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The challenges of using neuroimaging techniques to study pediatric and clinical subjects are described in detail along with suggestions concerning various strategies that can be used to collect higher quality data \citep{26754461}. The profound effects on structural MRI findings of even very small head movements were identified in a well designed study \citep{25498430}. Neuroimaging scans were performed on 12 healthy adults while they were still or engaged in specific types of movement including nodding, head shaking or a movement each subject invented and then repeated during the scan run. Even during scans when subjects attempted to remain still, there was an average of 3 mm/min of accumulated motion measured using RMSpm (root mean square displacement per minute). Not surprisingly, displacement was significantly higher during the motion conditions and substantial impact was found on gray matter volume and thickness estimates. An average apparent volume loss of approximately 0.7% mm/min of subject motion was calculated. The greatest reductions in gray matter were found in the pre- and post-central cortex, in the temporal lobes and pole, and entorhinal and parahippocampal regions. Motion-associated increases in thickness were seen in some frontal regions and deep sulci such as the medial orbital frontal region. Significant effects due to motion were still present even after excluding scans that failed a rigorous quality control procedure. Recommendations included reducing head motion during scans as much as possible, controlling for motion in statistical analyses, and using correlational analyses to determine the associations between head motion and the predictors of interest. \citet{26654788} described a method to limit the effects of movement artifacts by using a motion tracking system to provide prospective motion correction during scanning trials.   Researchers have used a variety of experimental paradigms to study motor response inhibition since tic expression seems related to motor inhibition difficulties. In healthy adults, performances on a stop-signal task and a continuous performance task were examined using positron emission tomography to measure striatal D1- and D2-type receptor availability \citep{25878272}. Stop-signal reaction time was negatively correlated with both D1- and D2-type receptor availability in both the associative striatum and the sensory motor striatum. Neither D1- nor D2-type receptor availability was associated with performance on the continuous performance task, suggesting that the stop-signal and continuous performance tasks are associated with different neurochemical mechanisms related to motor response inhibition.   A review examined TS task-based fMRI studies in TS including studies of tic suppression, voluntary motor execution, voluntary motor inhibition, and tic severity \citep{26402403}. Free-ticcing conditions (four studies) most commonly activated the left cerebellum, right cingulum, left middle frontal gyrus, the Rolandic operculum, right pallidum, right SMA and thalamus. A summary of studies examining motor response inhibition studies that on NoGo trials TS subjects exhibited greater activation in the bilateral prefrontal cortex, thalamus and caudate. In contrast, on voluntary motor execution tasks greater activation in TS subjects was seen in the left prefrontal cortex, right cingulum, and the anterior portion of the SMA. Tic severity ratings were correlated with greater activation of the right dorsal premotor and the SMA. The premotor cortices of the medial wall (SMA/anterior cingulate cortex) were found to be involved across task types. The thalamus was involved in all types of studies except for self-produced movements. The authors also briefly summarize the the many issues related to neuroimaging studies such as the associated comorbidities, medication effects, the need for longitudinal studies, and the confounding effect of ticcing during scanning.   A whole-brain analysis of cortical gray matter found reduced gray matter thickness in the insula and sensorimotor cortex for TS children and young adults compared to a matched control group \citep{26538289}. Premonitory Urge for Tics Scale scores were negatively correlated with grey matter thickness in these areas. These results demonstrate the value of examining neural substrates associated with premonitory urges separately from those associated with tic generation. 
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### Pharmacological studies  Dopamine involvement in tic generation has been a long-standing focus of TS researchers. Several recent studies sought to elucidate the role of dopamine in the basal ganglia. Positron emission tomography (PET)  was used to investigate striatal D2/D3 dopamine receptors using a D2/D3 receptor antagonist and an agonist with preferential binding to D3 dopamine receptors \citep{25788222} in TS subjects and controls. As expected, binding potential for the D3 preferential agonist was greater in the ventral striatum while it was greater for the D2/D3 receptor antagonist in the motor and associative regions of the dorsal striatum. However, no differences were found for these 3 regions when the TS subjects were compared with the controls, and there were no significant correlations between binding potentials and tic severity. Although the authors discuss the possibility that endogenous dopamine levels might have influenced the results or that striatal dopamine receptors are involved only in a subset of TS patients, they conclude that their results challenge the widely held view that striatal dopamine receptors have a fundamental role in TS pathophysiology. Another study Two studies  examined D1 and D2 receptors in healthy adults adults. Striatal D1- and D2-type receptor availability was measured on stop-signal and continuous performance tasks \citep{25878272}. Stop-signal reaction time was negatively correlated with both D1- and D2-type receptor availability in the the associative and sensory motor regions of the striatum. In contrast, neither D1- nor D2-type receptor availability was associated with performance on the continuous performance task, suggesting that the stop-signal  and continuous performance tasks are associated with different neurochemical mechanisms related to motor response inhibition.   Another study of healthy adults  found that learning from positive outcomes was positively correlated with D1 receptor binding in the putamen and caudate while there was an inverted U-shaped relationship (i.e., r2=0.19) between learning from negative outcomes and D2R binding in the putamen \citep{25562824}. A dietary manipulation that reduced dopamine precursor levels significantly improved learning from negative outcomes. These results were interpreted as providing evidence that dopamine acts as a reward prediction error signal rather than as a saliency signal. GABA involvement was studied in 23 TS children, aged 8-12, and 67 controls using a battery of vibrotactile tasks with a subset also undergoing GABA-edited magnetic resonance spectroscopy \citep{26041822}. Lower GABA concentrations in the right sensorimotor cortex was associated with greater motor tic severity (r=-0.55). There were no significant differences between groups on reaction time and baseline amplitude discrimination threshold. Control children showed the expected increase in discrimination threshold after being exposed to a dynamically increasing subthreshold stimulus while TS children did not. The authors suggest that this is related to abnormal GABAergic inhibition although they point out that larger studies are needed to determine to what extent the high proportion of TS subjects with ADHD influenced the results.