Pathophysiology: functional anatomy

On a systems level, major strides have been achieved in the field over the past two decades, though a generally accepted pathophysiological model of GTS remains elusive.

Although evidence from structural and functional Magnetic Resonance Imaging (MRI) studies is varied, these studies have repeatedly highlighted abnormalities within the lim-bic, associative and motor cortico-striatal-thalamo-cortical (CSTC) networks [28]. A summary of structural and functional neuroimaging studies is highlighted in the follow-ing subsections.

2.4.1 Structural neuroimaging studies

Despite the abundance of structural MRI studies, there are many inconsistencies in the literature. The diversity of results can be explained by variabilities in sample size, patient characteristics (e.g. age, presence of comorbidities, neuroleptic use), imaging methods (e.g. region-of-interest based vs. whole brain), and statistical analysis methods [29,30].

Nonetheless, there are some consistencies in structural investigations of GTS patients and these include: (a) a reduction in the volume of the caudate in both children and adults [31–34], and (b) cortical thinning in the sensorimotor, prefrontal and cingulate cortices [32, 35–37]. It is of note to mention that the specificity of cortical thinning seems to be dependent on the phenotype. For example, Worbe et al. [37] showed that patients with simple tics (cortical thinning in primary sensory and motor cortices) exhibit a different structural profile relative to patients with complex tics (cortical thinning in premotor, prefrontal and associative areas). Overall, structural MRI indicate that GTS is associated with dysfunction in associative, limbic and motor CTSC regions [28,29,38].

2.4.2 Functional neuroimaging studies

Evidence from task based functional MRI (fMRI) studies on the involvement of specific regions in the pathophysiology of GTS is relatively scarce and ambiguous. Task fMRI studies can be classified into four groups; investigations of motor behaviour, tic gener-ation, tic suppression and executive function. Groups investigating mechanisms of tic generation and control in GTS have compared (a) simple vs. complex tics [39]; (b) tic imitation vs. real tics [40]; (c) periods of tic suppression vs. periods of free ’ticking’

[41]; (d) pre-monitory urge periods and tic generation periods [42]; (e) suppression of eye blink in healthy controls vs. GTS patients [43]. Although these studies show that an extensive network of premotor, primary motor and sensorimotor networks are involved

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in tic generation, a critical distillation of the studies only ties the Supplementary Mo-tor Area (SMA) to tic generation [29]. A few other groups have aimed at investigating motor performance in GTS patients. These studies are limited and conflicting, as some groups showed over activations in the SMA and the sensorimotor cortex during a finger tapping task [6,44], while others show no group differences for the same task [45]. There is much debate on whether executive function is impaired in GTS. For example, (a) some behavioral studies have demonstrated impairments in several domains of executive function (response inhibition, selective attention, cognitive flexibility) [46–48];(b)others have argued that such impairments are driven by comorbid conditions [49]; (c) while a third group of studies presented evidence of enhanced performance by GTS patients on cognitive tasks [50,51].

Moreover, studies that implemented fMRI paradigms designed to investigate response inhibition in GTS patients also exhibited inconsistencies. First, using a Stroop task to investigate the neural correlates of response inhibition, Marsh et al. [52] demonstrated that tic severity and the persistence of GTS symptoms may be due to disrupted matura-tion of fronto-striatal circuits involved in self-regulatory control, since prefrontal activity correlated with tic severity and there was no age related change in frontostriatal cir-cuitry as exhibited by the control group. Second, also using a Stroop task in addition to a go/no-go task, Debes et al. [45] demonstrated that there were no differences between healthy controls and patients, however, activity in the posterior cingulate and superior temporal gyrus correlated with OCD symptoms. This suggests that response inhibition symptoms may be due to comorbidity as argued by Ozonoff [49] and [53]. Third, similar to Debes [45] using a go/no-go task, Hershey et al. [54] also failed to find any group difference between controls and patients. Fourth, using the Simon task, Raz et.al [55]

showed that increased activation in frontostriatal circuitry was associated with increased task related frontostriatal activity associated with better task performance. However, in contrast to the results of Marsh [52], Raz et al. [55] showed that frontostriatal activity correlates with age and tic severity. In conclusion, fMRI studies on response inhibition are highly inconsistent and further investigation of the neural correlates of GTS patients is warranted.

2.4.3 Key points gleaned from neuroimaging studies

Despite the substantial potential benefit afforded by structural and functional neuroimag-ing methods to further our understandneuroimag-ing of the pathophysiological mechanisms under-lying the GTS spectrum, a series of recently published papers have indicated that the quality of neuroimaging data is key in performing unbiased group comparisons [56–64].

One crucial factor that must be considered for the faithful evaluation of brain imaging

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data is related to motion artifacts that ensue as a result of displacements in head position within the head-coil during MRI data acquisition. As patients with GTS are essentially characterized by movement, the disruption of the acquired MRI signal leading to mo-tion contaminated data is inevitable. The presence of momo-tion artifacts in MRI data has been shown to: (a) lead to spurious correlations in estimates of functional connectivity [60, 65, 66] and (b) influence cortical thickness and grey-matter-volume morphometric estimates [56, 67]. While the inconsistencies in the published works investigating GTS pathophysiology may have been driven by variabilities in: (a) sample sizes, which range between N=10–60; (b) the clinical characteristics of the study samples; and (c) the status of psychoactive drug use, the inclusion of low-quality data may have also led to significant biases in the observed results.

Notwithstanding the aforementioned limitations which may have led to the inconsistent observations between different studies, these studies were crucial in implicating specific brain regions that exhibit altered structural or functional characteristics in GTS. Key points gleaned from structural and functional MRI studies investigating GTS pathophys-iology are summarized below:

• Both children and adult patients with GTS exhibit reductions in the volume of the caudate, which correlates negatively with tic-severity.

• Patients with simple tics exhibit cortical thinning in primary sensory and motor cortices, while patients with complex tics exhibit cortical thinning in premotor, prefrontal and associative areas.

• Results from fMRI studies of motor and cognitive control are generally inconsistent and may be biased by motion artifacts, small sample size and variabilities in the clinical characteristics of the study samples.

• Premonitory urges are associated with abnormalities in the supplementary motor area.

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