The clinical presentation, neurcognition and neural correlates of children with a tic disorder
Openneer, Thaïra
DOI:
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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General introduction
Chapter 1
“Tourette syndrome is much more than that cursing disease” ( https://nos.nl/artikel/2287991-gilles-de-la-tourette-is-veel-meer-dan-alleen-die-scheldziekte.html).
Indeed, Tourette syndrome (TS) is a complex disorder that may encompass a variety of tics, e.g., blinking, grunting and shaking (see Figure 1 for more examples of tics in Dutch). The growing number of news articles and research papers that emerged in recent years shows how little, generally and scientifically, is known about this disorder. Although epidemiological studies have consistently shown that TS is not a rare condition, with a prevalence rate up to 1% in youth across all cultures (Knight et al., 2012; Scharf et al., 2012), TS is still poorly understood and underdiagnosed. A better understanding of the clinical presentation and neural correlates of TS may further reveal valuable clues into its etiology, possibly aiding in the future development of effective personalized interventions, and timely and accurate diagnoses. The overall goal of this thesis is to increase our understanding of TS, by investigating various aspects of its clinical presentation, neurocognition, and brain activity. In the following introduction, I will first give a short overview of the key concepts that are central to the research articles that are at the heart of this thesis: 1. the clinical presentation of TS, including the onset of tics and premonitory urges, 2. neurocognition in TS, where I investigated executive function, specifically response inhibition, and 3. the neural correlates including task-based (response inhibition) brain activity and resting-state connectivity. Subsequently, I will explain the
Figure 1. An advertisement in a Dutch national newspaper (NRC) showing the
variety of tics (in Dutch) patients with TS may experience. Developed by students of the Willem de Kooning Academy. Reproduced from www.tourette.nl.
samples and methods we used and I will finish this section with the aims and outline of this thesis.
Symptoms and diagnosis
TS is a childhood-onset neurodevelopmental condition, involving the performance of sudden, nonrhythmic, rapid and recurrent motor movements and vocalizations, called motor and phonic tics, that persist for at least one year (American Psychiatric Association, 2013). Most tics are simple, such as eye blinks, head jerks, throat clearings, or grunts; however, other tics involve more complex coordinated actions by multiple muscle groups that may seem goal-oriented. Examples of complex tics include fixed sequences of simple tics, touching and tapping, and various vocalizations such as cursing. At present, three diagnostic categories are included in the tic disorders section of the Diagnostic Manual of Mental Disorders – 5th edition (DSM-5
American Psychiatric Association, 2013): (1) Tourette syndrome (or Tourette’s disorder) where multiple motor tics and at least one vocal tic have been present for more than one year, (2) chronic (persistent) motor or vocal tic disorder, where one or more motor or vocal tics have been present for more than one year, and (3) provisional tic disorder, where motor and/or vocal tics have been present for less than a year. For the sake of convenience, in this thesis we also refer to a chronic (persistent) tic disorder when mentioning TS.
TS has its onset around the age of six (Hirschtritt et al., 2015; Leckman et al., 1998), and tics typically start as simple facial motor tics (such as head jerks) often followed by vocal tics. These tics become more complex towards the teenage years (Leckman, 2003), with the most severe period in terms of frequency and intensity generally between ten to twelve years of age (Leckman et al., 1998). Tics usually wax and wane in severity and frequency, and the lifespan trajectory is highly variable: approximately one third of the people with TS may experience remission of tics in late adolescence/early adulthood, one third will remain to experience mild to moderate tics and one third of the patients will continue to have severe tics into adulthood (Cohen et al., 2013).
Tic disorders are often underdiagnosed. Reasons for first referral to mental healthcare are frequently due to other behavioral or emotional problems rather than tics (Khalifa & Von Knorring, 2005). Indeed, it has been calculated that the delay in diagnosis from the onset of tic symptoms is approximately three years, with as consequence a late or incorrect treatment, no support from the social authorities, and less understanding from the social environment, leading to higher psychological distress (Debes et al., 2008). As tic disorders and its comorbid conditions share a common genetic background (Brainstorm Consortium et al., 2018), an early
overall liability to the presence of (milder levels of) behavioral and emotional problems seems plausible. A body of research has focused on identifying early-life clinical characteristics that precede the onset of psychiatric disorders (for example inattention being a precursor of ASD; Bolton et al., 2012; Hafeman et al., 2017; Möricke et al., 2019). However, it is not yet known whether early subtle (clinical) characteristics precede the onset of tics, even though identifying these early-life clinical characteristics may possibly aid in the timely detection of tics, and perhaps in early intervention.
Comorbid conditions
An estimated 87.5% of children with TS have psychiatric comorbidity (Hirschtritt et al., 2015), most frequently attention-deficit/hyperactivity disorder (ADHD, 54%, Hirschtritt et al., 2015), and obsessive-compulsive disorder (OCD; 50%, Hirschtritt et al., 2015), but also autism spectrum disorder (ASD, 18%-21%, Darrow et al., 2017; Rizzo et al., 2017), disruptive behavior disorders (oppositional defiant disorder [ODD]/conduct disorder [CD] 12%, Freeman et al., 2007), and internalizing disorders (anxiety and depression; 30%-36%, Hirschtritt et al., 2015). That means that ‘pure’ TS (that is, without comorbidities) is rare (Hartmann & Worbe, 2018). The comorbid symptoms in TS may be even more troublesome than the tics themselves; studies have demonstrated that a lower quality of life, lower self-esteem, and poorer social functioning are more common in individuals with tics and comorbidities than in individuals with only tics (Cavanna et al., 2013; Debes et al., 2010; Eapen et al., 2016).
Premonitory urges
Tics are often preceded by aversive or uncomfortable sensations, known as premonitory urges (Leckman et al., 1993). Some patients have described these premonitory urges as sensory feelings, such as an ‘itch’ or ‘pressure’, whereas others reported mental phenomena such as ‘the feeling that something is not complete’ or ‘not just right’ (Cox et al., 2018; Woods et al., 2005). The aversive feeling of the premonitory urge is thought to be reduced by the expression of tics (Leckman et al., 1993), which has been confirmed in several experimental studies (Brandt et al., 2016; Capriotti et al., 2014; Himle et al., 2007; Specht et al., 2013). Consequently, tic expression may become negatively reinforced due to the reduction in the aversive premonitory urge, which makes tics more likely to reoccur when a premonitory urge is experienced again (see Figure 2 for a schematic overview of the premonitory urge cycle).
Behavioral interventions such as habit reversal training (HRT), the comprehensive behavioral intervention for tics (CBIT), and exposure with response prevention (ERP) aim to interrupt this negative reinforcement pattern. For example, in HRT competing responses are utilized so that the patient is unable to express tics when he or she notice the premonitory urge. A competing response is a behavior that is physically incompatible with the tic, socially discrete, and which can be maintained for up to one minute. HRT is also the core modality of CBIT. In CBIT, different psychoeducational elements, relaxation training and reward contingency plans are added to the HRT methods. In ERP a habituation mechanism is used through the prolonged suppression of tics with as result a gradual reduction in the premonitory urge. In general, these behavioral therapies have been proven very successful in relieving tic symptoms (Hoogduin et al., 1997; Piacentini et al., 2010; Verdellen et al., 2008; Viefhaus et al., 2020; Wilhelm et al., 2012).
Despite the success of behavioral therapies and the recent advances in our understanding of the role of premonitory urges as reflected in the increasing number of studies, the premonitory urge is perhaps still one of the least understood features in TS. For example, recent evidence showed that premonitory urges and tic suppression are not as tightly linked as previously thought, but address different neural pathways (Ganos & Martino, 2015). Also, it has been generally believed that young children under the age of 10 do not experience premonitory urges or are not aware of them (Baneschewski et al., 2003; Kwak et al., 2003; Leckman et al., 1993), although this has been recently contradicted by large sample-sized study observing premonitory urges in approximately 50% of the children with TS younger than 10 years (Sambrani et al., 2016). Thus, despite that premonitory urges take a pivotal role in commonly used behavioral therapies in TS, it is clear that more research is warranted to understand this characteristic feature in TS.
Figure 2. A schematic overview of the premonitory urge cycle
Neurobiology
The etiology of TS is not yet fully understood. However, it is believed that cortico–striato– thalamo–cortical (CSTC) circuits are affected in TS (Kalanithi et al., 2005; Mink, 2001; Peterson et al., 2003; Worbe et al., 2012). These circuits assure the communication between subcortical structures. The basal ganglia are central to the CSTC circuits, referring to a group of subcortical nuclei including the caudate, globus pallidum and nucleus accumbens, responsible for motor control, executive functions, behaviors, and emotions (Lanciego et al., 2012). There are three main CSTC circuits: the motor, limbic (emotional) and associative (cognitive) circuit (Alexander et al., 1986; see Figure 3 for a schematic overview). Although the CSTC circuits are running parallel, they are also highly integrated, which allows for the integration of information (Milad & Rauch, 2012). As a result, changes in the anatomy or function of any of the CSTC loops could affect in parallel motor and behavioral patterns (DeLong & Wichmann, 2007; Ganos et al., 2013; Obeso & Lanciego, 2011).
Abnormalities in CSTC circuits have been implicated in various neurodevelopmental disorders, including TS, OCD, and ADHD (Groenewegen & Uylings, 2000; Leisman & Melilo, 2003; McBride & Parker, 2015; Milad & Rauch, 2012), and the interaction between the circuits may account for the high level of comorbidity between the disorders (Van den Heuvel et al.,
Figure 3. Simplified schematic of the main cortico-striatal-thalamo-cortical loops.
Reproduced from Krack et al. (2010). Cn - caudate nucleus, GPe - globus pallidus pars externa, GPi - globus pallidus pars interna, Put - putamen, STN - sub-thalamic nucleus
2016). However, the results of studies investigating CSTC dysfunction in TS are mixed; some observed functional and structural abnormalities in the basal ganglia and frontostriatal circuits compared to healthy controls (see for review Ganos et al., 2013 and Plessen et al., 2009), pointing to CSTC dysfunction, whereas other studies observed no abnormalities in (areas involved in) CSTC circuits (see for review Ganos et al., 2013; Forde et al., 2017; Naaijen et al., 2016a). To date, the neurobiological origin of TS remains unknown, and it is not yet clear if, and/or how, abnormalities in CSTC circuits are involved in TS.
Neurocognition and neural correlates
Executive functioning
The frontal areas involved in the CSTC circuits subserve executive functions, i.e., the lateral orbitofrontal cortex, the dorsolateral prefrontal cortex, and the anterior cingulate cortex. Dysfunction within the CSTC circuits may therefore lead to executive function impairments (Eddy et al., 2009; Worbe et al., 2015). A considerable number of TS studies have shown impairments in executive function performance, most notably in response inhibition, working memory, and attentional flexibility, although some observed no executive function deficits in TS (see for reviews Eddy et al., 2009; Morand-Beaulieu et al., 2017a,b). Several factors may account for these discordant results, such as wide age ranges, the use of medication, and not taking comorbid disorders into account. Indeed, ADHD, which is one of the most frequently co-occurring disorders in TS (54%; Hirschtritt et al., 2015), is in itself characterized by executive function impairments (see for review Stevens et al., 2010). In studies with children and adolescents with TS, comorbid ADHD is associated with executive function impairments compared to TS without comorbid ADHD or healthy controls (Greimel et al., 2011; Lange et al., 2017; Thibeault et al., 2016), although normal performances were also found even in the presence of comorbid ADHD compared to healthy controls (for review see Morand-Beaulieu et al., 2017 a,b). Adding to these inconsistent results, a recent meta-analysis indicated mild executive dysfunction in those with TS without comorbidities, suggesting deficits inherent to TS (Morand-Beaulieu et al., 2017b). Clearly, it is still not fully known whether and to what degree potential deficits in executive functioning are intrinsic to TS, or can be attributed to comorbid ADHD in TS.
Response inhibition – behavioral performance
Impaired response inhibition has consistently been implicated in TS. Response inhibition is an important executive function, as it enables the suppression of prepotent behavior that is either
no longer required or inappropriate (Chambers et al., 2009). Tics typically resemble ‘disinhibited’ behaviors, which is suggestive of impairments in inhibitory control. Still, the results of studies in inhibitory control are inconclusive, with some studies pointing to an impaired inhibitory performance in children and adults with TS compared with healthy controls (Channon et al., 2009; Goudriaan et al., 2006; Wylie et al., 2013; Yaniv et al., 2017), whereas other studies found no impairment in inhibitory control (Eichele et al., 2010; Mancini et al., 2018; Ray Li et al., 2006; Roessner et al., 2008; Sukhodolsky et al., 2010). A recent meta-analysis concluded small to medium behavioral inhibitory deficits in patients with TS, with larger deficits in individuals with TS with comorbidities compared to those without comorbidities, particularly those with comorbid ADHD (Morand-Beaulieu et al., 2017b). This is not surprising, as Barkley already posited in 1997 that response inhibition may be the central neurocognitive function affected in ADHD (Barkley, 1997). Comorbid ADHD is therefore an important confounder in studies investigating inhibitory control and other executive functions in TS. However, given the sparsity of well-sized studies, we still lack unequivocal evidence whether and to what degree potential deficits in different executive function domains in TS can be attributed to comorbid ADHD, or are intrinsic to TS without comorbid ADHD.
Response inhibition – neural correlates
To understand behavioral results, one may also look at the neural processes that could influence response inhibition performance. A recently conducted meta-analysis on task-based magnetic resonance imaging (MRI) studies in TS (including tasks measuring response inhibition) reported wide-spread alterations in functional systems including prefrontal and motor areas, somatosensory and visual areas, and parieto-temporal areas compared to healthy controls (Polyanska et al., 2017). Importantly, however, only alterations in prefrontal and motor regions predicted tic severity, suggesting specificity of task-based neural reactivity within these areas to the core symptomatology of TS (Polyanska et al., 2017). Even though response inhibition is one of the most commonly investigated executive functions with functional MRI (fMRI) in psychiatric disorders (Zhang et al., 2017), few studies have investigated neural activity during response inhibition in TS, with inconsistent results. For example, Marsh et al. (2007) observed hyperactivation in fronto-striatal regions in children and adults with TS in relation to poorer inhibitory performance on a Stroop task, whereas decreased activation in the frontal and motor areas in children with TS has also been found during a conflict task (Jung et al., 2013). Additionally, Ganos and colleagues (2014) observed increased activation in the dorsal premotor cortex in adults with TS compared to healthy controls during a stop-signal task,
however, only during the go-phase, and not during the stopping-phase of the task. As mentioned before, several reasons can explain discordant results in inhibitory control, such as the wide variety of tasks that may recruit different neural dynamics (Simmonds et al., 2008; Zhang et al., 2017), and differ in cognitive requirements (Van Belle et al., 2014; Mancini et al., 2018). Other factors that may result in inconsistent outcomes in executive functioning are the wide age ranges, medication use, and, perhaps most importantly, not taking comorbidities into account. In TS, to my knowledge, only one study so far investigated response inhibition in TS with and without comorbid ADHD with fMRI, observing no difference in brain activity patterns during response inhibition (Debes et al., 2011), although it should be noted that that study only included five children with TS and comorbid ADHD. Overall, it is not yet clear if an impaired performance and/or atypical brain activity during response inhibition is inherent to TS, or driven by comorbid disorders such as ADHD.
Resting-state connectivity
In contrast to task-based fMRI, resting-state MRI captures brain activity unrelated to a particular task, which enables the investigation of the full organization of the brain (Van den Heuvel & Hulshoff-Pol, 2010). In TS, functional resting-state studies in adults and
adolescents have found significantly altered connectivity in the fronto-parietal network relative to healthy controls (Fan et al., 2018; Church et al., 2009). The fronto-parietal network is involved in attention processing and executive functions (Damoiseaux et al., 2006), and consists of the lateral prefrontal cortex along the middle frontal gyrus, the anterior inferior parietal lobule, the cingulate cortex, and the caudate nucleus (Uddin et al., 2019). In addition, a recent resting-state study in adults with TS observed low functional connectivity in the default mode network compared to healthy controls (Fan et al., 2018). The default mode network is thought to be essential for monitoring the world around us (Gusnard et al., 2001), mind-wandering (Mason et al., 2007), and integrating cognitive and emotional processes (Greicius et al., 2003), and consists of the medial frontal, inferior parietal and temporal regions, and posterior cingulate cortex/precuneus (Buckner & Vincent, 2007; Uddin et al., 2019).
Graph theoretical analysis is a popular method for analyzing resting-state fMRI data, as it provides a powerful mathematical framework for the characterization of connections of brain functional networks (Bullmore & Sporns, 2009; Power et al., 2011). Brain networks are thought to be organized according to small-world architecture, depending on the developmental stage (Fair et al., 2009). Overall, anatomically close brain regions (nodes) have more
connections (edges) than distant nodes, thereby satisfying the competitive demands of brain networks in information processing (Bullmore & Sporns, 2009). Therefore, graph theoretical analysis might be an important tool to unravel the underlying neural mechanisms of TS by investigating possible deviances in the topological brain organization. A few studies have used graph theoretical analysis to increase our understanding of the topological brain organization in TS, all pointing to an abnormal (decreased) pattern of functional connectivity in default-mode- and fronto-parietal areas (Church et al., 2009; Ramkiran et al., 2019; Wen et al., 2018; Worbe et al., 2012). However, none of abovementioned studies in TS took comorbid ADHD into account, despite the fact that ADHD in itself is associated with atypical functional connectivity patterns, specifically in the fronto-parietal- and default-mode networks. This has been suggested to be a result of developmental delays associated with ADHD (Castellanos et al., 2008; Marcos-Vidal et al., 2017; Tao et al., 2017). Overall, from the current literature, it is, as of yet, unclear to what extent children with TS and ADHD show similar or dissimilar functional brain connectivity patterns, and whether the frequently comorbid ADHD symptoms in TS might underlie possible abnormalities in functional connectivity in TS.
Samples and methods
Three large tic research projects have been conducted in the last years at the University Medical Center Groningen (UMCG; see Appendix 1 for more information about these projects). These have addressed several limitations of the existing literature, namely the lack of prospective studies, small sample sizes, wide age ranges, not taking medication use into account, and not controlling for comorbid ADHD. The results within this thesis are derived from two of these projects.
The first part of this thesis (Chapters 2 and 3) includes data from the baseline measurements of the large-scale longitudinal European Multicenter Tics in Children Study (EMTICS; Schrag et al., 2019); a study investigating the interplay between genetics, auto-immunity, and environmental factors as a possible cause for the onset and exacerbation of tics. This project was based on two separate cohort studies: ONSET and COURSE. The ONSET study examined the association of onset of tics with exposure to pharyngeal GAS carriage or infection and other environmental and genetic factors, using clinical and laboratory assessments, over a 3-year period in 259 children between 3-12 years of age. On average three years after regular study end, children without a tic onset during the study were reassessed for possible new onset of tics, by a brief telephone interview through the study clinician. The COURSE study investigated exacerbations of tics over a maximum period of 18 months in 715
children and adolescents with an age range of 3-16 years affected by a tic disorder. In both the ONSET and COURSE study, subjects had alternating 4-monthly planned hospital visits and telephone interviews as well as parental weekly diaries, aimed at identifying new onset of tics or tic exacerbations respectively. Clinical characteristics were gathered by a diagnostic interview and by parent-and child-rated questionnaires, that had to filled in before each visit. However, for both articles in this thesis (Chapter 2 and 3) only clinical data from the baseline measurements of EMTICS were used.
The second part of this thesis (Chapters 4 - 6) utilizes a study sample collected in collaboration between the TS-EUROTRAIN (Forde et al., 2016) and COMPULS (Naaijen et al., 2016b) studies. TS-EUROTRAIN is a European collaboration that concentrated on genetics, neuroimaging and animal models in TS. COMPULS is an international multi-site investigation of compulsivity and impulsivity across disorders (OCD and ASD). In addition, data was collected from participants with ADHD and healthy controls. The cohort studied here in Chapters 4 - 6 is from one neuroimaging site (Nijmegen) and comprises 8-12-year-old children with TS (n = 60; of whom n = 26 had comorbid ADHD), ADHD (n = 60) and healthy controls (n = 60). Data collection included structural and functional MRI scans, MR Spectroscopy data, diagnostic interviews, behavioral questionnaires, neuropsychological tests and blood (or saliva) samples for genetic testing. For this thesis, only the data gathered from the functional MRI scans, diagnostic interviews, behavioral questionnaires, and neuropsychological tests were used.
Aims and thesis outline
This thesis consists of two parts. The aim of the first part of this thesis was to extend our knowledge regarding the clinical presentation of TS, by using data from the EMTICS study. We focused on two under-investigated clinical topics in TS: precursors of tics and premonitory urges. Chapter 2 focuses on precursors of tics. In recent years early-life clinical characteristics have been identified that precede the onset of psychiatric disorders such as ADHD and ASD. Due to the lack of prospective studies so far, it was not known if there are clinical characteristics present prior to the onset of tics, although this knowledge may be very valuable in terms of early detection of tics. Therefore, in Chapter 2 I aimed to investigate clinical precursors of tic onset using prospective data from the ONSET cohort of EMTICS. To our knowledge, this is the first study to investigate this.
In Chapter 3, I focused on premonitory urges in children and adolescents, by investigating the psychometric properties of the widely used Premonitory Urge for Tics Scale
(Woods et al. 2005), using the largest pediatric sample size to date. I investigated the internal consistency of the PUTS, correlations with tic and OCD severity and other comorbid symptom domains (i.e., ADHD, ODD, ASD, and externalizing and internalizing symptoms), and conducted a factor analysis of the PUTS. I also explored age differences.
The second part of this thesis used data from TS-EUROTRAIN. In this part of the thesis, I aimed to investigate the influence of comorbid ADHD in children with TS on executive function and neural activity. In Chapter 4, I aimed to extend the sparse literature on executive functioning in children with TS, by investigating the role of comorbid ADHD and compare this to children with ADHD without tics and healthy children. As pointed out by a recent meta-analysis (Morand-Beaulieu et al., 2017), there is a need for investigating several executive functions using a large sample size, controlling for medication, and perhaps most importantly, taking comorbid ADHD into account.
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, on a behavioral and neural level, using the largest sample size to date.
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.
In Chapter 7 the findings from the abovementioned studies are discussed in light of the existing literature, clinical implications are considered and directions for future research are suggested. Additionally, although not formally part of this thesis, I refer to Appendix 1; presenting a Dutch article entailing an overview of three large projects focusing on tic disorders at the UMCG in the last few years, including EMTICS and TS-EUROTRAIN.
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