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The GABA-A antagonist picrotoxin was injected into targets throughout corticostriatal regions in adult mice \citep{25597650}. Infusions into the central and dorsolateral striatum produced intermittent non-rhythmic stereotyped lifting of the front or hind paw or head jerks. Infusions into the dorsomedial striatum did not have a significant behavioral effect. Infusion into the ventral striatum produced locomotor activation with sterotypical sniffing and wall licking. Infusions into the sensorimotor cortex produced similar movements in addition to exploration of the cage. sniffing and occasional licking. When an NMDA receptor antagonist was infused into the dorsolateral striatum prior to infusing picrotoxin into the same location, tic frequency decreased significantly, thus demonstrating the role of glutamatergic activity in tic generation. Infusion of a GABA-A antagonist into the sensorimotor cortex 10 minutes before picrotoxin infusion into the dorsolateral striatum also resulted in significant tic suppression. EEG recordings allowed experimenters to rule out seizures. The interpretation of these results was that the tic-like movements were generated from enhanced striatal responsivity to afferent glutamatergic synaptic input rather than to autonomous striatal activity.   The brain circuits underlying tics were studied using a genetically engineered mouse model of TS+OCD ("Ticcy" D1CT-7 transgenic mice) \citep{26453289}. In these mice a small region of dopaminoceptive D1-receptor-containing somatosensory cortical and limbic neurons is chronically potentiated, which results in cortical and amygdalar glutamatergic excitation of striatothalamic, striatopallidal and nigrostriatal subcircuits. Tics were decreased by the use of drugs that acted at different points in this "hyperglutamergic cortico-striato-thalmo-cortical cortico-striato-thalamo-cortical  circuit." Excitatory forebrain serotonin and norepinephrine activity was blocked by ritanserin (a serotonin 2a/2c antagonist) and prazosin (an \( \alpha_{1} \) adrenergic antagonist) respectively. In contrast, downstream striatothalamic neurons' glutamate-triggered GABA output and downstream nigrostriatal neurons' glutamate-triggered co-modulatory dopamine output were blocked by moxonidine (an imidazoline receptor subtype 1 agonist) and bromocriptine (a dopamine agonist) respectively. All four of these drugs decreased tic frequency and were considered to be "circuit-breakers" for the hyperglutamatergic cortico/amygdalo-striato-thalamo-cortical circuit, providing evidence for an important role of glutamate in generating the abnormal movements in this model. ### Neuroimaging and electrophysiology studies  Neuroimaging and electrophysiology studies continue to be a focus of many researchers. The challenges using neuroimaging techniques to study pediatric and clinical subjects are described in detail along with various strategies that can be used to collect higher quality data \citep{26754461}. One of these challenges  was an important (though frustrating) recent finding that even very small head movements can cause artifactual findings in structural MRI \citep{25498430} . Neroimaging \citep{25498430}. Neuroimaging  scans were performed on 12 healthy adults while they were still or while engaged in specific types of movements including nodding, headshaking and head shaking or  a movementthat  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/s RMSpm (RMS (root mean square  displacement per minute), but it was significantly higher during the motion conditions. In general there was a 1-3% local volume loss for each 1 mm/s RMSpm increase. The greatest thickness reductions were found in the pre- and post-central cortex, in the temporal lobes and pole, and enthorhinal entorhinal  and parahippocampal regions. Some motion-associated increases were seen when measured by thickness, but less so for gray matter volume measurements. Recommendations were made to reduce head motion during scans as much as possible and then control for motion in the statistical analysis, along with using correlational analyses to determine the associations between head motion and the predictors of interest. A more recent article provides an approach to addressing this concern with a system for motion tracking and prospective motion correction \citep{26654788}. Researchers have used a variety of experimental paradigms to study motor response inhibition since tic expression seems related to motor inhibition. In healthy adults, performance on a stop-signal task and a continuous performance task was 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 activation in both the associative striaum striatum  and the sensory motor striatum. Neither D1- nor D2-type receptor activation was associated with Go reaction time or Stop signal reaction time on the continuous performance task, suggesting that these two tasks are associated with different neurochemical mechanisms related to motor response inhibition. A review examined task-based fMRI studies in TS, including studies of premonitory urges, tic suppression and voluntary motor execution \citep{26402403}. Free-ticcing conditions (four studies) most commonly activated the left cerebellum, right cingulum, middle frontal gyrus, the Rolandic operculum, right pallidum, right SMA and thalamus. Two studies examined the neural regions associated with tic generation. Only the left middle frontal gyrus was activated during both tic generation and tic suppression. On NoGo trials TS subjects exhibited greater activation in the bilateral prefrontal cortex, thalamus and caudate while voluntary motor execution was associated with greater activation in the left prefrontal cortex, right cingulum, and the anterior portion of the SMA. The right dorsal premotor and the SMA were identified as the regions with activity correlated with tic severity ratings across studies. 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 remaining issues for neuroimaging studies.   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.  Resting-state functional magnetic resonance imaging identified greater functional connectivity between the right dorsal anterior insula (dAI)  and the bilateral supplementary motor area (SMA)  in TS adults compared to controls \citep{25855089}. Post-hoc analyses found significant correlations between PUTS scores and connectivity between right dAI and right SMA2 and between right dAI and left SMA1. These regions may be involved in the increased awareness of body sensations that tend to be associated with premonitory urges. The authors paid attention to head movement and removed high-movement frames. However, recent analyses suggest that the motion threshold of 0.4mm used in this analysis, and the choice not to regress global signal, may not adequately remove artifactual correlations between brain regions due to residual small head movements during the scan \citep{25462692}. Local field potentials were studied in 3 patients who had DBS surgery \citep{25435514} along with EMG recordings to identify the muscle contractions associated with spontaneous tics. In all 3 patients repetitive thalamo-cortical coherent activity was present from 800 to 1500 msec prior to muscle contractions related to spontaneous motor tics. The frequency range affected varied among the patients and there were also ongoing intermittent intra-thalamic coherences that were not synchronized to the tics. The authors speculated that specific DBS targets may not matter as much as whether the target is part of the striato-pallido-thalamo-cortical network. Since these patients were older and had very severe and complex tics, the authors acknowledge that it is not clear at this point to what extent these results generalize to the TS population as a whole.   | **Title** | **Comment** |  |:----------|:------------|  |Motor execution and motor imagery \citep{26566185}| An exploratory study found increased cortical premotor  neural hyperactivation activation  for both imagined and performed movements in TS adults compared to controls. However, basal ganglia and thalamic activation was smaller in the TS subjects than the controls. Premotor activation during the motor imagery tasks was correlated with tic severity. | |Brain structural MRI in pediatric Tourette syndrome \citep{TSANIC:VBM:London}| A large multisite preliminary report of a multi-site  study with over 200 subjects  found TS children had greater gray matter volume in the posterior thalamus thalamus, hypothalamus  and hypothalamus-midbrain midbrain  in addition to decreased white mater volume in the orbital prefrontal cortex and the anterior cingulate.| cortex. |  |DTI and the corpus callosum \citep{26747579} |Axial diffusivity (AD) was reduced in treatment-naive boys with "pure TS" compared to controls. AD was negatively correlated with tic severity although this result did not reach significance after Bonferroni correction. |  |Tourette syndrome and chronic tic disorder \citep{26531497} |Event-related potentials recorded during a stimulus-response compatibility task revealed increased parietal and central activation for both patient groups compared to the control group. The two patient groups did not differ significantly from each another.|  |Event-related topography and the effect of comorbidities \citep{Germain_2015}|P300 \citep{Germain_2015} | P300  amplitude in the frontal region was reduced for TS patients with comorbid symptoms compared to control subjects subjects,  while a medication-naive TS group with no comorbid conditions was similar to the control group.| |Magnetoencehalography and beta rhythms \citep{26649991}. |TS adults | Adults with TS  exhibited less beta suppression in the sensorimotor region and increased beta power in parieto-occipital brain regions during a Go/NoGo Go/No-Go  task. YGTSS motor scoresnegatively  correlated negatively  with average beta power and beta power increases over time time,  suggesting that compensatory mechanisms to control tics might involve both increased motor inhibitory processes and visuomotor attentional processes.| ### 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 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. The role of D1- and D2-type striatal activation was studied by \citet{25878272} using a Stop-signal task. D1- and D2-type activation in the dorsal, but not ventral, striatum was negatively correlated with Stop-signal reaction time. No significant correlations involving a continuous performance task were found, suggesting that different inhibitory mechanisms are involved in these two tasks. Another study examined D1 and D2 receptors in healthy adults and 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 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 \citep{26041822} with a subset also undergoing GABA-edited magnetic resonance spectroscopy. 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 dyanamically 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. A detailed review \cite{26275849} discusses histaminergic modulation of striatal function by the tuberomamillary nucleus of the hypothalamus. Histamine suppresses both the thalamic and cortical drive to medium-spiny projection neurons (MSNs), modulates thalamostriatal synapses resulting in a facilitation of thalamic input, and suppresses lateral feedback inhibition. The authors suggest that during wakefulness and increased attention the striatum will be more responsive to thalamostriatal input and feedforward feed-forward  inhibition will predominate. The role of histamine in TS was discussed in terms of a rare mutation involving histamine synthesizing enzyme histidine decarboxylase in one TS human adult, decreased prepulse pre-pulse  inhibition of startle responses, and in a rodent model an increase in a variety of amphetamine-induced stereotypies which decreased in response to histamine infusion or use of haloperidol. These effects were thought to occur as a result of the histaminergic control of the lateral GABAergic inhibitory connections between MSNs. The authors also discussed ongoing research on histaminergic treatment treatments  for TS. ### Clinical and neuropsychological studies  The effects of comorbidities on a variety of measures was examined in TS children and adolescents \citep{25631951}. Compared to age-matched controls the TS group did significantly worse on the parent-rated Social Responsiveness Scale which measures social skills impaired in autism. They also took significantly longer to complete forms of the Trail Making Tests. However, of the 31 TS subjects, 11 had OCD, 18 had ADHD and 9 had an anxiety disorder. Once these co-occurring conditions were taken into account, the group differences on the Trail Making Tests and the Social Responsiveness Scale were no longer significant. This study demonstrates the need for studies to include sufficient sample sizes so that it can be determined to what extent results are due to TS or to the associated comorbidities.  It is well-established well established  that many factors affect tic frequency. Two recent studies examined the effects of attention on tic frequency and the results have implications for how treatment protocols could be modified to increase effectiveness. The role of attention on tic frequency was examined under several conditions \citep{25185800}. In the first study mean tic frequencies were significantly higher for 12 TS subjects compared to baselines when they were alone in a room. Then they were recorded while looking at themselves in a mirror. A second study was performed to determine whether the increase in frequency was due to increased attention to the tics themselves or due to increased self-awareness in general. In addition to the conditions from the first study, the 16 subjects were also shown videos of themselves while they were not ticcing. Tic frequency was again lower during the baseline compared to the mirror condition. Tic frequency was lower when subjects were watching the video of themselves while not ticcing. The authors suggest that future treatments stress attention to states when patients experience fewer tics. Another study of TS adults \citep{25486384} compared tic frequency while subjects were engaged in tasks that involved attending to particular fingers, colored circles, or whether a tic had occurred during a specific 2 second 2-second  interval during tic suppression or free ticcing conditions. Not surprisingly, more tics were seen during a baseline free ticcing condition. During the attention tasks, tic frequency was greatest while they focused on their tics, decreased on the color attention condition, and decreased further on the finger attention condition. When subjects suppressed their tics, they reduced their baseline tic frequency similarly across all attention conditions. These The results are consistent with the idea that internally-directed attention, especially with focus on tics, may contribute to momentary tic severity. The report's  authors also  suggested that behavioral treatment might be more effective if it focused on teaching patients to focus on external events and voluntary actions when they are in situations that are most likely to result in ticcing. The stereotyped nature of tics has led some to suggest that the neural systems involved in habitual behavior may also be associated with tic generation. A complex,  three-stage instrumental-learning instrumental learning  paradigm was used to compare antipsychotic-medicated and unmedicated TS adults without ADHD with a control group\citep{26490329}  to determine whether their were differences they differed  interms of  goal-directed and _vs._  habitual behavior. behavior \citep{26490329}.  First subjects learned to associate six different stimuli with six specific outcome pictures and a specific response (i.e., left or right key press). During the second stage, subjects were presented with two outcomes with an indication that one outcome was devalued so that it was no longer associated with point rewards and subjects had to press the key associated with the outcome that would still generate points. During the third stage (i.e., (_i.e._,  "slip-of-action" stage) stage),  the six outcomes were presented simultaneously with indications that two were devalued so that responding to the associated stimuli would no longer be rewarded with points. Subjects were instructed to press the key associated with stimuli associated with the still valued outcomes and withhold the response for stimuli associated with devalued outcomes. Subjects also did a Go-No Go Go/No-Go  task in which two of six cueing stimuli were devalued with instructions to withhold the key press response when the devalued stimulus was presented. This task determined whether excessive "slips of action" were related to a working memory deficit or deficient response inhibition rather than outcome devaluation insensitivity. There were no group performance differences for the first two stages of the instrumental learning task or on the baseline Go-NoGo Go/No-Go  task. However, unmedicated patients showed a significantly higher response rate to devalued outcomes compared to controls (in Bonferroni-corrected post hoc analyses) _post hoc_ analyses),  while there was no difference between medicated subjects and controls. In addition, in unmedicated subjects tic severity was correlated with response rates to devalued outcomes and was also correlated with stronger structural connectivity between the right supplementary motor cortex and the posterior putamen. In addition, the The  results obtained in this study contrasted with results on similar tasks obtained with subjects withpure  obsessive-compulsive disorder without tics. The authors argued that over-reliance on habits inpure  OCD without tics  is associated with impaired knowledge of response-outcome associations, while this type of learning was intact in both TS groups in this study. They also concluded that habit formation is enhanced in unmedicated TS subjects. subjects but may be corrected with medication.  Sustained attention, using a continuous performance test, was examined in 48 children who had OCD alone, tic disorders (TD) alone or both OCD and TD \citep{25296570}. A high rate of ADHD was seen in all groups (i.e., 62% (62%  of the OCD+TD group, 27% in the TD alone group, and 20% in the OCD alone group. group).  Anxiety was also commonly seen (i.e., 77% frequent (77%  in the OCD+TD group compared to 49% for the other two groups combined). The OCD+TD group had more errors of omission and did performed  more poorly on other measures of sustained attention compared to the other two groups. Although an attempt was made to examine the specific effect of ADHD in the OCD+TD group,the group, the  subgroups were quite small (i.e., 8 (8  in the OCD+TD+ADHD, 5 in the OCD+TD-ADHD) OCD+TD-ADHD),  thereby limiting the power to detect additional differences. However, reaction time variability, which is commonly increased in ADHD, was higher in the OCD+TD group than for the groups with OCD alone or TD alone. This study exemplifies the challenges of trying to separate out the effects of comorbidities in children with TS. Anecdotal evidence has suggested that tics decrease when people are involved in musical activity, so \citet{Bodeck_2015} systematically studied the effects of music. Questionnaires completed by 29 patients supported the idea that listening to music and performing music decrease tic frequency. In a second study, tics almost completely stopped when subjects were performing music. Listening to music and mental imagery of musical performance also resulted in a decrease in tic frequency. The authors suggested that focused attention, along with fine motor control and goal-directed behavior, produced the decrease in tics.  In an intriguing report from a group studying social cognition in TS, people with TS and controls demonstrated intact mentalizing when observing animated triangles demonstrating simple and complex interactions \citep*{26177119}. However, people with TS also tended to attribute human-like intentions when the two triangles were moving randomly. This tendency was not explained by clinical symptoms or by  other constructs such as executive function, alexithymia function  or clinical symptoms. alexithymia.  Thresholds for externally applied sensory stimuli were similar in adults with "pure" TS and controls \citep{26818628}. These results, like those of a previous study \citep{22038938}, demonstrate that the sensory symptoms of TS are central in origin, perhaps indicating abnormalities in interoceptive awareness or central sensorimotor processing.  **Title** | **Comment** |  |:----------|:------------|  | The eyes have it \citep{26175694} | A In a clever analysis of video recordings of the eyes, a  measure of cognitive control explained half of the variance in tic severity. severity \citep{26175694}.  Blink rate—related to dopamine—was higher in children with TS than in controls. Pupil diameter—related to norepinephrine—was correlated with anxiety. |  |  |Postural stability \citep{25683311} | In an unrelated study,  TS children with "pure TS" without ADHD or OCD  had significantly greater difficulty maintaining postural stability--especially stability than did control children, especially  when they had to use only vestibular cues (rather than visual or somatosensory cues). cues) \citep{25683311}.