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### Pathological studies
An important study 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 proposed diagnostic criteria for
pediatric autoimmune streptococcal-associated neuropsychiatric disorders PANDAS or
pediatric acute onset neuropsychiatric syndrome. There was a lack of overlap between the PANS. The results obtained in the present study using brain tissue
and did not overlap with those of previous studies using blood samples. The authors
conclude that interpret their results
implicate as implicating disrupted basal ganglia interneuron signaling in the pathophysiology of severe TS.
### Animal models
Rodent and monkey tic models have been developed in order to study the mechanisms involved in tic generation more directly and a number of
studies, studies using rodent
models, models were published in 2015. Removing about half of the cholinergic interneurons in the dorsolateral striatum produced increased fragmented grooming behavior in response to repeated unpredictable acoustic startle stimuli in mice and also 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
were interpreted as suggesting that provide partial support for the autopsy data linking some characteristic TS symptoms
may be related to cholinergic interneuron deficits in the dorsolateral striatum.
Another rodent model, using rats, A rat model was used to determine to what extent cortical and striatal input affected the temporal and spatial properties of motor tics
\citep{26674861}. Biccuculline \citep*{26674861}. Focal blockade of GABA-A receptors with bicuculline injections into the anterior striatal motor region produced focal
tics in tic-like movements of the
forelimb area. forelimbs. Medium spiny neurons (MSNs) and fast spiking interneurons
(FSIs) exhibited increased activity during
tics. All these movements, and all of the MSNs were only active during
the tics. them. All of the FSIs were active during
tics tics, but a minority followed this increase in activity by a decrease. Four different patterns were seen in globus pallidus
(GP) neurons. About half of the
globus pallidus GP neurons demonstrated increased activity during the
tic tic-like movements, while the rest showed only inhibition or a combination of inhibition and excitation. The effects of cortical input were studied
by using short bursts of high-frequency
stimulus electrical pulses 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 both incoming excitatory cortical input and the
time delay since the previous
tic occurred. tic. These results support the
idea that fundamental involvement of the corticostriatal network
is fundamentally associated with tic occurrence.
Adult mice were used to examine the The role of GABA in tic
generation. The generation was also studied in adult mice by injecting the GABA-A antagonist picrotoxin
was injected into areas throughout the cortex and striatum \citep{25597650}. Infusions into the central and dorsolateral striatum produced tic-like movements of the front paw, hind paw or head. Infusions into the dorsomedial striatum did not have a significant behavioral effect. Infusion into the ventral striatum produced increased locomotor activation in addition to sterotypical sniffing and wall licking without
other tic-like movements. Infusions into the sensorimotor cortex produced tic-like movements in addition to increased behavioral activation involving cage exploration, 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 agonist into the sensorimotor cortex prior to picrotoxin infusion in the dorsolateral striatum also resulted in significant tic suppression. EEG recordings
allowed experimenters to rule ruled out
seizures as a cause of the tic-like movements. seizure activity. The authors summarize these results as providing evidence that
the generation of these tic-like movements
are related to require cortico-striatal interactions, with a key role for glutatmateric afferents, rather than
to autonomous striatal activity.
The brain circuits underlying tics were studied using In a genetically engineered mouse model of TS+OCD ("Ticcy" D1CT-7 transgenic mice)
\citep{26453289}. In these mice \citep{26453289}, a small population of
D1+ dopamine D1 receptor-expressing (D1+) somatosensory cortical and limbic neurons is chronically
potentiated potentiated, resulting 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-thalamo-cortical cortico/amygdalo-striato-thalamo-cortical [CSTC] 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 agmatine/imidazoline-1 agonist) and bromocriptine (a D2 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 CSTC circuit, thus
providing evidence for supporting an important role of glutamate in generating the abnormal tic-like
head and body movements seen in these mice.
### Neuroimaging studies
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
on structural MRI analyses were identified in a
well designed well-designed study \citep{25498430}.
Neuroimaging scans were performed on T1-weighted MRI of brain was acquired in 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 During the motion
conditions and conditions, substantial impact was found on gray matter volume and thickness estimates.
An average apparent Apparent volume loss
of averaged approximately 0.7% mm/min of subject
motion was calculated. motion. The greatest reductions in gray matter
were found occurred in
the pre- and post-central
cortex, cortex and in the temporal
lobes and pole, and entorhinal and parahippocampal regions. lobes. 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. scanning.
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 whole-brain analysis of
studies examining motor response inhibition studies that on NoGo trials TS subjects exhibited greater activation cortical gray matter found reduced gray matter (GM) thickness in the
bilateral prefrontal cortex, thalamus insula and
caudate. In contrast, on voluntary motor execution tasks greater activation in sensorimotor cortex for TS
subjects was seen in the left prefrontal cortex, right cingulum, children 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 young adults compared to
be involved across task types. The thalamus was involved a matched control group \citep{26538289}. GM thickness 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 these areas correlated negatively with Premonitory Urge for
longitudinal studies, and the confounding effect of ticcing during scanning. Tics Scale scores.
A whole-brain analysis of cortical gray matter found reduced gray matter thickness in Resting-state functional magnetic resonance imaging identified greater functional connectivity between the
right dorsal anterior insula
(dAI) and
sensorimotor cortex for the bilateral supplementary motor area (SMA) in TS
children and young adults compared to
a matched control group \citep{26538289}. Premonitory Urge for Tics Scale controls \citep{25855089}. Post-hoc analyses found significant correlations between PUTS scores
were negatively correlated with grey matter thickness in these areas. and connectivity between right dAI and right SMA2 and between right dAI and left SMA1. These
results demonstrate regions may be involved in the
value increased awareness of
examining neural substrates body sensations that tend to be associated with premonitory
urges separately from those associated with tic generation. 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}.
Resting-state functional magnetic resonance imaging identified greater functional connectivity between 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
dorsal anterior insula (dAI) cingulum, left middle frontal gyrus, the Rolandic operculum, right pallidum, right SMA and
thalamus. In motor response inhibition studies, on No-Go trials TS subjects exhibited greater activation in the bilateral
supplementary prefrontal cortex, thalamus and caudate. In contrast, on voluntary motor
area (SMA) execution tasks greater activation in TS
adults compared to controls \citep{25855089}. Post-hoc analyses found significant correlations between PUTS scores and connectivity between subjects was seen in the left prefrontal cortex, right
dAI cingulum, and
the anterior SMA. Tic severity ratings were correlated with greater activation of the right
SMA2 dorsal premotor cortex and
between right dAI the SMA. Anterior cingulate cortex and
left SMA1. These regions may be SMA were involved across task types. The thalamus was involved in
the increased awareness all types of
body sensations that tend to be associated with premonitory urges. studies except for self-produced movements. The authors
paid attention also briefly summarize the the many issues related to
head movement and removed high-movement frames. However, recent analyses suggest that neuroimaging studies such as the
motion threshold of 0.4mm used in this analysis, associated comorbidities, medication effects, the need for longitudinal studies, and the
choice not to regress global signal, may not adequately remove artifactual correlations between brain regions due to residual small head movements confounding effect of tics during
the scan \citep{25462692}. scanning.
| **Title** | **Comment** |
|:----------|:------------|
|Motor execution and motor imagery \citep{26566185}| An exploratory study found increased cortical premotor and prefrontal neural activation for both imagined and performed movements in TS subjects compared to controls. Premotor activation during the motor imagery task was correlated with tic severity. |
|Structural MRI in pediatric TS \citep{TSANIC:VBM:London}| A preliminary report of a multi-site study with over 200 subjects found TS children had greater gray matter volume in the posterior thalamus, hypothalamus and midbrain in addition to decreased white matter volume in orbital prefrontal and 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 severity, although this result was not significant after Bonferroni correction. |
### Electrophysiology
