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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 striaum 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 glutamateric 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 determine whether the infusions were causing seizures or not. 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 the first genetically engineered mouse model of TS+OCD ("Ticcy" D1CT-7) transgenic mice \cite{26453289}. \citep{26453289}.  In these mice a small region of dopaminoceptive D1+ 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 the "hyperglutamergic cortico-striato-thalmo-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 glutamate-triggered target striatothalamic neurons' GABA output and downstream glutamate-triggered target nigrostriatal neurons' 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 CSTC circuit. ### Neuroimaging and electrophysiology studies 
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Many 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 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 of task-based fMRI studies on TS in areas such as premonitory urges, tic suppression, and voluntary motor execution \cite{26402403}. \citep{26402403}.  A summary of free-ticcing conditions from four studies identified the regions that were most commonly activated as 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 with only the left middle frontal gyrus being activated in both tic generation and tic suppression. Greater activation for TS subjects on NoGo trials was seen in the bilateral prefrontal cortex, thalamus and caudate while voluntary motor execution was associated with greater activation in the left prefrontal cortex and the 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 the various types of studies. The thalamus was involved in all types of studies except for self-produced movements. A brief summary of the issues that still need to be addressed in neuroimaging studies is provided. 23 TS children aged 8-12 were compared to 67 controls on a battery A whole brain analysis  of vibrotactile tasks \cite{26041822} with a subset also undergoing GABA-edited magnetic resonance spectroscopy. Lower GABA concentrations cortical gray matter found reduced gray matter thickness  in the right insula and  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 increasing subthreshold stimulus while for  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 and young adults compared  to what extent the high proportion of TS subjects a matched control group \citep{26538289}. In addition, Premonitory Urge for Tics Scale scores were negatively correlated  with ADHD influenced the results. grey matter thickness in these areas.  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 \cite{26538289}. In addition, Premonitory Urge for Tics Scale scores were negatively correlated with grey matter thickness in these areas.   Several studies examined dopamine receptors. 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 \cite{25788222}. 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.  Stop-signal reaction time was negatively correlated with D1- and D2-type activation in the dorsal, but not ventral, striatum \citep{25878272}. No significant correlations involving the 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. Resting-state functional magnetic resonance imaging identified greater functional connectivity between the right dorsal anterior insula and the bilateral supplementary motor area in TS adults compared to controls \cite{25855089}. \citep{25855089}.  Post-hoc analyses found significant correlations between PUTS scores and both right dAI-right SMA2 and right dAI-left SMA1 connectivity suggesting that these regions might 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, but recent analyses suggest that the motion threshold of 0.4mm and the lack of global signal regression in this analysis may have introduced some 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 concluded 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 neural hyperactivation for both types of tasks imagined and performed movements  when TS adults were compared to controls. Interestingly, the exception to this was that 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 study found TS children had greater gray matter volume in the posterior thalamus and hypothalamus-midbrain in addition to decreased white mater volume in the orbital prefrontal cortex and the anterior cingulate.|  |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 recordings 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 were not significantly different from one another.|  |Event-related topography and the effect of comorbidities \citep{Germain_2015}|P300 amplitude in the frontal region was reduced for TS patients with comorbid symptoms compared to control 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 exhibited less beta suppression in the sensorimotor region and increased beta power in parieto-occipital brain regions during a Go/NoGo task. YGTSS motor scores negatively correlated with average beta power and beta power increases over time suggesting that compensatory mechanisms to control tics might involve both increased motor inhibitory processes and visuomotor attentional processes.|  ### Pharmacological studies  23 TS children aged 8-12 were compared to 67 controls on 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 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.   Several studies examined dopamine receptors. 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}. 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.  Stop-signal reaction time was negatively correlated with D1- and D2-type activation in the dorsal, but not ventral, striatum \citep{25878272}. No significant correlations involving the 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.  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 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 and decreased prepulse inhibition of startle responses and an increase in a variety of 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 for TS.  ### Clinical and neuropsychological studies  The effects of comorbidities on a variety of measures was examined in TS children and adolescents \cite{25631951}. \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. Many factors affect tic frequency and two studies examined the effects of attention on tic frequency. 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 \cite{25486384} \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 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 authors 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. A three-stage instrumental-learning paradigm was used to compare antipsychotic-medicated and unmedicated TS adults with a control group \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., "slip-of-action" 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 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 task. However, unmedicated patients showed a significantly higher response rate to devalued outcomes compared to controls (in Bonferroni-corrected 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. The influence of comorbidities was reduced by excluding subjects with ADHD from the study. In addition, the results obtained in this study contrasted with results on similar tasks obtained with subjects with pure obsessive-compulsive disorder without tics. The authors argued that over-reliance on habits in pure OCD 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.   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 \cite{25296570}. \citep{25296570}.  A high rate of ADHD was seen in all groups (i.e., 62% of the OCD+TD group, 27% in the TD alone group, and 20% in the OCD alone group. Anxiety was also commonly seen (i.e., 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 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 subgroups were quite small (i.e., 8 in the OCD+TD+ADHD, 5 in the OCD+TD-ADHD) thereby limiting the power to detect additional differences. However, reaction time variability, which is commonly seen 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. *Title** | **Comment** |  |:----------|:------------|  | Anthropomorphic triangles \citep*{26177119} | This clever study results from Dr. Eddy's research on social cognition in TS. People with TS and controls demonstrated intact mentalizing when observing animated triangles demonstrating simple and complex interactions. However, people with TS also tended to attribute human-like intentions when the two triangles were moving randomly. This tendency was not explained by other constructs such as executive function, alexithymia or clinical symptoms.|  | The eyes have it \citep{26175694} | A measure of cognitive control explained half of the variance in tic severity. 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} | TS children with "pure TS" had significantly greater difficulty maintaining postural stability, especially when they had to use only vestibular cues (rather than visual or somatosensory cues).  |Normal sensory thresholds \citep{26818628} | Thresholds for externally applied sensory stimuli were similar in adults with "pure" TS and controls. Like a previous study \cite{22038938}, \citep{22038938},  these results suggest that sensory abnormalities seen in TS are related to abnormalities in interoceptive awareness or central sensorimotor processing. |