investigate the validity of these new measures in comparison with the PUTS and in relation with tic severity.
Age differences in TS
TS has a clear age trajectory, with symptom onset mostly between ages 5 - 9, most severe tics
between 10 - 12, and with marked improvement or even remission after adolescence; although
a sizeable subgroup of patients (~60%) experience moderate to severe tics that persist into adulthood (Leckman et al., 1998). In line with this, I observed associations between age and premonitory urges in Chapter 3, using the data of 656 children with tics enrolled in the
COURSE study of EMTICS, indicating that this aspect of the clinical profile of patients with TS also changes over time. Indeed, not only reported children of 11 years and older more premonitory urges (97.5%) compared to children of 7 years and younger (81%; see Figure 1 of
Chapter 3), they also reported a higher severity of every PUTS item compared to the youngest
participants (see Table 2 of Chapter 3). Additionally, children of 11 years and older made a
distinction between premonitory urges related to tics versus premonitory urges associated with OCD-related behavior, in contrast to younger children (see Table 4 of Chapter 3).
Furthermore, I observed significant moderate associations between premonitory urges and symptom severity (e.g., tics, OCD, ADHD) for children between 8 - 10, but not for younger or
older children (see Table 3 and Supplementary Table S2d of Chapter 3). Plausibly, as clinical
characteristics such as tics and premonitory urges vary by age in TS, also brain structure and function vary by age. Indeed, several neuroimaging studies observed age-related differences in neural correlates in TS (Raz et al., 2009; Pépés et al., 2016; Peterson et al., 2001; Nielsen et al., 2021; Debes et al., 2011). For example, a study using transcranial magnetic stimulation observed that the motor threshold (defined as the minimum intensity of stimulation required to reliably induce a motor evoked potential in a targeted muscle) could be significantly predicted by age in the TS group, with higher motor thresholds in children compared to young adults (Pépés et al., 2016). A functional connectivity imaging study found stronger functional connectivity between sensorimotor and control networks in adulthood TS as compared to
childhood TS (Raz et al., 2009). Yet, only scattered knowledge is available regarding brain development in TS during different pivotal developmental periods, such as childhood or adolescence (Casey et al., 2008; Giedd et al., 1999). Instead, most studies of TS treat it as a singular disorder, unchanging across development, and are utilizing groups with wide age ranges, including children and adults. Longitudinal studies may therefore be necessary to investigate how the brain and associated clinical profile changes over time in patients with TS, as this may provide valuable clues about the etiology of this disorder.
Comorbid disorders in TS
The frequently co-occurring symptoms in TS (such as symptoms of ADHD and OCD) are thought to impact the quality of life more than tics themselves; children with TS who have a co-occurring disorder have been found to have poorer emotional, social, and academic functioning (Debes et al., 2010; Rizzo et al., 2007). In this thesis, the influence of comorbidity in TS played a substantial role; in Chapter 2 I observed that the frequent co-occurring
symptoms in TS are also precursors of tic onset. In Chapter 3 I observed that the severity of
premonitory urges is related to the severity of co-occurring ADHD, ASD, and OCD symptoms in children 8 - 10 years of age. I also found a distinct premonitory urge domain associated with
OCD-related behaviors based on factor analysis. In Chapter 4 and 5 I saw that ADHD
symptomatology influenced executive function and neural activity in TS. Overall, the results in this thesis extend our current knowledge by providing further evidence that comorbidity influences the clinical presentation, neurocognition, and neural correlates of children with TS.
Mechanisms underlying comorbidity
The mechanisms underlying comorbidity are not fully known. However, comorbid symptoms are likely to be due to a range of risk factors. Yet, there is little evidence of specific associations between particular risk factors and particular psychiatric disorders. The most reasonable explanation for the development of psychiatric disorders might be the combination, sequence and/or interaction of individual, familial, genetic, and environmental risk factors (Ford et al., 2004). One or more shared risk factors may explain why disorders tend to co-occur (Pennington, 2006). Regarding TS, a more specific theory was posed in 1997, suggesting that the comorbidity of tics and common co-occurring symptoms (OCD, ADHD) might be the result of shared underlying genetic factors that converge at the level of cortico–striato–thalamo– cortical (CSTC) circuits (Palumbo et al., 1997). It is generally believed that the CSTC circuits are affected in most neuropsychiatric disorders, including TS, OCD and ADHD (Mink, 2001;
Milad & Rauch, 2012; Groenewegen & Uylings, 2000; McBride & Parker, 2015). Anatomical or functional changes of any of the structures in these highly integrated CSTC loops could affect in parallel motor and behavioral patterns (DeLong & Wichmann, 2007; Obeso & Lanciego, 2011). The interaction between the circuits may therefore account for the high level of comorbidity between the disorders (Van den Heuvel et al., 2016). Still, results regarding abnormalities in CSTC circuits in patients with TS are inconsistent, with some studies pointing to structural and functional abnormalities (Plessen et al., 2004; Worbe et al. 2015; Serrien et al., 2005; Church et al., 2009), whereas others do not (Thomalla et al., 2009; Neuner et al., 2010; Naaijen et al., 2017). To date, the strongest evidence for a shared etiology stems from genetic- and family studies investigating the co-occurrence of TS, OCD and ADHD (Brainstorm Consortium et al., 2018; Mathews & Grados, 2011; Pinto et al., 2016; O’Rourke et al., 2009).
Comorbid OCD in TS
The comorbidity of TS and OCD has long been recognized in the literature, with approximately 50% of patients with TS meeting criteria for OCD (Hirschtritt et al., 2015). Several clinical characteristics are shared by OCD and TS, including juvenile onset (although TS develops generally at an earlier age than OCD), a chronic fluctuating course, repetitive behaviors and sensory phenomena (i.e., premonitory urges and not-just-right experiences; Eichstedt & Arnold, 2001; Coffey et al., 1998). Family studies have shown that OCD is more often present in relatives of probands with TS than in control families, independent of the proband having comorbid OCD (Eapen et al., 1993; Pauls & Leckman, 1986). Conversely, tics are more often present in relatives of probands with OCD than in the general population, independent of the proband having a comorbid tic disorder (Leonard et al., 1992; Pauls et al., 1993). These findings may suggest that a particular genetic vulnerability may be variably expressed as tics, OCD, or both symptoms in combination, although sometimes differentiation of overlapping symptoms can be difficult (Huisman-van Dijk et al., 2016). This is in line with the results of a recent Genome-Wide Association Study (GWAS) meta-analysis observing a high genetic correlation between TS and OCD (Brainstorm Consortium et al., 2018). Despite the results of genetic and family studies indicating a close relationship, studies directly comparing the two disorders are scarce, especially neuroimaging studies (see for review Kloft et al., 2018). Even scarcer are studies systematically investigating the role of comorbid OCD in TS (Kloft et al., 2018). From my results in Chapters 4 - 6 I concluded that OCD comorbidity does not influence
executive function and neural activity in TS, although this must be interpreted with caution as
there were only a few children with comorbid OCD limiting our power. Overall, the co-occurrence of OCD and TS is still severely understudied, and further studies are needed that systematically investigate the shared and unique characteristics of TS and OCD, and the influence of comorbid OCD symptoms in TS.
Comorbid ADHD in TS
While family and GWAS-studies provide convincing support for an etiological relationship between TS and OCD, the data are less clear with regard to the relationship between TS and ADHD. For example, family studies have shown that ADHD is not more often present in relatives of probands with TS. If present, it is usually as a co-occurring condition with TS (see O’Rourke et al., 2009 for review). Yet, a recent GWAS meta-analysis observed a medium-sized genetic correlation between TS and ADHD, thus indicating that TS and ADHD do share genetic determinants to some extent (Brainstorm Consortium et al., 2018). Regarding brain activity and neurocognitive function, only a limited number of studies systematically compared the two disorders, and investigated the role of ADHD comorbidity in TS. Therefore, in the second part of this thesis, I set out to extend the existing literature, to elucidate what neural (functional and connectivity) correlates and neurocognitive functioning are common and unique to TS with comorbid ADHD, TS without comorbid ADHD and ADHD without tics, compared to each other and to healthy controls.
The influence of comorbid ADHD on neurocognitive functioning
It has been hypothesized that dysfunction in the CSTC circuits may lead to executive function impairments (Eddy et al., 2009; Worbe et al., 2015). Unlike for ADHD, where response inhibition deficits have been repeatedly demonstrated (Willcutt et al., 2005), the relationship between inhibitory control and tics remains controversial (Ganos et al., 2014). Traditionally, tics were thought to originate from a lack of sufficient inhibitory motor control, whereas some studies suggested that TS patients may develop enhanced inhibitory control as a result of tic suppression in daily life (compensatory self-regulation mechanism). In fact, increasing evidence from both behavioral and neuroimaging studies indicates that patients with TS have shown enhanced cognitive control to achieve task performances (Baym et al., 2008; Jackson et al., 2007; Jackson et al., 2011; Mueller et al., 2006), although results are inconsistent (Channon et al., 2006; Greimel et al., 2011; Thibeault et al., 2016). In Chapters 4 and 5, I did not observe
impairments in cognitive control, or in executive function in general, related to tics. Instead, executive function impairments (cognitive control, working memory and response inhibition)
were associated with ADHD symptomatology. Yet, an interesting discrepancy was observed in Chapters 4 and 5 regarding response inhibition; I observed ‘normal’ inhibitory function in
children with TS (with and without comorbid ADHD) and ADHD without tics in Chapter 4,
whereas impaired response inhibition was found in children with TS and comorbid ADHD in
Chapter 5. These discrepant results may be due to the more demanding character of the
traditional stop-signal task (Chapter 5) versus the stop-signal task as utilized in the Amsterdam
Neuropsychological Task (ANT; De Sonneville et al., 1999; Chapter 4); the traditional
stop-signal task requires to explicitly withhold an already initiated response, whereas the stop-stop-signal task as used in the ANT does not. Overall, given the results of Chapter 4 and 5, one may
conclude that deficits in cognitive control are not inherent to tics, but related to (cross-disorder) ADHD symptomatology.
The influence of comorbid ADHD on neural activity
As previously mentioned, tics are presumed to originate from dysfunction in the CSTC circuits (Albin & Mink 2006; Peterson et al., 2003). In particular dysfunction of sensorimotor areas are suggested to underlie the occurrence of tics and other forms of disinhibited behavior (see for review Leckman et al., 2010). The inferior frontal gyrus together with the supplementary motor area have been identified as two of the principal hubs within the brain sensorimotor network using graph theoretical analysis (Worbe et al., 2012). Interestingly, in Chapter 5, I only
observed enhanced activity in the inferior frontal gyrus in children with comorbid ADHD and not in those with only tics, or a relation with tic severity. Furthermore, I did not observe (atypical) activation in motor regions, even though dysfunction in the motor regions, especially the supplementary motor area, is thought to be of key importance in the occurrence of tics (Leckman et al., 2010). My observations are somewhat in contrast to the compensatory self-regulation mechanism theory as mentioned earlier. This theory posits that self-self-regulation is implemented through changes in neural pathways linking prefrontal areas with primary and secondary motor regions, leading to enhanced activity in these brain regions to maintain a normal inhibitory performance (Baym et al., 2008; Jackson et al., 2007, 2011; Mueller et al., 2006; Jung et al., 2013). Although I did observe a normal inhibitory performance in children with TS without comorbid ADHD (Chapter 4 and 5), they did not display enhanced activity
in abovementioned regions. Although speculative, given the young age range (8 - 12 years of
age), perhaps compensatory mechanisms to deal with continued tic suppression have not yet fully developed. Plausibly, hyper-excitability of prefrontal areas and primary and secondary motor regions may develop over time, as a consequence to a continued effort to suppress tics.
The influence of comorbid ADHD on functional connectivity metrics
In Chapter 6 I observed a disrupted topological brain organization in TS, specifically
decreased short-range connectivity in children with TS without comorbid ADHD in the default mode network (implicated in ‘mind-wandering’; Buckner et al., 2008) compared with healthy controls, and in the frontoparietal network (involved in executive function and goal-oriented, cognitively demanding tasks; Church et al., 2009) compared with children with ADHD. It was unexpected that comorbid ADHD did not influence the results, as ADHD in itself is implicated in having atypical network connections (see for example Marcos-Vidal et al., 2017; Lin et al., 2015; Castellanos et al., 2008; Tao et al., 2017), although results are inconsistent regarding the strength and direction of connections (see Gao et al., 2019 for review). Yet, after removing healthy controls from my dimensional analyses, a positive relationship could be observed between connectivity measures in the default-mode network and ADHD symptoms, confirming that ADHD symptomatology influences the default-mode connectivity, although differently than tics (higher local connectivity in ADHD versus lower local connectivity in TS). These results imply that TS and ADHD have more distinctions in network connectivity than overlapping features, thus suggesting that the network architecture is disorder dependent. Interestingly, however, given that the local connectivity values of the frontoparietal network for TS with comorbid ADHD were more similar to TS without comorbid ADHD than to those of ADHD, one may speculate that presence of tics may be of more influence on the brain architecture than the presence of ADHD symptoms, despite a similar ADHD symptom count in TS with comorbid ADHD and ADHD without tics. Future research is warranted to replicate these findings.
Strengths and limitations
Strengths of the studies using EMTICS data were the prospectively gathered data, enabling me to investigate clinical precursors of tic onset in children with a heightened risk of developing tics. Furthermore, the large sample sizes and wide age range of EMTICS data allowed me to explore age-dependency in premonitory urges across a broad age range. Strengths of the studies using TS-EUROTRAIN data were the use of a sizeable sample of 8-12-year-old children with TS with and without ADHD, ADHD−TS, and healthy controls, combining behavioral and neural measures in group and dimensional analyses. Potential limitations of the studies using EMTICS data were, first, the use of multiple clinical sites across Europe in the EMTICS study, reflecting possible site differences in scoring and clinical populations. However, clinical
interviewers were regularly trained and standardization of the procedures was discussed bi-annually to reduce this bias. Second, the sample from the EMTICS COURSE cohort showed a relatively low number of comorbid ADHD and OCD diagnoses compared to previous studies. One possible explanation may be that recruitment also was done through patient organizations, which may have led to the inclusion of more study participants patients with mild tics whom are generally less accompanied by comorbid disorders (Huisman-Van Dijk et al., 2019). Furthermore, a diagnosis of OCD was an exclusion criterium of the ONSET cohort. These restrictions may also have led to a less severely affected sample. Yet, associations with ADHD and OCD severity could be observed in Chapter 3 and compulsions still appeared a predictor
of tic onset in Chapter 2. Limitations of the studies using TS-EUROTRAIN data included,
first, the high percentage of males in the TS group compared with ADHD and the control group, and second, the use of stimulant and non-stimulant medication of a few participants during the assessment day. However, the results did not change after removing females or medication-users from the analyses (Chapters 4 - 6). Yet, future studies may include sex-matched and
medication-free groups to confirm the present findings. Third, in the MRI-studies (Chapters 5 and 6) the possibility that some children may have suppressed their tics might have
influenced the results. Relatedly, while subtle tics may not necessarily cause motion artifacts, they may be associated with brain activation. Future research may benefit from careful monitoring of tics in the scanner. Fourth, although I assessed the effects of comorbid OCD in our studies (Chapters 2, 4 - 6), we were unable to thoroughly explore the role of comorbid
OCD due to the low number of subjects with comorbid OCD, possibly leading to an underestimation of the current effects. Relatedly, other comorbid disorders apart from ADHD and OCD may have influenced our results. Unfortunately, no further comorbid disorders were assessed to address these possibly confounding factors.
Conclusion
Overall, I observed a distinct clinical profile prior to tic onset compared to those without a tic onset. I also found that the clinical presentation in those with subsequent tics were age-and sex dependent. I furthermore observed that comorbidity plays a substantial role in the clinical presentation, neurocognitive functioning and the neural correlates of children with tics. I particularly investigated the influence of comorbid ADHD, observing that ADHD symptomatology is associated with cognitive control performance and inhibitory-related brain activity in TS. However, when purely looking at brain connectivity during rest, I observed an atypical brain network architecture in those with tics without comorbid ADHD, suggesting that
an atypical functional brain network organization is inherent to TS, and not due to comorbid ADHD symptomatology. Although more studies are needed that directly compare larger samples of TS and ADHD, the lack of overlap between TS and ADHD in my studies suggests that distinctions in neurocognitive and neural patterns between the disorders are more apparent than overlapping features.
Clinical importance of the current research and future directions
TS is often underdiagnosed, with a delay in diagnosis from the onset of tic symptoms up to three years (Debes et al., 2008). This may lead to late or incorrect treatment, lack of social support or stigmatization, causing higher psychological distress (Debes et al., 2008). From a clinical perspective it is important to be aware of the symptoms that are present prior to tics, as investigated in Chapter 2. Monitoring high-risk children for early-life subtle symptoms that
precede the onset of tics may possibly aid in the timely detection of tics, and perhaps in early intervention, subsequently diminishing the consequences of a late diagnosis. This is especially relevant for girls, as their clinical precursors may remain unmasked.
Chapter 2 also showed the importance of taking sex-differences into account. Very
little is known about sex-differences in TS, and current behavioral therapies or diagnostic criteria are not adapted to possible sex-differences. Future studies may therefore investigate sex-differences in depth regarding the clinical presentation of tics and co-occurring disorders. This would have important clinical implications for future treatment strategies, as externalizing disorders (e.g., ADHD) as observed as a precursor in males, and disorders such as OCD, observed as a precursor in females, are treated with markedly differing pharmacological and psychotherapeutic strategies (for example stimulants in ADHD compared to selective serotonin reuptake inhibitors [SSRIs] in OCD).
In Chapter 3 I observed that premonitory urges appear to be present at an early age,
possibly starting at the onset of tics in some children. This may be of clinical importance, as premonitory urges are a key component in common behavioral therapies [e.g., habit reversal training] in TS. Furthermore, from a clinical point of view it is also important to take the age-related differences in premonitory urges into account as observed in Chapter 3. As current
questionnaires assessing premonitory urges do not take these age differences into account, future studies may further investigate this in depth and develop age-appropriate questionnaires. The results from Chapter 4 – 5 shows that impaired executive functioning in children
with TS is largely driven by ADHD symptomatology. Future studies may therefore investigate if treating ADHD symptoms in children with TS may improve executive functioning.
Although there are no direct clinical implications of the MRI results (Chapter 5 - 6),
they provide an important step forward in understanding the etiology of TS and ADHD, which may feed psychoeducational programs. Future studies, behavioral as well as MRI studies, should consider the complex presentation of TS and take comorbid ADHD carefully into account, as the results in this thesis showed that comorbid ADHD influences executive functioning and neural correlates in children with TS. Although I investigated the influence of comorbid ADHD in this study, other comorbid disorders may also be relevant. OCD is also very common in TS (50%), as well as disruptive behavior disorders (30%), mood and anxiety disorders (30%), and ASD 21% – 22% (Hirschtritt et al., 2017; Darrow et al., 2017; Rizzo et
al., 2017). However, still little is known about the influence of these disorders on neurocognitive functioning and neural correlates in TS. Future studies involving a direct comparison of individuals with TS without comorbidities, those with TS and different comorbidities, and healthy controls, will be of particular value, although it requires sufficient sample sizes. Additionally, most studies are conducting between-group analyses or dimensional analyses, whereas the combination of both analyses in studies may reveal potential important information regarding the etiology of TS.
Further directions for future research may involve careful consideration regarding the approach to investigate brain metrics. An increased interest in task-related and resting-state fMRI studies of TS is apparent, as is evident in the number of recent publications. However, most studies are using seed-based (ROI) analysis, instead of reporting whole-brain results. The constrained use of ROI analysis can be valuable for testing specific hypotheses regarding putative neural mechanisms, yet the approach can lead to an artificially exaggerated role of some regions in psychiatric disorders while ignoring crucial contributions from others (Sprooten et al., 2017). Future studies may therefore rely more on a data-driven approach, using whole-brain analyses.
Finally, while a strength of this study regarding TS-EUROTRAIN data was the restricted age range (8-12-year-olds), future MRI studies may benefit from longitudinal designs, preferably starting at, or even before, the onset of tics in high-risk children. In earlier years, it has been assumed that major changes in the architecture and functioning of the brain were limited to the first years of life. In recent years, large-scale longitudinal studies have shown that a basic reorganization of the brain also occurs during adolescence, which is reflected in changes in neurocognitive functioning that are typical of this period of life (Casey et al., 2008; Giedd et al., 1999). In TS, adolescence is often characterized by a substantial decrease or complete remission of tics (Peterson et al., 1998). Despite this, longitudinal
neuroimaging studies in TS are lacking, and there is only scattered knowledge regarding the brain development in TS from childhood to adolescence, and whether different trajectories of brain development are associated with variations in outcomes such as disease persistence and comorbid disorders. Future studies may investigate how brain function and structure change from childhood to adolescence in relation to tic disorders, and to examine possible determinants in childhood that may influence disease persistence, neurocognitive dysfunction, and the development of comorbid disorders in adolescence.
Key findings
• Children with tics show a distinct clinical profile prior to tic onset compared to those without a tic onset: they are more frequently male, have higher baseline severity of conduct and emotional problems, compulsions and ASD symptoms.
• The clinical profile prior to tic onset appears sex-specific, with conduct and ASD problems being male-specific predictors, and severity of compulsions, oppositional and emotional problems being female-specific predictors.
• Tics most often persisted one year after tic onset, in contrast to common belief that tics are mostly transient.
• Premonitory urges exist in the majority of children with TS, also in very young children (< 7 years of age).
• The severity of premonitory urges and its correlation with other symptom dimensions (such as tics and obsessions/compulsions) are age-dependent.
• Executive dysfunction (that is, impairments in cognitive control, response inhibition and working memory) in children with TS are predominantly related to ADHD symptomatology.
• Children with TS without comorbid ADHD have lower short-range connectivity (lower local efficiency and clustering coefficient) in the default mode network compared with healthy controls, and in the fronto-parietal network compared to those with ADHD. • A suboptimal immature topological brain network organization seems to be inherently
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