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### Pathological studies  This An  important study \citep{25199956} by \citet{25199956}  follows up on the autopsy results from the Vaccarino lab by comparing RNA transcripts from the basal ganglia of 9 TS and 9 matched control subjects. The most strongly associated set of downregulated transcripts involved striatal interneurons, consistent with the autopsy studies. The leading set of upregulated transcripts involved immune-related genes even though none of the TS subjects met the diagnostic criteria for pediatric autoimmune streptococcal-associated neuropsychiatric disorders or pediatric acute onset neuropsychiatric syndrome. There was a lack of overlap between the results obtained in the present study using brain tissue and previous studies using blood samples. The authors conclude that their results "strongly [implicate] disrupted interneuron signaling in the pathophysiology of severe TS and suggests that metabolic alterations may be linked to their death or dysfunction." ### Animal models  Rodent and monkey tic models have been developed in an attempt to study the mechanisms involved in tic generation more directly and a number of studies were published in 2015 using rodent models. In a rodent model removing about half of the cholinergic interneurons in the dorsolateral striatum produced increased fragmented grooming behavior in response to a repeated unpredictable acoustic startle stimuli and increased repetitive sniffing in response to D-amphetamine challenge \citep{25561540}. Ablation in the dorsomedial striatum did not produce similar deficits. None of the experimental conditions produced a change in prepulse inhibition. These results provided support suggest  that some, but not all,of the  characteristic TS symptoms may be related to cholinergic interneuron deficits in the dorsolateral striatum. Another rodent model, using rats, was used to determine to what extent cortical input and striatal input affected the temporal and spatial properties of motor tics \citep{26674861}. Biccuculline injections into the anterior striatal motor region produced focal tics in the forelimb area. The medium spiny neurons (MSNs) and the fast spiking interneurons exhibited increased activity during tics. Almost all of the MSNs were only active during the tics while a minority of the FSIs exhibited a decrease in activity. About half of the globus pallidus neurons demonstrated increased activity during the tic while the rest showed only inhibition or a combination of inhibition and excitation. Short bursts of high-frequency stimulus pulses were applied at random intervals to the region of the primary motor cortex representing the forelimb. Stimulation was provided before and after the bicuculline injections. The results suggested that the precise timing of tic occurrence was related to the summation of incoming excitatory cortical input and the time since the previous tic. These results supported the idea that the corticostriatal network is fundamentally associated with tic occurrence.  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 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 significantly,  thus demonstrating the role of glutamateric 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 suppression. EEG  recordings allowed experimenters to determine whether the infusions were causing seizures or not. 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 the first a  genetically engineered mouse model of TS+OCD ("Ticcy" D1CT-7) D1CT-7  transgenic mice mice)  \citep{26453289}. In these mice a small region of dopaminoceptive D1+ D1-receptor-containing  somatosensory cortical and limbic neurons is chronically potentiated 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 this  "hyperglutamergic cortico-striato-thalmo-cortical circuit". 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, downstreamglutamate-triggered target  striatothalamic neurons' glutamate-triggered  GABA output and downstreamglutamate-triggered target  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 circuit,  providingmore  evidence that glutamate may have a fundamental for an important  role of glutamate  in tic generation. generating the abnormal movements in this model.  ### Neuroimaging and electrophysiology studies  Neuroimaging and electrophysiology studies continue to be a focus of many researchers since they provide information about the functional and structural differences between TS researchers. The challenges using neuroimaging techniques to study pediatric  and control subjects. An clinical subjects are described in detail along with various strategies that can be used to collect higher quality data \citep{26754461}. One of these was an  important (though frustrating) recent findingwas  that even very small head movements can cause artifactual findings in structural MRI \citep{25498430} . Neroimaging scans were performed on 12 healthy adults while they were still or while  engaged in specific types of movements including nodding, headshaking and a movement that they each subject  invented and then repeated during the scan run. Even during scans when subjects remained attempted to remain  still, there was an average of 3 mm/s RMSpm (RMS 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 and parahippocampal regions. Increased thickness associated with motion was seen in regions associated with deep sulci such as the medial orbital frontal and lateral frontal areas. 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 \citep{26654788} described the development of attempted to address this concern, describing  a system for motion tracking and prospective motion correction, correction  and mentions mentioning  similar systemsthat are available  for other scanner platforms.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}.  Many researchers Researchers  have used a variety of experimental paradigms to study motor response inhibition since tic expression seems related to motor inhibition. In healthy adults 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 task,  suggesting that these two tasks are associated with different neurochemical mechanisms related to motor response inhibition. A review examined task-based fMRI studieson TS  in areas such as TS, including studies of  premonitory urges, tic suppression, suppression  and voluntary motor execution \citep{26402403}. A summary of free-ticcing Free-ticcing  conditions from four studies identified the regions that were (four studies)  most commonly activatedas  the left cerebellum, right cingulum, middle frontal gyrus, the rolandic 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 the various types of studies. task types.  The thalamus was involved in all types of studies except for self-produced movements. The authors also provided a brief summary of the briefly summarize remaining  issues that still need to be addressed in for  neuroimaging studies. A whole brain 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}.In addition,  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 the ones those  associated with tic generation. 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 \citep{25855089}. Post-hoc analyses found significant correlations between PUTS scores and both connectivity between right dAI and  rightdAI-right  SMA2 and between  right dAI-left SMA1 connectivity suggesting that these dAI and left SMA1. These  regions might 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, but frames. However,  recent analyses suggest that the motion threshold of 0.4mm used in this analysis,  and the lack of choice not to regress  global signal regression in this analysis signal,  may have introduced some 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 concluded 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 neural hyperactivation for both imagined and performed movements when in  TS adultswere  compared to controls. Interestingly, the exception to this was that 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 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 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 were did  not differ  significantlydifferent  from one each  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 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.  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.  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 adult,  decreased prepulse inhibition of startle responses 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 for TS. ### Clinical and neuropsychological studies 
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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 \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 without ADHD  with a control group \citep{26490329}. First, 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 \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 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.  Sustained attention, using In an interesting report from  a continuous performance test, was examined group studying social cognition  in 48 children who had OCD alone, tic disorders (TD) alone or both OCD TS, people with TS  and TD \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, controls demonstrated intact mentalizing when observing animated triangles demonstrating simple  and 20% in the OCD alone group. Anxiety was complex interactions \citep*{26177119}. However, people with TS  also commonly seen (i.e., 77% in the OCD+TD group compared tended  to 49% for attribute human-like intentions when  theother  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 triangles  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 moving randomly. This tendency  was higher in the OCD+TD group than for the groups with OCD alone not explained by other constructs such as executive function, alexithymia  or TD alone. This study exemplifies the challenges of trying to separate out the effects of comorbidities in children with TS. clinical symptoms.  Since anecdotal evidence has suggested that tics decrease when people are involved in musical activity, the effects of music Thresholds for externally applied sensory stimuli  were systematically studied. Questionnaires completed by 29 patients supported the idea that listening to music and performing music were thought to decrease tic frequency \citep{Bodeck_2015}. In the 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 similar  in tic frequency. It was suggested that focused attention, along adults  with fine motor control "pure" TS  and goal-directed behavior, produced the decrease controls \citep{26818628}. Like a previous study \citep{22038938}, these results suggest that sensory abnormalities seen in TS are related to abnormalities  in tics. interoceptive awareness or central sensorimotor processing.  **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 \citep{22038938}, these results suggest that sensory abnormalities seen in TS are related to abnormalities in interoceptive awareness or central sensorimotor processing. |